Phytocompounds and modulatory effects of Anacardium microcarpum (cajui) on antibiotic drugs used in clinical infections

PubMed Central

Barbosa-Filho, Valter M; Waczuk, Emily P; Leite, Nadghia F; Menezes, Irwin RA; da Costa, José GM; Lacerda, Sírleis R; Adedara, Isaac A; Coutinho, Henrique Douglas Melo; Posser, Thais; Kamdem, Jean P

2015-01-01

Background The challenge of antibiotic resistance and the emergence of new infections have generated considerable interest in the exploration of natural products from plant origins as combination therapy. In this context, crude ethanolic extract (CEE), ethyl acetate fraction (EAF), and methanolic fraction (MF) from Anacardium microcarpum were tested alone or in combination with antibiotics (amikacin, gentamicin, ciprofloxacin, and imipenem) against Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus. Methods Antibiotic resistance-modifying activity was performed using the microdilution method by determining the minimal inhibitory concentration (MIC). In addition, phytochemical prospecting analyses of tested samples were carried out. Results Our results indicated that all the extracts showed low antibacterial activity against multidrug-resistant strains (MIC =512 μg/mL). However, addition of CEE, EAF, and MF to the growth medium at the subinhibitory concentration (MIC/8=64 μg/mL) significantly modulated amikacin- and gentamicin-resistant E. coli 06. CEE and EAF also demonstrated a significant (P<0.001) synergism with imipenem against S. aureus. In contrast, MF antagonized the antibacterial effect of ciprofloxacin and gentamicin against P. aeruginosa 03 and S. aureus 10, respectively. Qualitative phytochemical analysis of the extracts revealed the presence of secondary metabolites including phenols, flavonoids, xanthones, chalcones, and tannin pyrogallates. Conclusion Taken together, our results suggest that A. microcarpum is a natural resource with resistance-modifying antibacterial activity that needs to be further investigated to overcome the present resistant-infection problem. PMID:26604695

Antimicrobial activity of human pancreatic juice and its interaction with antibiotics.

PubMed Central

Minelli, E B; Benini, A; Bassi, C; Abbas, H; Falconi, M; Locatelli, F; de Marco, R; Pederzoli, P

1996-01-01

Pancreatic juice (PJ) should be a factor of variability in the antimicrobial activity of antibiotics eliminated by the pancreas during pancreatic infections. We studied its effects on the activity of antimicrobial drugs with different mechanisms of action. Samples of pure PJ were collected from 16 patients with stabilized external pancreatic fistulas. The antimicrobial activity of the juice at different concentrations (from 1.25 to 100%) alone and in combination with mezlocillin, imipenem, ceftriaxone, gentamicin, ofloxacin, and ciprofloxacin was studied by a microbiological method (continuous turbidimetric recording of bacterial growth). The human PJ showed dose-dependent antimicrobial activity that increased directly with the concentration. The activity of the antibiotics at bactericidal concentrations were not modified by the PJ, while the combination with subinhibitory concentrations produced the following variable and different effects: (i) additivity with mezlocillin, ceftriaxone, gentamicin, and ciprofloxacin and autonomy (no interaction) with imipenem and ofloxacin against Providencia rettgeri and (ii) additivity with ceftriaxone, ofloxacin, gentamicin, imipenem, and mezlocillin and autonomy with ciprofloxacin against Escherichia coli. In the presence of PJ, fluoroquinolones showed constant positive effects, while beta-lactams showed more variable antimicrobial activity. Antibiotic concentrations and PJ pharmacodynamics are the main factors determining the final effect of the interaction in vitro. These results may be useful in choosing antibiotics for the treatment of pancreatic infections when they are supplemented with the pharmacokinetic data for each drug. PMID:8878588

Are highly morphed peptide frameworks lurking silently in microbial genomes valuable as next generation antibiotic scaffolds?

PubMed

Walsh, Christopher T

2017-07-01

Antibiotics are a therapeutic class that, once deployed, select for resistant bacterial pathogens and so shorten their useful life cycles. As a consequence new versions of antibiotics are constantly needed. Among the antibiotic natural products, morphed peptide scaffolds, converting conformationally mobile, short-lived linear peptides into compact, rigidified small molecule frameworks, act on a wide range of bacterial targets. Advances in bacterial genome mining, biosynthetic gene cluster prediction and expression, and mass spectroscopic structure analysis suggests many more peptides, modified both in side chains and peptide backbones, await discovery. Such molecules may turn up new bacterial targets and be starting points for combinatorial or semisynthetic manipulations to optimize activity and pharmacology parameters.

Antibacterial Applications of Nanodiamonds

PubMed Central

Szunerits, Sabine; Barras, Alexandre; Boukherroub, Rabah

2016-01-01

Bacterial infectious diseases, sharing clinical characteristics such as chronic inflammation and tissue damage, pose a major threat to human health. The steady increase of multidrug-resistant bacteria infections adds up to the current problems modern healthcare is facing. The treatment of bacterial infections with multi-resistant germs is very difficult, as the development of new antimicrobial drugs is hardly catching up with the development of antibiotic resistant pathogens. These and other considerations have generated an increased interest in the development of viable alternatives to antibiotics. A promising strategy is the use of nanomaterials with antibacterial character and of nanostructures displaying anti-adhesive activity against biofilms. Glycan-modified nanodiamonds (NDs) revealed themselves to be of great promise as useful nanostructures for combating microbial infections. This review summarizes the current efforts in the synthesis of glycan-modified ND particles and evaluation of their antibacterial and anti-biofilm activities. PMID:27077871

Preparation of poly-o-phenylenediamine/TiO 2/fly-ash cenospheres and its photo-degradation property on antibiotics

NASA Astrophysics Data System (ADS)

Huo, Pengwei; Yan, Yongsheng; Li, Songtian; Li, Huaming; Huang, Weihong

2010-03-01

A series of poly-o-phenylenediamine/TiO 2/fly-ash cenospheres(POPD/TiO 2/fly-ash cenospheres) composites have been prepared from o-phenylenediamine and TiO 2/fly-ash cenospheres under various polymerization conditions. The properties of the samples were characterized by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), specific surface area (BET), X-ray diffraction (XRD), Fourier transform infrared (FT-IR) and UV-vis diffuse reflectance spectrum (UV-vis DRS). Photocatalytic activity was studied by degradation of antibiotics waste water under visible light. The results indicate that the photo-induced method is viable for preparing modified photocatalysts, and the modified photocatalysts have good absorption in visible light range. The photocatalysts of POPD/TiO 2/fly-ash cenospheres which have good performance are prepared at pH 3 and 4, and the polymerized time around 40 min. When the photocatalysts are prepared under the conditions of pH 3 and polymerized time 40 min, the degradation rate of roxithromycin waste water could reach near 60%, and it indicates that the way of POPD modified TiO 2/fly-ash cenospheres to degrade the antibiotics waste water is viable.

Therapeutic management of botulism in dairy cattle.

PubMed

Pandian, S Jegaveera; Subramanian, M; Vijayakumar, G; Balasubramaniam, G A; Sukumar, K

2015-11-01

To report the successful recovery of few dairy cattle from botulism in response to a modified therapeutic strategy. Seventy four naturally-occurring clinical cases of bovine botulism encountered during the period of 2012-2014 which were confirmed by mouse lethality test became material for this study. Affected animals were made into three groups based on the treatment modifications made during the course of study. With the modified therapeutic regimen, 17 animals recovered after 7-10 days of treatment. Clinical recovery took 2-30 days. Animals which were not given intravenous fluid and calcium recovered uneventfully. Cattle which were already treated with intravenous fluids, calcium borogluconate, and antibiotics did not recover. They were either died or slaughtered for salvage. In cattle with botulism, administration of Vitamin AD3E and activated charcoal aid the clinical recovery. Besides, strictly avoiding anti-clostridial antibiotics, fluid therapy, and calcium therapy may facilitate the clinical recovery. Upon fluid administration, the pulmonary congestion existed in the ailing cattle might have worsened the anoxia. Administration of antibiotics like penicillin, aminoglycosides, and tetracyclines further worsen the neuronal paralysis by increasing the availability of botulinum neurotoxin. Cattle in early botulism have fair chances of recovery with the modified therapy.

Antibacterial and antibiotic resistance modifying activity of the extracts from Allanblackia gabonensis, Combretum molle and Gladiolus quartinianus against Gram-negative bacteria including multi-drug resistant phenotypes.

PubMed

Fankam, Aimé G; Kuiate, Jules R; Kuete, Victor

2015-06-30

Bacterial resistance to antibiotics is becoming a serious problem worldwide. The discovery of new and effective antimicrobials and/or resistance modulators is necessary to tackle the spread of resistance or to reverse the multi-drug resistance. We investigated the antibacterial and antibiotic-resistance modifying activities of the methanol extracts from Allanblackia gabonensis, Gladiolus quartinianus and Combretum molle against 29 Gram-negative bacteria including multi-drug resistant (MDR) phenotypes. The broth microdilution method was used to determine the minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) of the samples meanwhile the standard phytochemical methods were used for the preliminary phytochemical screening of the plant extracts. Phytochemical analysis showed the presence of alkaloids, flavonoids, phenols and tannins in all studied extracts. Other chemical classes of secondary metabolites were selectively presents. Extracts from A. gabonensis and C. molle displayed a broad spectrum of activity with MICs varying from 16 to 1024 μg/mL against about 72.41% of the tested bacteria. The extract from the fruits of A. gabonensis had the best activity, with MIC values below 100 μg/mL on 37.9% of tested bacteria. Percentages of antibiotic-modulating effects ranging from 67 to 100% were observed against tested MDR bacteria when combining the leaves extract from C. molle (at MIC/2 and MIC/4) with chloramphenicol, kanamycin, streptomycin and tetracycline. The overall results of the present study provide information for the possible use of the studied plant, especially Allanblackia gabonensis and Combretum molle in the control of Gram-negative bacterial infections including MDR species as antibacterials as well as resistance modulators.

Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection

PubMed Central

Theriot, Casey M.; Koenigsknecht, Mark J.; Carlson, Paul E.; Hatton, Gabrielle E.; Nelson, Adam M.; Li, Bo; Huffnagle, Gary B.; Li, Jun; Young, Vincent B.

2014-01-01

Antibiotics can have significant and long lasting effects on the gastrointestinal tract microbiota, reducing colonization resistance against pathogens including Clostridium difficile. Here we show that antibiotic treatment induces substantial changes in the gut microbial community and in the metabolome of mice susceptible to C. difficile infection. Levels of secondary bile acids, glucose, free fatty acids, and dipeptides decrease, whereas those of primary bile acids and sugar alcohols increase, reflecting the modified metabolic activity of the altered gut microbiome. In vitro and ex vivo analyses demonstrate that C. difficile can exploit specific metabolites that become more abundant in the mouse gut after antibiotics, including primary bile acid taurocholate for germination, and carbon sources mannitol, fructose, sorbitol, raffinose and stachyose for growth. Our results indicate that antibiotic-mediated alteration of the gut microbiome converts the global metabolic profile to one that favors C. difficile germination and growth. PMID:24445449

Fine Tuning of Antibiotic Activity by a Tailoring Hydroxylase in a Trans-AT Polyketide Synthase Pathway.

PubMed

Mohammad, Hadi H; Connolly, Jack A; Song, Zhongshu; Hothersall, Joanne; Race, Paul R; Willis, Christine L; Simpson, Thomas J; Winn, Peter J; Thomas, Christopher M

2018-04-16

The addition or removal of hydroxy groups modulates the activity of many pharmacologically active biomolecules. It can be integral to the basic biosynthetic factory or result from associated tailoring steps. For the anti-MRSA antibiotic mupirocin, removal of a C8-hydroxy group late in the biosynthetic pathway gives the active pseudomonic acid A. An extra hydroxylation, at C4, occurs in the related but more potent antibiotic thiomarinol A. We report here in vivo and in vitro studies that show that the putative non-haem-iron(II)/α-ketoglutaratedependent dioxygenase TmuB, from the thiomarinol cluster, 4-hydroxylates various pseudomonic acids whereas C8-OH, and other substituents around the tetrahydropyran ring, block enzyme action but not substrate binding. Molecular modelling suggested a basis for selectivity, but mutation studies had a limited ability to rationally modify TmuB substrate specificity. 4-Hydroxylation had opposite effects on the potency of mupirocin and thiomarinol. Thus, TmuB can be added to the toolbox of polyketide tailoring technologies for the in vivo generation of new antibiotics in the future. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

One-pot synthesis and antiproliferative activity of novel double-modified derivatives of the polyether ionophore monensin A.

PubMed

Klejborowska, Greta; Maj, Ewa; Wietrzyk, Joanna; Stefańska, Joanna; Huczyński, Adam

2018-05-02

Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity. New MON derivatives such as double-modified ester-carbonates and double-modified amide-carbonates were obtained by a new and efficient one-pot synthesis with triphosgene as the activating reagent and the respective alcohol or amine. All new derivatives were tested for their antiproliferative activity against two drug-sensitive (MES-SA, LoVo) and two drug-resistant (MES-SA/DX5, LoVo/DX) cancer cell lines, and were also studied for their antimicrobial activity against different Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. For the first time, the activity of MON and its derivatives against MES-SA and MES-SA/DX5 were evaluated. © 2018 John Wiley & Sons A/S.

A new antibiotic produced by the cyanobacterium-symbiotic fungus Simplicillium lanosoniveum.

PubMed

Dong, Qinglin; Dong, Rongzhen; Xing, Xiangying; Li, Yukuan

2018-06-01

The culture broth of the cyanobacterium-symbiotic fungus Simplicillium lanosoniveum var. Tianjinienss Q. L. Dong exhibited unanticipated antibacterial activities against the Gram-positive bacteria, particularly the pathogenic bacterium Staphylococcus aureus, indicating the secretion of antibiotic-like metabolite, for which the modified Sabouraud medium was the suitable medium. The antibiotic-like metabolite was separated with macroporous resins CT-12 (absorption) and 95% ethanol (desorption), purified by ion-exchange resins D301T and displayed a characteristic absorption peak at 228 nm, suggesting the presence of nitrogen. The negative biuret and ninhydrin tests confirmed the absence of -NH 2 and -COOH groups. Further, HPLC and mass spectrometry analyses showed that the retention time and molecular weight of the antibiotic-like metabolite were 4.1031 min and 163.0182 (Δ ± 2.3 ppm), respectively. Taking together, we speculated that the antibiotic-like metabolite was a new antibiotic structurally similar to alkaloid, which was the first one isolated from the species of Simplicillium genus.

In Vitro Antibacterial and Antibiotic Resistance Modifying Effect of Bioactive Plant Extracts on Methicillin-Resistant Staphylococcus epidermidis

PubMed Central

Chovanová, Romana; Vaverková, Štefánia

2013-01-01

The crude extracts of plants from Asteraceae and Lamiaceae family and essential oils from Salvia officinalis and Salvia sclarea were studied for their antibacterial as well as antibiotic resistance modifying activity. Using disc diffusion and broth microdilution assays we determined higher antibacterial effect of three Salvia spp. and by evaluating the leakage of 260 nm absorbing material we detected effect of extracts and, namely, of essential oils on the disruption of cytoplasmic membrane. The evaluation of in vitro interactions between plant extracts and oxacillin described in terms of fractional inhibitory concentration (FIC) indices revealed synergistic or additive effects of plant extracts and clearly synergistic effects of essential oil from Salvia officinalis with oxacillin in methicillin-resistant Staphylococcus epidermidis. PMID:24222768

Nucleoside Derived Antibiotics to Fight Microbial Drug Resistance: New Utilities for an Established Class of Drugs?

PubMed

Serpi, Michaela; Ferrari, Valentina; Pertusati, Fabrizio

2016-12-08

Novel antibiotics are urgently needed to combat the rise of infections due to drug-resistant microorganisms. Numerous natural nucleosides and their synthetically modified analogues have been reported to have moderate to good antibiotic activity against different bacterial and fungal strains. Nucleoside-based compounds target several crucial processes of bacterial and fungal cells such as nucleoside metabolism and cell wall, nucleic acid, and protein biosynthesis. Nucleoside analogues have also been shown to target many other bacterial and fungal cellular processes although these are not well characterized and may therefore represent opportunities to discover new drugs with unique mechanisms of action. In this Perspective, we demonstrate that nucleoside analogues, cornerstones of anticancer and antiviral treatments, also have great potential to be repurposed as antibiotics so that an old drug can learn new tricks.

Therapeutic management of botulism in dairy cattle

PubMed Central

Pandian, S. Jegaveera; Subramanian, M.; Vijayakumar, G.; Balasubramaniam, G. A.; Sukumar, K.

2015-01-01

Aim: To report the successful recovery of few dairy cattle from botulism in response to a modified therapeutic strategy. Materials and Methods: Seventy four naturally-occurring clinical cases of bovine botulism encountered during the period of 2012-2014 which were confirmed by mouse lethality test became material for this study. Affected animals were made into three groups based on the treatment modifications made during the course of study. Results and Discussion: With the modified therapeutic regimen, 17 animals recovered after 7-10 days of treatment. Clinical recovery took 2-30 days. Animals which were not given intravenous fluid and calcium recovered uneventfully. Cattle which were already treated with intravenous fluids, calcium borogluconate, and antibiotics did not recover. They were either died or slaughtered for salvage. Conclusion: In cattle with botulism, administration of Vitamin AD3E and activated charcoal aid the clinical recovery. Besides, strictly avoiding anti-clostridial antibiotics, fluid therapy, and calcium therapy may facilitate the clinical recovery. Upon fluid administration, the pulmonary congestion existed in the ailing cattle might have worsened the anoxia. Administration of antibiotics like penicillin, aminoglycosides, and tetracyclines further worsen the neuronal paralysis by increasing the availability of botulinum neurotoxin. Cattle in early botulism have fair chances of recovery with the modified therapy. PMID:27047034

Modified protocol including topical minocycline in orabase to manage medication-related osteonecrosis of the jaw cases.

PubMed

Karasneh, Jumana A; Al-Eryani, Kamal; Clark, Glenn T; Sedghizadeh, Parish P

2016-10-01

Management of medication-related osteone-crosis of the jaw (MRONJ) with active infection can be a serious challenge for clinicians. Based on Association of Oral and Maxillofacial Surgeons (AAOMS) recommendations, we have tested a modified treatment protocol using topical minocycline. Five patients diagnosed with stage II or III MRONJ lesions were willing to consent to our protocol. In addition to conventional treatment as suggested by the AAOMS, such as, surgical debridement, chlorhexidine irrigation, and systemic antibiotics, we applied 10% minocycline to the lesions once a week for sustained local antibiotic delivery. All five patients reported pain relief after the first minocycline application. Complete healing occurred in three patients; case three healed completely after the third application, one case continues to improve toward resolution and one withdraws due to other non-relevant medical problem. In this study, we are reporting favorable results using a modified protocol with topical minocycline to treat MRONJ lesions. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Alkyl gallates, intensifiers of beta-lactam susceptibility in methicillin-resistant Staphylococcus aureus.

PubMed

Shibata, Hirofumi; Kondo, Kyoko; Katsuyama, Ryo; Kawazoe, Kazuyoshi; Sato, Yoichi; Murakami, Kotaro; Takaishi, Yoshihisa; Arakaki, Naokatu; Higuti, Tomihiko

2005-02-01

We found that ethyl gallate purified from a dried pod of tara (Caesalpinia spinosa) intensified beta-lactam susceptibility in methicillin-resistant and methicillin-sensitive strains of Staphylococcus aureus (MRSA and MSSA strains, respectively). This compound and several known alkyl gallates were tested with MRSA and MSSA strains to gain new insights into their structural functions in relation to antimicrobial and beta-lactam susceptibility-intensifying activities. The maximum activity of alkyl gallates against MRSA and MSSA strains occurred at 1-nonyl and 1-decyl gallate, with an MIC at which 90% of the isolates tested were inhibited of 15.6 microg/ml. At concentrations lower than the MIC, alkyl gallates synergistically elevated the susceptibility of MRSA and MSSA strains to beta-lactam antibiotics. Such a synergistic activity of the alkyl gallates appears to be specific for beta-lactam antibiotics, because no significant changes were observed in the MICs of other classes of antibiotics examined in this study. The length of the alkyl chain was also associated with the modifying activity of the alkyl gallates, and the optimum length was C5 to C6. The present work clearly demonstrates that the length of the alkyl chain has a key role in the elevation of susceptibility to beta-lactam antibiotics.

Sorption of norfloxacin, sulfamerazine and oxytetracycline by KOH-modified biochar under single and ternary systems.

PubMed

Luo, Jiwei; Li, Xue; Ge, Chengjun; Müller, Karin; Yu, Huamei; Huang, Peng; Li, Jiatong; Tsang, Daniel C W; Bolan, Nanthi S; Rinklebe, Jörg; Wang, Hailong

2018-05-08

Pollution of water by single antibiotics has been investigated in depth. However, in reality, a wide range of different contaminants is often mixed in the aquatic environment (contaminant cocktail). Here, single and competitive sorption dynamics of ionizable norfloxacin (NOR), sulfamerazine (SMR) and oxytetracycline (OTC) by both pristine and modified biochars were investigated. Sorption kinetics of the three antibiotics was faster in ternary-solute than single-solute system. Sorption efficiency was enhanced in the competitive system for NOR by the pristine biochar, and for OTC by both the pristine biochar and the modified biochar, while SMR sorption by the pristine biochar and the KOH-modified biochar was inhibited. Sorption was governed by electrostatic interactions, π-π EDA and H-bonds for antibiotics sorption by biochar. SMR and OTC sorption by biochar was influenced by cation bridging and surface complexation, respectively. This research finding will guide the development of treatment procedures for water polluted by multiple antibiotics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Structural and molecular basis for resistance to aminoglycoside antibiotics by the adenylyltransferase ANT(2″)-Ia.

PubMed

Cox, Georgina; Stogios, Peter J; Savchenko, Alexei; Wright, Gerard D

2015-01-06

The aminoglycosides are highly effective broad-spectrum antimicrobial agents. However, their efficacy is diminished due to enzyme-mediated covalent modification, which reduces affinity of the drug for the target ribosome. One of the most prevalent aminoglycoside resistance enzymes in Gram-negative pathogens is the adenylyltransferase ANT(2″)-Ia, which confers resistance to gentamicin, tobramycin, and kanamycin. Despite the importance of this enzyme in drug resistance, its structure and molecular mechanism have been elusive. This study describes the structural and mechanistic basis for adenylylation of aminoglycosides by the ANT(2″)-Ia enzyme. ANT(2″)-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2″-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core. The catalyzed reaction follows a direct AMP transfer mechanism from ATP to the substrate antibiotic. Central to catalysis is the coordination of two Mg(2+) ions, positioning of the modifiable substrate ring, and the presence of a catalytic base (Asp86). Comparative structural analysis revealed that ANT(2″)-Ia has a two-domain structure with an N-terminal active-site architecture that is conserved among other antibiotic nucleotidyltransferases, including Lnu(A), LinB, ANT(4')-Ia, ANT(4″)-Ib, and ANT(6)-Ia. There is also similarity between the nucleotidyltransferase fold of ANT(2″)-Ia and DNA polymerase β. This similarity is consistent with evolution from a common ancestor, with the nucleotidyltransferase fold having adapted for activity against chemically distinct molecules. IMPORTANCE  : To successfully manage the threat associated with multidrug-resistant infectious diseases, innovative therapeutic strategies need to be developed. One such approach involves the enhancement or potentiation of existing antibiotics against resistant strains of bacteria. The reduction in clinical usefulness of the aminoglycosides is a particular problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases. Copyright © 2015 Cox et al.

Structural and Molecular Basis for Resistance to Aminoglycoside Antibiotics by the Adenylyltransferase ANT(2″)-Ia

PubMed Central

Cox, Georgina; Stogios, Peter J.; Savchenko, Alexei

2015-01-01

ABSTRACT   The aminoglycosides are highly effective broad-spectrum antimicrobial agents. However, their efficacy is diminished due to enzyme-mediated covalent modification, which reduces affinity of the drug for the target ribosome. One of the most prevalent aminoglycoside resistance enzymes in Gram-negative pathogens is the adenylyltransferase ANT(2″)-Ia, which confers resistance to gentamicin, tobramycin, and kanamycin. Despite the importance of this enzyme in drug resistance, its structure and molecular mechanism have been elusive. This study describes the structural and mechanistic basis for adenylylation of aminoglycosides by the ANT(2″)-Ia enzyme. ANT(2″)-Ia confers resistance by magnesium-dependent transfer of a nucleoside monophosphate (AMP) to the 2″-hydroxyl of aminoglycoside substrates containing a 2-deoxystreptamine core. The catalyzed reaction follows a direct AMP transfer mechanism from ATP to the substrate antibiotic. Central to catalysis is the coordination of two Mg2+ ions, positioning of the modifiable substrate ring, and the presence of a catalytic base (Asp86). Comparative structural analysis revealed that ANT(2″)-Ia has a two-domain structure with an N-terminal active-site architecture that is conserved among other antibiotic nucleotidyltransferases, including Lnu(A), LinB, ANT(4′)-Ia, ANT(4″)-Ib, and ANT(6)-Ia. There is also similarity between the nucleotidyltransferase fold of ANT(2″)-Ia and DNA polymerase β. This similarity is consistent with evolution from a common ancestor, with the nucleotidyltransferase fold having adapted for activity against chemically distinct molecules. Importance   To successfully manage the threat associated with multidrug-resistant infectious diseases, innovative therapeutic strategies need to be developed. One such approach involves the enhancement or potentiation of existing antibiotics against resistant strains of bacteria. The reduction in clinical usefulness of the aminoglycosides is a particular problem among Gram-negative human pathogens, since there are very few therapeutic options for infections caused by these organisms. In order to successfully circumvent or inhibit the activity of aminoglycoside-modifying enzymes, and to thus rejuvenate the activity of the aminoglycoside antibiotics against Gram-negative pathogens, structural and mechanistic information is crucial. This study reveals the structure of a clinically prevalent aminoglycoside resistance enzyme [ANT(2″)-Ia] and depicts the molecular basis underlying modification of antibiotic substrates. Combined, these findings provide the groundwork for the development of broad-spectrum inhibitors against antibiotic nucleotidyltransferases. PMID:25564464

In vitro susceptibility and resistance phenotypes in contemporary Enterobacter isolates in a university hospital in Crete, Greece.

PubMed

Maraki, Sofia; Vardakas, Konstantinos Z; Samonis, George; Perdikis, Dimitrios; Mavromanolaki, Viktoria Eirini; Kofteridis, Diamantis P; Falagas, Matthew E

2017-06-01

To study the evolution in the susceptibility of Enterobacter spp. in Crete, Greece from 2010 to 2015. Non-duplicate isolates were studied using automated systems. Phenotypic confirmatory tests were applied. A total of 939 Enterobacter isolates were included. Colistin was the most active antibiotic (97.9%) followed by imipenem (96.1%), gentamicin (95.7%), tigecycline (91.8%), cefepime (89.4%), chloramphenicol (85.8%), fosfomycin (85.5%), trimethoprim/sulfamethoxazole (83.3%) and piperacillin/tazobactam (73.3%). Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility was observed among multidrug-resistant strains and carbapenem-nonsusceptible isolates. AmpC was the most common resistant mechanism (21%); carbapenemases (3.7%) and aminoglycoside-modifying enzymes (6.5%) were also detected. A significant proportion of Enterobacter spp. was resistant to several antibiotics, most notably β-lactams.

Development and application of a T7 RNA polymerase-dependent expression system for antibiotic production improvement in Streptomyces.

PubMed

Wei, Junhong; Tian, Jinjin; Pan, Guoqing; Xie, Jie; Bao, Jialing; Zhou, Zeyang

2017-06-01

To develop a reliable and easy to use expression system for antibiotic production improvement of Streptomyces. A two-compound T7 RNA polymerase-dependent gene expression system was developed to fulfill this demand. In this system, the T7 RNA polymerase coding sequence was optimized based on the codon usage of Streptomyces coelicolor. To evaluate the functionality of this system, we constructed an activator gene overexpression strain for enhancement of actinorhodin production. By overexpression of the positive regulator actII-ORF4 with this system, the maximum actinorhodin yield of engineered strain was 15-fold higher and the fermentation time was decreased by 48 h. The modified two-compound T7 expression system improves both antibiotic production and accelerates the fermentation process in Streptomyces. This provides a general and useful strategy for strain improvement of important antibiotic producing Streptomyces strains.

Antibiotic Algae by Chemical Surface Engineering.

PubMed

Kerschgens, Isabel P; Gademann, Karl

2018-03-02

Chemical cell-surface engineering is a tool for modifying and altering cellular functions. Herein, we report the introduction of an antibiotic phenotype to the green alga Chlamydomonas reinhardtii by chemically modifying its cell surface. Flow cytometry and confocal microscopy studies demonstrated that a hybrid of the antibiotic vancomycin and a 4-hydroxyproline oligomer binds reversibly to the cell wall without affecting the viability or motility of the cells. The modified cells were used to inhibit bacterial growth of Gram-positive Bacillus subtilis cultures. Delivery of the antibiotic from the microalgae to the bacterial cells was verified by microscopy. Our studies provide compelling evidence that 1) chemical surface engineering constitutes a useful tool for the introduction of new, previously unknown functionality, and 2) living microalgae can serve as new platforms for drug delivery. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antibiotic resistance in the wild: an eco-evolutionary perspective.

PubMed

Hiltunen, Teppo; Virta, Marko; Laine, Anna-Liisa

2017-01-19

The legacy of the use and misuse of antibiotics in recent decades has left us with a global public health crisis: antibiotic-resistant bacteria are on the rise, making it harder to treat infections. At the same time, evolution of antibiotic resistance is probably the best-documented case of contemporary evolution. To date, research on antibiotic resistance has largely ignored the complexity of interactions that bacteria engage in. However, in natural populations, bacteria interact with other species; for example, competition and grazing are import interactions influencing bacterial population dynamics. Furthermore, antibiotic leakage to natural environments can radically alter bacterial communities. Overall, we argue that eco-evolutionary feedback loops in microbial communities can be modified by residual antibiotics and evolution of antibiotic resistance. The aim of this review is to connect some of the well-established key concepts in evolutionary biology and recent advances in the study of eco-evolutionary dynamics to research on antibiotic resistance. We also identify some key knowledge gaps related to eco-evolutionary dynamics of antibiotic resistance, and review some of the recent technical advantages in molecular microbiology that offer new opportunities for tackling these questions. Finally, we argue that using the full potential of evolutionary theory and active communication across the different fields is needed for solving this global crisis more efficiently.This article is part of the themed issue 'Human influences on evolution, and the ecological and societal consequences'. © 2016 The Authors.

Antibiotic resistance in the wild: an eco-evolutionary perspective

PubMed Central

Virta, Marko

2017-01-01

The legacy of the use and misuse of antibiotics in recent decades has left us with a global public health crisis: antibiotic-resistant bacteria are on the rise, making it harder to treat infections. At the same time, evolution of antibiotic resistance is probably the best-documented case of contemporary evolution. To date, research on antibiotic resistance has largely ignored the complexity of interactions that bacteria engage in. However, in natural populations, bacteria interact with other species; for example, competition and grazing are import interactions influencing bacterial population dynamics. Furthermore, antibiotic leakage to natural environments can radically alter bacterial communities. Overall, we argue that eco-evolutionary feedback loops in microbial communities can be modified by residual antibiotics and evolution of antibiotic resistance. The aim of this review is to connect some of the well-established key concepts in evolutionary biology and recent advances in the study of eco-evolutionary dynamics to research on antibiotic resistance. We also identify some key knowledge gaps related to eco-evolutionary dynamics of antibiotic resistance, and review some of the recent technical advantages in molecular microbiology that offer new opportunities for tackling these questions. Finally, we argue that using the full potential of evolutionary theory and active communication across the different fields is needed for solving this global crisis more efficiently. This article is part of the themed issue ‘Human influences on evolution, and the ecological and societal consequences'. PMID:27920384

ISTA 14--impact of antibiotics from pig slurry on soil microbial communities, including the basidiomycete Trametes versicolor.

PubMed

Igel-Egalon, Angélique; Cheviron, Nathalie; Hedde, Mickael; Hernandez-Raquet, Guillermina; Mougin, Christian

2012-03-01

Livestock slurry containing antibiotics is a source of contamination of agricultural soils, with possible effects on soil function and micro-organisms. Extracellular oxido-reductases and hydrolases from the fungus T. versicolor and fungal growth were monitored in liquid cultures in the presence of tetracycline, lincomycine, sulfadiazine and ciprofloxacin for 10 days, in order to assess the suitability of these enzymes as biomarkers. Among the conditions of treatment, statistical analysis demonstrated an increase in manganese-dependent peroxidase after exposure to sulfadiazine at 1 mg/L when compared with the control. Acid phosphatase activity was decreased by lincomycine at 1 or 10 mg/L. Conversely, β-glucosidase activity increased in the presence of this antibiotic at 10 mg/L. In Terrestrial Model Ecosystems spiked with contaminated pig slurry, lincomycine at the concentration of 8 or 80 μg/kg dry soil, and ciprofloxacin at 250 ng/kg dry soil decreased the activity of soil dehydrogenase, when compared with a green slurry treatment, over 28-day incubations. Laccase activity was similarly decreased in the presence of the highest concentration of antibiotics. We determined bacterial and fungal biomasses using Q-PCR. Bacterial biomass was increased in the presence of lincomycine at 80 μg/kg whatever the time of exposure, and to a lesser extent in the presence of ciprofloxacin at 250 ng/kg, but only at day 28. In contrast, both antibiotics, whatever their concentrations, did not modify fungal biomass in soil. In conclusion, we were unable to demonstrate important effects of antibiotics at concentrations found in the agricultural environment. Copyright © 2011 Wiley Periodicals, Inc.

Structural and functional characterization of an arylamine N-acetyltransferase from the pathogen Mycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition.

PubMed

Cocaign, Angélique; Kubiak, Xavier; Xu, Ximing; Garnier, Guillaume; Li de la Sierra-Gallay, Inès; Chi-Bui, Linh; Dairou, Julien; Busi, Florent; Abuhammad, Areej; Haouz, Ahmed; Dupret, Jean Marie; Herrmann, Jean Louis; Rodrigues-Lima, Fernando

2014-11-01

Mycobacterium abscessus is the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies of M. abscessus proteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamine N-acetyltransferase (NAT) from M. abscessus [(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significant N-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid and p-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smooth M. abscessus morphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related to Nocardia farcinica NAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme from M. abscessus and provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance of M. abscessus.

Iterative Chemical Engineering of Vancomycin Leads to Novel Vancomycin Analogs With a High in Vitro Therapeutic Index.

PubMed

Mishra, Nigam M; Stolarzewicz, Izabela; Cannaerts, David; Schuermans, Joris; Lavigne, Rob; Looz, Yannick; Landuyt, Bart; Schoofs, Liliane; Schols, Dominique; Paeshuyse, Jan; Hickenbotham, Peter; Clokie, Martha; Luyten, Walter; Van der Eycken, Erik V; Briers, Yves

2018-01-01

Vancomycin is a glycopeptide antibiotic that inhibits transpeptidation during cell wall synthesis by binding to the D-Ala-D-Ala termini of lipid II. For long, it has been used as a last resort antibiotic. However, since the emergence of the first vancomycin-resistant enterococci in 1987, vancomycin resistance has become widespread, especially in hospitals. We have synthesized and evaluated 110 vancomycin analogs modified at the C-terminal carboxyl group of the heptapeptide moiety with R 2 NHR 1 NH 2 substituents. Through iterative optimizations of the substituents, we identified vancomycin analogs that fully restore (or even exceed) the original inhibitory activity against vancomycin-resistant enterococci (VRE), vancomycin-intermediate (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) strains. The best analogs have improved growth inhibitory activity and in vitro therapeutic indices against a broad set of VRE and methicillin-resistant S. aureus (MRSA) isolates. They also exceed the activity of vancomycin against Clostridium difficile ribotypes. Vanc-39 and Vanc-42 have a low probability to provoke antibiotic resistance, and overcome different vancomycin resistance mechanisms (VanA, VanB, and VanC1).

Antibacterial and Antibiotic-Modifying Activity of Methanol Extracts from Six Cameroonian Food Plants against Multidrug-Resistant Enteric Bacteria

PubMed Central

Dzotam, Joachim K.

2017-01-01

The present work was designed to investigate the antibacterial activities of methanol extracts from six Cameroonian edible plants and their synergistic effects with some commonly used antibiotics against multidrug-resistant (MDR) Gram-negative bacteria expressing active efflux pumps. The extracts were subjected to qualitative phytochemical screening and the microdilution broth method was used for antibacterial assays. The results of phytochemical tests indicate that all tested crude extracts contained polyphenols, flavonoids, triterpenes, and steroids. Extracts displayed selective antibacterial activities with the minimal inhibitory concentration (MIC) values ranging from 32 to 1024 μg/mL. The lowest MIC value (32 μg/mL) was recorded with Coula edulis extract against E. coli AG102 and K. pneumoniae K2 and with Mangifera indica bark extract against P. aeruginosa PA01 and Citrus sinensis extract against E. coli W3110 which also displayed the best MBC (256 μg/mL) value against E. coli ATCC8739. In combination with antibiotics, extracts from M. indica leaves showed synergistic effects with 75% (6/8) of the tested antibiotics against more than 80% of the tested bacteria. The findings of the present work indicate that the tested plants may be used alone or in combination in the treatment of bacterial infections including the multidrug-resistant bacteria. PMID:28904944

Antibacterial and Antibiotic-Modifying Activity of Methanol Extracts from Six Cameroonian Food Plants against Multidrug-Resistant Enteric Bacteria.

PubMed

Dzotam, Joachim K; Kuete, Victor

2017-01-01

The present work was designed to investigate the antibacterial activities of methanol extracts from six Cameroonian edible plants and their synergistic effects with some commonly used antibiotics against multidrug-resistant (MDR) Gram-negative bacteria expressing active efflux pumps. The extracts were subjected to qualitative phytochemical screening and the microdilution broth method was used for antibacterial assays. The results of phytochemical tests indicate that all tested crude extracts contained polyphenols, flavonoids, triterpenes, and steroids. Extracts displayed selective antibacterial activities with the minimal inhibitory concentration (MIC) values ranging from 32 to 1024  μ g/mL. The lowest MIC value (32  μ g/mL) was recorded with Coula edulis extract against E. coli AG102 and K. pneumoniae K2 and with Mangifera indica bark extract against P. aeruginosa PA01 and Citrus sinensis extract against E. coli W3110 which also displayed the best MBC (256  μ g/mL) value against E. coli ATCC8739. In combination with antibiotics, extracts from M. indica leaves showed synergistic effects with 75% (6/8) of the tested antibiotics against more than 80% of the tested bacteria. The findings of the present work indicate that the tested plants may be used alone or in combination in the treatment of bacterial infections including the multidrug-resistant bacteria.

Graphene-like boron nitride modified bismuth phosphate materials for boosting photocatalytic degradation of enrofloxacin.

PubMed

Chen, Zhigang; Chen, Xiaoliu; Di, Jun; Liu, Yiling; Yin, Sheng; Xia, Jiexiang; Li, Huaming

2017-04-15

A novel graphene-like BN modified BiPO 4 material was prepared for the first time via a simple solvothermal process with the assistance of reactable ionic liquid 1-decyl-3-methylimidazolium dihydrogen phosphate ([Omim]H 2 PO 4 ). The as-prepared photocatalyst was characterized by XRD, FT-IR, Raman, XPS, TEM, DRS, BET, PL, EIS and ESR to investigate the structure, morphology, optical property, surface area, electrical property and active species. The photocatalytic activities of graphene-like BN/BiPO 4 materials were evaluated by the degradation of antibiotic enrofloxacin (ENR) under UV light irradiation and the 1wt% graphene-like BN/BiPO 4 displayed the best activity among the BN/BiPO 4 composites. The enhanced photocatalytic activity for the removal of enrofloxacin was attributed to higher separation efficiency of photogenerated electron-hole pairs, and the generated more O 2 - and OH radicals when the BN was modified on BiPO 4 . Moreover, a probable degradation mechanism was proposed for the improved photocatalytic activity of BN modified BiPO 4 . Copyright © 2016 Elsevier Inc. All rights reserved.

Phytochemicals for human disease: An update on plant-derived compounds antibacterial activity.

PubMed

Barbieri, Ramona; Coppo, Erika; Marchese, Anna; Daglia, Maria; Sobarzo-Sánchez, Eduardo; Nabavi, Seyed Fazel; Nabavi, Seyed Mohammad

2017-03-01

In recent years, many studies have shown that phytochemicals exert their antibacterial activity through different mechanisms of action, such as damage to the bacterial membrane and suppression of virulence factors, including inhibition of the activity of enzymes and toxins, and bacterial biofilm formation. In this review, we summarise data from the available literature regarding the antibacterial effects of the main phytochemicals belonging to different chemical classes, alkaloids, sulfur-containing phytochemicals, terpenoids, and polyphenols. Some phytochemicals, besides having direct antimicrobial activity, showed an in vitro synergistic effect when tested in combination with conventional antibiotics, modifying antibiotic resistance. Review of the literature showed that phytochemicals represent a possible source of effective, cheap and safe antimicrobial agents, though much work must still be carried out, especially in in vivo conditions to ensure the selection of effective antimicrobial substances with low side and adverse effects. Copyright © 2016 Elsevier GmbH. All rights reserved.

Strategies for the Discovery and Development of New Antibiotics from Natural Products: Three Case Studies.

PubMed

Herrmann, Jennifer; Lukežič, Tadeja; Kling, Angela; Baumann, Sascha; Hüttel, Stephan; Petković, Hrvoje; Müller, Rolf

Natural products continue to be a predominant source for new anti-infective agents. Research at the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) and the Helmholtz Centre for Infection Research (HZI) is dedicated to the development of new lead structures against infectious diseases and, in particular, new antibiotics against hard-to-treat and multidrug-resistant bacterial pathogens. In this chapter, we introduce some of the concepts currently being employed in the field of antibiotic discovery. In particular, we will exemplarily illustrate three approaches: (1) Current sources for novel compounds are mainly soil-dwelling bacteria. In the course of our antimicrobial discovery program, a biodiverse collection of myxobacterial strains has been established and screened for antibiotic activities. Based on this effort, one successful example is presented in this chapter: Antibacterial cystobactamids were discovered and their molecular target, the DNA gyrase, was identified soon after the analysis of myxobacterial self-resistance making use of the information found in the respective biosynthesis gene cluster. (2) Besides our focus on novel natural products, we also apply strategies to further develop either neglected drugs or widely used antibiotics for which development of resistance in the clinical setting is an issue: Antimycobacterial griselimycins were first described in the 1960s but their development and use in tuberculosis therapy was not further pursued. We show how a griselimycin derivative with improved pharmacokinetic properties and enhanced potency against Mycobacterium tuberculosis revealed and validated a novel target for antibacterial therapy, the DNA sliding clamp. (3) In a third approach, biosynthetic engineering was used to modify and optimize natural products regarding their pharmaceutical properties and their production scale: The atypical tetracycline chelocardin is a natural product scaffold that was modified to yield a more potent derivative exhibiting activity against multidrug-resistant pathogens. This was achieved by genetic engineering of the producer strain and the resulting compound is now subject to further optimization by medicinal chemistry approaches.

Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

PubMed Central

2015-01-01

The design, synthesis, and characterization of enterobactin–antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition. PMID:24927110

In vitro susceptibility and resistance phenotypes in contemporary Citrobacter isolates in a University Hospital in Crete, Greece.

PubMed

Maraki, Sofia; Vardakas, Konstantinos Z; Mavromanolaki, Viktoria-Eirini; Kyriakidou, Margarita; Spais, George; Kofteridis, Diamantis P; Samonis, George; Falagas, Matthew E

2017-07-01

Data on Citrobacter spp. susceptibility are scarce. We sought to study the evolution in the susceptibility of 385 Citrobacter spp. at the University Hospital of Heraklion, Crete, Greece during a six-year period (2010-2015). Non-duplicate strains isolated from inpatients (intensive care unit, oncology, surgery, internal medicine, paediatrics) and outpatients were studied using Vitek 2. Phenotypic confirmatory tests were applied for detection of β-lactamases and aminoglycoside modifying enzymes. C. freundii (172, 44.7%) and C. koseri (166, 43.1%) were the most commonly isolated species. C. braakii (34), C. amalonaticus (6), C. youngae (6) and C. sedlakii (1) were the remaining isolates. Colistin and fosfomycin were the most active antibiotics (both 99.2%) followed by carbapenems (99%) aminoglycosides (96.6-98.4%), tigecycline (96.1%), cefepime (94.8%), ciprofloxacin (94.3%), tetracycline (92.7%), trimethoprim/sulphamethoxazole (91.4%), chloramphenicol (88.1%), piperacillin/tazobactam (86.5%) and 3rd generation cephalosporins (85.7%). C. freundii were more resistant than C. koseri. Antibiotic resistance did not increase during the study period for most antibiotics. Lower susceptibility to all antibiotics was observed among multi-drug resistant (MDR) strains. AmpC was the most common resistant mechanism (10.9%); carbapenemases (1.3%) and aminoglycoside modifying enzymes (2.9%) were also detected. All AmpC producers were resistant to cephalosporins but not to carbapenems. In all but one isolates aminoglycoside resistance was accompanied by acquired β-lactamases. Although Citrobacter species in general were susceptible, antibiotic susceptibility testing is required for the detection of resistant isolates.

Total synthesis of the thiopeptide antibiotic amythiamicin D.

PubMed

Hughes, Rachael A; Thompson, Stewart P; Alcaraz, Lilian; Moody, Christopher J

2005-11-09

The thiopeptide (or thiostrepton) antibiotics are a class of sulfur containing highly modified cyclic peptides with interesting biological properties, including reported activity against MRSA and malaria. Described herein is the total synthesis of the thiopeptide natural product amythiamicin D, which utilizes a biosynthesis-inspired hetero-Diels-Alder route to the pyridine core of the antibiotic as a key step. Preliminary studies using a range of serine-derived 1-ethoxy-2-azadienes established that hetero-Diels-Alder reaction with N-acetylenamines proceeded efficiently under microwave irradiation to give 2,3,6-trisubstituted pyridines. The thiazole building blocks of the antibiotic were obtained by either classical Hantzsch reactions or by dirhodium(II)-catalyzed chemoselective carbene N-H insertion followed by thionation, and were combined to give the bis-thiazole that forms the left-hand fragment of the antibiotic. The key Diels-Alder reaction of a tris-thiazolyl azadiene with benzyl 2-(1-acetylaminoethenyl)thiazole-4-carboxylate gave the core tetrathiazolyl pyridine, which was elaborated into the natural product by successive incorporation of glycine and bis-thiazole fragments followed by macrocyclization.

A Simple Method for Assessment of MDR Bacteria for Over-Expressed Efflux Pumps

PubMed Central

Martins, Marta; McCusker, Matthew P; Viveiros, Miguel; Couto, Isabel; Fanning, Séamus; Pagès, Jean-Marie; Amaral, Leonard

2013-01-01

It is known that bacteria showing a multi-drug resistance phenotype use several mechanisms to overcome the action of antibiotics. As a result, this phenotype can be a result of several mechanisms or a combination of thereof. The main mechanisms of antibiotic resistance are: mutations in target genes (such as DNA gyrase and topoisomerase IV); over-expression of efflux pumps; changes in the cell envelope; down regulation of membrane porins, and modified lipopolysaccharide component of the outer cell membrane (in the case of Gram-negative bacteria). In addition, adaptation to the environment, such as quorum sensing and biofilm formation can also contribute to bacterial persistence. Due to the rapid emergence and spread of bacterial isolates showing resistance to several classes of antibiotics, methods that can rapidly and efficiently identify isolates whose resistance is due to active efflux have been developed. However, there is still a need for faster and more accurate methodologies. Conventional methods that evaluate bacterial efflux pump activity in liquid systems are available. However, these methods usually use common efflux pump substrates, such as ethidium bromide or radioactive antibiotics and therefore, require specialized instrumentation, which is not available in all laboratories. In this review, we will report the results obtained with the Ethidium Bromide-agar Cartwheel method. This is an easy, instrument-free, agar based method that has been modified to afford the simultaneous evaluation of as many as twelve bacterial strains. Due to its simplicity it can be applied to large collections of bacteria to rapidly screen for multi-drug resistant isolates that show an over-expression of their efflux systems. The principle of the method is simple and relies on the ability of the bacteria to expel a fluorescent molecule that is substrate for most efflux pumps, ethidium bromide. In this approach, the higher the concentration of ethidium bromide required to produce fluorescence of the bacterial mass, the greater the efflux capacity of the bacterial cells. We have tested and applied this method to a large number of Gram-positive and Gram-negative bacteria to detect efflux activity among these multi-drug resistant isolates. The presumptive efflux activity detected by the Ethidium Bromide-agar Cartwheel method was subsequently confirmed by the determination of the minimum inhibitory concentration for several antibiotics in the presence and absence of known efflux pump inhibitors. PMID:23589748

The Antibacterial Activity of Metal Complexes Containing 1,10- phenanthroline: Potential as Alternative Therapeutics in the Era of Antibiotic Resistance.

PubMed

Viganor, Livia; Howe, Orla; McCarron, Pauraic; McCann, Malachy; Devereux, Michael

2017-01-01

The "antibiotic era", characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical "era of resistance". The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from "extensive drug resistance" to "pan-drug resistance" may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Effects of chlorophyll-derived efflux pump inhibitor pheophorbide a and pyropheophorbide a on growth and macrolide antibiotic resistance of indicator and anaerobic swine manure bacteria

USDA-ARS?s Scientific Manuscript database

Natural plant compounds, such as the chlorophyll a catabolites pheophorbide a (php) and pyropheophorbide a (pyp), are potentially active in the gastrointestinal tracts and wastes of livestock as antimicrobial resistance-modifying agents through inhibition of bacterial efflux pumps. To investigate w...

Bio-inspired synthesis yields a tricyclic indoline that selectively resensitizes methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics

PubMed Central

Podoll, Jessica D.; Liu, Yongxiang; Chang, Le; Walls, Shane; Wang, Wei; Wang, Xiang

2013-01-01

The continuous emergence of resistant bacteria has become a major worldwide health threat. The current development of new antibacterials has lagged far behind. To discover reagents to fight against resistant bacteria, we initiated a chemical approach by synthesizing and screening a small molecule library, reminiscent of the polycyclic indole alkaloids. Indole alkaloids are a class of structurally diverse natural products, many of which were isolated from plants that have been used as traditional medicine for millennia. Specifically, we adapted an evolutionarily conserved biosynthetic strategy and developed a concise and unified diversity synthesis pathway. Using this pathway, we synthesized 120 polycyclic indolines that contain 26 distinct skeletons and a wide variety of functional groups. A tricyclic indoline, Of1, was discovered to selectively potentiate the activity of β-lactam antibiotics in multidrug-resistant methicillin-resistant Staphylococcus aureus (MRSA), but not in methicillin-sensitive S. aureus. In addition, we found that Of1 itself does not have antiproliferative activity but can resensitize several MRSA strains to the β-lactam antibiotics that are widely used in the clinic, such as an extended-spectrum β-lactam antibiotic amoxicillin/clavulanic acid and a first-generation cephalosporin cefazolin. These data suggest that Of1 is a unique selective resistance-modifying agent for β-lactam antibiotics, and it may be further developed to fight against resistant bacteria in the clinic. PMID:24019472

A gold nanostar-based SERS platform for point-of-care diagnostics of carbapenemase-producing enterobacteriacae

NASA Astrophysics Data System (ADS)

Kang, Wei Cherng Malvin; Wong, Yen Lynn; Piotrowski, Marek; Teo, Woon Pei J.; He, Shuai; Kah, James C.

2017-04-01

The ever-increasing spread and emergence of antibiotic resistance poses a serious threat to global public health. With the existence of Carbapenem-resistant Enterobacteriaceae (CRE) produced by the Klebsiella Pneumoniae bacteria, it renders the use of carbapenems, the last-resort class of β-lactam antibiotics, useless against combating against bacterial infections. Such infections reduce the ability to treat complex infections due to the lack of antibiotic options for treatment, leading to CRE-associated mortalities. Current methods of detection, like CarbaNP test and Modified Hodge's Test, have significant limitations in that the time taken for detection of carbapenemase activity ranges between hours to days, and are non-specific in detecting the specific phenotype, making it challenging to isolate patients rapidly and to devise appropriate treatment for infected patients. We propose a methodology by utilising Surface Enhanced Raman Spectroscopy (SERS) to study bacterial β-lactamase activity. This is done via the use of gold nanostars (AuNS), which have reported excellent SERS properties, conjugated with a β-lactam antibiotic ceftriaxole, as a proof-of-concept study to analyse the changes in the SERS spectra associated with cleavage of the β-lactam ring upon interaction with the New Delhi Metalloproteinase (NDM)- producing Escherichia coli (Class B β-lactamase). We are able to obtain detection of carbapenemase activity within 25 minutes, with the associated changes in SERS spectra being diminishing of SERS peaks at 1358cm-1 and 1495cm-1. This project can be further extended to study the activity of other classes of β-lactamases and other β-lactam antibiotics to improve this state of technology for potential adoption by healthcare institutions.

Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: pharmacodynamic evaluation and comparison with isogenic normal-phenotype and revertant strains.

PubMed

Nguyen, Hoang Anh; Denis, Olivier; Vergison, Anne; Theunis, Anne; Tulkens, Paul M; Struelens, Marc J; Van Bambeke, Françoise

2009-04-01

Small-colony variant (SCV) strains of Staphylococcus aureus show reduced antibiotic susceptibility and intracellular persistence, potentially explaining therapeutic failures. The activities of oxacillin, fusidic acid, clindamycin, gentamicin, rifampin, vancomycin, linezolid, quinupristin-dalfopristin, daptomycin, tigecycline, moxifloxacin, telavancin, and oritavancin have been examined in THP-1 macrophages infected by a stable thymidine-dependent SCV strain in comparison with normal-phenotype and revertant isogenic strains isolated from the same cystic fibrosis patient. The SCV strain grew slowly extracellularly and intracellularly (1- and 0.2-log CFU increase in 24 h, respectively). In confocal and electron microscopy, SCV and the normal-phenotype bacteria remain confined in acid vacuoles. All antibiotics tested, except tigecycline, caused a net reduction in bacterial counts that was both time and concentration dependent. At an extracellular concentration corresponding to the maximum concentration in human serum (total drug), oritavancin caused a 2-log CFU reduction at 24 h; rifampin, moxifloxacin, and quinupristin-dalfopristin caused a similar reduction at 72 h; and all other antibiotics had only a static effect at 24 h and a 1-log CFU reduction at 72 h. In concentration dependence experiments, response to oritavancin was bimodal (two successive plateaus of -0.4 and -3.1 log CFU); tigecycline, moxifloxacin, and rifampin showed maximal effects of -1.1 to -1.7 log CFU; and the other antibiotics produced results of -0.6 log CFU or less. Addition of thymidine restored intracellular growth of the SCV strain but did not modify the activity of antibiotics (except quinupristin-dalfopristin). All drugs (except tigecycline and oritavancin) showed higher intracellular activity against normal or revertant phenotypes than against SCV strains. The data may help rationalizing the design of further studies with intracellular SCV strains.

[Modifying action of oxytocin on the biological properties of the causative agents of anaerobic non-clostridial infection].

PubMed

Abramzon, O M; Kirillov, D A; Pan'kov, A S; Perunova, N B; Elagina, N N; Valyshev, A V; Bukharin, O V

2003-01-01

In a number of in vitro experiments the effect of oxytocin on the antilysozyme and anticomplemental activity of Propiobacterium propionicum, Bacteroides fragilis, Prevotella melaninogenica and Peptostreprtococcus anaerobius, isolated from patients with acute pyoinflammatory pleuropulmonary diseases, was studied. Antibiotic resistance dynamics of the infective agents under study to lincomycin, clindamycin, thienam, vancomycin was also detected. The inhibiting activity of oxytocin on the persistence properties of B. fragilis, P. melanogenica and P. anaerobius was noted. Under the influence of the preparations used changes in the sensitivity of the strains to a number of antibiotics of the lincosamide, carbapenem and glycopeptide groups were found to occur. The data thus obtained were indicative of the possible mechanisms of action of oxytocin in the treatment of acute pyoinflammatory pleuropulmonary diseases of anaerobic nonclostridial etiology.

Residual antibiotics in decontaminated human cardiovascular tissues intended for transplantation and risk of falsely negative microbiological analyses.

PubMed

Buzzi, Marina; Guarino, Anna; Gatto, Claudio; Manara, Sabrina; Dainese, Luca; Polvani, Gianluca; Tóthová, Jana D'Amato

2014-01-01

We investigated the presence of antibiotics in cryopreserved cardiovascular tissues and cryopreservation media, after tissue decontamination with antibiotic cocktails, and the impact of antibiotic residues on standard tissue bank microbiological analyses. Sixteen cardiovascular tissues were decontaminated with bank-prepared cocktails and cryopreserved by two different tissue banks according to their standard operating procedures. Before and after decontamination, samples underwent microbiological analysis by standard tissue bank methods. Cryopreserved samples were tested again with and without the removal of antibiotic residues using a RESEP tube, after thawing. Presence of antibiotics in tissue homogenates and processing liquids was determined by a modified agar diffusion test. All cryopreserved tissue homogenates and cryopreservation media induced important inhibition zones on both Staphylococcus aureus- and Pseudomonas aeruginosa-seeded plates, immediately after thawing and at the end of the sterility test. The RESEP tube treatment markedly reduced or totally eliminated the antimicrobial activity of tested tissues and media. Based on standard tissue bank analysis, 50% of tissues were found positive for bacteria and/or fungi, before decontamination and 2 out of 16 tested samples (13%) still contained microorganisms after decontamination. After thawing, none of the 16 cryopreserved samples resulted positive with direct inoculum method. When the same samples were tested after removal of antibiotic residues, 8 out of 16 (50%) were contaminated. Antibiotic residues present in tissue allografts and processing liquids after decontamination may mask microbial contamination during microbiological analysis performed with standard tissue bank methods, thus resulting in false negatives.

Residual Antibiotics in Decontaminated Human Cardiovascular Tissues Intended for Transplantation and Risk of Falsely Negative Microbiological Analyses

PubMed Central

Gatto, Claudio; Manara, Sabrina; Dainese, Luca; Polvani, Gianluca; Tóthová, Jana D'Amato

2014-01-01

We investigated the presence of antibiotics in cryopreserved cardiovascular tissues and cryopreservation media, after tissue decontamination with antibiotic cocktails, and the impact of antibiotic residues on standard tissue bank microbiological analyses. Sixteen cardiovascular tissues were decontaminated with bank-prepared cocktails and cryopreserved by two different tissue banks according to their standard operating procedures. Before and after decontamination, samples underwent microbiological analysis by standard tissue bank methods. Cryopreserved samples were tested again with and without the removal of antibiotic residues using a RESEP tube, after thawing. Presence of antibiotics in tissue homogenates and processing liquids was determined by a modified agar diffusion test. All cryopreserved tissue homogenates and cryopreservation media induced important inhibition zones on both Staphylococcus aureus- and Pseudomonas aeruginosa-seeded plates, immediately after thawing and at the end of the sterility test. The RESEP tube treatment markedly reduced or totally eliminated the antimicrobial activity of tested tissues and media. Based on standard tissue bank analysis, 50% of tissues were found positive for bacteria and/or fungi, before decontamination and 2 out of 16 tested samples (13%) still contained microorganisms after decontamination. After thawing, none of the 16 cryopreserved samples resulted positive with direct inoculum method. When the same samples were tested after removal of antibiotic residues, 8 out of 16 (50%) were contaminated. Antibiotic residues present in tissue allografts and processing liquids after decontamination may mask microbial contamination during microbiological analysis performed with standard tissue bank methods, thus resulting in false negatives. PMID:25397402

Surprising Alteration of Antibacterial Activity of 5″-Modified Neomycin against Resistant Bacteria

PubMed Central

Zhang, Jianjun; Chiang, Fang-I; Wu, Long; Czyryca, Przemyslaw Greg; Li, Ding; Chang, Cheng-Wei Tom

2009-01-01

A facile synthetic protocol for the production of neomycin B derivatives with various modifications at the 5″ position has been developed. Structural activity relationship (SAR) against aminoglycoside resistant bacteria equipped with various aminoglycoside-modifying enzymes (AME's) was investigated. Enzymatic and molecular modeling studies reveal that the superb substrate promiscuity of AME's allows the resistant bacteria to cope with diverse structural modifications despite the observation that several derivatives show enhanced antibacterial activity than the parent neomycin. Surprisingly, when testing synthetic neomycin derivatives against other human pathogens, two leads exhibit prominent activity against both Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) that are known to exert high level of resistance against clinically used aminoglycosides. These findings can be extremely useful in developing new aminoglycoside antibiotics against resistant bacteria. Our result also suggests that new biological and antimicrobial activities can be obtained by chemical modifications of old drugs. PMID:19012394

Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study.

PubMed

Blommaert, A; Marais, C; Hens, N; Coenen, S; Muller, A; Goossens, H; Beutels, P

2014-02-01

To identify key determinants explaining country-year variations in antibiotic use and resistance. Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. Relative humidity, healthcare expenditure proportional to gross domestic product, feelings of distrust, proportion of population aged >65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

Broad spectrum antibiotic enrofloxacin modulates contact sensitivity through gut microbiota in a murine model.

PubMed

Strzępa, Anna; Majewska-Szczepanik, Monika; Lobo, Francis M; Wen, Li; Szczepanik, Marian

2017-07-01

Medical advances in the field of infection therapy have led to an increasing use of antibiotics, which, apart from eliminating pathogens, also partially eliminate naturally existing commensal bacteria. It has become increasingly clear that less exposure to microbiota early in life may contribute to the observed rise in "immune-mediated" diseases, including autoimmunity and allergy. We sought to test whether the change of gut microbiota with the broad spectrum antibiotic enrofloxacin will modulate contact sensitivity (CS) in mice. Natural gut microbiota were modified by oral treatment with enrofloxacin prior to sensitization with trinitrophenyl chloride followed by CS testing. Finally, adoptive cell transfers were performed to characterize the regulatory cells that are induced by microbiota modification. Oral treatment with enrofloxacin suppresses CS and production of anti-trinitrophenyl chloride IgG1 antibodies. Adoptive transfer experiments show that antibiotic administration favors induction of regulatory cells that suppress CS. Flow cytometry and adoptive transfer of purified cells show that antibiotic-induced suppression of CS is mediated by TCR αβ + CD4 + CD25 + FoxP3 + Treg, CD19 + B220 + CD5 + IL-10 + , IL-10 + Tr1, and IL-10 + TCR γδ + cells. Treatment with the antibiotic induces dysbiosis characterized by increased proportion of Clostridium coccoides (cluster XIVa), C coccoides-Eubacterium rectale (cluster XIVab), Bacteroidetes, and Bifidobacterium spp, but decreased segmented filamentous bacteria. Transfer of antibiotic-modified gut microbiota inhibits CS, but this response can be restored through oral transfer of control gut bacteria to antibiotic-treated animals. Oral treatment with a broad spectrum antibiotic modifies gut microbiota composition and promotes anti-inflammatory response, suggesting that manipulation of gut microbiota can be a powerful tool to modulate the course of CS. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Phytochemical Analysis and Modulation of Antibiotic Activity by Luehea paniculata Mart. & Zucc. (Malvaceae) in Multiresistant Clinical Isolates of Candida Spp.

PubMed Central

Calixto Júnior, João T.; Morais, Selene M.; Martins, Clécio G.; Vieira, Larissa G.; Morais-Braga, Maria Flaviana B.; Carneiro, Joara N. P.; Machado, Antonio J. P.; Menezes, Irwin R. A.; Tintino, Saulo R.; Coutinho, Henrique D. M.

2015-01-01

The high incidence of fungal infections has led to the continuous search for new drugs. Extracts of Luehea paniculata, a tree of multiple medicinal uses, were evaluated for anti-Candida activity, as well as its modulator potential of the Fluconazole antibiotic. Chemical prospecting of ethanol extracts of leaf and bark was carried out, the quantification of total phenols and flavonoids, characterized by the HPLC-DAD technique. The rosmarinic acid and the vitexin flavonoid were observed as major constituents in ELELP and ESWELP, respectively. Antioxidant activity was also evaluated by the method of scavenging the free radical DPPH, and quercetin was used as standard, obtaining IC50 values: 0.341 (mg/mL) for ELELP and 0.235 (mg/mL) for ESWELP. The microdilution assay was performed for antifungal activity against strains of Candida albicans, C. krusei, and C. tropicalis and showed minimum inhibitory concentrations values ≥1024 μg/mL. In the modulator action of extracts on Fluconazole against multiresistant clinical isolates of Candida (subinhibitory concentration minimum of 128 μg/mL), a significant synergism was observed, indicating that the extracts potentiated the antifungal effect against C. tropicalis, where antioxidant flavonoids could be responsible. This is the first report about modifying activity of the antibiotic action of a species of the genus Luehea. PMID:25821822

Modified Reporting of Positive Urine Cultures to Reduce Inappropriate Treatment of Asymptomatic Bacteriuria Among Nonpregnant, Noncatheterized Inpatients: A Randomized Controlled Trial.

PubMed

Daley, Peter; Garcia, David; Inayatullah, Raheel; Penney, Carla; Boyd, Sarah

2018-05-28

DESIGNWe conducted a randomized, parallel, unblinded, superiority trial of a laboratory reporting intervention designed to reduce antibiotic treatment of asymptomatic bacteriuria (ASB).METHODSResults of positive urine cultures from 110 consecutive inpatients at 2 urban acute-care hospitals were randomized to standard report (control) or modified report (intervention). The standard report included bacterial count, bacterial identification, and antibiotic susceptibility information including drug dosage and cost. The modified report stated: "This POSITIVE urine culture may represent asymptomatic bacteriuria or urinary tract infection. If urinary tract infection is suspected clinically, please call the microbiology laboratory … for identification and susceptibility results." We used the following exclusion criteria: age <18 years, pregnancy, presence of an indwelling urinary catheter, samples from patients already on antibiotics, neutropenia, or admission to an intensive care unit. The primary efficacy outcome was the proportion of appropriate antibiotic therapy prescribed.RESULTSAccording to our intention-to-treat (ITT) analysis, the proportion of appropriate treatment (urinary tract infection treated plus ASB not treated) was higher in the modified arm than in the standard arm: 44 of 55 (80.0%) versus 29 of 55 (52.7%), respectively (absolute difference, -27.3%; RR, 0.42; P = .002; number needed to report for benefit, 3.7).CONCLUSIONSModified reporting resulted in a significant reduction in inappropriate antibiotic treatment without an increase in adverse events. Safety should be further assessed in a large effectiveness trial before implementationTRIAL REGISTRATION. clinicaltrials.gov#NCT02797613Infect Control Hosp Epidemiol 2018;1-6.

Does appropriate empiric antibiotic therapy modify intensive care unit-acquired Enterobacteriaceae bacteraemia mortality and discharge?

PubMed

Pouwels, K B; Van Kleef, E; Vansteelandt, S; Batra, R; Edgeworth, J D; Smieszek, T; Robotham, J V

2017-05-01

Conflicting results have been found regarding outcomes of intensive care unit (ICU)-acquired Enterobacteriaceae bacteraemia and the potentially modifying effect of appropriate empiric antibiotic therapy. To evaluate these associations while adjusting for potential time-varying confounding using methods from the causal inference literature. Patients who stayed more than two days in two general ICUs in England between 2002 and 2006 were included in this cohort study. Marginal structural models with inverse probability weighting were used to estimate the mortality and discharge associated with Enterobacteriaceae bacteraemia and the impact of appropriate empiric antibiotic therapy on these outcomes. Among 3411 ICU admissions, 195 (5.7%) ICU-acquired Enterobacteriaceae bacteraemia cases occurred. Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU death [cause-specific hazard ratio (HR): 1.48; 95% confidence interval (CI): 1.10-1.99] and a reduced daily risk of ICU discharge (HR: 0.66; 95% CI: 0.54-0.80). Appropriate empiric antibiotic therapy did not significantly modify ICU mortality (HR: 1.08; 95% CI: 0.59-1.97) or discharge (HR: 0.91; 95% CI: 0.63-1.32). ICU-acquired Enterobacteriaceae bacteraemia was associated with an increased daily risk of ICU mortality. Furthermore, the daily discharge rate was also lower after acquiring infection, even when adjusting for time-varying confounding using appropriate methodology. No evidence was found for a beneficial modifying effect of appropriate empiric antibiotic therapy on ICU mortality and discharge. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Synthesis and Antibacterial Evaluation of Novel 3-Substituted Ocotillol-Type Derivatives as Leads.

PubMed

Bi, Yi; Liu, Xian-Xuan; Zhang, Heng-Yuan; Yang, Xiao; Liu, Ze-Yun; Lu, Jing; Lewis, Peter John; Wang, Chong-Zhi; Xu, Jin-Yi; Meng, Qing-Guo; Ma, Cong; Yuan, Chun-Su

2017-04-07

Due to the rapidly growing bacterial antibiotic-resistance and the scarcity of novel agents in development, bacterial infection is still a global problem. Therefore, new types of antibacterial agents, which are effective both alone and in combination with traditional antibiotics, are urgently needed. In this paper, a series of antibacterial ocotillol-type C-24 epimers modified from natural 20( S )-protopanaxadiol were synthesized and evaluated for their antibacterial activity. According to the screening results of Gram-positive bacteria ( B. subtilis 168 and MRSA USA300) and Gram-negative bacteria ( P. aer PAO1 and A. baum ATCC19606) in vitro, the derivatives exhibited good antibacterial activity, particularly against Gram-positive bacteria with an minimum inhibitory concentrations (MIC) value of 2-16 µg/mL. The subsequent synergistic antibacterial assay showed that derivatives 5c and 6c enhanced the susceptibility of B. subtilis 168 and MRSA USA300 to chloramphenicol (CHL) and kanamycin (KAN) (FICI < 0.5). Our data showed that ocotillol-type derivatives with long-chain amino acid substituents at C-3 were good leads against antibiotic-resistant pathogens MRSA USA300, which could improve the ability of KAN and CHL to exhibit antibacterial activity at much lower concentrations with reduced toxicity.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry.

PubMed

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng; Olsen, Rikke Heidemann

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens.

Treatment with high-dose antidepressants severely exacerbates the pathological outcome of experimental Escherichia coli infections in poultry

PubMed Central

Kromann, Sofie; Kudirkiene, Egle; Li, Lili; Thoefner, Ida; Daldorph, Elisabeth; Christensen, Jens Peter; Meng, Hecheng

2017-01-01

There is an urgent need for novel antibiotics as the current antibiotics are losing their value due to increased resistance among clinically important bacteria. Sertraline, an on-marked anti-depressive drug, has been shown to modify bacterial activity in vitro, including increasing the susceptibility of Escherichia coli to antibiotics. The aim of the present study was to investigate if the antimicrobial activity of sertraline could be documented under clinical settings, hereunder if sertraline could potentiate the effect of tetracycline in treatment of an experimentally induced ascending infection in poultry. A total of 40 chickens were divided in four groups of 10 chickens each. All chickens were challenged with 4x103 colony forming units (CFU) of a tetracycline resistant E. coli strain using a surgical infection model, and subsequently treated with either high-dose sertraline, tetracycline, a combination hereof or received no treatment. Seven days post challenge all birds were submitted to necropsy and scored pathologically for lesions. The average lesion scores were significantly higher (P<0.05) in the groups that were treated with high-dose sertraline or high-dose sertraline combined with tetracycline. In conclusion high-dose treatments (four times the maximum therapeutic dose for treating human depression) with sertraline as an adjuvant for treatment of antibiotic resistant E. coli infections exacerbate the pathological outcome of infection in chickens. PMID:29020098

Prospective evaluation of surgical site infection rate among patients with Mohs micrographic surgery without the use of prophylactic antibiotics.

PubMed

Maragh, Sherry L H; Brown, Marc D

2008-08-01

Antibiotics may be indiscriminately given to patients undergoing Mohs micrographic surgery (MMS) for the prevention of surgical site infections, despite a low risk of infection in these patients. We sought to evaluate the rate of wound infections among patients undergoing MMS without the use of prophylactic antibiotics. We prospectively evaluated 1000 consecutive patients undergoing MMS for nonmelanoma skin cancer or modified MMS/"slow Mohs" for lentigo maligna melanoma in situ. The overall wound infection rate among 1000 patients with 1115 tumors was 0.7% (8/1115 tumors). Five (62.5%) of 8 infections occurred on the nose with an overall 1.7% (5/302) nose infection rate. Seven (87.5%) of 8 infections occurred after flap reconstruction with an overall 2.4% (7/296) flap closure infection rate. Four (50%) of 8 infections occurred in patients requiring more than one Mohs stage for tumor clearance with a 0.8% (4/487) overall infection rate in cases requiring multiple Mohs stages. Two (25%) of 8 infections had cultures positive for oxacillin-resistant Staphylococcus aureus. No wound infections occurred in cases involving the lips or ears, skin-graft closures, or below-knee or modified MMS procedures. This was a prospective single institution uncontrolled study. Rates of infections among patients undergoing MMS or modified MMS are exceedingly low. Indiscriminate use of antibiotics increases patient risk to adverse drug reactions and antibiotic resistance. Administration of antibiotics to patients undergoing MMS should be on a case-by-case basis according to the known risk factors combined with clinical judgment.

Synergistic interaction of Helichrysum pedunculatum leaf extracts with antibiotics against wound infection associated bacteria.

PubMed

Aiyegoro, Olayinka A; Afolayan, Anthony J; Okoh, Anthony I

2009-01-01

The effect of combinations of the crude methanolic extract of the leaves of Helichrysum pedunculatum and eight first-line antibiotics were investigated by time kill assays against a panel of bacterial strains that have been implicated in wound infections. The plant extract showed appreciable antibacterial activities against the test bacteria with zones of inhibition ranging between 18 and 27 mm, and minimum inhibitory concentrations (MICs) varying between 0.1 and 5.0 mg/ml. The MICs of the test antibiotics range between 0.001 and 0.412 mg/ml, and combination of the plant extract and the antibiotics resulted in reduction of bacterial counts by between 0 and 6.63 Log10 cfu/ml. At V2 MIC, 56.81% synergy; 43.19% indifference and no antagonism were observed, and at MIC levels, 55.68% synergy; 44.32% indifference and no antagonism were observed when the extracts were combined with eight different antibiotics. In all, 60% of the interactions were synergistic. All combination regimes on Staphylococcus aureus ATCC 6538 yielded no synergy, neither was antagonism detected in any of the assays. We propose that extracts of the leaves of Helichrysum pedunculatum could be of relevance in combination therapy and as a source of resistance modifying principies that could be useful as treatment options for persistent wound infections.

Inhibition of intestinal microflora beta-glucuronidase modifies the distribution of the active metabolite of the antitumor agent, irinotecan hydrochloride (CPT-11) in rats.

PubMed

Takasuna, K; Hagiwara, T; Hirohashi, M; Kato, M; Nomura, M; Nagai, E; Yokoi, T; Kamataki, T

1998-01-01

SN-38, a metabolite of irinotecan hydrochloride (CPT-11), is considered to play a key role in the development of diarrhea as well as in the antitumor activity of CPT-11. We have previously found that the inhibition of beta-glucuronidase, which hydrolyzes detoxified SN-38 (SN-38 glucuronide) to reform SN-38, in the lumen by eliminating the intestinal microflora with antibiotics, markedly ameliorates the intestinal toxicity of CPT-11 in rats. In this study we compared the disposition of CPT-11 and its metabolites in rats treated with and without antibiotics. Rats were given drinking water containing 1 mg/ml penicillin and 2 mg/ml streptomycin from 5 days before the administration of CPT-11 (60 mg/kg i.v.) and throughout the experiment. CPT-11, SN-38 glucuronide and SN-38 concentrations in the blood, intestinal tissues and intestinal luminal contents were determined by HPLC. Antibiotics had little or no effect on the pharmacokinetics of CPT-11, SN-38 glucuronide or SN-38 in the blood, or in the tissues or contents of the small intestine, which has less beta-glucuronidase activity in its luminal contents. In contrast, antibiotics markedly reduced the AUC1-24 h of SN-38 (by about 85%) in the large intestine tissue without changing that of CPT-11, and this was accompanied by a complete inhibition of the deconjugation of SN-38 glucuronide in the luminal contents. These results suggest that SN-38, which results from the hydrolysis of SN-38 glucuronide by beta-glucuronidase in the intestinal microflora, contributes considerably to the distribution of SN-38 in the large intestine tissue, and that inhibition of the beta-glucuronidase activity by antibiotics results in decreased accumulation of SN-38 in the large intestine.

Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria

PubMed Central

Yosef, Ido; Manor, Miriam; Kiro, Ruth

2015-01-01

The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance-conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones. PMID:26060300

Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria.

PubMed

Yosef, Ido; Manor, Miriam; Kiro, Ruth; Qimron, Udi

2015-06-09

The increasing threat of pathogen resistance to antibiotics requires the development of novel antimicrobial strategies. Here we present a proof of concept for a genetic strategy that aims to sensitize bacteria to antibiotics and selectively kill antibiotic-resistant bacteria. We use temperate phages to deliver a functional clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated (Cas) system into the genome of antibiotic-resistant bacteria. The delivered CRISPR-Cas system destroys both antibiotic resistance-conferring plasmids and genetically modified lytic phages. This linkage between antibiotic sensitization and protection from lytic phages is a key feature of the strategy. It allows programming of lytic phages to kill only antibiotic-resistant bacteria while protecting antibiotic-sensitized bacteria. Phages designed according to this strategy may be used on hospital surfaces and hand sanitizers to facilitate replacement of antibiotic-resistant pathogens with sensitive ones.

Structure–Activity Relationship Studies of the Tricyclic Indoline Resistance-Modifying Agent

PubMed Central

2015-01-01

Previously we discovered a tricyclic indoline, N-[2-(6-bromo-4-methylidene-2,3,4,4a,9,9a-hexahydro-1H-carbazol-4a-yl)ethyl]-4-chlorobenzene-1-sulfonamide (1, Of1), from bioinspired synthesis of a highly diverse polycyclic indoline alkaloid library, that selectively resensitizes methicillin-resistant Staphylococcus aureus strains to β-lactam antibiotics. Herein, we report a thorough structure–activity relationship investigation of 1, which identified regions of 1 that tolerate modifications without compromising activity and afforded the discovery of a more potent analogue with reduced mammalian toxicity. PMID:24694192

Phytochemical Prospection and Modulation of Antibiotic Activity In Vitro by Lippia origanoides H.B.K. in Methicillin Resistant Staphylococcus aureus

PubMed Central

Medeiros Barreto, Humberto; Cerqueira Fontinele, Filipe; Pereira de Oliveira, Aldeídia; Arcanjo, Daniel Dias Rufino; Cavalcanti dos Santos, Bernadete Helena; de Abreu, Aislan Pereira Lira; Douglas Melo Coutinho, Henrique; Alves Carvalho da Silva, Romezio; Oliveira de Sousa, Taciana; Freire de Medeiros, Maria das Graças; Lopes Citó, Antonia Maria das Graças; Dantas Lopes, José Arimateia

2014-01-01

The Lippia origanoides H.B.K. ethanol extract (LOEE) and hexane (LOHEX), dichloromethane (LODCM), and ethyl acetate (LOEA) fractions were tested for their antimicrobial activity alone or in combination with antibiotics against a methicillin resistant Staphylococcus aureus (MRSA) strain. The natural products did not show antimicrobial activity against multidrug resistant strain at the clinically significant concentrations tested. However, a modulatory effect in the antibacterial activity of the neomycin and amikacin was verified when LOEE, LOHEX and LODCM were added to the growth medium at subinhibitory concentrations. A similar modulation was found when the natural products were changed for chlorpromazine, an inhibitor of bacterial efflux pumps, suggesting the involvement of resistance mediated by efflux system in the MRSA tested. The fractions LOHEX and LODCM showed a modulatory activity bigger than their majority compounds (carvacrol, thymol, and naringenin), indicating that this activity is not due to their majority compounds only, but it is probably due to a synergism between their chemical components. These results indicate that L. origanoides H.B.K. can be a source of phytochemicals able to modify the phenotype of resistance to aminoglycosides in MRSA. PMID:24683545

Antibacterial activity of sulfamethoxazole transformation products (TPs): general relevance for sulfonamide TPs modified at the para position.

PubMed

Majewsky, Marius; Wagner, Danny; Delay, Markus; Bräse, Stefan; Yargeau, Viviane; Horn, Harald

2014-10-20

Sulfonamide antibiotics undergo transformation in the aquatic environment through biodegradation, photolysis, or hydrolysis. In this study, the residual antibacterial activity of 11 transformation products (TPs) of sulfamethoxazole (SMX) was investigated with regard to their in vitro growth and luminescence inhibition on Vibrio fischeri (30 min and 24 h exposure). Two transformation products, 4-hydroxy-SMX and N(4)-hydroxy-acetyl-SMX, were synthesized in-house and confirmed by nuclear magnetic resonance and high-resolution mass spectrometry. Results of individual compound experiments showed that TPs modified at the para amino group still exhibit clear antibacterial effects, whereas TPs resulting from breakdown of the SMX structure lost this mechanism of action. 4-NO2- and 4-OH-SMX were found to inhibit growth to a clearly greater extent than the parent compound, SMX. In contrast, the N(4)-acetyl- and N(4)-hydroxy-acetyl-derivatives retain less than 10 and 5% of the effect of SMX on growth and luminescence inhibition, respectively. The effect of a mixture of para-modified TPs was observed to be additive. Considering the homologous series of sulfa drugs widely prescribed and their common mechanism of action, the potential environmental impact must consider the total amount of sulfonamide antibiotics and their derivative TPs, which might end up in a water body. Extrapolating the results obtained here for the para TPs of SMX to other sulfa drugs and determining the persistence and occurrence of these compounds in the aquatic environment is required for improved risk assessment.

In-vitro activity of several antimicrobial agents against methicillin-resistant Staphylococcus aureus (MRSA) isolates expressing aminoglycoside-modifying enzymes: potency of plazomicin alone and in combination with other agents.

PubMed

López Díaz, María Carmen; Ríos, Esther; Rodríguez-Avial, Iciar; Simaluiza, Rosa Janneth; Picazo, Juan José; Culebras, Esther

2017-08-01

This study investigated the in-vitro activity of clinically relevant aminoglycosides and new antimicrobial agents-plazomicin, ceftobiprole and dalbavancin-against 55 methicillin-resistant Staphylococcus aureus (MRSA) isolates producing aminoglycoside-modifying enzymes (AMEs). The checkerboard method was used to assess synergism between plazomicin and four antibiotics (fosfomycin, ceftobiprole, cefoxitin and meropenem), and time-kill assays were performed for the most active combinations. Among the aminoglycosides tested, plazomicin was the most active agent against MRSA, with >90% of isolates being inhibited at a minimum inhibitory concentration (MIC) of ≤1 mg/L. MIC 50 and MIC 90 values for ceftobiprole and dalbavancin were 2 and 4 mg/L, and 0.125 and 0.125 mg/L, respectively. The most prevalent AME gene was aac(6')Ie-aph(2″)Ia (87.3%), followed by ant(4')Ia (52.7%) and aph(3')IIIa (52.7%). Plazomicin activity was not affected by the type or number of enzymes detected. In checkerboard and time-kill assays, indifference was the most common result achieved for the antibiotic combinations. Notably, no antagonism was observed with any combination tested. Overall, plazomicin in combination with meropenem had the highest synergistic effect, demonstrating synergy against seven isolates in the checkerboard assay and three isolates in time-kill curves. In conclusion, plazomicin showed potent activity against aminoglycoside-resistant MRSA isolates, regardless of the number and type of AMEs present. These findings indicate the potential utility of plazomicin in combination with meropenem for the treatment of MRSA infections. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Effects of the 1- N-(4-Amino-2 S-hydroxybutyryl) and 6'- N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics.

PubMed

Sonousi, Amr; Sarpe, Vikram A; Brilkova, Margarita; Schacht, Jochen; Vasella, Andrea; Böttger, Erik C; Crich, David

2018-05-10

Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1- N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6'- N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside-modifying enzymes, while the 1- N-(4-amino-2 S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates.

Broad-Spectrum Antibiotic Treatment and Subsequent Childhood Type 1 Diabetes: A Nationwide Danish Cohort Study.

PubMed

Clausen, Tine D; Bergholt, Thomas; Bouaziz, Olivier; Arpi, Magnus; Eriksson, Frank; Rasmussen, Steen; Keiding, Niels; Løkkegaard, Ellen C

2016-01-01

Studies link antibiotic treatment and delivery by cesarean section with increased risk of chronic diseases through changes of the gut-microbiota. We aimed to evaluate the association of broad-spectrum antibiotic treatment during the first two years of life with subsequent onset of childhood type 1 diabetes and the potential effect-modification by mode of delivery. A Danish nationwide cohort study including all singletons born during 1997-2010. End of follow-up by December 2012. Four national registers provided information on antibiotic redemptions, outcome and confounders. Redemptions of antibiotic prescriptions during the first two years of life was classified into narrow-spectrum or broad-spectrum antibiotics. Children were followed from age two to fourteen, both inclusive. The risk of type 1 diabetes with onset before the age of 15 years was assessed by Cox regression. A total of 858,201 singletons contributed 5,906,069 person-years, during which 1,503 children developed type 1 diabetes. Redemption of broad-spectrum antibiotics during the first two years of life was associated with an increased rate of type 1 diabetes during the following 13 years of life (HR 1.13; 95% CI 1.02 to 1.25), however, the rate was modified by mode of delivery. Broad-spectrum antibiotics were associated with an increased rate of type 1 diabetes in children delivered by either intrapartum cesarean section (HR 1.70; 95% CI 1.15 to 2.51) or prelabor cesarean section (HR 1.63; 95% CI 1.11 to 2.39), but not in vaginally delivered children. Number needed to harm was 433 and 562, respectively. The association with broad-spectrum antibiotics was not modified by parity, genetic predisposition or maternal redemption of antibiotics during pregnancy or lactation. Redemption of broad-spectrum antibiotics during infancy is associated with an increased risk of childhood type 1 diabetes in children delivered by cesarean section.

Low Temperature and Modified Atmosphere: Hurdles for Antibiotic Resistance Transfer?

PubMed

Van Meervenne, Eva; Van Coillie, Els; Van Weyenberg, Stephanie; Boon, Nico; Herman, Lieve; Devlieghere, Frank

2015-12-01

Food is an important dissemination route for antibiotic-resistant bacteria. Factors used during food production and preservation may contribute to the transfer of antibiotic resistance genes, but research on this subject is scarce. In this study, the effect of temperature (7 to 37°C) and modified atmosphere packaging (air, 50% CO2-50% N2, and 100% N2) on antibiotic resistance transfer from Lactobacillus sakei subsp. sakei to Listeria monocytogenes was evaluated. Filter mating was performed on nonselective agar plates with high-density inocula. A more realistic setup was created by performing modified atmosphere experiments on cooked ham using high-density and low-density inocula. Plasmid transfer was observed between 10 and 37°C, with plasmid transfer also observed at 7°C during a prolonged incubation period. When high-density inocula were used, transconjugants were detected, both on agar plates and cooked ham, under the three atmospheres (air, 50% CO2-50% N2, and 100% N2) at 7°C. This yielded a median transfer ratio (number of transconjugants/number of recipients) with an order of magnitude of 10(-4) to 10(-6). With low-density inocula, transfer was only detected under the 100% N2 atmosphere after 10-day incubation at 7°C, yielding a transfer ratio of 10(-5). Under this condition, the highest bacterial density was obtained. The results indicate that low temperature and modified atmosphere packaging, two important hurdles in the food industry, do not necessarily prevent plasmid transfer from Lactobacillus sakei subsp. sakei to Listeria monocytogenes.

Photocatalytic activity and antimicrobial properties of paper sheets modified with TiO2/Sodium alginate nanocomposites.

PubMed

Abdel Rehim, Mona H; El-Samahy, Magda A; Badawy, Abdelrahman A; Mohram, Maysa E

2016-09-05

Photocatalytic paper sheets were prepared by addition of different ratios of TiO2/Sodium alginate (TSA) nanocomposite. The modified paper sheets were characterized by XRD, TGA. Their morphology was studied by scanning electron microscope (SEM) and energy dispersive X-ray (EDX). Photocatalytic activity of modified paper has been studied by analysis of chemical oxygen demand (COD) of waste-water. The results confirmed the mineralization of the waste-water and enhanced removal of chemical oxygen demand (COD) by increasing the amount of photocatalyst in the paper. Moreover, the results also confirmed that presence of sodium alginate as biopolymer increased adhesion of nanoparticles to paper fibers and reduced the harmful effect of the photocatalyst on them. The paper sheets containing 7% as well as 15% TSA showed high photocatalytic activity and anti-bacterial effect against Salmonella typhimurium higher than standard antibiotic beside other microorganisms such as Candida albicans. The maximum antimicrobial effect was found in case of specimen loaded with 15% TSA. Moreover, it was found that by adding 20% TSA to the paper matrix, the properties of the paper composite collapse. The obtained results confirm the possible utilization of the modified paper in both hygienic and food packaging applications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sorting Out Antibiotics' Mechanisms of Action: a Double Fluorescent Protein Reporter for High-Throughput Screening of Ribosome and DNA Biosynthesis Inhibitors

PubMed Central

Osterman, Ilya A.; Komarova, Ekaterina S.; Shiryaev, Dmitry I.; Korniltsev, Ilya A.; Khven, Irina M.; Lukyanov, Dmitry A.; Tashlitsky, Vadim N.; Serebryakova, Marina V.; Efremenkova, Olga V.; Ivanenkov, Yan A.; Bogdanov, Alexey A.; Dontsova, Olga A.

2016-01-01

In order to accelerate drug discovery, a simple, reliable, and cost-effective system for high-throughput identification of a potential antibiotic mechanism of action is required. To facilitate such screening of new antibiotics, we created a double-reporter system for not only antimicrobial activity detection but also simultaneous sorting of potential antimicrobials into those that cause ribosome stalling and those that induce the SOS response due to DNA damage. In this reporter system, the red fluorescent protein gene rfp was placed under the control of the SOS-inducible sulA promoter. The gene of the far-red fluorescent protein, katushka2S, was inserted downstream of the tryptophan attenuator in which two tryptophan codons were replaced by alanine codons, with simultaneous replacement of the complementary part of the attenuator to preserve the ability to form secondary structures that influence transcription termination. This genetically modified attenuator makes possible Katushka2S expression only upon exposure to ribosome-stalling compounds. The application of red and far-red fluorescent proteins provides a high signal-to-background ratio without any need of enzymatic substrates for detection of the reporter activity. This reporter was shown to be efficient in high-throughput screening of both synthetic and natural chemicals. PMID:27736765

In vitro characterization of DNA gyrase inhibition by microcin B17 analogs with altered bisheterocyclic sites

PubMed Central

Zamble, Deborah B.; Miller, Deborah A.; Heddle, Jonathan G.; Maxwell, Anthony; Walsh, Christopher T.; Hollfelder, Florian

2001-01-01

Microcin B17 (MccB17) is a 3.1-kDa Escherichia coli antibiotic that contains thiazole and oxazole heterocycles in a peptide backbone. MccB17 inhibits its cellular target, DNA gyrase, by trapping the enzyme in a complex that is covalently bound to double-strand cleaved DNA, in a manner similar to the well-known quinolone drugs. The identification of gyrase as the target of MccB17 provides an opportunity to analyze the relationship between the structure of this unusual antibiotic and its activity. In this report, steady-state parameters are used to describe the induction of the cleavable complex by MccB17 analogs containing modified bisheterocyclic sites. The relative potency of these analogs corresponds to the capacity of the compounds to prevent growth of sensitive cells. In contrast to previously reported experiments, inhibition of DNA gyrase supercoiling activity by wild-type MccB17 also was observed. These results suggest that DNA gyrase is the main intracellular target of MccB17. This study probes the structure-function relationship of a new class of gyrase inhibitors and demonstrates that these techniques could be used to analyze compounds in the search for clinically useful antibiotics that block DNA gyrase. PMID:11427730

Contrasting Effects of Physical Wear on Elution of Two Antibiotics from Orthopedic Cement

PubMed Central

Dodds, S.; Akid, R.; Stephenson, J.; Nichol, T.; Banerjee, R. D.; Stockley, I.; Townsend, R.

2012-01-01

The use of antibiotics as a supplement to bone cement for the purposes of providing a local release of antibiotics is common practice in arthroplasty surgery and the kinetics of elution of the antibiotics in such systems have been investigated previously. However, in these previous studies no account was taken of the potential effects that wear may have on the elution kinetics of the antibiotic. Here, we have modified an existing wear testing rig to allow the simultaneous study of the elution kinetics of bone cement samples containing antibiotics being subjected to immersion only and immersion and conjoint wear. The results show contrasting effects with two commonly used antibiotics. Bone cement containing daptomycin showed no substantial change in antibiotic elution due to wear, while cement containing gentamicin (the most commonly used antibiotic in this application) in contrast demonstrated a substantial reduction in the rate of antibiotic elution when wear was applied. Scanning electron microscopy revealed a possible explanation for these diverse results, due to wear-induced “sealing” of the surface in conjunction with the crystal morphology of the antibiotic. PMID:22155831

Insights into aquatic toxicities of the antibiotics oxytetracycline and ciprofloxacin in the presence of metal: complexation versus mixture.

PubMed

Zhang, Yu; Cai, Xiyun; Lang, Xianming; Qiao, Xianliang; Li, Xuehua; Chen, Jingwen

2012-07-01

Co-contamination of ligand-like antibiotics (e.g., tetracyclines and quinolones) and heavy metals prevails in the environment, and thus the complexation between them is involved in environmental risks of antibiotics. To understand toxicological significance of the complex, effects of metal coordination on antibiotics' toxicity were investigated. The complexation of two antibiotics, oxytetracycline and ciprofloxacin, with three heavy metals, copper, zinc, and cadmium, was verified by spectroscopic techniques. The antibiotics bound metals via multiple coordination sites and rendered a mixture of various complexation speciations. Toxicity analysis indicated that metal coordination did modify the toxicity of the antibiotics and that antibiotic, metal, and their complex acted primarily as concentration addition. Comparison of EC(50) values revealed that the complex commonly was highest toxic and predominately correlated in toxicity to the mixture. Finally, environmental scenario analysis demonstrated that ignoring complexation would improperly classify environmental risks of the antibiotics. Copyright © 2012 Elsevier Ltd. All rights reserved.

Evaluation of a national programme to reduce inappropriate use of antibiotics for upper respiratory tract infections: effects on consumer awareness, beliefs, attitudes and behaviour in Australia.

PubMed

Wutzke, Sonia E; Artist, Margaret A; Kehoe, Linda A; Fletcher, Miriam; Mackson, Judith M; Weekes, Lynn M

2007-03-01

The over-use of antibiotics, in particular, inappropriate use to treat upper respiratory tract infections (URTIs), is a global public health concern. In an attempt to reduce inappropriate use of antibiotics for URTIs, and, in particular, to modify patient misconceptions about the effectiveness of antibiotics for URTIs, Australia's National Prescribing Service Ltd (NPS) has undertaken a comprehensive, multistrategic programme for health professionals and the community. Targeted strategies for the community, via the NPS common colds community campaign, commenced in 2000 and have been repeated annually during the winter months. Community strategies were closely integrated, using the same tagline, key messages and visual images, and were delivered in numerous settings including general practice, community pharmacy, child-care centres and community groups. Strategies included written information via newsletters and brochures, mass media activity using billboards, television, radio and magazines and small grants to promote local community education. The evaluation used multiple methods and data sources to measure process, impact and outcomes. Consistent with intervention messages, the integrated nationwide prescriber and consumer programme is associated with modest but consistent positive changes in consumer awareness, beliefs, attitudes and behaviour to the appropriate use of antibiotics for URTIs. These positive changes among the community are corroborated by a national decline in total antibiotic prescriptions dispensed in the community (from 23.08 million prescriptions in 1998-99 to 21.44 million in 2001-02) and, specifically, by a decline among the nine antibiotics commonly used for URTI such that by 2003 nationally 216,000 fewer prescriptions for URTI are written each year by general practitioners.

Antimicrobial activity of Eucalyptus camaldulensis essential oils and their interactions with conventional antimicrobial agents against multi-drug resistant Acinetobacter baumannii.

PubMed

Knezevic, Petar; Aleksic, Verica; Simin, Natasa; Svircev, Emilija; Petrovic, Aleksandra; Mimica-Dukic, Neda

2016-02-03

Traditional herbal medicine has become an important issue on the global scale during the past decade. Among drugs of natural origin, special place belongs to essential oils, known as strong antimicrobial agents that can be used to combat antibiotic-resistant bacteria. Eucalyptus camaldulensis leaves are traditional herbal remedy used for various purposes, including treatment of infections. The aim of this study was to determine antimicrobial potential of two E. camaldulensis essential oils against multi-drug resistant (MDR) Acinetobacter baumannii wound isolates and to examine possible interactions of essential oils with conventional antimicrobial agents. Chemical composition of essential oils was determined by gas chromatography-mass spectrometry analysis (GC-MS). MIC values of essential oils against A. baumannii strains were estimated by modified broth microdilution method. The components responsible for antimicrobial activity were detected by bioautographic analysis. The potential synergy between the essential oils and antibiotics (ciprofloxacin, gentamicin and polymyxin B) was examined by checkerboard method and time kill curve. The dominant components of both essential oils were spatulenol, cryptone, p-cimene, 1,8-cineole, terpinen-4-ol and β-pinene. The detected MICs for the E. camaldulensis essential oils were in range from 0.5 to 2 μl mL(-1). The bioautographic assay confirmed antibacterial activity of polar terpene compounds. In combination with conventional antibiotics (ciprofloxacin, gentamicin and polymyxin B), the examined essential oils showed synergistic antibacterial effect in most of the cases, while in some even re-sensitized MDR A. baumannii strains. The synergistic interaction was confirmed by time-kill curves for E. camaldulensis essential oil and polymyxin B combination which reduced bacterial count under detection limit very fast, i.e. after 6h of incubation. The detected anti-A. baumannii activity of E. camaldulensis essential oils justifies traditional use of this plant. The proven E. camaldulensis essential oil synergistic interactions with conventional antibiotics could lead to the development of new treatment strategies of infections caused by MDR A. baumannii strains in the term of antibiotic dose reduction. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Enzyme-coated mesoporous silica nanoparticles as efficient antibacterial agents in vivo.

PubMed

Li, Li-Li; Wang, Hao

2013-10-01

Despite the fact that pathogenic infections are widely treated by antibiotics in the clinic nowadays, the increasing risk of multidrug-resistance associated with abuse of antibiotics is becoming a major concern in global public health. The increased death toll caused by pathogenic bacterial infection calls for effective antibiotic alternatives. Lysozyme-coated mesoporous silica nanoparticles (MSNs⊂Lys) are reported as antibacterial agents that exhibit efficient antibacterial activity both in vitro and in vivo with low cytotoxicity and negligible hemolytic side effect. The Lys corona provides multivalent interaction between MSNs⊂Lys and bacterial walls and consequently raises the local concentration of Lys on the surface of cell walls, which promotes hydrolysis of peptidoglycans and increases membrane-perturbation abilities. The minimal inhibition concentration (MIC) of MSNs⊂Lys is fivefold lower than that of free Lys in vitro. The antibacterial efficacy of MSNs⊂Lys is evaluated in vivo by using an intestine-infected mouse model. Experimental results indicate that the number of bacteria surviving in the colon is three orders of magnitude lower than in the untreated group. These natural antibacterial enzyme-modified nanoparticles open up a new avenue for design and synthesis of next-generation antibacterial agents as alternatives to antibiotics. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Changes of the serum antibiotic levels during open heart surgery (ceftazidim, ciprofloxacin, clindamycin).

PubMed

Lonský, V; Dominik, J; Mand'ák, J; Pozlerová, E; Hejzlar, M; Lonská, V; Marsíková, M; Kubícek, J; Snítilová, M

2000-01-01

Wound, mediastinal and intracardiac infections are still very serious complications of open-heart surgery. The incidence of it is still in the range of 0.4%-5%. The aims of our study were to assess the adequacy of regimen using ceftazidim (CTZ), ciprofloxacin (CPF) and clindamycin (CLIN) as prophylactic antibiotics and to verify whether cardiopulmonary bypass (CPB) can modify the time of antibiotic serum concentrations. That is why the serum levels of them were measured during open heart procedures. The prospective study comprised 75 consequent coronary patients randomized in to three groups receiving 1 g of CTZ or 400 mg of CPF or 900 mg of CLIN i.v. with anesthesia induction. Routine coronary surgery with left internal mammary artery harvesting, moderate body hypothermic (30 degrees C) CPB with crystaloid cardioplegia was performed. Serum antibiotic levels were determined before application, with skin incision, prior CPB induction, after cardioplegia infusion, every 20 minutes of CPB, prior end of CPB, in time of chest closure. Conventional cylinder-plate microbiological assay was used for antibiotic level measurement. All serum antibiotic concentrations showed a sharp decrease immediately after starting CPB and lasted until CPB ended. After initiating of CPB after cardioplegia administration serum concentrations of CTZ (105 min after initial dose) decreased by, on average 55%, CPF (97 min) by 42% and CLIN (116 min) by 78%. CPB can modify the time course of antibiotic serum concentrations. The serum levels of CTZ at the end of the longest procedures were found to be below the MICs for some of the suspected pathogens. We recommend to use higher antibiotic doses for prophylaxis and to administer the second dose with protamin sulphate to obtain maximum concentration in newly formed blood clots.

Gentamicin: effect on E. coli in space

NASA Technical Reports Server (NTRS)

Kacena, M. A.; Todd, P.

1999-01-01

Previous investigations have shown that liquid bacterial cultures grown in space flight were not killed as effectively by antibiotic treatments as were cultures grown on Earth. However, the cause for the decreased antibiotic effectiveness remains unknown. Possible explanations include modified cell proliferation and modified antibiotic transport in the culture medium. Escherichia coli cultures were grown in space flight (STS-69 and STS-73), with and without gentamicin, on a solid agar substrate thus eliminating fluid effects and reducing the unknowns associated with space-flight bacterial cultures in suspension. This research showed that E. coli cultures grown in flight on agar for 24 to 27 hours experienced a heightened growth compared to simultaneous controls. However, addition of gentamicin to the agar killed the bacteria such that both flight and ground control E. coli samples had similar final cell concentrations. Therefore, while the reported existence of a decrease in antibiotic effectiveness in liquid cultures remains unexplained, these data suggest that gentamicin in space flight was at least as effective as, if not more effective than, on Earth, when E. coli cells were grown on agar.

Effect of plasma superficial treatments on antibacterial functionalization and coloration of cellulosic fabrics

NASA Astrophysics Data System (ADS)

Ibrahim, Nabil A.; Eid, Basma M.; Abdel-Aziz, Mohamed S.

2017-01-01

Remarkable improvement in antibacterial activity and durability of different cellulosic substrates namely cotton, linen, viscose and lyocell was achieved by pre-surface modification using N2-plasma to create new active and binding sites, -NH2 groups, onto the modified fabric surfaces followed by subsequent loading of biosynthesized silver nanoparticles (Ag NPs) alone and in combination with certain antibiotics using exhaustion method. The imparted antibacterial activity against both G+ve (S. aureus) and G-ve (E. coli) pathogens was governed by type of substrate, extent of modification and subsequent loading of antibacterial agent, synergistic effect, and antibacterial activity as well as type of harmful bacteria. A remarkable antibacterial activity still retained even after 15 washings. In addition, incorporation of Ag NPs into pigment printing paste and into acid dyeing bath for combined coloration and functionalization of O2-plasma and N2-plasma pre-modified substrates respectively were successfully achieved. Moreover, both SEM images and EDS spectra of selected substrates revealed the change in surface morphology as well as the presence of the loaded Ag element onto the post-treated substrates.

Management of complicated shunt infections: a clinical report.

PubMed

James, Hector E; Bradley, John S

2008-03-01

The authors present their experience with a protocol for the treatment of patients with complicated shunt infections. Complicated shunt infections are defined for the purpose of this protocol as multiple compartment hydrocephalus, multiple organism shunt infection, severe peritonitis, or infections in other sites of the body. The initial treatment protocol for these patients was 3 weeks of intravenous antibiotic therapy and 2 weeks of twice daily intraventricular/intrashunt antibiotic therapy. Cerebrospinal fluid (CSF) cultures were monitored during therapy and obtained again 48 hours after completion. The shunt was completely replaced. Additionally, follow-up cultures were obtained in all patients 3-6 months after therapy was completed. A cure of the infection was achieved in all patients as defined by negative cultures obtained at completion of antibiotic therapy and in follow-up studies. The follow-up period was 2-11 years (mean 4.4 +/- 2.5 years). The treatment protocol was modified in the patients treated after 1991, and 18 patients were treated with this modified treatment regime. In these patients, intraventricular antibiotics were administered only once daily for 14 days, and the CSF was cultured 24 hours after antibiotic therapy had been stopped instead of after 48 hours. The results were similar to those obtained with the initial protocol. Based on their prospective nonrandomized series, the authors believe that patients with complicated shunt infections can be successfully treated with 2 weeks of intraventricular antibiotic therapy administered once daily, concurrent with 3 weeks of intravenous antibiotic therapy. This protocol reduces length of treatment and hospital stay, and avoids recurrence of infection.

Strategic alliance between the infectious diseases specialist and intensive care unit physician for change in antibiotic use.

PubMed

Curcio, D; Belloni, R

2005-02-01

There is a general consensus that antimicrobial use in intensive care units (ICU) is greater than that in general wards. By implementing a strategy of systematic infectious disease consultations in agreement with the ICU chief, we have modified the antibiotic prescription habits of the ICU physician. A reduction was observed in the use of selected antibiotics (third-generation cephalosporins, vancomycin, carbapenems and piperacillin-tazobactam), with a significant reduction in the length of hospital stay for ICU patients and lower antibiotic costs without negative impact on patient mortality. Leadership by the infectious diseases consultant in combination with commitment by ICU physicians is a simple and effective method to change antibiotic prescription habits in the ICU.

Plasmid acquisition in microgravity

NASA Technical Reports Server (NTRS)

Juergensmeyer, Margaret A.; Juergensmeyer, Elizabeth A.; Guikema, James A.

1995-01-01

In microgravity, bacteria often show an increased resistance to antibiotics. Bacteria can develop resistance to an antibiotic after transformation, the acquisition of DNA, usually in the form of a plasmid containing a gene for resistance to one or more antibiotics. In order to study the capacity of bacteria to become resistant to antibiotics in microgravity, we have modified the standard protocol for transformation of Escherichia coli for use in the NASA-flight-certified hardware package, The Fluid Processing Apparatus (FPA). Here we report on the ability of E. coli to remain competent for long periods of time at temperatures that are readily available on the Space Shuttle, and present some preliminary flight results.

RecA Inhibitors Potentiate Antibiotic Activity and Block Evolution of Antibiotic Resistance.

PubMed

Alam, Md Kausar; Alhhazmi, Areej; DeCoteau, John F; Luo, Yu; Geyer, C Ronald

2016-03-17

Antibiotic resistance arises from the maintenance of resistance mutations or genes acquired from the acquisition of adaptive de novo mutations or the transfer of resistance genes. Antibiotic resistance is acquired in response to antibiotic therapy by activating SOS-mediated DNA repair and mutagenesis and horizontal gene transfer pathways. Initiation of the SOS pathway promotes activation of RecA, inactivation of LexA repressor, and induction of SOS genes. Here, we have identified and characterized phthalocyanine tetrasulfonic acid RecA inhibitors that block antibiotic-induced activation of the SOS response. These inhibitors potentiate the activity of bactericidal antibiotics, including members of the quinolone, β-lactam, and aminoglycoside families in both Gram-negative and Gram-positive bacteria. They reduce the ability of bacteria to acquire antibiotic resistance mutations and to transfer mobile genetic elements conferring resistance. This study highlights the advantage of including RecA inhibitors in bactericidal antibiotic therapies and provides a new strategy for prolonging antibiotic shelf life. Copyright © 2016 Elsevier Ltd. All rights reserved.

Improving the prescribing of antibiotics for urinary tract infection.

PubMed

Peterson, G M; Stanton, L A; Bergin, J K; Chapman, G A

1997-04-01

In recent years there have been changes in the recommended antibiotic treatment for urinary tract infections (UTIs). In particular, the use of amoxycillin or co-trimoxazole is now discouraged, with amoxycillin-potassium clavulanate, cephalexin and trimethoprim becoming first-line agents for uncomplicated lower UTIs. To examine whether academic detailing, performed by a pharmacist, could modify prescribing practices for antibiotics used in the treatment of UTI in the community setting. The intervention was conducted in Southern Tasmania, using the remainder of the State as a control area. The target group of general practitioners was sent educational material designed to assist in the appropriate prescribing of antibiotics in the treatment of UTI. A pharmacist then visited each general practitioner and discussed the rational use of antibiotics for UTIs directly with him/her. Outcomes were measured using evaluation feedback from the general practitioners and pharmacoepidemiological data, which were not linked to diagnosis. The key variable examined was the total defined daily doses (DDDs) dispensed for the recommended first-line agents (amoxycillin-potassium clavulanate, cephalexin and trimethoprim) compared with amoxycillin (3 g single-dose form) and co-trimoxazole. The educational programme was very well received by the general practitioners. Changes in the prescribing of antibiotics commonly used for UTIs were evident in both study regions over the course of the study, but the improvements were significantly greater in the intervention area. Educational programmes utilizing academic detailing by pharmacists can modify prescribing practices within the community setting.

Spaceflight Modifies Escherichia coli Gene Expression in Response to Antibiotic Exposure and Reveals Role of Oxidative Stress Response.

PubMed

Aunins, Thomas R; Erickson, Keesha E; Prasad, Nripesh; Levy, Shawn E; Jones, Angela; Shrestha, Shristi; Mastracchio, Rick; Stodieck, Louis; Klaus, David; Zea, Luis; Chatterjee, Anushree

2018-01-01

Bacteria grown in space experiments under microgravity conditions have been found to undergo unique physiological responses, ranging from modified cell morphology and growth dynamics to a putative increased tolerance to antibiotics. A common theory for this behavior is the loss of gravity-driven convection processes in the orbital environment, resulting in both reduction of extracellular nutrient availability and the accumulation of bacterial byproducts near the cell. To further characterize the responses, this study investigated the transcriptomic response of Escherichia coli to both microgravity and antibiotic concentration. E. coli was grown aboard International Space Station in the presence of increasing concentrations of the antibiotic gentamicin with identical ground controls conducted on Earth. Here we show that within 49 h of being cultured, E. coli adapted to grow at higher antibiotic concentrations in space compared to Earth, and demonstrated consistent changes in expression of 63 genes in response to an increase in drug concentration in both environments, including specific responses related to oxidative stress and starvation response. Additionally, we find 50 stress-response genes upregulated in response to the microgravity when compared directly to the equivalent concentration in the ground control. We conclude that the increased antibiotic tolerance in microgravity may be attributed not only to diminished transport processes, but also to a resultant antibiotic cross-resistance response conferred by an overlapping effect of stress response genes. Our data suggest that direct stresses of nutrient starvation and acid-shock conveyed by the microgravity environment can incidentally upregulate stress response pathways related to antibiotic stress and in doing so contribute to the increased antibiotic stress tolerance observed for bacteria in space experiments. These results provide insights into the ability of bacteria to adapt under extreme stress conditions and potential strategies to prevent antimicrobial-resistance in space and on Earth.

Spaceflight Modifies Escherichia coli Gene Expression in Response to Antibiotic Exposure and Reveals Role of Oxidative Stress Response

PubMed Central

Aunins, Thomas R.; Erickson, Keesha E.; Prasad, Nripesh; Levy, Shawn E.; Jones, Angela; Shrestha, Shristi; Mastracchio, Rick; Stodieck, Louis; Klaus, David; Zea, Luis; Chatterjee, Anushree

2018-01-01

Bacteria grown in space experiments under microgravity conditions have been found to undergo unique physiological responses, ranging from modified cell morphology and growth dynamics to a putative increased tolerance to antibiotics. A common theory for this behavior is the loss of gravity-driven convection processes in the orbital environment, resulting in both reduction of extracellular nutrient availability and the accumulation of bacterial byproducts near the cell. To further characterize the responses, this study investigated the transcriptomic response of Escherichia coli to both microgravity and antibiotic concentration. E. coli was grown aboard International Space Station in the presence of increasing concentrations of the antibiotic gentamicin with identical ground controls conducted on Earth. Here we show that within 49 h of being cultured, E. coli adapted to grow at higher antibiotic concentrations in space compared to Earth, and demonstrated consistent changes in expression of 63 genes in response to an increase in drug concentration in both environments, including specific responses related to oxidative stress and starvation response. Additionally, we find 50 stress-response genes upregulated in response to the microgravity when compared directly to the equivalent concentration in the ground control. We conclude that the increased antibiotic tolerance in microgravity may be attributed not only to diminished transport processes, but also to a resultant antibiotic cross-resistance response conferred by an overlapping effect of stress response genes. Our data suggest that direct stresses of nutrient starvation and acid-shock conveyed by the microgravity environment can incidentally upregulate stress response pathways related to antibiotic stress and in doing so contribute to the increased antibiotic stress tolerance observed for bacteria in space experiments. These results provide insights into the ability of bacteria to adapt under extreme stress conditions and potential strategies to prevent antimicrobial-resistance in space and on Earth. PMID:29615983

Impact of chlortetracycline and sulfapyridine antibiotics on soil enzyme activities

NASA Astrophysics Data System (ADS)

Molaei, Ali; Lakzian, Amir; Datta, Rahul; Haghnia, Gholamhosain; Astaraei, Alireza; Rasouli-Sadaghiani, MirHassan; Ceccherini, Maria T.

2017-10-01

Pharmaceutical antibiotics are frequently used in the livestock and poultry industries to control infectious diseases. Due to the lack of proper guidance for use, the majority of administrated antibiotics and their metabolites are excreted to the soil environment through urine and feces. In the present study, we used chlortetracycline and sulfapyridine antibiotics to screen out their effects on dehydrogenase, alkaline phosphatase and urease activity. Factorial experiments were conducted with different concentrations of antibiotic (0, 10, 25 and 100 mg kg-1 of soil) mixed with soil samples, and the enzyme activity was measured at intervals of 1, 4 and 21 days. The results show that the chlortetracycline and sulfapyridine antibiotics negatively affect the dehydrogenase activity, but the effect of sulfapyridine decreases with time of incubation. Indeed, sulfapyridine antibiotic significantly affect the alkaline phosphatase activity for the entire three-time interval, while chlortetracycline seems to inhibit its activity within 1 and 4 days of incubation. The effects of chlortetracycline and sulfapyridine antibiotics on urease activity appear similar, as they both significantly affect the urease activity on day 1 of incubation. The present study concludes that chlortetracycline and sulfapyridine antibiotics have harmful effects on soil microbes, with the extent of effects varying with the duration of incubation and the type of antibiotics used.

The effect of a beta-lactamase inhibitor peptide on bacterial membrane structure and integrity: a comparative study.

PubMed

Alaybeyoglu, Begum; Uluocak, Bilge Gedik; Akbulut, Berna Sariyar; Ozkirimli, Elif

2017-05-01

Co-administration of beta-lactam antibiotics and beta-lactamase inhibitors has been a favored treatment strategy against beta-lactamase-mediated bacterial antibiotic resistance, but the emergence of beta-lactamases resistant to current inhibitors necessitates the discovery of novel non-beta-lactam inhibitors. Peptides derived from the Ala46-Tyr51 region of the beta-lactamase inhibitor protein are considered as potent inhibitors of beta-lactamase; unfortunately, peptide delivery into the cell limits their potential. The properties of cell-penetrating peptides could guide the design of beta-lactamase inhibitory peptides. Here, our goal is to modify the peptide with the sequence RRGHYY that possesses beta-lactamase inhibitory activity under in vitro conditions. Inspired by the work on the cell-penetrating peptide pVEC, our approach involved the addition of the N-terminal hydrophobic residues, LLIIL, from pVEC to the inhibitor peptide to build a chimera. These residues have been reported to be critical in the uptake of pVEC. We tested the potential of RRGHYY and its chimeric derivative as a beta-lactamase inhibitory peptide on Escherichia coli cells and compared the results with the action of the antimicrobial peptide melittin, the beta-lactam antibiotic ampicillin, and the beta-lactamase inhibitor potassium clavulanate to get mechanistic details on their action. Our results show that the addition of LLIIL to the N-terminus of the beta-lactamase inhibitory peptide RRGHYY increases its membrane permeabilizing potential. Interestingly, the addition of this short stretch of hydrophobic residues also modified the inhibitory peptide such that it acquired antimicrobial property. We propose that addition of the hydrophobic LLIIL residues to the peptide N-terminus offers a promising strategy to design novel antimicrobial peptides in the battle against antibiotic resistance. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Phototherapeutic spectrum expansion through synergistic effect of mesoporous silica trio-nanohybrids against antibiotic-resistant gram-negative bacterium.

PubMed

Kuthati, Yaswanth; Kankala, Ranjith Kumar; Busa, Prabhakar; Lin, Shi-Xiang; Deng, Jin-Pei; Mou, Chung-Yuan; Lee, Chia-Hung

2017-04-01

The extensive impact of antibiotic resistance has led to the exploration of new anti-bacterial modalities. We designed copper impregnated mesoporous silica nanoparticles (Cu-MSN) with immobilizing silver nanoparticles (SNPs) to apply photodynamic inactivation (PDI) of antibiotic-resistant E. coli. SNPs were decorated over the Cu-MSN surfaces by coordination of silver ions on diamine-functionalized Cu-MSN and further reduced to silver nanoparticles with formalin. We demonstrate that silver is capable of sensitizing the gram-negative bacteria E. coli to a gram-positive specific phototherapeutic agent in vitro; thereby expanding curcumin's phototherapeutic spectrum. The mesoporous structure of Cu-MSN remains intact after the exterior decoration with silver nanoparticles and subsequent curcumin loading through an enhanced effect from copper metal-curcumin affinity interaction. The synthesis, as well as successful assembly of the functional nanomaterials, was confirmed by various physical characterization techniques. Curcumin is capable of producing high amounts of reactive oxygen species (ROS) under light irradiation, which can further improve the silver ion release kinetics for antibacterial activity. In addition, the positive charged modified surfaces of Cu-MSN facilitate antimicrobial response through electrostatic attractions towards negatively charged bacterial cell membranes. The antibacterial action of the synthesized nanocomposites can be activated through a synergistic mechanism of energy transfer of the absorbed light from SNP to curcumin. Copyright © 2017 Elsevier B.V. All rights reserved.

Modeling economic implications of alternative treatment strategies for acute bacterial skin and skin structure infections.

PubMed

Revankar, Nikhil; Ward, Alexandra J; Pelligra, Christopher G; Kongnakorn, Thitima; Fan, Weihong; LaPensee, Kenneth T

2014-10-01

The economic implications from the US Medicare perspective of adopting alternative treatment strategies for acute bacterial skin and skin structure infections (ABSSSIs) are substantial. The objective of this study is to describe a modeling framework that explores the impact of decisions related to both the location of care and switching to different antibiotics at discharge. A discrete event simulation (DES) was developed to model the treatment pathway of each patient through various locations (emergency department [ED], inpatient, and outpatient) and the treatments prescribed (empiric antibiotic, switching to a different antibiotic at discharge, or a second antibiotic). Costs are reported in 2012 USD. The mean number of days on antibiotic in a cohort assigned to a full course of vancomycin was 11.2 days, with 64% of the treatment course being administered in the outpatient setting. Mean total costs per patient were $8671, with inpatient care accounting for 58% of the costs accrued. The majority of outpatient costs were associated with parenteral administration rather than drug acquisition or monitoring. Scenarios modifying the treatment pathway to increase the proportion of patients receiving the first dose in the ED, and then managing them in the outpatient setting or prescribing an oral antibiotic at discharge to avoid the cost associated with administering parenteral therapy, therefore have a major impact and lower the typical cost per patient by 11-20%. Since vancomycin is commonly used as empiric therapy in clinical practice, based on these analyses, a shift in treatment practice could result in substantial savings from the Medicare perspective. The choice of antibiotic and location of care influence the costs and resource use associated with the management of ABSSSIs. The DES framework presented here can provide insight into the potential economic implications of decisions that modify the treatment pathway.

Penicillin resistance compromises Nod1-dependent proinflammatory activity and virulence fitness of neisseria meningitidis.

PubMed

Zarantonelli, Maria Leticia; Skoczynska, Anna; Antignac, Aude; El Ghachi, Meriem; Deghmane, Ala-Eddine; Szatanik, Marek; Mulet, Céline; Werts, Catherine; Peduto, Lucie; d'Andon, Martine Fanton; Thouron, Françoise; Nato, Faridabano; Lebourhis, Lionel; Philpott, Dana J; Girardin, Stephen E; Vives, Francina Langa; Sansonetti, Philippe; Eberl, Gérard; Pedron, Thierry; Taha, Muhamed-Kheir; Boneca, Ivo G

2013-06-12

Neisseria meningitidis is a life-threatening human bacterial pathogen responsible for pneumonia, sepsis, and meningitis. Meningococcal strains with reduced susceptibility to penicillin G (Pen(I)) carry a mutated penicillin-binding protein (PBP2) resulting in a modified peptidoglycan structure. Despite their antibiotic resistance, Pen(I) strains have failed to expand clonally. We analyzed the biological consequences of PBP2 alteration among clinical meningococcal strains and found that peptidoglycan modifications of the Pen(I) strain resulted in diminished in vitro Nod1-dependent proinflammatory activity. In an influenza virus-meningococcal sequential mouse model mimicking human disease, wild-type meningococci induced a Nod1-dependent inflammatory response, colonizing the lungs and surviving in the blood. In contrast, isogenic Pen(I) strains were attenuated for such response and were out-competed by meningococci sensitive to penicillin G. Our results suggest that antibiotic resistance imposes a cost to the success of the pathogen and may potentially explain the lack of clonal expansion of Pen(I) strains. Copyright © 2013 Elsevier Inc. All rights reserved.

Urine Antibiotic Activity in Patients Presenting to Hospitals in Laos: Implications for Worsening Antibiotic Resistance

PubMed Central

Khennavong, Manisone; Davone, Viengmon; Vongsouvath, Manivanh; Phetsouvanh, Rattanaphone; Silisouk, Joy; Rattana, Olay; Mayxay, Mayfong; Castonguay-Vanier, Josée; Moore, Catrin E.; Strobel, Michel; Newton, Paul N.

2011-01-01

Widespread use of antibiotics may be important in the spread of antimicrobial resistance. We estimated the proportion of Lao in- and outpatients who had taken antibiotics before medical consultation by detecting antibiotic activity in their urine added to lawns of Bacillus stearothermophilus, Escherichia coli, and Streptococcus pyogenes. In the retrospective (N = 2,058) and prospective studies (N = 1,153), 49.7% (95% confidence interval [CI] = 47.4–52.0) and 36.2% (95% CI = 33.4–38.9), respectively, of Vientiane patients had urinary antibiotic activity detected. The highest frequency of estimated antibiotic pre-treatment was found in patients recruited with suspected central nervous system infections and community-acquired septicemia (both 56.8%). In Vientiane, children had a higher frequency of estimated antibiotic pre-treatment than adults (60.0% versus 46.5%; P < 0.001). Antibiotic use based on patients histories was significantly less frequent than when estimated from urinary antibiotic activity (P < 0.0001). PMID:21813851

Integrated amperometric affinity biosensors using Co2+-tetradentate nitrilotriacetic acid modified disposable carbon electrodes: application to the determination of β-lactam antibiotics.

PubMed

Conzuelo, Felipe; Gamella, María; Campuzano, Susana; Martínez-Ruiz, Paloma; Esteban-Torres, María; de las Rivas, Blanca; Reviejo, A Julio; Muñoz, Rosario; Pingarrón, José M

2013-03-19

A novel strategy for the construction of disposable amperometric affinity biosensors is described in this work. The approach uses a recombinant bacterial penicillin binding protein (PBP) tagged by an N-terminal hexahistidine tail which was immobilized onto Co(2+)-tetradentate nitrilotriacetic acid (NTA)-modified screen-printed carbon electrodes (SPCEs). The biosensor was employed for the specific detection and quantification of β-lactam antibiotics residues in milk, which was accomplished by means of a direct competitive assay using a tracer with horseradish peroxidase (HRP) for the enzymatic labeling. The amperometric response measured at -0.20 V versus the Ag pseudoreference electrode of the SPCE upon the addition of H2O2 in the presence of hydroquinone (HQ) as redox mediator was used as the transduction signal. The developed affinity sensor allowed limits of detection to be obtained in the low part-per-billion level for the antibiotics tested in untreated milk samples. Moreover, the biosensor exhibited a good selectivity against other antibiotics residues frequently detected in milk and dairy products. The analysis time was of approximately 30 min.

A bacteria antibiotic system in space (23-F ANTIBIO)

NASA Technical Reports Server (NTRS)

Tixador, Rene; Gasset, G.; Eche, B.; Moatti, N.; Lapchine, L.; Woldringh, C.; Toorop, P.; Moatti, J. P.; Delmotte, F.; Tap, G.

1995-01-01

In order to evaluate the effects of weightlessness and cosmic radiations on the bacteria resistance to antibiotics, the Antibio 23F experiment was undertaken onboard Discovery during the 1st International Microgravity Laboratory (IML-1) mission. The effects of various antibiotic concentrations (dihydrostreptomycin) on Escherichia coli growth and cell division behavior were studied. The antibiotic binding was investigated using a radioactive tracer (tritium). The results showed that microgravity did not affect E. coli cells in regards the growth and the cell division. The antibiotic added to the culture medium induced an inhibition of the cultures both in the flight and ground controls. However, the antibiotic was less efficient in flight. The behavior of bacteria was modified, and the exponential growth rate was increased in flight. The incorporation of radioactive antibiotics in flight was comparatively different to ground incorporation, which indicated some perturbations in antibiotic binding. The experiments performed in the 1 g centrifuge did not show any difference in the cultures developed on the static rack, and could support a radiative effect of cosmic radiation to explain the results.

Epigallocatechin gallate as a modulator of Campylobacter resistance to macrolide antibiotics.

PubMed

Kurinčič, Marija; Klančnik, Anja; Smole Možina, Sonja

2012-11-01

Comprehensive therapeutic use of macrolides in humans and animals is important in the selection of macrolide-resistant Campylobacter isolates. This study shows high co-resistance to erythromycin, azithromycin, clarithromycin, dirithromycin and tylosin, with contributions from the 23S rRNA gene and drug efflux systems. The CmeABC efflux pump plays an important role in reduced macrolide susceptibility, accompanied by contributions from the CmeDEF efflux pump and potentially a third efflux pump. To improve clinical performance of licensed antibiotics and chemotherapeutic agents, it is important to understand the factors in Campylobacter that affect susceptibility to macrolide antibiotics. Using mutants that lack the functional genes coding for the CmeB and CmeF efflux pump proteins and the CmeR transcriptional repressor, we show that these efflux pumps are potential targets for the development of therapeutic strategies that use a combination of a macrolide with an efflux pump inhibitor (EPI) to restore macrolide efficacy. The natural phenolic compound epigallocatechin gallate (EGCG) has good modulatory activity over the extrusion across the outer membrane of the macrolides tested, both in sensitive and resistant Campylobacter isolates. Comparing EGCG with known chemical EPIs, correlations in the effects on the particular macrolide antibiotics were seen. EGCG modifies Campylobacter multidrug efflux systems and thus could have an impact on restoring macrolide efficacy in resistant strains. Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Transference of bioactive compounds from support plants to the termites Constrictotermes cyphergaster (Isoptera).

PubMed

Policarpo, Iamara Silva; Vasconcellos, Alexandre; Chaves, Thiago Pereira; Raimundo, Joanda Paolla; Medeiros, Ana Cláudia D; Coutinho, Henrique D M; Alves, Rômulo Romeu Nóbrega

2018-10-15

This study aims to investigate the microbiological potential of the termite species Constrictotermes cyphergaster (Silvestri, 1901) and its support plants. We collected five C. cyphergaster nests from three different support plant species. Microbiological assays were performed on these extracts using the serial microdilution method in triplicate to measure the minimum inhibitory concentration (MIC) of each microorganism for the analysed extract. The ethanol extracts of the termite C. cyphergaster showed no significant activity against strains of Staphylococcus aureus and Escherichia coli, with an MIC >1000 μg mL-1. Only the extracts of the nests and termites with the nest had the same MICs. These results were in contrast to the extracts of Spondias tuberosa (Umbuzeiro), Poincianella pyramidalis (Catingueira), and Amburana cearensis (Cumaru), which demonstrated significant activity against S. aureus with MICs <1000 μg mL-1. The modulating activity of the extracts tested in the present study demonstrated potentiation of most antibiotics across the bacterial strains tested when combined with the extracts for both S. aureus and E. coli. These results indicate that the extracts tested in the present study may be composed of animal and vegetable origins with the potential to modify the activity of antibiotics and thus may aid in antimicrobial therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

Correlates of parental antibiotic knowledge, demand, and reported use.

PubMed

Kuzujanakis, Marianne; Kleinman, Ken; Rifas-Shiman, Sheryl; Finkelstein, Jonathan A

2003-01-01

Clinicians cite parental misconceptions and requests for antibiotics as reasons for inappropriate prescribing. To identify misconceptions regarding antibiotics and predictors of parental demand for antibiotics and to determine if parental knowledge and attitudes are associated with use. Survey of parents in 16 Massachusetts communities. Domains included antibiotic-related knowledge, attitudes about antibiotics, antibiotic use during a 12-month period, demographics, and access to health information. Bivariate and multivariate analyses evaluated predictors of knowledge and proclivity to demand antibiotics. A multivariate model evaluated the associations of knowledge, demand, and demographic factors with parent-reported antibiotic use. A total of 1106 surveys were returned (response rates: 54% and 32% for commercially-insured and Medicaid-insured families). Misconceptions were common regarding bronchitis (92%) and green nasal discharge (78%). Two hundred sixty-five (24%) gave responses suggesting a proclivity to demand antibiotics. Antibiotic knowledge was associated with increased parental age and education, having more than 1 child, white race, and receipt of media information on resistance. Factors associated with a proclivity to demand antibiotics included decreased knowledge, pressure from day-care settings, lack of alternatives offered by clinicians, and lack of access to media information. Among all respondents, reported antibiotic use was associated with younger child age and day-care attendance. Among Medicaid-insured children only, less antibiotic knowledge and tendency to demand antibiotics were associated with higher rates of antibiotic use. Misconceptions regarding antibiotic use are widespread and potentially modifiable by clinicians and media sources. Particular attention should be paid to Medicaid-insured patients in whom such misconceptions may contribute to inappropriate prescribing.

Substituted Hydroxyapatites with Antibacterial Properties

PubMed Central

Kolmas, Joanna; Groszyk, Ewa; Kwiatkowska-Różycka, Dagmara

2014-01-01

Reconstructive surgery is presently struggling with the problem of infections located within implantation biomaterials. Of course, the best antibacterial protection is antibiotic therapy. However, oral antibiotic therapy is sometimes ineffective, while administering an antibiotic at the location of infection is often associated with an unfavourable ratio of dosage efficiency and toxic effect. Thus, the present study aims to find a new factor which may improve antibacterial activity while also presenting low toxicity to the human cells. Such factors are usually implemented along with the implant itself and may be an integral part of it. Many recent studies have focused on inorganic factors, such as metal nanoparticles, salts, and metal oxides. The advantages of inorganic factors include the ease with which they can be combined with ceramic and polymeric biomaterials. The following review focuses on hydroxyapatites substituted with ions with antibacterial properties. It considers materials that have already been applied in regenerative medicine (e.g., hydroxyapatites with silver ions) and those that are only at the preliminary stage of research and which could potentially be used in implantology or dentistry. We present methods for the synthesis of modified apatites and the antibacterial mechanisms of various ions as well as their antibacterial efficiency. PMID:24949423

The intriguing role of Rifaximin in gut barrier chronic inflammation and in the treatment of Crohn's disease.

PubMed

Lopetuso, Loris R; Napoli, Marco; Rizzatti, Gianenrico; Gasbarrini, Antonio

2018-06-04

The gastrointestinal tract acts as a functional unit organized as a semipermeable multilayer system, in which commensal gut microbiota represents the anatomical barrier. Recently,, several studies have highlighted the involvement of gut microbiota in IBD pathogenesis, in sustaining gut barrier chronic inflammation, and in conditioning disease course and therapeutical response. This evidence provides a rationale for treating patients with gut microbiota modifiers. Among these, Rifaximin represents a non-traditional antibiotic able to act as a "eubiotic" on intestinal barrier. Area covered: The purpose of this narrative review is to explore the impact of Rifaximin on gut barrier and gut microbiota in IBD, in particular in Crohn's disease, and to analyze its potential therapeutic applications. Expert opinion: The possibility of a beneficial activity of Rifaximin in chronic intestinal inflammation and Crohn's disease has been debated and evaluated with different studies having obtained promising but still preliminary data. Larger trials are therefore needed. This gut-specific antibiotic could represent an alternative to systemic antibiotics thanks to its favorable safety profile and promising efficacy data. Rifaximin could exert, when appropriate, a synergic effect with immunomodulators in IBD, acting on both the microbial and immunological sides of gut barrier impairment.

Modulation of release kinetics by plasma polymerization of ampicillin-loaded β-TCP ceramics

NASA Astrophysics Data System (ADS)

Labay, C.; Buxadera-Palomero, J.; Avilés, M.; Canal, C.; Ginebra, M. P.

2016-08-01

Beta-tricalcium phosphate (β-TCP) bioceramics are employed in bone repair surgery. Their local implantation in bone defects puts them in the limelight as potential materials for local drug delivery. However, obtaining suitable release patterns fitting the required therapeutics is a challenge. Here, plasma polymerization of ampicillin-loaded β-TCP is studied for the design of a novel antibiotic delivery system. Polyethylene glycol-like (PEG-like) coating of β-TCP by low pressure plasma polymerization was performed using diglyme as precursor, and nanometric PEG-like layers were obtained by simple and double plasma polymerization processes. A significant increase in hydrophobicity, and the presence of plasma polymer was visible on the surface by SEM and quantified by XPS. As a main consequence of the plasma polymerisation, the release kinetics were successfully modified, avoiding burst release, and slowing down the initial rate of release leading to a 4.5 h delay in reaching the same antibiotic release percentage, whilst conservation of the activity of the antibiotic was simultaneously maintained. Thus, plasma polymerisation on the surface of bioceramics may be a good strategy to design controlled drug delivery matrices for local bone therapies.

Potential use of Bacillus thuringiensis bacteriocins to control antibiotic-resistant bacteria associated with mastitis in dairy goats.

PubMed

Gutiérrez-Chávez, A J; Martínez-Ortega, E A; Valencia-Posadas, M; León-Galván, M F; de la Fuente-Salcido, N M; Bideshi, D K; Barboza-Corona, J E

2016-01-01

Mastitis caused by microbial infections in dairy goats reduces milk yield, modifies milk composition, and potentially contributes to morbidity in herds and consumers of dairy products. Microorganisms associated with mastitis in dairy goats are commonly controlled with antibiotics, but it is known that continued use of these chemical agents promotes antibiotic resistance among bacterial populations. Recently, it has been shown that bacteriocins of Bacillus thuringiensis inhibit growth of food-borne pathogens and also bacteria associated with bovine mastitis. However, there is no report on their ability to inhibit microorganisms linked to mastitis in dairy goats. In this study, using 16S rDNA and ITS regions of rDNA, we identified nine bacterial isolates and an encapsulated yeast associated with mastitis in dairy goats. Enterococcus durans, Brevibacillus sp., and Staphylococcus epidermidis 2 were resistant to, respectively, 75, ~67, ~42, and ~42 % of the antibiotics screened. In addition, 60 % of the bacterial isolates were resistant to penicillin, ampicillin, vancomycin, and dicloxacillin. Importantly, 60 % of the isolates were inhibited by the bacteriocins, but S. epidermidis 1, Enterobacter sp., Escherichia vulneris, and Cryptococcus neoformans were not susceptible to these antimicrobial peptides. Using Brevibacillus sp. and Staphylococcus chromogenes as indicator bacteria, we show that peptides of ~10 kDa that correspond to the molecular mass of bacteriocins used in this study are responsible for the inhibitory activity. Our results demonstrate that multiple antibiotic-resistant bacteria associated with subclinical mastitis in dairy goats from Guanajuato, Mexico, are susceptible to bacteriocins produced by B. thuringiensis.

The sludge loading rate regulates the growth and release of heterotrophic bacteria resistant to six types of antibiotics in wastewater activated sludge.

PubMed

Yuan, Qing-Bin; Guo, Mei-Ting; Yang, Jian

2015-01-01

Wastewater treatment plants are considered as hot reservoirs of antimicrobial resistance. However, the fates of antibiotic-resistant bacteria during biological treatment processes and relevant influencing factors have not been fully understood. This study evaluated the effects of the sludge loading rate on the growth and release of six kinds of antibiotic-resistant bacteria in an activated sludge system. The results indicated that higher sludge loading rates amplified the growth of all six types of antibiotic resistant bacteria. The release of most antibiotic-resistant bacteria through both the effluent and biosolids was amplified with increased sludge loading rate. Biosolids were the main pattern for all antibiotic-resistant bacteria release in an activated sludge system, which was determined primarily by their growth in the activated sludge. A higher sludge loading rate reactor tended to retain more antibiotic resistance. An activated sludge system with lower sludge loading rates was considered more conducive to the control of antibiotic resistance.

Antibiotic Production by Anaerobic Bacteria1

PubMed Central

Sturgen, Nancy O.; Casida, L. E.

1962-01-01

Soils from aerobic and anaerobic sources were investigated for the possible presence of bacteria which produce antibiotics under anaerobic conditions of growth. The screening techniques devised for this study yielded 157 soil bacteria which, during anaerobic growth, produced antibiotic activity against aerobic test bacteria. Studies on choice of media, presence of oxygen, and changes in antibiotic activity during growth indicated that representative strains of these bacteria produced mixtures of antibiotics. The activity was heat labile. PMID:13918037

Occurrence and distribution of antibiotics in coastal water of the Bohai Bay, China: impacts of river discharge and aquaculture activities.

PubMed

Zou, Shichun; Xu, Weihai; Zhang, Ruijie; Tang, Jianhui; Chen, Yingjun; Zhang, Gan

2011-10-01

The presence of 21 antibiotics in six different groups was investigated in coastal water of the Bohai Bay. Meantime, to illuminate the potential effects caused by the river discharge and aquaculture activities, wastewater from three breeding plants and surface water from six rivers flowing into the Bohai Bay were also analyzed for the selected antibiotics. The result revealed that measured antibiotics in the North Bobai Bay were generally higher than those in the South, highlighting the remarkable effects of high density of human activities on the exposure of antibiotics in environment. The antibiotics found in the six rivers were generally higher than those in the Bohai Bay reflecting the important antibiotics source of river discharge. This study reveals that the high consumption of some antibiotics in aquaculture activities may pose high ecological risk to the bay. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Anti-amebic effect of polyenic antibiotics].

PubMed

Liubimova, L K; Ovnanian, K O; Ivanova, L N

1985-03-01

All-Union Research technological Institute of Antibiotics and Medical Enzymes, Leningrad. Institute of Epidemiology, Virology and medical parasitology, Ministry of Health of the Armenian SSR. The effect of polyenic antibiotics made in the USSR on development of E. histolytica and E. moshkovski was studied. The following antibiotics were used: levorin and its derivatives, mycoheptin, amphotericin B, amphoglucamine and nystatin. The antibiotics were compared with emetine and metronidazole. Some drugs of the imidazole group were also included into the study. On the whole 15 drugs were tested for their antiamebic activity. All the polyenic antibiotics showed a high antiamebic activity. Levorin and its derivatives were the most active. Their MICs ranged from 0.1 to 5.38 micrograms/ml. The most active of the new imidazoles was 100 times less effective than sodium levorin. The studies show that the polyenic antibiotics have an antiamebic activity and a broad antiprotozoal spectrum.

Treating cattle with antibiotics affects greenhouse gas emissions, and microbiota in dung and dung beetles.

PubMed

Hammer, Tobin J; Fierer, Noah; Hardwick, Bess; Simojoki, Asko; Slade, Eleanor; Taponen, Juhani; Viljanen, Heidi; Roslin, Tomas

2016-05-25

Antibiotics are routinely used to improve livestock health and growth. However, this practice may have unintended environmental impacts mediated by interactions among the wide range of micro- and macroorganisms found in agroecosystems. For example, antibiotics may alter microbial emissions of greenhouse gases by affecting livestock gut microbiota. Furthermore, antibiotics may affect the microbiota of non-target animals that rely on dung, such as dung beetles, and the ecosystem services they provide. To examine these interactions, we treated cattle with a commonly used broad-spectrum antibiotic and assessed downstream effects on microbiota in dung and dung beetles, greenhouse gas fluxes from dung, and beetle size, survival and reproduction. We found that antibiotic treatment restructured microbiota in dung beetles, which harboured a microbial community distinct from those in the dung they were consuming. The antibiotic effect on beetle microbiota was not associated with smaller size or lower numbers. Unexpectedly, antibiotic treatment raised methane fluxes from dung, possibly by altering the interactions between methanogenic archaea and bacteria in rumen and dung environments. Our findings that antibiotics restructure dung beetle microbiota and modify greenhouse gas emissions from dung indicate that antibiotic treatment may have unintended, cascading ecological effects that extend beyond the target animal. © 2016 The Author(s).

Treating cattle with antibiotics affects greenhouse gas emissions, and microbiota in dung and dung beetles

PubMed Central

Fierer, Noah; Hardwick, Bess; Simojoki, Asko; Slade, Eleanor; Taponen, Juhani; Viljanen, Heidi; Roslin, Tomas

2016-01-01

Antibiotics are routinely used to improve livestock health and growth. However, this practice may have unintended environmental impacts mediated by interactions among the wide range of micro- and macroorganisms found in agroecosystems. For example, antibiotics may alter microbial emissions of greenhouse gases by affecting livestock gut microbiota. Furthermore, antibiotics may affect the microbiota of non-target animals that rely on dung, such as dung beetles, and the ecosystem services they provide. To examine these interactions, we treated cattle with a commonly used broad-spectrum antibiotic and assessed downstream effects on microbiota in dung and dung beetles, greenhouse gas fluxes from dung, and beetle size, survival and reproduction. We found that antibiotic treatment restructured microbiota in dung beetles, which harboured a microbial community distinct from those in the dung they were consuming. The antibiotic effect on beetle microbiota was not associated with smaller size or lower numbers. Unexpectedly, antibiotic treatment raised methane fluxes from dung, possibly by altering the interactions between methanogenic archaea and bacteria in rumen and dung environments. Our findings that antibiotics restructure dung beetle microbiota and modify greenhouse gas emissions from dung indicate that antibiotic treatment may have unintended, cascading ecological effects that extend beyond the target animal. PMID:27226475

Bacterial adaptation to sublethal antibiotic gradients can change the ecological properties of multitrophic microbial communities

PubMed Central

Friman, Ville-Petri; Guzman, Laura Melissa; Reuman, Daniel C.; Bell, Thomas

2015-01-01

Antibiotics leak constantly into environments due to widespread use in agriculture and human therapy. Although sublethal concentrations are well known to select for antibiotic-resistant bacteria, little is known about how bacterial evolution cascades through food webs, having indirect effect on species not directly affected by antibiotics (e.g. via population dynamics or pleiotropic effects). Here, we used an experimental evolution approach to test how temporal patterns of antibiotic stress, as well as migration within metapopulations, affect the evolution and ecology of microcosms containing one prey bacterium, one phage and two protist predators. We found that environmental variability, autocorrelation and migration had only subtle effects for population and evolutionary dynamics. However, unexpectedly, bacteria evolved greatest fitness increases to both antibiotics and enemies when the sublethal levels of antibiotics were highest, indicating positive pleiotropy. Crucially, bacterial adaptation cascaded through the food web leading to reduced predator-to-prey abundance ratio, lowered predator community diversity and increased instability of populations. Our results show that the presence of natural enemies can modify and even reverse the effects of antibiotics on bacteria, and that antibiotic selection can change the ecological properties of multitrophic microbial communities by having indirect effects on species not directly affected by antibiotics. PMID:25833854

Bacterial adaptation to sublethal antibiotic gradients can change the ecological properties of multitrophic microbial communities.

PubMed

Friman, Ville-Petri; Guzman, Laura Melissa; Reuman, Daniel C; Bell, Thomas

2015-05-07

Antibiotics leak constantly into environments due to widespread use in agriculture and human therapy. Although sublethal concentrations are well known to select for antibiotic-resistant bacteria, little is known about how bacterial evolution cascades through food webs, having indirect effect on species not directly affected by antibiotics (e.g. via population dynamics or pleiotropic effects). Here, we used an experimental evolution approach to test how temporal patterns of antibiotic stress, as well as migration within metapopulations, affect the evolution and ecology of microcosms containing one prey bacterium, one phage and two protist predators. We found that environmental variability, autocorrelation and migration had only subtle effects for population and evolutionary dynamics. However, unexpectedly, bacteria evolved greatest fitness increases to both antibiotics and enemies when the sublethal levels of antibiotics were highest, indicating positive pleiotropy. Crucially, bacterial adaptation cascaded through the food web leading to reduced predator-to-prey abundance ratio, lowered predator community diversity and increased instability of populations. Our results show that the presence of natural enemies can modify and even reverse the effects of antibiotics on bacteria, and that antibiotic selection can change the ecological properties of multitrophic microbial communities by having indirect effects on species not directly affected by antibiotics. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

The Origins of Specificity in the Microcin-Processing Protease TldD/E.

PubMed

Ghilarov, Dmitry; Serebryakova, Marina; Stevenson, Clare E M; Hearnshaw, Stephen J; Volkov, Dmitry S; Maxwell, Anthony; Lawson, David M; Severinov, Konstantin

2017-10-03

TldD and TldE proteins are involved in the biosynthesis of microcin B17 (MccB17), an Escherichia coli thiazole/oxazole-modified peptide toxin targeting DNA gyrase. Using a combination of biochemical and crystallographic methods we show that E. coli TldD and TldE interact to form a heterodimeric metalloprotease. TldD/E cleaves the N-terminal leader sequence from the modified MccB17 precursor peptide, to yield mature antibiotic, while it has no effect on the unmodified peptide. Both proteins are essential for the activity; however, only the TldD subunit forms a novel metal-containing active site within the hollow core of the heterodimer. Peptide substrates are bound in a sequence-independent manner through β sheet interactions with TldD and are likely cleaved via a thermolysin-type mechanism. We suggest that TldD/E acts as a "molecular pencil sharpener": unfolded polypeptides are fed through a narrow channel into the active site and processively truncated through the cleavage of short peptides from the N-terminal end. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Calcined Eggshell Waste for Mitigating Soil Antibiotic-Resistant Bacteria/Antibiotic Resistance Gene Dissemination and Accumulation in Bell Pepper.

PubMed

Ye, Mao; Sun, Mingming; Feng, Yanfang; Li, Xu; Schwab, Arthur P; Wan, Jinzhong; Liu, Manqiang; Tian, Da; Liu, Kuan; Wu, Jun; Jiang, Xin

2016-07-13

The combined accumulation of antibiotics, heavy metals, antibiotic-resistant bacteria (ARB)/antibiotic resistance genes (ARGs) in vegetables has become a new threat to human health. This is the first study to investigate the feasibility of calcined eggshells modified by aluminum sulfate as novel agricultural wastes to impede mixed contaminants from transferring to bell pepper (Capsicum annuum L.). In this work, calcined eggshell amendment mitigated mixed pollutant accumulation in bell pepper significantly, enhanced the dissipation of soil tetracycline, sulfadiazine, roxithromycin, and chloramphenicol, decreased the water-soluble fractions of antibiotics, and declined the diversity of ARB/ARGs inside the vegetable. Moreover, quantitative polymerase chain reaction analysis detected that ARG levels in the bell pepper fruits significantly decreased to 10(-10) copies/16S copies, indicating limited risk of ARGs transferring along the food chain. Furthermore, the restoration of soil microbial biological function suggests that calcined eggshell is an environmentally friendly amendment to control the dissemination of soil ARB/ARGs in the soil-vegetable system.

Fungal and Bacterial Infection Mitigation with Antibiotic and Antifungal Loaded Biopolymer Sponges

NASA Astrophysics Data System (ADS)

Parker, Ashley Cox

Musculoskeletal injuries are some of the most prevalent injuries in both civilian and military populations and their infections can be difficult to treat, often resulting in multiple surgeries and increased costs. In both previous and recent military operations, extremity injuries have been the most common battlefield injuries and many involve complex, open fractures. These extremity injuries are especially susceptible to multiple pathogenic, and sometimes drug resistant, bacteria and fungi. Fungal infections have recently become increasingly problematic in both military and civilian populations and have significantly higher amputation rates than those from bacterial infections. Many of these bacterial and fungal strains adhere to tissue and implanted orthopaedic hardware within wounds, forming biofilms. These problematic, often polymicrobial, infections threaten the health of the patient, but the risk also exists of spreading within hospitals to become prominent resistant infections. Local antimicrobial delivery releases high levels of antimicrobials directly to injured wound tissue, overcoming sub-bactericidal or subfungicidal antimicrobial levels present in the avascular wound zones. This research will determine the ability of modified chitosan sponges, buffered with sodium acetate or blended with polyethylene glycol (PEG), to act as short term adjunctive therapies to initial surgical treatment for delivering both antibiotics and/or antifungals for early abatement of infection. The objective of this work was to evaluate both types of modified sponges for in vitro and in vivo material characteristics and device functionality. In vitro analysis demonstrated both the buffered and PEG modified chitosan sponges exhibited increased degradation and functional cytocompatibility. The chitosan/PEG sponges were able to be loaded with hydrophobic antifungals and the sponges released in vitro biologically active concentrations, alone or in combination with the antibiotic vancomycin. Both types of modified sponges exhibited good biocompatibility and slight, but not complete, degradation in an in vivo rat intramuscular degradation and biocompatibility model. In an in vivo bacteria biofilm infection prevention mouse model, vancomycin loaded chitosan/PEG sponges also cleared more bacteria than the unmodified chitosan sponges. These experimental results led to the conclusion that with additional research and in vivo studies, the buffered and PEG blended chitosan sponge local delivery systems exhibit potential for use as adjunctive bacterial or fungal infection prevention therapies to standard surgical treatment of musculoskeletal wounds.

The Effect of Early Life Antibiotic Exposures on Diarrheal Rates Among Young Children in Vellore, India

PubMed Central

Westreich, Daniel; Becker-Dreps, Sylvia; Adair, Linda S.; Sandler, Robert S.; Sarkar, Rajiv; Kattula, Deepthi; Ward, Honorine D.; Meshnick, Steven R.; Kang, Gagandeep

2015-01-01

Background: Antibiotic treatment of childhood illnesses is common in India. In addition to contributing to antimicrobial resistance, antibiotics might result in increased susceptibility to diarrhea through interactions with the gastrointestinal microbiota. Breast milk, which enriches the microbiota early in life, may increase the resilience of the microbiota against perturbations by antibiotics. Methods: In a prospective observational cohort study, we assessed whether antibiotic exposures from birth to 6 months affected rates of diarrhea up to age 3 years among 465 children from Vellore, India. Adjusting for treatment indicators, we modeled diarrheal rates among children exposed and unexposed to antibiotics using negative binomial regression. We further assessed whether the effect of antibiotics on diarrheal rates was modified by exclusive breastfeeding at 6 months. Results: More than half of the children (n = 267, 57.4%) were given at least one course of antibiotics in the first 6 months of life. The adjusted relative incidence rate of diarrhea was 33% higher among children who received antibiotics under 6 months of age compared with those who did not (incidence rate ratio: 1.33, 95% confidence interval: 1.12, 1.57). Children who were exclusively breastfed until 6 months of age did not have increased diarrheal rates following antibiotic use. Conclusions: Antibiotic exposures early in life were associated with increased rates of diarrhea in early childhood. Exclusive breastfeeding might protect against this negative impact. PMID:25742244

Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs).

PubMed

Benjdia, Alhosna; Balty, Clémence; Berteau, Olivier

2017-01-01

Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large and diverse family of natural products. They possess interesting biological properties such as antibiotic or anticancer activities, making them attractive for therapeutic applications. In contrast to polyketides and non-ribosomal peptides, RiPPs derive from ribosomal peptides and are post-translationally modified by diverse enzyme families. Among them, the emerging superfamily of radical SAM enzymes has been shown to play a major role. These enzymes catalyze the formation of a wide range of post-translational modifications some of them having no counterparts in living systems or synthetic chemistry. The investigation of radical SAM enzymes has not only illuminated unprecedented strategies used by living systems to tailor peptides into complex natural products but has also allowed to uncover novel RiPP families. In this review, we summarize the current knowledge on radical SAM enzymes catalyzing RiPP post-translational modifications and discuss their mechanisms and growing importance notably in the context of the human microbiota.

Removal of antibiotics from water in the coexistence of suspended particles and natural organic matters using amino-acid-modified-chitosan flocculants: A combined experimental and theoretical study.

PubMed

Jia, Shuying; Yang, Zhen; Ren, Kexin; Tian, Ziqi; Dong, Chang; Ma, Ruixue; Yu, Ge; Yang, Weiben

2016-11-05

Contamination of trace antibiotics is widely found in surface water sources. This work delineates removal of trace antibiotics (norfloxacin (NOR), sulfadiazine (SDZ) or tylosin (TYL)) from synthetic surface water by flocculation, in the coexistence of inorganic suspended particles (kaolin) and natural organic matter (humic acid, HA). To avoid extra pollution caused by petrochemical products-based modification reagents, environmental-friendly amino-acid-modified-chitosan flocculants, Ctrp and Ctyr, with different functional aromatic-rings structures were employed. Jar tests at various pHs exhibited that, Ctyr, owning phenol groups as electron donors, was favored for elimination of cationic NOR (∼50% removal; optimal pH: 6; optimal dosage: 4mg/L) and TYL (∼60% removal; optimal pH: 7; optimal dosage: 7.5mg/L), due to π-π electron donator-acceptor (EDA) effect and unconventional H-bonds. Differently, Ctrp with indole groups as electron acceptor had better removal rate (∼50%) of SDZ anions (electron donator). According to correlation analysis, the coexisted kaolin and HA played positive roles in antibiotics' removal. Detailed pairwise interactions in molecular level among different components were clarified by spectral analysis and theoretical calculations (density functional theory), which are important for both the structural design of new flocculants aiming at targeted contaminants and understanding the environmental behaviors of antibiotics in water. Copyright © 2016 Elsevier B.V. All rights reserved.

Rapid optical determination of β-lactamase and antibiotic activity

PubMed Central

2014-01-01

Background The absence of rapid tests evaluating antibiotic susceptibility results in the empirical prescription of antibiotics. This can lead to treatment failures due to escalating antibiotic resistance, and also furthers the emergence of drug-resistant bacteria. This study reports a rapid optical method to detect β-lactamase and thereby assess activity of β-lactam antibiotics, which could provide an approach for targeted prescription of antibiotics. The methodology is centred on a fluorescence quenching based probe (β-LEAF – β-Lactamase Enzyme Activated Fluorophore) that mimics the structure of β-lactam antibiotics. Results The β-LEAF assay was performed for rapid determination of β-lactamase production and activity of β-lactam antibiotic (cefazolin) on a panel of Staphylococcus aureus ATCC strains and clinical isolates. Four of the clinical isolates were determined to be lactamase producers, with the capacity to inactivate cefazolin, out of the twenty-five isolates tested. These results were compared against gold standard methods, nitrocefin disk test for β-lactamase detection and disk diffusion for antibiotic susceptibility, showing results to be largely consistent. Furthermore, in the sub-set of β-lactamase producers, it was demonstrated and validated that multiple antibiotics (cefazolin, cefoxitin, cefepime) could be assessed simultaneously to predict the antibiotic that would be most active for a given bacterial isolate. Conclusions The study establishes the rapid β-LEAF assay for β-lactamase detection and prediction of antibiotic activity using S. aureus clinical isolates. Although the focus in the current study is β-lactamase-based resistance, the overall approach represents a broad diagnostic platform. In the long-term, these studies form the basis for the development of assays utilizing a broader variety of targets, pathogens and drugs. PMID:24708478

A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens.

PubMed

Hubick, Shelby; Jayaraman, Arumugam; McKeen, Alexander; Reid, Shelby; Alcorn, Jane; Stavrinides, John; Sterenberg, Brian T

2017-02-06

The acronymously named "ESKAPE" pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to "eskape" antibiotic treatment. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.

A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens

PubMed Central

Hubick, Shelby; Jayaraman, Arumugam; McKeen, Alexander; Reid, Shelby; Alcorn, Jane; Stavrinides, John; Sterenberg, Brian T.

2017-01-01

The acronymously named “ESKAPE” pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to “eskape” antibiotic treatment12. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment. PMID:28165020

Adjuvant strategies for potentiation of antibiotics to overcome antimicrobial resistance.

PubMed

Pieren, Michel; Tigges, Marcel

2012-10-01

Alarming facts about the occurrence and spreading of multiple antibiotic resistant bacteria have caught the attention of global surveillance authorities and public media. The demand for novel effective antimicrobial drugs is high and on the rise while, at the same time, the supply of fresh 'magic bullets' is drying up. This review summarizes examples of recent strategies for development of adjunctive antibiotic therapies that overcome microbial resistance and thus rejuvenate the existing arsenal of drugs. Recent studies have demonstrated the potential of compounds that inhibit the action of the repressor protein implicated in ethionamide resistance, thus stimulating activation of the drug and thereby restoring the activity of the antibiotic for treatment of Mycobacterium tuberculosis. Such specific interference with regulators or signal transduction mechanisms involved in antibiotic resistance or virulence provides a new toolbox for novel combinations of antimicrobial drugs with adjuvant molecules lacking intrinsic antibiotic activity. In addition to the development of new antibiotics and vaccination initiatives this strategy of restoring or potentiating the activity of existing antibiotics may help to postpone the day when antibiotics are no longer generally efficacious. Copyright © 2012 Elsevier Ltd. All rights reserved.

[First Argentine consensus guidelines for in vitro antimicrobial susceptibility testing of clinically relevant anaerobic bacteria in humans/ Anaerobic Subcommittee of the Asociación Argentina de Microbiología].

PubMed

Legaria, María C; Bianchini, Hebe M; Castello, Liliana; Carloni, Graciela; Di Martino, Ana; Fernández Canigia, Liliana; Litterio, Mirta; Rollet, Raquel; Rossetti, Adelaida; Predari, Silvia C

2011-01-01

Through time, anaerobic bacteria have shown good susceptibility to clinically useful antianaerobic agents. Nevertheless, the antimicrobial resistance profile of most of the anaerobic species related to severe infections in humans has been modified in the last years and different kinds of resistance to the most active agents have emerged, making their effectiveness less predictable. With the aim of finding an answer and for the purpose of facilitating the detection of anaerobic antimicrobial resistance, the Anaerobic Subcommittee of the Asociación Argentina de Microbiología developed the First Argentine consensus guidelines for in vitro antimicrobial susceptibility testing of clinically relevant anaerobic bacteria in humans. This document resulted from the compatibilization of the Clinical and Laboratory Standards Institute recommendations, the international literature and the work and experience of the Subcommittee. The Consensus document provides a brief taxonomy review, and exposes why and when anaerobic antimicrobial susceptibility tests should be conducted, and which antimicrobial agents can be used according to the species involved. The recommendations on how to perform, read and interpret in vitro anaerobic antimicrobial susceptibility tests with each method are exposed. Finally, the antibiotic susceptibility profile, the classification of antibiotics according to their in vitro activities, the natural and acquired mechanisms of resistance, the emerging resistance and the regional antibiotic resistance profile of clinically relevant anaerobic species are shown.

CrpP Is a Novel Ciprofloxacin-Modifying Enzyme Encoded by the Pseudomonas aeruginosa pUM505 Plasmid.

PubMed

Chávez-Jacobo, Víctor M; Hernández-Ramírez, Karen C; Romo-Rodríguez, Pamela; Pérez-Gallardo, Rocío Viridiana; Campos-García, Jesús; Gutiérrez-Corona, J Félix; García-Merinos, Juan Pablo; Meza-Carmen, Víctor; Silva-Sánchez, Jesús; Ramírez-Díaz, Martha I

2018-06-01

The pUM505 plasmid, isolated from a clinical Pseudomonas aeruginosa isolate, confers resistance to ciprofloxacin (CIP) when transferred into the standard P. aeruginosa strain PAO1. CIP is an antibiotic of the quinolone family that is used to treat P. aeruginosa infections. In silico analysis, performed to identify CIP resistance genes, revealed that the 65-amino-acid product encoded by the orf131 gene in pUM505 displays 40% amino acid identity to the Mycobacterium smegmatis aminoglycoside phosphotransferase (an enzyme that phosphorylates and inactivates aminoglycoside antibiotics). We cloned orf131 (renamed crpP , for c iprofloxacin r esistance p rotein, p lasmid encoded) into the pUCP20 shuttle vector. The resulting recombinant plasmid, pUC- crpP , conferred resistance to CIP on Escherichia coli strain J53-3, suggesting that this gene encodes a protein involved in CIP resistance. Using coupled enzymatic analysis, we determined that the activity of CrpP on CIP is ATP dependent, while little activity against norfloxacin was detected, suggesting that CIP may undergo phosphorylation. Using a recombinant His-tagged CrpP protein and liquid chromatography-tandem mass spectrometry, we also showed that CIP was phosphorylated prior to its degradation. Thus, our findings demonstrate that CrpP, encoded on the pUM505 plasmid, represents a new mechanism of CIP resistance in P. aeruginosa , which involves phosphorylation of the antibiotic. Copyright © 2018 American Society for Microbiology.

Sugar-Grafted Cyclodextrin Nanocarrier as a "Trojan Horse" for Potentiating Antibiotic Activity.

PubMed

Li, Min; Neoh, Koon Gee; Xu, Liqun; Yuan, Liang; Leong, David Tai; Kang, En-Tang; Chua, Kim Lee; Hsu, Li Yang

2016-05-01

The use of "Trojan Horse" nanocarriers for antibiotics to enhance the activity of antibiotics against susceptible and resistant bacteria is investigated. Antibiotic carriers (CD-MAN and CD-GLU) are prepared from β-cyclodextrin grafted with sugar molecules (D-mannose and D-glucose, respectively) via azide-alkyne click reaction. The sugar molecules serve as a chemoattractant enticing the bacteria to take in higher amounts of the antibiotic, resulting in rapid killing of the bacteria. Three types of hydrophobic antibiotics, erythromycin, rifampicin and ciprofloxacin, are used as model drugs and loaded into the carriers. The minimum inhibitory concentration of the antibiotics in the CD-MAN-antibiotic and CD-GLU-antibiotic complexes for Gram-negative Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii strains, and a number of Gram-positive Staphylococcus aureus strains, including the methicillin-resistant strains (MRSA), are reduced by a factor ranging from 3 to >100. The CD-MAN-antibiotic complex is also able to prolong the stability of the loaded antibiotic and inhibit development of intrinsic antibiotic resistance in the bacteria. These non-cytotoxic sugar-modfied nanocarriers can potentiate the activity of existing antibiotics, especially against multidrug-resistant bacteria, which is highly advantageous in view of the paucity of new antibiotics in the pipeline.

Antibiotic resistance shaping multi-level population biology of bacteria

PubMed Central

Baquero, Fernando; Tedim, Ana P.; Coque, Teresa M.

2013-01-01

Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent “population biologies.” Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of “clinical” antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi-level population biology of bacteria. PMID:23508522

Antibiotic resistance shaping multi-level population biology of bacteria.

PubMed

Baquero, Fernando; Tedim, Ana P; Coque, Teresa M

2013-01-01

Antibiotics have natural functions, mostly involving cell-to-cell signaling networks. The anthropogenic production of antibiotics, and its release in the microbiosphere results in a disturbance of these networks, antibiotic resistance tending to preserve its integrity. The cost of such adaptation is the emergence and dissemination of antibiotic resistance genes, and of all genetic and cellular vehicles in which these genes are located. Selection of the combinations of the different evolutionary units (genes, integrons, transposons, plasmids, cells, communities and microbiomes, hosts) is highly asymmetrical. Each unit of selection is a self-interested entity, exploiting the higher hierarchical unit for its own benefit, but in doing so the higher hierarchical unit might acquire critical traits for its spread because of the exploitation of the lower hierarchical unit. This interactive trade-off shapes the population biology of antibiotic resistance, a composed-complex array of the independent "population biologies." Antibiotics modify the abundance and the interactive field of each of these units. Antibiotics increase the number and evolvability of "clinical" antibiotic resistance genes, but probably also many other genes with different primary functions but with a resistance phenotype present in the environmental resistome. Antibiotics influence the abundance, modularity, and spread of integrons, transposons, and plasmids, mostly acting on structures present before the antibiotic era. Antibiotics enrich particular bacterial lineages and clones and contribute to local clonalization processes. Antibiotics amplify particular genetic exchange communities sharing antibiotic resistance genes and platforms within microbiomes. In particular human or animal hosts, the microbiomic composition might facilitate the interactions between evolutionary units involved in antibiotic resistance. The understanding of antibiotic resistance implies expanding our knowledge on multi-level population biology of bacteria.

Monitoring bacterial resistance to chloramphenicol and other antibiotics by liquid chromatography electrospray ionization tandem mass spectrometry using selected reaction monitoring.

PubMed

Haag, Anthony M; Medina, Audrie M; Royall, Ariel E; Herzog, Norbert K; Niesel, David W

2013-06-01

Antibiotic resistance is a growing problem worldwide. For this reason, clinical laboratories often determine the susceptibility of the bacterial isolate to a number of different antibiotics in order to establish the most effective antibiotic for treatment. Unfortunately, current susceptibility assays are time consuming. Antibiotic resistance often involves the chemical modification of an antibiotic to an inactive form by an enzyme expressed by the bacterium. Selected reaction monitoring (SRM) has the ability to quickly monitor and identify these chemical changes in an unprecedented time scale. In this work, we used SRM as a technique to determine the susceptibility of several different antibiotics to the chemically modifying enzymes β-lactamase and chloramphenicol acetyltransferase, enzymes used by bacteria to confer resistance to major classes of commonly used antibiotics. We also used this technique to directly monitor the effects of resistant bacteria grown in a broth containing a specific antibiotic. Because SRM is highly selective and can also identify chemical changes in a multitude of antibiotics in a single assay, SRM has the ability to detect organisms that are resistant to multiple antibiotics in a single assay. For these reasons, the use of SRM greatly reduces the time it takes to determine the susceptibility or resistance of an organism to a multitude of antibiotics by eliminating the time-consuming process found in other currently used methods. Copyright © 2013 John Wiley & Sons, Ltd.

Association of antibiotics in infancy with early childhood obesity.

PubMed

Bailey, L Charles; Forrest, Christopher B; Zhang, Peixin; Richards, Thomas M; Livshits, Alice; DeRusso, Patricia A

2014-11-01

Obesity in children and adults is associated with significant health burdens, making prevention a public health imperative. Infancy may be a critical period when environmental factors exert a lasting effect on the risk for obesity; identifying modifiable factors may help to reduce this risk. To assess the impact of antibiotics prescribed in infancy (ages 0-23 months) on obesity in early childhood (ages 24-59 months). We conducted a cohort study spanning 2001-2013 using electronic health records. Cox proportional hazard models were used to adjust for demographic, practice, and clinical covariates. The study spanned a network of primary care practices affiliated with the Children's Hospital of Philadelphia including both teaching clinics and private practices in urban Philadelphia, Pennsylvania, and the surrounding region. All children with annual visits at ages 0 to 23 months, as well 1 or more visits at ages 24 to 59 months, were enrolled. The cohort comprised 64,580 children. Treatment episodes for prescribed antibiotics were ascertained up to 23 months of age. Obesity outcomes were determined directly from anthropometric measurements using National Health and Nutrition Examination Survey 2000 body mass index norms. Sixty-nine percent of children were exposed to antibiotics before age 24 months, with a mean (SD) of 2.3 (1.5) episodes per child. Cumulative exposure to antibiotics was associated with later obesity (rate ratio [RR], 1.11; 95% CI, 1.02-1.21 for ≥ 4 episodes); this effect was stronger for broad-spectrum antibiotics (RR, 1.16; 95% CI, 1.06-1.29). Early exposure to broad-spectrum antibiotics was also associated with obesity (RR, 1.11; 95% CI, 1.03-1.19 at 0-5 months of age and RR, 1.09; 95% CI, 1.04-1.14 at 6-11 months of age) but narrow-spectrum drugs were not at any age or frequency. Steroid use, male sex, urban practice, public insurance, Hispanic ethnicity, and diagnosed asthma or wheezing were also predictors of obesity; common infectious diagnoses and antireflux medications were not. Repeated exposure to broad-spectrum antibiotics at ages 0 to 23 months is associated with early childhood obesity. Because common childhood infections were the most frequent diagnoses co-occurring with broad-spectrum antibiotic prescription, narrowing antibiotic selection is potentially a modifiable risk factor for childhood obesity.

Bioavailability of Antibiotics at Soil-Water Interfaces: A Comparison of Measured Activities and Equilibrium Partitioning Estimates.

PubMed

Menz, Jakob; Müller, Julia; Olsson, Oliver; Kümmerer, Klaus

2018-06-05

There are growing concerns that antibiotic pollution impacts environmental microbiota and facilitates the propagation of antibiotic resistance. However, the prediction or analytical determination of bioavailable concentrations of antibiotics in soil is still subject to great uncertainty. Biological assays are increasingly recognized as valuable complementary tools that allow a more direct determination of the residual antibiotic activity. This study assessed the bioavailability of structurally diverse antibiotics at a soil-water interface applying activity-based analyses in conjunction with equilibrium partitioning (EqP) modeling. The activity against Gram-positive and Gram-negative bacteria of nine antibiotics from different classes was determined in the presence and absence of standard soil (LUFA St. 2.2). The addition of soil affected the activity of different antibiotics to highly varying degrees. Moreover, a highly significant correlation ( p < 0.0001) between the experimentally observed and the EqP-derived log EC 50 (half-maximal effective concentration) values was observed. The innovative experimental design of this study provided new insights on the bioavailability of antibiotics at soil-water interfaces. EqP appears to be applicable to a broad range of antibiotics for the purpose of screening-level risk assessment. However, EqP estimates cannot replace soil-specific ecotoxicity testing in higher-tier assessments, since their accuracy is still compromised by a number of factors.

Influence of lung function on course of disease and response to antibiotic therapy in adult primary care patients with acute cough: a post hoc analysis of patients enrolled in a prospective multicentre study.

PubMed

van Erp, Nicole; Little, Paul; Stuart, Beth; Moore, Michael; Thomas, Mike; Butler, Chris C; Hood, Kerenza; Coenen, Samuel; Goossens, Herman; Leven, Margareta; Verheij, Theo J M

2014-09-25

In acute cough patients, impaired lung function as present in chronic lung conditions like asthma and chronic obstructive pulmonary disease (COPD) are often thought to negatively influence course of disease, but clear evidence is lacking. To investigate the influence of lung function abnormalities on course of disease and response to antibiotic therapy in primary care patients with acute cough. A total of 3,104 patients with acute cough (⩽28 days) were included in a prospective observational study with a within-nested trial, of which 2,427 underwent spirometry 28-35 days after inclusion. Influence of the lung function abnormalities fixed obstruction (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7) and bronchodilator responsiveness (FEV1 increase of ⩾12% or 200 ml after 400 μg salbutamol) on symptom severity, duration and worsening were evaluated using uni- and multivariable regression models. Antibiotic use was defined as the reported use of antibiotics ⩾5 days in the first week. Interaction terms were calculated to investigate modifying effects of lung function on antibiotic effect. The only significant association was the effect of severe airway obstruction on symptom severity on days 2-4 (difference=0.31, 95% confidence interval (CI)=0.03-0.60, P=0.03). No evidence of a differential effect of lung function on the effect of antibiotics was found. Prior use of inhaled steroids was associated with a 30% slower resolution of symptoms rated 'moderately bad' or worse (hazard ratio=0.75, 95% CI=0.63-0.90, P=0.00). In adult patients with acute cough, lung function abnormalities were neither significantly associated with course of disease nor did they modify the effect of antibiotics.

Effect of various concentrations of antibiotics on osteogenic cell viability and activity.

PubMed

Rathbone, Christopher R; Cross, Jessica D; Brown, Kate V; Murray, Clinton K; Wenke, Joseph C

2011-07-01

Infection is a common complication of open fractures. Systemic antibiotics often cause adverse events before eradication of infected bone occurs. The local delivery of antibiotics and the use of implants that deliver both growth factors and antimicrobials are ways to circumvent systemic toxicity while decreasing infection and to reach extremely high levels required to treat bacterial biofilms. When choosing an antibiotic for a local delivery system, one should consider the effect that the antibiotic has on cell viability and osteogenic activity. To address this concern, osteoblasts were treated with 21 different antibiotics over 8 concentrations from 0 to 5000 µg/ml. Osteoblast deoxyribonucleic acid content and alkaline phosphatase activity (ALP) were measured to determine cell number and osteogenic activity, respectively. Antibiotics that caused the greatest decrement include rifampin, minocycline, doxycycline, nafcillin, penicillin, ciprofloxacin, colistin methanesulfonate, and gentamicin; their cell number and ALP were significantly less than control at drug concentrations ≤ 200 µg/ml. Conversely, amikacin, tobramycin, and vancomycin were the least cytotoxic and did not appreciably affect cell number and ALP until very high concentrations were used. This comprehensive evaluation of numerous antibiotics' effects on osteoblast viability and activity will enable clinicians and researchers to choose the optimal antibiotic for treatment of infection and maintenance of healthy host bone. Copyright © 2011 Orthopaedic Research Society.

Antibiotic Adjuvants: Rescuing Antibiotics from Resistance.

PubMed

Wright, Gerard D

2016-11-01

Rooted in the mechanism of action of antibiotics and subject to bacterial evolution, antibiotic resistance is difficult and perhaps impossible to overcome. Nevertheless, strategies can be used to minimize the emergence and impact of resistance. Antibiotic adjuvants offer one such approach. These are compounds that have little or no antibiotic activity themselves but act to block resistance or otherwise enhance antibiotic action. Antibiotic adjuvants are therefore delivered in combination with antibiotics and can be divided into two groups: Class I agents that act on the pathogen, and Class II agents that act on the host. Adjuvants offer a means to both suppress the emergence of resistance and rescue the activity of existing drugs, offering an orthogonal strategy complimentary to new antibiotic discovery VIDEO ABSTRACT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stability and Activities of Antibiotics Produced during Infection of the Insect Galleria mellonella by Two Isolates of Xenorhabdus nematophilus

PubMed Central

Maxwell, Philip W.; Chen, Genhui; Webster, John M.; Dunphy, Gary B.

1994-01-01

Xenorhabdus nematophilus subsp. dutki, an entomopathogenic bacterium, is vectored by steinernematid nematodes into insects, where it produces broad-spectrum antibiotics. The use of the nematode-bacterium complex against soil-dwelling pest insects could introduce antibiotics into the soil via the dead insect fragments during the emergence phase of the nematodes. Studies on the stability and activities of these antibiotics produced in the insect Galleria mellonella may contribute to assessing the possible impact of antibiotics on soil bacteria. Two isolates of X. nematophilus subsp. dutki (isolates GI and SFU) produced xenocoumacins 1 and 2 in cadavers of G. mellonella larvae in a 1:1 ratio. Total xenocoumacin 1 and 2 production was 800 ng/200 mg (wet weight) of insect tissue for the GI isolate. Antibiotic activity of water extracts from insects that had been infected with X. nematophilus was stable at 60°C for 1 h and after repeated freeze-thaw cycles. The antibiotic titer of extracts held at 27°C declined by day 10. The spectrum of bacterial species killed by antibiotics produced in insect cadavers varied with the isolate of X. nematophilus. Levels of antibiotic activity were greater in vivo than in tryptic soy broth, which may represent a nutrient effect. The bacterial isolate, culture condition, and presence of nematodes influenced the total antibiotic production in vivo. However, the levels of activity were not correlated with bacterial levels in the different growth environments. Insect cadavers with antibiotic activity transiently lowered the numbers of the bacteria in the soil, the extent of decline varying with the strain of X. nematophilus and the time of sampling. PMID:16349198

Potentiating antibiotics in drug-resistant clinical isolates via stimuli-activated superoxide generation.

PubMed

Courtney, Colleen M; Goodman, Samuel M; Nagy, Toni A; Levy, Max; Bhusal, Pallavi; Madinger, Nancy E; Detweiler, Corrella S; Nagpal, Prashant; Chatterjee, Anushree

2017-10-01

The rise of multidrug-resistant (MDR) bacteria is a growing concern to global health and is exacerbated by the lack of new antibiotics. To treat already pervasive MDR infections, new classes of antibiotics or antibiotic adjuvants are needed. Reactive oxygen species (ROS) have been shown to play a role during antibacterial action; however, it is not yet understood whether ROS contribute directly to or are an outcome of bacterial lethality caused by antibiotics. We show that a light-activated nanoparticle, designed to produce tunable flux of specific ROS, superoxide, potentiates the activity of antibiotics in clinical MDR isolates of Escherichia coli , Salmonella enterica , and Klebsiella pneumoniae . Despite the high degree of antibiotic resistance in these isolates, we observed a synergistic interaction between both bactericidal and bacteriostatic antibiotics with varied mechanisms of action and our superoxide-producing nanoparticles in more than 75% of combinations. As a result of this potentiation, the effective antibiotic concentration of the clinical isolates was reduced up to 1000-fold below their respective sensitive/resistant breakpoint. Further, superoxide-generating nanoparticles in combination with ciprofloxacin reduced bacterial load in epithelial cells infected with S. enterica serovar Typhimurium and increased Caenorhabditis elegans survival upon infection with S. enterica serovar Enteriditis, compared to antibiotic alone. This demonstration highlights the ability to engineer superoxide generation to potentiate antibiotic activity and combat highly drug-resistant bacterial pathogens.

Structural and Functional Survey of Environmental Aminoglycoside Acetyltransferases Reveals Functionality of Resistance Enzymes.

PubMed

Xu, Zhiyu; Stogios, Peter J; Quaile, Andrew T; Forsberg, Kevin J; Patel, Sanket; Skarina, Tatiana; Houliston, Scott; Arrowsmith, Cheryl; Dantas, Gautam; Savchenko, Alexei

2017-09-08

Aminoglycoside N-acetyltransferases (AACs) confer resistance against the clinical use of aminoglycoside antibiotics. The origin of AACs can be traced to environmental microbial species representing a vast reservoir for new and emerging resistance enzymes, which are currently undercharacterized. Here, we performed detailed structural characterization and functional analyses of four metagenomic AAC (meta-AACs) enzymes recently identified in a survey of agricultural and grassland soil microbiomes ( Forsberg et al. Nature 2014 , 509 , 612 ). These enzymes are new members of the Gcn5-Related-N-Acetyltransferase superfamily and confer resistance to the aminoglycosides gentamicin C, sisomicin, and tobramycin. Moreover, the meta-AAC0020 enzyme demonstrated activity comparable with an AAC(3)-I enzyme that serves as a model AAC enzyme identified in a clinical bacterial isolate. The crystal structure of meta-AAC0020 in complex with sisomicin confirmed an unexpected AAC(6') regiospecificity of this enzyme and revealed a drug binding mechanism distinct from previously characterized AAC(6') enzymes. Together, our data highlights the presence of highly active antibiotic-modifying enzymes in the environmental microbiome and reveals unexpected diversity in substrate specificity. These observations of additional AAC enzymes must be considered in the search for novel aminoglycosides less prone to resistance.

Antibiotic distribution channels in Thailand: results of key-informant interviews, reviews of drug regulations and database searches.

PubMed

Sommanustweechai, Angkana; Chanvatik, Sunicha; Sermsinsiri, Varavoot; Sivilaikul, Somsajee; Patcharanarumol, Walaiporn; Yeung, Shunmay; Tangcharoensathien, Viroj

2018-02-01

To analyse how antibiotics are imported, manufactured, distributed and regulated in Thailand. We gathered information, on antibiotic distribution in Thailand, in in-depth interviews - with 43 key informants from farms, health facilities, pharmaceutical and animal feed industries, private pharmacies and regulators- and in database and literature searches. In 2016-2017, licensed antibiotic distribution in Thailand involves over 700 importers and about 24 000 distributors - e.g. retail pharmacies and wholesalers. Thailand imports antibiotics and active pharmaceutical ingredients. There is no system for monitoring the distribution of active ingredients, some of which are used directly on farms, without being processed. Most antibiotics can be bought from pharmacies, for home or farm use, without a prescription. Although the 1987 Drug Act classified most antibiotics as "dangerous drugs", it only classified a few of them as prescription-only medicines and placed no restrictions on the quantities of antibiotics that could be sold to any individual. Pharmacists working in pharmacies are covered by some of the Act's regulations, but the quality of their dispensing and prescribing appears to be largely reliant on their competences. In Thailand, most antibiotics are easily and widely available from retail pharmacies, without a prescription. If the inappropriate use of active pharmaceutical ingredients and antibiotics is to be reduced, we need to reclassify and restrict access to certain antibiotics and to develop systems to audit the dispensing of antibiotics in the retail sector and track the movements of active ingredients.

Lack of formylated methionyl-tRNA has pleiotropic effects on Bacillus subtilis.

PubMed

Cai, Yanfei; Chandrangsu, Pete; Gaballa, Ahmed; Helmann, John D

2017-02-01

Bacteria initiate translation using a modified amino acid, N-formylmethionine (fMet), adapted specifically for this function. Most proteins are processed co-translationally by peptide deformylase (PDF) to remove this modification. Although PDF activity is essential in WT cells and is the target of the antibiotic actinonin, bypass mutations in the fmt gene that eliminate the formylation of Met-tRNAMet render PDF dispensable. The extent to which the emergence of fmt bypass mutations might compromise the therapeutic utility of actinonin is determined, in part, by the effects of these bypass mutations on fitness. Here, we characterize the phenotypic consequences of an fmt null mutation in the model organism Bacillus subtilis. An fmt null mutant is defective for several post-exponential phase adaptive programmes including antibiotic resistance, biofilm formation, swarming and swimming motility and sporulation. In addition, a survey of well-characterized stress responses reveals an increased sensitivity to metal ion excess and oxidative stress. These diverse phenotypes presumably reflect altered synthesis or stability of key proteins involved in these processes.

Crystallization and preliminary crystallographic analysis of hygromycin B phosphotransferase from Escherichia coli

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iino, Daisuke; Takakura, Yasuaki; Kuroiwa, Mika

2007-08-01

The crystallization and preliminary X-ray studies of the aminoglycoside antibiotic-modifying enzyme hygromycin B phosphotransferase from E. coli are reported. Aminoglycoside antibiotics, such as hygromycin, kanamycin, neomycin, spectinomycin and streptomycin, inhibit protein synthesis by acting on bacterial and eukaryotic ribosomes. Hygromycin B phosphotransferase (Hph; EC 2.7.1.119) converts hygromycin B to 7′′-O-phosphohygromycin using a phosphate moiety from ATP, resulting in the loss of its cell-killing activity. The Hph protein has been crystallized for the first time using a thermostable mutant and the hanging-drop vapour-diffusion method. The crystal provided diffraction data to a resolution of 2.1 Å and belongs to space group P3{submore » 2}21, with unit-cell parameters a = b = 71.0, c = 125.0 Å. Crystals of complexes of Hph with hygromycin B and AMP-PNP or ADP have also been obtained in the same crystal form as that of the apoprotein.« less

Associations of prenatal and childhood antibiotic use with child body mass index at age 3 years.

PubMed

Poulsen, Melissa N; Pollak, Jonathan; Bailey-Davis, Lisa; Hirsch, Annemarie G; Glass, Thomas A; Schwartz, Brian S

2017-02-01

Early-life antibiotic exposure, whether through prenatal or childhood antibiotic use, may contribute to increased child body mass. Associations of prenatal and childhood antibiotic use with body mass index z-score (BMIz) were evaluated at age 3 years. Electronic health records were utilized from 8,793 mothers and singleton children delivered at Geisinger Clinic in Pennsylvania between 2006 and 2012. Antibiotic orders were ascertained for mothers during pregnancy and for children through their age-3 BMI measurement. Linear mixed-effects regression models evaluated associations of prenatal and childhood antibiotic use with child BMIz. Prenatal antibiotic orders were not associated with child BMIz. Children in the three largest categories of lifetime antibiotic orders had higher BMIz compared with children with no orders; associations persisted when controlling for prenatal antibiotics (β [95% confidence interval]) (4-5 child orders: 0.090 [0.011 to 0.170]; 6 to 8: 0.113 [0.029 to 0.197]; ≥9: 0.175 [0.088 to 0.263]; trend P value <0.001). Two or more first-year orders were also associated with BMIz (1: 0.021 [-0.038 to 0.081]; 2: 0.088 [0.017 to 0.160]; ≥3: 0.104 [0.038 to 0.170]; trend P value < 0.001). Associations of early-life and lifetime childhood antibiotic use with increased child BMI highlight antibiotic exposure as a modifiable factor for reducing population-level excess weight. © 2017 The Obesity Society.

Associations of Prenatal and Childhood Antibiotic Use with Child Body Mass Index at Age Three Years

PubMed Central

Poulsen, Melissa N.; Pollak, Jonathan; Bailey-Davis, Lisa; Hirsch, Annemarie G.; Glass, Thomas A.; Schwartz, Brian S.

2016-01-01

Objective Early-life antibiotic exposure, whether through prenatal or childhood antibiotic use, may contribute to increased child body mass. We evaluated associations of prenatal and childhood antibiotic use with body mass index z-score (BMIz) at age three years. Methods We utilized electronic health records from 8793 mothers and singleton children delivered at Geisinger Clinic in Pennsylvania, USA, between 2006–2012. Antibiotic orders were ascertained for mothers during pregnancy and for children through their age-three BMI measurement. Linear mixed-effects regression models evaluated associations of prenatal and childhood antibiotic use with child BMIz. Results Prenatal antibiotic orders were not associated with child BMIz. Children in the three largest categories of lifetime antibiotic orders had higher BMIz compared to children with no orders; associations persisted when controlling for prenatal antibiotics (beta [95% confidence interval]) (4–5 child orders: 0.090 [0.011, 0.170]; 6–8: 0.113 [0.029, 0.197]; ≥ 9: 0.175 [0.088, 0.263]; trend p-value < 0.001). Two or more first-year orders were also associated with BMIz (1: 0.021 [−0.038, 0.081]; 2: 0.088 [0.017, 0.160]; ≥ 3: 0.104 [0.038, 0.170]; trend p-value < 0.001). Conclusions Associations of early-life and lifetime childhood antibiotic use with increased child BMI highlights antibiotic exposure as a modifiable factor for reducing population-level excess weight. PMID:28124504

The human milk protein-lipid complex HAMLET sensitizes bacterial pathogens to traditional antimicrobial agents.

PubMed

Marks, Laura R; Clementi, Emily A; Hakansson, Anders P

2012-01-01

The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal.

The Human Milk Protein-Lipid Complex HAMLET Sensitizes Bacterial Pathogens to Traditional Antimicrobial Agents

PubMed Central

Marks, Laura R.; Clementi, Emily A.; Hakansson, Anders P.

2012-01-01

The fight against antibiotic resistance is one of the most significant challenges to public health of our time. The inevitable development of resistance following the introduction of novel antibiotics has led to an urgent need for the development of new antibacterial drugs with new mechanisms of action that are not susceptible to existing resistance mechanisms. One such compound is HAMLET, a natural complex from human milk that kills Streptococcus pneumoniae (the pneumococcus) using a mechanism different from common antibiotics and is immune to resistance-development. In this study we show that sublethal concentrations of HAMLET potentiate the effect of common antibiotics (penicillins, macrolides, and aminoglycosides) against pneumococci. Using MIC assays and short-time killing assays we dramatically reduced the concentrations of antibiotics needed to kill pneumococci, especially for antibiotic-resistant strains that in the presence of HAMLET fell into the clinically sensitive range. Using a biofilm model in vitro and nasopharyngeal colonization in vivo, a combination of HAMLET and antibiotics completely eradicated both biofilms and colonization in mice of both antibiotic-sensitive and resistant strains, something each agent alone was unable to do. HAMLET-potentiation of antibiotics was partially due to increased accessibility of antibiotics to the bacteria, but relied more on calcium import and kinase activation, the same activation pathway HAMLET uses when killing pneumococci by itself. Finally, the sensitizing effect was not confined to species sensitive to HAMLET. The HAMLET-resistant respiratory species Acinetobacter baumanii and Moraxella catarrhalis were all sensitized to various classes of antibiotics in the presence of HAMLET, activating the same mechanism as in pneumococci. Combined these results suggest the presence of a conserved HAMLET-activated pathway that circumvents antibiotic resistance in bacteria. The ability to activate this pathway may extend the lifetime of the current treatment arsenal. PMID:22905269

Antibiotic Use in Cold and Flu Season and Prescribing Quality: A Retrospective Cohort Study.

PubMed

Alsan, Marcella; Morden, Nancy E; Gottlieb, Joshua D; Zhou, Weiping; Skinner, Jonathan

2015-12-01

Excessive antibiotic use in cold and flu season is costly and contributes to antibiotic resistance. The study objective was to develop an index of excessive antibiotic use in cold and flu season and determine its correlation with other indicators of prescribing quality. We included Medicare beneficiaries in the 40% random sample denominator file continuously enrolled in fee-for-service benefits for 2010 or 2011 (7,961,201 person-years) and extracted data on prescription fills for oral antibiotics that treat respiratory pathogens. We collapsed the data to the state level so they could be merged with monthly flu activity data from the Centers for Disease Control and Prevention. Linear regression, adjusted for state-specific mean antibiotic use and demographic characteristics, was used to estimate how antibiotic prescribing responded to state-specific flu activity. Flu-activity associated antibiotic use varied substantially across states-lowest in Vermont and Connecticut, highest in Mississippi and Florida. There was a robust positive correlation between flu-activity associated prescribing and use of medications that often cause adverse events in the elderly (0.755; P<0.001), whereas there was a strong negative correlation with beta-blocker use after a myocardial infarction (-0.413; P=0.003). Adjusted flu-activity associated antibiotic use was positively correlated with prescribing high-risk medications to the elderly and negatively correlated with beta-blocker use after myocardial infarction. These findings suggest that excessive antibiotic use reflects low-quality prescribing. They imply that practice and policy solutions should go beyond narrow, antibiotic specific, approaches to encourage evidence-based prescribing for the elderly Medicare population.

An eco-friendly in situ activatable antibiotic via cucurbit[8]uril-mediated supramolecular crosslinking of branched polyethylenimine.

PubMed

Li, Shengke; Jiang, Nan; Zhao, Wenxuan; Ding, Yuan-Fu; Zheng, Ying; Wang, Lian-Hui; Zheng, Jun; Wang, Ruibing

2017-05-30

We report an unprecedented, eco-friendly, in situ activatable model antibiotic, phenylalanyl-polyethylenimine (PhePEI), to potentially diminish antibiotic pollution of the environment and associated antibiotic resistance. The inactive PhePEI can be reversibly activated upon supramolecular crosslinking by cucurbit[8]uril, conferring potent antibacterial activity.

Treatment of acute otitis media - challenges in the era of antibiotic resistance.

PubMed

Dagan, R

2000-12-08

The last decade is characterized by the increase in antibiotic resistance among respiratory bacterial pathogens in the presence of only modest progress in the development of new antibacterial agents to overcome this resistance. A series of recent studies show clearly that the increased resistance among the main AOM pathogens (namely Streptococcus pneumoniae and Haemophilus influenzae) is associated with a dramatic decrease in bacteriologic response to antibiotic treatment, which in turn has an impact on clinical response. Thus, the individual patient is affected by the increasing antibiotic resistance. Moreover, the society as a whole is now also affected because the carriage and spread of antibiotic resistant AOM pathogens is remarkably impacted by antibiotic treatment. New studies show the remarkable ability of antibiotics to rapidly promote nasopharyngeal carriage and spread of antibiotic-resistant AOM pathogens. In these studies, the increase in carriage of antibiotic resistant S. pneumoniae is shown already after 3-4 days from initiation of antibiotic treatment and may last for weeks to months after treatment. Children carrying antibiotic-resistant organisms transmit those organisms to their family and to their day care centers and thus a vicious cycle is created in which increased antibiotic resistance with decreased response leads to increased antibiotic use, which in turn leads to further increase in resistance. New antibiotics are not likely to improve this situation. It is clear that the challenge in the next decade is to prevent AOM rather than to treat it. Efforts to prevent AOM include improved environmental factors, immunization with bacterial and viral vaccines and some creative measures such as prevention of colonization and attachment to epithelium of AOM pathogens. Whether these efforts will prove successful or, even if successful, will only modify the clinical and bacteriologic picture presenting new challenges, only time will tell.

Mechanistic and structural basis of stereospecific Cbeta-hydroxylation in calcium-dependent antibiotic, a daptomycin-type lipopeptide.

PubMed

Strieker, Matthias; Kopp, Florian; Mahlert, Christoph; Essen, Lars-Oliver; Marahiel, Mohamed A

2007-03-20

Non-ribosomally synthesized lipopeptide antibiotics of the daptomycin type are known to contain unnatural beta-modified amino acids, which are essential for bioactivity. Here we present the biochemical and structural basis for the incorporation of 3-hydroxyasparagine at position 9 in the 11-residue acidic lipopeptide lactone calcium-dependent antibiotic (CDA). Direct hydroxylation of l-asparagine by AsnO, a non-heme Fe(2+)/alpha-ketoglutarate-dependent oxygenase encoded by the CDA biosynthesis gene cluster, was validated by Fmoc derivatization of the reaction product and LC/MS analysis. The 1.45, 1.92, and 1.66 A crystal structures of AsnO as apoprotein, Fe(2+) complex, and product complex, respectively, with (2S,3S)-3-hydroxyasparagine and succinate revealed the stereoselectivity and substrate specificity of AsnO. The comparison of native and product-complex structures of AsnO showed a lid-like region (residues F208-E223) that seals the active site upon substrate binding and shields it from sterically demanding peptide substrates. Accordingly, beta-hydroxylated asparagine is synthesized prior to its incorporation into the growing CDA peptide. The AsnO structure could serve as a template for engineering novel enzymes for the synthesis of beta-hydroxylated amino acids.

Use of artificial intelligence in the design of small peptide antibiotics effective against a broad spectrum of highly antibiotic-resistant superbugs.

PubMed

Cherkasov, Artem; Hilpert, Kai; Jenssen, Håvard; Fjell, Christopher D; Waldbrook, Matt; Mullaly, Sarah C; Volkmer, Rudolf; Hancock, Robert E W

2009-01-16

Increased multiple antibiotic resistance in the face of declining antibiotic discovery is one of society's most pressing health issues. Antimicrobial peptides represent a promising new class of antibiotics. Here we ask whether it is possible to make small broad spectrum peptides employing minimal assumptions, by capitalizing on accumulating chemical biology information. Using peptide array technology, two large random 9-amino-acid peptide libraries were iteratively created using the amino acid composition of the most active peptides. The resultant data was used together with Artificial Neural Networks, a powerful machine learning technique, to create quantitative in silico models of antibiotic activity. On the basis of random testing, these models proved remarkably effective in predicting the activity of 100,000 virtual peptides. The best peptides, representing the top quartile of predicted activities, were effective against a broad array of multidrug-resistant "Superbugs" with activities that were equal to or better than four highly used conventional antibiotics, more effective than the most advanced clinical candidate antimicrobial peptide, and protective against Staphylococcus aureus infections in animal models.

Avoidable Antibiotic Exposure for Uncomplicated Skin and Soft Tissue Infections in the Ambulatory Care Setting

PubMed Central

Hurley, Hermione J.; Knepper, Bryan C.; Price, Connie S.; Mehler, Philip S.; Burman, William J.; Jenkins, Timothy C.

2014-01-01

Background Uncomplicated skin and soft tissue infections are among the most frequent indications for outpatient antibiotics. A detailed understanding of current prescribing practices is necessary to optimize antibiotic use for these conditions. Methods This was a retrospective cohort study of children and adults treated in the ambulatory care setting for uncomplicated cellulitis, wound infection, or cutaneous abscess between March 1, 2010 and February 28, 2011. We assessed the frequency of avoidable antibiotic exposure, defined as: use of antibiotics with broad gram-negative activity, combination antibiotic therapy, or treatment for 10 or more days. Total antibiotic-days prescribed for the cohort were compared to antibiotic-days in four hypothetical short-course (5 – 7 days), single-antibiotic treatment models consistent with national guidelines. Results 364 cases were included for analysis (155 cellulitis, 41 wound infection, and 168 abscess). Antibiotics active against methicillin-resistant Staphylococcus aureus were prescribed in 61% of cases of cellulitis. Of 139 cases of abscess where drainage was performed, antibiotics were prescribed in 80% for a median of 10 (interquartile range 7 – 10) days. Of 292 total cases where complete prescribing data were available, avoidable antibiotic exposure occurred in 46%. This included use of antibiotics with broad gram-negative activity in 4%, combination therapy in 12%, and treatment for 10 or more days in 42%. Use of the short-course, single-antibiotic treatment strategies would have reduced prescribed antibiotic-days by 19 – 55%. Conclusions Nearly half of uncomplicated skin infections involved avoidable antibiotic exposure. Antibiotic use could be reduced through treatment approaches utilizing short courses of a single antibiotic. PMID:24262724

Transcriptome analysis of the responses of Staphylococcus aureus to antimicrobial peptides and characterization of the roles of vraDE and vraSR in antimicrobial resistance

PubMed Central

Pietiäinen, Milla; François, Patrice; Hyyryläinen, Hanne-Leena; Tangomo, Manuela; Sass, Vera; Sahl, Hans-Georg; Schrenzel, Jacques; Kontinen, Vesa P

2009-01-01

Background Understanding how pathogens respond to antimicrobial peptides, and how this compares to currently available antibiotics, is crucial for optimizing antimicrobial therapy. Staphylococcus aureus has several known resistance mechanisms against human cationic antimicrobial peptides (CAMPs). Gene expression changes in S. aureus strain Newman exposed to linear CAMPs were analyzed by DNA microarray. Three antimicrobial peptides were used in the analysis, two are derived from frog, temporin L and dermaseptin K4-S4(1-16), and the ovispirin-1 is obtained from sheep. Results The peptides induced the VraSR cell-wall regulon and several other genes that are also up-regulated in cells treated with vancomycin and other cell wall-active antibiotics. In addition to this similarity, three genes/operons were particularly strongly induced by the peptides: vraDE, SA0205 and SAS016, encoding an ABC transporter, a putative membrane-bound lysostaphin-like peptidase and a small functionally unknown protein, respectively. Ovispirin-1 and dermaseptin K4-S4(1-16), which disrupt lipid bilayers by the carpet mechanism, appeared to be strong inducers of the vraDE operon. We show that high level induction by ovispirin-1 is dependent on the amide modification of the peptide C-terminus. This suggests that the amide group has a crucial role in the activation of the Aps (GraRS) sensory system, the regulator of vraDE. In contrast, temporin L, which disrupts lipid bilayers by forming pores, revealed a weaker inducer of vraDE despite the C-terminal amide modification. Sensitivity testing with CAMPs and other antimicrobials suggested that VraDE is a transporter dedicated to resist bacitracin. We also showed that SA0205 belongs to the VraSR regulon. Furthermore, VraSR was shown to be important for resistance against a wide range of cell wall-active antibiotics and other antimicrobial agents including the amide-modified ovispirin-1, bacitracin, teicoplanin, cefotaxime and 10 other β-lactam antibiotics, chlorpromazine, thioridazine and EGTA. Conclusion Defense against different CAMPs involves not only general signaling pathways but also CAMP-specific ones. These results suggest that CAMPs or a mixture of CAMPs could constitute a potential additive to standard antibiotic treatment. PMID:19751498

Antibiotic-containing polymers for localized, sustained drug delivery

PubMed Central

Stebbins, Nicholas D.; Ouimet, Michelle A.; Uhrich, Kathryn E.

2014-01-01

Many currently used antibiotics suffer from issues such as systemic toxicity, short half-life, and increased susceptibility to bacterial resistance. Although most antibiotic classes are administered systemically through oral or intravenous routes, a more efficient delivery system is needed. This review discusses the chemical conjugation of antibiotics to polymers, achieved by forming covalent bonds between antibiotics and a pre-existing polymer or by developing novel antibiotic-containing polymers. Through conjugating antibiotics to polymers, unique polymer properties can be taken advantage of. These polymeric antibiotics display controlled, sustained drug release and vary in antibiotic class type, synthetic method, polymer composition, bond lability, and antibacterial activity. The polymer synthesis, characterization, drug release, and antibacterial activities, if applicable, will be presented to offer a detailed overview of each system. PMID:24751888

Antibiotic-resistant bacteria in the guts of insects feeding on plants: prospects for discovering plant-derived antibiotics.

PubMed

Ignasiak, Katarzyna; Maxwell, Anthony

2017-12-01

Although plants produce many secondary metabolites, currently none of these are commercial antibiotics. Insects feeding on specific plants can harbour bacterial strains resistant to known antibiotics suggesting that compounds in the plant have stimulated resistance development. We sought to determine whether the occurrence of antibiotic-resistant bacteria in insect guts was a widespread phenomenon, and whether this could be used as a part of a strategy to identify antibacterial compounds from plants. Six insect/plant pairs were selected and the insect gut bacteria were identified and assessed for antibiotic susceptibilities compared with type strains from culture collections. We found that the gut strains could be more or less susceptible to antibiotics than the type strains, or show no differences. Evidence of antibacterial activity was found in the plant extracts from five of the six plants, and, in one case Catharanthus roseus (Madagascar Periwinkle), compounds with antibacterial activity were identified. Bacterial strains isolated from insect guts show a range of susceptibilities to antibiotics suggesting a complex interplay between species in the insect gut microbiome. Extracts from selected plants can show antibacterial activity but it is not easy to isolate and identify the active components. We found that vindoline, present in Madagascar Periwinkle extracts, possessed moderate antibacterial activity. We suggest that plant-derived antibiotics are a realistic possibility given the advances in genomic and metabolomic methodologies.

Antibiotic distribution channels in Thailand: results of key-informant interviews, reviews of drug regulations and database searches

PubMed Central

Chanvatik, Sunicha; Sermsinsiri, Varavoot; Sivilaikul, Somsajee; Patcharanarumol, Walaiporn; Yeung, Shunmay; Tangcharoensathien, Viroj

2018-01-01

Abstract Objective To analyse how antibiotics are imported, manufactured, distributed and regulated in Thailand. Methods We gathered information, on antibiotic distribution in Thailand, in in-depth interviews – with 43 key informants from farms, health facilities, pharmaceutical and animal feed industries, private pharmacies and regulators– and in database and literature searches. Findings In 2016–2017, licensed antibiotic distribution in Thailand involves over 700 importers and about 24 000 distributors – e.g. retail pharmacies and wholesalers. Thailand imports antibiotics and active pharmaceutical ingredients. There is no system for monitoring the distribution of active ingredients, some of which are used directly on farms, without being processed. Most antibiotics can be bought from pharmacies, for home or farm use, without a prescription. Although the 1987 Drug Act classified most antibiotics as “dangerous drugs”, it only classified a few of them as prescription-only medicines and placed no restrictions on the quantities of antibiotics that could be sold to any individual. Pharmacists working in pharmacies are covered by some of the Act’s regulations, but the quality of their dispensing and prescribing appears to be largely reliant on their competences. Conclusion In Thailand, most antibiotics are easily and widely available from retail pharmacies, without a prescription. If the inappropriate use of active pharmaceutical ingredients and antibiotics is to be reduced, we need to reclassify and restrict access to certain antibiotics and to develop systems to audit the dispensing of antibiotics in the retail sector and track the movements of active ingredients. PMID:29403113

Toll-Like Receptor Stimulation Induces Nondefensin Protein Expression and Reverses Antibiotic-Induced Gut Defense Impairment

PubMed Central

Wu, Ying-Ying; Hsu, Ching-Mei; Chen, Pei-Hsuan; Fung, Chang-Phone

2014-01-01

Prior antibiotic exposure is associated with increased mortality in Gram-negative bacteria-induced sepsis. However, how antibiotic-mediated changes of commensal bacteria promote the spread of enteric pathogenic bacteria in patients remains unclear. In this study, the effects of systemic antibiotic treatment with or without Toll-like receptor (TLR) stimulation on bacterium-killing activity, antibacterial protein expression in the intestinal mucosa, and bacterial translocation were examined in mice receiving antibiotics with or without oral supplementation of dead Escherichia coli or Staphylococcus aureus. We developed a systemic ampicillin, vancomycin, and metronidazole treatment protocol to simulate the clinical use of antibiotics. Antibiotic treatment decreased the total number of bacteria, including aerobic bacteria belonging to the family Enterobacteriaceae and the genus Enterococcus as well as organisms of the anaerobic genera Lactococcus and Bifidobacterium in the intestinal mucosa and lumen. Antibiotic treatment significantly decreased the bacterium-killing activity of the intestinal mucosa and the expression of non-defensin-family proteins, such as RegIIIβ, RegIIIγ, C-reactive protein-ductin, and RELMβ, but not the defensin-family proteins, and increased Klebsiella pneumoniae translocation. TLR stimulation after antibiotic treatment increased NF-κB DNA binding activity, nondefensin protein expression, and bacterium-killing activity in the intestinal mucosa and decreased K. pneumoniae translocation. Moreover, germfree mice showed a significant decrease in nondefensin proteins as well as intestinal defense against pathogen translocation. Since TLR stimulation induced NF-κB DNA binding activity, TLR4 expression, and mucosal bacterium-killing activity in germfree mice, we conclude that the commensal microflora is critical in maintaining intestinal nondefensin protein expression and the intestinal barrier. In turn, we suggest that TLR stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment. PMID:24595141

Toll-like receptor stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment.

PubMed

Wu, Ying-Ying; Hsu, Ching-Mei; Chen, Pei-Hsuan; Fung, Chang-Phone; Chen, Lee-Wei

2014-05-01

Prior antibiotic exposure is associated with increased mortality in Gram-negative bacteria-induced sepsis. However, how antibiotic-mediated changes of commensal bacteria promote the spread of enteric pathogenic bacteria in patients remains unclear. In this study, the effects of systemic antibiotic treatment with or without Toll-like receptor (TLR) stimulation on bacterium-killing activity, antibacterial protein expression in the intestinal mucosa, and bacterial translocation were examined in mice receiving antibiotics with or without oral supplementation of dead Escherichia coli or Staphylococcus aureus. We developed a systemic ampicillin, vancomycin, and metronidazole treatment protocol to simulate the clinical use of antibiotics. Antibiotic treatment decreased the total number of bacteria, including aerobic bacteria belonging to the family Enterobacteriaceae and the genus Enterococcus as well as organisms of the anaerobic genera Lactococcus and Bifidobacterium in the intestinal mucosa and lumen. Antibiotic treatment significantly decreased the bacterium-killing activity of the intestinal mucosa and the expression of non-defensin-family proteins, such as RegIIIβ, RegIIIγ, C-reactive protein-ductin, and RELMβ, but not the defensin-family proteins, and increased Klebsiella pneumoniae translocation. TLR stimulation after antibiotic treatment increased NF-κB DNA binding activity, nondefensin protein expression, and bacterium-killing activity in the intestinal mucosa and decreased K. pneumoniae translocation. Moreover, germfree mice showed a significant decrease in nondefensin proteins as well as intestinal defense against pathogen translocation. Since TLR stimulation induced NF-κB DNA binding activity, TLR4 expression, and mucosal bacterium-killing activity in germfree mice, we conclude that the commensal microflora is critical in maintaining intestinal nondefensin protein expression and the intestinal barrier. In turn, we suggest that TLR stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment.

Nature's combinatorial biosynthesis and recently engineered production of nucleoside antibiotics in Streptomyces.

PubMed

Chen, Shawn; Kinney, William A; Van Lanen, Steven

2017-04-01

Modified nucleosides produced by Streptomyces and related actinomycetes are widely used in agriculture and medicine as antibacterial, antifungal, anticancer and antiviral agents. These specialized small-molecule metabolites are biosynthesized by complex enzymatic machineries encoded within gene clusters in the genome. The past decade has witnessed a burst of reports defining the key metabolic processes involved in the biosynthesis of several distinct families of nucleoside antibiotics. Furthermore, genome sequencing of various Streptomyces species has dramatically increased over recent years. Potential biosynthetic gene clusters for novel nucleoside antibiotics are now apparent by analysis of these genomes. Here we revisit strategies for production improvement of nucleoside antibiotics that have defined mechanisms of action, and are in clinical or agricultural use. We summarize the progress for genetically manipulating biosynthetic pathways for structural diversification of nucleoside antibiotics. Microorganism-based biosynthetic examples are provided and organized under genetic principles and metabolic engineering guidelines. We show perspectives on the future of combinatorial biosynthesis, and present a working model for discovery of novel nucleoside natural products in Streptomyces.

Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

PubMed Central

Leclercq, Sophie; Mian, Firoz M.; Stanisz, Andrew M.; Bindels, Laure B.; Cambier, Emmanuel; Ben-Amram, Hila; Koren, Omry; Forsythe, Paul; Bienenstock, John

2017-01-01

There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria. PMID:28375200

Effect of various antibiotics on modulation of intestinal microbiota and bile acid profile in mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Youcai; Limaye, Pallavi B.; Renaud, Helen J.

Antibiotic treatments have been used to modulate intestinal bacteria and investigate the role of intestinal bacteria on bile acid (BA) homeostasis. However, knowledge on which intestinal bacteria and bile acids are modified by antibiotics is limited. In the present study, mice were administered various antibiotics, 47 of the most abundant bacterial species in intestine, as well as individual BAs in plasma, liver, and intestine were quantified. Compared to the two antibiotic combinations (vancomycin + imipenem and cephalothin + neomycin), the three single antibiotics (metronidazole, ciprofloxacin and aztreonam) have less effect on intestinal bacterial profiles, and thus on host BA profilesmore » and mRNA expression of genes that are important for BA homeostasis. The two antibiotic combinations decreased the ratio of Firmicutes to Bacteroidetes in intestine, as well as most secondary BAs in serum, liver and intestine. Additionally, the two antibiotic combinations significantly increased mRNA of the hepatic BA uptake transporters (Ntcp and Oatp1b2) and canalicular BA efflux transporters (Bsep and Mrp2), but decreased mRNA of the hepatic BA synthetic enzyme Cyp8b1, suggesting an elevated enterohepatic circulation of BAs. Interestingly, the two antibiotic combinations tended to have opposite effect on the mRNAs of most intestinal genes, which tended to be inhibited by vancomycin + imipenem but stimulated by cephalothin + neomycin. To conclude, the present study clearly shows that various antibiotics have distinct effects on modulating intestinal bacteria and host BA metabolism. - Highlights: • Various antibiotics have different effects on intestinal bacteria. • Antibiotics alter bile acid composition in mouse liver and intestine. • Antibiotics influence genes involved in bile acid homeostasis. • Clostridia appear to be important for secondary bile acid formation.« less

Systematic Review of Factors Associated with Antibiotic Prescribing for Respiratory Tract Infections

PubMed Central

Mah, Allison; McGrail, Kimberlyn; Patrick, David M.

2016-01-01

Antibiotic use is a modifiable driver of antibiotic resistance. In many circumstances, antibiotic use is overly broad or unnecessary. We systematically assessed factors associated with antibiotic prescribing for respiratory tract infections (RTI). Studies were included if they used actual (not self-reported or intended) prescribing data, assessed factors associated with antibiotic prescribing for RTIs, and performed multivariable analysis of associations. We searched Medline, Embase, and International Pharmaceutical Abstracts using keyword and MeSH (medical subject headings) search terms. Two authors reviewed each abstract and independently appraised all included texts. Data on factors affecting antibiotic prescribing were extracted. Our searches retrieved a total of 2,848 abstracts, with 97 included in full-text review and 28 meeting full inclusion criteria. Compared to other factors, diagnosis of acute bronchitis was associated with increased antibiotic prescribing (range of adjusted odds ratios [aOR], 1.56 to 15.9). Features on physical exam, such as fever, purulent sputum, abnormal respiratory exam, and tonsillar exudate, were also associated with higher odds of antibiotic prescribing. Patient desire for an antibiotic was not associated or was modestly associated with prescription (range of aORs, 0.61 to 9.87), in contrast to physician perception of patient desire for antibiotics, which showed a stronger association (range of aORs, 2.11 to 23.3). Physician's perception of patient desire for antibiotics was strongly associated with antibiotic prescribing. Antimicrobial stewardship programs should continue to expand in the outpatient setting and should emphasize clear and direct communication between patients and physicians, as well as signs and symptoms that do and do not predict bacterial etiology of upper respiratory tract infections. PMID:27139474

Utilizing a Modified Care Coordination Measurement Tool to Capture Value for a Pediatric Outpatient Parenteral and Prolonged Oral Antibiotic Therapy Program.

PubMed

Vaz, Louise E; Farnstrom, Cindi L; Felder, Kimberly K; Guzman-Cottrill, Judith; Rosenberg, Hannah; Antonelli, Richard C

2017-04-17

Outpatient parenteral or prolonged oral antibiotic therapy (OPAT) programs reduce inpatient healthcare costs by shifting care to outpatient settings. Care coordination (CC) is a necessary component to successfully transition patients. Our objective was to assess outcomes of provider time spent on nonreimbursable CC activities in a pediatric OPAT program. We used a qualitative feasibility pilot design and modified the Care Coordination Measurement Tool. We captured nonreimbursable CC activity and associated outcome(s) among pediatric patients enrolled in OPAT from March 1 to April 30, 2015 (44 work days) at Doernbecher Children's Hospital. We generated summary statistics for this institutional review board-waived QI project. There were 154 nonreimbursable CC encounters conducted by 2 infectious diseases (ID) providers for 29 patients, ages 17 months-15 years, with complex infections. Total estimated time spent on CC was 54 hours, equivalent to at least 6 workdays. Five patients with complex social issues used 37% of total CC time. Of 129 phone events, 38% involved direct contact with families, pharmacies (13%), primary care providers (13%), and home health nursing (11%). Care coordination prevented 10 emergency room (ER) visits and 2 readmissions. Care coordination led to 16 additional, not previously scheduled subspecialist and 13 primary care visits. The OPAT providers billed for 32 clinic visits during the study period. Nonreimbursable CC work by OPAT providers prevented readmissions and ER visits and helped facilitate appropriate healthcare use. The value of pediatric OPAT involvement in patient care would have been underestimated based on reimbursable ID consultations and clinic visits alone. © The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Do piperacillin/tazobactam and other antibiotics with inhibitory activity against Clostridium difficile reduce the risk for acquisition of C. difficile colonization?

PubMed

Kundrapu, Sirisha; Sunkesula, Venkata C K; Jury, Lucy A; Cadnum, Jennifer L; Nerandzic, Michelle M; Musuuza, Jackson S; Sethi, Ajay K; Donskey, Curtis J

2016-04-18

Systemic antibiotics vary widely in in vitro activity against Clostridium difficile. Some agents with activity against C. difficile (e.g., piperacillin/tazobactam) inhibit establishment of colonization in mice. We tested the hypothesis that piperacillin/tazobactam and other agents with activity against C. difficile achieve sufficient concentrations in the intestinal tract to inhibit colonization in patients. Point-prevalence culture surveys were conducted to compare the frequency of asymptomatic rectal carriage of toxigenic C. difficile among patients receiving piperacillin/tazobactam or other inhibitory antibiotics (e.g. ampicillin, linezolid, carbapenems) versus antibiotics lacking activity against C. difficile (e.g., cephalosporins, ciprofloxacin). For a subset of patients, in vitro inhibition of C. difficile (defined as a reduction in concentration after inoculation of vegetative C. difficile into fresh stool suspensions) was compared among antibiotic treatment groups. Of 250 patients, 32 (13 %) were asymptomatic carriers of C. difficile. In comparison to patients receiving non-inhibitory antibiotics or prior antibiotics within 90 days, patients currently receiving piperacillin/tazobactam were less likely to be asymptomatic carriers (1/36, 3 versus 7/36, 19 and 15/69, 22 %, respectively; P = 0.024) and more likely to have fecal suspensions with in vitro inhibitory activity against C. difficile (20/28, 71 versus 3/11, 27 and 4/26, 15 %; P = 0.03). Patients receiving other inhibitory antibiotics were not less likely to be asymptomatic carriers than those receiving non-inhibitory antibiotics. Our findings suggest that piperacillin/tazobactam achieves sufficient concentrations in the intestinal tract to inhibit C. difficile colonization during therapy.

[Potentialization of antibiotics by lytic enzymes].

PubMed

Brisou, J; Babin, P; Babin, R

1975-01-01

Few lytic enzymes, specially papaine and lysozyme, acting on the membrane and cell wall structures facilitate effects of bacitracine, streptomycine and other antibiotics. Streptomycino resistant strains became sensibles to this antibiotic after contact with papaine and lysozyme. The results of tests in physiological suspensions concern only the lytic activity of enzymes. The results on nutrient medium concern together lytic, and antibiotic activities.

A Chemoinformatics Approach to the Discovery of Lead-Like Molecules from Marine and Microbial Sources En Route to Antitumor and Antibiotic Drugs

PubMed Central

Pereira, Florbela; Latino, Diogo A. R. S.; Gaudêncio, Susana P.

2014-01-01

The comprehensive information of small molecules and their biological activities in the PubChem database allows chemoinformatic researchers to access and make use of large-scale biological activity data to improve the precision of drug profiling. A Quantitative Structure–Activity Relationship approach, for classification, was used for the prediction of active/inactive compounds relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1804 compounds from PubChem. Using the best classification models for antibiotic and antitumor activities a data set of marine and microbial natural products from the AntiMarin database were screened—57 and 16 new lead compounds for antibiotic and antitumor drug design were proposed, respectively. All compounds proposed by our approach are classified as non-antibiotic and non-antitumor compounds in the AntiMarin database. Recently several of the lead-like compounds proposed by us were reported as being active in the literature. PMID:24473174

Monitoring of microbial cell viability using nanostructured electrodes modified with Graphene/Alumina nanocomposite.

PubMed

Hassan, Rabeay Y A; Mekawy, Moataz M; Ramnani, Pankaj; Mulchandani, Ashok

2017-05-15

Microbial infections are rapidly increasing; however most of the existing microbiological and molecular detection methods are time consuming and/or cannot differentiate between the viable and dead cells which may overestimate the risk of infections. Therefore, a bioelectrochemical sensing platform with a high potential to the microbial-electrode interactions was designed based on decorated graphene oxide (GO) sheet with alumina (Al 2 O 3 ) nanocrystals. GO-Al 2 O 3 nanocomposite was synthesized using self-assembly of GO and Al 2 O 3 and characterized using the scanning electron microscopy (SEM), transmission electron microscopy (TEM), x-ray diffraction (XRD), Raman-spectroscopy, electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). Enhancement of electrocatalytic activity of the composite-modified electrode was demonstrated. Thus, using the GO-Al 2 O 3 nanocomposite modified electrode, the cell viability was determined by monitoring the bioelectrochemical response of the living microbial cells (bacteria and yeast) upon stimulation with carbon source. The bioelectrochemical assay was optimized to obtain high sensitivity and the method was applied to monitor cell viability and screen susceptibility of metabolically active cells (E. coli, B. subtilis, Enterococcus, P. aeruginosa and Salmonella typhi) to antibiotics such as ampicillin and kanamycin. Therefore, the developed assay is suitable for cell proliferation and cytotoxicity testing. Copyright © 2017 Elsevier B.V. All rights reserved.

Membrane-active macromolecules kill antibiotic-tolerant bacteria and potentiate antibiotics towards Gram-negative bacteria

PubMed Central

Uppu, Divakara S. S. M.; Konai, Mohini M.; Sarkar, Paramita; Samaddar, Sandip; Fensterseifer, Isabel C. M.; Farias-Junior, Celio; Krishnamoorthy, Paramanandam; Shome, Bibek R.; Franco, Octávio L.

2017-01-01

Chronic bacterial biofilms place a massive burden on healthcare due to the presence of antibiotic-tolerant dormant bacteria. Some of the conventional antibiotics such as erythromycin, vancomycin, linezolid, rifampicin etc. are inherently ineffective against Gram-negative bacteria, particularly in their biofilms. Here, we report membrane-active macromolecules that kill slow dividing stationary-phase and antibiotic tolerant cells of Gram-negative bacteria. More importantly, these molecules potentiate antibiotics (erythromycin and rifampicin) to biofilms of Gram-negative bacteria. These molecules eliminate planktonic bacteria that are liberated after dispersion of biofilms (dispersed cells). The membrane-active mechanism of these molecules forms the key for potentiating the established antibiotics. Further, we demonstrate that the combination of macromolecules and antibiotics significantly reduces bacterial burden in mouse burn and surgical wound infection models caused by Acinetobacter baumannii and Carbapenemase producing Klebsiella pneumoniae (KPC) clinical isolate respectively. Colistin, a well-known antibiotic targeting the lipopolysaccharide (LPS) of Gram-negative bacteria fails to kill antibiotic tolerant cells and dispersed cells (from biofilms) and bacteria develop resistance to it. On the contrary, these macromolecules prevent or delay the development of bacterial resistance to known antibiotics. Our findings emphasize the potential of targeting the bacterial membrane in antibiotic potentiation for disruption of biofilms and suggest a promising strategy towards developing therapies for topical treatment of Gram-negative infections. PMID:28837596

Bezlotoxumab for Prevention of Recurrent Clostridium difficile Infection.

PubMed

Wilcox, Mark H; Gerding, Dale N; Poxton, Ian R; Kelly, Ciaran; Nathan, Richard; Birch, Thomas; Cornely, Oliver A; Rahav, Galia; Bouza, Emilio; Lee, Christine; Jenkin, Grant; Jensen, Werner; Kim, You-Sun; Yoshida, Junichi; Gabryelski, Lori; Pedley, Alison; Eves, Karen; Tipping, Robert; Guris, Dalya; Kartsonis, Nicholas; Dorr, Mary-Beth

2017-01-26

Clostridium difficile is the most common cause of infectious diarrhea in hospitalized patients. Recurrences are common after antibiotic therapy. Actoxumab and bezlotoxumab are human monoclonal antibodies against C. difficile toxins A and B, respectively. We conducted two double-blind, randomized, placebo-controlled, phase 3 trials, MODIFY I and MODIFY II, involving 2655 adults receiving oral standard-of-care antibiotics for primary or recurrent C. difficile infection. Participants received an infusion of bezlotoxumab (10 mg per kilogram of body weight), actoxumab plus bezlotoxumab (10 mg per kilogram each), or placebo; actoxumab alone (10 mg per kilogram) was given in MODIFY I but discontinued after a planned interim analysis. The primary end point was recurrent infection (new episode after initial clinical cure) within 12 weeks after infusion in the modified intention-to-treat population. In both trials, the rate of recurrent C. difficile infection was significantly lower with bezlotoxumab alone than with placebo (MODIFY I: 17% [67 of 386] vs. 28% [109 of 395]; adjusted difference, -10.1 percentage points; 95% confidence interval [CI], -15.9 to -4.3; P<0.001; MODIFY II: 16% [62 of 395] vs. 26% [97 of 378]; adjusted difference, -9.9 percentage points; 95% CI, -15.5 to -4.3; P<0.001) and was significantly lower with actoxumab plus bezlotoxumab than with placebo (MODIFY I: 16% [61 of 383] vs. 28% [109 of 395]; adjusted difference, -11.6 percentage points; 95% CI, -17.4 to -5.9; P<0.001; MODIFY II: 15% [58 of 390] vs. 26% [97 of 378]; adjusted difference, -10.7 percentage points; 95% CI, -16.4 to -5.1; P<0.001). In prespecified subgroup analyses (combined data set), rates of recurrent infection were lower in both groups that received bezlotoxumab than in the placebo group in subpopulations at high risk for recurrent infection or for an adverse outcome. The rates of initial clinical cure were 80% with bezlotoxumab alone, 73% with actoxumab plus bezlotoxumab, and 80% with placebo; the rates of sustained cure (initial clinical cure without recurrent infection in 12 weeks) were 64%, 58%, and 54%, respectively. The rates of adverse events were similar among these groups; the most common events were diarrhea and nausea. Among participants receiving antibiotic treatment for primary or recurrent C. difficile infection, bezlotoxumab was associated with a substantially lower rate of recurrent infection than placebo and had a safety profile similar to that of placebo. The addition of actoxumab did not improve efficacy. (Funded by Merck; MODIFY I and MODIFY II ClinicalTrials.gov numbers, NCT01241552 and NCT01513239 .).

Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C.

PubMed

Lamontagne Boulet, Maxime; Isabelle, Charles; Guay, Isabelle; Brouillette, Eric; Langlois, Jean-Philippe; Jacques, Pierre-Étienne; Rodrigue, Sébastien; Brzezinski, Ryszard; Beauregard, Pascale B; Bouarab, Kamal; Boyapelly, Kumaraswamy; Boudreault, Pierre-Luc; Marsault, Éric; Malouin, François

2018-06-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti- Staphylococcus antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against S. aureus small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of in vitro -generated TO-resistant S. aureus strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the atpE gene in S. aureus SCVs or introducing the mutation found in the atpE gene of one of the high-level TO-resistant S. aureus mutants into the Bacillus subtilis atpE gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >10 5 -fold for FC04-100. Copyright © 2018 American Society for Microbiology.

Antibiotic efficacy is linked to bacterial cellular respiration

PubMed Central

Lobritz, Michael A.; Belenky, Peter; Porter, Caroline B. M.; Gutierrez, Arnaud; Yang, Jason H.; Schwarz, Eric G.; Dwyer, Daniel J.; Khalil, Ahmad S.; Collins, James J.

2015-01-01

Bacteriostatic and bactericidal antibiotic treatments result in two fundamentally different phenotypic outcomes—the inhibition of bacterial growth or, alternatively, cell death. Most antibiotics inhibit processes that are major consumers of cellular energy output, suggesting that antibiotic treatment may have important downstream consequences on bacterial metabolism. We hypothesized that the specific metabolic effects of bacteriostatic and bactericidal antibiotics contribute to their overall efficacy. We leveraged the opposing phenotypes of bacteriostatic and bactericidal drugs in combination to investigate their activity. Growth inhibition from bacteriostatic antibiotics was associated with suppressed cellular respiration whereas cell death from most bactericidal antibiotics was associated with accelerated respiration. In combination, suppression of cellular respiration by the bacteriostatic antibiotic was the dominant effect, blocking bactericidal killing. Global metabolic profiling of bacteriostatic antibiotic treatment revealed that accumulation of metabolites involved in specific drug target activity was linked to the buildup of energy metabolites that feed the electron transport chain. Inhibition of cellular respiration by knockout of the cytochrome oxidases was sufficient to attenuate bactericidal lethality whereas acceleration of basal respiration by genetically uncoupling ATP synthesis from electron transport resulted in potentiation of the killing effect of bactericidal antibiotics. This work identifies a link between antibiotic-induced cellular respiration and bactericidal lethality and demonstrates that bactericidal activity can be arrested by attenuated respiration and potentiated by accelerated respiration. Our data collectively show that antibiotics perturb the metabolic state of bacteria and that the metabolic state of bacteria impacts antibiotic efficacy. PMID:26100898

[The structure and antimicrobial activity of the partial degradation products of the antibiotic eremomycin].

PubMed

Berdnikova, T F; Lomakina, N N; Olsuf'eva, E N; Aleksandrova, L G; Potapova, N P; Rozynov, B V; Malkova, I V; Orlova, G I

1991-06-01

Antimicrobial activity of partial degradation products of eremomycin, a new glycopeptide antibiotic, was studied. The products formed by eremomycin deglycosylation (deseremosaminyl eremomycin, eremosaminyl aglycone and aglycone) and elimination of the chlorine atom from the molecule aglycone moiety (dechloroeremomycin). The spectral data in favour of the compounds structure are presented. It was found that partial degradation led to a decrease in the antimicrobial activity of the antibiotic. Dechloreremomycin had the highest activity among the products. Its MIC for the methicillin-resistant strains of Staphylococcus aureus was only twice as low as that of the initial antibiotic.

Multirate state and parameter estimation in an antibiotic fermentation with delayed measurements.

PubMed

Gudi, R D; Shah, S L; Gray, M R

1994-12-01

This article discusses issues related to estimation and monitoring of fermentation processes that exhibit endogenous metabolism and time-varying maintenance activity. Such culture-related activities hamper the use of traditional, software sensor-based algorithms, such as the extended kalman filter (EKF). In the approach presented here, the individual effects of the endogenous decay and the true maintenance processes have been lumped to represent a modified maintenance coefficient, m(c). Model equations that relate measurable process outputs, such as the carbon dioxide evolution rate (CER) and biomass, to the observable process parameters (such as net specific growth rate and the modified maintenance coefficient) are proposed. These model equations are used in an estimator that can formally accommodate delayed, infrequent measurements of the culture states (such as the biomass) as well as frequent, culture-related secondary measurements (such as the CER). The resulting multirate software sensor-based estimation strategy is used to monitor biomass profiles as well as profiles of critical fermentation parameters, such as the specific growth for a fed-batch fermentation of Streptomyces clavuligerus.

Zero-magnetic field effect in pathogen bacteria

NASA Astrophysics Data System (ADS)

Creanga, D. E.; Poiata, A.; Morariu, V. V.; Tupu, P.

2004-05-01

Two lots of Gram-negative bacterial strains were tested for antibiotic drug resistance after exposure to zero-magnetic field. We found that the magneto-sensitive strains represent half of the analyzed samples (three Pseudomonas and five Enterobacter strains), some of them presenting two-three times modified resistance to antibiotic, while others revealed eight or 16 times changed resistance. Pseudomonas strain magnetic sensitivity is revealed better by ampicillin and tetracycline, while Enterobacter strain magnetic sensitivity is revealed better by ampicillin, kanamycin and ofloxacin.

Total Synthesis of the Post-translationally Modified Polyazole Peptide Antibiotic Goadsporin.

PubMed

Dexter, Hannah L; Williams, Huw E L; Lewis, William; Moody, Christopher J

2017-03-06

The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)-catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Radical SAM Enzymes in the Biosynthesis of Ribosomally Synthesized and Post-translationally Modified Peptides (RiPPs)

PubMed Central

Benjdia, Alhosna; Balty, Clémence; Berteau, Olivier

2017-01-01

Ribosomally-synthesized and post-translationally modified peptides (RiPPs) are a large and diverse family of natural products. They possess interesting biological properties such as antibiotic or anticancer activities, making them attractive for therapeutic applications. In contrast to polyketides and non-ribosomal peptides, RiPPs derive from ribosomal peptides and are post-translationally modified by diverse enzyme families. Among them, the emerging superfamily of radical SAM enzymes has been shown to play a major role. These enzymes catalyze the formation of a wide range of post-translational modifications some of them having no counterparts in living systems or synthetic chemistry. The investigation of radical SAM enzymes has not only illuminated unprecedented strategies used by living systems to tailor peptides into complex natural products but has also allowed to uncover novel RiPP families. In this review, we summarize the current knowledge on radical SAM enzymes catalyzing RiPP post-translational modifications and discuss their mechanisms and growing importance notably in the context of the human microbiota. PMID:29167789

[Assessment of antibiotic use and impact of an intervention intended to modify the prescribing behavior in surgical prophylaxis in 6hospitals in the metropolitan area of Monterrey, Mexico].

PubMed

Palacios-Saucedo, Gerardo Del Carmen; de la Garza-Camargo, Mauricio; Briones-Lara, Evangelina; Carmona-González, Sandra; García-Cabello, Ricardo; Islas-Esparza, Luis Arturo; Saldaña-Flores, Gustavo; González-Cano, Juan Roberto; González-Ruvalcaba, Román; Valadez-Botello, Francisco Javier; Muñoz-Maldonado, Gerardo Enrique; Montero-Cantú, Carlos Alberto; Díaz-Ramos, Rita Delia; Solórzano-Santos, Fortino

Improper use of antibiotics increases antimicrobial resistance. Evaluate the use of antibiotics and the impact of an intervention designed to improve antibiotic prescription for surgical prophylaxis in 6 hospitals of Monterrey, Mexico. Design: A prospective multicenter survey and a pretest-postest experimental study. Phase 1: Survey to evaluate the use of antibiotics through an especially designed guide. Phase 2: Intervention designed to improve antibiotic prescription for surgical prophylaxis by the medical staff by using printed, audiovisual and electronic messages. Phase 3: Survey to evaluate the impact of the intervention. Frequencies, percentages, medians, ranges and X 2 test. Phase 1: We evaluated 358 surgical patients, 274 prophylactic antibiotic regimens. A total of 96% of antibiotics regimens began with inappropriate timing (290/302), 82.8% were inappropriate regimens (274/331), 77.7% were in inappropriate dosage (230/296), 86% of inadequate length (241/280), and in 17.4% restricted antibiotics were used (52/299). Phase 2: 9 sessions including 189 physicians (14 department chairs, 58 general practitioners and 117 residents). Phase 3: We evaluated 303 surgical patients, 218 prophylactic antibiotics regimens. Inappropriate treatment commencement was reduced to 84.1% (180/214) (P<0.001), inappropriate regimens to 75.3% (162/215) (P=0.03), inappropriate dosages to 51.2% (110/215) (P<0.001), and use of restricted antibiotics to 8.3% (18/215) (P=0.003). Inappropriate use of prophylactic antibiotics in surgery is a frequent problem in Monterrey. The intervention improved the antibiotic prescription for surgical prophylaxis by reducing inappropriate treatment commencement, regimens, dosages, and overuse of restricted antibiotics. It is necessary to strengthen strategies to improve the prescription of antibiotics in surgical prophylaxis. Copyright © 2016 Academia Mexicana de Cirugía A.C. Publicado por Masson Doyma México S.A. All rights reserved.

Antibiotic Fermentation Broth Treatment by a pilot upflow anaerobic sludge bed reactor and kinetic modeling.

PubMed

Coskun, T; Kabuk, H A; Varinca, K B; Debik, E; Durak, I; Kavurt, C

2012-10-01

In this study, an upflow anaerobic sludge blanket (UASB) mesophilic reactor was used to remove antibiotic fermentation broth wastewater. The hydraulic retention time was held constant at 13.3 days. The volumetric organic loading value increased from 0.33 to 7.43 kg(COD)m(-3)d(-1) using antibiotic fermentation broth wastewater gradually diluted with various ratios of domestic wastewater. A COD removal efficiency of 95.7% was obtained with a maximum yield of 3,700 L d(-1) methane gas production. The results of the study were interpreted using the modified Stover-Kincannon, first-order, substrate mass balance and Van der Meer and Heertjes kinetic models. The obtained kinetic coefficients showed that antibiotic fermentation broth wastewater can be successfully treated using a UASB reactor while taking COD removal and methane production into account. Copyright © 2012 Elsevier Ltd. All rights reserved.

Antimicrobial Activity of Endodontic Medicaments and Vehicles using Agar Well Diffusion Method on Facultative and Obligate Anaerobes

PubMed Central

Bhat, Kishore G; Sogi, Suma

2016-01-01

Aims The aim of this study was to determine the relative antimicrobial effectiveness of these endodontic medicaments and various vehicles using an agar well diffusion assay. Materials and methods Double Antibiotic Paste(DAP), modified DAP, 2% Chlorhexidine gluconate and their combination with four vehicles namely Polyethylene glycol 400 (PEG), Propylene glycol (PG), combinations of PG with PEG and lastly Glycerine were tested using agar well diffusion assay. The minimum bactericidal concentration was noted against four standard strains of organisms ie Streptococcus mutans ATCC( American Type Culture Collection) 25175, Staphylococcus aureus ATCC 12598, Enterococcus faecalis ATCC 35550 and Eschericia coli ATCC 25922. Successful endodontic therapy depends upon thorough disinfection of root canals. In some refractory cases, routine endodontic therapy is not sufficient, so intracanal medicaments are used for proper disinfection of canals. Issues of resistance, limited spectrum of activity and lack of antifungal properties, the hunt for the ideal intracanal medicament continues. In this regard, the vehicles used to form the pastes play a supportive role by forming the appropriate consistency for placement and may dramatically influence their chemical characteristics like their solubility and diffusion. Thus, inorder to use safer and equally effective intracanal medicaments, Chlorhexidine gluconate is being unveiled in this study. Results The difference between the four vehicles when combined with the same endodontic medicament studied above is nonsignificant (NS) except against Porphyromonas gingivalis. Propylene glycol is significantly effective than Glycerine when used with DAP ie C+M medicament combination. (p = 0.029) Conclusion 2% chlorhexidine gluconate and modified DAP can definitely replace DAP and triple antibiotic paste as end-odontic medicaments with chlorhexidine having an added advantage of bactericidal action, substantivity, biocompatibility, low toxicity, and lesser chances of developing resistance. How to cite this article Nalawade TM, Bhat KG, Sogi S. Antimicrobial Activity of Endodontic Medicaments and Vehicles using Agar Well Diffusion Method on Facultative and Obligate Anaerobes. Int J Clin Pediatr Dent 2016;9(4):335-341. PMID:28127166

New polyenic antibiotics active against gram-positive and gram-negative bacteria. VIII. Construction of synthetic medium for production of mono-chloro-congeners of enacyloxins.

PubMed

Watanabe, T; Sugiyama, T; Chino, K; Suzuki, T; Wakabayashi, S; Hayashi, H; Itami, R; Shima, J; Izaki, K

1992-04-01

New antibiotics enacyloxins (ENXs) are a family of non-lactonic polyene antibiotics produced by Frateuria sp. W-315. For the production of antibiotics, we had to employ two-step fermentations, the first is the production of spent medium of Neurospora crassa and the second is the production of antibiotics by Frateuria. To simplify the production of antibiotics, systematic analyses have been done on the spent medium, and factors which affect the production of antibiotics characterized. From the above results, we constructed a new medium for antibiotic production. Moreover, we could get a new antibiotic named enacyloxin IIIa (1), C33H48O11NCl (m/z 669). 1 was deduced to be one of the congeners of enacyloxins because it was similar to ENX IIa or ENX IVa both in biological and physico-chemical properties. Chlorine of 1 could be replaced by bromine, biosynthetically, and the resultant bromine-containing antibiotic also showed an antibacterial activity comparable to 1.

Structural Features Governing the Activity of Lactoferricin-Derived Peptides That Act in Synergy with Antibiotics against Pseudomonas aeruginosa In Vitro and In Vivo▿ †

PubMed Central

Sánchez-Gómez, Susana; Japelj, Bostjan; Jerala, Roman; Moriyón, Ignacio; Fernández Alonso, Mirian; Leiva, José; Blondelle, Sylvie E.; Andrä, Jörg; Brandenburg, Klaus; Lohner, Karl; Martínez de Tejada, Guillermo

2011-01-01

Pseudomonas aeruginosa is naturally resistant to many antibiotics, and infections caused by this organism are a serious threat, especially to hospitalized patients. The intrinsic low permeability of P. aeruginosa to antibiotics results from the coordinated action of several mechanisms, such as the presence of restrictive porins and the expression of multidrug efflux pump systems. Our goal was to develop antimicrobial peptides with an improved bacterial membrane-permeabilizing ability, so that they enhance the antibacterial activity of antibiotics. We carried out a structure activity relationship analysis to investigate the parameters that govern the permeabilizing activity of short (8- to 12-amino-acid) lactoferricin-derived peptides. We used a new class of constitutional and sequence-dependent descriptors called PEDES (peptide descriptors from sequence) that allowed us to predict (Spearman's ρ = 0.74; P < 0.001) the permeabilizing activity of a new peptide generation. To study if peptide-mediated permeabilization could neutralize antibiotic resistance mechanisms, the most potent peptides were combined with antibiotics, and the antimicrobial activities of the combinations were determined on P. aeruginosa strains whose mechanisms of resistance to those antibiotics had been previously characterized. A subinhibitory concentration of compound P2-15 or P2-27 sensitized P. aeruginosa to most classes of antibiotics tested and counteracted several mechanisms of antibiotic resistance, including loss of the OprD porin and overexpression of several multidrug efflux pump systems. Using a mouse model of lethal infection, we demonstrated that whereas P2-15 and erythromycin were unable to protect mice when administered separately, concomitant administration of the compounds afforded long-lasting protection to one-third of the animals. PMID:20956602

Structural features governing the activity of lactoferricin-derived peptides that act in synergy with antibiotics against Pseudomonas aeruginosa in vitro and in vivo.

PubMed

Sánchez-Gómez, Susana; Japelj, Bostjan; Jerala, Roman; Moriyón, Ignacio; Fernández Alonso, Mirian; Leiva, José; Blondelle, Sylvie E; Andrä, Jörg; Brandenburg, Klaus; Lohner, Karl; Martínez de Tejada, Guillermo

2011-01-01

Pseudomonas aeruginosa is naturally resistant to many antibiotics, and infections caused by this organism are a serious threat, especially to hospitalized patients. The intrinsic low permeability of P. aeruginosa to antibiotics results from the coordinated action of several mechanisms, such as the presence of restrictive porins and the expression of multidrug efflux pump systems. Our goal was to develop antimicrobial peptides with an improved bacterial membrane-permeabilizing ability, so that they enhance the antibacterial activity of antibiotics. We carried out a structure activity relationship analysis to investigate the parameters that govern the permeabilizing activity of short (8- to 12-amino-acid) lactoferricin-derived peptides. We used a new class of constitutional and sequence-dependent descriptors called PEDES (peptide descriptors from sequence) that allowed us to predict (Spearman's ρ = 0.74; P < 0.001) the permeabilizing activity of a new peptide generation. To study if peptide-mediated permeabilization could neutralize antibiotic resistance mechanisms, the most potent peptides were combined with antibiotics, and the antimicrobial activities of the combinations were determined on P. aeruginosa strains whose mechanisms of resistance to those antibiotics had been previously characterized. A subinhibitory concentration of compound P2-15 or P2-27 sensitized P. aeruginosa to most classes of antibiotics tested and counteracted several mechanisms of antibiotic resistance, including loss of the OprD porin and overexpression of several multidrug efflux pump systems. Using a mouse model of lethal infection, we demonstrated that whereas P2-15 and erythromycin were unable to protect mice when administered separately, concomitant administration of the compounds afforded long-lasting protection to one-third of the animals.

Fluorescent aptasensor for antibiotic detection using magnetic bead composites coated with gold nanoparticles and a nicking enzyme.

PubMed

Luo, Zewei; Wang, Yimin; Lu, Xiaoyong; Chen, Junman; Wei, Fujing; Huang, Zhijun; Zhou, Chen; Duan, Yixiang

2017-09-01

Antibiotic abuse has been bringing serious pollution in water, which is closely related to human health. It is desirable to develop a new strategy for antibiotic detection. To address this problem, a sensitive fluorescent aptasensor for antibiotic detection was developed by utilizing gold nanoparticles modified magnetic bead composites (AuNPs/MBs) and nicking enzyme. AuNPs/MBs were synthesized with the help of polyethylenimine (PEI). The prepared AuNPs/MBs acted as dual-functional scaffolds that owned excellent magnetic separation capacity and strong covalent bio-conjugation. The non-specifically absorbed aptamers in AuNPs/MBs were less than that in MBs. Hence, the fluorescent aptasensor based on AuNPs/MBs show a better signal to background ratio than that based on carboxyl modified magnetic beads (MBs). In this work, ampicillin was employed as a model analyte. In the presence of ampicillin, the specific binding between ampicillin and aptamer induced structure-switching that led to the release of partial complementary DNA (cDNA) of aptamer. Then, the released cDNA initiated the cycle of nicking enzyme assisted signal amplification (NEASA). Therefore, a large amount of taqman probes were cleaved and fluorescence signal was amplified. The prepared fluorescent aptasensor bring sensitive detection in range of 0.1-100 ng mL -1 with the limit of detection of 0.07 ng mL -1 . Furthermore, this aptasensor was also successfully applied in real sample detection with acceptable accuracy. The fluorescent aptasensor provides a promising method for efficient, rapid and sensitive antibiotic detection. Copyright © 2017 Elsevier B.V. All rights reserved.

Adjunctive Systemic Antimicrobial Therapy vs Asepsis in Conjunction with Guided Tissue Regeneration: A Randomized, Controlled Clinical Trial.

PubMed

Abu-Ta'a, Mahmoud

2016-01-01

This randomized clinical trial compares the usefulness of adjunctive antibiotics, while strict asepsis was followed during periodontal surgery involving guided tissue regeneration. Two groups of 20 consecutive patients each with advanced periodontal disease were randomly assigned to treatment. They displayed one angular defect each with an intrabony component ≥3 mm, probing pocket depth and probing attachment level (PAL) ≥7 mm. Test group included 13 males, mean age 60 years, treated with enamel matrix derivative (EMD) and demineralized freeze-dried bone allograft with modified papilla preservation technique, received oral amoxicillin 1 gm, 1 hour preoperatively and 2 gm for 2 days postoperatively. Control group included 10 males, mean age 57 years, treated with EMD and demineralized freeze-dried bone allograft with modified papilla preservation technique, received no antibiotics. Outcome measures were clinical attachment level (CAL) gain, residual periodontal pocket depth (res. PD), gingival recession (GR), bleeding on probing (BOP), adverse events and postoperative complications. Patients were followed up to 12 months after periodontal surgery involving guided tissue regeneration. There were no significant differences between both groups for CAL gain, res. PD, GR, BOP nor other clinical parameters, though patients' subjective perception of postoperative discomfort was significantly smaller in the group receiving antibiotics. Antibiotics do not provide significant advantages concerning clinical periodontal parameters nor concerning postoperative infections in case of proper asepsis. It does, on the contrary, reduce postoperative discomfort. Regarding the results of this study, adjunc-tive systemic antibiotics in combination with guided tissue regeneration may be useful in reducing postoperative discomfort but may not be helpful for improving periodontal regeneration outcomes.

Liposomes as potential carrier system for targeted delivery of polyene antibiotics.

PubMed

Naik, Suresh R; Desai, Sandhya K; Shah, Priyank D; Wala, Santosh M

2013-09-01

The development of new therapeutic modalities involves the use of drug carrier, such as liposomes, which can modify pharmacokinetic and bio-distribution of drug profile. Polyene antibiotics incorporation into liposomes improves its availability at the site, bio-distribution and therapeutic index mainly through the engulfment of liposomes by circulating monocytes/macrophages and transportation to the site of infection. Polyene antibiotics (AmB, SJA-95, HA-1-92) and other antibiotics (streptomycin, tobramycin, quinolones, anti-tubercular and anti-cancer drugs), liposomal preparations are described with possible advantages from therapeutic efficacy and toxicity point of view. The polyene macrolide antibiotics liposomal preparations proved to be more effective in the treatment of systemic mycosis. The AmB-cyclodextrin derivatives inclusion complex is a major breakthrough in liposomal preparation which can be converted into aqueous phase of liposome. Liposomal drug incorporated preparation has been one of the important areas of research for developing the existing polyene antibiotics into useful chemotherapeutic agents in clinical medicine. In recent past other antibiotics have also been incorporated into liposomes using wide variety of materials, phosphatidylethanolamine derivatives (pegylated liposomes, enzyme sensitive conjugates, fluidosomes of anti-cancer drugs and poly lactic/glycolic acid microspheres for anti-tuberculosis drugs). In addition, attempts were also made to extend the receptor mediated drug targeting and to review some relevant patents.

Non-adherence to antibiotic therapy in patients visiting community pharmacies.

PubMed

Fernandes, Milene; Leite, Andreia; Basto, Maria; Nobre, Miguel Araújo; Vieira, Nuno; Fernandes, Rui; Nogueira, Paulo; Nicola, Paulo Jorge; Jorge, Paulo

2014-02-01

Patient non-adherence to antibiotic therapy may lead to therapeutic failure, re-infection, and bacterial resistance. Assessing the factors associated with this problem is important for promoting rational use of antibiotics. This study aimed to measure prevalence and reasons for non-adherence to antibiotic treatment and to identify associated factors. Patients were recruited for the study in community pharmacies in Lisbon, Portugal, from February to April, 2009. Data from prescriptions for oral antibiotics were collected for adult subjects. Adherence to treatment was assessed with a modified Portuguese version of the Morisky scale. Factors associated with non-adherence were identified through bivariate analysis and logistic regression models. A total of 243 patients were included in the study. They had a mean age 46.5 ± 16.6 years and 74.5 % of the sample was female. The prevalence of non-adherence was 57.7 % and was related to delays and failures in taking the prescribed medicine. Increasing age (OR 0.97), difficulty in buying the antibiotic (OR 2.34), duration of treatment (OR 1.28), difficulty with ingestion (OR 3.08), and satisfaction with the information given by physician (OR 0.33) were identified as independent factors associated with non-adherence. Non-adherence to antibiotics is common in the community setting. Factors related to the antibiotic, the patient, and the patient-physician relationship should be addressed to promote adherence. Pharmacists should provide information to patients about correct use of antibiotics and address barriers to adherence.

Modified Misgav Ladach method for cesarean section: clinical experience.

PubMed

Kulas, Tomislav; Habek, Dubravko; Karsa, Matija; Bobić-Vuković, Mirna

2008-01-01

To determine the advantages of modified a Misgav Ladach method over conventional (Pfannenstiel-Dorffler) cesarean section. From October 2002 to March 2005, 217 cesarean sections performed according to a modified Misgav Ladach method (without routine preoperative urinary catheterization, blunt separation of the fascia after a small incision, and unprepared plica vesicouterina) were prospectively compared with 153 randomly selected conventional cesarean sections. Maternal age, parity, gestational age, neonatal birth weight, procedure duration, operative complications and postoperative course were analyzed. The incidence of postoperative fever was 2.30 and 4.57% (p = 0.001), wound seroma 0.46 and 1.96% (p = 0.01), local wound infection 0.92 and 1.96% (p = 0.01), wound dehiscence 0 and 0.65% (NS), anemia 3.68 and 7.84% (p = 0.001), and need of blood transfusion 1.38 and 1.96% (NS) in the modified Misgav Ladach and conventional group, respectively. The mean duration of the operation was 26.24 min with the Misgav Ladach versus 39.41 min with the conventional operation (p < 0.001). The postoperative use of antibiotics and analgesics/antipyretics was significantly lower in the modified Misgav Ladach group (p = 0.001). Study results demonstrated that the modified Misgav Ladach method of cesarean section is associated with faster postoperative recovery, lower morbidity and blood loss, shorter length of operative procedure, lower incidence of operative complications, lesser postoperative use of antibiotics and analgesics/antipyretics, and lower utilization of surgical material. The modified Misgav Ladach method of cesarean section is suitable for emergency and elective procedures, justifying its use in daily routine. (c) 2008 S. Karger AG, Basel

Occurrence of Diverse Antimicrobial Resistance Determinants in Genetically Unrelated Biocide Tolerant Klebsiella pneumoniae

PubMed Central

Mondal, Amitabha; Venkataramaiah, Manjunath; Rajamohan, Govindan; Srinivasan, Vijaya Bharathi

2016-01-01

Nosocomial infections due to Klebsiella pneumoniae is a significant problem in health care settings worldwide. In this study, we examined the antimicrobial susceptibility, genetic profiles and mechanisms of antibiotic resistance in K. pneumoniae isolates of Indian origin. To our knowledge this is the first report demonstrating the high prevalence of β-lactamases, aminoglycoside modifying enzymes, quinolone resistance genes besides demonstrating the involvement of active efflux in K. pneumoniae Indian isolates. This study has enabled us to correlate the phenotypic and genotypic characteristics in K. pneumoniae, providing an important base for continued monitoring and epidemiological studies of this emerging nosocomial pathogen in Indian hospitals. PMID:27870879

Human Health Risk Assessment (HHRA) for environmental development and transfer of antibiotic resistance.

PubMed

Ashbolt, Nicholas J; Amézquita, Alejandro; Backhaus, Thomas; Borriello, Peter; Brandt, Kristian K; Collignon, Peter; Coors, Anja; Finley, Rita; Gaze, William H; Heberer, Thomas; Lawrence, John R; Larsson, D G Joakim; McEwen, Scott A; Ryan, James J; Schönfeld, Jens; Silley, Peter; Snape, Jason R; Van den Eede, Christel; Topp, Edward

2013-09-01

Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens. The authors participated in a workshop held 4-8 March 2012 in Québec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development "hot spots," exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental "hot spot" compartments; and c) modifying traditional dose-response approaches to address doses of ARB for various health outcomes and pathways. We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers.

[Antibacterial activity of sulopenem, a new parenteral penem antibiotic].

PubMed

Inoue, E; Komoto, E; Taniyama, Y; Mitsuhashi, S

1996-04-01

Sulopenem, a new penem antibiotic, was compared with other antibiotics with regard to in vitro antibacterial and bactericidal activities, stabilization against beta-lactamases, and effect on the release of lipopolysaccharide from Gram-negative bacteria. The results are summarized as follows. 1. Sulopenem showed more potent activities than other antibiotics against both Gram-positive and Gram-negative bacteria except Pseudomonas aeruginosa. 2. Sulopenem showed potent bactericidal activities (MIC/MBC) against both Gram-positive and Gram-negative bacteria. Time kill studies against Staphylococcus aureus, Escherichia coli, Enterobacter cloacae and Citrobacter freundii showed potent bactericidal activities of sulopenem. 3. Sulopenem was found to possess a stronger activity than other antibiotics against beta-lactamase-producing strains except P. aeruginosa and Stenotrophomonas maltophilia. 4. In particular, sulopenem was found to be more stable to the hydrolysis by various beta-lactamases produced by Gram-negative bacteria than any other antibiotics tested. Vmax/Km values of sulopenem were smaller than those of cefotiam for all tested beta-lactamases, which reflected a broad antibacterial spectrum of sulopenem. 5. E. coli ML4707 exposed to sulopenem and imipenem released less endotoxin than did controls at all concentration ranges tested. In contrast, the strain exposed to ceftazidime at bacteriostatic concentrations released a large amount of endotoxin.

Assessment of some cultural experimental methods to study the effects of antibiotics on microbial activities in a soil: An incubation study

PubMed Central

Molaei, Ali; Haghnia, Gholamhosain; Astaraei, Alireza; Rasouli-Sadaghiani, MirHassan; Teresa Ceccherini, Maria; Datta, Rahul

2017-01-01

Oxytetracycline (OTC) and sulfamethoxazole (SMX) are two of most widely used antibiotics in livestock and poultry industry. After consumption of antibiotics, a major portion of these compounds is excreted through the feces and urine of animals. Land application of antibiotic-treated animal wastes has caused increasing concern about their adverse effects on ecosystem health. In this regard, inconsistent results have been reported regarding the effects of antibiotics on soil microbial activities. This study was conducted based on the completely randomized design to the measure microbial biomass carbon, cumulative respiration and iron (III) reduction bioassays. Concentrations of OTC and SMX including 0, 1, 10, 25, 50, and 100 mg/kg were spiked in triplicate to a sandy loam soil and incubated for 21 days at 25°C. Results showed that the effects of OTC and SMX antibiotics on cumulative respiration and microbial biomass carbon were different. SMX antibiotic significantly affected soil microbial biomass carbon and cumulative respiration at different treatments compared to control with increasing incubation time. OTC antibiotic, on the other hand, negatively affected cumulative respiration compared to control treatment throughout the incubation period. Although OTC antibiotic positively affected microbial biomass carbon at day one of incubation, there was no clear trend in microbial biomass carbon between different treatments of this antibiotic after that time period. Nevertheless, sulfamethoxazole and oxytetracycline antibiotics had similar effects on iron (III) reduction such that they considerably affected iron (III) reduction at 1 and 10 mg/kg, and iron (III) reduction was completely inhibited at concentrations above 10 mg/kg. Hence, according to our results, microbial biomass carbon and cumulative respiration experiments are not able alone to exhibit the effect of antibiotics on soil microbial activity, but combination of these two experiments with iron (III) reduction test could well display the effects of sulfamethoxazole (SMX) and oxytetracycline (OTC) antibiotics on soil biochemical activities. PMID:28683144

In vitro effectiveness of triterpenoids and their synergistic effect with antibiotics against Staphylococcus aureus strains.

PubMed

Hamza, Muhammad; Nadir, Maha; Mehmood, Nadir; Farooq, Adeel

2016-01-01

The aim of this study is to evaluate the effect of four triterpenoids such as oleanolic acid, ursolic acid, cycloastragenol, and beta-boswellic acid alone and in combination with antibiotics against Staphylococcus aureus strains. Sixteen clinical strains of S. aureus from infected wounds were isolated. Eight were methicillin-sensitive S. aureus (MSSA), and the other eight were methicillin-resistant S. aureus (MRSA). The activity was also seen in reference S. aureus American Type Culture Collection ™ strains. The activity of all the triterpenoids and antibiotics against S. aureus was evaluated by broth microdilution method. The effectiveness was judged by comparing the minimum inhibitory concentrations (MICs) of the compounds with antibiotics. The combination of antibiotics with compounds was evaluated by their fractional inhibitory concentrations (FIC). Against both clinical and reference MSSA strains, none of the compounds exhibited comparable activity to antibiotics vancomycin or cefradine except for ursolic acid (MIC 7.8 μg/ml). Against MRSA, all compounds (MIC 16-128 μg/ml) showed lesser activity than vancomycin (MIC 5.8 μg/ml). Among triterpenoid-antibiotic combinations, the most effective were ursolic acid and vancomycin against clinical strain MSSA (FIC S 0.17). However, overall, different combinations between triterpenoids and antibiotics showed 95%-46% ( P < 0.05) reduction in MICs of antibiotics compared to when antibiotics were used alone. Cefradine, a drug not suitable for treating MRSA (MIC = 45 μg/ml), showed a remarkable decrease in its MIC (87% P< 0.01) when it was used in combination with oleanolic acid or ursolic acid in both clinical and reference strains. The tested triterpenoids are relatively weaker than antibiotics. However, when used in combination with antibiotics, they showed remarkable synergistic effect and thus can help in prolonging the viability of these antibiotics against S. aureus infections. Furthermore, reduction in MIC of cefradine with oleanolic acid indicates their potential use against MRSA.

Lipid-lipid and lipid-drug interactions in biological membranes

NASA Astrophysics Data System (ADS)

Martynowycz, Michael W.

Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the air-liquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray reflectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the in-plane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances. Circumventing deficiencies in small, hydrophobic drugs is approached by using biologically mimetic oligomers. Peptoids, mimetic of host defense peptides from the innate immune system, are active against bacteria, and avoid developed antibiotic resistance. Optimization of peptoids by modulation of hydrophobicity and structural rigidity are explored.

Empirical validation of guidelines for the management of pharyngitis in children and adults.

PubMed

McIsaac, Warren J; Kellner, James D; Aufricht, Peggy; Vanjaka, Anita; Low, Donald E

2004-04-07

Recent guidelines for management of pharyngitis vary in their recommendations concerning empirical antibiotic treatment and the need for laboratory confirmation of group A streptococcus (GAS). To assess the impact of guideline recommendations and alternative approaches on identification and treatment of GAS pharyngitis in children and adults. Throat cultures and rapid antigen tests were performed on 787 children and adults aged 3 to 69 years with acute sore throat attending a family medicine clinic in Calgary, Alberta, from September 1999 to August 2002. Recommendations from 2 guidelines (those of the Infectious Diseases Society of America and of the American College of Physicians-American Society of Internal Medicine/American Academy of Family Physicians/US Centers for Disease Control and Prevention) were compared with rapid testing alone, a clinical prediction rule (ie, the modified Centor score), and a criterion standard of treatment for positive throat culture results only. Sensitivity and specificity of each strategy for identifying GAS pharyngitis, total antibiotics recommended, and unnecessary antibiotic prescriptions. In children, sensitivity for streptococcal infection ranged from 85.8% (133/155; 95% confidence interval [CI], 79.3%-90.0%) for rapid testing to 100% for culturing all. In adults, sensitivity ranged from 76.7% (56/73; 95% CI, 65.4%-85.8%) for rapid testing without culture confirmation of negative results to 100% for culturing all. In children, specificity ranged from 90.3% (270/299; 95% CI, 86.4%-93.4%) for use of modified Centor score and throat culture to 100% for culturing all. In adults, specificity ranged from 43.8% (114/260; 95% CI, 37.7%-50.1%) for empirical treatment based on a modified Centor score of 3 or 4 to 100% for culturing all. Total antibiotic prescriptions were lowest with rapid testing (24.7% [194/787]; 95% CI, 21.7%-27.8%) and highest with empirical treatment of high-risk adults (45.7% [360/787]; 95% CI, 42.2%-49.3%), due to a high rate of unnecessary prescriptions in adults (43.8% [146/333]; 95% CI, 38.4%-49.4%). Guideline recommendations for the selective use of throat cultures but antibiotic treatment based only on positive rapid test or throat culture results can reduce unnecessary use of antibiotics for treatment of pharyngitis. However, empirical treatment of adults having a Centor score of 3 or 4 is associated with a high rate of unnecessary antibiotic use. In children, strategies incorporating throat culture or throat culture confirmation of negative rapid antigen test results are highly sensitive and specific. Throat culture of all adults or those selected on the basis of a clinical prediction rule had the highest sensitivity and specificity.

Temporal relationship between antibiotic use and respiratory virus activities in the Republic of Korea: a time-series analysis.

PubMed

Ryu, Sukhyun; Kim, Sojung; Kim, Bryan I; Klein, Eili Y; Yoon, Young Kyung; Chun, Byung Chul

2018-01-01

Inappropriate use of antibiotics increases resistance and reduces their effectiveness. Despite evidence-based guidelines, antibiotics are still commonly used to treat infections likely caused by respiratory viruses. In this study, we examined the temporal relationships between antibiotic usage and respiratory infections in the Republic of Korea. The number of monthly antibiotic prescriptions and the incidence of acute respiratory tract infections between 2010 and 2015 at all primary care clinics were obtained from the Korean Health Insurance Review and Assessment Service. The monthly detection rates of respiratory viruses, including adenovirus, respiratory syncytial virus, influenza virus, human coronavirus, and human rhinovirus, were collected from Korea Centers for Disease Control and Prevention. Cross-correlation analysis was conducted to quantify the temporal relationship between antibiotic use and respiratory virus activities as well as respiratory infections in primary clinics. The monthly use of different classes of antibiotic, including penicillins, other beta-lactam antibacterials, macrolides and quinolones, was significantly correlated with influenza virus activity. These correlations peaked at the 0-month lag with cross-correlation coefficients of 0.45 ( p  < 0.01), 0.46 ( p  < 0.01), 0.40 ( p  < 0.01), and 0.35 (< 0.01), respectively. Furthermore, a significant correlation was found between acute bronchitis and antibiotics, including penicillin (0.73, p  < 0.01), macrolides (0.74, p  < 0.01), and quinolones (0.45, p  < 0.01), at the 0-month lag. Our findings suggest that there is a significant temporal relationship between influenza virus activity and antibiotic use in primary clinics. This relationship indicates that interventions aimed at reducing influenza cases in addition to effort to discourage the prescription of antibiotics by physicians may help to decrease unnecessary antibiotic consumption.

Novel Group of Leaderless Multipeptide Bacteriocins from Gram-Positive Bacteria.

PubMed

Ovchinnikov, Kirill V; Chi, Hai; Mehmeti, Ibrahim; Holo, Helge; Nes, Ingolf F; Diep, Dzung B

2016-09-01

From raw milk we found 10 Lactococcus garvieae isolates that produce a new broad-spectrum bacteriocin. Though the isolates were obtained from different farms, they turned out to possess identical inhibitory spectra, fermentation profiles of sugars, and repetitive sequence-based PCR (rep-PCR) DNA patterns, indicating that they produce the same bacteriocin. One of the isolates (L. garvieae KS1546) was chosen for further assessment. Purification and peptide sequencing combined with genome sequencing revealed that the antimicrobial activity was due to a bacteriocin unit composed of three similar peptides of 32 to 34 amino acids. The three peptides are produced without leader sequences, and their genes are located next to each other in an operon-like structure, adjacent to the genes normally involved in bacteriocin transport (ABC transporter) and self-immunity. The bacteriocin, termed garvicin KS (GarKS), showed sequence homology to four multipeptide bacteriocins in databases: the known staphylococcal aureocin A70, consisting of four peptides, and three unannotated putative multipeptide bacteriocins produced by Bacillus cereus All these multipeptide bacteriocin loci show conserved genetic organization, including being located adjacent to conserved genetic determinants (Cro/cI and integrase) which are normally associated with mobile genetic elements or genome rearrangements. The antimicrobial activity of all multipeptide bacteriocins was confirmed with synthetic peptides, and all were shown to have broad antimicrobial spectra, with GarKS being the most active of them. The inhibitory spectrum of GarKS includes important pathogens belonging to the genera Staphylococcus, Bacillus, Listeria, and Enterococcus Bacterial resistance to antibiotics is a very serious global problem. There are no new antibiotics with novel antimicrobial mechanisms in clinical trials. Bacteriocins use antimicrobial mechanisms different from those of antibiotics and can kill antibiotic-resistant bacteria, but the number of bacteriocins with very broad antimicrobial spectra is very small. In this study, we have found and purified a novel three-peptide bacteriocin, garvicin KS. By homology search, we were able to find one known and three novel sequence-related bacteriocins consisting of 3 or 4 peptides. None of the peptides has modified amino acids in its sequence. Thus, the activity of all bacteriocins was confirmed with chemically synthesized peptides. All of them, especially garvicin KS, have very broad antibacterial spectra, thus representing a great potential in antimicrobial applications in the food industry and medicine. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Novel Group of Leaderless Multipeptide Bacteriocins from Gram-Positive Bacteria

PubMed Central

Chi, Hai; Mehmeti, Ibrahim; Holo, Helge; Nes, Ingolf F.

2016-01-01

ABSTRACT From raw milk we found 10 Lactococcus garvieae isolates that produce a new broad-spectrum bacteriocin. Though the isolates were obtained from different farms, they turned out to possess identical inhibitory spectra, fermentation profiles of sugars, and repetitive sequence-based PCR (rep-PCR) DNA patterns, indicating that they produce the same bacteriocin. One of the isolates (L. garvieae KS1546) was chosen for further assessment. Purification and peptide sequencing combined with genome sequencing revealed that the antimicrobial activity was due to a bacteriocin unit composed of three similar peptides of 32 to 34 amino acids. The three peptides are produced without leader sequences, and their genes are located next to each other in an operon-like structure, adjacent to the genes normally involved in bacteriocin transport (ABC transporter) and self-immunity. The bacteriocin, termed garvicin KS (GarKS), showed sequence homology to four multipeptide bacteriocins in databases: the known staphylococcal aureocin A70, consisting of four peptides, and three unannotated putative multipeptide bacteriocins produced by Bacillus cereus. All these multipeptide bacteriocin loci show conserved genetic organization, including being located adjacent to conserved genetic determinants (Cro/cI and integrase) which are normally associated with mobile genetic elements or genome rearrangements. The antimicrobial activity of all multipeptide bacteriocins was confirmed with synthetic peptides, and all were shown to have broad antimicrobial spectra, with GarKS being the most active of them. The inhibitory spectrum of GarKS includes important pathogens belonging to the genera Staphylococcus, Bacillus, Listeria, and Enterococcus. IMPORTANCE Bacterial resistance to antibiotics is a very serious global problem. There are no new antibiotics with novel antimicrobial mechanisms in clinical trials. Bacteriocins use antimicrobial mechanisms different from those of antibiotics and can kill antibiotic-resistant bacteria, but the number of bacteriocins with very broad antimicrobial spectra is very small. In this study, we have found and purified a novel three-peptide bacteriocin, garvicin KS. By homology search, we were able to find one known and three novel sequence-related bacteriocins consisting of 3 or 4 peptides. None of the peptides has modified amino acids in its sequence. Thus, the activity of all bacteriocins was confirmed with chemically synthesized peptides. All of them, especially garvicin KS, have very broad antibacterial spectra, thus representing a great potential in antimicrobial applications in the food industry and medicine. PMID:27316965

Urine culture guided antibiotic interventions: A pharmacist driven antimicrobial stewardship effort in the ED.

PubMed

Zhang, Xi; Rowan, Nicole; Pflugeisen, Bethann Mangel; Alajbegovic, Sanjin

2017-04-01

Antibiotics are overprescribed for abnormal urine tests including asymptomatic bacteriuria (AB), contributing to rising antimicrobial resistance rates. Pharmacists reviewed urine cultures daily from emergency department (ED) encounters to assess antibiotic appropriateness. We studied antibiotic prescribing practices and assessed compliance to national guidelines, correlations with urine analysis (UA) components, and opportunities for antimicrobial stewardship in the ED. This quality improvement project (QIP) was a prospective cohort study at a community hospital ED, with data collected from finalized urine cultures resulting October 30, 2014 through January 5, 2015. Analyses were conducted using Chi-squared and Fisher Exact tests and stepwise multiple logistic regression. Urine cultures from 457 encounters were reviewed, of which 136 met the inclusion criteria as non-pregnant and asymptomatic for urinary tract infection (UTI). 43% of 136 patients were treated with antibiotics, for a total of 426 antibiotic days. Pharmacist interventions for these patients resulted in 122/426 (29%) of potential antibiotic days saved. Factors found to significantly increase the odds of antibiotic prescribing in asymptomatic patients included presence of leukocyte esterase (OR=4.5, 95% CI: 1.2-17.2; p=0.03) or nitrites (OR=10.8, 95% CI: 1.7-68.1; p=0.01) in the urine and age≥75 (OR=3.5, 95% CI: 1.2-9.6, p=0.02). Pharmacist intervention in discontinuing or modifying antibiotics for asymptomatic patients with urine cultures reduced unnecessary antibiotic exposure and was a first step in antimicrobial stewardship efforts in the ED. Future work includes limiting urine tests and subsequent antibiotic therapy for non-pregnant asymptomatic patients. Copyright © 2016 Elsevier Inc. All rights reserved.

The Impact of Efflux Pump Inhibitors on the Activity of Selected Non-Antibiotic Medicinal Products against Gram-Negative Bacteria.

PubMed

Laudy, Agnieszka E; Kulińska, Ewa; Tyski, Stefan

2017-01-11

The potential role of non-antibiotic medicinal products in the treatment of multidrug-resistant Gram-negative bacteria has recently been investigated. It is highly likely that the presence of efflux pumps may be one of the reasons for the weak activity of non-antibiotics, as in the case of some non-steroidal anti-inflammatory drugs (NSAIDs), against Gram-negative rods. The activity of eight drugs of potential non-antibiotic activity, active substance standards, and relevant medicinal products were analysed with and without of efflux pump inhibitors against 180 strains of five Gram-negative rod species by minimum inhibitory concentration (MIC) value determination in the presence of 1 mM MgSO₄. Furthermore, the influence of non-antibiotics on the susceptibility of clinical strains to quinolones with or without PAβN (Phe-Arg-β-naphthylamide) was investigated. The impacts of PAβN on the susceptibility of bacteria to non-antibiotics suggests that amitriptyline, alendronate, nicergoline, and ticlopidine are substrates of efflux pumps in Gram-negative rods. Amitriptyline/Amitriptylinum showed the highest direct antibacterial activity, with MICs ranging 100-800 mg/L against all studied species. Significant decreases in the MIC values of other active substances (acyclovir, atorvastatin, and famotidine) tested with pump inhibitors were not observed. The investigated non-antibiotic medicinal products did not alter the MICs of quinolones in the absence and in the presence of PAβN to the studied clinical strains of five groups of species.

Antibiotics Suppress Activation of Intestinal Mucosal Mast Cells and Reduce Dietary Lipid Absorption in Sprague-Dawley Rats.

PubMed

Sato, Hirokazu; Zhang, Linda S; Martinez, Kristina; Chang, Eugene B; Yang, Qing; Wang, Fei; Howles, Philip N; Hokari, Ryota; Miura, Soichiro; Tso, Patrick

2016-11-01

The gut microbiota affects intestinal permeability and mucosal mast cells (MMCs) responses. Activation of MMCs has been associated with absorption of dietary fat. We investigated whether the gut microbiota contributes to the fat-induced activation of MMCs in rats, and how antibiotics might affect this process. Adult male Sprague-Dawley rats were given streptomycin and penicillin for 4 days (n = 6-8) to reduce the abundance of their gut flora, or normal drinking water (controls, n = 6-8). They underwent lymph fistula surgery and after an overnight recovery were given an intraduodenal bolus of intralipid. We collected intestinal tissues and lymph fluid and assessed activation of MMCs, intestinal permeability, and fat transport parameters. Compared with controls, intestinal lymph from rats given antibiotics had reduced levels of mucosal mast cell protease II (produced by MMCs) and decreased activity of diamine oxidase (produced by enterocytes) (P < .05). Rats given antibiotics had reduced intestinal permeability in response to dietary lipid compared with controls (P < .01). Unexpectedly, antibiotics also reduced lymphatic transport of triacylglycerol and phospholipid (P < .01), concomitant with decreased levels of mucosal apolipoproteins B, A-I, and A-IV (P < .01). No differences were found in intestinal motility or luminal pancreatic lipase activity between rats given antibiotics and controls. These effects were not seen with an acute dose of antibiotics or 4 weeks after the antibiotic regimen ended. The intestinal microbiota appears to activate MMCs after the ingestion of fat in rats; this contributes to fat-induced intestinal permeability. We found that the gut microbiome promotes absorption of lipid, probably by intestinal production of apolipoproteins and secretion of chylomicrons. Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.

An In Vitro Study on the Effects of Nisin on the Antibacterial Activities of 18 Antibiotics against Enterococcus faecalis

PubMed Central

Ling, Junqi; Ma, Jinglei; Huang, Lijia; Zhang, Luodan

2014-01-01

Enterococcus faecalis rank among the leading causes of nosocomial infections worldwide and possesses both intrinsic and acquired resistance to a variety of antibiotics. Development of new antibiotics is limited, and pathogens continually generate new antibiotic resistance. Many researchers aim to identify strategies to effectively kill this drug-resistant pathogen. Here, we evaluated the effect of the antimicrobial peptide nisin on the antibacterial activities of 18 antibiotics against E. faecalis. The MIC and MBC results showed that the antibacterial activities of 18 antibiotics against E. faecalis OG1RF, ATCC 29212, and strain E were significantly improved in the presence of 200 U/ml nisin. Statistically significant differences were observed between the results with and without 200 U/ml nisin at the same concentrations of penicillin or chloramphenicol (p<0.05). The checkerboard assay showed that the combination of nisin and penicillin or chloramphenicol had a synergetic effect against the three tested E. faecalis strains. The transmission electron microscope images showed that E. faecalis was not obviously destroyed by penicillin or chloramphenicol alone but was severely disrupted by either antibiotic in combination with nisin. Furthermore, assessing biofilms by a confocal laser scanning microscope showed that penicillin, ciprofloxacin, and chloramphenicol all showed stronger antibiofilm actions in combination with nisin than when these antibiotics were administered alone. Therefore, nisin can significantly improve the antibacterial and antibiofilm activities of many antibiotics, and certain antibiotics in combination with nisin have considerable potential for use as inhibitors of this drug-resistant pathogen. PMID:24586598

Evaluation of combinations of putative anti-biofilm agents and antibiotics to eradicate biofilms of Staphylococcus aureus and Pseudomonas aeruginosa.

PubMed

Belfield, Katherine; Bayston, Roger; Hajduk, Nadzieja; Levell, Georgia; Birchall, John P; Daniel, Matija

2017-09-01

To evaluate potential anti-biofilm agents for their ability to enhance the activity of antibiotics for local treatment of localized biofilm infections. Staphylococcus aureus and Pseudomonas aeruginosa in vitro biofilm models were developed. The putative antibiotic enhancers N-acetylcysteine, acetylsalicylic acid, sodium salicylate, recombinant human deoxyribonuclease I, dispersin B, hydrogen peroxide and Johnson's Baby Shampoo (JBS) were tested for their anti-biofilm activity alone and their ability to enhance the activity of antibiotics for 7 or 14 days, against 5 day old biofilms. The antibiotic enhancers were paired with rifampicin and clindamycin against S. aureus and gentamicin and ciprofloxacin against P. aeruginosa. Isolates from biofilms that were not eradicated were tested for antibiotic resistance. Antibiotic levels 10× MIC and 100× MIC significantly reduced biofilm, but did not consistently eradicate it. Antibiotics at 100× MIC with 10% JBS for 14 days was the only treatment to eradicate both staphylococcal and pseudomonal biofilms. Recombinant human deoxyribonuclease I significantly reduced staphylococcal biofilm. Emergence of resistance of surviving isolates was minimal and was often associated with the small colony variant phenotype. JBS enhanced the activity of antibiotics and several other promising anti-biofilm agents were identified. Antibiotics with 10% JBS eradicated biofilms produced by both organisms. Such combinations might be useful in local treatment of localized biofilm infections. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

77 FR 67239 - National Organic Program; Periodic Residue Testing

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-09

... genetically modified organisms (GMOs). AMS does not intend for the testing conducted under section 205.670 to..., but not limited to, pesticides, hormones, antibiotics, and GMOs. AMS notes that, under section 205.671...

Antisense antibiotics: a brief review of novel target discovery and delivery.

PubMed

Bai, Hui; Xue, Xiaoyan; Hou, Zheng; Zhou, Ying; Meng, Jingru; Luo, Xiaoxing

2010-06-01

The nightmare of multi-drug resistant bacteria will still haunt if no panacea is ever found. Efforts on seeking desirable natural products with bactericidal property and screening chemically modified derivatives of traditional antibiotics have lagged behind the emergence of new multi-drug resistant bacteria. The concept of using antisense antibiotics, now as revolutionary as is on threshold has experienced ups and downs in the past decade. In the past five years, however, significant technology advances in the fields of microbial genomics, structural modification of oligonucleotides and efficient delivery system have led to fundamental progress in the research and in vivo application of this paradigm. The wealthy information provided in the microbial genomics era has allowed the identification and/or validation of a number of essential genes that may serve as possible targets for antisense inhibition; antisense oligodeoxynucleotides (ODNs) based on the 3rd generation of modified structures, e.g., peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) have shown great potency in gene expression inhibition in a sequence-specific and dosedependent manner at low micromolar concentrations; and cell penetrating peptide mediated delivery system has enabled the effective display of intracellular antisense inhibition of targeted genes both in vitro and in vivo. The new methods show promise in the discovery of novel gene-specific antisense antibiotics that will be useful in the future battle against drug-resistant bacterial infections. This review describes this promising paradigm, the targets that have been identified and the recent technologies on which it is delivered.

Mechanical, material, and antimicrobial properties of acrylic bone cement impregnated with silver nanoparticles.

PubMed

Slane, Josh; Vivanco, Juan; Rose, Warren; Ploeg, Heidi-Lynn; Squire, Matthew

2015-03-01

Prosthetic joint infection is one of the most serious complications that can lead to failure of a total joint replacement. Recently, the rise of multidrug resistant bacteria has substantially reduced the efficacy of antibiotics that are typically incorporated into acrylic bone cement. Silver nanoparticles (AgNPs) are an attractive alternative to traditional antibiotics resulting from their broad-spectrum antimicrobial activity and low bacterial resistance. The purpose of this study, therefore, was to incorporate metallic silver nanoparticles into acrylic bone cement and quantify the effects on the cement's mechanical, material and antimicrobial properties. AgNPs at three loading ratios (0.25, 0.5, and 1.0% wt/wt) were incorporated into a commercial bone cement using a probe sonication technique. The resulting cements demonstrated mechanical and material properties that were not substantially different from the standard cement. Testing against Staphylococcus aureus and Staphylococcus epidermidis using Kirby-Bauer and time-kill assays demonstrated no antimicrobial activity against planktonic bacteria. In contrast, cements modified with AgNPs significantly reduced biofilm formation on the surface of the cement. These results indicate that AgNP-loaded cement is of high potential for use in primary arthroplasty where prevention of bacterial surface colonization is vital. Copyright © 2014 Elsevier B.V. All rights reserved.

Synthetic membrane-targeted antibiotics.

PubMed

Vooturi, S K; Firestine, S M

2010-01-01

Antimicrobial resistance continues to evolve and presents serious challenges in the therapy of both nosocomial and community-acquired infections. The rise of resistant strains like methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin-resistant enterococci (VRE) suggests that antimicrobial resistance is an inevitable evolutionary response to antimicrobial use. This highlights the tremendous need for antibiotics against new bacterial targets. Agents that target the integrity of bacterial membrane are relatively novel in the clinical armamentarium. Daptomycin, a lipopeptide is a classical example of membrane-bound antibiotic. Nature has also utilized this tactic. Antimicrobial peptides (AMPs), which are found in all kingdoms, function primarily by permeabilizing the bacterial membrane. AMPs have several advantages over existing antibiotics including a broad spectrum of activity, rapid bactericidal activity, no cross-resistance with the existing antibiotics and a low probability for developing resistance. Currently, a small number of peptides have been developed for clinical use but therapeutic applications are limited because of poor bioavailability and high manufacturing cost. However, their broad specificity, potent activity and lower probability for resistance have spurred the search for synthetic mimetics of antimicrobial peptides as membrane-active antibiotics. In this review, we will discuss the different classes of synthetic membrane-bound antibiotics published since 2004.

Dead bacteria reverse antibiotic-induced host defense impairment in burns.

PubMed

Chen, Lee-Wei; Chen, Pei-Hsuan; Fung, Chang-Phone; Hsu, Ching-Mei

2014-10-01

Burn patients can incur high rates of hospital-acquired infections. The mechanism of antibiotic exposure on inducing infection vulnerability has not been determined. This study aimed to examine the effects of antibiotic treatment on host defense mechanisms. First we treated C57/BL6 mice with combined antibiotic treatment after 30% to 35% total body surface area burn. Animals were sacrificed at 48 hours after sham or thermal injury treatment. Bacterial counts in intestinal lumen and mucosa were measured. Next, we treated animals with or without oral dead Escherichia coli or Staphylococcus aureus supplementation to stimulate Toll-like receptor in the intestinal mucosa. Toll-like receptor 4, antibacterial protein expression, nuclear factor (NF)-κB DNA-binding activity, and bacteria-killing activity in the intestinal mucosa; intestinal permeability; bacterial translocation to mesenteric lymph nodes; Klebsiella pneumoniae translocation; interleukin-6 in the blood; and phagocytic activity of alveolar macrophages, were assessed. Thermal injury increased microflora and NF-κB DNA-binding activity of the intestine. Systemic antibiotic treatment decreased gut microflora and increased bacterial translocation to mesenteric lymph nodes, intestinal permeability, and interleukin-6 levels in the blood. Antibiotic treatment also decreased bacteria-killing activity in intestinal mucosa and phagocytic activity of alveolar macrophages. Oral dead E coli and S aureus supplementation induced NF-κB DNA-binding activity, Toll-like receptor 4, and antibacterial protein expression of the intestinal mucosa. Taken together with the fact that dead bacteria reversed antibiotic-induced K pneumoniae translocation and intestinal and pulmonary defense impairment, we conclude that combined antibiotic treatment results in systemic host defense impairment in burns through the decrease in intestinal flora. We suggest that dead bacteria supplementation could induce nondefensin protein expression and reverse antibiotic-induced gut and lung defense impairment in burn patients. Copyright © 2014 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

Antibiotics as immunomodulant agents in COPD.

PubMed

Blasi, Francesco; Mantero, Marco; Aliberti, Stefano

2012-06-01

It is widely accepted that some antibiotics have activities beyond their direct antibacterial effects. Macrolide is the antibiotic class with more convincing studies and evidence on its immunomodulatory and anti-inflammatory activities. Different clinical studies have shown that macrolide prophylaxis in patients with moderate-severe chronic obstructive pulmonary disease (COPD) can have a significant impact on the exacerbation rate reducing morbidity and, potentially, mortality of the disease. Other antibiotics, such as fluoroquinolones, demonstrate a variety of immunomodulatory effects but only few clinical data are available in COPD. New macrolide derivatives devoid of antibacterial activity have been synthetized. This review analyses the relevance of immunomodulatory and anti-inflammatory effects of antibiotics in the management of COPD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Effect of Various Concentrations of Antibiotics on Osteogenic Cell Viability and Activity

DTIC Science & Technology

2011-07-01

antibiotic-supple- mented bone allografts in the guinea pig . J Oral Maxillofac Surg 42:631–636. 32. McKeeMD,WildLM,SchemitschEH, et al. 2002. Theuse of an...and Antibiotic Treatments Human osteoblasts (Promocell, Heidelberg, Germany) were maintained in media consisting of alpha-MEM containing 10% fetal calf...that when antibiotics are extremely toxic to cells, subtle differences between metabolic activity and overt cell death are not discernable

Development of fiber optic spectroscopy for in-vitro and in-planta detection of fluorescent proteins

NASA Astrophysics Data System (ADS)

Liew, Oi Wah; Chen, Jun-Wei; Asundi, Anand K.

2001-10-01

The objective of this project is to apply photonics technology to bio-safety management of genetically modified (GM) plants. The conventional method for screening GM plants is through selection using antibiotic resistance markers. There is public concern with such approaches and these are associated with food safety issues, escape of antibiotic resistance genes to pathogenic microorganisms and interference with antibiotic therapy. Thus, the strategy taken in this project is to replace antibiotic resistance markers with fluorescent protein markers that allow for rapid and non-invasive optical screening of genetically modified plants. In this paper, fibre optic spectroscopy was developed to detect and quantify recombinant green (EGFP) and red (DsRED) fluorescent proteins in vitro and in planta. In vitro detection was first carried out to optimize the sensitivity of the optical system. The bacterial expression vectors carrying the coding regions of EGFP and DsRED were introduced into Escherichia coli host cells and fluorescent proteins were produced following induction with IPTG. Soluble EGFP and DsRED proteins were isolated from lysed bacterial cells and serially diluted for quantitative analysis by fibre optic spectroscopy using different light sources, namely, blue LED (475 nm), tungsten halogen (350 - 1000 nm) and double frequency Nd:YAG green laser (532 nm). Fluorescence near the expected emission wavelengths could be detected up to 320X dilution for EGFP and DsRED with blue LED and 532 nm green laser, respectively, as the excitation source. Tungsten halogen was found to be unsuitable for excitation of both EGFP and DsRED. EGFP was successfully purified by size separation under non-denaturing electrophoretic conditions and quantified. The minimum concentration of EGFP detectable with blue LED excitation was 5 mg/ml. To determine the capability of spectroscopy detection in planta, transgenic potato hairy roots and whole modified plant lines expressing the fluorescent markers were regenerated. T

Antimicrobial Activity of Nitric Oxide-Releasing Ti-6Al-4V Metal Oxide

PubMed Central

Reger, Nina A.; Meng, Wilson S.; Gawalt, Ellen S.

2017-01-01

Titanium and titanium alloy materials are commonly used in joint replacements, due to the high strength of the materials. Pathogenic microorganisms can easily adhere to the surface of the metal implant, leading to an increased potential for implant failure. The surface of a titanium-aluminum-vanadium (Ti-6Al-4V) metal oxide implant material was functionalized to deliver an small antibacterial molecule, nitric oxide. S-nitroso-penicillamine, a S-nitrosothiol nitric oxide donor, was covalently immobilized on the metal oxide surface using self-assembled monolayers. Infrared spectroscopy was used to confirm the attachment of the S-nitrosothiol donor to the Ti-Al-4V surface. Attachment of S-nitroso-penicillamine resulted in a nitric oxide (NO) release of 89.6 ± 4.8 nmol/cm2 under physiological conditions. This low concentration of nitric oxide reduced Escherichia coli and Staphylococcus epidermidis growth by 41.5 ± 1.2% and 25.3 ± 0.6%, respectively. Combining the S-nitrosothiol releasing Ti-6Al-4V with tetracycline, a commonly-prescribed antibiotic, increased the effectiveness of the antibiotic by 35.4 ± 1.3%, which allows for lower doses of antibiotics to be used. A synergistic effect of ampicillin with S-nitroso-penicillamine-modified Ti-6Al-4V against S. epidermidis was not observed. The functionalized Ti-6Al-4V surface was not cytotoxic to mouse fibroblasts. PMID:28635681

Nonviral Genome Editing Based on a Polymer-Derivatized CRISPR Nanocomplex for Targeting Bacterial Pathogens and Antibiotic Resistance.

PubMed

Kang, Yoo Kyung; Kwon, Kyu; Ryu, Jea Sung; Lee, Ha Neul; Park, Chankyu; Chung, Hyun Jung

2017-04-19

The overuse of antibiotics plays a major role in the emergence and spread of multidrug-resistant bacteria. A molecularly targeted, specific treatment method for bacterial pathogens can prevent this problem by reducing the selective pressure during microbial growth. Herein, we introduce a nonviral treatment strategy delivering genome editing material for targeting antibacterial resistance. We apply the CRISPR-Cas9 system, which has been recognized as an innovative tool for highly specific and efficient genome engineering in different organisms, as the delivery cargo. We utilize polymer-derivatized Cas9, by direct covalent modification of the protein with cationic polymer, for subsequent complexation with single-guide RNA targeting antibiotic resistance. We show that nanosized CRISPR complexes (= Cr-Nanocomplex) were successfully formed, while maintaining the functional activity of Cas9 endonuclease to induce double-strand DNA cleavage. We also demonstrate that the Cr-Nanocomplex designed to target mecA-the major gene involved in methicillin resistance-can be efficiently delivered into Methicillin-resistant Staphylococcus aureus (MRSA), and allow the editing of the bacterial genome with much higher efficiency compared to using native Cas9 complexes or conventional lipid-based formulations. The present study shows for the first time that a covalently modified CRISPR system allows nonviral, therapeutic genome editing, and can be potentially applied as a target specific antimicrobial.

Immobilized antibiotics to prevent orthopedic implant infections

PubMed Central

Hickok, Noreen J.; Shapiro, Irving M.

2012-01-01

Many surgical procedures require the placement of an inert or tissue-derived implant deep within the body cavity. While the majority of these implants do not become colonized by bacteria, a small percentage develops a biofilm layer that harbors invasive microorganisms. In orthopaedic surgery, unresolved periprosthetic infections can lead to implant loosening, arthrodeses, amputations and sometimes death. The focus of this review is to describe development of an implant in which an antibiotic tethered to the metal surface is used to prevent bacterial colonization and biofilm formation. Building on well-established chemical syntheses, studies show that antibiotics can be linked to titanium through a self-assembled monolayer of siloxy amines. The stable metal-antibiotic construct resists bacterial colonization and biofilm formation while remaining amenable to osteoblastic cell adhesion and maturation. In an animal model, the antibiotic modified implant resists challenges by bacteria that are commonly present in periprosthetic infections. While the long-term efficacy and stability is still to be established, ongoing studies support the view that this novel type of bioactive surface has a real potential to mitigate or prevent the devastating consequences of orthopaedic infection. PMID:22512927

Rapid, low-cost fluorescent assay of β-lactamase-derived antibiotic resistance and related antibiotic susceptibility

NASA Astrophysics Data System (ADS)

Erdem, S. Sibel; Khan, Shazia; Palanisami, Akilan; Hasan, Tayyaba

2014-10-01

Antibiotic resistance (AR) is increasingly prevalent in low and middle income countries (LMICs), but the extent of the problem is poorly understood. This lack of knowledge is a critical deficiency, leaving local health authorities essentially blind to AR outbreaks and crippling their ability to provide effective treatment guidelines. The crux of the problem is the lack of microbiology laboratory capacity available in LMICs. To address this unmet need, we demonstrate a rapid and simple test of β-lactamase resistance (the most common form of AR) that uses a modified β-lactam structure decorated with two fluorophores quenched due to their close proximity. When the β-lactam core is cleaved by β-lactamase, the fluorophores dequench, allowing assay speeds of 20 min to be obtained with a simple, streamlined protocol. Furthermore, by testing in competition with antibiotics, the β-lactamase-associated antibiotic susceptibility can also be extracted. This assay can be easily implemented into standard lab work flows to provide near real-time information of β-lactamase resistance, both for epidemiological purposes as well as individualized patient care.

Self-defensive antibiotic-loaded layer-by-layer coatings: Imaging of localized bacterial acidification and pH-triggering of antibiotic release.

PubMed

Albright, Victoria; Zhuk, Iryna; Wang, Yuhao; Selin, Victor; van de Belt-Gritter, Betsy; Busscher, Henk J; van der Mei, Henny C; Sukhishvili, Svetlana A

2017-10-01

Self-defensive antibiotic-loaded coatings have shown promise in inhibiting growth of pathogenic bacteria adhering to biomaterial implants and devices, but direct proof that their antibacterial release is triggered by bacterially-induced acidification of the immediate environment under buffered conditions remained elusive. Here, we demonstrate that Staphylococcus aureus and Escherichia coli adhering to such coatings generate highly localized acidification, even in buffered conditions, to activate pH-triggered, self-defensive antibiotic release. To this end, we utilized chemically crosslinked layer-by-layer hydrogel coatings of poly(methacrylic acid) with a covalently attached pH-sensitive SNARF-1 fluorescent label for imaging, and unlabeled-antibiotic (gentamicin or polymyxin B) loaded coatings for antibacterial studies. Local acidification of the coatings induced by S. aureus and E. coli adhering to the coatings was demonstrated by confocal-laser-scanning-microscopy via wavelength-resolved imaging. pH-triggered antibiotic release under static, small volume conditions yielded high bacterial killing efficiencies for S. aureus and E. coli. Gentamicin-loaded films retained their antibacterial activity against S. aureus under fluid flow in buffered conditions. Antibacterial activity increased with the number of polymer layers in the films. Altogether, pH-triggered, self-defensive antibiotic-loaded coatings become activated by highly localized acidification in the immediate environment of an adhering bacterium, offering potential for clinical application with minimized side-effects. Polymeric coatings were created that are able to uptake and selectively release antibiotics upon stimulus by adhering bacteria in order to understand the fundamental mechanisms behind pH-triggered antibiotic release as a potential way to prevent biomaterial-associated infections. Through fluorescent imaging studies, this work importantly shows that adhering bacteria produce highly localized pH changes even in buffer. Accordingly such coatings only demonstrate antibacterial activity by antibiotic release in the presence of adhering bacteria. This is clinically important, because ad libitum releasing antibiotic coatings usually show a burst release and have often lost their antibiotic content when bacteria adhere. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Lack of formylated methionyl-tRNA has pleiotropic effects on Bacillus subtilis

PubMed Central

Cai, Yanfei; Chandrangsu, Pete; Gaballa, Ahmed; Helmann, John D

2017-01-01

Bacteria initiate translation using a modified amino acid, N-formylmethionine (fMet), adapted specifically for this function. Most proteins are processed co-translationally by peptide deformylase (PDF) to remove this modification. Although PDF activity is essential in WT cells and is the target of the antibiotic actinonin, bypass mutations in the fmt gene that eliminate the formylation of Met-tRNAMet render PDF dispensable. The extent to which the emergence of fmt bypass mutations might compromise the therapeutic utility of actinonin is determined, in part, by the effects of these bypass mutations on fitness. Here, we characterize the phenotypic consequences of an fmt null mutation in the model organism Bacillus subtilis. An fmt null mutant is defective for several post-exponential phase adaptive programmes including antibiotic resistance, biofilm formation, swarming and swimming motility and sporulation. In addition, a survey of well-characterized stress responses reveals an increased sensitivity to metal ion excess and oxidative stress. These diverse phenotypes presumably reflect altered synthesis or stability of key proteins involved in these processes. PMID:27983482

Killing bacteria within biofilms by sustained release of tetracycline from triple-layered electrospun micro/nanofibre matrices of polycaprolactone and poly(ethylene-co-vinyl acetate).

PubMed

Alhusein, Nour; De Bank, Paul A; Blagbrough, Ian S; Bolhuis, Albert

2013-12-01

We report the controlled release of the antibiotic tetracycline (tet) HCl from a triple-layered electrospun matrix consisting of a central layer of poly(ethylene-co-vinyl acetate (PEVA) sandwiched between outer layers of poly-ε-caprolactone (PCL). These micro/nanofibre layers with tet successfully encapsulated (essentially quantitatively at 3 and 5 % w/w) in each layer, efficiently inhibited the growth of a panel of bacteria, including clinical isolates, as shown by a modified Kirby-Bauer disc assay. Furthermore, they demonstrated high biological activity in increasingly complex models of biofilm formation (models that are moving closer to the situation in a wound) by stopping biofilm formation, by killing preformed biofilms and killing mature, dense biofilm colonies of Staphylococcus aureus MRSA252. Tet is clinically useful with potential applications in wound healing and especially in complicated skin and skin-structure infections; electrospinning provides good encapsulation efficiency of tet within PCL/PEVA/PCL polymers in micro/nanofibre layers which display sustained antibiotic release in formulations that are anti-biofilm.

Recent Development of Benzimidazole-Containing Antibacterial Agents.

PubMed

Song, Di; Ma, Shutao

2016-04-05

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. However, new antibacterial agents are currently being developed at a much slower pace than our growing need for such drugs. Given their diverse biological activities and clinical applications, many bioactive heterocyclic compounds containing a benzimidazole nucleus have been the focus of interest for many researchers. The benzimidazole nucleus is a structural isostere of naturally occurring nucleotides. This advantage allows benzimidazoles to readily interact with the various biopolymers found in living systems. In view of this situation, much attention has been given to the exploration of benzimidazole-based antibacterial agents, leading to the discovery of many new chemical entities with intriguing profiles. In this minireview we summarize novel benzimidazole derivatives active against various bacterial strains. In particular, we outline the relationship between the structures of variously modified benzimidazoles and their antibacterial activity. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Falling Leaves Inspired ZnO Nanorods-Nanoslices Hierarchical Structure for Implant Surface Modification with Two Stage Releasing Features.

PubMed

Liao, Hang; Miao, Xinxin; Ye, Jing; Wu, Tianlong; Deng, Zhongbo; Li, Chen; Jia, Jingyu; Cheng, Xigao; Wang, Xiaolei

2017-04-19

Inspired from falling leaves, ZnO nanorods-nanoslices hierarchical structure (NHS) was constructed to modify the surfaces of two widely used implant materials: titanium (Ti) and tantalum (Ta), respectively. By which means, two-stage release of antibacterial active substances were realized to address the clinical importance of long-term broad-spectrum antibacterial activity. At early stages (within 48 h), the NHS exhibited a rapid releasing to kill the bacteria around the implant immediately. At a second stage (over 2 weeks), the NHS exhibited a slow releasing to realize long-term inhibition. The excellent antibacterial activity of ZnO NHS was confirmed once again by animal test in vivo. According to the subsequent experiments, the ZnO NHS coating exhibited the great advantage of high efficiency, low toxicity, and long-term durability, which could be a feasible manner to prevent the abuse of antibiotics on implant-related surgery.

Enhanced membrane disruption and antibiotic action against pathogenic bacteria by designed histidine-rich peptides at acidic pH.

PubMed

Mason, A James; Gasnier, Claire; Kichler, Antoine; Prévost, Gilles; Aunis, Dominique; Metz-Boutigue, Marie-Hélène; Bechinger, Burkhard

2006-10-01

The histidine-rich amphipathic cationic peptide LAH4 has antibiotic and DNA delivery capabilities. Here, we explore the interaction of peptides from this family with model membranes as monitored by solid-state (2)H nuclear magnetic resonance and their antibiotic activities against a range of bacteria. At neutral pH, the membrane disruption is weak, but at acidic pH, the peptides strongly disturb the anionic lipid component of bacterial membranes and cause bacterial lysis. The peptides are effective antibiotics at both pH 7.2 and pH 5.5, although the antibacterial activity is strongly affected by the change in pH. At neutral pH, the LAH peptides were active against both methicillin-resistant and -sensitive Staphylococcus aureus strains but ineffective against Pseudomonas aeruginosa. In contrast, the LAH peptides were highly active against P. aeruginosa in an acidic environment, as is found in the epithelial-lining fluid of cystic fibrosis patients. Our results show that modest antibiotic activity of histidine-rich peptides can be dramatically enhanced by inducing membrane disruption, in this case by lowering the pH, and that histidine-rich peptides have potential as future antibiotic agents.

Harnessing the synthetic capabilities of glycopeptide antibiotic tailoring enzymes: characterization of the UK-68,597 biosynthetic cluster.

PubMed

Yim, Grace; Kalan, Lindsay; Koteva, Kalinka; Thaker, Maulik N; Waglechner, Nicholas; Tang, Irene; Wright, Gerard D

2014-11-24

In this study, a draft genome sequence of Actinoplanes sp. ATCC 53533 was assembled, and an 81-kb biosynthetic cluster for the unusual sulfated glycopeptide UK-68,597 was identified. Glycopeptide antibiotics are important in the treatment of infections caused by Gram-positive bacteria. Glycopeptides contain heptapeptide backbones that are modified by many tailoring enzymes, including glycosyltransferases, sulfotransferases, methyltransferases, and halogenases, generating extensive chemical and functional diversity. Several tailoring enzymes in the cluster were examined in vitro for their ability to modify glycopeptides, resulting in the synthesis of novel molecules. Tailoring enzymes were also expressed in the producer of the glycopeptide aglycone A47934, generating additional chemical diversity. This work characterizes the biosynthetic program of UK-68,597 and demonstrates the capacity to expand glycopeptide chemical diversity by harnessing the unique chemistry of tailoring enzymes. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Modification of Salmonella Lipopolysaccharides Prevents the Outer Membrane Penetration of Novobiocin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nobre, Thatyane M.; Martynowycz, Michael W.; Andreev, Konstantin

Small hydrophilic antibiotics traverse the outer membrane of Gram-negative bacteria through porin channels. Large lipophilic agents traverse the outer membrane through its bilayer, containing a majority of lipopolysaccharides in its outer leaflet. Genes controlled by the two-component regulatory system PhoPQ modify lipopolysaccharides. We isolate lipopolysaccharides from isogenic mutants of Salmonella sp., one lacking the modification, the other fully modified. These lipopolysaccharides were reconstituted asmonolayers at the air-water interface, and their properties, aswell as their interaction with a large lipophilic drug, novobiocin, was studied. X-ray reflectivity showed that the drug penetrated the monolayer of the unmodified lipopolysaccharides reaching the hydrophobic region,butwasmore » prevented fromthis penetration intothemodified lipopolysaccharides.Results correlatewith behavior of bacterial cells, which become resistant to antibiotics after PhoPQ-regulated modifications. Grazing incidence x-ray diffraction showed that novobiocin produced a striking increase in crystalline coherence length, and the size of the near-crystalline domains.« less

Synergy between antibiotics and natural agents results in increased antimicrobial activity against Staphylococcus epidermidis.

PubMed

Abidi, Syed Hani; Ahmed, Khalid; Sherwani, Sikander Khan; Kazmi, Shahana Urooj

2015-09-27

Staphylococcus epidermidis is one of the most frequent causes of biofilm-associated infections on indwelling medical devices. With the emergence of methicillin-resistant S. epidermidis (MRSE), there is an urgent need to discover novel active agents against a range of Gram-positive pathogens. We screened the clinical isolates of S. epidermidis for susceptibility/resistance against commonly prescribed antibiotics. Furthermore, we tested some natural agents alone and in combination with antibiotics to find possible synergistic antimicrobial effects. S. epidermidis clinical isolates were screened for susceptibility/resistance against vancomycin, erythromycin, tetracycline, chloramphenicol, ampicillin, ofloxacin, cephalexin, and gentamicin using the Kirby-Bauer disk diffusion method. The antimicrobial potential of Camellia sinensis, Juglans regia, and Hippophae rhamnoides alone and in combination with antibiotics were examined using the disk diffusion method, where the antimicrobial potential activity was measured in terms of formation of zones of inhibition. Most S. epidermidis isolates were found to be resistant to one or more antibiotics. Gentamycin and ofloxacin were found to be the most effective antibiotics against S. epidermidis isolates. Extracts of Hippophae rhamnoides, Juglans regia, and Camellia sinensis were found to be equally effective against S. epidermidis isolates. In combination with antibiotics, these extracts exhibited appreciable synergistic activity; the highest synergistic activity was observed with erythromycin and cephalexin. In the case of cephalexin, a reversion in resistance was observed. The plant extracts used in the study exhibited additive and synergistic antibacterial activity against S. epidermidis, hence providing an effective alternative to deal with the problem of multidrug resistance.

RNA Futile Cycling in Model Persisters Derived from MazF Accumulation (Open Access)

DTIC Science & Technology

2015-11-17

they remained highly metabolically active . We further uncovered a futile cycle driven by continued transcription and MazF-mediated transcript degradation...presence of antibiotics (7), although exceptions have been noted for prod- rugs that require activation (8). Rather, they are rare phenotypic variants...arise from slowly grow- ing or nongrowing bacteria with reduced metabolic activity , where antibiotic targets are inactive and resilient to antibiotic

Antimicrobial Synthetic Polymers: An Update on Structure-Activity Relationships.

PubMed

Ergene, Cansu; Palermo, Edmund F

2018-01-01

The rising incidence of antibiotic-resistant infections, combined with a declining number of new antibiotic drug approvals, has generated an alarming therapeutic gap that critically undermines public health. Host Defense Peptides (HDPs), sometimes referred to as "Nature's Antibiotics", are short chain, amphiphilic and cationic peptide sequences found in all multicellular organisms as part of their innate immunity. While there is a vast diversity in terms of HDP sequence and secondary structure, they all seem to share physiochemical characteristics that can be appropriated for macromolecular design by the synthetic polymer chemist. Over the past decade, remarkable progress has been made in the design and synthesis of polymer-based materials that effectively mimic HDP action - broad-spectrum antibacterial potency, rapid bactericidal kinetics, and minimal toxicity to human cells - while offering the additional benefits of low cost, high scalability, and lower propensity to induce resistance, relative to their peptide-based counterparts. A broad range of different macromolecular structures and architectures have been explored in this design space, including polynorbornenes, poly(meth)acrylates, poly(meth)acrylamides, nylon-2 polymers, and polycarbonates, to name a just few. Across all of these diverse chemical categories, the key determinants of antibacterial and hemolytic activity are the same as in HDPs: net cationic charge at neutral pH, well-balanced facial amphiphilicity, and the molecular weight of the compounds. In this review, we focus in particular on recent progress in the polymethacrylate category first pioneered by Kuroda and DeGrado and later modified, expanded upon and rigorously optimized by Kuroda's and many other groups. Key findings and future challenges will be highlighted. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

3,4-Dimethoxyphenyl bis-benzimidazole, a novel DNA topoisomerase inhibitor that preferentially targets Escherichia coli topoisomerase I

PubMed Central

Bansal, Sandhya; Sinha, Devapriya; Singh, Manish; Cheng, Bokun; Tse-Dinh, Yuk-Ching; Tandon, Vibha

2012-01-01

Objectives Antibiotic resistance in bacterial pathogens is a serious clinical problem. Novel targets are needed to combat increasing drug resistance in Escherichia coli. Our objective is to demonstrate that 2-(3,4-dimethoxyphenyl)-5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2yl]-1H-benzimidazole (DMA) inhibits E. coli DNA topoisomerase I more strongly than human topoisomerase I. In addition, DMA is non-toxic to mammalian cells at antibiotic dosage level. Methods In the present study, we have established DMA as an antibacterial compound by determining MICs, post-antibiotic effects (PAEs) and MBCs for different standard as well as clinical strains of E. coli. We have described the differential catalytic inhibitory mechanism of bis-benzimidazole, DMA, for human and E. coli topoisomerase I and topoisomerase II by performing different assays, including relaxation assays, cleavage–religation assays, DNA unwinding assays, ethidium bromide displacement assays, decatenation assays and DNA gyrase supercoiling assays. Results DMA significantly inhibited bacterial growth at a very low concentration, but did not affect human cell viability at higher concentrations. Activity assays showed that it preferentially targeted E. coli topoisomerase I over human topoisomerase I, topoisomerase II and gyrase. Cleavage–religation assays confirmed DMA as a poison inhibitor of E. coli topoisomerase I. This study illuminates new properties of DMA, which may be further modified to develop an efficient topoisomerase inhibitor that is selective towards bacterial topoisomerase I. Conclusions This is the first report of a bis-benzimidazole acting as an E. coli topoisomerase I inhibitor. DMA is a safe, non-cytotoxic molecule to human cells at concentrations that are needed for antibacterial activity. PMID:22945915

Pseudomonas fluorescens CHA0 maintains carbon delivery to Fusarium graminearum-infected roots and prevents reduction in biomass of barley shoots through systemic interactions

PubMed Central

Henkes, Gunnar J.; Jousset, Alexandre; Bonkowski, Michael; Thorpe, Michael R.; Scheu, Stefan; Lanoue, Arnaud; Schurr, Ulrich; Röse, Ursula S. R.

2011-01-01

Soil bacteria such as pseudomonads may reduce pathogen pressure for plants, both by activating plant defence mechanisms and by inhibiting pathogens directly due to the production of antibiotics. These effects are hard to distinguish under field conditions, impairing estimations of their relative contributions to plant health. A split-root system was set up with barley to quantify systemic and local effects of pre-inoculation with Pseudomonas fluorescens on the subsequent infection process by the fungal pathogen Fusarium graminearum. One root half was inoculated with F. graminearum in combination with P. fluorescens strain CHA0 or its isogenic antibiotic-deficient mutant CHA19. Bacteria were inoculated either together with the fungal pathogen or in separate halves of the root system to separate local and systemic effects. The short-term plant response to fungal infection was followed by using the short-lived isotopic tracer 11CO2 to track the delivery of recent photoassimilates to each root half. In the absence of bacteria, fungal infection diverted carbon from the shoot to healthy roots, rather than to infected roots, although the overall partitioning from the shoot to the entire root system was not modified. Both local and systemic pre-inoculation with P. fluorescens CHA0 prevented the diversion of carbon as well as preventing a reduction in plant biomass in response to F. graminearum infection, whereas the non-antibiotic-producing mutant CHA19 lacked this ability. The results suggest that the activation of plant defences is a central feature of biocontrol bacteria which may even surpass the effects of direct pathogen inhibition. PMID:21561952

Some chemical and physical properties of nisin, a small-protein antibiotic produced by Lactococcus lactis.

PubMed Central

Liu, W; Hansen, J N

1990-01-01

Nisin is a small gene-encoded antimicrobial protein produced by Lactococcus lactis that contains unusual dehydroalanine and dehydrobutyrine residues. The reactivity of these residues toward nucleophiles was explored by reacting nisin with a variety of mercaptans. The kinetics of reaction with 2-mercaptoethane-sulfonate and thioglycolate indicated that the reaction pathway includes a binding step. Reaction of nisin at high pH resulted in the formation of multimeric products, apparently as a result of intramolecular and intermolecular reactions between nucleophilic groups and the dehydro residues. One of the nucleophiles had a pKa of about 9.8. The unique vinyl protons of the dehydro residues that give readily identifiable proton nuclear magnetic resonances were used to observe the addition of nucleophiles to the dehydro moiety. After reaction with nucleophiles, nisin lost its antibiotic activity and no longer showed the dehydro resonances, indicating that the dehydro groups had been modified. The effect of pH on the solubility of nisin was determined; the solubility was quite high at low pH (57 mg/ml at pH 2) and was much lower at high pH (0.25 mg/ml at pH 8 to 12), as measured before significant pH-induced chemical modification had occurred. High-performance liquid chromatography on a C18 column was an effective technique for separating unmodified nisin from its reaction products. The cyanogen bromide cleavage products of nisin were about 90% less active toward inhibition of bacterial spore outgrowth than was native nisin. These results are consistent with earlier observations, which suggested that the dehydro residues of nisin have a role in the mechanism of antibiotic action, in which they act as electrophilic Michael acceptors toward nucleophiles in the cellular target. Images PMID:2119570

Biological Characterization of the Biocontrol Agent Bacillus amyloliquefaciens CPA-8: The Effect of Temperature, pH and Water Activity on Growth, Susceptibility to Antibiotics and Detection of Enterotoxic Genes.

PubMed

Gotor-Vila, Amparo; Teixidó, Neus; Sisquella, María; Torres, Rosario; Usall, Josep

2017-09-01

This work focuses on the biological understanding of the biocontrol agent Bacillus amyloliquefaciens CPA-8 in order to accomplish the characterization required in the registration process for the development of a microorganism-based product. The tolerance of CPA-8 to grow under different pH-temperature and water activity (a w )-temperature conditions was widely demonstrated. Regarding the pH results, optimum growth at the evaluated conditions was observed at 37 °C and pH between 7 and 5. On the contrary, the slowest growth was recorded at 20 °C and pH 4.5. Moreover, the type of solute used to reduce a w had a great influence on the minimum a w at which the bacterium was able to grow. The lowest a w values for CPA-8 growth in media modified with glycerol and glucose were 0.950 and 0.960, respectively. Besides, the lowest a w for CPA-8 growth increased when the temperature decreased to 20 °C, at which CPA-8 was not able to grow at less than 0.990 a w , regardless of the type of solute. Antibiotic susceptibility tests were carried out to determine which antibiotic could affect the behavior of the bacteria and revealed that CPA-8 was clearly resistant to hygromycin. Finally, a PCR amplification assay to detect the presence of enterotoxic genes from Bacillus cereus in CPA-8 was also performed. CPA-8 gave negative results for all the genes tested except for nheA gene, which is not enough for the toxicity expression, suggesting that fruit treated with this antagonist will not be a potential vehicle for foodborne illnesses.

Diabetic foot infections: Current treatment and delaying the 'post-antibiotic era'.

PubMed

Lipsky, Benjamin A

2016-01-01

Treatment for diabetic foot infections requires properly diagnosing infection, obtaining an appropriate specimen for culture, assessing for any needed surgical procedures and selecting an empiric antibiotic regimen. Therapy will often need to be modified based on results of culture and sensitivity testing. Because of excessive and inappropriate use of antibiotics for treating diabetic foot infections, resistance to the usually employed bacteria has been increasing to alarming levels. This article reviews recommendations from evidence-based guidelines, informed by results of systematic reviews, on treating diabetic foot infections. Data from the pre-antibiotic era reported rates of mortality of about 9% and of high-level leg amputations of about 70%. Outcomes have greatly improved with appropriate antibiotic therapy. While there are now many oral and parenteral antibiotic agents that have demonstrated efficacy in treating diabetic foot infections, the rate of infection with multidrug-resistant pathogens is growing. This problem requires a multi-focal approach, including providing education to both clinicians and patients, developing robust antimicrobial stewardship programmes and using new diagnostic and therapeutic technologies. Recently, new methods have been developed to find novel antibiotic agents and to resurrect old treatments, like bacteriophages, for treating these difficult infections. Medical and political leaders have recognized the serious global threat posed by the growing problem of antibiotic resistance. By a multipronged approach that includes exerting administrative pressure on clinicians to do the right thing, investing in new technologies and encouraging the profitable development of new antimicrobials, we may be able to stave off the coming 'post-antibiotic era'. Copyright © 2016 John Wiley & Sons, Ltd.

Quality indicators for responsible antibiotic use in the inpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.

PubMed

Monnier, Annelie A; Schouten, Jeroen; Le Maréchal, Marion; Tebano, Gianpiero; Pulcini, Céline; Stanic Benic, Mirjana; Vlahovic-Palcevski, Vera; Milanic, Romina; Adriaenssens, Niels; Versporten, Ann; Huttner, Benedikt; Zanichelli, Veronica; Hulscher, Marlies E; Gyssens, Inge C

2018-06-01

This study was conducted as part of the Driving Reinvestment in Research and Development and Responsible Antibiotic Use (DRIVE-AB) project and aimed to develop generic quality indicators (QIs) for responsible antibiotic use in the inpatient setting. A RAND-modified Delphi method was applied. First, QIs were identified by a systematic review. A complementary search was performed on web sites of relevant organizations. Duplicates were removed and disease and patient-specific QIs were combined into generic indicators. The relevance of these QIs was appraised by a multidisciplinary international stakeholder panel through two questionnaires and an in-between consensus meeting. The systematic review retrieved 70 potential generic QIs. The QIs were appraised by 25 international stakeholders with diverse backgrounds (medical community, public health, patients, antibiotic research and development, regulators, governments). Ultimately, 51 QIs were selected in consensus. QIs with the highest relevance score included: (i) an antibiotic plan should be documented in the medical record at the start of the antibiotic treatment; (ii) the results of bacteriological susceptibility testing should be documented in the medical record; (iii) the local guidelines should correspond to the national guidelines but should be adapted based on local resistance patterns; (iv) an antibiotic stewardship programme should be in place at the healthcare facility; and (v) allergy status should be taken into account when antibiotics are prescribed. This systematic and stepwise method combining evidence from literature and stakeholder opinion led to multidisciplinary international consensus on generic inpatient QIs that can be used globally to assess the quality of antibiotic use.

Impact of a computer-generated alert system prompting review of antibiotic use in hospitals.

PubMed

Lesprit, Philippe; Duong, Trung; Girou, Emmanuelle; Hemery, François; Brun-Buisson, Christian

2009-05-01

The aim of this study was to measure the impact on antibiotic use of a computer-generated alert prompting post-prescription review and direct counselling in hospital wards. A computer-generated alert on new prescriptions of 15 antibiotics was reviewed weekly by an infectious disease physician for 41 weeks. During the first 6 months of the study, criteria selected for potential intervention were: (i) a planned duration of treatment of > or =10 days; (ii) discordance between the spectrum of the prescribed antibiotic and available microbiological results; or (iii) prescriptions of broad-spectrum beta-lactams, fluoroquinolones, glycopeptides or linezolid. During the following 5 months, the alert was restricted to any prescription of the 15 antibiotics in the 9 wards where overall antibiotic use had not decreased in the past year. We analysed 2385 prescriptions, 932 (39%) of which generated an alert for potential intervention. Among the latter, 482 (51.7%) prescriptions prompted direct counselling, mainly for shortening the planned duration of therapy (18.9%), withdrawing antibiotics (16.2%) or streamlining therapy (15.5%). The attending physicians' compliance with the recommendations was 80%. The overall median (interquartile range) days of therapy prescribed by the attending physicians was reduced from an initial duration of 8 (7-14) to 7 (6-11) days (P < 0.0001), resulting in 26.5% less antibiotic days prescribed. The time required for the intervention was 6 h per week. This computer-prompted post-prescription review led physicians to modify one half of the antibiotic courses initially prescribed and was well accepted by the majority, although they had not requested counselling.

Oral antibiotics enhance antibody responses to keyhole limpet hemocyanin in orally but not muscularly immunized chickens.

PubMed

Murai, Atsushi; Kitahara, Kazuki; Okumura, Shouta; Kobayashi, Misato; Horio, Fumihiko

2016-02-01

Recent studies have emphasized the crucial role of gut microbiota in triggering and modulating immune response. We aimed to determine whether the modification of gut microbiota by oral co-administration of two antibiotics, ampicillin and neomycin, would lead to changes in the antibody response to antigens in chickens. Neonatal chickens were given or not given ampicillin and neomycin (0.25 and 0.5 g/L, respectively) in drinking water. At 2 weeks of age, the chicks were muscularly or orally immunized with antigenic keyhole limpet hemocyanin (KLH), and then serum anti-KLH antibody levels were examined by ELISA. In orally immunized chicks, oral antibiotics treatment enhanced antibody responses (IgM, IgA, IgY) by 2-3-fold compared with the antibiotics-free control, while the antibiotics did not enhance antibody responses in the muscularly immunized chicks. Concomitant with their enhancement of antibody responses, the oral antibiotics also lowered the Lactobacillus species in feces. Low doses of antibiotics (10-fold and 100-fold lower than the initial trial), which failed to change the fecal Lactobacillus population, did not modify any antibody responses when chicks were orally immunized with KLH. In conclusion, oral antibiotics treatment enhanced the antibody response to orally exposed antigens in chickens. This enhancement of antibody response was associated with a modification of the fecal Lactobacillus content, suggesting a possible link between gut microbiota and antibody response in chickens. © 2015 Japanese Society of Animal Science.

Sustained release of antibiotics from injectable and thermally responsive polypeptide depots.

PubMed

Adams, Samuel B; Shamji, Mohammed F; Nettles, Dana L; Hwang, Priscilla; Setton, Lori A

2009-07-01

Biodegradable polymeric scaffolds are of interest for delivering antibiotics to local sites of infection in orthopaedic applications, such as bone and diarthrodial joints. The objective of this study was to develop a biodegradable scaffold with ease of drug loading in aqueous solution, while providing for drug depot delivery via syringe injection. Elastin-like polypeptides (ELPs) were used for this application, biopolymers of repeating pentapeptide sequences that were thermally triggered to undergo in situ depot formation at body temperature. ELPs were modified to enable loading with the antibiotics, cefazolin, and vancomycin, followed by induction of the phase transition in vitro. Cefazolin and vancomycin concentrations were monitored, as well as bioactivity of the released antibiotics, to test an ability of the ELP depot to provide for prolonged release of bioactive drugs. Further tests of formulation viscosity were conducted to test suitability as an injectable drug carrier. Results demonstrate sustained release of therapeutic concentrations of bioactive antibiotics by the ELP, with first-order time constants for drug release of approximately 25 h for cefazolin and approximately 500 h for vancomycin. These findings illustrate that an injectable, in situ forming ELP depot can provide for sustained release of antibiotics with an effect that varies across antibiotic formulation. ELPs have important advantages for drug delivery, as they are known to be biocompatible, biodegradable, and elicit no known immune response. These benefits suggest distinct advantages over currently used carriers for antibiotic drug delivery in orthopedic applications. (c) 2008 Wiley Periodicals, Inc.

Effect of Physicians' Attitudes and Knowledge on the Quality of Antibiotic Prescription: A Cohort Study.

PubMed

Gonzalez-Gonzalez, Cristian; López-Vázquez, Paula; Vázquez-Lago, Juan Manuel; Piñeiro-Lamas, María; Herdeiro, Maria Teresa; Arzamendi, Pilar Chávarri; Figueiras, Adolfo

2015-01-01

Resistance increases with the use and abuse of antibiotics. Since physicians are primarily responsible for the decision to use antibiotics, ascertaining the attitudes and knowledge that underlie their prescribing habits is thus a prerequisite for improving prescription. Three-year follow-up cohort study (2008-2010) targeting primary-care physicians (n = 2100) in Galicia, a region in NW Spain. We used data obtained from a postal survey to assess knowledge and attitudes. A physician was deemed to have demonstrated Appropriate Quality Prescription of Antibiotics (dependent variable) in any case where half or more of the indicators proposed by the European Surveillance of Antimicrobial Consumption had values that were better than the reference values for Spain. The mail-questionnaire response rate was 68·0% (1428/2100). The adjusted increase in the interquartile OR of displaying good prescribing of antibiotics for each attitude was: 205% for fear ("When in doubt, it is better to ensure that a patient is cured of an infection by using a broad-spectrum antibiotic"; 95%CI: 125% to 321%); 119% for better knowledge ("Amoxicillin is useful for resolving most respiratory infections in primary care"; 95%CI: 67% to 193%); and 21% for complacency with patients' demands ("Antibiotics are often prescribed due to patients' demands"; 95%CI: 0% to 45%). Due to the fact that physicians' knowledge and attitudes are potentially modifiable, the implementation of purpose-designed educational interventions based on the attitudes identified may well serve to improve antibiotic prescription.

Permanent antibiotic impregnated intramedullary nail in diabetic limb salvage: a case report and literature review

PubMed Central

Woods, Jason B.; Lowery, Nicholas J.; Burns, Patrick R.

2012-01-01

Managing complications after attempted hind foot and ankle arthrodesis with intramedullary nail fixation is a challenge. This situation becomes more problematic in the patient with diabetes mellitus and multiple comorbidities. Infection and subsequent osteomyelitis can be a devastating, limb threatening complication associated with these procedures. The surgeon must manage both the infectious process and the skeletal instability concurrently. This article provides a literature review and detailed management strategies for a modified technique of employing antibiotic impregnated polymethylmethacrylate-coated intramedullary nailing. PMID:22396833

Identification of an antibacterial compound, benzylideneacetone, from Xenorhabdus nematophila against major plant-pathogenic bacteria.

PubMed

Ji, Dongjin; Yi, Youngkeun; Kang, Ga-Hwa; Choi, Yong-Hwa; Kim, Pankyung; Baek, Nam-In; Kim, Yonggyun

2004-10-15

An entomopathogenic bacterium, Xenorhabdus nematophila, is known to have potent antibiotic activities to maintain monoxenic condition in its insect host for effective pathogenesis and ultimately for optimal development of its nematode symbiont, Steinernema carpocapsae. In this study we assess its antibacterial activity against plant-pathogenic bacteria and identify its unknown antibiotics. The bacterial culture broth had significant antibacterial activity that increased with development of the bacteria and reached its maximum at the stationary growth phase. The antibiotic activities were significant against five plant-pathogenic bacterial strains: Agrobacterium vitis, Pectobacterium carotovorum subsp. atrosepticum, P. carotovorum subsp. carotovorum, Pseudomonas syringae pv. tabaci, and Ralstonia solanacearum. The antibacterial factors were extracted with butanol and fractionated using column chromatography with the eluents of different hydrophobic intensities. Two active antibacterial subfractions were purified, and the higher active fraction was further fractionated and identified as a single compound of benzylideneacetone (trans-4-phenyl-3-buten-2-one). With heat stability, the synthetic compound showed equivalent antibiotic activity and spectrum to the purified compound. This study reports a new antibiotic compound synthesized by X. nematophila, which is a monoterpenoid compound and active against some Gram-negative bacteria.

Antibiotic-resistant bacteria: a challenge for the food industry.

PubMed

Capita, Rosa; Alonso-Calleja, Carlos

2013-01-01

Antibiotic-resistant bacteria were first described in the 1940s, but whereas new antibiotics were being discovered at a steady rate, the consequences of this phenomenon were slow to be appreciated. At present, the paucity of new antimicrobials coming into the market has led to the problem of antibiotic resistance fast escalating into a global health crisis. Although the selective pressure exerted by the use of antibiotics (particularly overuse or misuse) has been deemed the major factor in the emergence of bacterial resistance to these antimicrobials, concerns about the role of the food industry have been growing in recent years and have been raised at both national and international levels. The selective pressure exerted by the use of antibiotics (primary production) and biocides (e.g., disinfectants, food and feed preservatives, or decontaminants) is the main driving force behind the selection and spread of antimicrobial resistance throughout the food chain. Genetically modified (GM) crops with antibiotic resistance marker genes, microorganisms added intentionally to the food chain (probiotic or technological) with potentially transferable antimicrobial resistance genes, and food processing technologies used at sub-lethal doses (e.g., alternative non-thermal treatments) are also issues for concern. This paper presents the main trends in antibiotic resistance and antibiotic development in recent decades, as well as their economic and health consequences, current knowledge concerning the generation, dissemination, and mechanisms of antibacterial resistance, progress to date on the possible routes for emergence of resistance throughout the food chain and the role of foods as a vehicle for antibiotic-resistant bacteria. The main approaches to prevention and control of the development, selection, and spread of antibacterial resistance in the food industry are also addressed.

Early-life antibiotic use and subsequent diagnosis of food allergy and allergic diseases.

PubMed

Hirsch, A G; Pollak, J; Glass, T A; Poulsen, M N; Bailey-Davis, L; Mowery, J; Schwartz, B S

2017-02-01

Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. We used longitudinal data on 30 060 children up to age 7 years from Geisinger Clinic's electronic health record to conduct a sex- and age-matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins and macrolides. There were 484 milk allergy cases, 598 non-milk food allergy cases and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (Odds Ratio; 95% Confidence interval) (1.78; 1.28-2.48), non-milk food allergy (1.65; 1.27-2.14), and other allergies (3.07; 2.72-3.46) compared with children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with paediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform paediatric treatment decisions. © 2016 John Wiley & Sons Ltd.

Early Life Antibiotic Use and Subsequent Diagnosis of Food Allergy and Allergic Diseases

PubMed Central

Hirsch, Annemarie G.; Pollak, Jonathan; Glass, Thomas A.; Poulsen, Melissa N.; Bailey-Davis, Lisa; Mowery, Jacob; Schwartz, Brian S.

2016-01-01

Background Antibiotic use in early life has been linked to disruptions in the microbiome. Such changes can disturb immune system development. Differences have been observed in the microbiota of children with and without allergies, but there have been few studies on antibiotic use and allergic disease. Objective We evaluated associations of early-life antibiotic use with subsequent occurrence of food allergy and other allergies in childhood using electronic health record data. Methods We used longitudinal data on 30,060 children up to age 7 years from Geisinger Clinic’s electronic health record to conduct a sex and age matched case-control study to evaluate the association between antibiotic use and milk allergy, non-milk food allergies, and other allergies. For each outcome, we estimated conditional logistic regression models adjusting for race/ethnicity, history of Medical Assistance, and mode of birth delivery. Models were repeated separately for penicillins, cephalosporins, and macrolides. Results There were 484 milk allergy cases, 598 non-milk food allergy cases, and 3652 other allergy cases. Children with three or more antibiotic orders had a greater odds of milk allergy (odds ratio; 95% confidence interval) (1.78; 1.28–2.48), non-milk food allergy (1.65; 1.27–2.14), and other allergies (3.07; 2.72–3.46) compared to children with no antibiotic orders. Associations were strongest at younger ages and differed by antibiotic class. Conclusions and Clinical Relevance We observed associations between antibiotic orders and allergic diseases, providing evidence of a potentially modifiable clinical practice associated with pediatric allergic disease. Differences by antibiotic class should be further explored, as this knowledge could inform pediatric treatment decisions. PMID:27562571

Cryptic antifungal compounds active by synergism with polyene antibiotics.

PubMed

Kinoshita, Hiroshi; Yoshioka, Mariko; Ihara, Fumio; Nihira, Takuya

2016-04-01

The majority of antifungal compounds reported so far target the cell wall or cell membrane of fungi, suggesting that other types of antibiotics cannot exert their activity because they cannot penetrate into the cells. Therefore, if the permeability of the cell membrane could be enhanced, many antibiotics might be found to have antifungal activity. We here used the polyene antibiotic nystatin, which binds to ergosterol and forms pores at the cell membrane, to enhance the cellular permeability. In the presence of nystatin, many culture extracts from entomopathogenic fungi displayed antifungal activity. Among all the active extracts, two active components were purified and identified as helvolic acid and terramide A. Because the minimum inhibitory concentration of either compound was reduced four-fold in the presence of nystatin, it can be concluded that this screening method is useful for detecting novel antifungal activity. Copyright © 2015 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Impact of anthropogenic activities on the dissemination of antibiotic resistance across ecological boundaries.

PubMed

Tripathi, Vijay; Cytryn, Eddie

2017-02-28

Antibiotics are considered to be one of the major medical breakthroughs in history. Nonetheless, over the past four decades, antibiotic resistance has reached alarming levels worldwide and this trend is expected to continue to increase, leading some experts to forecast the coming of a 'post-antibiotic' era. Although antibiotic resistance in pathogens is traditionally linked to clinical environments, there is a rising concern that the global propagation of antibiotic resistance is also associated with environmental reservoirs that are linked to anthropogenic activities such as animal husbandry, agronomic practices and wastewater treatment. It is hypothesized that the emergence and dissemination of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs) within and between environmental microbial communities can ultimately contribute to the acquisition of antibiotic resistance in human pathogens. Nonetheless, the scope of this phenomenon is not clear due to the complexity of microbial communities in the environment and methodological constraints that limit comprehensive in situ evaluation of microbial genomes. This review summarizes the current state of knowledge regarding antibiotic resistance in non-clinical environments, specifically focusing on the dissemination of antibiotic resistance across ecological boundaries and the contribution of this phenomenon to global antibiotic resistance. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

An efflux pump (MexAB-OprM) of Pseudomonas aeruginosa is associated with antibacterial activity of Epigallocatechin-3-gallate (EGCG).

PubMed

Kanagaratnam, Rashmi; Sheikh, Rida; Alharbi, Fahad; Kwon, Dong H

2017-12-01

Pseudomonas aeruginosa is a notorious multidrug resistant nosocomial pathogen. An efflux pump (MexAB-OprM) is the main contributor to the multidrug resistance in clinical isolates of P. aeruginosa. Epigallocatechin-3-gallate (EGCG), a polyphenolic compound extracted from green tea, exhibits antibacterial activity. It is unclear that molecular details of the antibacterial activity of EGCG, EGCG-effect on antibiotic susceptibility, and clinical relevance of EGCG in bacteria. This study aimed to determine the roles of the efflux pump and an efflux pump inhibitor (phenylalanine-arginine β-naphthylamide; PAβN) in the antibacterial activity of EGCG and the EGCG-effect on antibiotic susceptibility. Twenty-two multidrug resistant clinical isolates of P. aeruginosa and a wild type P. aeruginosa PAO1 were used to determine antibacterial activity of EGCG and EGCG-effect on antibiotic susceptibility. An efflux pump (MexAB-OPrM) mutant strain, its complemented strain carrying an intact mexAB-oprM, and their parental strain were used to determine roles of MexAB-OprM in the antibacterial activity of EGCG and EGCG-mediated antibiotic susceptibility. PAβN was also used to evaluate EGCG as a possible efflux pump inhibitor. EGCG inhibited cellular growth and killed 100% of cells at 64-512 µg/ml and at 256-1024 µg/ml, respectively, in all tested 22 clinical isolates including the wild type strain. A subinhibitory concentration of EGCG significantly enhanced susceptibility to antibiotics, unexceptionally to chloramphenicol and tetracyclines (≥4-fold) of the clinical isolates. Both the antibacterial activity of EGCG and the EGCG-mediated antibiotic susceptibility were enhanced more in the efflux pump mutant strain (mexB::Gm) than the parental strain, suggesting additionally accumulated-EGCG produced the more antibacterial activity in the mutant strain. EGCG was synergistically interacted with PAβN with enhancing susceptibility to all tested antibiotics (up to >500-fold) at higher levels than either EGCG alone or PAβN alone, suggesting EGCG may also inhibit the efflux pump with additional accumulation of the antibiotics. The results demonstrate that EGCG exhibits antibacterial activity and enhances antibiotic effects against clinical isolates of P. aeruginosa. EGCG may inhibit the efflux pump (MexAB-OprM) through which are associated with the antibacterial activity of EGCG and the EGCG-mediated antibiotic susceptibility in P. aeruginosa. Copyright © 2017 Elsevier GmbH. All rights reserved.

The effect of intrapartum antibiotics on early-onset neonatal sepsis in Dhaka, Bangladesh: a propensity score matched analysis

PubMed Central

2014-01-01

Background We estimate the effect of antibiotics given in the intrapartum period on early-onset neonatal sepsis in Dhaka, Bangladesh using propensity score techniques. Methods We followed 600 mother-newborn pairs as part of a cohort study at a maternity center in Dhaka. Some pregnant women received one dose of intravenous antibiotics during labor based on clinician discretion. Newborns were followed over the first seven days of life for early-onset neonatal sepsis defined by a modified version of the World Health Organization Young Infants Integrated Management of Childhood Illnesses criteria. Using propensity scores we matched women who received antibiotics with similar women who did not. A final logistic regression model predicting sepsis was run in the matched sample controlling for additional potential confounders. Results Of the 600 mother-newborn pairs, 48 mothers (8.0%) received antibiotics during the intrapartum period. Seventy-seven newborns (12.8%) were classified with early-onset neonatal sepsis. Antibiotics appeared to be protective (odds ratio 0.381, 95% confidence interval 0.115–1.258), however this was not statistically significant. The results were similar after adjusting for prematurity, wealth status, and maternal colonization status (odds ratio 0.361, 95% confidence interval 0.106–1.225). Conclusions Antibiotics administered during the intrapartum period may reduce the risk of early-onset neonatal sepsis in high neonatal mortality settings like Dhaka. PMID:24742087

Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age.

PubMed

Chow, Angela L P; Lye, David C; Arah, Onyebuchi A

2015-11-30

Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital's antibiotic CDSS on patients' clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS's recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26-1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20-1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91-1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34-3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42-2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48-2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations.

Childhood BMI in relation to microbiota in infancy and lifetime antibiotic use.

PubMed

Korpela, K; Zijlmans, M A C; Kuitunen, M; Kukkonen, K; Savilahti, E; Salonen, A; de Weerth, C; de Vos, W M

2017-03-03

Children with high body mass index (BMI) at preschool age are at risk of developing obesity. Early identification of factors that increase the risk of excessive weight gain could help direct preventive actions. The intestinal microbiota and antibiotic use have been identified as potential modulators of early metabolic programming and weight development. To test if the early microbiota composition is associated with later BMI, and if antibiotic use modifies this association, we analysed the faecal microbiota composition at 3 months and the BMI at 5-6 years in two cohorts of healthy children born vaginally at term in the Netherlands (N = 87) and Finland (N = 75). We obtained lifetime antibiotic use records and measured weight and height of all children. The relative abundance of streptococci was positively and the relative abundance of bifidobacteria negatively associated with the BMI outcome. The association was especially strong among children with a history of antibiotic use. Bacteroides relative abundance was associated with BMI only in the children with minimal lifetime antibiotic exposure. The intestinal microbiota of infants are predictive of later BMI and may serve as an early indicator of obesity risk. Bifidobacteria and streptococci, which are indicators of microbiota maturation in infants, are likely candidates for metabolic programming of infants, and their influence on BMI appears to depend on later antibiotic use.

Accumulation of the antibiotic phenazine-1-carboxylic acid in the rhizosphere of dryland wheat

USDA-ARS?s Scientific Manuscript database

Natural antibiotics are thought to function in microbial defense, fitness, competitiveness, biocontrol, communication and gene regulation activity, and antibiotic-producing species are commonly found in microbial communities throughout nature. However, the frequency and amount of antibiotic producti...

Nitric Oxide from IFNγ-Primed Macrophages Modulates the Antimicrobial Activity of β-Lactams against the Intracellular Pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella

PubMed Central

Jones-Carson, Jessica; Zweifel, Adrienne E.; Tapscott, Timothy; Austin, Chad; Brown, Joseph M.; Jones, Kenneth L.; Voskuil, Martin I.; Vázquez-Torres, Andrés

2014-01-01

Our investigations show that nonlethal concentrations of nitric oxide (NO) abrogate the antibiotic activity of β-lactam antibiotics against Burkholderia pseudomallei, Escherichia coli and nontyphoidal Salmonella enterica serovar Typhimurium. NO protects B. pseudomallei already exposed to β-lactams, suggesting that this diatomic radical tolerizes bacteria against the antimicrobial activity of this important class of antibiotics. The concentrations of NO that elicit antibiotic tolerance repress consumption of oxygen (O2), while stimulating hydrogen peroxide (H2O2) synthesis. Transposon insertions in genes encoding cytochrome c oxidase-related functions and molybdenum assimilation confer B. pseudomallei a selective advantage against the antimicrobial activity of the β-lactam antibiotic imipenem. Cumulatively, these data support a model by which NO induces antibiotic tolerance through the inhibition of the electron transport chain, rather than by potentiating antioxidant defenses as previously proposed. Accordingly, pharmacological inhibition of terminal oxidases and nitrate reductases tolerizes aerobic and anaerobic bacteria to β-lactams. The degree of NO-induced β-lactam antibiotic tolerance seems to be inversely proportional to the proton motive force (PMF), and thus the dissipation of ΔH+ and ΔΨ electrochemical gradients of the PMF prevents β-lactam-mediated killing. According to this model, NO generated by IFNγ-primed macrophages protects intracellular Salmonella against imipenem. On the other hand, sublethal concentrations of imipenem potentiate the killing of B. pseudomallei by NO generated enzymatically from IFNγ-primed macrophages. Our investigations indicate that NO modulates the antimicrobial activity of β-lactam antibiotics. PMID:25121731

Histopathology of valves in infective endocarditis, diagnostic criteria and treatment considerations.

PubMed

Brandão, Tatiana J D; Januario-da-Silva, Carolina A; Correia, Marcelo G; Zappa, Monica; Abrantes, Jaime A; Dantas, Angela M R; Golebiovski, Wilma; Barbosa, Giovanna Ianini F; Weksler, Clara; Lamas, Cristiane C

2017-04-01

Infective endocarditis (IE) is a severe disease. Pathogen isolation is fundamental so as to treat effectively and reduce morbidity and mortality. Blood and valve culture and histopathology (HP) are routinely employed for this purpose. Valve HP is the gold standard for diagnosis. To determine the sensitivity and specificity of clinical criteria for IE (the modified Duke and the St Thomas' minor modifications, STH) of blood and valve culture compared to valve HP, and to evaluate antibiotic treatment duration. Prospective case series of patients, from 2006 to 2014 with surgically treated IE. Statistical analysis was done by the R software. There were 136 clinically definite episodes of IE in 133 patients. Mean age ± SD was 43 ± 15.6 years and IE was left sided in 81.6 %. HP was definite in 96 valves examined, which were used as gold standard. Sensitivity of blood culture was 61 % (CI 0.51, 0.71) and of valve culture 15 % (CI 0.07, 0.26). The modified Duke criteria were 65 % (CI 0.55, 0.75) sensitive and 33 % specific, while the STH's sensitivity was 72 % (CI 0.61, 0.80) with similar specificity. In multivariate analysis and logistic regression, the only variable with statistical significance was duration of antibiotic therapy postoperatively. Valve HP had high sensitivity and valve culture low sensitivity in the diagnosis of IE. The STH's criteria were more sensitive than the modified Duke criteria. Valve HP should guide duration of postoperative antibiotic treatment.

Use of benchmarking techniques to justify the evolution of antibiotic management programs in healthcare systems.

PubMed

Schentag, J J; Paladino, J A; Birmingham, M C; Zimmer, G; Carr, J R; Hanson, S C

1995-01-01

To apply basic benchmarking techniques to hospital antibiotic expenditures and clinical pharmacy personnel and their duties, to identify cost savings strategies for clinical pharmacy services. Prospective survey of 18 hospitals ranging in size from 201 to 942 beds. Each was asked to provide antibiotic expenditures, an overview of their clinical pharmacy services, and to describe the duties of clinical pharmacists involved in antibiotic management activities. Specific information was sought on the use of pharmacokinetic dosing services, antibiotic streamlining, and oral switch in each of the hospitals. Most smaller hospitals (< 300 beds) did not employ clinical pharmacists with the specific duties of antibiotic management or streamlining. At these institutions, antibiotic management services consisted of formulary enforcement and aminoglycoside and/or vancomycin dosing services. The larger hospitals we surveyed employed clinical pharmacists designated as antibiotic management specialists, but their usual activities were aminoglycoside and/or vancomycin dosing services and formulary enforcement. In virtually all hospitals, the yearly expenses for antibiotics exceeded those of Millard Fillmore Hospitals by $2,000-3,000 per occupied bed. In a 500-bed hospital, this difference in expenditures would exceed $1.5 million yearly. Millard Fillmore Health System has similar types of patients, but employs clinical pharmacists to perform streamlining and/or switch functions at days 2-4, when cultures come back from the laboratory. The antibiotic streamlining and oral switch duties of clinical pharmacy specialists are associated with the majority of cost savings in hospital antibiotic management programs. The savings are considerable to the extent that most hospitals with 200-300 beds could readily cost-justify a full-time clinical pharmacist to perform these activities on a daily basis. Expenses of the program would be offset entirely by the reduction in the actual pharmacy expenditures on antibiotics.

Structure-guided optimization of protein kinase inhibitors reverses aminoglycoside antibiotic resistance

PubMed Central

Stogios, Peter J.; Spanogiannopoulos, Peter; Evdokimova, Elena; Egorova, Olga; Shakya, Tushar; Todorovic, Nick; Capretta, Alfredo; Wright, Gerard D.; Savchenko, Alexei

2013-01-01

SYNOPSIS Activity of the aminoglycoside phosphotransferase APH(3’)-Ia leads to resistance to aminoglycoside antibiotics in pathogenic Gram-negative bacteria, and contributes to the clinical obsolescence of this class of antibiotics. One strategy to rescue compromised antibiotics such as aminoglycosides is targeting the enzymes that confer resistance with small molecules. Previously we demonstrated that eukaryotic protein kinase (ePK) inhibitors could inhibit APH enzymes, due to the structural similarity between these two enzyme families. However, limited structural information of enzyme-inhibitor complexes hindered interpretation of the results. As well, cross-reactivity of compounds between APHs and ePKs represents an obstacle to their use as aminoglycoside adjuvants to rescue aminoglycoside antibiotic activity. Here, we structurally and functionally characterize inhibition of APH(3’)-Ia by three diverse chemical scaffolds – anthrapyrazolone, 4-anilinoquinazoline and pyrazolopyrimidine (PP) – and reveal distinctions in the binding mode of anthrapyrazolone and PP compounds to APH(3’)-Ia versus ePKs. Using this observation, we identify PP-derivatives that select against ePKs, attenuate APH(3’)-Ia activity and rescue aminoglycoside antibiotic activity against a resistant E. coli strain. The structures presented here and these inhibition studies provide an important opportunity for structure-based design of compounds to target aminoglycoside phosphotransferases for inhibition, potentially overcoming this form of antibiotic resistance. PMID:23758273

Functional synergy of α-helical antimicrobial peptides and traditional antibiotics against Gram-negative and Gram-positive bacteria in vitro and in vivo.

PubMed

Feng, Q; Huang, Y; Chen, M; Li, G; Chen, Y

2015-01-01

In this study, the antimicrobial activities based on the synergistic effects of traditional antibiotics (imipenem, cefepime, levofloxacin hydrochloride and vancomycin) and antimicrobial peptides (AMPs; PL-5, PL-31, PL-32, PL-18, PL-29 and PL-26), alone or in combination, against three Gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae and Staphylococcus epidermidis) and three Gram-negative bacteria (Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae) were investigated. In addition, the antimicrobial activity that was based on the synergistic effects of levofloxacin hydrochloride and PL-5 against Staphylococcus aureus in vivo was explored in a mouse infection model. Traditional antibiotics and AMPs showed significant synergistic effects on the antibacterial activities against the different Gram-positive and Gram-negative bacteria in vitro. A strong synergistic effect in the PL-5 and levofloxacin hydrochloride combination against Staphylococcus aureus was observed in the mouse infection model in vivo. The mechanism of synergistic action was due to the different targets of AMPs and traditional antibiotics. The combination of AMPs and traditional antibiotics can dramatically enhance antimicrobial activity and may help prevent or delay the emergence of antibiotic resistance. Thus, this combination therapy could be a promising approach to treat bacterial infections, particularly mixed infections and multi-antibiotic-resistant infections, in the clinics.

Increasing awareness about antibiotic use and resistance: a hands-on project for high school students.

PubMed

Fonseca, Maria João; Santos, Catarina L; Costa, Patrício; Lencastre, Leonor; Tavares, Fernando

2012-01-01

Health-promoting education is essential to foster an informed society able to make decisions about socio-scientific issues based on scientifically sustained criteria. Antibiotic resistance is currently a major public health issue. Considering that irrational antibiotic use has been associated with the development and widespread of antibiotic resistant bacteria, educational interventions to promote prudent antibiotic consumption are required. This study focuses on the outcomes of an interventional program implemented at the University of Porto, Portugal, to promote awareness about antibiotic resistance at high school levels (15-17 year old). The project Microbiology recipes: antibiotics à la carte articulates a set of wet and dry lab activities designed to promote the participants' understanding of concepts and processes underlying antibiotics' production and activity, such as the notion of mechanisms of action of antibiotics. Following a mix-method approach based on a pre-/post design, the effectiveness of this project was assessed by gathering data from surveys, direct observation and analysis of artifacts of 42 high school students (aged 15 and 16 years). The results indicate that the participants developed a more comprehensive picture of antibiotic resistance. The project was shown to promote more sophisticated conceptualizations of bacteria and antibiotics, increased awareness about the perils of antibiotic resistance, and enhanced consciousness towards measures that can be undertaken to mitigate the problem. The participants regarded their experiences as enjoyable and useful, and believed that the project contributed to improve their understanding and raise their interest about the issues discussed. Furthermore, there were also improvements in their procedural skills concerning the laboratory techniques performed. This study evidences the possibility of increasing high school students' awareness about the consequences of antibiotic resistance and the importance of judicious antibiotic use. The findings inform about the educational benefits of incorporating hands-on activities in science education programs.

Are Patient Views about Antibiotics Related to Clinician Perceptions, Management and Outcome? A Multi-Country Study in Outpatients with Acute Cough

PubMed Central

Coenen, Samuel; Francis, Nick; Kelly, Mark; Hood, Kerenza; Nuttall, Jacqui; Little, Paul; Verheij, Theo J. M.; Melbye, Hasse; Goossens, Herman; Butler, Christopher C.

2013-01-01

Background Outpatients with acute cough who expect, hope for or ask for antibiotics may be more unwell, benefit more from antibiotic treatment, and be more satisfied with care when they are prescribed antibiotics. Clinicians may not accurately identify those patients. Objective To explore whether patient views (expecting, hoping for or asking for antibiotics) are associated with illness presentation and resolution, whether patient views are accurately perceived by clinicians, and the association of all these factors with antibiotic prescribing and patient satisfaction with care. Methods Prospective observational study of 3402 adult patients with acute cough presenting in 14 primary care networks. Correlations and associations tested with multilevel logistic regression and McNemar ‘s tests, and Cohen’s Kappa, positive agreement (PA) and negative agreement (NA) calculated as appropriate. Results 1,213 (45.1%) patients expected, 1,093 (40.6%) hoped for, and 275 (10.2%) asked for antibiotics. Clinicians perceived 840 (31.3%) as wanting to be prescribed antibiotics (McNemar’s test, p<0.05). Their perception agreed modestly with the three patient views (Kappa’s = 0.29, 0.32 and 0.21, PA’s = 0.56, 0.56 and 0.33, NA’s = 0.72, 0.75 and 0.82, respectively). 1,464 (54.4%) patients were prescribed antibiotics. Illness presentation and resolution were similar for patients regardless their views. These associations were not modified by antibiotic treatment. Patient expectation and hope (OR:2.08, 95% CI:[1.48,2.93] and 2.48 [1.73,3.55], respectively), and clinician perception (12.18 [8.31,17.84]) were associated with antibiotic prescribing. 2,354 (92.6%) patients were satisfied. Only those hoping for antibiotics were less satisfied when antibiotics were not prescribed (0.39 [0.17,0.90]). Conclusion Patient views about antibiotic treatment were not useful for identifying those who will benefit from antibiotics. Clinician perceptions did not match with patient views, but particularly influenced antibiotic prescribing. Patients were generally satisfied with care, but those hoping for but not prescribed antibiotics were less satisfied. Clinicians need to more effectively elicit and address patient views about antibiotics. PMID:24194845

Effect of Physician Tutorials on Prescribing Patterns of Graduate Physicians.

ERIC Educational Resources Information Center

Klein, Lawrence E.; And Others

1981-01-01

Physicians in an experimental group were surveyed to assess their knowledge of the effectiveness, cost, and side effects of antibiotics, and a tutorial was developed to modify some prescribing patterns. Prescribing patterns were statistically different. (Author/MLW)

Identification of antibiotics using small molecule variable ligand display on gold nanoparticles.

PubMed

Bresee, Jamee; Maier, Keith E; Melander, Christian; Feldheim, Daniel L

2010-10-28

Here we describe the use of simple 1-pot thiol exchange reactions to generate a library of mixed ligand-coated gold nanoparticles that was screened for antibiotic activity. A library of 120 nanoparticle conjugates was assembled and antibiotic activity toward E. coli was determined and found to depend upon the combination of thiols assembled onto the nanoparticles. The most active conjugate displayed 99.9% growth inhibition at 0.5 μM.

Metabolic engineering of antibiotic factories: new tools for antibiotic production in actinomycetes.

PubMed

Weber, Tilmann; Charusanti, Pep; Musiol-Kroll, Ewa Maria; Jiang, Xinglin; Tong, Yaojun; Kim, Hyun Uk; Lee, Sang Yup

2015-01-01

Actinomycetes are excellent sources for novel bioactive compounds, which serve as potential drug candidates for antibiotics development. While industrial efforts to find and develop novel antimicrobials have been severely reduced during the past two decades, the increasing threat of multidrug-resistant pathogens and the development of new technologies to find and produce such compounds have again attracted interest in this field. Based on improvements in whole-genome sequencing, novel methods have been developed to identify the secondary metabolite biosynthetic gene clusters by genome mining, to clone them, and to express them in heterologous hosts in much higher throughput than before. These technologies now enable metabolic engineering approaches to optimize production yields and to directly manipulate the pathways to generate modified products. Copyright © 2014 Elsevier Ltd. All rights reserved.

The impact of antibiotics (benzylpenicillin, and nystatin) on the biological properties of ordinary chernozems

NASA Astrophysics Data System (ADS)

Akimenko, Yu. V.; Kazeev, K. Sh.; Kolesnikov, S. I.

2014-09-01

In recent years, the input of antibiotics into soils has sharply increased. We studied the impact antibiotics (benzylpenicillin, pharmasin, and nystatin) at different concentrations (100 and 600 mg/kg) on population densities of microorganisms and enzymatic activity of ordinary chernozems in model experiments. The applied doses of antibiotics had definite suppressing effects on population densities of microorganisms (up to 30-70% of the control) and on the soil enzymatic activity (20-70% of the control). Correlation analysis showed close correlation between the concentrations of antibiotics and the population densities of soil microorganisms ( r = -0.68-0.86). Amylolytic bacteria had the highest resistance to the antibiotics, whereas ammonifying bacteria had the lowest resistance. Among the studied enzymes belonging to oxidoreductases and hydrolases, catalase and phosphatase had the highest and the lowest resistance to the antibiotics, respectively. The effect of antibiotics on the biological properties of the chernozem lasted for a long time. The studied parameters were not completely recovered in 120 days.

[Hygienic substantiation of the permissible levels for tetracycline-group antibiotics in food].

PubMed

Onishchenko, G G; Sheveleva, S A; Khotimchenko, S A

2012-01-01

For the purpose of justification of the hygienic standard for tetracycline-group antibiotics in the food production established in the Russian Federation at more rigid level, than maximum and admissible levels (MAL) of the Codex Alimentarius Commission, the analysis of data of literature on negative nature of impact of low concentration of these antibiotics on an organism and the environmental conditions and risk for health has been performed. Inadequacy of the accepted admissible daily dose (ADD) accepted by The Joint FAO/WHO Expert Committee on Food Additives (JECFA) on action on selection of resistant E. coli in intestines, for the wide contingent of consumers in connection with ignoring of obvious factors of uncertainty (gastrointestinal dysbiosis, age and individual variations in the microbiota of people synergy with other antibiotics residues in food and indirect impact on an organism through microflora from the natural habitat (resistance genes, modified causative organisms with altered properties).. By the analysis of information received with the use of modern molecular and genetic methods, the role of Subinhibitory concentrations (sub-MICs) of tetracyclines as biologically active substances, signaling molecules which, without causing obvious negative consequences in a macroorganism, serve as a major factor of regulation of a transcription in microorganisms and activation of a horizontal gene transfer coding resistance, transferred on conjugative transposons of Tn916-Tn1545 family. Reasonable scientific data on a dominating contribution of minor levels of tetracyclines in globalization in the nature of the most adverse transmissive type of the antibiotic resistance interfaced to formation new bacterial pathotypes, as consequences of irrationally high scales of application in agriculture and strengthened impact on microbic ecosystems of live organisms and objects of habitat are presented. For minimization of this mediated risk for health the need of preservation of operating level of the tetracyclines residues (by < or = 0,01 mg/kg of a product), MAL which were unlike Codex MAL (< or = 0,1-1,2 mg/kg) in a zone of concentrations below 0,1 Misc not capable to initiation of the above described changes has been proved, till up to receipt of new scientific data on influence on macro - or microorganisms of the doses equal or below this value on macro - or microorganisms.

[Evolution of the concept of residues in the products of animals raised with the use of antibiotics].

PubMed

Wal, J M

1979-01-01

The concept of residues of antibiotics used as feed additives or veterinary drugs in food producing animals is analysed, and implications on human public health are discussed. The examples of Tylosin and Penicillin are developed to illustrate the both notions of "high risk residue" and "toxicodisponibility" of residues. The "high risk residue" may be an active metabolite different by its chemical structure and by its pharmacological properties from the original drug administered. Slight modifications of the molecule, as the rupture of the beta lactam ring of the Penicillin, occuring in vivo, lead to a metabolite, e.g. penicilloyl group, that has lost all antibiotic activity but possesses allergenic potential. Toxicity of the residue, compared with that of the original drug, can then be modified or increased. On the other hand, such an active metabolite having a definite chemical structure, even if different from the original compound, can be present in the organism, either free or bound to serum or tissues proteins. Moreover, it is shown here, that in the case of a covalent binding of the drug or its metabolite (e.g. penicilloyl group) to serum albumin, the residues are mostly masked inside the tertiary structure of the albumin molecule, and are not accessible to antibodies. These different forms have then an effect upon the biodisponibility, the "toxicodisponibility", of the residues for the human consumer of animal products where they are present. These forms are only accessible with more and more specific and sensitive analytical methods which relates also the qualitative and quantitative notions of residue to the technological degree used for investigation, determination and identification. As to cooking techniques, they can lead to a thermodegradation of the residue or, on the opposite, to an unmasking of the residue present as a protein conjugate, e.g. penicilloyl-protein conjugate in milk.

Silver enhances antibiotic activity against gram-negative bacteria.

PubMed

Morones-Ramirez, J Ruben; Winkler, Jonathan A; Spina, Catherine S; Collins, James J

2013-06-19

A declining pipeline of clinically useful antibiotics has made it imperative to develop more effective antimicrobial therapies, particularly against difficult-to-treat Gram-negative pathogens. Silver has been used as an antimicrobial since antiquity, yet its mechanism of action remains unclear. We show that silver disrupts multiple bacterial cellular processes, including disulfide bond formation, metabolism, and iron homeostasis. These changes lead to increased production of reactive oxygen species and increased membrane permeability of Gram-negative bacteria that can potentiate the activity of a broad range of antibiotics against Gram-negative bacteria in different metabolic states, as well as restore antibiotic susceptibility to a resistant bacterial strain. We show both in vitro and in a mouse model of urinary tract infection that the ability of silver to induce oxidative stress can be harnessed to potentiate antibiotic activity. Additionally, we demonstrate in vitro and in two different mouse models of peritonitis that silver sensitizes Gram-negative bacteria to the Gram-positive-specific antibiotic vancomycin, thereby expanding the antibacterial spectrum of this drug. Finally, we used silver and antibiotic combinations in vitro to eradicate bacterial persister cells, and show both in vitro and in a mouse biofilm infection model that silver can enhance antibacterial action against bacteria that produce biofilms. This work shows that silver can be used to enhance the action of existing antibiotics against Gram-negative bacteria, thus strengthening the antibiotic arsenal for fighting bacterial infections.

[New antibiotics produced by Bacillus subtilis strains].

PubMed

Malanicheva, I A; Kozlov, D G; Efimenko, T A; Zenkova, V A; Kastrukha, G S; Reznikova, M I; Korolev, A M; Borshchevskaia, L N; Tarasova, O D; Sineokiĭ, S P; Efremenkova, O V

2014-01-01

Two Bacillus subtilis strains isolated from the fruiting body of a basidiomycete fungus Pholiota squarrosa exhibited a broad range of antibacterial activity, including those against methicillin-resistant Staphylococcus aureus INA 00761 (MRSA) and Leuconostoc mes6nteroides VKPM B-4177 resistant to glycopep-> tide antibiotics, as well as antifungal activity. The strains were identified as belonging to the "B. subtilis" com- plex based on their morphological and physiological characteristics, as well as by sequencing of the 16S rRNA gene fragments. Both strains (INA 01085 and INA 01086) produced insignificant amounts of polyene antibiotics (hexaen and pentaen, respectively). Strain INA 01086 produced also a cyclic polypeptide antibiotic containing Asp, Gly, Leu, Pro, Tyr, Thr, Trp, and Phe, while the antibiotic of strain INA 01085 contained, apart from these, two unidentified nonproteinaceous amino acids. Both polypeptide antibiotics were new compounds efficient against gram-positive bacteria and able to override the natural bacterial antibiotic resistance.

Diversity and natural functions of antibiotics produced by beneficial and plant pathogenic bacteria.

PubMed

Raaijmakers, Jos M; Mazzola, Mark

2012-01-01

Soil- and plant-associated environments harbor numerous bacteria that produce antibiotic metabolites with specific or broad-spectrum activities against coexisting microorganisms. The function and ecological importance of antibiotics have long been assumed to yield a survival advantage to the producing bacteria in the highly competitive but resource-limited soil environments through direct suppression. Although specific antibiotics may enhance producer persistence when challenged by competitors or predators in soil habitats, at subinhibitory concentrations antibiotics exhibit a diversity of other roles in the life history of the producing bacteria. Many processes modulated by antibiotics may be inherently critical to the producing bacterium, such as the acquisition of substrates or initiation of developmental changes that will ensure survival under stressful conditions. Antibiotics may also have roles in more complex interactions, including in virulence on host plants or in shaping the outcomes of multitrophic interactions. The innate functions of antibiotics to producing bacteria in their native ecosystem are just beginning to emerge, but current knowledge already reveals a breadth of activities well beyond the historical perspective of antibiotics as weaponry in microbial conflicts.

Inhibitory effect of soy saponins on the activity of β-lactamases, including New Delhi metallo-β-lactamase 1.

PubMed

Horie, Hitoshi; Chiba, Asuka; Wada, Shigeo

2018-05-01

β-Lactamase-producing bacteria encode enzymes that inactivate β-lactam antibiotics by catalyzing the hydrolysis of the β-lactam ring. Crude soy saponins were observed to have synergistic effects on the antimicrobial activity of β-lactam antibiotics against β-lactamase-producing Staphylococcus aureus strains. Furthermore, the activities of β-lactamases derived from Enterobacter cloacae , Escherichia coli , and S. aureus were decreased significantly in the presence of crude soy saponins. This inhibitory effect was also observed against the New Delhi metallo-β-lactamase 1 (NDM-1), an enzyme whose activity is not inhibited by the current β-lactamase inhibitors. The synergistic effect on the antimicrobial activity of β-lactam antibiotics by crude soy saponins was thought to result from the inhibition the β-lactamase activity. The components of crude soy saponins include several kinds of soyasaponins and soyasapogenols. It was revealed that soyasaponin V has the highest inhibitory activity against NDM-1. The combined use of soy saponins with β-lactam antibiotics is expected to serve as a new therapeutic modality, potentially enhancing the effectiveness of β-lactam antibiotics against infectious diseases caused by β-lactamase-producing bacteria, including those encoding NDM-1.

Structure and Function of the Glycopeptide N-methyltransferase MtfA, a Tool for the Biosynthesis of Modified Glycopeptide Antibiotics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Rong; Lamb, Sherry S.; Zakeri, Bijan

2009-06-01

There is a considerable interest in the modification of existing antibiotics to generate new antimicrobials. Glycopeptide antibiotics (GPAs) are effective against serious Gram-positive bacterial pathogens including methicillin-resistant Staphylococcus aureus. However, resistance to these antibiotics is becoming a serious problem requiring new strategies. We show that the Amycolatopsis orientalis (S)-adenosyl-L-methionine-dependent methyltransferase MtfA, from the vancomycin-class GPA chloroeremomycin biosynthetic pathway, catalyzes in vivo and in vitro methyl transfer to generate methylated GPA derivatives of the teicoplanin class. The crystal structure of MtfA complexed with (S)-adenosyl-L-methionine, (S)-adenosylhomocysteine, or sinefungin inhibitor, coupled with mutagenesis, identified His228 as a likely general base required for methylmore » transfer to the N terminus of the glycopeptide. Computational docking and molecular dynamics simulations were used to model binding of demethyl-vancomycin aglycone to MtfA. These results demonstrate its utility as a tool for engineering methylated analogs of GPAs.« less

Antibiotic research and development: business as usual?

PubMed

Harbarth, S; Theuretzbacher, U; Hackett, J

2015-01-01

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a €9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Activation of Antibiotic Production in Bacillus spp. by Cumulative Drug Resistance Mutations

PubMed Central

Tojo, Shigeo; Tanaka, Yukinori

2015-01-01

Bacillus subtilis strains produce a wide range of antibiotics, including ribosomal and nonribosomal peptide antibiotics, as well as bacilysocin and neotrehalosadiamine. Mutations in B. subtilis strain 168 that conferred resistance to drugs such as streptomycin and rifampin resulted in overproduction of the dipeptide antibiotic bacilysin. Cumulative drug resistance mutations, such as mutations in the mthA and rpsL genes, which confer low- and high-level resistance, respectively, to streptomycin, and mutations in rpoB, which confer resistance to rifampin, resulted in cells that overproduced bacilysin. Transcriptional analysis demonstrated that the enhanced transcription of biosynthesis genes was responsible for the overproduction of bacilysin. This approach was effective also in activating the cryptic genes of Bacillus amyloliquefaciens, leading to actual production of antibiotic(s). PMID:26369962

An unusual class of anthracyclines potentiate Gram-positive antibiotics in intrinsically resistant Gram-negative bacteria

PubMed Central

Cox, Georgina; Koteva, Kalinka; Wright, Gerard D.

2014-01-01

Objectives An orthogonal approach taken towards novel antibacterial drug discovery involves the identification of small molecules that potentiate or enhance the activity of existing antibacterial agents. This study aimed to identify natural-product rifampicin adjuvants in the intrinsically resistant organism Escherichia coli. Methods E. coli BW25113 was screened against 1120 actinomycete fermentation extracts in the presence of subinhibitory (2 mg/L) concentrations of rifampicin. The active molecule exhibiting the greatest rifampicin potentiation was isolated using activity-guided methods and identified using mass and NMR spectroscopy. Susceptibility testing and biochemical assays were used to determine the mechanism of antibiotic potentiation. Results The anthracycline Antibiotic 301A1 was isolated from the fermentation broth of a strain of Streptomyces (WAC450); the molecule was shown to be highly synergistic with rifampicin (fractional inhibitory concentration index = 0.156) and moderately synergistic with linezolid (FIC index = 0.25) in both E. coli and Acinetobacter baumannii. Activity was associated with inhibition of efflux and the synergistic phenotype was lost when tested against E. coli harbouring mutations within the rpoB gene. Structure–activity relationship studies revealed that other anthracyclines do not synergize with rifampicin and removal of the sugar moiety of Antibiotic 301A1 abolishes activity. Conclusions Screening only a subsection of our natural product library identified a small-molecule antibiotic adjuvant capable of sensitizing Gram-negative bacteria to antibiotics to which they are ordinarily intrinsically resistant. This result demonstrates the great potential of this approach in expanding antibiotic effectiveness in the face of the growing challenge of resistance in Gram-negatives. PMID:24627312

Development of Ciprofloxacin-loaded contact lenses using fluorous chemistry

PubMed Central

Zhu, Zhiling; Li, Siheng; McDermott, Alison M.

2017-01-01

In this work, we developed a simple method to load drugs into commercially available contact lenses utilizing fluorous chemistry. We demonstrated this method using model compounds including fluorous-tagged fluorescein and antibiotic ciprofloxacin. We showed that fluorous interactions facilitated the loading of model molecules into fluorocarbon-containing contact lenses, and that the release profiles exhibited sustained release. Contact lenses loaded with fluorous-tagged ciprofloxacin exhibited antimicrobial activity against Pseudomonas aeruginosa in vitro, while no cytotoxicity towards human corneal epithelial cells was observed. To mimic the tear turnover, we designed a porcine eye infection model under flow conditions. Significantly, the modified lenses also exhibited antimicrobial efficacy against Pseudomonas aeruginosa in the ex vivo infection model. Overall, utilizing fluorous chemistry, we can construct a drug delivery system that exhibits high drug loading capacity, sustained drug release, and robust biological activity. PMID:28188995

Effect of cooking and cold storage on biologically active antibiotic residues in meat.

PubMed Central

O'Brien, J. J.; Campbell, N.; Conaghan, T.

1981-01-01

An investigation was undertaken to see if cooking or cold storage would destroy or decrease the level of biologically active antibiotic in tissues from animals given therapeutic doses of antibiotic on three occasions prior to slaughter. The effects of cooking and cold storage on the biological activity of the residues of ampicillin, chloramphenicol, oxytetracycline, streptomycin and sulphadimidine were varied; in some instances the effects were minimal, in others nil. PMID:7310129

Virantmycin, a new antiviral antibiotic produced by a strain of Streptomyces.

PubMed

Nakagawa, A; Iwai, Y; Hashimoto, H; Miyazaki, N; Oiwa, R; Takahashi, Y; Hirano, A; Shibukawa, N; Kojima, Y; Omura, S

1981-11-01

Virantmycin, a novel chlorine-containing antiviral antibiotic, has been isolated from Streptomyces nitrosporeus No. AM-2722. The active substance in culture broth is isolated as colorless needles by solvent extraction followed by high performance liquid chromatography on silicic acid. The molecular formula is C19H26NO3Cl (molecular weight 351) from the elemental analysis and mass spectrum. The antibiotic possesses antifungal activity and potent inhibitory activity against various RNA and DNA viruses.

[Historical and Hygienic Aspects on Roles of Quality Requirements for Antibiotic Products in Japan: Part 1--Development of Antibiotic Products].

PubMed

Yagisawa, Morimasa; Foster, Patrick J; Kurokawa, Tatsuo

2015-01-01

Antibiotic products have contributed greatly to keep Japanese people healthy by controlling lethal infections. In the early days, antibiotics such as penicillin and streptomycin were produced using microbial fermentation processes. Therefore, the component ratio of the active element and related substances varied lot by lot. For the purpose of efficacy and assuring safety, minimum requirements for penicillin and streptomycin products were enacted. Both variations and the number of clinically available antibiotic products have increased due to the pharmaceutical development of novel natural antibiotics. In addition, semi-synthetic derivatives of various antibiotics have been developed for the purpose of enhancing antimicrobial activity or improving pharmacological properties. As a result, 202 entities of antibiotic products have been approved and used clinically as of 2012. We conducted a detailed investigation of the progress made in the field of antibiotic products, and analyzed the characteristics of those belonging to each class of antibiotics by means of setting up a system of classification that reflects clinical applications. This report is intended to serve as an introduction to our series of investigations into the role and influence of quality requirements on development of antibacterial antibiotic products in Japan. As described here, the general view of antibacterial antibiotic products spanning a time frame of 67 years in Japan might serve as an ideal reference for future reports.

Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

DOE PAGES

Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.; ...

2016-10-21

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less

Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less

Combined effects of prenatal medication use and delivery type are associated with eczema at age 2 years.

PubMed

Wegienka, G; Havstad, S; Zoratti, E M; Kim, H; Ownby, D R; Johnson, C C

2015-03-01

Separately, prenatal antibiotics and Caesarian delivery have been found to be associated with increased risk of allergic diseases. It is not clear whether these factors may modify the effect of each other. To assess whether the associations between delivery types and eczema, sensitization and total IgE at age 2 years were modified by maternal use of prenatal medications. Prenatal charts of women enrolled in the WHEALS birth cohort were reviewed for delivery mode and medications prescribed and administered throughout their entire pregnancy, including systemic antibiotics and vaginally applied antifungal medications. The associations between the delivery mode and select medications and, eczema, sensitization (≥ 1 of 10 allergen-specific IgE ≥ 0.35 IU/mL) and total IgE at age 2 years were assessed. There was a lower risk of eczema among vaginally vs. c-section born children (relative risk adjusted for race = aRR = 0.77, 95% CI 0.56, 1.05). Although not statistically significantly different, this association was stronger among the subset of children born vaginally to a mother who did not use systemic antibiotics or vaginal antifungal medications (aRR = 0.69, 95% CI 0.44, 1.08) compared to those born vaginally to mothers who used systemic antibiotics or vaginal antifungals (aRR = 0.81, 95% CI 0.57, 1.14). A protective association between vaginal birth and sensitization (aRR = 0.86, 95% CI 0.72, 1.03) was similar for those children born vaginally to a mother who did not (aRR = 0.87, 95% CI 0.69, 1.10) and who did (RR = 0.85, 95% CI 0.70, 1.04) use systemic antibiotics or vaginal antifungal medications. There were no associations with total IgE. Children born vaginally had lower risk of eczema and sensitization compared with those born via c-section; however, the protective association with eczema may be slightly weakened when mothers took systemic antibiotics or vaginally applied medications during pregnancy. © 2014 John Wiley & Sons Ltd.

Bioprospecting saline gradient of a Wildlife Sanctuary for bacterial diversity and antimicrobial activities.

PubMed

DeLuca, Mara; King, Riley; Morsy, Mustafa

2017-08-11

Antibiotic-resistant bacteria are becoming a global crisis, causing death of thousands of people and significant economic impact. The discovery of novel antibiotics is crucial to saving lives and reducing healthcare costs. To address the antibiotic-resistant crisis, in collaboration the Small World Initiative, which aims to crowdsource novel antibiotic discovery, this study aimed to identify antimicrobial producing bacteria and bacterial diversity in the soil of the Stimpson Wildlife Sanctuary, an inland area with a soil salt gradient. Approximately 4500 bacterial colonies were screened for antimicrobial activity and roughly 100 bacteria were identified as antimicrobial producers, which belong to Entrococcaceae (74%), Yersiniaceae (19%), and unidentified families (7%). Several bacterial isolates showed production of broad spectrum inhibitory compounds, while others were more specific to certain pathogens. The data obtained from the current study provide a resource for further characterization of the soil bacteria with antimicrobial activity, with an aim to discover novel ones. The study showed no correlation between soil salt level and the presence of bacteria with antimicrobial activities. However, most of the identified antimicrobial producing bacteria do not belong to actinomycetes, the most common phyla of antibiotic producing bacteria and this could potentially lead to the discovery of novel antibiotics.

Photo-activated porphyrin in combination with antibiotics: therapies against Staphylococci

PubMed Central

Dastgheyb, Sana S.; Eckmann, David M.; Composto, Russell J.

2013-01-01

Staphylococcal infections have become difficult to treat due to antibiotic insensitivity and resistance. Antimicrobial combination therapies may minimize acquisition of resistance and photodynamic therapy is an attractive candidate for these combinations. In this manuscript, we explore combined use of antibiotics and meso-tetra (4-aminophenyl) porphine (TAPP), a cationic porphyrin, for treatment of Staphylococcus aureus contamination. We characterize the antimicrobial activity of photoactivated TAPP and show that activity is largely lost in the presence of a radical scavenger. Importantly, TAPP can be reactivated with continued, albeit attenuated, antibacterial activity. We then show that the antimicrobial activity of illuminated TAPP is additive with chloramphenicol and tobramycin for Staphylococcus aureus and Escherichia coli, and synergistic for MRSA and Staphylococcus epidermidis. Chloramphenicol + methylene blue, another photosensitizer, also show additivity against Staphylococcus aureus. In contrast, ceftriaxone and vancomycin do not strongly augment the low level effects of TAPP against S. aureus. Eukaryotic cells exhibit a dose-dependent toxicity with illuminated TAPP. Our results suggest that even sub-minimum inhibitory concentration levels of photo-activated TAPP could be used to boost the activity of waning antibiotics. This may play an important role in treatments reliant on antibiotic controlled release systems where augmentation with photo-active agents could extend their efficacy. PMID:24148969

Cecum Lymph Node Dendritic Cells Harbor Slow-Growing Bacteria Phenotypically Tolerant to Antibiotic Treatment

PubMed Central

Dolowschiak, Tamas; Wotzka, Sandra Y.; Lengefeld, Jette; Slack, Emma; Grant, Andrew J.; Ackermann, Martin; Hardt, Wolf-Dietrich

2014-01-01

In vivo, antibiotics are often much less efficient than ex vivo and relapses can occur. The reasons for poor in vivo activity are still not completely understood. We have studied the fluoroquinolone antibiotic ciprofloxacin in an animal model for complicated Salmonellosis. High-dose ciprofloxacin treatment efficiently reduced pathogen loads in feces and most organs. However, the cecum draining lymph node (cLN), the gut tissue, and the spleen retained surviving bacteria. In cLN, approximately 10%–20% of the bacteria remained viable. These phenotypically tolerant bacteria lodged mostly within CD103+CX3CR1−CD11c+ dendritic cells, remained genetically susceptible to ciprofloxacin, were sufficient to reinitiate infection after the end of the therapy, and displayed an extremely slow growth rate, as shown by mathematical analysis of infections with mixed inocula and segregative plasmid experiments. The slow growth was sufficient to explain recalcitrance to antibiotics treatment. Therefore, slow-growing antibiotic-tolerant bacteria lodged within dendritic cells can explain poor in vivo antibiotic activity and relapse. Administration of LPS or CpG, known elicitors of innate immune defense, reduced the loads of tolerant bacteria. Thus, manipulating innate immunity may augment the in vivo activity of antibiotics. PMID:24558351

[Antimicrobial Activity of Substances Produced by Trichoderma citrinoviride Strain VKPM F-1228: Optimization of Cultivation and Assessment of Spectrum of Individual Peptaibols].

PubMed

Sadykova, V S; Kurakov, A V; Korshun, V A; Rogozhin, E A; Gromovykh, T I; Kuvarina, A E; Baranova, A A

2015-01-01

The Trichoderma citrinoviride VKPM F-1228 strain produces a complex of peptide-based antibiotics with antibacterial and antimycotic action. Synthesis of peptaibols is closely related to the conidiogenesis in the culture. The optimal procedure of the strain cultivation for production of peptaibols is stationary growing for 14 days at a temperature of 28 degrees C and pH 7.5 followed by formation of a dense mycelium film on the modified Saburo medium containing 30 gr/l of glucose and 12.5 gr/l of peptone. Eight individual peptaibols were extracted. The spectrum of their activity was estimated with the use of opportunistic bacteria and micromycetes as well as pathogenic clinical aspergilli. Compounds 9, 13, 14, 15 and 16 were shown active against opportunistic fungi and bacteria including methicillin resistant S. aureus, whereas compounds 9, 13 and 14 in addition showed antimycotic activity against clinical aspergilli.

A novel role of cytosolic protein synthesis inhibition in aminoglycoside ototoxicity

PubMed Central

Francis, Shimon P.; Katz, Joshua; Fanning, Kathryn D.; Harris, Kimberly A.; Nicholas, Brian D.; Lacy, Michael; Pagana, James; Agris, Paul F.; Shin, Jung-Bum

2013-01-01

Ototoxicity is a main dose-limiting factor in the clinical application of aminoglycoside antibiotics. Despite longstanding research efforts, our understanding of the mechanisms underlying aminoglycoside ototoxicity remains limited. Here we report the discovery of a novel stress pathway that contributes to aminoglycoside-induced hair cell degeneration. Modifying the recently developed bioorthogonal noncanonical amino acid tagging (BONCAT) method, we used click-chemistry to study the role of protein synthesis activity in aminoglycoside-induced hair cell stress. We demonstrate that aminoglycosides inhibit protein synthesis in hair cells and activate a signaling pathway similar to ribotoxic stress response, contributing to hair cell degeneration. The ability of a particular aminoglycoside to inhibit protein synthesis and to activate the c-Jun N-terminal kinase (JNK) pathway correlated well with its ototoxic potential. Finally, we report that a FDA-approved drug known to inhibit ribotoxic stress response also prevents JNK activation and improves hair cell survival, opening up novel strategies to prevent and treat aminoglycoside ototoxicity. PMID:23407963

Bactericidal activity of antibiotics against Legionella micdadei (Pittsburgh pneumonia agent).

PubMed Central

Dowling, J N; Weyant, R S; Pasculle, A W

1982-01-01

The bactericidal activity of five antibiotics for Legionella micdadei was determined by the construction of time-kill curves. Erythromycin, rifampin, penicillin G, cephalothin, and gentamicin were bactericidal for L. micdadei at readily achievable concentrations. The minimal bactericidal concentrations, defined as those producing 99.9% killing within 24 h, were: erythromycin, 4.6; rifampin, 0.13; penicillin G, 0.25; cephalothin, 2.5; and gentamicin, 0.25 micrograms/ml. The ratios of the minimal bactericidal to minimal inhibitory concentrations for these antibiotics ranged from 1 to 8. Thus, the poor in vivo activity of beta-lactam and aminoglycoside antibiotics against L. micdadei cannot be ascribed to a lack of killing by these agents. PMID:6927637

Phenotypic and genotypic characterisation of multiple antibiotic-resistant Staphylococcus aureus exposed to subinhibitory levels of oxacillin and levofloxacin.

PubMed

Jo, Ara; Ahn, Juhee

2016-07-29

The emergence and spread of multidrug resistant methicillin-resistant Staphylococcus aureus (MDR-MRSA) has serious health consequences in the presence of sub-MIC antibiotics. Therefore, this study was designed to evaluate β-lactamase activity, efflux activity, biofilm formation, and gene expression pattern in Staphylococcus aureus KACC 10778, S. aureus ATCC 15564, and S. aureus CCARM 3080 exposed to sublethal concentrations of levofloxacin and oxacillin. The decreased MICs were observed in S. aureus KACC and S. aureus ATCC when exposed to levofloxacin and oxacillin, while and S. aureus CCARM remained resistance to streptomycin (512 μg/mL) in the presence of levofloxacin and imipenem (>512 μg/mL) in the presence of oxacillin. The considerable increase in extracellular and membrane-bound β-lactamase activities was observed in S. aureus ATCC exposed to oxacillin (>26 μmol/min/mL). The antibiotic susceptibility of all strains exposed to EPIs (CCCP and PAβN) varied depending on the classes of antibiotics. The relative expression levels of adhesion-related genes (clfA, clfB, fnbA, fnnB, and icaD), efflux-related genes (norB, norC, and qacA/B), and enterotoxin gene (sec) were increased more than 5-fold in S. aureus CCARM. The eno and qacA/B genes were highly overexpressed by more than 12- and 9-folds, respectively, in S. aureus CCARM exposed to levofloxacin. The antibiotic susceptibility, lactamase activity, biofilm-forming ability, efflux activity, and gene expression pattern varied with the intrinsic antibiotic resistance of S. aureus KACC, S. aureus ATCC, and S. aureus CCARM exposed to levofloxacin and oxacillin. This study would provide useful information for better understating of combination therapy related to antibiotic resistance mechanisms and open the door for designing effective antibiotic treatment protocols to prevent excessive use of antibiotics in clinical practice.

Astrobiology as a framework for investigating antibiotic susceptibility: a study of Halomonas hydrothermalis

PubMed Central

Cockell, Charles S.

2017-01-01

Physical and chemical boundaries for microbial multiplication on Earth are strongly influenced by interactions between environmental extremes. However, little is known about how interactions between multiple stress parameters affect the sensitivity of microorganisms to antibiotics. Here, we assessed how 12 distinct permutations of salinity, availability of an essential nutrient (iron) and atmospheric composition (aerobic or microaerobic) affect the susceptibility of a polyextremotolerant bacterium, Halomonas hydrothermalis, to ampicillin, kanamycin and ofloxacin. While salinity had a significant impact on sensitivity to all three antibiotics (as shown by turbidimetric analyses), the nature of this impact was modified by iron availability and the ambient gas composition, with differing effects observed for each compound. These two parameters were found to be of particular importance when considered in combination and, in the case of ampicillin, had a stronger combined influence on antibiotic tolerance than salinity. Our data show how investigating microbial responses to multiple extremes, which are more representative of natural habitats than single extremes, can improve our understanding of the effects of antimicrobial compounds and suggest how studies of habitability, motivated by the desire to map the limits of life, can be used to systematically assess the effectiveness of antibiotics. PMID:28123098

Astrobiology as a framework for investigating antibiotic susceptibility: a study of Halomonas hydrothermalis.

PubMed

Harrison, Jesse P; Angel, Roey; Cockell, Charles S

2017-01-01

Physical and chemical boundaries for microbial multiplication on Earth are strongly influenced by interactions between environmental extremes. However, little is known about how interactions between multiple stress parameters affect the sensitivity of microorganisms to antibiotics. Here, we assessed how 12 distinct permutations of salinity, availability of an essential nutrient (iron) and atmospheric composition (aerobic or microaerobic) affect the susceptibility of a polyextremotolerant bacterium, Halomonas hydrothermalis, to ampicillin, kanamycin and ofloxacin. While salinity had a significant impact on sensitivity to all three antibiotics (as shown by turbidimetric analyses), the nature of this impact was modified by iron availability and the ambient gas composition, with differing effects observed for each compound. These two parameters were found to be of particular importance when considered in combination and, in the case of ampicillin, had a stronger combined influence on antibiotic tolerance than salinity. Our data show how investigating microbial responses to multiple extremes, which are more representative of natural habitats than single extremes, can improve our understanding of the effects of antimicrobial compounds and suggest how studies of habitability, motivated by the desire to map the limits of life, can be used to systematically assess the effectiveness of antibiotics. © 2017 The Author(s).

A questionnaire-based survey to ascertain the views of clinicians regarding rational use of antibiotics in teaching hospitals of Kolkata.

PubMed

Chatterjee, Dattatreyo; Sen, Sukanta; Begum, Sabnam Ara; Adhikari, Anjan; Hazra, Avijit; Das, Anup Kumar

2015-01-01

The objective was to assess the views of clinicians in teaching hospitals of Kolkata regarding the use of antibiotics in their own hospitals, focusing on perceived misuse, reasons behind such misuse and feasible remedial measures. A total of 200 clinicians from core clinical disciplines was approached in six teaching hospitals of Kolkata through purposive sampling. A structured, validated questionnaire adopted from published studies and modified to suit the responding population was completed by consenting respondents through face-to-face interaction with a single interviewer. Respondents were free to leave out questions they did not wish to answer. Among 130 participating clinicians (65% of approached), all felt that antibiotic misuse occurs in various hospital settings; 72 (55.4% of the respondents) felt it was a frequent occurrence and needed major rectification. Cough and cold (78.5%), fever (65.4%), and diarrhea (62.3%) were perceived to be the commonest conditions of antibiotic misuse. About half (50.76%) felt that oral preparations were more misused compared to injectable or topical ones. Among oral antibiotics, co-amoxiclav (66.9%) and cefpodoxime (63.07%) whereas among parenteral ones, ceftriaxone and other third generation cephalosporins (74.6%) followed by piperacillin-tazobactam (61.5%) were selected as the most misused ones. Deficient training in rational use of medicines (70.7%) and absence of institutional antibiotic policy (67.7%) were listed as the two most important predisposing factors. Training of medical students and interns in rational antibiotic use (78.5%), implementation of antibiotic policy (76.9%), improvement in microbiology support (70.7%), and regular surveillance on this issue (64.6%) were cited as the principal remedial measures. Clinicians acknowledge that the misuse of antibiotics is an important problem in their hospitals. A system of clinical audit of antibiotic usage, improved microbiology support and implementation of antibiotic policy can help to promote rational use of antimicrobial agents.

[Antibiotic consumption in active French soldiers in 2007].

PubMed

Desjeux, G; Balaire, C; Thevenin-Garron, V

2009-07-01

Analysis of antibiotic consumption among active duty soldiers can contribute to the development of actions designed to avoid unsuitable population exposure to antibiotics. This survey was conducted among active soldiers to establish a reference year for refund data on antibiotic prescriptions by gender and age. Another aim was to use the refund data among soldiers to learn more about the pattern of antibiotic prescriptions by general practitioners. A standardized dose of antibiotics prescribed by general practitioners in 2007 for the active duty military population in France was determined from an analysis of the Health fund database. The defined daily dose (DDD), as well as the DDD/1000 contributors to the national healthcare insurance fund, was then used as a technical unit of measurement. For the military population under study, the DDD was 15.76 per 1000 people. It was higher for women than for men (25.1 DDD for 1000 women vs 14.2 DDD for 1000 men). The DDD increased regularly with age: from 11.4 DDD for 1000 people aged less than 20 to 19.3 DDD for 1000 people aged over 50. Military physicians accounted for only 4% of the prescribing practitioners. Careful analysis of antibiotic consumption together with closer cooperation between the military healthcare center and the National healthcare fund will enable the development of a prevention policy concerning health and better control of infectious risk.

Cost-Effectiveness Analysis of the Use of a Prophylactic Antibiotic for Patients Undergoing Lower Limb Amputation due to Diabetes or Vascular Illness in Colombia.

PubMed

Ceballos, Mateo; Orozco, Luis Esteban; Valderrama, Carlos Oliver; Londoño, Diana Isabel; Lugo, Luz Helena

2017-04-01

The use of a prophylactic antibiotic in an amputation surgery is a key element for the successful recovery of the patient. We aim to determine, from the perspective of the Colombian health system, the cost-effectiveness of administering a prophylactic antibiotic among patients undergoing lower limb amputation due to diabetes or vascular illness in Colombia. A decision tree was constructed to compare the use and nonuse of a prophylactic antibiotic. The probabilities of transition were obtained from studies identified from a systematic review of the clinical literature. The chosen health outcome was reduction in mortality due to prevention of infection. The costs were measured by expert consensus using the standard case methodology, and the resource valuation was carried out using national-level pricing manuals. Deterministic sensitivity, scenarios, and probabilistic analyses were conducted. In the base case, the use of a prophylactic antibiotic compared with nonuse was a dominant strategy. This result was consistent when considering different types of medications and when modifying most of the variables in the model. The use of a prophylactic antibiotic ceases to be dominant when the probability of infection is greater than 48%. The administration of a prophylactic antibiotic was a dominant strategy, which is a conclusion that holds in most cases examined; therefore, it is unlikely that the uncertainty around the estimation of costs and benefits change the results. We recommend creating policies oriented toward promoting the use of a prophylactic antibiotic during amputation surgery in Colombia. Copyright © 2016 Elsevier Inc. All rights reserved.

Metrics to assess the quantity of antibiotic use in the outpatient setting: a systematic review followed by an international multidisciplinary consensus procedure.

PubMed

Versporten, Ann; Gyssens, Inge C; Pulcini, Céline; Monnier, Annelie A; Schouten, Jeroen; Milanic, Romina; Stanic Benic, Mirjana; Tebano, Gianpiero; Le Maréchal, Marion; Zanichelli, Veronica; Huttner, Benedikt; Vlahovic-Palcevski, Vera; Goossens, Herman; Hulscher, Marlies E; Adriaenssens, Niels

2018-06-01

The international Innovative Medicines Initiative (IMI) project DRIVE-AB (Driving Reinvestment in Research and Development and Responsible Antibiotic Use) aims to develop a global definition of 'responsible' antibiotic use. To identify consensually validated quantity metrics for antibiotic use in the outpatient setting. First, outpatient quantity metrics (OQMs) were identified by a systematic search of literature and web sites published until 12 December 2014. Identified OQMs were evaluated by a multidisciplinary, international stakeholder panel using a RAND-modified Delphi procedure. Two online questionnaires and a face-to-face meeting between them were conducted to assess OQM relevance for measuring the quantity of antibiotic use on a nine-point Likert scale, to add comments or to propose new metrics. A total of 597 articles were screened, 177 studies met criteria for full-text screening and 138 were finally included. Twenty different OQMs were identified and appraised by 23 stakeholders. During the first survey, 14 OQMs were excluded and 6 qualified for discussion. During the face-to-face meeting, 10 stakeholders retained five OQMs and suggestions were made considering context and combination of metrics. The final set of metrics included defined daily doses, treatments/courses and prescriptions per defined population, treatments/courses and prescriptions per defined number of physician contacts and seasonal variation of total antibiotic use. A small set of consensually validated metrics to assess the quantity of antibiotic use in the outpatient setting was obtained, enabling (inter)national comparisons. The OQMs will help build a global conceptual framework for responsible antibiotic use.

Covalent Immobilization of Enoxacin onto Titanium Implant Surfaces for Inhibiting Multiple Bacterial Species Infection and In Vivo Methicillin-Resistant Staphylococcus aureus Infection Prophylaxis

PubMed Central

Nie, Bin'en; Long, Teng; Ao, Haiyong; Zhou, Jianliang; Tang, Tingting

2016-01-01

ABSTRACT Infection is one of the most important causes of titanium implant failure in vivo. A developing prophylactic method involves the immobilization of antibiotics, especially vancomycin, onto the surface of the titanium implant. However, these methods have a limited effect in curbing multiple bacterial infections due to antibiotic specificity. In the current study, enoxacin was covalently bound to an amine-functionalized Ti surface by use of a polyethylene glycol (PEG) spacer, and the bactericidal effectiveness was investigated in vitro and in vivo. The titanium surface was amine functionalized with 3-aminopropyltriethoxysilane (APTES), through which PEG spacer molecules were covalently immobilized onto the titanium, and then the enoxacin was covalently bound to the PEG, which was confirmed by X-ray photoelectron spectrometry (XPS). A spread plate assay, confocal laser scanning microscopy (CLSM), and scanning electron microscopy (SEM) were used to characterize the antimicrobial activity. For the in vivo study, Ti implants were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and implanted into the femoral medullary cavity of rats. The degree of infection was assessed by radiography, micro-computed tomography, and determination of the counts of adherent bacteria 3 weeks after surgery. Our data demonstrate that the enoxacin-modified PEGylated Ti surface effectively prevented bacterial colonization without compromising cell viability, adhesion, or proliferation in vitro. Furthermore, it prevented MRSA infection of the Ti implants in vivo. Taken together, our results demonstrate that the use of enoxacin-modified Ti is a potential approach to the alleviation of infections of Ti implants by multiple bacterial species. PMID:27799220

In vitro transport activity of the fully assembled MexAB-OprM efflux pump from Pseudomonas aeruginosa

NASA Astrophysics Data System (ADS)

Verchère, Alice; Dezi, Manuela; Adrien, Vladimir; Broutin, Isabelle; Picard, Martin

2015-04-01

Antibiotic resistance is a major public health issue and many bacteria responsible for human infections have now developed a variety of antibiotic resistance mechanisms. For instance, Pseudomonas aeruginosa, a disease-causing Gram-negative bacteria, is now resistant to almost every class of antibiotics. Much of this resistance is attributable to multidrug efflux pumps, which are tripartite membrane protein complexes that span both membranes and actively expel antibiotics. Here we report an in vitro procedure to monitor transport by the tripartite MexAB-OprM pump. By combining proteoliposomes containing the MexAB and OprM portions of the complex, we are able to assay energy-dependent substrate translocation in a system that mimics the dual-membrane architecture of Gram-negative bacteria. This assay facilitates the study of pump transport dynamics and could be used to screen pump inhibitors with potential clinical use in restoring therapeutic activity of old antibiotics.

Activation of Antibiotic Production in Bacillus spp. by Cumulative Drug Resistance Mutations.

PubMed

Tojo, Shigeo; Tanaka, Yukinori; Ochi, Kozo

2015-12-01

Bacillus subtilis strains produce a wide range of antibiotics, including ribosomal and nonribosomal peptide antibiotics, as well as bacilysocin and neotrehalosadiamine. Mutations in B. subtilis strain 168 that conferred resistance to drugs such as streptomycin and rifampin resulted in overproduction of the dipeptide antibiotic bacilysin. Cumulative drug resistance mutations, such as mutations in the mthA and rpsL genes, which confer low- and high-level resistance, respectively, to streptomycin, and mutations in rpoB, which confer resistance to rifampin, resulted in cells that overproduced bacilysin. Transcriptional analysis demonstrated that the enhanced transcription of biosynthesis genes was responsible for the overproduction of bacilysin. This approach was effective also in activating the cryptic genes of Bacillus amyloliquefaciens, leading to actual production of antibiotic(s). Copyright © 2015, American Society for Microbiology. All Rights Reserved.

[L forms of Staphylococcus aureus. Behavior of coagulase, hemolytic and desoxyribonuclease activities and antibiotic sensitivity].

PubMed

Loschiavo, F; Giarrizzo, S

1977-01-01

L Forms derived from strains of coagulase positive Staphylococcus aureus, have, on the whole, preserved their DNAsic, haemolitic and coagulastic activities. L. forms showed high resistence to antibiotics acting on the bacterial cell-wall. The sensibility to other antibiotics was, roughly, analogous for the L forms as well as for the bacterial strains ones, with the exception of the clortetraciclin and the diidrostreptomicin, ehich proved to be comparatively more active on the L forms.

The Use of Micro and Nano Particulate Fillers to Modify the Mechanical and Material Properties of Acrylic Bone Cement

NASA Astrophysics Data System (ADS)

Slane, Joshua A.

Acrylic bone cement (polymethyl methacrylate) is widely used in total joint replacements to provide long-term fixation of implants. In essence, bone cement acts as a grout by filling in the voids left between the implant and the patient's bone, forming a mechanical interlock. While bone cement is considered the `gold standard' for implant fixation, issues such as mechanical failure of the cement mantle (aseptic loosening) and the development of prosthetic joint infection (PJI) still plague joint replacement procedures and often necessitate revision arthroplasty. In an effort to address these failures, various modifications are commonly made to bone cement such as mechanical reinforcement with particles/fibers and the addition of antibiotics to mitigate PJI. Despite these attempts, issues such as poor particle interfacial adhesion, inadequate drug release, and the development of multidrug resistant bacteria limit the effectiveness of bone cement modifications. Therefore, the overall goal of this work was to use micro and nanoparticles to enhance the properties of acrylic bone cement, with particular emphasis placed on improving the mechanical properties, cumulative antibiotic release, and antimicrobial properties. An acrylic bone cement (Palacos R) was modified with three types of particles in various loading ratios: mesoporous silica nanoparticles (for mechanical reinforcement), xylitol microparticles (for increased antibiotic release), and silver nanoparticles (as an antimicrobial agent). These particles were used as sole modifications, not in tandem with one another. The resulting cement composites were characterized using a variety of mechanical (macro to nano, fatigue, fracture, and dynamic), imaging, chemical, thermal, biological, and antimicrobial testing techniques. The primary outcomes of this dissertation demonstrate that: (1) mesoporous silica, as used in this work, is a poor reinforcement phase for acrylic bone cement, (2) xylitol can significantly increase the cumulative antibiotic release from acrylic cement, and (3) silver nanoparticles are a potential alternative to traditional antibiotics in cement, such as gentamicin.

Antitumor and Antimicrobial Activity of Some Cyclic Tetrapeptides and Tripeptides Derived from Marine Bacteria

PubMed Central

Chakraborty, Subrata; Tai, Dar-Fu; Lin, Yi-Chun; Chiou, Tzyy-Wen

2015-01-01

Marine derived cyclo(Gly-l-Ser-l-Pro-l-Glu) was selected as a lead to evaluate antitumor-antibiotic activity. Histidine was chosen to replace the serine residue to form cyclo(Gly-l-His-l-Pro-l-Glu). Cyclic tetrapeptides (CtetPs) were then synthesized using a solution phase method, and subjected to antitumor and antibiotic assays. The benzyl group protected CtetPs derivatives, showed better activity against antibiotic-resistant Staphylococcus aureus in the range of 60–120 μM. Benzyl group protected CtetPs 3 and 4, exhibited antitumor activity against several cell lines at a concentration of 80–108 μM. However, shortening the size of the ring to the cyclic tripeptide (CtriP) scaffold, cyclo(Gly-l-Ser-l-Pro), cyclo(Ser-l-Pro-l-Glu) and their analogues showed no antibiotic or antitumor activity. This phenomenon can be explained from their backbone structures. PMID:25988520

Antitumor and antimicrobial activity of some cyclic tetrapeptides and tripeptides derived from marine bacteria.

PubMed

Chakraborty, Subrata; Tai, Dar-Fu; Lin, Yi-Chun; Chiou, Tzyy-Wen

2015-05-15

Marine derived cyclo(Gly-l-Ser-l-Pro-l-Glu) was selected as a lead to evaluate antitumor-antibiotic activity. Histidine was chosen to replace the serine residue to form cyclo(Gly-l-His-l-Pro-l-Glu). Cyclic tetrapeptides (CtetPs) were then synthesized using a solution phase method, and subjected to antitumor and antibiotic assays. The benzyl group protected CtetPs derivatives, showed better activity against antibiotic-resistant Staphylococcus aureus in the range of 60-120 μM. Benzyl group protected CtetPs 3 and 4, exhibited antitumor activity against several cell lines at a concentration of 80-108 μM. However, shortening the size of the ring to the cyclic tripeptide (CtriP) scaffold, cyclo(Gly-l-Ser-l-Pro), cyclo(Ser-l-Pro-l-Glu) and their analogues showed no antibiotic or antitumor activity. This phenomenon can be explained from their backbone structures.

Lassomycin, a ribosomally synthesized cyclic peptide, kills Mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2

PubMed Central

Gavrish, Ekaterina; Sit, Clarissa S.; Cao, Shugeng; Kandror, Olga; Spoering, Amy; Peoples, Aaron; Ling, Losee; Fetterman, Ashley; Hughes, Dallas; Bissell, Anthony; Torrey, Heather; Akopian, Tatos; Mueller, Andreas; Epstein, Slava; Goldberg, Alfred; Clardy, Jon; Lewis, Kim

2014-01-01

Summary Languishing antibiotic discovery and flourishing antibiotic resistance have prompted development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against M. tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells. Lassomycin is a highly basic, ribosomally-encoded cyclic peptide with an unusual structural fold that only partially resembles that of other lasso peptides. We show that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2 catalyzed protein breakdown, which is essential for viability of mycobacteria. This mechanism, uncoupling ATPase from proteolytic activity, accounts for lassomycin's bacteriocidal activity. PMID:24684906

[Antibiotics in the critically ill].

PubMed

Kolak, Radmila R

2010-01-01

Antibiotics are one the most common therapies administered in the intensive care unit setting. This review outlines the strategy for optimal use of antimicrobial agents in the critically ill. In severely ill patients, empirical antimicrobial therapy should be used when a suspected infection may impair the outcome. It is necessary to collect microbiological documentation before initiating empirical antimicrobial therapy. In addition to antimicrobial therapy, it is recommended to control a focus of infection and to modify factors that promote microbial growth or impair the host's antimicrobial defence. A judicious choice of antimicrobial therapy should be based on the host characteristics, the site of injection, the local ecology, and the pharmacokinetics/pharmacodynamics of antibiotics. This means treating empirically with broad-spectrum antimicrobials as soon as possible and narrowing the spectrum once the organism is identified (de-escalation), and limiting duration of therapy to the minimum effective period. Despite theoretical advantages, a combined antibiotic therapy is nor more effective than a mono-therapy in curing infections in most clinical trials involving intensive care patients. Nevertheless, textbooks and guidelines recommend a combination for specific pathogens and for infections commonly caused by these pathogens. Avoiding unnecessary antibiotic use and optimizing the administration of antimicrobial agents will improve patient outcomes while minimizing risks for the development of bacterial resistance. It is important to note that each intensive care unit should have a program in place which monitors antibiotic utilisation and its effectiveness. Only in this way can the impact of interventions aimed at improving antibiotic use be evaluated at the local level.

Prophylactic antibiotics in plastic surgery: trends of use over 25 years of an evolving specialty.

PubMed

Lyle, W Glenn; Outlaw, Kitti; Krizek, Thomas J; Koss, Neal; Payne, Wyatt G; Robson, Martin C

2003-05-01

Infection complicating a plastic-surgery procedure can be a catastrophic event, both for the patient and the surgeon. Surveys published in 1975 and 1985 demonstrated the "usual and customary" practices of plastic surgeons with regard to the use of prophylactic antibiotics. The objective of this study was to determine plastic surgeons' current use of prophylactic antibiotics, to compare these data with similar data from 1975 and 1985, and to gain relevant information regarding newer aesthetic procedures. We conducted a survey of members of the American Society of Plastic Surgeons to elicit information on the frequency and timing of and modifying influences on their use of prophylactic antibiotics for plastic surgery procedures. The data we compiled were compared with the 1985 and 1975 data. Respondents returned 1804 questionnaires, for a 35% response rate. Antibiotic usage increased by 100% in nearly half of the operative categories surveyed since 1985 (P = .001). Aesthetic procedures were most common in this group. In 7 procedures, usage increased by 200% (P = 0.001). These categories included rhinoplasty, blepharoplasty, rhytidectomy, and arm contouring. The use of prophylactic antibiotics by plastic surgeons is increasing, especially in aesthetic procedures. A review of the literature indicates that this increase in use is not based on scientific evidence of increased incidence of infection or on increased evidence of efficacy. The necessary data to provide scientific guidelines for antibiotic usage in plastic surgery do not exist. (Aesthetic Surg J 2003;23:177-183.).

Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age

PubMed Central

Chow, Angela L. P.; Lye, David C.; Arah, Onyebuchi A.

2015-01-01

Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital’s antibiotic CDSS on patients’ clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS’s recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26–1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20–1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91–1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34–3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42–2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48–2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations. PMID:26617195

Lactobacillus rhamnosus GG Intake Modifies Preschool Children's Intestinal Microbiota, Alleviates Penicillin-Associated Changes, and Reduces Antibiotic Use.

PubMed

Korpela, Katri; Salonen, Anne; Virta, Lauri J; Kumpu, Minna; Kekkonen, Riina A; de Vos, Willem M

2016-01-01

Antibiotic use is considered among the most severe causes of disturbance to children's developing intestinal microbiota, and frequently causes adverse gastrointestinal effects ranging from mild and transient diarrhoea to life-threatening infections. Probiotics are commonly advocated to help in preventing antibiotic-associated gastrointestinal symptoms. However, it is currently unknown whether probiotics alleviate the antibiotic-associated changes in children's microbiota. Furthermore, it is not known how long-term probiotic consumption influences the developing microbiota of children. We analysed the influence of long-term Lactobacillus rhamnosus GG intake on preschool children's antibiotic use, and antibiotic-associated gastrointestinal complaints in a double blind, randomized placebo-controlled trial with 231 children aged 2-7. In addition, we analysed the effect of L. rhanmosus GG on the intestinal microbiota in a subset of 88 children. The results show that long-term L. rhamnosus GG supplementation has an influence on the composition of the intestinal microbiota in children, causing an increase in the abundance of Prevotella, Lactococcus, and Ruminococcus, and a decrease in Escherichia. The treatment appeared to prevent some of the changes in the microbiota associated with penicillin use, but not those associated with macrolide use. The treatment, however, did reduce the frequency of gastrointestinal complaints after a macrolide course. Finally, the treatment appeared to prevent certain bacterial infections for up to 3 years after the trial, as indicated by reduced antibiotic use. ClinicalTrials.gov NCT01014676.

Mortality Benefits of Antibiotic Computerised Decision Support System: Modifying Effects of Age

NASA Astrophysics Data System (ADS)

Chow, Angela L. P.; Lye, David C.; Arah, Onyebuchi A.

2015-11-01

Antibiotic computerised decision support systems (CDSSs) are shown to improve antibiotic prescribing, but evidence of beneficial patient outcomes is limited. We conducted a prospective cohort study in a 1500-bed tertiary-care hospital in Singapore, to evaluate the effectiveness of the hospital’s antibiotic CDSS on patients’ clinical outcomes, and the modification of these effects by patient factors. To account for clustering, we used multilevel logistic regression models. One-quarter of 1886 eligible inpatients received CDSS-recommended antibiotics. Receipt of antibiotics according to CDSS’s recommendations seemed to halve mortality risk of patients (OR 0.54, 95% CI 0.26-1.10, P = 0.09). Patients aged ≤65 years had greater mortality benefit (OR 0.45, 95% CI 0.20-1.00, P = 0.05) than patients that were older than 65 (OR 1.28, 95% CI 0.91-1.82, P = 0.16). No effect was observed on incidence of Clostridium difficile (OR 1.02, 95% CI 0.34-3.01), and multidrug-resistant organism (OR 1.06, 95% CI 0.42-2.71) infections. No increase in infection-related readmission (OR 1.16, 95% CI 0.48-2.79) was found in survivors. Receipt of CDSS-recommended antibiotics reduced mortality risk in patients aged 65 years or younger and did not increase the risk in older patients. Physicians should be informed of the benefits to increase their acceptance of CDSS recommendations.

Lactobacillus rhamnosus GG Intake Modifies Preschool Children’s Intestinal Microbiota, Alleviates Penicillin-Associated Changes, and Reduces Antibiotic Use

PubMed Central

Korpela, Katri; Salonen, Anne; Virta, Lauri J.; Kumpu, Minna; Kekkonen, Riina A.; de Vos, Willem M.

2016-01-01

Antibiotic use is considered among the most severe causes of disturbance to children’s developing intestinal microbiota, and frequently causes adverse gastrointestinal effects ranging from mild and transient diarrhoea to life-threatening infections. Probiotics are commonly advocated to help in preventing antibiotic-associated gastrointestinal symptoms. However, it is currently unknown whether probiotics alleviate the antibiotic-associated changes in children’s microbiota. Furthermore, it is not known how long-term probiotic consumption influences the developing microbiota of children. We analysed the influence of long-term Lactobacillus rhamnosus GG intake on preschool children’s antibiotic use, and antibiotic-associated gastrointestinal complaints in a double blind, randomized placebo-controlled trial with 231 children aged 2–7. In addition, we analysed the effect of L. rhanmosus GG on the intestinal microbiota in a subset of 88 children. The results show that long-term L. rhamnosus GG supplementation has an influence on the composition of the intestinal microbiota in children, causing an increase in the abundance of Prevotella, Lactococcus, and Ruminococcus, and a decrease in Escherichia. The treatment appeared to prevent some of the changes in the microbiota associated with penicillin use, but not those associated with macrolide use. The treatment, however, did reduce the frequency of gastrointestinal complaints after a macrolide course. Finally, the treatment appeared to prevent certain bacterial infections for up to 3 years after the trial, as indicated by reduced antibiotic use. Trial Registration: ClinicalTrials.gov NCT01014676 PMID:27111772

Metabolomic approach to optimizing and evaluating antibiotic treatment in the axenic culture of cyanobacterium Nostoc flagelliforme.

PubMed

Han, Pei-pei; Jia, Shi-ru; Sun, Ying; Tan, Zhi-lei; Zhong, Cheng; Dai, Yu-jie; Tan, Ning; Shen, Shi-gang

2014-09-01

The application of antibiotic treatment with assistance of metabolomic approach in axenic isolation of cyanobacterium Nostoc flagelliforme was investigated. Seven antibiotics were tested at 1-100 mg L(-1), and order of tolerance of N. flagelliforme cells was obtained as kanamycin > ampicillin, tetracycline > chloromycetin, gentamicin > spectinomycin > streptomycin. Four antibiotics were selected based on differences in antibiotic sensitivity of N. flagelliforme and associated bacteria, and their effects on N. flagelliforme cells including the changes of metabolic activity with antibiotics and the metabolic recovery after removal were assessed by a metabolomic approach based on gas chromatography-mass spectrometry combined with multivariate analysis. The results showed that antibiotic treatment had affected cell metabolism as antibiotics treated cells were metabolically distinct from control cells, but the metabolic activity would be recovered via eliminating antibiotics and the sequence of metabolic recovery time needed was spectinomycin, gentamicin > ampicillin > kanamycin. The procedures of antibiotic treatment have been accordingly optimized as a consecutive treatment starting with spectinomycin, then gentamicin, ampicillin and lastly kanamycin, and proved to be highly effective in eliminating the bacteria as examined by agar plating method and light microscope examination. Our work presented a strategy to obtain axenic culture of N. flagelliforme and provided a method for evaluating and optimizing cyanobacteria purification process through diagnosing target species cellular state.

Activity of some aminoglycoside antibiotics against true fungi, Phytophthora and Pythium species.

PubMed

Lee, H B; Kim, Y; Kim, J C; Choi, G J; Park, S-H; Kim, C-J; Jung, H S

2005-01-01

To investigate the in vitro antifungal and antioomycete activities of some aminoglycosides against true fungi and Phytophthora and Pythium species and to evaluate the potential of the antibiotics against Phytophthora late blight on plants. Antifungal and antioomycete activities of aminoglycoside antibiotics (neomycin, paromomycin, ribostamycin and streptomycin) and a paromomycin-producing strain (Streptomyces sp. AMG-P1) against Phytophthora and Pythium species and 10 common fungi were measured in potato dextrose broth (PDB) and on seedlings in pots. Paromomycin was the most active against Phytophthora and Pythium species with a minimal inhibitory concentration of 1-10 microg ml(-1) in PDB, but displayed low to moderate activities towards other common fungi at the same concentration. Paromomycin also showed potent in vivo activity against red pepper and tomato late blight diseases with 80 and 99% control value, respectively, at 100 microg ml(-1). In addition, culture broth of Streptomyces sp. AMG-P1 as a paromomycin producer exhibited high in vivo activity against late blight at 500 microg freeze-dried weight per millilitre. Among tested aminoglycoside antibiotics, paromomycin was the most active against oomycetes both in vitro and in vivo. Data from this study show that aminoglycoside antibiotics have in vitro and in vivo activities against oomycetes, suggesting that Streptomyces sp. AMG-P1 may be used as a biocontrol agent against oomycete diseases.

How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function

PubMed Central

Otero, Lisandro H.; Rojas-Altuve, Alzoray; Llarrull, Leticia I.; Carrasco-López, Cesar; Kumarasiri, Malika; Lastochkin, Elena; Fishovitz, Jennifer; Dawley, Matthew; Hesek, Dusan; Lee, Mijoon; Johnson, Jarrod W.; Fisher, Jed F.; Chang, Mayland; Mobashery, Shahriar; Hermoso, Juan A.

2013-01-01

The expression of penicillin binding protein 2a (PBP2a) is the basis for the broad clinical resistance to the β-lactam antibiotics by methicillin-resistant Staphylococcus aureus (MRSA). The high-molecular mass penicillin binding proteins of bacteria catalyze in separate domains the transglycosylase and transpeptidase activities required for the biosynthesis of the peptidoglycan polymer that comprises the bacterial cell wall. In bacteria susceptible to β-lactam antibiotics, the transpeptidase activity of their penicillin binding proteins (PBPs) is lost as a result of irreversible acylation of an active site serine by the β-lactam antibiotics. In contrast, the PBP2a of MRSA is resistant to β-lactam acylation and successfully catalyzes the dd-transpeptidation reaction necessary to complete the cell wall. The inability to contain MRSA infection with β-lactam antibiotics is a continuing public health concern. We report herein the identification of an allosteric binding domain—a remarkable 60 Å distant from the dd-transpeptidase active site—discovered by crystallographic analysis of a soluble construct of PBP2a. When this allosteric site is occupied, a multiresidue conformational change culminates in the opening of the active site to permit substrate entry. This same crystallographic analysis also reveals the identity of three allosteric ligands: muramic acid (a saccharide component of the peptidoglycan), the cell wall peptidoglycan, and ceftaroline, a recently approved anti-MRSA β-lactam antibiotic. The ability of an anti-MRSA β-lactam antibiotic to stimulate allosteric opening of the active site, thus predisposing PBP2a to inactivation by a second β-lactam molecule, opens an unprecedented realm for β-lactam antibiotic structure-based design. PMID:24085846

An unusual class of anthracyclines potentiate Gram-positive antibiotics in intrinsically resistant Gram-negative bacteria.

PubMed

Cox, Georgina; Koteva, Kalinka; Wright, Gerard D

2014-07-01

An orthogonal approach taken towards novel antibacterial drug discovery involves the identification of small molecules that potentiate or enhance the activity of existing antibacterial agents. This study aimed to identify natural-product rifampicin adjuvants in the intrinsically resistant organism Escherichia coli. E. coli BW25113 was screened against 1120 actinomycete fermentation extracts in the presence of subinhibitory (2 mg/L) concentrations of rifampicin. The active molecule exhibiting the greatest rifampicin potentiation was isolated using activity-guided methods and identified using mass and NMR spectroscopy. Susceptibility testing and biochemical assays were used to determine the mechanism of antibiotic potentiation. The anthracycline Antibiotic 301A(1) was isolated from the fermentation broth of a strain of Streptomyces (WAC450); the molecule was shown to be highly synergistic with rifampicin (fractional inhibitory concentration index = 0.156) and moderately synergistic with linezolid (FIC index = 0.25) in both E. coli and Acinetobacter baumannii. Activity was associated with inhibition of efflux and the synergistic phenotype was lost when tested against E. coli harbouring mutations within the rpoB gene. Structure-activity relationship studies revealed that other anthracyclines do not synergize with rifampicin and removal of the sugar moiety of Antibiotic 301A(1) abolishes activity. Screening only a subsection of our natural product library identified a small-molecule antibiotic adjuvant capable of sensitizing Gram-negative bacteria to antibiotics to which they are ordinarily intrinsically resistant. This result demonstrates the great potential of this approach in expanding antibiotic effectiveness in the face of the growing challenge of resistance in Gram-negatives. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase.

PubMed

González, Mariano M; Kosmopoulou, Magda; Mojica, Maria F; Castillo, Valerie; Hinchliffe, Philip; Pettinati, Ilaria; Brem, Jürgen; Schofield, Christopher J; Mahler, Graciela; Bonomo, Robert A; Llarrull, Leticia I; Spencer, James; Vila, Alejandro J

2015-11-13

Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are "last line therapies" for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with β-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 μM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.

Broad Range Amino Acid Specificity of RNA-dependent Lipid Remodeling by Multiple Peptide Resistance Factors*

PubMed Central

Roy, Hervé; Ibba, Michael

2009-01-01

Aminoacylphosphatidylglycerol synthases (aaPGSs) are multiple peptide resistance factors that transfer amino acids from aminoacyl-tRNAs to phosphatidylglycerol (PG) in the cytoplasmic membrane. Aminoacylation of PG is used by bacteria to decrease the net negative charge of the cell envelope, diminishing affinity for charged molecules and allowing for adaptation to environmental changes. Lys-PGS, which transfers lysine to PG, is essential for the virulence of certain pathogens, providing resistance to both host cationic antimicrobial peptides and therapeutic antibiotics. Ala-PGS was also recently described, but little is known about the possible activities of other members of the highly diverse aaPGS family of proteins. Systematic deletion of the predicted membrane-inserted domains of several aaPGSs revealed that the carboxyl-terminal hydrophilic domain alone is sufficient for aminoacylphosphatidylglycerol transferase catalytic activity. In contrast to previously characterized aaPGSs, the Enterococcus faecium enzyme used an expanded repertoire of amino acids to modify PG with Ala, Arg, or Lys. Reexamination of previously characterized aaPGSs also revealed broader than anticipated substrate specificity, for example Bacillus subtilis Lys-PGS was shown to also catalyze Ala-PG synthesis. The relaxed substrate specificities of these aaPGSs allows for more elaborate remodeling of membrane lipids than previously thought, potentially providing bacteria that harbor these enzymes resistance to a broad spectrum of antibiotics and environmental stresses. PMID:19734140

Reprioritizing Research Activity for the Post-Antibiotic Era: Ethical, Legal, and Social Considerations.

PubMed

Hey, Spencer Phillips; Kesselheim, Aaron S

2017-03-01

Many hold that the so-called golden era of antibiotic discovery has passed, leaving only a limited clinical pipeline for new antibiotics. A logical conclusion of such arguments is that we need to reform the current system of antibiotic drug research-including clinical trials and regulatory requirements-to spur activity in discovery and development. The United States Congress in the past few years has debated a number of bills to address this crisis, including the 2012 Generating Antibiotic Incentives Now Act and the 2016 21st Century Cures Act. Experts have also sought to advance antibiotic development by encouraging greater use of trials with noninferiority hypotheses, which are thought to be easier to conduct. The goal underlying these proposals is to stave off the post-antibiotic era by expanding the pharmaceutical armamentarium as quickly as possible. But although new antibiotic agents are necessary to combat the long-term threat of drug-resistant disease, we argue that these research policies, which effectively lower the bar for antibiotic approval, are ethically problematic. Rather, given broader public health considerations related to the full lifecycle of antibiotic use-including development of resistance-we should reject an overly permissive approach to new antibiotic approval and instead set the bar for regulatory approval at a point that will naturally direct research resources toward the most transformative chemical or social interventions. © 2017 The Hastings Center.

Invited review: Essential oils as modifiers of rumen microbial fermentation.

PubMed

Calsamiglia, S; Busquet, M; Cardozo, P W; Castillejos, L; Ferret, A

2007-06-01

Microorganisms in the rumen degrade nutrients to produce volatile fatty acids and synthesize microbial protein as an energy and protein supply for the ruminant, respectively. However, this fermentation process has energy (losses of methane) and protein (losses of ammonia N) inefficiencies that may limit production performance and contribute to the release of pollutants to the environment. Antibiotic ionophores have been very successful in reducing these energy and protein losses in the rumen, but the use of antibiotics in animal feeds is facing reduced social acceptance, and their use has been banned in the European Union since January 2006. For this reason, scientists have become interested in evaluating other alternatives to control specific microbial populations to modulate rumen fermentation. Essential oils can interact with microbial cell membranes and inhibit the growth of some gram-positive and gram-negative bacteria. As a result of such inhibition, the addition of some plant extracts to the rumen results in an inhibition of deamination and methanogenesis, resulting in lower ammonia N, methane, and acetate, and in higher propionate and butyrate concentrations. Results have indicated that garlic oil, cinnamaldehyde (the main active component of cinnamon oil), eugenol (the main active component of the clove bud), capsaicin (the active component of hot peppers), and anise oil, among others, may increase propionate production, reduce acetate or methane production, and modify proteolysis, peptidolysis, or deamination in the rumen. However, the effects of some of these essential oils are pH and diet dependent, and their use may be beneficial only under specific conditions and production systems. For example, capsaicin appears to have small effects in high-forage diets, whereas the changes observed in high-concentrate diets (increases in dry matter intake and total VFA, and reduction in the acetateto-propionate ratio and ammonia N concentration) may be beneficial. Because plant extracts may act at different levels in the carbohydrate and protein degradation pathways, their careful selection and combination may provide a useful tool to manipulate rumen microbial fermentation effectively. However, additional research is required to establish the optimal dose in vivo in units of the active component, to consider the potential adaptation of microbial populations to their activities, to examine the presence of residues in the products (milk or meat), and to demonstrate improvements in animal performance.

Laser activation of a nutrient medium and antibiotic solutions and its estimation by of bacteria growth dynamics

NASA Astrophysics Data System (ADS)

Malov, Alexander N.; Neupokoeva, Anna V.; Kokorina, Lubov A.; Simonova, Elena V.

2016-11-01

A laser photomodifacation of nutrient mediums and antibiotics results at the microbiological supervision of bacteria colonies growth are discussed. It is experimentally shown, that on the irradiated media there is a delay of bacterial colonies growth number. Influence of laser radiation on activity of an antibiotic also is experimentally studied. It is revealed, that laser photomodifacation increases antimicrobic activity of a preparation. The mechanism of biological solutions activation is connected with the phenomenon laser nanoclusterization. Parameters of bacteria growth bacteria growth dynamics allow to numerically estimate degree of laser activation of nutrient mediums and pharmaceutical preparations.

The multilevel antibiotic-induced perturbations to biological systems: Early-life exposure induces long-lasting damages to muscle structure and mitochondrial metabolism in flies.

PubMed

Renault, David; Yousef, Hesham; Mohamed, Amr A

2018-06-07

Antibiotics have been increasingly used over the past decades for human medicine, food-animal agriculture, aquaculture, and plant production. A significant part of the active molecules of antibiotics can be released into the environment, in turn affecting ecosystem functioning and biogeochemical processes. At lower organizational scales, these substances affect bacterial symbionts of insects, with negative consequences on growth and development of juveniles, and population dynamics. Yet, the multiple alterations of cellular physiology and metabolic processes have remained insufficiently explored in insects. We evaluated the effects of five antibiotics with different mode of action, i.e. ampicillin, cefradine, chloramphenicol, cycloheximide, and tetracycline, on the survival and ultrastructural organization of the flight muscles of newly emerged blow flies Chrysomya albiceps. Then, we examined the effects of different concentrations of antibiotics on mitochondrial protein content, efficiency of oxidative phosphorylation, and activity of transaminases (Glutamate oxaloacetate transaminase and glutamate pyruvate transaminase) and described the cellular metabolic perturbations of flies treated with antibiotics. All antibiotics affected the survival of the insects and decreased the total mitochondrial protein content in a dose-dependent manner. Ultrastructural organization of flight muscles in treated flies differs dramatically compared to the control groups and severe pathological damages/structures disorganization of mitochondria appeared. The activities of mitochondrial transaminases significantly increased with increased antibiotic concentrations. The oxidation rate of pyruvate + proline from isolated mitochondria of the flight muscles of 1-day-old flies was significantly reduced at high doses of antibiotics. In parallel, the level of several metabolites, including TCA cycle intermediates, was reduced in antibiotics-treated flies. Overall, antibiotics provoked a system-wide alteration of the structure and physiology of flight muscles of the blow fly Ch. albiceps, and may have fitness consequences at the organism level. Environmental antibiotic pollution is likely to have unwanted cascading ecological effects of insect population dynamics and community structure. Copyright © 2018 Elsevier Ltd. All rights reserved.

Substitutions in PBP2b from β-Lactam-resistant Streptococcus pneumoniae Have Different Effects on Enzymatic Activity and Drug Reactivity*

PubMed Central

Calvez, Philippe; Breukink, Eefjan; Roper, David I.; Dib, Mélanie; Contreras-Martel, Carlos; Zapun, André

2017-01-01

Pneumococcus resists β-lactams by expressing variants of its target enzymes, the penicillin-binding proteins (PBPs), with many amino acid substitutions. Up to 10% of the sequence can be modified. These altered PBPs have a much reduced reactivity with the drugs but retain their physiological activity of cross-linking the peptidoglycan, the major constituent of the bacterial cell wall. However, because β-lactams are chemical and structural mimics of the natural substrate, resistance mediated by altered PBPs raises the following paradox: how PBPs that react poorly with the drugs maintain a sufficient level of activity with the physiological substrate. This question is addressed for the first time in this study, which compares the peptidoglycan cross-linking activity of PBP2b from susceptible and resistant strains with their inhibition by different β-lactams. Unexpectedly, the enzymatic activity of the variants did not correlate with their antibiotic reactivity. This finding indicates that some of the numerous amino acid substitutions were selected to restore a viable level of enzymatic activity by a compensatory molecular mechanism. PMID:28062575

Building and Breaking the Cell Wall in Four Acts: A Kinesthetic and Tactile Role-Playing Exercise for Teaching Beta-Lactam Antibiotic Mechanism of Action and Resistance †

PubMed Central

Popovich, John; Stephens, Michelle; Celaya, Holly; Suwarno, Serena; Barclay, Shizuka; Yee, Emily; Dean, David A.; Farris, Megan; Haydel, Shelley E.

2018-01-01

“Building and breaking the cell wall” is designed to review the bacterial cell envelope, previously learned in lower-division biology classes, while introducing new topics such as antibiotics and bacterial antibiotic resistance mechanisms. We developed a kinesthetic and tactile modeling activity where students act as cellular components and construct the cell wall. In the first two acts, students model a portion of the gram-positive bacterial cell envelope and then demonstrate in detail how the peptidoglycan is formed. Act III involves student demonstration of the addition of β-lactam antibiotics to the environment and how they inhibit the formation of peptidoglycan, thereby preventing bacterial replication. Using Staphylococcus aureus as a model for gram-positive bacteria, students finish the activity (Act IV) by acting out how S. aureus often becomes resistant to β-lactam antibiotics. A high level of student engagement was observed, and the activity received positive feedback. In an assessment administered prior to and two months after the activity, significant improvements in scores were observed (p < 0.0001), demonstrating increased understanding and retention. This activity allows students to (i) visualize, role play, and kinesthetically “build” the cell envelope and form the peptidoglycan layer, (ii) understand the mechanism of action for β-lactam antibiotics, as well as how gene acquisition and protein changes result in resistance, and (iii) work cooperatively and actively to promote long-term retention of the subject material. PMID:29904519

Spectrophotometric Investigations of Macrolide Antibiotics: A Brief Review

PubMed Central

Keskar, Mrudul R; Jugade, Ravin M

2015-01-01

Macrolides, one of the most commonly used class of antibiotics, are a group of drugs produced by Streptomyces species. They belong to the polyketide class of natural products. Their activity is due to the presence of a large macrolide lactone ring with deoxy sugar moieties. They are protein synthesis inhibitors and broad-spectrum antibiotics, active against both gram-positive and gram-negative bacteria. Different analytical techniques have been reported for the determination of macrolides such as chromatographic methods, flow injection methods, spectrofluorometric methods, spectrophotometric methods, and capillary electrophoresis methods. Among these methods, spectrophotometric methods are sensitive and cost effective for the analysis of various antibiotics in pharmaceutical formulations as well as biological samples. This article reviews different spectrophotometric methods for the determination of macrolide antibiotics. PMID:26609215

Antibiotic prescribing at the transition from hospitalization to discharge: a target for antibiotic stewardship

PubMed Central

Yogo, Norihiro; Haas, Michelle K; Knepper, Bryan C; Burman, William J; Mehler, Philip S; Jenkins, Timothy C

2016-01-01

Of 300 patients prescribed oral antibiotics at the time of hospital discharge, urinary tract infection, community-acquired pneumonia , and skin infections accounted for 181 (60%) of the treatment indications. Half of the prescriptions were antibiotics with broad gram-negative activity. Discharge prescriptions were inappropriate in 79 (53%) of 150 cases reviewed. PMID:25782905

Antibiotic prescribing for upper respiratory-tract infections in primary care.

PubMed

Patterson, Craig A; Mackson, Judith M; Weekes, Lynn M

2003-01-01

The use and overuse of antibiotics in humans is a major contributor to the selection of antibiotic resistance organisms. Recent evidence has shown that primary care prescribing selects for resistances of clinical importance. The National Prescribing Service runs both educational and audit activities. The latter provide some insight into general practice attitudes toward antibiotic prescribing.

Antimicrobial activity of lactobacillus strains against uropathogens.

PubMed

Shim, Yoon Hee; Lee, Seung Joo; Lee, Jung Won

2016-10-01

The use of lactobacillus probiotics has been proposed as an alternative to prophylactic antibiotics for preventing urinary tract infection (UTI) in the era of antibiotic resistance. In this study, the antimicrobial activity of lactobacillus strains against uropathogens, was evaluated and compared with that of antibiotics. To evaluate inhibitory activities of lactobacilli against uropathogens, six lactobacillus strains (L. gasseri, L. rhamnosus, L. acidophilus, L. plantarum, L. paracasei, L. acidophilus) and four representative uropathogens of infantile UTI (extended-spectrum beta-lactamase [ESBL](-) Escherichia coli, ESBL(+) E. coli, Proteus vulgaris, Enterococcus fecalis) were selected. Lactobacillus strain in vitro inhibition of each uropathogen was evaluated on MRS agar well diffusion assay and compared with that of commercial antibiotic discs. Average inhibitory zone for each of the six lactobacillus strains against the four uropathogens showed slightly different but consistent inhibition (inhibitory zone diameter, 10.5-20.0 mm). This was different to that of the antibiotic discs, which had a wider range of inhibition (inhibitory zone diameter, <6.0-27.5 mm) depending on the uropathogen resistance pattern. The inhibitory zone of the six lactobacillus strains was between that of sensitive and resistant antibiotics (P < 0.05). Lactobacillus strains had similar moderate antimicrobial activities against uropathogens. Further research is needed to ascertain the strains with the best probiotic potential. © 2016 Japan Pediatric Society.

FabH Mutations Confer Resistance to FabF-Directed Antibiotics in Staphylococcus aureus

PubMed Central

Parsons, Joshua B.; Yao, Jiangwei; Frank, Matthew W.

2014-01-01

Delineating the mechanisms for genetically acquired antibiotic resistance is a robust approach to target validation and anticipates the evolution of clinical drug resistance. This study defines a spectrum of mutations in fabH that render Staphylococcus aureus resistant to multiple natural products known to inhibit the elongation condensing enzyme (FabF) of bacterial type II fatty acid synthesis. Twenty independently isolated clones resistant to platensimycin, platencin, or thiolactomycin were isolated. All mutants selected against one antibiotic were cross-resistant to the other two antibiotics. Mutations were not detected in fabF, but the resistant strains harbored missense mutations in fabH. The altered amino acids clustered in and around the FabH active-site tunnel. The mutant FabH proteins were catalytically compromised based on the low activities of the purified enzymes, a fatty acid-dependent growth phenotype, and elevated expression of the fabHF operon in the mutant strains. Independent manipulation of fabF and fabH expression levels showed that the FabH/FabF activity ratio was a major determinant of antibiotic sensitivity. Missense mutations that reduce FabH activity are sufficient to confer resistance to multiple antibiotics that bind to the FabF acyl-enzyme intermediate in S. aureus. PMID:25403676

Antibiotic contamination in a typical developing city in south China: occurrence and ecological risks in the Yongjiang River impacted by tributary discharge and anthropogenic activities.

PubMed

Xue, Baoming; Zhang, Ruijie; Wang, Yinghui; Liu, Xiang; Li, Jun; Zhang, Gan

2013-06-01

The occurrence and distribution of ten selected antibiotics from three groups (sulfonamides, macrolides, and trimethoprim) were investigated in the Yongjiang River, which flows through Nanning City, a typical developing city in China. The study also assessed the ecological risks and the potential effects caused by discharge from tributaries and anthropogenic activities. Concentrations of most of the antibiotics were elevated along the section of the river in the urban area, highlighting the significant impact of high population density and human activities on the presence of antibiotics in the environment. The concentrations in the tributaries (ranged from not detected to 1336ngL(-1)) were generally higher than those in the main stream (ranged from not detected to 78.8ngL(-1)), but both areas contained the same predominant antibiotics, revealing the importance of tributary discharge as a source of antibiotic pollution. A risk assessment for the surface water contamination revealed that sulfamethoxazole and erythromycin posed high ecological risks to the most sensitive aquatic organisms (Synechococcus leopoliensis and Pseudokirchneriella subcapitata, respectively) in the midstream and some tributaries. Most of the selected antibiotics presented high ecological risks (risk quotients up to 95) in the sediments. Copyright © 2013 Elsevier Inc. All rights reserved.

The use of antimicrobial-impregnated PMMA to manage periprosthetic infections: controversial issues and the latest developments.

PubMed

Tan, H L; Lin, W T; Tang, T T

2012-10-01

Despite improvements in intraoperative antimicrobial procedures, in surgical techniques and in implant design for joint replacement, periprosthetic infection after arthroplasty is still one of the most challenging problems encountered by orthopedic surgeons. Systemic antibiotics are not sufficiently effective to eradicate such deep infections because of the impaired blood circulation and low antibiotic concentration at the implantation site. As a local drug delivery system, antibiotic-impregnated PMMA (polymethylmethacrylate) bone cements have been widely used for prophylaxis or treatment of deep infections after total joint replacement. However, the effectiveness of antibiotic-loaded PMMA in preventing infections after arthroplasty is still controversial. Furthermore, the outcomes of established deep infections treated with this technique are not consistent. The local use of antibiotics has led to the emergence of antibiotic-resistant bacterial strains and has adverse effects on the function of osteogenic cells. Recently, many efforts have been made to identify new antibacterial agents that can be loaded into PMMA. These antimicrobial agents should exhibit good antibacterial activity against antibiotic-resistant strains and should simultaneously enhance osteointegration between the PMMA and the bone tissue. PMMA loaded with chitosan or chitosan derivatives has been demonstrated to induce improved osteogenic activity and to exhibit antibacterial activity in a preclinical study.

The expression of antibiotic resistance genes in antibiotic-producing bacteria.

PubMed

Mak, Stefanie; Xu, Ye; Nodwell, Justin R

2014-08-01

Antibiotic-producing bacteria encode antibiotic resistance genes that protect them from the biologically active molecules that they produce. The expression of these genes needs to occur in a timely manner: either in advance of or concomitantly with biosynthesis. It appears that there have been at least two general solutions to this problem. In many cases, the expression of resistance genes is tightly linked to that of antibiotic biosynthetic genes. In others, the resistance genes can be induced by their cognate antibiotics or by intermediate molecules from their biosynthetic pathways. The regulatory mechanisms that couple resistance to antibiotic biosynthesis are mechanistically diverse and potentially relevant to the origins of clinical antibiotic resistance. © 2014 John Wiley & Sons Ltd.

Calcium and Magnesium Ions Are Membrane-Active against Stationary-Phase Staphylococcus aureus with High Specificity

NASA Astrophysics Data System (ADS)

Xie, Yuntao; Yang, Lihua

2016-02-01

Staphylococcus aureus (S. aureus) is notorious for its ability to acquire antibiotic-resistance, and antibiotic-resistant S. aureus has become a wide-spread cause of high mortality rate. Novel antimicrobials capable of eradicating S. aureus cells including antibiotic-resistant ones are thus highly desired. Membrane-active bactericides and species-specific antimicrobials are two promising sources of novel anti-infective agents for fighting against bacterial antibiotic-resistance. We herein show that Ca2+ and Mg2+, two alkaline-earth-metal ions physiologically essential for diverse living organisms, both disrupt model S. aureus membranes and kill stationary-phase S. aureus cells, indicative of membrane-activity. In contrast to S. aureus, Escherichia coli and Bacillus subtilis exhibit unaffected survival after similar treatment with these two cations, indicative of species-specific activity against S. aureus. Moreover, neither Ca2+ nor Mg2+ lyses mouse red blood cells, indicative of hemo-compatibility. This works suggests that Ca2+ and Mg2+ may have implications in targeted eradication of S. aureus pathogen including the antibiotic-resistant ones.

Long-term adherence to a 5 day antibiotic course guideline for treatment of intensive care unit (ICU)-associated Gram-negative infections.

PubMed

Edgeworth, Jonathan D; Chis Ster, Irina; Wyncoll, Duncan; Shankar-Hari, Manu; McKenzie, Catherine A

2014-06-01

To determine long-term adherence to a 5 day antibiotic course guideline for treating intensive care unit (ICU)-acquired Gram-negative bacteria (GNB) infections. Descriptive analysis of patient-level data on all GNB-active antibiotics prescribed from day 3 and all GNB identified in clinical samples in 5350 patients admitted to a 30 bed general ICU between 2002 and 2009. Four thousand five hundred and eleven of 5350 (84%) patients were treated with one or more antibiotics active against GNB commenced from day 3. Gentamicin was the most frequently prescribed antibiotic (92.2 days of therapy/1000 patient-days). Only 6% of courses spanned >6 days of therapy and 89% of antibiotic therapy days were with a single antibiotic active against GNB. There was no significant difference between gentamicin and meropenem in the number of first courses in which a resistant GNB was identified in blood cultures [11/1177 (0.9%) versus 5/351 (1.4%); P = 0.43] or respiratory tract specimens [59/951 (6.2%) versus 17/246 (6.9%); P = 0.68] at the time of starting therapy. This study demonstrates long-term adherence to a 5 day course antibiotic guideline for treatment of ICU-associated GNB infections. This guideline is a potential antibiotic-sparing alternative to currently recommended dual empirical courses extending to ≥7 days. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Effect of citral and carvacrol on the susceptibility of Listeria monocytogenes and Listeria innocua to antibiotics.

PubMed

Zanini, S F; Silva-Angulo, A B; Rosenthal, A; Rodrigo, D; Martínez, A

2014-05-01

The aim of this study was to evaluate the antibiotic susceptibility of Listeria innocua (L. innocua) and Listeria monocytogenes (L. monocytogenes) cells in the presence of citral and carvacrol at sublethal concentrations in an agar medium. The presence of terpenes in the L. monocytogenes and L. innocua culture medium provided a reduction in the minimal inhibitory concentration (MIC) of all the antibiotics tested. These effects were dependent on the concentration of terpenes present in the culture medium. The combination of citral and carvacrol potentiated antibiotic activity by reducing the MIC values of bacitracin and colistin from 32.0 and 128.0 μg ml⁻¹ to 1.0 and 2.0 μg ml⁻¹, respectively. Thus, both Listeria species became more susceptible to these drugs. In this way, the colistin and bacitracin resistance of L. monocytogenes and L. innocua was reversed in the presence of terpenes. Results obtained in this study show that the phytochemicals citral and carvacrol potentiate antibiotic activity, reducing the MIC values of cultured L. monocytogenes and L. innocua. Phytochemicals citral and carvacrol potentiate antibiotic activity of erythromycin, bacitracin and colistin by reducing the MIC values of cultured Listeria monocytogenes and Listeria innocua. This effect in reducing the MIC values of the antibiotics tested in both micro-organisms was increased when natural antimicrobials were combined. This finding indicated that the combination among terpenes and antibiotic may contribute in reducing the required dosage of antibiotics due to the possible effect of terpenes on permeation barrier of the micro-organism cell membrane. © 2014 The Society for Applied Microbiology.

Isolation of a potent antibiotic producer bacterium, especially against MRSA, from northern region of the Persian Gulf

PubMed Central

Darabpour, Esmaeil; Ardakani, Mohammad Roayaei; Motamedi, Hossein; Ronagh, Mohammad Taghi

2012-01-01

Nowadays, emergence and prevalence of MRSA (Methicillin Resistant Staphylococcus aureus) strain have become a great global concern in 21st century, so, it is necessary to discover new antibiotics against this pathogen. The aim of this study was isolation and evaluation marine bacteria from the Persian Gulf in order to finding antibiotic compounds against some pathogenic bacteria. For this purpose, water and sediment samples were collected from the Persian Gulf during March to October 2009. The antibacterial activity of the isolated bacteria was assessed using disc diffusion method. The Growth Curve Interference (GCI) parameter against MRSA was determined for the high potential antibiotic producing strain. The most important factors affecting fermentation conditions in antibiotic production were also optimized. Definite identification of intended isolate was confirmed by 16S rRNA sequencing. Altogether, 51 bacterial colony was isolated and among them only 3 bacterium showed antibacterial activity. Pseudoalteromonaspiscicida PG-01 isolated from a sediment sample was chosen as the best antibiotic producing strain. This strain was effective against all tested Gram-positive bacteria, had good anti-MRSA activity and also GCI value against MRSA was two times lower than MIC value. Among the optimized fermentation parameters, carbon and nitrogen sources play major role in efficacy of optimized antibiotic production. Ultrastructural study on the effect of intended antibiotic compounds on MRSA using TEM revealed that the target site for this compound is cell wall. Considering the antibacterial effect of PG-01 strain especially against MRSA, intended antibiotic compounds can gives hope for treatment of diseases caused by multi-drug resistant bacteria. PMID:22642595

Current issues connected with usage of genetically modified crops in production of feed and livestock feeding.

PubMed

Kwiatek, K; Mazur, M; Sieradzki, Z

2008-01-01

Progress, which is brought by new advances in modern molecular biology, allowed interference in the genome of live organisms and gene manipulation. Introducing new genes to the recipient organism enables to give them new features, absent before. Continuous increase in the area of the biotech crops triggers continuous discussion about safety of genetically modified (GM) crops, including food and feed derived from them. Important issue connected with cultivation of genetically modified crops is a horizontal gene transfer and a bacterial antibiotic resistance. Discussion about safety of GM crops concerns also food allergies caused by eating genetically modified food. The problem of genetic modifications of GM crops used for livestock feeding is widely discussed, taking into account Polish feed law.

Background Nutrients Affect the Biotransformation of Tetracycline by Stenotrophomonas maltophilia as Revealed by Genomics and Proteomics.

PubMed

Leng, Yifei; Bao, Jianguo; Song, Dandan; Li, Jing; Ye, Mao; Li, Xu

2017-09-19

Certain bacteria are resistant to antibiotics and can even transform antibiotics in the environment. It is unclear how the molecular mechanisms underlying the resistance and biotransformation processes vary under different environmental conditions. The objective of this study is to investigate the molecular mechanisms of tetracycline resistance and biotransformation by Stenotrophomonas maltophilia strain DT1 under various background nutrient conditions. Strain DT1 was exposed to tetracycline for 7 days with four background nutrient conditions: no background (NB), peptone (P), peptone plus citrate (PC), and peptone plus glucose (PG). The biotransformation rate follows the order of PC > P > PG > NB ≈ 0. Genomic analysis showed that strain DT1 contained tet(X1), a gene encoding an FAD-binding monooxygenase, and eight peroxidase genes that could be relevant to tetracycline biotransformation. Quantitative proteomic analyses revealed that nodulation protein transported tetracycline outside of cells; hypoxanthine-guanine phosphoribosyltransferase facilitated the activation of the ribosomal protection proteins to prevent the binding of tetracycline to the ribosome and superoxide dismutase and peroxiredoxin-modified tetracycline molecules. Comparing different nutrient conditions showed that the biotransformation rates of tetracycline were positively correlated with the expression levels of superoxide dismutase.

Potential burden of antibiotic resistance on surgery and cancer chemotherapy antibiotic prophylaxis in the USA: a literature review and modelling study.

PubMed

Teillant, Aude; Gandra, Sumanth; Barter, Devra; Morgan, Daniel J; Laxminarayan, Ramanan

2015-12-01

The declining efficacy of existing antibiotics potentially jeopardises outcomes in patients undergoing medical procedures. We investigated the potential consequences of increases in antibiotic resistance on the ten most common surgical procedures and immunosuppressing cancer chemotherapies that rely on antibiotic prophylaxis in the USA. We searched the published scientific literature and identified meta-analyses and reviews of randomised controlled trials or quasi-randomised controlled trials (allocation done on the basis of a pseudo-random sequence-eg, odd/even hospital number or date of birth, alternation) to estimate the efficacy of antibiotic prophylaxis in preventing infections and infection-related deaths after surgical procedures and immunosuppressing cancer chemotherapy. We varied the identified effect sizes under different scenarios of reduction in the efficacy of antibiotic prophylaxis (10%, 30%, 70%, and 100% reductions) and estimated the additional number of infections and infection-related deaths per year in the USA for each scenario. We estimated the percentage of pathogens causing infections after these procedures that are resistant to standard prophylactic antibiotics in the USA. We estimate that between 38·7% and 50·9% of pathogens causing surgical site infections and 26·8% of pathogens causing infections after chemotherapy are resistant to standard prophylactic antibiotics in the USA. A 30% reduction in the efficacy of antibiotic prophylaxis for these procedures would result in 120,000 additional surgical site infections and infections after chemotherapy per year in the USA (ranging from 40,000 for a 10% reduction in efficacy to 280,000 for a 70% reduction in efficacy), and 6300 infection-related deaths (range: 2100 for a 10% reduction in efficacy, to 15,000 for a 70% reduction). We estimated that every year, 13,120 infections (42%) after prostate biopsy are attributable to resistance to fluoroquinolones in the USA. Increasing antibiotic resistance potentially threatens the safety and efficacy of surgical procedures and immunosuppressing chemotherapy. More data are needed to establish how antibiotic prophylaxis recommendations should be modified in the context of increasing rates of resistance. DRIVE-AB Consortium. Copyright © 2015 Elsevier Ltd. All rights reserved.

[Justification of off-label antibiotics uses in hospitalized children].

PubMed

Berthod, Christelle; Kassaï, Behrouz; Boussageon, Remy; Adelaide, Léopold; Jacquet-Lagrèze, Matthias; Lajoinie, Audrey

2017-12-01

Unlicensed and off-label (UL/OL) drugs are commonly used in pediatrics wards, especially the antibiotics. It remains unclear if this strategy is justified by randomized controlled trials of good quality? The aim of this study was to compare the level of evidence of UL/OL antibiotics prescription in hospitalized children. The initial hypothesis was that the UL/OL antibiotics prescriptions had a lower level of evidence than licensed antibiotics. This observational study assessed the antibiotics prescription in the children mother and women hospital of Lyon. Each antibiotic medicine courses was classified depending on: (i) they were licensed, UL or OL, (ii) their level of evidence for efficiency (sufficient evidence, insufficient evidence, no evidence) and (iii) the existence or not of randomized controlled trials (RCT) or not. The antibiotics medicine courses in atypical cases were excluded (rare disease, lack of diagnosis, comorbidities modifying antibiotic use). Data were collected with computerized patient file data. The data were compared using Fisher exact test and χ 2 . One hundred and eight medicine courses were identified, corresponding to 72 mono, bi or tri-antibiotic therapies administered to 62 patients; 34% were OL and 66% were licensed. No prescriptions were UL. Thirty-two prescriptions were excluded from the evidence assessment. No proof of efficiency was found for any of the 76 analyzed medicine courses. RCTs were found for 36 of the analyzed medicine courses (47%); licensed medicine courses were significantly more justified by RCTs than UL/OL medicine courses (63% vs. 16%, P<0.001). This study has shown the absence of RCTs of good quality to justify the prescriptions of antibiotics in pediatrics, regardless their license status. Nevertheless, the licensed prescriptions have shown more data of efficiency than OL prescriptions. Still, even when data were found, no antibiotics prescriptions reach the threshold of good quality studies. New clinical trials should respond to the patient needs. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

Simple electro-assisted immobilization of ciprofloxacin on carbon nanotube modified electrodes: its selective hydrogen peroxide electrocatalysis.

PubMed

Sornambikai, Sundaram; Kumar, Annamalai Senthil

2014-09-01

Ciprofloxacin (Cf) is a synthetic fourth generation fluoroquinolone class antibiotic used for the treatment of gram-positive, gram-negative and mycobacterium species infections. Electrochemical characteristic of the Cf antibiotic on carbon nanotube modified glassy carbon electrode (GCE/CNT) in pH 7 phosphate buffer solution has been investigated. Electrochemically oxidized radical byproduct of the Cf drug, which is formed as intermediate, gets immobilized on the GCE/CNT (GCE/Cf@CNT) and showed stable and well defined surface confined redox peak at -0.220 V versus Ag/AgCl. Control electrochemical experiment with unmodified GCE failed to show any such immobilization and redox features. Physicochemical characterizations of the Cf@CNT by transmission electron microscope, scanning electron microscope, infrared spectroscopy, UV-Vis and gas chromatography coupled mass spectroscopic analyses of Cf@CNT collectively revealed presence of native form of the Cf antibiotic molecule onto the CNT. The interaction between the Cf molecule and the CNT tubes are revealed from the decreased intensity in the Raman spectrum. The GCE/Cf@CNT showed excellent electrocatalytic response to hydrogen peroxide reduction reaction in pH 7 phosphate buffer solution. Amperometric i-t analysis for the detection of H2O2 showed a current linearity plot upto [H2O2] = 200 μM at an applied potential - 0.1 V versus Ag/AgCl with a current sensitivity value 678 μA mM(-1) cm(-2). No interferences were noticed with ascorbic acid, uric acid, cysteine and nitrite. The present study can be highly helpful to understand the interaction between the Cf and H2O2 in physiological systems and for the removal of Cf from the antibiotic polluted water samples especially in the aquaculture and agricultural systems.

Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: a prospective cohort study.

PubMed

Azad, M B; Konya, T; Persaud, R R; Guttman, D S; Chari, R S; Field, C J; Sears, M R; Mandhane, P J; Turvey, S E; Subbarao, P; Becker, A B; Scott, J A; Kozyrskyj, A L

2016-05-01

Dysbiosis of the infant gut microbiota may have long-term health consequences. This study aimed to determine the impact of maternal intrapartum antibiotic prophylaxis (IAP) on infant gut microbiota, and to explore whether breastfeeding modifies these effects. Prospective pregnancy cohort of Canadian infants born in 2010-2012: the Canadian Healthy Infant Longitudinal Development (CHILD) Study. General community. Representative sub-sample of 198 healthy term infants from the CHILD Study. Maternal IAP exposures and birth method were documented from hospital records and breastfeeding was reported by mothers. Infant gut microbiota was characterised by Illumina 16S rRNA sequencing of faecal samples at 3 and 12 months. Infant gut microbiota profiles. In this cohort, 21% of mothers received IAP for Group B Streptococcus prophylaxis or pre-labour rupture of membranes; another 23% received IAP for elective or emergency caesarean section (CS). Infant gut microbiota community structures at 3 months differed significantly with all IAP exposures, and differences persisted to 12 months for infants delivered by emergency CS. Taxon-specific composition also differed, with the genera Bacteroides and Parabacteroides under-represented, and Enterococcus and Clostridium over-represented at 3 months following maternal IAP. Microbiota differences were especially evident following IAP with emergency CS, with some changes (increased Clostridiales and decreased Bacteroidaceae) persisting to 12 months, particularly among non-breastfed infants. Intrapartum antibiotics in caesarean and vaginal delivery are associated with infant gut microbiota dysbiosis, and breastfeeding modifies some of these effects. Further research is warranted to explore the health consequences of these associations. Maternal #antibiotics during childbirth alter the infant gut #microbiome. © 2015 Royal College of Obstetricians and Gynaecologists.

Fourier transform infrared and Raman spectroscopy studies on magnetite/Ag/antibiotic nanocomposites

NASA Astrophysics Data System (ADS)

Ivashchenko, Olena; Jurga-Stopa, Justyna; Coy, Emerson; Peplinska, Barbara; Pietralik, Zuzanna; Jurga, Stefan

2016-02-01

This article presents a study on the detection of antibiotics in magnetite/Ag/antibiotic nanocomposites using Fourier transform infrared (FTIR) and Raman spectroscopy. Antibiotics with different spectra of antimicrobial activities, including rifampicin, doxycycline, cefotaxime, and ceftriaxone, were studied. Mechanical mixtures of antibiotics and magnetite/Ag nanocomposites, as well as antibiotics and magnetite nanopowder, were investigated in order to identify the origin of FTIR bands. FTIR spectroscopy was found to be an appropriate technique for this task. The spectra of the magnetite/Ag/antibiotic nanocomposites exhibited very weak (for doxycycline, cefotaxime, and ceftriaxone) or even no (for rifampicin) antibiotic bands. This FTIR "invisibility" of antibiotics is ascribed to their adsorbed state. FTIR and Raman measurements show altered Csbnd O, Cdbnd O, and Csbnd S bonds, indicating adsorption of the antibiotic molecules on the magnetite/Ag nanocomposite structure. In addition, a potential mechanism through which antibiotic molecules interact with magnetite/Ag nanoparticle surfaces is proposed.

Antibacterial effects of gum kondagogu reduced/stabilized silver nanoparticles in combination with various antibiotics: a mechanistic approach

NASA Astrophysics Data System (ADS)

Rastogi, Lori; Kora, Aruna Jyothi; Sashidhar, R. B.

2015-06-01

Gum kondagogu reduced/stabilized silver nanoparticles (GK-AgNPs) were evaluated for their increased antibacterial and antibiofilm activities in combination with various antibiotics (ciprofloxacin, streptomycin and gentamicin) against Gram-positive ( Staphylococcus aureus 25923, Staphylococcus aureus 49834) and Gram-negative ( Escherichia coli 25922, Pseudomonas aeruginosa 27853) bacteria. The micro-broth dilution assay suggested an enhanced antibacterial activity of GK-AgNPs in combination with ciprofloxacin and aminoglycosides (streptomycin and gentamicin) against tested strains. Though the antibacterial activity of GK-AgNPs was found to increase significantly in the presence of antibiotics, the % enhancement was found to depend on both types of antibiotic and bacterial strain. It was also found that GK-AgNPs (1 µg/mL) in combination with various antibiotics at sub-MIC concentrations could inhibit 70 % of the bacterial biofilm formation as compared to respective controls. The enhanced antibacterial activity was due to the increased production of intracellular reactive oxygen species in bacteria when treated with a combination of GK-AgNPs and streptomycin as compared to individual treatment. The increased oxidative stress led to increased membrane damage as assessed by live/dead assay and higher levels of potassium ion release from the cells treated with both silver nanoparticles and streptomycin. The results suggested that the combination of antibiotics with GK-AgNPs has an enhanced antibacterial action. Further, the GK-AgNPs were found to be biocompatible up to a concentration of 2.5 µg/mL as assessed with MTT assay on HeLa cell line. The results suggest that GK-AgNPs could potentially be used as in vivo antibacterial agent in combination with antibiotics to overcome the problem of antibiotic resistance.

Comparative Susceptibility of Haemophilus Species to Cefaclor, Cefamandole, and Five Other Cephalosporins and Ampicillin, Chloramphenicol, and Tetracycline

PubMed Central

Watanakunakorn, Chatrchai; Glotzbecker, Cheryl

1979-01-01

The minimal inhibitory concentration of cefaclor, cephalexin, cephradine, cefamandole, cephalothin, cephapirin, cefazolin, ampicillin, chloramphenicol, and tetracycline for inhibition of 198 freshly isolated clinical strains of Haemophilus species (23 H. influenzae type b, 157 H. influenzae non-type b, 14 H. parainfluenzae, and 4 H. aphrophilus) was determined simultaneously by a slightly modified WHO-ICS agar dilution method. Nine strains were resistant to ampicillin. There was no correlation between ampicillin resistance and minimal inhibitory concentration of other antibiotics. All strains were susceptible to chloramphenicol, and all except five were susceptible to tetracycline. Cefaclor was the most active oral cephalosporin, and cefamandole was the most active parenteral cephalosporin. Among the seven cephalosporins tested, cefamandole was the most effective compound. All but two strains were inhibited by cefamandole at 2 μg or less per ml. PMID:258112

Antibiotic Use in Early Life, Rural Residence, and Allergic Diseases in Argentinean Children.

PubMed

Han, Yueh-Ying; Forno, Erick; Badellino, Héctor A; Celedón, Juan C

Little is known about differential effects of antibiotic use on allergic diseases in rural versus urban environments. To examine whether area of residence in the first year of life modifies the relation between antibiotic use in early life and allergic diseases during childhood. Cross-sectional study of allergic diseases in 1517 children (ages 6-7 years) attending 101 schools in urban and rural areas of San Francisco (Córdoba, Argentina). Current asthma, wheeze, and allergic rhinoconjunctivitis were defined on the basis of responses to a validated questionnaire from the International Study of Asthma and Allergies in Childhood. Multivariate logistic regression was used for the analysis of antibiotic use and allergic diseases. After adjustment for paracetamol use, bronchiolitis, and other covariates, antibiotic use in the first year of life was associated with increased odds of current wheeze (odds ratio [OR], 1.8; 95% CI, 1.3-2.6) and allergic rhinoconjunctivitis (OR, 1.9; 95% CI, 1.3-2.7). After stratification by area of residence, antibiotic use was associated with current wheeze (OR, 2.4; 95% CI, 1.5-4.0) and allergic rhinoconjunctivitis (OR, 2.1; 95% CI, 1.3-3.4) among children who lived in an urban area in their first year of life, but not among those who lived in a rural area in their first year of life. Early-life antibiotic use is associated with current wheeze and allergic rhinoconjunctivitis in Argentinean children who lived in urban areas during their first year of life. Exposure to a rural environment early in life may protect against the adverse effects of antibiotics on atopic diseases in children. Copyright © 2017 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Adjuvant use of antibiotics with corticosteroids in inflammatory bowel disease exacerbations requiring hospitalisation: a retrospective cohort study and meta-analysis.

PubMed

Gupta, V; Rodrigues, R; Nguyen, D; Sauk, J; Khalili, H; Yajnik, V; Ananthakrishnan, A N

2016-01-01

Patients hospitalised with an exacerbation of inflammatory bowel disease (IBD) often receive antibiotics in addition to intravenous steroids. However, their efficacy in this setting is unclear. To ascertain if the addition of antibiotics to intravenous steroids modifies short and long-term clinical outcomes. Our study included IBD patients hospitalised between 2009 and 2014 who received intravenous (IV) steroids with or without adjuvant antibiotics. Outcomes of interest included length of stay (LOS), need for medical and surgical rescue therapy during the hospitalisation, and at 90 and 365 days. A meta-analysis of previously published randomised trials was additionally performed. A total of 354 patients were included [145 ulcerative colitis (UC); 209 Crohn's disease (CD)]. In CD, combination of IV steroids and antibiotics did not change need for in-hospital medical rescue therapy, surgery or hospitalisations at 1 year but was associated with greater LOS (6.1 vs. 4.6 days, P = 0.02). In UC, patients receiving antibiotics were less likely to require in-hospital medical rescue therapy [odds ratio (OR): 0.42, 95% confidence interval (CI): 0.19-0.93] but experienced no statistically significant differences in LOS, in-hospital surgery, re-hospitalisations or surgery by 1 year. A meta-analysis of three relevant randomised trials demonstrated no difference in clinical improvement with antibiotics over placebo (OR: 1.08, 95% CI: 0.50-2.32). The addition of antibiotics to intravenous steroids for treatment of IBD exacerbations was associated with a reduced need for in-hospital medical rescue therapy in ulcerative colitis without significant long-term benefit, and did not affect short- or long-term outcomes in Crohn's disease. © 2015 John Wiley & Sons Ltd.

Adjuvant Use of Antibiotics to Corticosteroids in Inflammatory Bowel Disease Exacerbations requiring Hospitalization: A Retrospective Cohort Study and Meta-analysis

PubMed Central

Gupta, Vikas; Rodrigues, Rodrigo; Nguyen, Deanna; Sauk, Jenny; Khalili, Hamed; Yajnik, Vijay; Ananthakrishnan, Ashwin N

2015-01-01

Background Patients hospitalized with an exacerbation of inflammatory bowel disease (IBD) often receive antibiotics in addition to intravenous steroids. However, their efficacy in this setting is unclear. Aim To ascertain if the addition of antibiotics to intravenous steroids modifies short and long-term clinical outcomes. Methods Our study included IBD patients hospitalized between 2009 – 2014 who received intravenous (IV) steroids with or without adjuvant antibiotics. Outcomes of interest included length of stay, need for medical and surgical rescue therapy during the hospitalization, and at 90 and 365 days. A meta-analysis of previously published randomized trials was additionally performed. Results A total of 354 patients were included (145 ulcerative colitis (UC); 209 Crohn’s disease (CD)). In CD, combination of IV steroids and antibiotics did not change need for in-hospital medical rescue therapy, surgery or hospitalizations at 1 year but was associated with greater LOS (6.1 vs. 4.6 days, p=0.02). In UC, patients receiving antibiotics were less likely to require in-hospital medical rescue therapy (Odds ratio (OR) 0.42, 95% confidence interval (CI) 0.19 – 0.93) but experienced no statistically significant differences in LOS, in-hospital surgery, re-hospitalizations or surgery by 1 year. A meta-analysis of 3 relevant randomized trials demonstrated no difference in clinical improvement with antibiotics over placebo (OR 1.08, 95% CI 0.50 – 2.32). Conclusions The addition of antibiotics to intravenous steroids for treatment of IBD exacerbations was associated with a reduced need for in-hospital medical rescue therapy in UC without significant long-term benefit and did not affect short- or long-term outcomes in CD. PMID:26541937

The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice.

PubMed

Deshmukh, Hitesh S; Liu, Yuhong; Menkiti, Ogechukwu R; Mei, Junjie; Dai, Ning; O'Leary, Claire E; Oliver, Paula M; Kolls, Jay K; Weiser, Jeffrey N; Worthen, G Scott

2014-05-01

Neonatal colonization by microbes, which begins immediately after birth, is influenced by gestational age and the mother's microbiota and is modified by exposure to antibiotics. In neonates, prolonged duration of antibiotic therapy is associated with increased risk of late-onset sepsis (LOS), a disorder controlled by neutrophils. A role for the microbiota in regulating neutrophil development and susceptibility to sepsis in the neonate remains unclear. We exposed pregnant mouse dams to antibiotics in drinking water to limit transfer of maternal microbes to the neonates. Antibiotic exposure of dams decreased the total number and composition of microbes in the intestine of the neonates. This was associated with decreased numbers of circulating and bone marrow neutrophils and granulocyte/macrophage-restricted progenitor cells in the bone marrow of antibiotic-treated and germ-free neonates. Antibiotic exposure of dams reduced the number of interleukin-17 (IL-17)-producing cells in the intestine and production of granulocyte colony-stimulating factor (G-CSF). Granulocytopenia was associated with impaired host defense and increased susceptibility to Escherichia coli K1 and Klebsiella pneumoniae sepsis in antibiotic-treated neonates, which could be partially reversed by administration of G-CSF. Transfer of a normal microbiota into antibiotic-treated neonates induced IL-17 production by group 3 innate lymphoid cells (ILCs) in the intestine, increasing plasma G-CSF levels and neutrophil numbers in a Toll-like receptor 4 (TLR4)- and myeloid differentiation factor 88 (MyD88)-dependent manner and restored IL-17-dependent resistance to sepsis. Specific depletion of ILCs prevented IL-17- and G-CSF-dependent granulocytosis and resistance to sepsis. These data support a role for the intestinal microbiota in regulation of granulocytosis, neutrophil homeostasis and host resistance to sepsis in neonates.

Appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria.

PubMed

Saengcharoen, Woranuch; Jaisawang, Pornchanok; Udomcharoensab, Palita; Buathong, Kittika; Lerkiatbundit, Sanguan

2016-10-01

Background Inappropriate use of antibiotic treatment for pharyngitis by community pharmacists is prevalent in developing countries. Little is known about how the pharmacists identify patients with bacterial pharyngitis. Objective To ascertain the appropriateness of diagnosis of streptococcal pharyngitis among Thai community pharmacists according to the Centor criteria and to identify factors related to antibiotic dispensing. Setting 1040 Thai community pharmacists. Method A cross-sectional survey of community pharmacists was conducted in November 2012 to March 2013. The self-administered questionnaires were mailed to 57 % of community pharmacists in the south of Thailand (n = 1040). The survey included questions on diagnosis of streptococcal pharyngitis, knowledge on pharyngitis, and attitudes and control beliefs regarding antibiotic dispensing. Main outcome measure The appropriateness of diagnosis of streptococcal pharyngitis according to the original and modified Centor criteria and determinants of antibiotic dispensing including demographic characteristics of pharmacists, knowledge on pharyngitis, and attitudes and control beliefs on antibiotic dispensing. Results Approximately 68 % completed the questionnaires (n = 703). Compared to the pharmacists who reported not dispensing antibiotics in the hypothetical case with common cold, those reported dispensing antibiotics were more likely to consider the following conditions-presence of cough, mild sore throat and patients with age >60 years as cues for diagnosis of streptococcal pharyngitis (p < 0.05). The use of fewer scores of the clinical prediction rules for diagnosis was observed in antibiotic dispensers, compared to who did not do so (p < 0.005). Antibiotic dispensing was positively associated with period of dispensing experience (>5 years) [odds ratio (OR) 1.52; 95 % confidence interval (CI) 1.03-2.23], belief that antibiotics could shorten duration of pharyngitis (OR 1.48; 95 % CI 1.11-1.99), belief that antibiotics could prevent the complications (OR 1.44; 95 % CI 1.09-1.91) and belief that dispensing antibiotics could satisfy the patients (OR 1.31; 95 % CI 1.01-1.71). Nonetheless, antibiotic dispensing was negatively associated with knowledge about pharyngitis (OR 0.83; 95 % CI 0.75-0.93). Conclusion Pharmacists who are knowledgeable on the Centor criteria are more likely to appropriately diagnose streptococcal pharyngitis and less likely to dispense antibiotics in such case.

Adverse reactions to two intravenous antibiotics (Augmentin and Zinacef) used for surgical prophylaxis in dogs.

PubMed

Gosling, Mark James; Martínez-Taboada, Fernando

2018-01-20

Antibiotic prophylaxis in dogs undergoing surgical procedures frequently involves the administration of a product without a veterinary licence. Two drugs commonly used for this purpose are the clavulanate amoxicillin Augmentin and the cefuroxime Zinacef. This prospective observational study aims to compare the incidence of adverse events associated with these two antibiotics in a clinical setting. The authors hypothesised that a higher incidence of adverse effects would be observed with Augmentin. Sixty-five dogs were included in the study and adverse events were recorded using a modified scoring system. A significantly higher incidence of adverse events to Augmentin (8/22; 36 per cent) was observed compared with Zinacef (1/43; 2 per cent) (P=0.0003). The majority of these adverse events involved cutaneous signs and/or hypotension. These findings might be taken into consideration when selecting one of these intravenous antibiotics for prophylaxis in anaesthetised dogs undergoing surgery. © British Veterinary Association (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Semi-quantitative MALDI-TOF for antimicrobial susceptibility testing in Staphylococcus aureus.

PubMed

Maxson, Tucker; Taylor-Howell, Cheryl L; Minogue, Timothy D

2017-01-01

Antibiotic resistant bacterial infections are a significant problem in the healthcare setting, in many cases requiring the rapid administration of appropriate and effective antibiotic therapy. Diagnostic assays capable of quickly and accurately determining the pathogen resistance profile are therefore crucial to initiate or modify care. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is a standard method for species identification in many clinical microbiology laboratories and is well positioned to be applied towards antimicrobial susceptibility testing. One recently reported approach utilizes semi-quantitative MALDI-TOF MS for growth rate analysis to provide a resistance profile independent of resistance mechanism. This method was previously successfully applied to Gram-negative pathogens and mycobacteria; here, we evaluated this method with the Gram-positive pathogen Staphylococcus aureus. Specifically, we used 35 strains of S. aureus and four antibiotics to optimize and test the assay, resulting in an overall accuracy rate of 95%. Application of the optimized assay also successfully determined susceptibility from mock blood cultures, allowing both species identification and resistance determination for all four antibiotics within 3 hours of blood culture positivity.

Antibiotic resistance genes in surface water of eutrophic urban lakes are related to heavy metals, antibiotics, lake morphology and anthropic impact.

PubMed

Yang, Yuyi; Xu, Chen; Cao, Xinhua; Lin, Hui; Wang, Jun

2017-08-01

Urban lakes are impacted by heavy human activities and represent potential reservoirs for antibiotic resistance genes. In this study, six urban lakes in Wuhan, central China were selected to analyze the distribution of sulfonamide resistance (sul) genes, tetracycline resistance (tet) genes and quinolone resistance (qnr) genes and their relationship with heavy metals, antibiotics, lake morphology and anthropic impact. sul1 and sul2 were detected in all six lakes and dominated the types of antibiotic resistance genes, which accounted for 86.28-97.79% of the total antibiotic resistance gene abundance. For eight tested tet genes, antibiotic efflux pumps (tetA, tetB, tetC, and tetG) genes were all observed in six lakes and had higher relative abundance than ribosomal protection protein genes (tetM and tetQ). For 4 plasmid mediated quinolone resistance genes, only qnrD is found in all six lakes. The class I integron (intI1) is also found to be a very important media for antibiotic resistance gene propagation in urban lakes. The results of redundancy analysis and variation partitioning analysis showed that antibiotic and co-selection with heavy metals were the major factors driving the propagation of antibiotic resistance genes in six urban lakes. The heavily eutrophic Nanhu Lake and Shahu Lake which located in a high density building area with heavy human activities had the higher relative abundance of total antibiotic resistance genes. Our study could provide a useful reference for antibiotic resistance gene abundance in urban lakes with high anthropic impact.

Antibiotics in frozen bone grafts can cause allergic reactions in recipient patients.

PubMed

Crnogaca, Kresimir; Bicanic, Goran; Delimar, Domagoj

2015-02-01

Antibiotic prophylaxis is a routine procedure during total hip arthroplasty (THA), and the vast majority of cadavers within the multitissue procurement receive one or more antibiotics. Upon harvesting, bone grafts are stored in the bone banks on the temperature as low as -80°C for up to 5 years. It is shown in the literature that the antibiotics remain active and viable in the bone grafts even after being exposed to extremely low temperatures in the prolonged periods. Possibility of remnant antibiotic concentrations in the bone grafts and the fact that these antibiotic remnants maintain active even after being exposed to extremely low temperatures create the environment in which the possibility for the allergic reaction in sensitive patient receiving bone graft exists. We hypothesize that harvested bone grafts containing active antibiotic substance have the potential for local and systemic allergic reaction in sensitive recipient patients thus increasing morbidity and the costs of the treatment. Allergic reactions can mimic surgical site infections as well with the consequent substantial pitfalls in the treatment. Following that, in the setting of an assumed but not confirmed surgical site infection, the immunological evaluation on antibiotics for recipients of bone grafts could be added to the standard diagnostic algorithms. In addition, bone banks should be obliged to provide information of all potential drugs that can be found in every specific bone graft to the end users. Copyright © 2014 Elsevier Ltd. All rights reserved.

Presence and biological activity of antibiotics used in fuel ethanol and corn co-product production.

PubMed

Compart, D M Paulus; Carlson, A M; Crawford, G I; Fink, R C; Diez-Gonzalez, F; Dicostanzo, A; Shurson, G C

2013-05-01

Antibiotics are used in ethanol production to control bacteria from competing with yeast for nutrients during starch fermentation. However, there is no published scientific information on whether antibiotic residues are present in distillers grains (DG), co-products from ethanol production, or whether they retain their biological activity. Therefore, the objectives of this study were to quantify concentrations of various antibiotic residues in DG and determine whether residues were biologically active. Twenty distillers wet grains and 20 distillers dried grains samples were collected quarterly from 9 states and 43 ethanol plants in the United States. Samples were analyzed for DM, CP, NDF, crude fat, S, P, and pH to describe the nutritional characteristics of the samples evaluated. Samples were also analyzed for the presence of erythromycin, penicillin G, tetracycline, tylosin, and virginiamycin M1, using liquid chromatography and mass spectrometry. Additionally, virginiamycin residues were determined, using a U.S. Food and Drug Administration-approved bioassay method. Samples were extracted and further analyzed for biological activity by exposing the sample extracts to 10(4) to 10(7) CFU/mL concentrations of sentinel bacterial strains Escherichia coli ATCC 8739 and Listeria monocytogenes ATCC 19115. Extracts that inhibited bacterial growth were considered to have biological activity. Physiochemical characteristics varied among samples but were consistent with previous findings. Thirteen percent of all samples contained low (≤1.12 mg/kg) antibiotic concentrations. Only 1 sample extract inhibited growth of Escherichia coli at 10(4) CFU/mL, but this sample contained no detectable concentrations of antibiotic residues. No extracts inhibited Listeria monocytogenes growth. These data indicate that the likelihood of detectable concentrations of antibiotic residues in DG is low; and if detected, they are found in very low concentrations. The inhibition in only 1 DG sample by sentinel bacteria suggests that antibiotic residues in DG were inactivated during the production process or are present in sublethal concentrations.

Influence of montmorillonite on antimicrobial activity of tetracycline and ciprofloxacin

NASA Astrophysics Data System (ADS)

Lv, Guocheng; Pearce, Cody W.; Gleason, Andrea; Liao, Libing; MacWilliams, Maria P.; Li, Zhaohui

2013-11-01

Antibiotics are used not only to fight infections and inhibit bacterial growth, but also as growth promotants in farm livestock. Farm runoff and other farm-linked waste have led to increased antibiotic levels present in the environment, the impact of which is not completely understood. Soil, more specifically clays, that the antibiotic contacts may alter its effectiveness against bacteria. In this study a swelling clay mineral montmorillonite was preloaded with antibiotics tetracycline and ciprofloxacin at varying concentrations and bioassays were conducted to examine whether the antibiotics still inhibited bacterial growth in the presence of montmorillonite. Escherichia coli was incubated with montmorillonite or antibiotic-adsorbed montmorillonite, and then the number of viable bacteria per mL was determined. The antimicrobial activity of tetracycline was affected in the presence of montmorillonite, as the growth of non-resistant bacteria was still found even when extremely high TC doses were used. Conversely, in the presence of montmorillonite, ciprofloxacin did inhibit E. coli bacterial growth at high concentrations. These results suggest that the effectiveness of antimicrobial agents in clayey soils depends on the amount of antibiotic substance present, and on the interactions between the antibiotic and the clays in the soil, as well.

Hybrid antibiotics - clinical progress and novel designs.

PubMed

Parkes, Alastair L; Yule, Ian A

2016-07-01

There is a growing need for new antibacterial agents, but success in development of antibiotics in recent years has been limited. This has led researchers to investigate novel approaches to finding compounds that are effective against multi-drug resistant bacteria, and that delay onset of resistance. One such strategy has been to link antibiotics to produce hybrids designed to overcome resistance mechanisms. The concept of dual-acting hybrid antibiotics was introduced and reviewed in this journal in 2010. In the present review the authors sought to discover how clinical candidates described had progressed, and to examine how the field has developed. In three sections the authors cover the clinical progress of hybrid antibiotics, novel agents produced from hybridisation of two or more small-molecule antibiotics, and novel agents produced from hybridisation of antibiotics with small-molecules that have complementary activity. Many key questions regarding dual-acting hybrid antibiotics remain to be answered, and the proposed benefits of this approach are yet to be demonstrated. While Cadazolid in particular continues to progress in the clinic, suggesting that there is promise in hybridisation through covalent linkage, it may be that properties other than antibacterial activity are key when choosing a partner molecule.

Antagonistic activities of some probiotic lactobacilli culture supernatant on Serratia marcescens swarming motility and antibiotic resistance.

PubMed

Vahedi-Shahandashti, Roya; Kasra-Kermanshahi, Rouha; Shokouhfard, Maliheh; Ghadam, Parinaz; Feizabadi, Mohammad Mehdi; Teimourian, Shahram

2017-12-01

Serratia marcescens , a potentially pathogenic bacterium, benefits from its swarming motility and resistance to antibiotic as two important virulence factors. Inappropriate use of antibiotics often results in drug resistance phenomenon in bacterial population. Use of probiotic bacteria has been recommended as partial replacement. In this study, we investigated the effects of some lactobacilli culture supernatant on swarming, motility and antibiotic resistance of S. marcescens . Antimicrobial activity of lactobacilli supernatant and susceptibility testing carried out on S. marcescens isolates. Pretreatment effect of lactobacilli culture supernatant on antibiotic - resistance pattern in S. marcescens was determined by comparison of the MIC of bacteria before and after the treatment. Our results showed that pretreatment with L. acidophilus ATCC 4356 supernatant can affect the resistance of Serratia strains against ceftriaxone, but it had no effect on the resistance to other antibiotics. Furthermore, culture supernatant of lactobacilli with concentrations greater than 2%, had an effect on the swarming ability of S. marcescens ATCC 13880 and inhibited it. Probiotic bacteria and their metabolites have the ability to inhibit virulence factors such as antibiotic resistance and swarming motility and can be used as alternatives to antibiotics.

Synthesis and study of antibacterial activities of antibacterial glycopeptide antibiotics conjugated with benzoxaboroles.

PubMed

Printsevskaya, S S; Reznikova, M I; Korolev, A M; Lapa, G B; Olsufyeva, E N; Preobrazhenskaya, M N; Plattner, J J; Zhang, Y K

2013-04-01

The ability of boron-containing compounds to undergo a number of novel binding interactions with drug target functional groups has recently been described. In an extension of this work, we have incorporated a boron-containing scaffold, the benzoxaborole, into several glycopeptides antibiotics. The aim of this work is to exploit the inherent reactivity of boron to gain additional interactions with the bacterial cell wall components to improve binding affinity and to thereby overcome resistance. Three antibacterial glycopeptides (vancomycin, eremomycin and teicoplanin aglycone) have been selected for the construction of a series of 12 new benzoxaborole-glycopeptide conjugates. The hybrid antibiotics, in which the benzoxaborole and glycopeptide moieties were separated by a linker, exhibited excellent antibacterial activity against Gram-positive bacteria, including those with intermediate susceptibility to glycopeptides. Some analogs also demonstrated activity against vancomycin-resistant enterococci. Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin.

Antibiotic and synergistic effect of Leu-Lys rich peptide against antibiotic resistant microorganisms isolated from patients with cholelithiasis.

PubMed

Jeong, Nari; Kim, Jin-Young; Park, Seong-Cheol; Lee, Jong-Kook; Gopal, Ramamourthy; Yoo, Suyeon; Son, Byoung Kwan; Hahm, Joon Soo; Park, Yoonkyung; Hahm, Kyung-Soo

2010-09-03

Pseudomonas aeruginosa has eventually developed resistance against flomoxef sodium, isepamicin and cefpiramide. Therefore, in this study, the antibacterial activity and synergistic effects of the amphipathic-derived P5-18mer antimicrobial peptide were tested against pathogens associated with cholelithiasis that have developed resistance against commonly used antibiotics. The results were then compared with the activities of the amphipathic-derived peptide, P5-18mer, melittin and common antibiotics. Growth inhibition of planktonic bacteria was tested using the National Committee for Clinical Laboratory Standards (NCCLS). The bactericidal activity of the antimicrobial peptides was measured using time-kill curves. Synergistic effects were evaluated by testing the effects of P5-18mer alone and in combination with flomoxef sodium, isepamicin or cefpiramide at 0.5xMIC. P5-18mer peptide displayed strong activity against pathogens and flomoxef sodium, isepamicin and cefpiramide-resistant bacteria cell lines obtained from a patient with gallstones; however, it did not exert cytotoxicity against the human keratinocyte HaCat cell line. In addition, the results of time-kill curves indicated that P5-18mer peptide exerted bactericidal activity against four strains of P. aeruginosa. Finally, the use of P5-18mer and antibiotics exerted synergistic effects against cell lines that were resistant to commonly used antibiotics. These results indicate that this class of peptides has a rapid microbicidal effect on flomoxef sodium, isepamicin and cefpiramide-resistant strains of P. aeruginosa. Therefore, these peptides may be used as a lead drug for the treatment of acquired pathogens from patients with cholelithiasis who are affected with antibiotic-resistant bacteria. Copyright 2010 Elsevier Inc. All rights reserved.

Crisamicin A, a new antibiotic from Micromonospora. I. Taxonomy of the producing strain, fermentation, isolation, physico-chemical characterization and antimicrobial properties.

PubMed

Nelson, R A; Pope, J A; Luedemann, G M; McDaniel, L E; Schaffner, C P

1986-03-01

A microorganism, designated as RV-79-9-101 and now identified as Micromonospora purpureochromogenes subsp. halotolerans, isolated from a mud sample in the Philippines, has been shown to produce a complex of antibiotics called crisamicins. Thin-layer chromatography and bioautography, employing solvent extracts of whole fermentation broths, revealed a minimum of five antimicrobial components. The major biologically-active component of the antibiotic complex, crisamicin A, was obtained in pure form after preparative silica gel column chromatography followed by crystallization. Based on physico-chemical data crisamicin A has been identified as a novel member of the isochromanequinone group of antibiotics. It exhibits excellent in vitro activity against Gram-positive bacteria but little or no activity towards Gram-negative bacteria or fungi.

Toxoplasma gondii: activity of the polyether ionophorous antibiotic nigericin on tachyzoites in cell culture.

PubMed

Couzinet, S; Dubremetz, J F; David, L; Prensier, G

1994-06-01

Polyether ionophorous antibiotics are widely used prophylactically to prevent coccidiosis in livestock production. The study of the effects of the nigericin on tachyzoites of Toxoplasma gondii clearly demonstrated that very low concentrations of this ionophore (0.05 microgram/ml) were sufficient to inhibit strongly the penetration and totally inhibit the intracellular development of parasites. Both nigericin and epinigericin showed a similar activity against tachyzoite development. However, the activity of abierixicin was 50-fold lower. Such antibiotic concentrations did not seem to affect host cells. Immunofluorescence and electron microscopy showed important changes in the cytology of the antibiotic-treated parasites: they were vacuolated or swollen and were sometimes found burst open, having lost their original shape. The magnitude and the frequency of alterations rose as concentrations in ionophore increased.

Lassomycin, a ribosomally synthesized cyclic peptide, kills mycobacterium tuberculosis by targeting the ATP-dependent protease ClpC1P1P2.

PubMed

Gavrish, Ekaterina; Sit, Clarissa S; Cao, Shugeng; Kandror, Olga; Spoering, Amy; Peoples, Aaron; Ling, Losee; Fetterman, Ashley; Hughes, Dallas; Bissell, Anthony; Torrey, Heather; Akopian, Tatos; Mueller, Andreas; Epstein, Slava; Goldberg, Alfred; Clardy, Jon; Lewis, Kim

2014-04-24

Languishing antibiotic discovery and flourishing antibiotic resistance have prompted the development of alternative untapped sources for antibiotic discovery, including previously uncultured bacteria. Here, we screen extracts from uncultured species against Mycobacterium tuberculosis and identify lassomycin, an antibiotic that exhibits potent bactericidal activity against both growing and dormant mycobacteria, including drug-resistant forms of M. tuberculosis, but little activity against other bacteria or mammalian cells. Lassomycin is a highly basic, ribosomally encoded cyclic peptide with an unusual structural fold that only partially resembles that of other lasso peptides. We show that lassomycin binds to a highly acidic region of the ClpC1 ATPase complex and markedly stimulates its ATPase activity without stimulating ClpP1P2-catalyzed protein breakdown, which is essential for viability of mycobacteria. This mechanism, uncoupling ATPase from proteolytic activity, accounts for the bactericidal activity of lassomycin. Copyright © 2014 Elsevier Ltd. All rights reserved.

The bacteriology of children prior to 1st stage autologous ear reconstruction.

PubMed

Eley, Karen A; Gault, David T

2010-12-01

In virtually all surgical specialities the use of peri-operative antibiotic prophylaxis to minimise wound site infection is routine practice. Antibiotic selection is targeted towards the pathogens most commonly encountered at the surgical site. The surgical management of microtia is by autologous rib cartilage reconstruction, a process that involves at least two surgical stages. The pits and recesses of the microtia ear are difficult to clean and may shelter unusual pathogens not routinely found as skin commensals, requiring modified prophylaxis. This retrospective review of 37 patients undergoing 1st stage ear reconstruction, examines the pre-operative ear site, nose and throat swabs to determine the common pre-operative bacteria encountered in children prior to ear reconstruction, to aid in appropriate antibiotic selection. Copyright © 2010 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

A probiotic approach to caries management.

PubMed

Anderson, M H; Shi, W

2006-01-01

The surgical approach has been the predominate mode of caries management for the past 150 years. Dentistry has, however, in recent years moved toward an antibiotic/antimicrobial model of disease management. This approach, however, raises serious questions: (1) do the antibiotic/antimicrobial agents (chlorhexidine, povidone iodine, fluoride, etc) kill all offending organisms?; (2) if so, do the agents preclude the re-entry of the same organisms from external sources?; and (3) if the agents do kill all the offending organisms, do any remaining pathogenic organisms have selective advantage in repopulating the tooth surfaces? To overcome the problems inherent in an antibiotic/antimicrobial approach, probiotic methods are currently under study as means of caries management. This paper discusses probiotic approaches, such as genetically modified Streptococcus mutans and targeted antimicrobials in the management of dental caries. Implications for this approach in the management of other diseases are also presented.

Bioactive Organocopper Compound from Pseudomonas aeruginosa Inhibits the Growth of Xanthomonas citri subsp. citri.

PubMed

de Oliveira, Admilton G; Spago, Flavia R; Simionato, Ane S; Navarro, Miguel O P; da Silva, Caroline S; Barazetti, André R; Cely, Martha V T; Tischer, Cesar A; San Martin, Juca A B; de Jesus Andrade, Célia G T; Novello, Cláudio R; Mello, João C P; Andrade, Galdino

2016-01-01

Citrus canker is a very destructive disease of citrus species. The challenge is to find new compounds that show strong antibiotic activity and low toxicity to plants and the environment. The objectives of the present study were (1) to extract, purify and evaluate the secondary metabolites with antibiotic activity produced by Pseudomonas aeruginosa LV strain in vitro against Xanthomonas citri subsp. citri (strain 306), (2) to determine the potential of semi-purified secondary metabolites in foliar application to control citrus canker under greenhouse conditions, and (3) to identify antibiotic activity in orange leaf mesophyll infected with strain 306, by electron microscopy. Two pure bioactive compounds were isolated, an organocopper antibiotic compound (OAC) and phenazine-1-carboxamide. Phenazine-1-carboxamide did not show any antibiotic activity under the experimental conditions used in this study. The OAC showed a high level of antibiotic activity with a minimum inhibitory concentration of 0.12 μg mL(-1). In greenhouse tests for control of citrus canker in orange trees, the semi-purified fraction F3d reduced lesion formation by about 97%. The concentration used was 500 times lower than that for the recommended commercial copper-based product. Electron microscopy showed that F3d altered the exopolysaccharide matrix and caused cell lysis of the pathogen inside the citrus canker lesions. These results suggest that secondary metabolites produced by inducing P. aeruginosa LV strain have a high potential to be used as a bioproduct to control citrus canker.

Chemical composition and evaluation of modulatory of the antibiotic activity from extract and essential oil of Myracrodruon urundeuva.

PubMed

Figueredo, Fernando G; Lucena, Bruno F F; Tintino, Saulo R; Matias, Edinardo F F; Leite, Nadghia F; Andrade, Jacqueline C; Nogueira, Lavouisier F B; Morais, Edson C; Costa, José G M; Coutinho, Henrique D M; Rodrigues, Fabiola F G

2014-05-01

The combination of antibiotics with natural products has demonstrated promising synergistic effects in several therapeutic studies. The aim of this study was to determine the effect of a combination of an ethanol extract of Myracrodruon urundeuva Fr. All. (Anacardiaceae) (aroeira plant) and its essential oil with six antimicrobial drugs against multiresistant strains of Staphylococcus aureus and Escherichia coli from clinical isolates. After identification of the chemical components by GC-MS, the antibacterial activity of the natural products and antibiotics was assessed by determining the minimal inhibitory concentration (MIC) using the microdilution method and concentrations ranging 8-512 μg/mL and 0.0012-2.5 mg/mL, respectively. Assays were performed to test for a possible synergistic action between the plant products and the antimicrobials, using the extract and the oil at a sub-inhibitory concentration (128 μg/mL) and antibiotic at concentrations varying between 8 and 512 μg/mL. The GC-MS analysis identified the main compound as δ-carene (80.41%). The MIC of the natural products was >1024 μg/mL, except against S. aureus ATCC25923. Only the combinations of the natural products with gentamicin, amikacin and clindamycin were effective against S. aureus 358, enhancing the antibiotic activity by reducing the MIC. The extract from aroeira showed a higher antibacterial activity and the oil was more effective in potentiating the activity of conventional antibiotics.

Nordihydroguaiaretic acid enhances the activities of aminoglycosides against methicillin- sensitive and resistant Staphylococcus aureus in vitro and in vivo.

PubMed

Cunningham-Oakes, Edward; Soren, Odel; Moussa, Caroline; Rathor, Getika; Liu, Yingjun; Coates, Anthony; Hu, Yanmin

2015-01-01

Infections caused by methicillin-sensitive Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) are prevalent. MRSA infections are difficult to treat and there are no new classes of antibiotics produced to the market to treat infections caused by the resistant bacteria. Therefore, using antibiotic enhancers to rescue existing classes of antibiotics is an attractive strategy. Nordihydroguaiaretic acid (NDGA) is an antioxidant compound found in extracts from plant Larrea Tridentata. It exhibits antimicrobial activity and may target bacterial cell membrane. Combination efficacies of NDGA with many classes of antibiotics were examined by chequerboard method against 200 clinical isolates of MRSA and MSSA. NDGA in combination with gentamicin, neomycin, and tobramycin was examined by time-kill assays. The synergistic combinations of NDGA and aminoglycosides were tested in vivo using a murine skin infection model. Calculations of the fractional inhibitory concentration index (FICI) showed that NDGA when combined with gentamicin, neomycin, or tobramycin displayed synergistic activities in more than 97% of MSSA and MRSA, respectively. Time kill analysis demonstrated that NDGA significantly augmented the activities of these aminoglycosides against MRSA and MSSA in vitro and in murine skin infection model. The enhanced activity of NDGA resides on its ability to damage bacterial cell membrane leading to accumulation of the antibiotics inside bacterial cells. We demonstrated that NDGA strongly revived the therapeutic potencies of aminoglycosides in vitro and in vivo. This combinational strategy could contribute major clinical implications to treat antibiotic resistant bacterial infections.

Bioactive Organocopper Compound from Pseudomonas aeruginosa Inhibits the Growth of Xanthomonas citri subsp. citri

PubMed Central

de Oliveira, Admilton G.; Spago, Flavia R.; Simionato, Ane S.; Navarro, Miguel O. P.; da Silva, Caroline S.; Barazetti, André R.; Cely, Martha V. T.; Tischer, Cesar A.; San Martin, Juca A. B.; de Jesus Andrade, Célia G. T.; Novello, Cláudio R.; Mello, João C. P.; Andrade, Galdino

2016-01-01

Citrus canker is a very destructive disease of citrus species. The challenge is to find new compounds that show strong antibiotic activity and low toxicity to plants and the environment. The objectives of the present study were (1) to extract, purify and evaluate the secondary metabolites with antibiotic activity produced by Pseudomonas aeruginosa LV strain in vitro against Xanthomonas citri subsp. citri (strain 306), (2) to determine the potential of semi-purified secondary metabolites in foliar application to control citrus canker under greenhouse conditions, and (3) to identify antibiotic activity in orange leaf mesophyll infected with strain 306, by electron microscopy. Two pure bioactive compounds were isolated, an organocopper antibiotic compound (OAC) and phenazine-1-carboxamide. Phenazine-1-carboxamide did not show any antibiotic activity under the experimental conditions used in this study. The OAC showed a high level of antibiotic activity with a minimum inhibitory concentration of 0.12 μg mL-1. In greenhouse tests for control of citrus canker in orange trees, the semi-purified fraction F3d reduced lesion formation by about 97%. The concentration used was 500 times lower than that for the recommended commercial copper-based product. Electron microscopy showed that F3d altered the exopolysaccharide matrix and caused cell lysis of the pathogen inside the citrus canker lesions. These results suggest that secondary metabolites produced by inducing P. aeruginosa LV strain have a high potential to be used as a bioproduct to control citrus canker. PMID:26903992

Amino Acid Residues That Contribute to Substrate Specificity of Class A β-Lactamase SME-1

PubMed Central

Majiduddin, Fahd K.; Palzkill, Timothy

2005-01-01

Carbapenem antibiotics are used as antibiotics of last resort because they possess a broad spectrum of antimicrobial activity and are not easily hydrolyzed by β-lactamases. Recently, class A enzymes, such as the SME-1, NMC-A, and IMI-1 β-lactamases, have been identified with the capacity to hydrolyze carbapenem antibiotics. Traditional class A β-lactamases, such as TEM-1 and SHV-1, are unable to hydrolyze carbapenem antibiotics and exhibit some differences in sequence from those that are able to hydrolyze carbapenem antibiotics. The positions that differ may contribute to the unique substrate specificity of the class A carbapenemase SME-1. Codons in the SME-1 gene representing residues 104, 105, 132, 167, 237, and 241 were randomized by site-directed mutagenesis, and functional mutants were selected for the ability to hydrolyze imipenem, ampicillin, or cefotaxime. Although several positions are important for hydrolysis of β-lactam antibiotics, no single position was found to uniquely contribute to carbapenem hydrolysis. The results of this study support a model whereby the carbapenemase activity of SME-1 is due to a highly distributed set of interactions that subtly alter the structure of the active-site pocket. PMID:16048956

Amino acid residues that contribute to substrate specificity of class A beta-lactamase SME-1.

PubMed

Majiduddin, Fahd K; Palzkill, Timothy

2005-08-01

Carbapenem antibiotics are used as antibiotics of last resort because they possess a broad spectrum of antimicrobial activity and are not easily hydrolyzed by beta-lactamases. Recently, class A enzymes, such as the SME-1, NMC-A, and IMI-1 beta-lactamases, have been identified with the capacity to hydrolyze carbapenem antibiotics. Traditional class A beta-lactamases, such as TEM-1 and SHV-1, are unable to hydrolyze carbapenem antibiotics and exhibit some differences in sequence from those that are able to hydrolyze carbapenem antibiotics. The positions that differ may contribute to the unique substrate specificity of the class A carbapenemase SME-1. Codons in the SME-1 gene representing residues 104, 105, 132, 167, 237, and 241 were randomized by site-directed mutagenesis, and functional mutants were selected for the ability to hydrolyze imipenem, ampicillin, or cefotaxime. Although several positions are important for hydrolysis of beta-lactam antibiotics, no single position was found to uniquely contribute to carbapenem hydrolysis. The results of this study support a model whereby the carbapenemase activity of SME-1 is due to a highly distributed set of interactions that subtly alter the structure of the active-site pocket.

Prophylactic antibiotics in pediatric shunt surgery.

PubMed

Biyani, N; Grisaru-Soen, G; Steinbok, P; Sgouros, S; Constantini, S

2006-11-01

The optimal antibiotic prophylaxis for pediatric shunt-related procedures is not clear. There is much inconsistency among different medical centers. This paper summarizes and analyzes the various prophylactic antibiotic regiments used for shunt-related surgeries at different pediatric neurosurgery centers in the world. A survey questionnaire was distributed through the Pediatric Neurosurgery list-server (an e-mail-based special interest group in pediatric neurosurgery). Forty-five completed questionnaires were received, one per medical center, primarily from pediatric neurosurgeons with the following geographic breakdown: 25 from North America, 13 from Europe, and 7 from Asia and other countries. All centers routinely administered prophylactic antibiotics for shunt-related procedures. The drugs of choice were first-generation cephalosporins (23), second-generation cephalosporins (10), naficillin/oxacillin (4), vancomycin (3), clindamycin (1), amoxicillin (1), and mixed protocols in three centers. The initial drug administration ("first dose") was: in the department before transfer to operating room (5), upon arrival to operating room (11), at induction of anesthesia (13), and at initial skin incision (16). The duration of antibiotic dosage also varied: single dose (13), 24-h administration (26), 48-h administration (2), and longer than 48 h in four centers. Two general tendencies were noted, common to the majority of participating centers. There was a general trend to modify antibiotic treatment protocol in "high-risk" populations. The second common theme noted in more than half of responding centers was the use of long-term antibiotic treatment for externalized devices (such as externalized shunts, external ventricular drains or lumbar drains), usually till the device was in place.

Antibiotic-Induced Rash in Patients With Infectious Mononucleosis.

PubMed

Thompson, Dennis F; Ramos, Carroll L

2017-02-01

To provide an extensive review of case reports, epidemiological data, and the underlying mechanism of antibiotic-induced skin rash in patients with concurrent infectious mononucleosis (IM). A MEDLINE literature search inclusive of the dates 1946 to June 2016 was performed using the search terms anti-bacterial agents and infectious mononucleosis. EMBASE (1980 to June 2016) was searched using the terms mononucleosis and antibiotic agent and drug eruption. References of all relevant articles were reviewed for additional citations and information. We selected English-language, primary literature, review articles, and mechanistic articles that addressed antibiotic-induced skin rash in patients with concurrent IM. We assessed all case reports available for causality utilizing a modified Naranjo nomogram specifically designed for this subject. We assembled the available epidemiological data into tables to identify trends in incidence rates over the years. We identified 17 case reports of antibiotic-associated rash in patients with IM. The median Naranjo score was 6 (range = 1 to 8). The top 3 reported drugs were ampicillin, azithromycin, and amoxicillin. Incidence of this adverse effect was higher in the 1960s (55.6%, 45%, and 33%) than in 2013 (33% and 15%). The mechanism most commonly proposed is a transient virus-mediated immune alteration that sets the stage for loss of antigenic tolerance and the development of a reversible, delayed-type hypersensitivity reaction to the antibiotic. A reassessment of the long-held belief of the high incidence (80%-100%) of antibiotic-induced skin rash in patients with IM seems prudent. Additional studies will be necessary to clarify this issue.

Antibiotic mixture effects on growth of the leaf-shredding stream detritivore Gammarus fossarum.

PubMed

Bundschuh, Mirco; Hahn, Torsten; Gessner, Mark O; Schulz, Ralf

2017-05-01

Pharmaceuticals contribute greatly to human and animal health. Given their specific biological targets, pharmaceuticals pose a significant environmental risk by affecting organisms and ecosystem processes, including leaf-litter decomposition. Although litter decomposition is a central process in forest streams, the consequences of exposure to pharmaceuticals remain poorly known. The present study assessed the impact of antibiotics as an important class of pharmaceuticals on the growth of the leaf-shredding amphipod Gammarus fossarum over 24 days. Exposure scenarios involved an antibiotic mixture (i.e. sulfamethoxazole, trimethoprim, erythromycin-H 2 O, roxithromycin, clarithromycin) at 0, 2 and 200 µg/L to assess impacts resulting from exposure to both water and food. The antibiotics had no effect on either leaf-associated fungal biomass or bacterial abundance. However, modification of leaf quality (e.g. through shifts in leaf-associated microbial communities) may have triggered faster growth of gammarids (assessed in terms of body mass gain) at the low antibiotic concentration relative to the control. At 200 µg/L, however, gammarid growth was not stimulated. This outcome might be due to a modified ability of the gut microflora to assimilate nutrients and carbon. Furthermore, the observed lack of increases in the diameter of the gammarids' peduncles, despite an increase in gammarid mass, suggests antibiotic-induced effects in the moulting cycle. Although the processes responsible for the observed effects have not yet been identified, these results suggest a potential role of food-quality, gammarid gut microflora and alteration in the moulting cycle in mediating impacts of antibiotics on these detritivores and the leaf decomposition process in streams.

Sperm Quality during Storage Is Not Affected by the Presence of Antibiotics in EquiPlus Semen Extender but Is Improved by Single Layer Centrifugation

PubMed Central

Spergser, Joachim; Kuhl, Juliane; Schmidt, Kathrin; Johannisson, Anders

2017-01-01

Contamination of semen with bacteria arises during semen collection and handling. This bacterial contamination is typically controlled by adding antibiotics to semen extenders but intensive usage of antibiotics can lead to the development of bacterial resistance and may be detrimental to sperm quality. The objective of this study was to determine the effects of antibiotics in a semen extender on sperm quality and to investigate the effects of removal of bacteria by modified Single Layer Centrifugation (MSLC) through a colloid. Semen was collected from six adult pony stallions (three ejaculates per male). Aliquots of extended semen were used for MSLC with Equicoll, resulting in four treatment groups: control and MSLC in extender with antibiotics (CA and SA, respectively); control and MSLC in extender without antibiotics (CW and SW, respectively). Sperm motility, membrane integrity, mitochondrial membrane potential and chromatin integrity were evaluated daily by computer-assisted sperm analysis (CASA) and flow cytometry. There were no differences in sperm quality between CA and CW, or between SA and SW, although progressive motility was negatively correlated to total bacterial counts at 0 h. However, MSLC groups showed higher mean total motility (P < 0.001), progressive motility (P < 0.05), membrane integrity (P < 0.0001) and mitochondrial membrane potential (P < 0.05), as well as better chromatin integrity (P < 0.05), than controls. Sperm quality remained higher in the MSLC groups than controls throughout storage. These results indicate that sperm quality was not adversely affected by the presence of antibiotics but was improved considerably by MSLC. PMID:29267226

Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of l-aspartic acid.

PubMed

Falzone, Maria; Crespo, Emmanuel; Jones, Klarissa; Khan, Gulaba; Korn, Victoria L; Patel, Amreen; Patel, Mira; Patel, Krishnaben; Perkins, Carrie; Siddiqui, Sana; Stenger, Drew; Yu, Eileen; Gelber, Michael; Scheffler, Robert; Nayda, Vasyl; Ravin, Ariela; Komal, Ronica; Rudolf, Jeffrey D; Shen, Ben; Gullo, Vincent; Demain, Arnold L

2017-07-01

Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models. Platensimycin also has activity against diabetes in a mouse model. We have been interested in studying the effects of primary metabolites on production of these antibiotics in our chemically defined production medium. In the present work, we tested 32 primary metabolites for their effect. They included 20 amino acids, 7 vitamins and 5 nucleic acid derivatives. Of these, only l-aspartic acid showed stimulation of antibiotic production. We conclude that the stimulatory effect of aspartic acid is due to its role as a precursor involved in the biosynthesis of aspartate-4-semialdehyde, which is the starting point for the biosynthesis of the 3-amino-2,4-dihydroxy benzoic acid portion of the platensimycin molecule.

Nutritional control of antibiotic production by Streptomyces platensis MA7327: importance of L-aspartic acid

PubMed Central

Falzone, Maria; Crespo, Emmanuel; Jones, Klarissa; Khan, Gulaba; Korn, Victoria L; Patel, Amreen; Patel, Mira; Patel, Krishnaben; Perkins, Carrie; Siddiqui, Sana; Stenger, Drew; Yu, Eileen; Gelber, Michael; Scheffler, Robert; Nayda, Vasyl; Ravin, Ariela; Komal, Ronica; Rudolf, Jeffrey D; Shen, Ben; Gullo, Vincent; Demain, Arnold L

2017-01-01

Streptomyces platensis MA7327 is a bacterium producing interesting antibiotics, which act by the novel mechanism of inhibiting fatty acid biosynthesis. The antibiotics produced by this actinomycete are platensimycin and platencin plus some minor related antibiotics. Platensimycin and platencin have activity against antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus; they also lack toxicity in animal models. Platensimycin also has activity against diabetes in a mouse model. We have been interested in studying the effects of primary metabolites on production of these antibiotics in our chemically defined production medium. In the present work, we tested 32 primary metabolites for their effect. They included 20 amino acids, 7 vitamins and 5 nucleic acid derivatives. Of these, only L-aspartic acid showed stimulation of antibiotic production. We conclude that the stimulatory effect of aspartic acid is due to its role as a precursor involved in the biosynthesis of aspartate-4-semialdehyde, which is the starting point for the biosynthesis of the 3-amino-2,4-dihydroxy benzoic acid portion of the platensimycin molecule. PMID:28465627

The Impact of Policy Guidelines on Hospital Antibiotic Use over a Decade: A Segmented Time Series Analysis

PubMed Central

Chandy, Sujith J.; Naik, Girish S.; Charles, Reni; Jeyaseelan, Visalakshi; Naumova, Elena N.; Thomas, Kurien; Lundborg, Cecilia Stalsby

2014-01-01

Introduction Antibiotic pressure contributes to rising antibiotic resistance. Policy guidelines encourage rational prescribing behavior, but effectiveness in containing antibiotic use needs further assessment. This study therefore assessed the patterns of antibiotic use over a decade and analyzed the impact of different modes of guideline development and dissemination on inpatient antibiotic use. Methods Antibiotic use was calculated monthly as defined daily doses (DDD) per 100 bed days for nine antibiotic groups and overall. This time series compared trends in antibiotic use in five adjacent time periods identified as ‘Segments,’ divided based on differing modes of guideline development and implementation: Segment 1– Baseline prior to antibiotic guidelines development; Segment 2– During preparation of guidelines and booklet dissemination; Segment 3– Dormant period with no guidelines dissemination; Segment 4– Booklet dissemination of revised guidelines; Segment 5– Booklet dissemination of revised guidelines with intranet access. Regression analysis adapted for segmented time series and adjusted for seasonality assessed changes in antibiotic use trend. Results Overall antibiotic use increased at a monthly rate of 0.95 (SE = 0.18), 0.21 (SE = 0.08) and 0.31 (SE = 0.06) for Segments 1, 2 and 3, stabilized in Segment 4 (0.05; SE = 0.10) and declined in Segment 5 (−0.37; SE = 0.11). Segments 1, 2 and 4 exhibited seasonal fluctuations. Pairwise segmented regression adjusted for seasonality revealed a significant drop in monthly antibiotic use of 0.401 (SE = 0.089; p<0.001) for Segment 5 compared to Segment 4. Most antibiotic groups showed similar trends to overall use. Conclusion Use of overall and specific antibiotic groups showed varied patterns and seasonal fluctuations. Containment of rising overall antibiotic use was possible during periods of active guideline dissemination. Wider access through intranet facilitated significant decline in use. Stakeholders and policy makers are urged to develop guidelines, ensure active dissemination and enable accessibility through computer networks to contain antibiotic use and decrease antibiotic pressure. PMID:24647339

Local audit: How tightly should we police antibiotic prescribing for urinary tract infection and how should we modify national policy?

PubMed

Brair, Amallia; Toozs-Hobson, Philip; Gray, Jim

2015-12-01

In 2010, our hospital, in line with National guidance, changed advice on antibiotic prescribing for UTI to reduce use of cephalosporins in favour of penicillins. We hypothesized that this change in policy would have no impact on the pattern of antibiotic resistance of the organisms causing UTI. Audit review of all urine samples sent to BWH from 2009 to 2013 and positive cultures showing Enterobacteriaceae were then tested for antibiotic susceptibility. There has been an increase in the resistance of both Co-amoxiclav and Ciprofloxacin since 2009. Co-amoxiclav and trimethoprim now have similar resistance rates. Ciprofloxacin resistance has risen fairly quickly in the last four years from 1% to 8%. Resistance to nitrofurantoin has remained low. Gentamicin resistance remained stable and very low, second best to meroponem. The results have been fed back to commissioners and internally and are being used as part of the guideline updating process. Hospital protocols for treating infections should be reviewed and updated based on accurate local data. These data should be used for formulating regional specific protocols. Our results suggest that meroponem and ciprofloxacin should be reserved for microbiologically proven resistance to other antibiotics. © The Author(s) 2015.

Acquisition of extended spectrum β-lactamases during travel abroad—A qualitative study among Swedish travellers examining their knowledge, risk assessment, and behaviour

PubMed Central

Fagerberg, Ingegerd; Örtqvist, Åke; Broliden, Kristina; Tammelin, Ann

2016-01-01

Background Travel to foreign countries involves the risk of becoming a carrier of antibiotic-resistant bacteria, especially when the destination is a country with a high prevalence of this type of bacteria. Aim and methods The aim of this study was to learn about the knowledge of antibiotic resistance, and the behaviour and risk-taking among travellers, who had become carriers of extended spectrum beta-lactamases (ESBL)-producing bacteria during travel to a high-prevalence country. A modified version of grounded theory was used to analyse 15 open interviews. Results The analysis resulted in a core category: A need for knowledge to avoid risk-taking. Before the journey, the participants did not perceive there to be any risk of becoming a carrier of antibiotic- resistant bacteria. The low level of knowledge of antibiotic-resistant bacteria and transmission routes influenced their behaviour and risk-taking during their journey, resulting in them exposing themselves to risk situations. After their trip, the majority did not believe that their personal risk behaviour could have caused them to become carriers of ESBL. Conclusion The participants’ lack of knowledge of antibiotic-resistant bacteria resulted in unconscious risk-taking during their journey, which may have resulted in becoming carriers of ESBL-producing bacteria. PMID:27806830

A fluorescent glycosyl-imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic.

PubMed

Chen, Kuncai; He, Rong; Luo, Xiaoyan; Qin, Pengzhe; Tan, Lei; Tang, Youwen; Yang, Zhicong

2017-08-15

This paper demonstrates a new strategy for developing a fluorescent glycosyl-imprinted polymer for pH and temperature regulated sensing of target glycopeptide antibiotic. The technique provides amino modified Mn-doped ZnS QDs as fluorescent supports, 4-vinylphenylbronic acid as a covalent monomer, N-isopropyl acrylamide as a thermo-responsive monomer in combination with acrylamide as a non-covalent monomer, and glycosyl moiety of a glycopeptide antibiotic as a template to produce fluorescent molecularly imprinted polymer (FMIP) in aqueous solution. The FMIP can alter its functional moieties and structure with pH and temperature stimulation. This allows recognition of target molecules through control of pH and temperature. The fluorescence intensity of the FMIP was enhanced gradually as the concentration of telavancin increased, and showed selective recognition toward the target glycopeptide antibiotic preferentially among other antibiotics. Using the FMIP as a sensing material, good linear correlations were obtained over the concentration range of 3.0-300.0μg/L and with a low limit of detection of 1.0μg/L. The analysis results of telavancin in real samples were consistent with that obtained by liquid chromatography tandem mass spectrometry. Copyright © 2017 Elsevier B.V. All rights reserved.

Acquisition of extended spectrum β-lactamases during travel abroad-A qualitative study among Swedish travellers examining their knowledge, risk assessment, and behaviour.

PubMed

Wiklund, Susanne; Fagerberg, Ingegerd; Örtqvist, Åke; Broliden, Kristina; Tammelin, Ann

2016-01-01

Travel to foreign countries involves the risk of becoming a carrier of antibiotic-resistant bacteria, especially when the destination is a country with a high prevalence of this type of bacteria. The aim of this study was to learn about the knowledge of antibiotic resistance, and the behaviour and risk-taking among travellers, who had become carriers of extended spectrum beta-lactamases (ESBL)-producing bacteria during travel to a high-prevalence country. A modified version of grounded theory was used to analyse 15 open interviews. The analysis resulted in a core category: A need for knowledge to avoid risk-taking . Before the journey, the participants did not perceive there to be any risk of becoming a carrier of antibiotic- resistant bacteria. The low level of knowledge of antibiotic-resistant bacteria and transmission routes influenced their behaviour and risk-taking during their journey, resulting in them exposing themselves to risk situations. After their trip, the majority did not believe that their personal risk behaviour could have caused them to become carriers of ESBL. The participants' lack of knowledge of antibiotic-resistant bacteria resulted in unconscious risk-taking during their journey, which may have resulted in becoming carriers of ESBL-producing bacteria.

Antibiotic and Modulation of Microbiota: A New Paradigm?

PubMed

Rizzatti, Gianenrico; Ianiro, Gianluca; Gasbarrini, Antonio

2018-06-16

Recently new insights on gut microbiota have revolutionized many concepts of the modern medicine. The alteration of microbiota, which is called dysbiosis, has been associated with an expanding list of diseases and conditions. The development of next-generation sequencing techniques allowed comprehensive analysis of gut microbiota composition without the limitations of classic culture methods. Furthermore, introduction of functional techniques such as metabolomics and proteomics allowed for integrated analysis thus obtaining more robust insights on microbiota functions in health and disease. These tools allow to address the role of factors able to modify the gut microbiota, the so called "microbiota influencers." These data are useful to explain the physiopathology of several disease and thus to identify new potential therapeutic targets. Among microbiota influencers, many studies focused on the impact of antibiotic administration on the gut microbiota, because of their widespread use. Notably, beside the known beneficial effect of antibiotic in treating infectious diseases, these drugs have shown detrimental effects on gut microbiota which, in turn, might have long-term consequences on the host. Finally, therapeutic modulation of gut microbiota, by means of selected antibiotics with eubiotic effects, probiotics and with fecal microbiota transplantation seems of great interest as it might be able to prevent or even revert antibiotic-induced dysbiosis.

Alternative indicators for monitoring the quality of a continuous intervention program on antibiotic prescribing during changing healthcare conditions.

PubMed

Bantar, C; Franco, D; Heft, C; Vesco, E; Arango, C; Izaguirre, M; Alcázar, G; Boleas, M; Oliva, M E

2005-06-01

We recently published on the impact of a four-phase hospital-wide intervention program designed to optimize the quality of antibiotic use, where a multidisciplinary team (MDT) could modify prescription at the last phase. Because health care quality was changing during the last 5 years (late 1999 to early 2004), we developed certain indicators to monitor the quality of our intervention over time. Different periods were defined as baseline (pre-intervention), initial intervention-active control, pre-crisis control, crisis control, post-crisis control and end of crisis control. Major indicators were rates of prescription modification by the MDT; prescription for an uncertain infection and a novel index formula (RIcarb) to estimate the rationale for carbapenem use. We assessed 2115 antimicrobial prescriptions. Modification of prescription rate was 30% at the beginning and decreased thereafter up to stable levels. Rate of prescriptions ordered for cases of both uncertain infection and unknown source of infection decreased significantly after intervention (i.e. from baseline to active control). In contrast, a doubling of culture-directed prescriptions was observed between these periods. RIcarb values lower and higher than 60% (modal, cut-off) were assumed as carbapenem overuse and underuse, respectively. Overuse was observed at the pre-intervention, while pronounced underuse was shown during the crisis (RIcarb, 45% and 87%, respectively). The present study demonstrates that certain indicators, other than the widely adopted impact outcomes, are a suitable tool for monitoring the quality of a continuous, long-term, active intervention on antimicrobial prescribing practice, especially when applied in a changing healthcare setting.

A novel chimeric peptide with antimicrobial activity.

PubMed

Alaybeyoglu, Begum; Akbulut, Berna Sariyar; Ozkirimli, Elif

2015-04-01

Beta-lactamase-mediated bacterial drug resistance exacerbates the prognosis of infectious diseases, which are sometimes treated with co-administration of beta-lactam type antibiotics and beta-lactamase inhibitors. Antimicrobial peptides are promising broad-spectrum alternatives to conventional antibiotics in this era of evolving bacterial resistance. Peptides based on the Ala46-Tyr51 beta-hairpin loop of beta-lactamase inhibitory protein (BLIP) have been previously shown to inhibit beta-lactamase. Here, our goal was to modify this peptide for improved beta-lactamase inhibition and cellular uptake. Motivated by the cell-penetrating pVEC sequence, which includes a hydrophobic stretch at its N-terminus, our approach involved the addition of LLIIL residues to the inhibitory peptide N-terminus to facilitate uptake. Activity measurements of the peptide based on the 45-53 loop of BLIP for enhanced inhibition verified that the peptide was a competitive beta-lactamase inhibitor with a K(i) value of 58 μM. Incubation of beta-lactam-resistant cells with peptide decreased the number of viable cells, while it had no effect on beta-lactamase-free cells, indicating that this peptide had antimicrobial activity via beta-lactamase inhibition. To elucidate the molecular mechanism by which this peptide moves across the membrane, steered molecular dynamics simulations were carried out. We propose that addition of hydrophobic residues to the N-terminus of the peptide affords a promising strategy in the design of novel antimicrobial peptides not only against beta-lactamase but also for other intracellular targets. Copyright © 2015 European Peptide Society and John Wiley & Sons, Ltd.

Antibiotic-Resistant Bacteria: There is Hope.

ERIC Educational Resources Information Center

Offner, Susan

1998-01-01

Argues that reduction in the use of antibiotics would enable antibiotic-sensitive bacteria to flourish. Presents an activity designed to show students how a small, seemingly unimportant difference in doubling time can, over a period of time, make an enormous difference in population size. (DDR)

Using Chemoinformatics, Bioinformatics, and Bioassay to Predict and Explain the Antibacterial Activity of Nonantibiotic Food and Drug Administration Drugs.

PubMed

Kahlous, Nour Aldin; Bawarish, Muhammad Al Mohdi; Sarhan, Muhammad Arabi; Küpper, Manfred; Hasaba, Ali; Rajab, Mazen

2017-04-01

Discovering of new and effective antibiotics is a major issue facing scientists today. Luckily, the development of computer science offers new methods to overcome this issue. In this study, a set of computer software was used to predict the antibacterial activity of nonantibiotic Food and Drug Administration (FDA)-approved drugs, and to explain their action by possible binding to well-known bacterial protein targets, along with testing their antibacterial activity against Gram-positive and Gram-negative bacteria. A three-dimensional virtual screening method that relies on chemical and shape similarity was applied using rapid overlay of chemical structures (ROCS) software to select candidate compounds from the FDA-approved drugs database that share similarity with 17 known antibiotics. Then, to check their antibacterial activity, disk diffusion test was applied on Staphylococcus aureus and Escherichia coli. Finally, a protein docking method was applied using HYBRID software to predict the binding of the active candidate to the target receptor of its similar antibiotic. Of the 1,991 drugs that were screened, 34 had been selected and among them 10 drugs showed antibacterial activity, whereby drotaverine and metoclopramide activities were without precedent reports. Furthermore, the docking process predicted that diclofenac, drotaverine, (S)-flurbiprofen, (S)-ibuprofen, and indomethacin could bind to the protein target of their similar antibiotics. Nevertheless, their antibacterial activities are weak compared with those of their similar antibiotics, which can be potentiated further by performing chemical modifications on their structure.

Chemically modified tetracycline-3 (CMT-3): a novel inhibitor of the serine proteinase, elastase.

PubMed

Gu, Ying; Lee, Hsi-Ming; Simon, Sanford R; Golub, Lorne M

2011-12-01

Two classes of enzymes play an important role in connective tissue breakdown during various inflammatory diseases: serine proteinases and matrix metalloproteinases (MMPs). Tetracyclines (TCs) exhibit important anti-inflammatory and MMP-inhibitory properties that are unrelated to their antibacterial activities. Of the various TCs and their chemically modified NON-antibiotic analogs (CMTs) tested in vitro and in vivo, CMT-3 (6-demethyl-6-deoxy 4 de-dimethylamino tetracycline) has repeatedly been shown to be the most potent inhibitor of MMP activity and cytokine production. In addition to its anti-MMP function, we have shown that among all CMTs, CMT-3 is the only CMT that can also directly inhibit both the amidolytic activity of human leukocyte elastase (HLE, a serine proteinase) and the extracellular matrix degradation mediated by HLE. In addition, CMT-3 has been found to reduce leukocyte elastase activity in vivo in gingival extracts of rats with experimental periodontal disease. Thus, CMT-3 can inhibit pathologic connective tissue breakdown by (at least) two mechanisms: direct inhibition of neutral proteinases (elastase and MMPs); and protecting their endogenous inhibitors, α(1)-PI and TIMPs, from being digested and inactivated by MMPs and HLE, respectively. The pleiotropic properties of CMT-3 including (but not limited to) inhibition of serine proteinases, MMPs, and cytokines provide impressive therapeutic potential to reduce excessive connective tissue breakdown during various pathologic processes including inflammatory diseases, cancer metastasis and metabolic bone diseases. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Antimicrobial consumption reported through standardized reports on infection control activities, relationship with the ICATB public reporting indicator].

PubMed

Henard, S; Rahib, D; Léon, L; Amadéo, B; Dumartin, C; Cavalié, P; Coignard, B

2011-04-01

The study's objective was to describe the evolution of antibiotic consumption between 2006 and 2008 in French health care facilities (HCF) its relations with the national policy of good antibiotics use using the ICATB score. Data from standardized reports on infection control activities collected from 2006 to 2008 by the Ministry of Health (antibiotic consumptions and elements of antibiotic stewardship of every HCF) were analyzed with linear regression models to multilevel random intercept adjusted on HCF characteristics (public or private) and activity. The analysis was performed on 4062 (48,2%) observations after exclusion of HCF not concerned by the ICATB public reporting indicator (7.2% of observations), invalid or missing data (21,2% of observations) and irrelevant values (23.4%). The global antibiotic consumption was 343 defined daily doses (DDD) per 1000 patient-days (PD) and varied little between 2006 and 2008. However, the linear regression model showed an increase of 5.7 DDD per 1000 PDs per year (P<0.001). There was a positive association between antibiotic consumption and ICATB score, mainly concerning sub-scores ICATB-action and ICATB-organization. The recent lack of decrease in antibiotic consumption in French HCF between 2006 and 2008 is coherent with other available national data, but exclusion of more than 50% of observations limits the impact of this analysis. The relationship between policy of good use and consumption of antibiotics remain difficult to specify, because of the short (three years) study length and because of the nature of ICATB, a composite indicator assessing only partly antibiotic policies. Copyright © 2010 Elsevier Masson SAS. All rights reserved.

Intervention to Reduce Broad-Spectrum Antibiotics and Treatment Durations Prescribed at the Time of Hospital Discharge: A Novel Stewardship Approach

PubMed Central

Yogo, Norihiro; Shihadeh, Katherine; Young, Heather; Calcaterra, Susan; Knepper, Bryan C; Burman, William J; Mehler, Philip S; Jenkins, Timothy C

2017-01-01

Objective For most common infections requiring hospitalization, antibiotic treatment is completed after hospital discharge. Post-discharge therapy is often unnecessarily broad-spectrum and prolonged. We developed an intervention to improve antibiotic selection and shorten treatment durations. Design Single center, quasi-experimental retrospective cohort study. Methods Patients prescribed oral antibiotics at hospital discharge before (July 2012 – June 2013) and after (October 2014 – February 2015) an intervention consisting of: 1) institutional guidance for oral step-down antibiotic selection and duration of therapy, and 2) pharmacy audit of discharge prescriptions with real-time prescribing recommendations to providers. The primary outcomes were total prescribed duration of therapy and use of antibiotics with broad gram-negative activity (fluoroquinolones or amoxicillin-clavulanate). Results 300 cases from the pre-intervention period and 200 from the intervention period were included. Compared with the pre-intervention period, use of antibiotics with broad gramnegative activity decreased during the intervention (51% vs 40%, p = 0.02), particularly fluoroquinolones (38% vs 25%, p = 0.002). The difference in total duration of therapy did not reach statistical significance (10 days [interquartile range (IQR) 7–13] vs 9 [IQR 6–13], p = 0.13); however, the duration prescribed at discharge declined from 6 days (IQR 4–10) to 5 (IQR 3–7) (p = 0.003). During the intervention, there was a non-significant increase in the overall appropriateness of discharge prescriptions (52% vs 66%, p = 0.15). Conclusions A multifaceted intervention to optimize antibiotic prescribing at hospital discharge was associated with less frequent use of antibiotics with broad gram-negative activity and shorter post-hospital treatment durations. PMID:28260538

Synergistic activity of synthetic N-terminal peptide of human lactoferrin in combination with various antibiotics against carbapenem-resistant Klebsiella pneumoniae strains.

PubMed

Morici, P; Florio, W; Rizzato, C; Ghelardi, E; Tavanti, A; Rossolini, G M; Lupetti, A

2017-10-01

The spread of multi-drug resistant (MDR) Klebsiella pneumoniae strains producing carbapenemases points to a pressing need for new antibacterial agents. To this end, the in-vitro antibacterial activity of a synthetic N-terminal peptide of human lactoferrin, further referred to as hLF1-11, was evaluated against K. pneumoniae strains harboring different carbapenemase genes (i.e. OXA-48, KPC-2, KPC-3, VIM-1), with different susceptibility to colistin and other antibiotics, alone or in combination with conventional antibiotics (gentamicin, tigecycline, rifampicin, clindamycin, and clarithromycin). An antimicrobial peptide susceptibility assay was used to assess the bactericidal activity of hLF1-11 against the different K. pneumoniae strains tested. The synergistic activity was evaluated by a checkerboard titration method, and the fractional inhibitory concentration (FIC) index was calculated for the various combinations. hLF1-11 was more efficient in killing a K. pneumoniae strain susceptible to most antimicrobials (including colistin) than a colistin-susceptible strain and a colistin-resistant MDR K. pneumoniae strain. In addition, hLF1-11 exhibited a synergistic effect with the tested antibiotics against MDR K. pneumoniae strains. The results of this study indicate that resistance to hLF1-11 and colistin are not strictly associated, and suggest an hLF1-11-induced sensitizing effect of K. pneumoniae to antibiotics, especially to hydrophobic antibiotics, which are normally not effective on Gram-negative bacteria. Altogether, these data indicate that hLF1-11 in combination with antibiotics is a promising candidate to treat infections caused by MDR-K. pneumoniae strains.

The Antibacterial Activity of Selected Labiatae (Lamiaceae) Essential Oils against Brucella melitensis.

PubMed

Al-Mariri, Ayman; Safi, Mazen

2013-03-01

Brucellosis, a zoonosis caused by four species of brucella, has a high morbidity. The major cause of brucellosis worldwide is brucella melitensis. Medicinal plants are considered as new antibacterial sources that could replace conventional antibiotics in the treatment of antibiotic-resistant bacteria. The aim of this study was to evaluate the efficacy of some native plants, alone and in combination with some antibiotics, in the treatment of brucellosis. The present experimental in vitro study was carried out to evaluate the anti-brucella activities of essential oils of Rosmarinus officinalis L., Origanum syriacum, Thymus syriacus, Salvia palaestina Benth, Mentha piperia, and Lavandula stoechas L., alone and in combination with some antibiotics. The activity against 16 tetracycline-resistant B. melitensis isolates was determined by disc diffusion method incorporating a concentration of 5%. Antibiotic discs were also used as a control. Microdilution brucella broth susceptibility assay was used in order to determine the MICs of essential oils and five antibiotics. Among all the herbs evaluated, only the essential oils of O. syriacum and T. syriacus plants demonstrated most effective anti-brucella activity, and were then chosen for MIC study. The minimal inhibitory concentrations (MIC50) of essential oils of O. syriacum and T. syriacus against tetracycline-resistant B. melitensis were 3.125 µl/ml and 6.25 µl/ml, respectively. Among the essential oils studied, those of O. syriacum and T. syriacus were most effective. Since a combination of levofloxacin and Thymus syriacus essential oil increased the efficacy of this antibiotic, O. syriacum and T. syriacus are recommended to be used as bactericidal agents against B. melitensis.

Molecular characterization and antibiotic susceptibility of Haemophilus influenzae clinical isolates.

PubMed

K L Ç, Hüseyin; Akyol, Selcan; Parkan, Õmür Mustafa; Dinç, Gõkçen; Sav, Hafize; Aydemir, Gonca

2017-03-01

Haemophilus influenzae can cause invasive and severe infections in both adults and children such as otitis media, sinusitis, pneumonia, meningitis and bacteremia. The emerging antibiotic resistance in recent years against ampicillin and several other antibiotics among strains of H. influenzae gives cause for serious concern. Here, we investigate ß-lactamase (BL) activity in clinical isolates of H. influenzae, profile their resistance to antibiotics, and characterize the clonal relationship of the isolates. Antibiotic susceptibilities of 92 clinical isolates of H. influenzae (March 2011-May 2012) were determined using the disk diffusion method according to the Clinical & Laboratory Standards Institute (CLSI), and BL activity was detected using the nitrocefin disk method. The Rep-PCR method was used to characterize clonality of the isolates. All strains were found to be susceptible to levofloxacin and cefotaxime. Four isolates out of 92 (4.3%) were found resistant to ampicillin, one isolate (1.1%) was resistant to amoxicillin/clavulanic acid, 21 isolates (22.8%) were resistant to trimethoprim-sulfamethoxazole (SXT), and three isolates (3.3%) showed BL activity. One strain was BL-negative but resistant to ampicillin. The three isolates with BL activity and four isolates with resistance to ampicillin did not have a clonal relationship. Three distinct clones [clone A (with subclones A1 and A2), clone B, and clone C] were identified among the SXT-resistant strains. Most of the H. influenzae isolates in this study were susceptible to the antibiotics while SXT resistance was relatively more prevalent, which suggests that significant obstacles in the therapeutic use of antibiotics against H. influenzae strains are not expected in our region.

[Methodology of Screening New Antibiotics: Present Status and Prospects].

PubMed

Trenin, A S

2015-01-01

Due to extensive distribution of pathogen resistance to available pharmaceuticals and serious problems in the treatment of various infections and tumor diseases, the necessity of new antibiotics is urgent. The basic methodological approaches to chemical synthesis of antibiotics and screening of new antibiotics among natural products, mainly among microbial secondary metabolites, are considered in the review. Since the natural compounds are very much diverse, screening of such substances gives a good opportunity to discover antibiotics of various chemical structure and mechanism of action. Such an approach followed by chemical or biological transformation, is capable of providing the health care with new effective pharmaceuticals. The review is mainly concentrated on screening of natural products and methodological problems, such as: isolation of microbial producers from the habitats, cultivation of microorganisms producing appropriate substances, isolation and chemical characterization of microbial metabolites, identification of the biological activity of the metabolites. The main attention is paid to the problems of microbial secondary metabolism and design of new models for screening biologically active compounds. The last achievements in the field of antibiotics and most perspective approaches to future investigations are discussed. The main methodological approach to isolation and cultivation of the producers remains actual and needs constant improvement. The increase of the screening efficiency can be achieved by more rapid chemical identification of antibiotics and design of new screening models based on the biological activity detection.

Role of antibiotics for treatment of inflammatory bowel disease

PubMed Central

Nitzan, Orna; Elias, Mazen; Peretz, Avi; Saliba, Walid

2016-01-01

Inflammatory bowel disease is thought to be caused by an aberrant immune response to gut bacteria in a genetically susceptible host. The gut microbiota plays an important role in the pathogenesis and complications of the two main inflammatory bowel diseases: Crohn’s disease (CD) and ulcerative colitis. Alterations in gut microbiota, and specifically reduced intestinal microbial diversity, have been found to be associated with chronic gut inflammation in these disorders. Specific bacterial pathogens, such as virulent Escherichia coli strains, Bacteroides spp, and Mycobacterium avium subspecies paratuberculosis, have been linked to the pathogenesis of inflammatory bowel disease. Antibiotics may influence the course of these diseases by decreasing concentrations of bacteria in the gut lumen and altering the composition of intestinal microbiota. Different antibiotics, including ciprofloxacin, metronidazole, the combination of both, rifaximin, and anti-tuberculous regimens have been evaluated in clinical trials for the treatment of inflammatory bowel disease. For the treatment of active luminal CD, antibiotics may have a modest effect in decreasing disease activity and achieving remission, and are more effective in patients with disease involving the colon. Rifamixin, a non absorbable rifamycin has shown promising results. Treatment of suppurative complications of CD such as abscesses and fistulas, includes drainage and antibiotic therapy, most often ciprofloxacin, metronidazole, or a combination of both. Antibiotics might also play a role in maintenance of remission and prevention of post operative recurrence of CD. Data is more sparse for ulcerative colitis, and mostly consists of small trials evaluating ciprofloxacin, metronidazole and rifaximin. Most trials did not show a benefit for the treatment of active ulcerative colitis with antibiotics, though 2 meta-analyses concluded that antibiotic therapy is associated with a modest improvement in clinical symptoms. Antibiotics show a clinical benefit when used for the treatment of pouchitis. The downsides of antibiotic treatment, especially with recurrent or prolonged courses such as used in inflammatory bowel disease, are significant side effects that often cause intolerance to treatment, Clostridium dificile infection, and increasing antibiotic resistance. More studies are needed to define the exact role of antibiotics in inflammatory bowel diseases. PMID:26811648

Role of antibiotics for treatment of inflammatory bowel disease.

PubMed

Nitzan, Orna; Elias, Mazen; Peretz, Avi; Saliba, Walid

2016-01-21

Inflammatory bowel disease is thought to be caused by an aberrant immune response to gut bacteria in a genetically susceptible host. The gut microbiota plays an important role in the pathogenesis and complications of the two main inflammatory bowel diseases: Crohn's disease (CD) and ulcerative colitis. Alterations in gut microbiota, and specifically reduced intestinal microbial diversity, have been found to be associated with chronic gut inflammation in these disorders. Specific bacterial pathogens, such as virulent Escherichia coli strains, Bacteroides spp, and Mycobacterium avium subspecies paratuberculosis, have been linked to the pathogenesis of inflammatory bowel disease. Antibiotics may influence the course of these diseases by decreasing concentrations of bacteria in the gut lumen and altering the composition of intestinal microbiota. Different antibiotics, including ciprofloxacin, metronidazole, the combination of both, rifaximin, and anti-tuberculous regimens have been evaluated in clinical trials for the treatment of inflammatory bowel disease. For the treatment of active luminal CD, antibiotics may have a modest effect in decreasing disease activity and achieving remission, and are more effective in patients with disease involving the colon. Rifamixin, a non absorbable rifamycin has shown promising results. Treatment of suppurative complications of CD such as abscesses and fistulas, includes drainage and antibiotic therapy, most often ciprofloxacin, metronidazole, or a combination of both. Antibiotics might also play a role in maintenance of remission and prevention of post operative recurrence of CD. Data is more sparse for ulcerative colitis, and mostly consists of small trials evaluating ciprofloxacin, metronidazole and rifaximin. Most trials did not show a benefit for the treatment of active ulcerative colitis with antibiotics, though 2 meta-analyses concluded that antibiotic therapy is associated with a modest improvement in clinical symptoms. Antibiotics show a clinical benefit when used for the treatment of pouchitis. The downsides of antibiotic treatment, especially with recurrent or prolonged courses such as used in inflammatory bowel disease, are significant side effects that often cause intolerance to treatment, Clostridium dificile infection, and increasing antibiotic resistance. More studies are needed to define the exact role of antibiotics in inflammatory bowel diseases.

Feasibility and effectiveness of a low cost campaign on antibiotic prescribing in Italy: community level, controlled, non-randomised trial.

PubMed

Formoso, Giulio; Paltrinieri, Barbara; Marata, Anna Maria; Gagliotti, Carlo; Pan, Angelo; Moro, Maria Luisa; Capelli, Oreste; Magrini, Nicola

2013-09-12

To test the hypothesis that a multifaceted, local public campaign could be feasible and influence antibiotic prescribing for outpatients. Community level, controlled, non-randomised trial. Provinces of Modena and Parma in Emilia-Romagna, northern Italy, November 2011 to February 2012. 1,150,000 residents of Modena and Parma (intervention group) and 3,250,000 residents in provinces in the same region but where no campaign had been implemented (control group). Campaign materials (mainly posters, brochures, and advertisements on local media, plus a newsletter on local antibiotic resistance targeted at doctors and pharmacists). General practitioners and paediatricians in the intervention area participated in designing the campaign messages. Primary outcome was the average change in prescribing rates of antibiotics for outpatient in five months, measured as defined daily doses per 1000 inhabitants/day, using health districts as the unit of analysis. Antibiotic prescribing was reduced in the intervention area compared with control area (-4.3%, 95% confidence interval -7.1% to -1.5%). This result was robust to "sensitivity analysis" modifying the baseline period from two months (main analysis) to one month. A higher decrease was observed for penicillins resistant to β lactamase and a lower decrease for penicillins susceptible to β lactamase, consistent with the content of the newsletter on antibiotic resistance directed at health professionals. The decrease in expenditure on antibiotics was not statistically significant in a district level analysis with a two month baseline period (main analysis), but was statistically significant in sensitivity analyses using either a one month baseline period or a more powered doctor level analysis. Knowledge and attitudes of the target population about the correct use of antibiotics did not differ between the intervention and control areas. A local low cost information campaign targeted at citizens, combined with a newsletter on local antibiotic resistance targeted at doctors and pharmacists, was associated with significantly decreased total rates of antibiotic prescribing but did not affect the population's knowledge and attitudes about antibiotic resistance. ClinicalTrials.gov NCT01604096.

Human Health Risk Assessment (HHRA) for Environmental Development and Transfer of Antibiotic Resistance

PubMed Central

Amézquita, Alejandro; Backhaus, Thomas; Borriello, Peter; Brandt, Kristian K.; Collignon, Peter; Coors, Anja; Finley, Rita; Gaze, William H.; Heberer, Thomas; Lawrence, John R.; Larsson, D.G. Joakim; McEwen, Scott A.; Ryan, James J.; Schönfeld, Jens; Silley, Peter; Snape, Jason R.; Van den Eede, Christel; Topp, Edward

2013-01-01

Background: Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. Objective: We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens. Methods: The authors participated in a workshop held 4–8 March 2012 in Québec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development “hot spots,” exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. Discussion: Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental “hot spot” compartments; and c) modifying traditional dose–response approaches to address doses of ARB for various health outcomes and pathways. Conclusions: We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers. Citation: Ashbolt NJ, Amézquita A, Backhaus T, Borriello P, Brandt KK, Collignon P, Coors A, Finley R, Gaze WH, Heberer T, Lawrence JR, Larsson DG, McEwen SA, Ryan JJ, Schönfeld J, Silley P, Snape JR, Van den Eede C, Topp E. 2013. Human health risk assessment (HHRA) for environmental development and transfer of antibiotic resistance. Environ Health Perspect 121:993–1001; http://dx.doi.org/10.1289/ehp.1206316 PMID:23838256

Gramicidin A Mutants with Antibiotic Activity against Both Gram-Positive and Gram-Negative Bacteria.

PubMed

Zerfas, Breanna L; Joo, Yechaan; Gao, Jianmin

2016-03-17

Antimicrobial peptides (AMPs) have shown potential as alternatives to traditional antibiotics for fighting infections caused by antibiotic-resistant bacteria. One promising example of this is gramicidin A (gA). In its wild-type sequence, gA is active by permeating the plasma membrane of Gram-positive bacteria. However, gA is toxic to human red blood cells at similar concentrations to those required for it to exert its antimicrobial effects. Installing cationic side chains into gA has been shown to lower its hemolytic activity while maintaining the antimicrobial potency. In this study, we present the synthesis and the antibiotic activity of a new series of gA mutants that display cationic side chains. Specifically, by synthesizing alkylated lysine derivatives through reductive amination, we were able to create a broad selection of structures with varied activities towards Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Importantly, some of the new mutants were observed to have an unprecedented activity towards important Gram-negative pathogens, including Escherichia coli, Klebsiella pneumoniae and Psuedomonas aeruginosa. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis.

PubMed

Bleich, Rachel; Watrous, Jeramie D; Dorrestein, Pieter C; Bowers, Albert A; Shank, Elizabeth A

2015-03-10

Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called "secondary" metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin's antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects--acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes.

Biotransformation of macrolide antibiotics using enriched activated sludge culture: Kinetics, transformation routes and ecotoxicological evaluation.

PubMed

Terzic, Senka; Udikovic-Kolic, Nikolina; Jurina, Tamara; Krizman-Matasic, Ivona; Senta, Ivan; Mihaljevic, Ivan; Loncar, Jovica; Smital, Tvrtko; Ahel, Marijan

2018-05-05

The biotransformation of three prominent macrolide antibiotics (azithromycin, clarithromycin and erythromycin) by an activated sludge culture, which was adapted to high concentrations of azithromycin (10 mg/L) was investigated. The study included determination of removal kinetics of the parent compounds, identification of their major biotransformation products (TPs) and assessment of ecotoxicological effects of biotransformation. The chemical analyses were performed by ultra-performance liquid chromatography/quadrupole-time-of-flight mass spectrometry, which enabled a tentative identification of TPs formed during the experiments. The ecotoxicological evaluation included two end-points, residual antibiotic activity and toxicity to freshwater algae. The enriched activated sludge culture was capable of degrading all studied macrolide compounds with high removal efficiencies (>99%) of the parent compounds at elevated concentrations (10 mg/L). The elimination of all three macrolide antibiotics was associated with the formation of different TPs, including several novel compounds previously unreported in the literature. Some of the TPs were rather abundant and contributed significantly to the overall mass balance at the end of the biodegradation experiments. Biodegradation of all investigated macrolides was associated with a pronounced reduction of the residual antibiotic activity and algal toxicity, indicating a rather positive ecotoxicological outcome of the biotransformation processes achieved by the enriched sludge culture. Copyright © 2018 Elsevier B.V. All rights reserved.

Modified live Edwardsiella ictaluri vaccine, AQUAVAC-ESC, lacks multidrug resistance plasmids

USDA-ARS?s Scientific Manuscript database

Plasmid mediated antibiotic resistance was first discovered in Edwardsiella ictaluri in the early 1990’s, and in 2007 an E. ictaluri isolate harboring an IncA/C plasmid was recovered from a moribund channel catfish infected with the bacterium. Due to the identification of multidrug resistance plasm...

Teaching Evolution through Inquiry-Based Lessons of Uncontroversial Science

ERIC Educational Resources Information Center

DeSantis, Larisa R. G.

2009-01-01

Antibiotic resistance, genetically modified produce, avian flu, and invasive species persistence are just a few scientific issues pulled from the headlines that affect society on a daily basis. Understanding these issues requires knowledge of evolutionary processes. Educating students about evolution may never have been as necessary as it is…

Relationship between consumption of MRSA-active antibiotics and burden of MRSA in acute care hospitals in Catalonia, Spain.

PubMed

Grau, Santiago; Fondevilla, Esther; Freixas, Núria; Mojal, Sergi; Sopena, Nieves; Bella, Feliu; Gudiol, Francesc

2015-04-01

To analyse the possible relationship between consumption of old and new MRSA-active antibiotics and burden of MRSA in acute care hospitals in Catalonia during the period 2007-12. Fifty-four hospitals participating in the VINCat Programme were included. Proportion of MRSA (resistant isolates of Staphylococcus aureus per 100 isolates of S. aureus tested), incidence of new cases of infection [new cases of MRSA per 1000 occupied bed-days (OBD)] and incidence of cases of bacteraemia (MRSA bacteraemia cases per 1000 OBD) were determined to estimate the annual MRSA burden. Antibiotic consumption was calculated in DDD/100 OBD. Cost was expressed in euros/100 OBD. MRSA rates remained stable over the study period, with the proportion of MRSA ranging from 20% to 22.82% in 2007 and 2012, respectively (P=0.864). Consumption of old MRSA-active antibiotics (vancomycin and teicoplanin) did not change significantly, with values from 1.51 to 2.07 DDD/100 OBD (P=0.693). Consumption of new MRSA-active antibiotics (linezolid and daptomycin) increased significantly, with values rising from 0.24 to 1.49 DDD/100 OBD (P<0.001). Cost increased by almost 200%. A widespread and steady increase in consumption of new MRSA-active antibiotics was observed among acute care hospitals in Catalonia, in spite of a stable MRSA burden. At the same time, consumption of old drugs remained stable. Such trends resulted in a significant increase in cost. Our findings suggest that factors other than the proportion of methicillin resistance among S. aureus may influence the use of old and new MRSA-active antibiotics in the clinical setting. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Accumulation of the Antibiotic Phenazine-1-Carboxylic Acid in the Rhizosphere of Dryland Cereals

USDA-ARS?s Scientific Manuscript database

Natural antibiotics are thought to function in the defense, fitness, competitiveness, biocontrol activity, communication and gene regulation of microorganisms. However, the scale and quantitative aspects of antibiotic production in natural settings are poorly understood. We addressed these fundament...

Treponemycin, a nitrile antibiotic active against Treponema hyodysenteriae.

PubMed

Singh, S K; Gurusiddaiah, S; Whalen, J W

1985-02-01

Two strains of Streptomyces sp. (isolates 275 and 124) were isolated from soil samples collected from the fields around Lewiston, Idaho. Based on their cellular morphology and physiology, the two isolates were identified as Streptomyces albovinaceous. Both isolates produced an antibiotic when grown in liquid culture medium containing homogenized oats. The antibiotic (treponemycin) was isolated from the culture broth by solvent extraction and purified by silica gel column and preparative thin-layer chromatographies. Treponemycin is a crystalline light-yellow compound with an mp of 93 to 95 degrees C, levorotatory, and soluble in most organic solvents. It is sparingly soluble in water but insoluble in petroleum ether. On the basis of elemental analysis and mass spectral data, the molecular formula of the antibiotic was deduced to be C28H43O6N. The infrared spectrum of the antibiotic indicated the presence of unsaturation, nitrile, lactone, or ester or all three functions, and carbonyl functions in the molecule. A sharp infrared absorption band for nitrile at 2,220 cm-1 and the presence of an unsaturated group indicated that the nitrile function may be attached to an unsaturated carbon atom. The presence of dienenitrile functions was further supported by the UV absorption spectrum of the antibiotic, which gave a UVmax at 257 nm. The proton magnetic resonance spectrum of the antibiotic did not give any peak which could be exchanged with deuterated water, which is an indication of the absence of carboxylic and hydroxyl functions in the molecule. All of the functional groupings indicated by the infrared and UV spectra of the molecule were further confirmed by the 13C-magnetic resonance spectrum of the compound. A brief hydrogenation of the antibiotic yielded a biologically active tetrahydro derivative, whereas extended hydrogenation produced an inactive primary amine. Mild alkaline hydrolysis and subsequent esterification of the antibiotic with diazomethane produced an inactive dimethyl ester. Apparently both the nitrile and the lactone functions are essential for the treponomycin molecule to show antimicrobial activity. The antibiotic showed inhibitory activity against several species of bacteria, especially Treponema hyodysenteriae, the causative agent of swine dysentery. In view of the oral 50% lethal dose of 400 mg/g and its low MIC against four stains of T.hyodysenteriae, the antibiotic may have value as a swine dysentery therapeutic.

Treponemycin, a nitrile antibiotic active against Treponema hyodysenteriae.

PubMed Central

Singh, S K; Gurusiddaiah, S; Whalen, J W

1985-01-01

Two strains of Streptomyces sp. (isolates 275 and 124) were isolated from soil samples collected from the fields around Lewiston, Idaho. Based on their cellular morphology and physiology, the two isolates were identified as Streptomyces albovinaceous. Both isolates produced an antibiotic when grown in liquid culture medium containing homogenized oats. The antibiotic (treponemycin) was isolated from the culture broth by solvent extraction and purified by silica gel column and preparative thin-layer chromatographies. Treponemycin is a crystalline light-yellow compound with an mp of 93 to 95 degrees C, levorotatory, and soluble in most organic solvents. It is sparingly soluble in water but insoluble in petroleum ether. On the basis of elemental analysis and mass spectral data, the molecular formula of the antibiotic was deduced to be C28H43O6N. The infrared spectrum of the antibiotic indicated the presence of unsaturation, nitrile, lactone, or ester or all three functions, and carbonyl functions in the molecule. A sharp infrared absorption band for nitrile at 2,220 cm-1 and the presence of an unsaturated group indicated that the nitrile function may be attached to an unsaturated carbon atom. The presence of dienenitrile functions was further supported by the UV absorption spectrum of the antibiotic, which gave a UVmax at 257 nm. The proton magnetic resonance spectrum of the antibiotic did not give any peak which could be exchanged with deuterated water, which is an indication of the absence of carboxylic and hydroxyl functions in the molecule. All of the functional groupings indicated by the infrared and UV spectra of the molecule were further confirmed by the 13C-magnetic resonance spectrum of the compound. A brief hydrogenation of the antibiotic yielded a biologically active tetrahydro derivative, whereas extended hydrogenation produced an inactive primary amine. Mild alkaline hydrolysis and subsequent esterification of the antibiotic with diazomethane produced an inactive dimethyl ester. Apparently both the nitrile and the lactone functions are essential for the treponomycin molecule to show antimicrobial activity. The antibiotic showed inhibitory activity against several species of bacteria, especially Treponema hyodysenteriae, the causative agent of swine dysentery. In view of the oral 50% lethal dose of 400 mg/g and its low MIC against four stains of T.hyodysenteriae, the antibiotic may have value as a swine dysentery therapeutic. Images PMID:3838636

Carbohydrate-Based Host-Guest Complexation of Hydrophobic Antibiotics for the Enhancement of Antibacterial Activity.

PubMed

Jeong, Daham; Joo, Sang-Woo; Shinde, Vijay Vilas; Cho, Eunae; Jung, Seunho

2017-08-08

Host-guest complexation with various hydrophobic drugs has been used to enhance the solubility, permeability, and stability of guest drugs. Physical changes in hydrophobic drugs by complexation have been related to corresponding increases in the bioavailability of these drugs. Carbohydrates, including various derivatives of cyclodextrins, cyclosophoraoses, and some linear oligosaccharides, are generally used as host complexation agents in drug delivery systems. Many antibiotics with low bioavailability have some limitations to their clinical use due to their intrinsically poor aqueous solubility. Bioavailability enhancement is therefore an important step to achieve the desired concentration of antibiotics in the treatment of bacterial infections. Antibiotics encapsulated in a complexation-based drug delivery system will display improved antibacterial activity making it possible to reduce dosages and overcome the serious global problem of antibiotic resistance. Here, we review the present research trends in carbohydrate-based host-guest complexation of various hydrophobic antibiotics as an efficient delivery system to improve solubility, permeability, stability, and controlled release.

Effects of pesticides and antibiotics on penaeid shrimp with special emphases on behavioral and biomarker responses.

PubMed

Tu, Huynh Thi; Silvestre, Frederic; Phuong, Nguyen Thanh; Kestemont, Patrick

2010-04-01

The purpose of the present study is to provide information on the current state of knowledge regarding the effects of pesticides and antibiotics used in aquaculture on penaeid shrimp, one of the most common aquatic products for human consumption, with a special emphasis on the use of behavioral, physiological, and biochemical response. These include behavior; feeding rate changes; respiration rate, oxygen consumption, and osmoregulation alterations; nucleic acids, protein, and glycogen synthesis; cholinesterase activity inhibition; ATPase activity; and oxidative stress responses. This paper also deals with residues of antibiotics and pesticides in penaeid shrimp. Antibiotics and pesticides used in aquaculture may have adverse effects on treated animals and human consumers health if they are not correctly used. As a complement to the measurement of antibiotic and pesticide residues in tissues, the use of behavioral and biomarker responses can provide more relevant biological information on the potential adverse effects of antibiotics and pesticides on penaeid shrimp health. (c) 2009 SETAC.

Essential Oils and Their Components as Modulators of Antibiotic Activity against Gram-Negative Bacteria

PubMed Central

Aelenei, Petruta; Miron, Anca; Trifan, Adriana; Bujor, Alexandra; Gille, Elvira; Aprotosoaie, Ana Clara

2016-01-01

Gram-negative bacteria cause infections that are difficult to treat due to the emergence of multidrug resistance. This review summarizes the current status of the studies investigating the capacity of essential oils and their components to modulate antibiotic activity against Gram-negative bacteria. Synergistic interactions are particularly discussed with reference to possible mechanisms by which essential oil constituents interact with antibiotics. Special emphasis is given to essential oils and volatile compounds that inhibit efflux pumps, thus reversing drug resistance in Gram-negative bacteria. In addition, indifference and antagonism between essential oils/volatile compounds and conventional antibiotics have also been reported. Overall, this literature review reveals that essential oils and their purified components enhance the efficacy of antibiotics against Gram-negative bacteria, being promising candidates for the development of new effective formulations against Gram-negative bacteria. PMID:28930130

Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs

PubMed Central

Munguia, Jason; Nizet, Victor

2017-01-01

The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies “outside-the-box” of current antibiotic paradigms. PMID:28283200

Performance evaluation of powdered activated carbon for removing 28 types of antibiotics from water.

PubMed

Zhang, Xinbo; Guo, Wenshan; Ngo, Huu Hao; Wen, Haitao; Li, Nan; Wu, Wei

2016-05-01

Currently, the occurrence and fate of antibiotics in the aquatic environment has become a very serious problem in that they can potentially and irreversibly damage the ecosystem and human health. For this reason, interest has increased in developing strategies to remove antibiotics from water. This study evaluated the performance of powdered activated carbon (PAC) in removing from water 6 representative groups of 28 antibiotics, namely Tetracyclines (TCs), Macrolides (MCs), Chloramphenicols (CPs), Penicillins (PNs), Sulfonamides (SAs) and Quinolones (QNs). Results indicate that PAC demonstrated superior adsorption capacity for all selected antibiotics. The removal efficiency was up to 99.9% in deionized water and 99.6% in surface water at the optimum conditions with PAC dosage of 20 mg/L and contact time of 120 min. According to the Freundlich model's adsorption isotherm, the values of n varied among these antibiotics and most were less than 1, suggesting that the adsorption of antibiotics onto PAC was nonlinear. Adsorption of antibiotics followed well the pseudo-second-order kinetic model (R(2) = 0.99). Analysis using the Weber-Morris model revealed that the intra-particle diffusion was not the only rate-controlling step. Overall, the findings in this study confirm that PAC is a feasible and viable option for removing antibiotics from water in terms of water quality improvement and urgent antibiotics pollution control. Further research is essential on the following subjects: (i) removing more types of antibiotics by PAC; (ii) the adsorption process; and (iii) the mechanism of the competitive adsorption existing between natural organic matters (NOMs) and antibiotics. Copyright © 2016 Elsevier Ltd. All rights reserved.

Update of the Preventive Antibiotics in Stroke Study (PASS): statistical analysis plan.

PubMed

Westendorp, Willeke F; Vermeij, Jan-Dirk; Dippel, Diederik W J; Dijkgraaf, Marcel G W; van der Poll, Tom; Prins, Jan M; Vermeij, Frederique H; Roos, Yvo B W E M; Brouwer, Matthijs C; Zwinderman, Aeilko H; van de Beek, Diederik; Nederkoorn, Paul J

2014-10-01

Infections occur in 30% of stroke patients and are associated with unfavorable outcomes. Preventive antibiotic therapy lowers the infection rate after stroke, but the effect of preventive antibiotic treatment on functional outcome in patients with stroke is unknown. The PASS is a multicenter, prospective, phase three, randomized, open-label, blinded end-point (PROBE) trial of preventive antibiotic therapy in acute stroke. Patients are randomly assigned to either ceftriaxone at a dose of 2 g, given every 24 h intravenously for 4 days, in addition to standard stroke-unit care, or standard stroke-unit care without preventive antibiotic therapy. The aim of this study is to assess whether preventive antibiotic treatment improves functional outcome at 3 months by preventing infections. This paper presents in detail the statistical analysis plan (SAP) of the Preventive Antibiotics in Stroke Study (PASS) and was submitted while the investigators were still blinded for all outcomes. The primary outcome is the score on the modified Rankin Scale (mRS), assessed by ordinal logistic regression analysis according to a proportional odds model. Secondary analysis of the primary outcome is the score on the mRS dichotomized as a favorable outcome (mRS 0 to 2) versus unfavorable outcome (mRS 3 to 6). Secondary outcome measures are death rate at discharge and 3 months, infection rate during hospital admission, length of hospital admission, volume of post-stroke care, use of antibiotics during hospital stay, quality-adjusted life years and costs. Complications of treatment, serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) are reported as safety outcomes. The data from PASS will establish whether preventive antibiotic therapy in acute stroke improves functional outcome by preventing infection and will be analyzed according to this pre-specified SAP. Current controlled trials; ISRCTN66140176. Date of registration: 6 April 2010.

Use of radioimmunoassay as a screen for antibiotics in confined animal feeding operations and confirmation by liquid chromatography/mass spectrometry

USGS Publications Warehouse

Meyer, M.T.; Bumgarner, J.E.; Varns, J.L.; Daughtridge, J.V.; Thurman, E.M.; Hostetler, K.A.

2000-01-01

Approximately one-half of the 50 000000 lb of antibiotics produced in the USA are used in agriculture. Because of the intensive use of antibiotics in the management of confined livestock operations, the potential exists for the transport of these compounds and their metabolites into our nation's water resources. A commercially available radioimmunoassay method, developed as a screen for tetracycline antibiotics in serum, urine, milk, and tissue, was adapted to analyze water samples at a detection level of approximately 1.0 ppb and a semiquantitative analytical range of 1-20 ppb. Liquid waste samples were obtained from 13 hog lagoons in three states and 52 surface- and ground-water samples were obtained primarily from areas associated with intensive swine and poultry production in seven states. These samples were screened for the tetracycline antibiotics by using the modified radioimmunoassay screening method. The radioimmunoassay tests yielded positive results for tetracycline antibiotics in samples from all 13 of the hog lagoons. Dilutions of 10-100-fold of the hog lagoon samples indicated that tetracycline antibiotic concentrations ranged from approximately 5 to several hundred parts per billion in liquid hog lagoon waste. Of the 52 surface- and ground-water samples collected all but two tested negative and these two samples contained tetracycline antibiotic concentrations less than 1 ppb. A new liquid chromatography/mass spectrometry method was used to confirm the radioimmunoassay results in 9 samples and also to identify the tetracycline antibiotics to which the radioimmunoassay test was responding. The new liquid chromatography/mass spectrometry method with online solid-phase extraction and a detection level of 0.5 ??g/l confirmed the presence of chlorotetracycline in the hog lagoon samples and in one of the surface-water samples. The concentrations calculated from the radioimmunoassay were a factor of 1-5 times less than those calculated by the liquid chromatography/mass spectrometry concentrations for chlorotetracycline. Copyright (C) 2000 Elsevier Science B.V.

A DELPHI STUDY OF RISK FACTORS FOR ACHILLES TENDINOPATHY- OPINIONS OF WORLD TENDON EXPERTS

PubMed Central

Watson, Paul J.; Barry, Simon

2016-01-01

Background and Purpose Achilles tendinopathy can be a debilitating chronic condition for both active and inactive individuals. The identification of risk facors is important both in preventing but also treating tendinopathy, many factors have been proposed but there is a lack of primary epidemiological data. The purpose of this study was to develop a statement of expert consensus on risk factors for Achilles tendinopathy in active and sedentary patient populations to inform a primary epidemiological study. Study design Delphi study Methods and Measures An online Delphi study was completed inviting participation from world tendon experts. The consensus was developed using three rounds of the Delphi technique. The first round developed a complete list of potential risk factors, the second round refined this list but also separated the factors into two population groups – active/athletic and inactive/sedentary. The third round ranked this list in order of perceived importance. Results Forty-four experts were invited to participate, 16 participated in the first round (response rate 40%) and two dropped out in the second round (resulting in a response rate of 35%). A total of 27 intrinsic and eight extrinsic risk factors were identified during round one. During round two only 12 intrinsic and five extrinsic risk factors were identified as important in active/athletic tendinopathy while 14 intrinsic and three extrinsic factors were identified as important for inactive/sedentary tendinopathy. Conclusions Risk factors for Achilles tendinopathy were identified based on expert consensus, and these factors provide a basis for primary epidemiological studies. Plantarflexor strength was identified as the primary modifiable factor in the active/athletic group while systemic factors were identified as important in the inactive/sedentary group, many of the potential factors suggested for either group were non-modifiable. Non-modifiable factors include: previous tendinopathy, previous injury, advancing age, sex, steroid exposure, and antibiotic treatment. Level of evidence Level V PMID:27757281

Fosfomycin

PubMed Central

Vouloumanou, Evridiki K.; Samonis, George; Vardakas, Konstantinos Z.

2016-01-01

SUMMARY The treatment of bacterial infections suffers from two major problems: spread of multidrug-resistant (MDR) or extensively drug-resistant (XDR) pathogens and lack of development of new antibiotics active against such MDR and XDR bacteria. As a result, physicians have turned to older antibiotics, such as polymyxins, tetracyclines, and aminoglycosides. Lately, due to development of resistance to these agents, fosfomycin has gained attention, as it has remained active against both Gram-positive and Gram-negative MDR and XDR bacteria. New data of higher quality have become available, and several issues were clarified further. In this review, we summarize the available fosfomycin data regarding pharmacokinetic and pharmacodynamic properties, the in vitro activity against susceptible and antibiotic-resistant bacteria, mechanisms of resistance and development of resistance during treatment, synergy and antagonism with other antibiotics, clinical effectiveness, and adverse events. Issues that need to be studied further are also discussed. PMID:26960938

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin.

PubMed

Mor, Felix; Cohen, Irun R

2013-02-19

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell-mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.

Occurrence, distribution, and potential sources of antibiotics pollution in the water-sediment of the northern coastline of the Persian Gulf, Iran.

PubMed

Kafaei, Raheleh; Papari, Fatemeh; Seyedabadi, Mohammad; Sahebi, Soleyman; Tahmasebi, Rahim; Ahmadi, Mehdi; Sorial, George A; Asgari, Ghorban; Ramavandi, Bahman

2018-06-15

Occurrence and frequency of six most prescribed antibiotics (tetracycline, norfloxacin, azithromycin, anhydro erythromycin, cephalexin, and amoxicillin) were assessed in three wastewater treatment plants (WWTPs), and in water and sediments of the Persian Gulf at Bushehr coastline, Iran. The antibiotics concentration in the influent and effluent of septic tank (the hospital WWTP), activated sludge (the hospital WWTP), and stabilization pond (municipal WWTP) ranged between 7.89 and 149.63, 13.49-198.47, 6.55-16.37 ng/L, respectively. Conventional treatment resulted in incomplete removal of most of the studied antibiotics. Furthermore, the activated sludge was more effective in terms of antibiotic elimination compared to the stabilization pond or septic tank. The mean concentration of antibiotics ranged 1.21-51.50 ng/L in seawater and 1.40-25.32 ng/g in sediments during summer and winter. Norfloxacin was the dominant detected antibiotic in seawater, sediments, and influent of two hospital WWTPs. Seasonal comparisons showed significant differences for erythromycin and amoxicillin concentrations in seawater. Spatial variation indicated the role of physicochemical properties on distribution of antibiotics in seawater and sediments. The results emphasize the need to pay attention to antibiotic contamination in water and sediments of the Persian Gulf. Copyright © 2018 Elsevier B.V. All rights reserved.

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis

PubMed Central

Coupet, Charles-Antoine; Gouanvic, Marie; Schmitt, Doris; Ray, Aurélie; Hoffmann, Chantal; Schultz, Huguette; Tyagi, Sandeep; Soni, Heena; Converse, Paul J.; Arias, Lilibeth; Kleinpeter, Patricia; Sansas, Benoît; Mdluli, Khisimuzi; Vilaplana, Cristina; Cardona, Pere-Joan; Nuermberger, Eric; Marchand, Jean-Baptiste; Silvestre, Nathalie; Inchauspé, Geneviève

2018-01-01

Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host’s immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections. PMID:29718990

A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis.

PubMed

Leung-Theung-Long, Stéphane; Coupet, Charles-Antoine; Gouanvic, Marie; Schmitt, Doris; Ray, Aurélie; Hoffmann, Chantal; Schultz, Huguette; Tyagi, Sandeep; Soni, Heena; Converse, Paul J; Arias, Lilibeth; Kleinpeter, Patricia; Sansas, Benoît; Mdluli, Khisimuzi; Vilaplana, Cristina; Cardona, Pere-Joan; Nuermberger, Eric; Marchand, Jean-Baptiste; Silvestre, Nathalie; Inchauspé, Geneviève

2018-01-01

Despite the existence of the prophylactic Bacille Calmette-Guérin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host's immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections.

Factors Which Influence Synergism by Neomycin and Oxytetracycline

PubMed Central

Williams, B. J.

1971-01-01

Six strains of enteropathogenic gram-negative bacteria were tested for susceptibility to neomycin or oxytetracycline alone and combined in fixed ratios. The minimal inhibitory concentration for the combination was less than one-half of that expected if the antibiotic activities were simply additive. Neomycin alone was more effective against bacteria multiplying in the presence of abundant oxygen, whereas oxytetracycline alone was more effective against bacteria multiplying in relatively anaerobic environments; when combined, the antibiotics complemented each other by their opposing optima for activity. Oxygen concentration, pH, and neomycin activity are related, and the depression of acid production by oxytetracycline is believed to be partially responsible for the synergistic activity of this pair of antibiotics. Images PMID:4930276

Staffing for infectious diseases, clinical microbiology and infection control in hospitals in 2015: results of an ESCMID member survey.

PubMed

Dickstein, Y; Nir-Paz, R; Pulcini, C; Cookson, B; Beović, B; Tacconelli, E; Nathwani, D; Vatcheva-Dobrevska, R; Rodríguez-Baño, J; Hell, M; Saenz, H; Leibovici, L; Paul, M

2016-09-01

We aimed to assess the current status of infectious diseases (ID), clinical microbiology (CM) and infection control (IC) staffing in hospitals and to analyse modifiers of staffing levels. We conducted an Internet-based survey of European Society of Clinical Microbiology and Infectious Diseases members and affiliates, collecting data on hospital characteristics, ID management infrastructure, ID/IC-related activities and the ratio of physicians per 100 hospital beds. Regression analyses were conducted to examine factors associated with the physician-bed ratio. Five hundred sixty-seven hospital responses were collected between April and June 2015 from 61 countries, 81.2% (384/473) from Europe. A specialized inpatient ward for ID patients was reported in 58.4% (317/543) of hospitals. Rates of antibiotic stewardship programmes (ASP) and surveillance activities in survey hospitals were high, ranging from 88% to 90% for local antibiotic guidelines and 70% to 82% for programmes monitoring hospital-acquired infections. The median ID/CM/IC physician per 100 hospital beds ratio was 1.12 (interquartile range 0.56-2.13). In hospitals performing basic ASP and IC (including local antibiotic guidelines and monitoring device-related or surgical site infections), the ratio was 1.21 (interquartile range 0.57-2.14). Factors independently associated with higher ratios included compliance with European Union of Medical Specialists standards, smaller hospital size, tertiary-care institution, presence of a travel clinic, beds dedicated to ID and a CM unit. More than half of respondents estimated that additional staffing is needed for appropriate IC or ID management. No standard of physician staffing for ID/CM/IC in hospitals is available. A ratio of 1.21/100 beds will serve as an informed point of reference enabling ASP and infection surveillance. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Advances in macrocyclic peptide-based antibiotics.

PubMed

Luther, Anatol; Bisang, Christian; Obrecht, Daniel

2018-06-01

Macrocyclic peptide-based natural products have provided powerful new antibiotic drugs, drug candidates, and scaffolds for medicinal chemists as a source of inspiration to design novel antibiotics. While most of those natural products are active mainly against Gram-positive pathogens, novel macrocyclic peptide-based compounds have recently been described, which exhibit potent and specific activity against some of the most problematic Gram-negative ESKAPE pathogens. This mini-review gives an up-date on recent developments. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antibacterial properties of Chinese herbal medicines against nosocomial antibiotic resistant strains of Pseudomonas aeruginosa in Taiwan.

PubMed

Liu, Ching-Shen; Cham, Thau-Ming; Yang, Cheng-Hong; Chang, Hsueh-Wei; Chen, Chia-Hong; Chuang, Li-Yeh

2007-01-01

Pseudomonas aeruginosa is well-recognized as a nosocomial pathogen, which exhibits inherent drug resistance. In this study, the antibacterial activity of ethanol extracts of 58 Chinese herbal medicines used in Taiwan were tested against 89 nosocomial antibiotic resistant strains of Pseudomonas aeruginosa. The results gathered by the disc diffusion method showed that 26 out of the 58 herbal extracts exhibited antibacterial activity. Among the 26 herbal extracts, 10 extracts showed broad-spectrum antibacterial activities and were selected for further antibacterial property assay. The minimum inhibitory concentrations (MIC) of the active partition fractions ranged from 0.25 to 11.0 mg/L. The presence of flavonoid compounds in the active fractions of test herbal extracts was observed by the TLC-bioautography. The results from the time-kill assay revealed that most of the herbal extracts completely killed the test organisms within 4 hours. Exposure of the test strains to a sub-MIC level of the herbal extracts for 10 consecutive subcultures did not induce resistance to the active components. A combination of the active herbal fractions with antibiotics showed that one of the herbal medicines, the hexane fraction of Ramulus Cinnamomi, possessed a synergistic effect with tetracycline, gentamycin, and streptomycin. In conclusion, the tested Chinese medical herbs have the potential to be developed into natural antibiotics. This is the first evaluation for screening large amounts of medical plants against nosocomial antibiotic resistant bacteria in Taiwan.

A Simple Assay to Screen Antimicrobial Compounds Potentiating the Activity of Current Antibiotics

PubMed Central

Iqbal, Junaid; Kazmi, Shahana Urooj; Khan, Naveed Ahmed

2013-01-01

Antibiotic resistance continues to pose a significant problem in the management of bacterial infections, despite advances in antimicrobial chemotherapy and supportive care. Here, we suggest a simple, inexpensive, and easy-to-perform assay to screen antimicrobial compounds from natural products or synthetic chemical libraries for their potential to work in tandem with the available antibiotics against multiple drug-resistant bacteria. The aqueous extract of Juglans regia tree bark was tested against representative multiple drug-resistant bacteria in the aforementioned assay to determine whether it potentiates the activity of selected antibiotics. The aqueous extract of J. regia bark was added to Mueller-Hinton agar, followed by a lawn of multiple drug-resistant bacteria, Salmonella typhi or enteropathogenic E. coli. Next, filter paper discs impregnated with different classes of antibiotics were placed on the agar surface. Bacteria incubated with extract or antibiotics alone were used as controls. The results showed a significant increase (>30%) in the zone of inhibition around the aztreonam, cefuroxime, and ampicillin discs compared with bacteria incubated with the antibiotics/extract alone. In conclusion, our assay is able to detect either synergistic or additive action of J. regia extract against multiple drug-resistant bacteria when tested with a range of antibiotics. PMID:23865073

Neutral β-Lactams Inactivate High Molecular Mass Penicillin-Binding Proteins of Class B1, Including PBP2a of MRSA.

PubMed

Dave, Kinjal; Palzkill, Timothy; Pratt, R F

2014-02-13

The targets of β-lactam antibiotics are bacterial DD-peptidases (penicillin-binding proteins). β-Lactam SAR studies over many years have demonstrated the importance of a specifically placed negative charge, usually carboxylate, on these molecules. We show here that neutral analogues of classical β-lactam antibiotics are of comparable activity to the originals against β-lactam-resistant high molecular mass DD-peptidases of the B1 class, a group that includes PBP2a of methicillin-resistant Staphylococcus aureus. These neutral β-lactams may direct new development of antibiotics against certain penicillin-resistant bacteria. These molecules do have antibiotic activity against Gram-positive bacteria.

Sorption and biodegradation of sulfonamide antibiotics by activated sludge: experimental assessment using batch data obtained under aerobic conditions.

PubMed

Yang, Sheng-Fu; Lin, Cheng-Fang; Lin, Angela Yu-Chen; Hong, Pui-Kwan Andy

2011-05-01

This study investigated the adsorption, desorption, and biodegradation characteristics of sulfonamide antibiotics in the presence of activated sludge with and without being subjected to NaN(3) biocide. Batch experiments were conducted and the relative contributions of adsorption and biodegradation to the observed removal of sulfonamide antibiotics were determined. Three sulfonamide antibiotics including sulfamethoxazole (SMX), sulfadimethoxine (SDM), and sulfamonomethoxine (SMM), which had been detected in the influent and the activated sludge of wastewater treatment plants (WWTP) in Taiwan, were selected for this study. Experimental results showed that the antibiotic compounds were removed via sorption and biodegradation by the activated sludge, though biodegradation was inhibited in the first 12 h possibly due to competitive inhibition of xenobiotic oxidation by readily biodegradable substances. The affinity of sulfonamides to sterilized sludge was in the order of SDM > SMM > SMX. The sulfonamides existed predominantly as anions at the study pH of 6.8, which resulted in a low level of adsorption to the activated sludge. The adsorption/desorption isotherms were of a linear form, as well described by the Freundlich isotherm with the n value approximating unity. The linear distribution coefficients (K(d)) were determined from batch equilibrium experiments with values of 28.6 ± 1.9, 55.7 ± 2.2, and 110.0 ± 4.6 mL/g for SMX, SMM, and SDM, respectively. SMX, SMM, and SDM desorb reversibly from the activated sludge leaving behind on the solids 0.9%, 1.6%, and 5.2% of the original sorption dose of 100 μg/L. The sorbed antibiotics can be introduced into the environment if no further treatments were employed to remove them from the biomass. Copyright © 2011 Elsevier Ltd. All rights reserved.

Mapping the resistance-associated mobilome of a carbapenem-resistant Klebsiella pneumoniae strain reveals insights into factors shaping these regions and facilitates generation of a 'resistance-disarmed' model organism.

PubMed

Bi, Dexi; Jiang, Xiaofei; Sheng, Zi-Ke; Ngmenterebo, David; Tai, Cui; Wang, Minggui; Deng, Zixin; Rajakumar, Kumar; Ou, Hong-Yu

2015-10-01

This study aims to investigate the landscape of the mobile genome, with a focus on antibiotic resistance-associated factors in carbapenem-resistant Klebsiella pneumoniae. The mobile genome of the completely sequenced K. pneumoniae HS11286 strain (an ST11, carbapenem-resistant, near-pan-resistant, clinical isolate) was annotated in fine detail. The identified mobile genetic elements were mapped to the genetic contexts of resistance genes. The blaKPC-2 gene and a 26 kb region containing 12 clustered antibiotic resistance genes and one biocide resistance gene were deleted, and the MICs were determined again to ensure that antibiotic resistance had been lost. HS11286 contains six plasmids, 49 ISs, nine transposons, two separate In2-related integron remnants, two integrative and conjugative elements (ICEs) and seven prophages. Sixteen plasmid-borne resistance genes were identified, 14 of which were found to be directly associated with Tn1721-, Tn3-, Tn5393-, In2-, ISCR2- and ISCR3-derived elements. IS26 appears to have actively moulded several of these genetic regions. The deletion of blaKPC-2, followed by the deletion of a 26 kb region containing 12 clustered antibiotic resistance genes, progressively decreased the spectrum and level of resistance exhibited by the resultant mutant strains. This study has reiterated the role of plasmids as bearers of the vast majority of resistance genes in this species and has provided valuable insights into the vital role played by ISs, transposons and integrons in shaping the resistance-coding regions in this important strain. The 'resistance-disarmed' K. pneumoniae ST11 strain generated in this study will offer a more benign and readily genetically modifiable model organism for future extensive functional studies. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The Intestinal Microbiome and Health

PubMed Central

Tuddenham, Susan; Sears, Cynthia L.

2015-01-01

Purpose of Review A diverse array of microbes colonizes the human intestine. In this review we seek to outline the current state of knowledge on what characterizes a “healthy” or “normal” intestinal microbiome, what factors modify the intestinal microbiome in the healthy state and how the intestinal microbiome affects normal host physiology Recent Findings What constitutes a “normal” or “healthy” intestinal microbiome is an area of active research, but key characteristics may include diversity, richness and a microbial community’s resilience and ability to resist change. A number of factors, including age, the host immune system, host genetics, diet and antibiotic use appear to modify the intestinal microbiome in the normal state. New research shows that the microbiome likely plays a critical role in the healthy human immune system and metabolism. Summary It is clear that there is a complicated bi-directional relationship between the intestinal microbiota and host which is vital to health. An enhanced understanding of this relationship will be critical not only to maximize and maintain human health but also to shape our understanding of disease and to foster new therapeutic approaches. PMID:26237547

Development of new antibiotics: taking off finally?

PubMed

Bettiol, Esther; Harbarth, Stephan

2015-01-01

Since 2010, awareness of the global threat caused by antimicrobial resistance (AMR) has risen considerably and multiple policy and research initiatives have been implemented. Research and development (R&D) of much-needed new antibiotics active against multiresistant pathogens is a key component of all programmes aiming at fighting AMR, but it has been lagging behind owing to scientific, regulatory and economic challenges. Although a few new antibiotics might be available in Switzerland in the next 5 years, these new agents are not based on new mechanisms of action and are not necessarily active against resistant pathogens for which there is the highest unmet medical need, i.e. multiresistant Gram-negative bacteria. Of the three new antibiotics with pending authorisation in Switzerland for systemic treatment of severe infections, oritavancin and tedizolid target Gram-positive pathogens, while only ceftolozane+tazobactam partially covers multiresistant Gram-negative pathogens. Among six antibiotics currently in phase III of clinical development, delafloxacin and solithromycin will also be useful mostly for Gram-positive infections. Importantly, the four other compounds are active against multiresistant Gram-negative pathogens: ceftazidime+avibactam, meropenem+RPX7009, eravacycline and plazomicin. The three last compounds are also active against carbapenem-resistant Enterobacteriaceae (CRE). A few compounds active against such pathogens are currently in earlier clinical development, but their number may decrease, considering the risk of failure over the course of clinical development. At last, through public and political awareness of pathogens with high public health impact and unmet medical need, development of innovative economic incentives and updated regulatory guidance, R&D of new antibiotics is slowly taking off again.

Development of Diazaquinomycin Class Antibiotics for the Treatment of Drug-Resistant TB Infections

DTIC Science & Technology

2016-10-01

exhibited weak antibacterial activity by targeting thymidylate synthase, though no reports of their anti-TB activity existed and our studies have suggested...Murphy, B. T. Diaza-anthracene antibiotics from a freshwater-derived actinomycete with selective antibacterial activity toward M. tuberculosis. ACS Inf...freshwater-derived actinomycete with selective antibacterial activity toward M. tuberculosis. ACS Infectious Diseases, 2015. 1: p. 168-174. (17) Mullowney

Preventing Ototoxic Synergy of Prior Noise Trauma during Aminoglycoside Therapy

DTIC Science & Technology

2017-06-01

with aminoglycoside antibiotics that have broad-spectrum bactericidal activity for treating or preventing life-threatening infections. However...with aminoglycoside antibiotics that have broad- spectrum bactericidal activity for treating or preventing life-threatening infections. However...aminoglycoside uptake. What was accomplished under these goals? 1) Major activities Due to lab relocation, the project was interrupted in 2015, and

Methanobactin: a copper binding compound having antibiotic and antioxidant activity isolated from methanotrophic bacteria

DOEpatents

DiSpirito, Alan A [Ames, IA; Zahn, James A [Harbor Beach, MI; Graham, David W [Lawrence, KS; Kim, Hyung J [St. Paul, MN; Alterman, Michail [Lawrence, KS; Larive, Cynthia [Lawrence, KS

2007-04-03

A means and method for treating bacterial infection, providing antioxidant activity, and chelating copper using a copper binding compound produced by methanotrophic bacteria is described. The compound, known as methanobactin, is the first of a new class of antibiotics having gram-positive activity. Methanobactin has been sequenced, and its structural formula determined.

OXIDATION OF ANTIBIOTICS IN WASTEWATER: IDENTIFYING PRODUCTS AND IMPACTS ON ANTIBACTERIAL ACTIVITY

EPA Science Inventory

It is hypothesized that advanced oxidation can be applied effectively and in an economically responsible manner for the removal of the antibacterial activity of antibiotics. Ultimately, this study will develop a set of recommendations for the application of advanced oxidation ...

Antibacterial Activity of Ciprofloxacin-Encapsulated Cockle Shells Calcium Carbonate (Aragonite) Nanoparticles and Its Biocompatability in Macrophage J774A.1

PubMed Central

Isa, Tijani; Zakaria, Zuki Abu Bakar; Rukayadi, Yaya; Mohd Hezmee, Mohd Noor; Jaji, Alhaji Zubair; Imam, Mustapha Umar; Hammadi, Nahidah Ibrahim; Mahmood, Saffanah Khuder

2016-01-01

The use of nanoparticle delivery systems to enhance intracellular penetration of antibiotics and their retention time is becoming popular. The challenge, however, is that the interaction of nanoparticles with biological systems at the cellular level must be established prior to biomedical applications. Ciprofloxacin–cockle shells-derived calcium carbonate (aragonite) nanoparticles (C-CSCCAN) were developed and characterized. Antibacterial activity was determined using a modified disc diffusion protocol on Salmonella Typhimurium (S. Typhimurium). Biocompatibilittes with macrophage were evaluated using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Bromo-2′-deoxyuridine (BrdU) assays. Transcriptional regulation of interleukin 1 beta (IL-1β) was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). C-CSCCAN were spherical in shape, with particle sizes ranging from 11.93 to 22.12 nm. Encapsulation efficiency (EE) and loading content (LC) were 99.5% and 5.9%, respectively, with negative ζ potential. X-ray diffraction patterns revealed strong crystallizations and purity in the formulations. The mean diameter of inhibition zone was 18.6 ± 0.5 mm, which was better than ciprofloxacin alone (11.7 ± 0.9 mm). Study of biocompatability established the cytocompatability of the delivery system without upregulation of IL-1β. The results indicated that ciprofloxacin–nanoparticles enhanced the antibacterial efficacy of the antibiotic, and could act as a suitable delivery system against intracellular infections. PMID:27213349

Antibacterial Activity of Ciprofloxacin-Encapsulated Cockle Shells Calcium Carbonate (Aragonite) Nanoparticles and Its Biocompatability in Macrophage J774A.1.

PubMed

Isa, Tijani; Zakaria, Zuki Abu Bakar; Rukayadi, Yaya; Mohd Hezmee, Mohd Noor; Jaji, Alhaji Zubair; Imam, Mustapha Umar; Hammadi, Nahidah Ibrahim; Mahmood, Saffanah Khuder

2016-05-19

The use of nanoparticle delivery systems to enhance intracellular penetration of antibiotics and their retention time is becoming popular. The challenge, however, is that the interaction of nanoparticles with biological systems at the cellular level must be established prior to biomedical applications. Ciprofloxacin-cockle shells-derived calcium carbonate (aragonite) nanoparticles (C-CSCCAN) were developed and characterized. Antibacterial activity was determined using a modified disc diffusion protocol on Salmonella Typhimurium (S. Typhimurium). Biocompatibilittes with macrophage were evaluated using the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5-Bromo-2'-deoxyuridine (BrdU) assays. Transcriptional regulation of interleukin 1 beta (IL-1β) was determined using reverse transcriptase-polymerase chain reaction (RT-PCR). C-CSCCAN were spherical in shape, with particle sizes ranging from 11.93 to 22.12 nm. Encapsulation efficiency (EE) and loading content (LC) were 99.5% and 5.9%, respectively, with negative ζ potential. X-ray diffraction patterns revealed strong crystallizations and purity in the formulations. The mean diameter of inhibition zone was 18.6 ± 0.5 mm, which was better than ciprofloxacin alone (11.7 ± 0.9 mm). Study of biocompatability established the cytocompatability of the delivery system without upregulation of IL-1β. The results indicated that ciprofloxacin-nanoparticles enhanced the antibacterial efficacy of the antibiotic, and could act as a suitable delivery system against intracellular infections.

Targeting Antibacterial Agents by Using Drug-Carrying Filamentous Bacteriophages

PubMed Central

Yacoby, Iftach; Shamis, Marina; Bar, Hagit; Shabat, Doron; Benhar, Itai

2006-01-01

Bacteriophages have been used for more than a century for (unconventional) therapy of bacterial infections, for half a century as tools in genetic research, for 2 decades as tools for discovery of specific target-binding proteins, and for nearly a decade as tools for vaccination or as gene delivery vehicles. Here we present a novel application of filamentous bacteriophages (phages) as targeted drug carriers for the eradication of (pathogenic) bacteria. The phages are genetically modified to display a targeting moiety on their surface and are used to deliver a large payload of a cytotoxic drug to the target bacteria. The drug is linked to the phages by means of chemical conjugation through a labile linker subject to controlled release. In the conjugated state, the drug is in fact a prodrug devoid of cytotoxic activity and is activated following its dissociation from the phage at the target site in a temporally and spatially controlled manner. Our model target was Staphylococcus aureus, and the model drug was the antibiotic chloramphenicol. We demonstrated the potential of using filamentous phages as universal drug carriers for targetable cells involved in disease. Our approach replaces the selectivity of the drug itself with target selectivity borne by the targeting moiety, which may allow the reintroduction of nonspecific drugs that have thus far been excluded from antibacterial use (because of toxicity or low selectivity). Reintroduction of such drugs into the arsenal of useful tools may help to combat emerging bacterial antibiotic resistance. PMID:16723570

Characterizing the structure-function relationship reveals the mode of action of a novel antimicrobial peptide, P1, from jumper ant Myrmecia pilosula.

PubMed

Tseng, Tien-Sheng; Tsai, Keng-Chang; Chen, Chinpan

2017-06-01

Microbial infections of antibiotic-resistant strains cause serious diseases and have a significant impact on public health worldwide, so novel antimicrobial drugs are urgently needed. Insect venoms, a rich source of bioactive components containing antimicrobial peptides (AMPs), are attractive candidates for new therapeutic agents against microbes. Recently, a novel peptide, P1, identified from the venom of the Australian jumper ant Myrmecia pilosula, showed potent antimicrobial activities against both Gram-negative and Gram-positive bacteria, but its structure-function relationship is unknown. Here, we used biochemical and biophysical techniques coupled with computational simulations to explore the mode of action of P1 interaction with dodecylphosphocholine (DPC) micelles as a model membrane system. Our circular dichroism (CD) and NMR studies revealed an amphipathic α-helical structure for P1 upon interaction with DPC micelles. A paramagnetic relaxation enhancement approach revealed that P1 orients its α-helix segment (F6-G14) into DPC micelles. In addition, the α-helix segment could be essential for membrane permeabilization and antimicrobial activity. Moreover, the arginine residues R8, R11, and R15 significantly contribute to helix formation and membrane-binding affinity. The lysine residue K19 of the C-terminus functionally guides P1 to interact with DPC micelles in the early interaction stage. Our study provides insights into the mode of action of P1, which is valuable in modifying and developing potent AMPs as antibiotic drugs.

[Strategy for choosing antibiotics for treating bacterial infections associated with chronic tick-borne encephalitis].

PubMed

Malenko, G V; Pogodina, V V; Frolova, M P; Ivannikova, T A

1996-01-01

The capacity of wide-spectrum antibiotics kefzol and ristomycin to activate the persisting tick-borne encephalitis (TBE) virus and cause an exacerbation of chronic process was investigated in Syrian hamsters in whom a prolonged (77 to 270 days) persistent TBE infection was induced by three TBE strains: Vasilchenko, V-383, and 205. The degree of antibiotic-induced activation was assessed using the criteria characterizing the reproduction and peculiarities of persisting TBE virus, immunodepression, and morphologic changes in the central nervous system. Effects of kefzol and ristomycin were compared with those of 8 antibiotics studied previously. Ristomycin, levomycetin (chloramphycin), penicillin, ampicillin (ampital), and levoridan were referred to drugs devoid of evident provoking effect. Kefzol (cefamezin), florimycin (viomycin), and kanamycin (kanamytrex) were characterized as weak activators and streptomycin and tetracycline as potent activators of the persisting TBE virus. These data may be used when selecting alternative agents for therapy of secondary bacterial infections concomitant with TBE.

Computer-Aided Drug Design Methods.

PubMed

Yu, Wenbo; MacKerell, Alexander D

2017-01-01

Computational approaches are useful tools to interpret and guide experiments to expedite the antibiotic drug design process. Structure-based drug design (SBDD) and ligand-based drug design (LBDD) are the two general types of computer-aided drug design (CADD) approaches in existence. SBDD methods analyze macromolecular target 3-dimensional structural information, typically of proteins or RNA, to identify key sites and interactions that are important for their respective biological functions. Such information can then be utilized to design antibiotic drugs that can compete with essential interactions involving the target and thus interrupt the biological pathways essential for survival of the microorganism(s). LBDD methods focus on known antibiotic ligands for a target to establish a relationship between their physiochemical properties and antibiotic activities, referred to as a structure-activity relationship (SAR), information that can be used for optimization of known drugs or guide the design of new drugs with improved activity. In this chapter, standard CADD protocols for both SBDD and LBDD will be presented with a special focus on methodologies and targets routinely studied in our laboratory for antibiotic drug discoveries.

Antibacterial activities of metabolites from Platanus occidentalis (American sycamore) against fish pathogenic bacteria

USDA-ARS?s Scientific Manuscript database

One approach to the management of common fish diseases in aquaculture is the use of antibiotic-laden feed. However, there are public concerns about the use of antibiotics in agriculture and the potential development of antibiotic resistant bacteria. Therefore, the discovery of other environmentall...

Polyphenolic Extract from Maple Syrup Potentiates Antibiotic Susceptibility and Reduces Biofilm Formation of Pathogenic Bacteria

PubMed Central

Maisuria, Vimal B.; Hosseinidoust, Zeinab

2015-01-01

Phenolic compounds are believed to be promising candidates as complementary therapeutics. Maple syrup, prepared by concentrating the sap from the North American maple tree, is a rich source of natural and process-derived phenolic compounds. In this work, we report the antimicrobial activity of a phenolic-rich maple syrup extract (PRMSE). PRMSE exhibited antimicrobial activity as well as strong synergistic interaction with selected antibiotics against Gram-negative clinical strains of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Among the phenolic constituents of PRMSE, catechol exhibited strong synergy with antibiotics as well as with other phenolic components of PRMSE against bacterial growth. At sublethal concentrations, PRMSE and catechol efficiently reduced biofilm formation and increased the susceptibility of bacterial biofilms to antibiotics. In an effort to elucidate the mechanism for the observed synergy with antibiotics, PRMSE was found to increase outer membrane permeability of all bacterial strains and effectively inhibit efflux pump activity. Furthermore, transcriptome analysis revealed that PRMSE significantly repressed multiple-drug resistance genes as well as genes associated with motility, adhesion, biofilm formation, and virulence. Overall, this study provides a proof of concept and starting point for investigating the molecular mechanism of the reported increase in bacterial antibiotic susceptibility in the presence of PRMSE. PMID:25819960

Polyphenolic extract from maple syrup potentiates antibiotic susceptibility and reduces biofilm formation of pathogenic bacteria.

PubMed

Maisuria, Vimal B; Hosseinidoust, Zeinab; Tufenkji, Nathalie

2015-06-01

Phenolic compounds are believed to be promising candidates as complementary therapeutics. Maple syrup, prepared by concentrating the sap from the North American maple tree, is a rich source of natural and process-derived phenolic compounds. In this work, we report the antimicrobial activity of a phenolic-rich maple syrup extract (PRMSE). PRMSE exhibited antimicrobial activity as well as strong synergistic interaction with selected antibiotics against Gram-negative clinical strains of Escherichia coli, Proteus mirabilis, and Pseudomonas aeruginosa. Among the phenolic constituents of PRMSE, catechol exhibited strong synergy with antibiotics as well as with other phenolic components of PRMSE against bacterial growth. At sublethal concentrations, PRMSE and catechol efficiently reduced biofilm formation and increased the susceptibility of bacterial biofilms to antibiotics. In an effort to elucidate the mechanism for the observed synergy with antibiotics, PRMSE was found to increase outer membrane permeability of all bacterial strains and effectively inhibit efflux pump activity. Furthermore, transcriptome analysis revealed that PRMSE significantly repressed multiple-drug resistance genes as well as genes associated with motility, adhesion, biofilm formation, and virulence. Overall, this study provides a proof of concept and starting point for investigating the molecular mechanism of the reported increase in bacterial antibiotic susceptibility in the presence of PRMSE. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The economics and timing of preoperative antibiotics for orthopaedic procedures.

PubMed

Norman, B A; Bartsch, S M; Duggan, A P; Rodrigues, M B; Stuckey, D R; Chen, A F; Lee, B Y

2013-12-01

The efficacy of antibiotics in preventing surgical site infections (SSIs) depends on the timing of administration relative to the start of surgery. However, currently, both the timing of and recommendations for administration vary substantially. To determine how the economic value from the hospital perspective of preoperative antibiotics varies with the timing of administration for orthopaedic procedures. Computational decision and operational models were developed from the hospital perspective. Baseline analyses looked at current timing of administration, while additional analyses varied the timing of administration, compliance with recommended guidelines, and the goal time-interval. Beginning antibiotic administration within 0-30 min prior to surgery resulted in the lowest costs and SSIs. Operationally, linking to a pre-surgical activity, administering antibiotics prior to incision but after anaesthesia-ready time was optimal, as 92.1% of the time, antibiotics were administered in the optimal time-interval (0-30 min prior to incision). Improving administration compliance from 80% to 90% for this pre-surgical activity results in cost savings of $447 per year for a hospital performing 100 orthopaedic operations a year. This study quantifies the potential cost-savings when antibiotic administration timing is improved, which in turn can guide the amount hospitals should invest to address this issue.

Functional Characterization of Bacteria Isolated from Ancient Arctic Soil Exposes Diverse Resistance Mechanisms to Modern Antibiotics

PubMed Central

Perron, Gabriel G.; Whyte, Lyle; Turnbaugh, Peter J.; Goordial, Jacqueline; Hanage, William P.; Dantas, Gautam; Desai, Michael M.

2015-01-01

Using functional metagenomics to study the resistomes of bacterial communities isolated from different layers of the Canadian high Arctic permafrost, we show that microbial communities harbored diverse resistance mechanisms at least 5,000 years ago. Among bacteria sampled from the ancient layers of a permafrost core, we isolated eight genes conferring clinical levels of resistance against aminoglycoside, β-lactam and tetracycline antibiotics that are naturally produced by microorganisms. Among these resistance genes, four also conferred resistance against amikacin, a modern semi-synthetic antibiotic that does not naturally occur in microorganisms. In bacteria sampled from the overlaying active layer, we isolated ten different genes conferring resistance to all six antibiotics tested in this study, including aminoglycoside, β-lactam and tetracycline variants that are naturally produced by microorganisms as well as semi-synthetic variants produced in the laboratory. On average, we found that resistance genes found in permafrost bacteria conferred lower levels of resistance against clinically relevant antibiotics than resistance genes sampled from the active layer. Our results demonstrate that antibiotic resistance genes were functionally diverse prior to the anthropogenic use of antibiotics, contributing to the evolution of natural reservoirs of resistance genes. PMID:25807523

Pharmacological Targeting of the Host-Pathogen Interaction: Alternatives to Classical Antibiotics to Combat Drug-Resistant Superbugs.

PubMed

Munguia, Jason; Nizet, Victor

2017-05-01

The rise of multidrug-resistant pathogens and the dearth of new antibiotic development place an existential strain on successful infectious disease therapy. Breakthrough strategies that go beyond classical antibiotic mechanisms are needed to combat this looming public health catastrophe. Reconceptualizing antibiotic therapy in the richer context of the host-pathogen interaction is required for innovative solutions. By defining specific virulence factors, the essence of a pathogen, and pharmacologically neutralizing their activities, one can block disease progression and sensitize microbes to immune clearance. Likewise, host-directed strategies to boost phagocyte bactericidal activity, enhance leukocyte recruitment, or reverse pathogen-induced immunosuppression seek to replicate the success of cancer immunotherapy in the field of infectious diseases. The answer to the threat of multidrug-resistant pathogens lies 'outside the box' of current antibiotic paradigms. Copyright © 2017 Elsevier Ltd. All rights reserved.

Microscale insights into pneumococcal antibiotic mutant selection windows

PubMed Central

Sorg, Robin A.; Veening, Jan-Willem

2015-01-01

The human pathogen Streptococcus pneumoniae shows alarming rates of antibiotic resistance emergence. The basic requirements for de novo resistance emergence are poorly understood in the pneumococcus. Here we systematically analyse the impact of antibiotics on S. pneumoniae at concentrations that inhibit wild type cells, that is, within the mutant selection window. We identify discrete growth-inhibition profiles for bacteriostatic and bactericidal compounds, providing a predictive framework for distinction between the two classifications. Cells treated with bacteriostatic agents show continued gene expression activity, and real-time mutation assays link this activity to the development of genotypic resistance. Time-lapse microscopy reveals that antibiotic-susceptible pneumococci display remarkable growth and death bistability patterns in response to many antibiotics. We furthermore capture the rise of subpopulations with decreased susceptibility towards cell wall synthesis inhibitors (heteroresisters). We show that this phenomenon is epigenetically inherited, and that heteroresistance potentiates the accumulation of genotypic resistance. PMID:26514094

Elution characteristics of teicoplanin-loaded biodegradable borate glass/chitosan composite.

PubMed

Jia, Wei-Tao; Zhang, Xin; Zhang, Chang-Qing; Liu, Xin; Huang, Wen-Hai; Rahaman, Mohamed N; Day, Delbert E

2010-03-15

Local antibiotic delivery system has an advantage over systemic antibiotic for osteomyelitis treatment due to the delivery of high local antibiotic concentration while avoiding potential systemic toxicity. Composite biomaterials with multifunctional roles, consisting of a controlled antibiotic release, a mechanical (load-bearing) function, and the ability to promote bone regeneration, gradually become the most active area of investigation and development of local antibiotic delivery vehicles. In the present study, a composite of borate glass and chitosan (designated BG/C) was developed as teicoplanin delivery vehicle. The in vitro elution kinetics and antibacterial activity of teicoplanin released from BG/C composite as a function of immersion time were determined. Moreover, the pH changes of eluents and the bioactivity of the composite were characterized using scanning electron microscopy coupled with energy-dispersive spectroscopy and X-ray diffraction analysis. 2009 Elsevier B.V. All rights reserved.

In vitro activity of solithromycin and its metabolites, CEM-214 and N-acetyl-CEM-101, against 100 clinical Ureaplasma spp. isolates compared with azithromycin.

PubMed

Furfaro, Lucy L; Spiller, O Brad; Keelan, Jeffrey A; Payne, Matthew S

2015-09-01

There is a strong association between vaginal and/or amniotic fluid Ureaplasma spp. colonisation and risk of preterm birth. The novel fluoroketolide antibiotic solithromycin (CEM-101) is active against Ureaplasma spp. in vitro. Evidence from ex vivo and in vivo models suggests that, unlike most macrolide antibiotics, solithromycin readily crosses the placenta. Solithromycin metabolism varies according to species; in pregnant sheep, the bioactive metabolites CEM-214 and N-acetyl-CEM-101 (NAc-CEM-101) have been shown to accumulate in the amniotic cavity following maternal solithromycin administration, potentially contributing to its antimicrobial effects. To determine the antimicrobial activity of these metabolites against Ureaplasma spp., the effects of solithromycin, CEM-214, NAc-CEM-101 and the comparator azithromycin were tested on a collection of 100 clinical Ureaplasma spp. isolates from the UK and Australia using a modified 96-well broth microdilution method. MIC90 values observed for the combined cohort were: solithromycin, 0.125 mg/L; CEM-214, 0.5mg/L; NAc-CEM-101, 0.5mg/L; and azithromycin, 2mg/L. Solithromycin showed 34-fold greater activity against Ureaplasma spp. isolates than azithromycin, whilst CEM-214 and NAc-CEM-101 possessed ca. 22% and 17% of the activity of solithromycin, respectively, significantly greater than that of azithromycin. One bacterial isolate showed resistance to azithromycin (MIC=16 mg/L) but had a much lower MIC for solithromycin (MIC=0.25mg/L). In conclusion, the metabolites of solithromycin had reduced, but still potent, activity against 100 clinical Ureaplasma spp. isolates in vitro. This may be important in some instances such as pregnancy, however studies to determine levels of the metabolites in these settings are required. Copyright © 2015 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

How to avoid the inappropriate use of antibiotics in upper respiratory tract infections? A position statement from an expert panel.

PubMed

Piltcher, Otávio Bejzman; Kosugi, Eduardo Macoto; Sakano, Eulalia; Mion, Olavo; Testa, José Ricardo Gurgel; Romano, Fabrizio Ricci; Santos, Marco Cesar Jorge; Di Francesco, Renata Cantisani; Mitre, Edson Ibrahim; Bezerra, Thiago Freire Pinto; Roithmann, Renato; Padua, Francini Greco; Valera, Fabiana Cardoso Pereira; Lubianca Neto, José Faibes; Sá, Leonardo Conrado Barbosa; Pignatari, Shirley Shizue Nagata; Avelino, Melissa Ameloti Gomes; Caixeta, Juliana Alves de Souza; Anselmo-Lima, Wilma Terezinha; Tamashiro, Edwin

Bacterial resistance burden has increased in the past years, mainly due to inappropriate antibiotic use. Recently it has become an urgent public health concern due to its impact on the prolongation of hospitalization, an increase of total cost of treatment and mortality associated with infectious disease. Almost half of the antimicrobial prescriptions in outpatient care visits are prescribed for acute upper respiratory infections, especially rhinosinusitis, otitis media, and pharyngotonsillitis. In this context, otorhinolaryngologists play an important role in orienting patients and non-specialists in the utilization of antibiotics rationally and properly in these infections. To review the most recent recommendations and guidelines for the use of antibiotics in acute otitis media, acute rhinosinusitis, and pharyngotonsillitis, adapted to our national reality. A literature review on PubMed database including the medical management in acute otitis media, acute rhinosinusitis, and pharyngotonsillitis, followed by a discussion with a panel of specialists. Antibiotics must be judiciously prescribed in uncomplicated acute upper respiratory tract infections. The severity of clinical presentation and the potential risks for evolution to suppurative and non-suppurative complications must be taken into 'consideration'. Periodic revisions on guidelines and recommendations for treatment of the main acute infections are necessary to orient rationale and appropriate use of antibiotics. Continuous medical education and changes in physicians' and patients' behavior are required to modify the paradigm that all upper respiratory infection needs antibiotic therapy, minimizing the consequences of its inadequate and inappropriate use. Copyright © 2018 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Association Between Antibiotic Exposure, Bronchiolitis, and TLR4 (rs1927911) Polymorphisms in Childhood Asthma

PubMed Central

Lee, Eun; Kwon, Ji-Won; Kim, Hyo-Bin; Yu, Ho-Sung; Kang, Mi-Jin; Hong, Kyungmo; Yang, Song I; Jung, Young Ho; Lee, Seung-Hwa; Choi, Kil Young; Shin, Hye Lim; Hong, Seo Ah; Kim, Hyung Young; Seo, Ju-Hee; Kim, Byoung-Ju; Lee, So Yeon; Song, Dae Jin; Kim, Woo-Kyung; Jang, Gwang Cheon; Shim, Jung Yeon

2015-01-01

Purpose The complex interplay between environmental and genetic factors plays an important role in the development of asthma. Several studies have yielded conflicting results regarding the 2 asthma-related risk factors: antibiotic usage during infancy and/or a history of bronchiolitis during early life and the development of asthma. In addition to these risk factors, we also explored the effects of Toll-like receptor 4 (TLR4) polymorphism on the development of childhood asthma. Methods This cross-sectional study involved 7,389 middle school students who were from 8 areas of Seoul, Korea, and completed the International Study of Asthma and Allergies in Childhood questionnaire. The TLR4 polymorphism rs1927911 was genotyped in 1,395 middle school students from two areas using the TaqMan assay. Results Bronchiolitis in the first 2 years of life, antibiotic exposure during the first year of life, and parental history of asthma were independent risk factors for the development of asthma. When combined, antibiotic use and a history of bronchiolitis increased the risk of asthma (adjusted odds ratio [aOR]: 4.64, 95% confidence interval [CI]: 3.09-6.97, P value for interaction=0.02). In subjects with CC genotype of TLR4, antibiotic exposure and a history of bronchiolitis during infancy, the risk of asthma was increased, compared to subjects without these risk factors (aOR: 5.72, 95% CI: 1.74-18.87). Conclusions Early-life antibiotic exposures and a history of bronchiolitis are risk factors for asthma in young adolescents. Polymorphisms of TLR4 modified the influence of these environmental factors. Reducing antibiotic exposure and preventing bronchiolitis during infancy may prevent the development of asthma, especially in genetically susceptible subjects. PMID:25729624

A state-wide assessment of the association between epidural analgesia, maternal fever and neonatal antibiotics in Colorado, 2007-2012.

PubMed

White, Alice; Olson, Daniel; Messacar, Kevin

2017-03-01

To determine if an association exists between epidural analgesia, maternal fever and neonatal antibiotic exposure in a state-wide birth cohort. We performed a retrospective cohort study of the population-based Colorado Department of Public Health and Environment birth certificate database. Data included all reported births in the state of Colorado between 2007 and 2012. Live, non-preterm, vaginal, singleton, in-hospital births were included in analysis. Maternal epidural analgesia and maternal fever. Neonatal antibiotic treatment for suspected sepsis. A stratified analysis was conducted to evaluate whether epidural use was an effect modifier of the association between maternal fever and neonatal antibiotic treatment. The final cohort included 261 457 births. 2.2% of women who received an epidural had a fever, as compared with 0.4% of women who did not receive an epidural (OR: 5.4; 95% CI 4.9 to 6.0), and neonates born to women who received an epidural had 1.26 times increased odds of antibiotic treatment (95% CI 1.1 to 1.4). Stratification by epidural use did not alter the association between maternal fever and neonatal antibiotic treatment. Colorado providers treat neonates born to mothers with maternal fever without respect to whether the mother had an epidural. Further research into improved criteria for neonatal sepsis evaluation that accounts for the contribution of maternal epidural fever should be developed to decrease unnecessary neonatal antibiotic exposure. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

RelA Mutant Enterococcus faecium with Multiantibiotic Tolerance Arising in an Immunocompromised Host.

PubMed

Honsa, Erin S; Cooper, Vaughn S; Mhaissen, Mohammed N; Frank, Matthew; Shaker, Jessica; Iverson, Amy; Rubnitz, Jeffrey; Hayden, Randall T; Lee, Richard E; Rock, Charles O; Tuomanen, Elaine I; Wolf, Joshua; Rosch, Jason W

2017-01-03

Serious bacterial infections in immunocompromised patients require highly effective antibacterial therapy for cure, and thus, this setting may reveal novel mechanisms by which bacteria circumvent antibiotics in the absence of immune pressure. Here, an infant with leukemia developed vancomycin-resistant Enterococcus faecium (VRE) bacteremia that persisted for 26 days despite appropriate antibiotic therapy. Sequencing of 22 consecutive VRE isolates identified the emergence of a single missense mutation (L152F) in relA, which constitutively activated the stringent response, resulting in elevated baseline levels of the alarmone guanosine tetraphosphate (ppGpp). Although the mutant remained susceptible to both linezolid and daptomycin in clinical MIC testing and during planktonic growth, it demonstrated tolerance to high doses of both antibiotics when growing in a biofilm. This biofilm-specific gain in resistance was reflected in the broad shift in transcript levels caused by the mutation. Only an experimental biofilm-targeting ClpP-activating antibiotic was able to kill the mutant strain in an established biofilm. The relA mutation was associated with a fitness trade-off, forming smaller and less-well-populated biofilms on biological surfaces. We conclude that clinically relevant relA mutations can emerge during prolonged VRE infection, causing baseline activation of the stringent response, subsequent antibiotic tolerance, and delayed eradication in an immunocompromised state. The increasing prevalence of antibiotic-resistant bacterial pathogens is a major challenge currently facing the medical community. Such pathogens are of particular importance in immunocompromised patients as these individuals may favor emergence of novel resistance determinants due to lack of innate immune defenses and intensive antibiotic exposure. During the course of chemotherapy, a patient developed prolonged bacteremia with vancomycin-resistant Enterococcus faecium that failed to clear despite multiple front-line antibiotics. The consecutive bloodstream isolates were sequenced, and a single missense mutation identified in the relA gene, the mediator of the stringent response. Strains harboring the mutation had elevated baseline levels of the alarmone and displayed heightened resistance to the bactericidal activity of multiple antibiotics, particularly in a biofilm. Using a new class of compounds that modulate ClpP activity, the biofilms were successfully eradicated. These data represent the first clinical emergence of mutations in the stringent response in vancomycin-resistant entereococci. Copyright © 2017 Honsa et al.

In vitro pharmacokinetics of antimicrobial cationic peptides alone and in combination with antibiotics against methicillin resistant Staphylococcus aureus biofilms.

PubMed

Dosler, Sibel; Mataraci, Emel

2013-11-01

Antibiotic therapy for methicillin-resistant Staphylococcus aureus (MRSA) infections is becoming more difficult in hospitals and communities because of strong biofilm-forming properties and multidrug resistance. Biofilm-associated MRSA is not affected by therapeutically achievable concentrations of antibiotics. Therefore, we investigated the in vitro pharmacokinetic activities of antimicrobial cationic peptides (AMPs; indolicidin, cecropin [1-7]-melittin A [2-9] amide [CAMA], and nisin), either alone or in combination with antibiotics (daptomycin, linezolid, teicoplanin, ciprofloxacin, and azithromycin), against standard and 2 clinically obtained MRSA biofilms. The minimum inhibitory concentrations (MIC) and minimum biofilm-eradication concentrations (MBEC) were determined by microbroth dilution technique. The time-kill curve (TKC) method was used to determine the bactericidal activities of the AMPs alone and in combination with the antibiotics against standard and clinically obtained MRSA biofilms. The MIC values of the AMPs and antibiotics ranged between 2 to 16 and 0.25 to 512 mg/L, and their MBEC values were 640 and 512 to 5120 mg/L, respectively. The TKC studies demonstrated that synergistic interactions occurred most frequently when using nisin+daptomycin/ciprofloxacin, indolicidin+teicoplanin, and CAMA+ciprofloxacin combinations. No antagonism was observed with any combination. AMPs appear to be good candidates for the treatment of MRSA biofilms, as they act as both enhancers of anti-biofilm activities and help to prevent or delay the emergence of resistance when used either alone or in combination with antibiotics. Copyright © 2013 Elsevier Inc. All rights reserved.

Antibiotic discovery throughout the Small World Initiative: A molecular strategy to identify biosynthetic gene clusters involved in antagonistic activity.

PubMed

Davis, Elizabeth; Sloan, Tyler; Aurelius, Krista; Barbour, Angela; Bodey, Elijah; Clark, Brigette; Dennis, Celeste; Drown, Rachel; Fleming, Megan; Humbert, Allison; Glasgo, Elizabeth; Kerns, Trent; Lingro, Kelly; McMillin, MacKenzie; Meyer, Aaron; Pope, Breanna; Stalevicz, April; Steffen, Brittney; Steindl, Austin; Williams, Carolyn; Wimberley, Carmen; Zenas, Robert; Butela, Kristen; Wildschutte, Hans

2017-06-01

The emergence of bacterial pathogens resistant to all known antibiotics is a global health crisis. Adding to this problem is that major pharmaceutical companies have shifted away from antibiotic discovery due to low profitability. As a result, the pipeline of new antibiotics is essentially dry and many bacteria now resist the effects of most commonly used drugs. To address this global health concern, citizen science through the Small World Initiative (SWI) was formed in 2012. As part of SWI, students isolate bacteria from their local environments, characterize the strains, and assay for antibiotic production. During the 2015 fall semester at Bowling Green State University, students isolated 77 soil-derived bacteria and genetically characterized strains using the 16S rRNA gene, identified strains exhibiting antagonistic activity, and performed an expanded SWI workflow using transposon mutagenesis to identify a biosynthetic gene cluster involved in toxigenic compound production. We identified one mutant with loss of antagonistic activity and through subsequent whole-genome sequencing and linker-mediated PCR identified a 24.9 kb biosynthetic gene locus likely involved in inhibitory activity in that mutant. Further assessment against human pathogens demonstrated the inhibition of Bacillus cereus, Listeria monocytogenes, and methicillin-resistant Staphylococcus aureus in the presence of this compound, thus supporting our molecular strategy as an effective research pipeline for SWI antibiotic discovery and genetic characterization. © 2017 The Authors. MicrobiologyOpen published by John Wiley & Sons Ltd.

Antibiotic Desensitization Therapy in Secondary Syphilis and Listeria Infection: Case Reports and Review of Desensitization Therapy

PubMed Central

Magpantay, Gil; Madar, Cristian S; Hsue, Gunther; Belnap, Conrad

2011-01-01

Two adult cases, one of secondary syphilis and one of Listeria monocytogenes bacteremia, in which antibiotic desensitization therapy was utilized to assist treatment of active infection in the face of severe penicillin allergy. Clinical considerations are discussed that led to the decision to employ a formal desensitization procedure. Antibiotic desensitization protocols can facilitate optimal and safe antibiotic therapy in the appropriate clinical setting. PMID:22187514

Optical control of antibacterial activity

NASA Astrophysics Data System (ADS)

Velema, Willem A.; van der Berg, Jan Pieter; Hansen, Mickel J.; Szymanski, Wiktor; Driessen, Arnold J. M.; Feringa, Ben L.

2013-11-01

Bacterial resistance is a major problem in the modern world, stemming in part from the build-up of antibiotics in the environment. Novel molecular approaches that enable an externally triggered increase in antibiotic activity with high spatiotemporal resolution and auto-inactivation are highly desirable. Here we report a responsive, broad-spectrum, antibacterial agent that can be temporally activated with light, whereupon it auto-inactivates on the scale of hours. The use of such a ‘smart’ antibiotic might prevent the build-up of active antimicrobial material in the environment. Reversible optical control over active drug concentration enables us to obtain pharmacodynamic information. Precisely localized control of activity is achieved, allowing the growth of bacteria to be confined to defined patterns, which has potential for the development of treatments that avoid interference with the endogenous microbial population in other parts of the organism.

Pipeline of Known Chemical Classes of Antibiotics

PubMed Central

d’Urso de Souza Mendes, Cristina; de Souza Antunes, Adelaide Maria

2013-01-01

Many approaches are used to discover new antibiotic compounds, one of the most widespread being the chemical modification of known antibiotics. This type of discovery has been so important in the development of new antibiotics that most antibiotics used today belong to the same chemical classes as antibiotics discovered in the 1950s and 1960s. Even though the discovery of new classes of antibiotics is urgently needed, the chemical modification of antibiotics in known classes is still widely used to discover new antibiotics, resulting in a great number of compounds in the discovery and clinical pipeline that belong to existing classes. In this scenario, the present article presents an overview of the R&D pipeline of new antibiotics in known classes of antibiotics, from discovery to clinical trial, in order to map out the technological trends in this type of antibiotic R&D, aiming to identify the chemical classes attracting most interest, their spectrum of activity, and the new subclasses under development. The result of the study shows that the new antibiotics in the pipeline belong to the following chemical classes: quinolones, aminoglycosides, macrolides, oxazolidinones, tetracyclines, pleuromutilins, beta-lactams, lipoglycopeptides, polymyxins and cyclic lipopeptides. PMID:27029317

Antibiotics in the aquatic environment of Vietnam: Sources, concentrations, risk and control strategy.

PubMed

Binh, Vu Ngan; Dang, Nhung; Anh, Nguyen Thi Kieu; Ky, Le Xuan; Thai, Phong K

2018-04-01

The presence of antibiotics in the aquatic environment is a serious concern because it may lead to the emergence of antibiotic resistance, thus lowering the therapeutic effect of antibiotics. In Vietnam, the problem is aggravated by the irrational use of antibiotics in different sectors of agriculture and human health service. Moreover, the residues of antibiotics in the aquatic environment can be spread widely due to the lack of proper wastewater treatment systems. In this paper, we aim to comprehensively review all relevant sources that discharge antibiotics to the aquatic environment in Vietnam. Apart from the common source of antibiotics from aquaculture, other activities that release considerable amounts of antibiotics into water environment are also included. Environmental concentrations of antibiotics related to those sources are studied to demonstrate their contributions to the presence of antibiotics in the aquatic environment in Vietnam. As antibiotic-contained water may be used as water supply for irrigation and even human consumption in rural areas, the essence of wastewater treatment is highlighted. Finally, we also discuss the new National Action plan from the Ministry of Health for controlling the issue of antibiotic resistance in Vietnam. Copyright © 2018 Elsevier Ltd. All rights reserved.

Antibiotic Use in Cold and Flu Season and Prescribing Quality: A Retrospective Cohort Study

PubMed Central

Alsan, Marcella; Morden, Nancy; Gottlieb, Joshua D.; Zhou, Weiping; Skinner, Jonathan

2016-01-01

Background Excessive antibiotic use in cold and flu season is costly and contributes to antibiotic resistance. The study objective was to develop an index of excessive antibiotic use in cold and flu season and determine its correlation with other indicators of prescribing quality. Methods and Findings We included Medicare beneficiaries in the 40% random sample denominator continuously enrolled in fee for service benefits for 2010 and/or 2011 (7,961,201 person-years (PY)) and extracted data on prescription fills for oral antibiotics that treat respiratory pathogens. We collapsed the data to the state-level so that it could be merged with monthly flu activity data from the Centers for Disease Control and Prevention (CDC). Linear regression, adjusted for state-specific mean antibiotic use and demographic characteristics, was used to estimate how antibiotic prescribing responded to state-specific flu activity. There was considerable geographic variation in flu-associated antibiotic use across states—lowest in Vermont and Connecticut and highest in Mississippi and Florida. There was a robust positive correlation between medications that often cause adverse events in the elderly and flu-associated prescribing (0.755; p<0.001), while there was a strong negative correlation with beta-blocker use after a myocardial infarction (MI) (−0.413; p=0.003). Conclusion Adjusted flu-associated antibiotic use was positively correlated with high-risk medications to the elderly and negatively correlated with beta-blocker use post MI. These findings suggest excessive antibiotic use reflects low quality prescribing, and imply that practice and policy solutions should go beyond narrow, antibiotic-specific, approaches to encourage evidence-based prescribing for the elderly Medicare population. PMID:26569644

Of Two Make One: The Biosynthesis of Phenazines

USDA-ARS?s Scientific Manuscript database

Phenazine compounds produced by certain species of bacteria have antibiotic activity against a wide range of bacterial and fungal pathogens including many that cause important root diseases of plants. The antibiotic activity of these compounds has long been known but the mechanism of synthesis is po...

Reinventing the Wheel: Impact of Prolonged Antibiotic Exposure on Multi-Drug Resistant Ventilator-Associated Pneumonia in Trauma Patients.

PubMed

Lewis, Richard H; Sharpe, John P; Swanson, Joseph M; Fabian, Timothy C; Croce, Martin A; Magnotti, Louis J

2018-04-16

Multi-drug resistant (MDR) strains of both Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) as causative VAP pathogens are becoming increasingly common. Still, the risk factors associated with this increased resistance have yet to be elucidated. The purpose of this study was to examine the changing sensitivity patterns of these pathogens over time and determine which risk factors predict MDR in trauma patients with VAP. Patients with either AB or PA VAP over 10 years were stratified by pathogen sensitivity (sensitive (SEN) and MDR), age, severity of shock and injury severity. Prophylactic and empiric antibiotic days, risk factors for severe VAP and mortality were compared. Multivariable logistic regression (MLR) was performed to determine which risk factors were independent predictors of MDR. 397 patients were identified with AB or PA VAP. There were 173 episodes of AB (91 SEN and 82 MDR) and 224 episodes of PA (170 SEN and 54 MDR). The incidence of MDR VAP did not change over the study (p=0.633). Groups were clinically similar with the exception of 24-hour transfusions (14 vs 19 units, p = 0.009) and extremity AIS (1 vs 3, p<0.001), both significantly increased in the MDR group. Antibiotic exposure as well as mIEAT (63% vs 81%, p<0.001) were significantly increased in the MDR group. MLR identified prophylactic antibiotic days (OR 23.1; 95%CI 16.7-28, p<0.001) and mIEAT (OR 18.1; 95%CI 12.2-26.1, p=0.001) as independent predictors of MDR after adjusting for severity of shock, injury severity, severity of VAP and antibiotic exposure. Prolonged exposure to unnecessary antibiotics remains one of the strongest predictors for the development of antibiotic resistance. MLR identified prophylactic antibiotic days and mIEAT an independent risk factors for MDR VAP. Thus, limiting prophylactic antibiotic days is the only potentially modifiable risk factor for the development of MDR VAP in trauma patients. Level III, Prognostic LEVEL OF EVIDENCE: Multi-drug resistant, antibiotic exposure.

Therapeutic concentrations of antibiotics inhibit Shiga toxin release from enterohemorrhagic E. coli O104:H4 from the 2011 German outbreak

PubMed Central

2012-01-01

Background The shiga toxin-producing E. coli (STEC) O104:H4 caused a major outbreak in Germany in spring 2011. STEC are usually susceptible to common antibiotics. However, antibiotic treatment of STEC-infected patients is not recommended because STEC may enhance production and release of shiga toxins (STX) in response to antibiotics, which eventually enhances the frequency and severity of clinical symptoms, including haemolytic uraemic syndrome (HUS) and fatalities. Results We characterized the response to antibiotics of STEC O104:H4 isolates from two HUS patients during the German STEC outbreak in spring 2011 in comparison to the common STEC O157:H7. Liquid cultures of STEC O157:H7 and O104:H4 were incubated with graded dilutions of the antibiotics ciprofloxacin, meropenem, fosfomycin, gentamicin, rifampicin, and chloramphenicol. At defined times of antibiotic treatment, transcriptional activation of the STX2 gene, contents of STX and STX-activity in the culture supernatants were quantified. Unlike the common serotype O157:H7, STEC O104:H4 does not release STX in response to therapeutic concentrations of ciprofloxacin, meropenem, fosfomycin, and chloramphenicol. Conclusions In future outbreaks, the response of the respective epidemiologic STEC strain to antibiotics should be rapidly characterized in order to identify antibiotics that do not enhance the release of STX. This will eventually allow clinical studies tackling the question whether antibiotic treatment impacts on the eradication of STEC, clinical course of disease, and frequency of carriers. PMID:22853739

Genome-wide dynamics of a bacterial response to antibiotics that target the cell envelope

PubMed Central

2011-01-01

Background A decline in the discovery of new antibacterial drugs, coupled with a persistent rise in the occurrence of drug-resistant bacteria, has highlighted antibiotics as a diminishing resource. The future development of new drugs with novel antibacterial activities requires a detailed understanding of adaptive responses to existing compounds. This study uses Streptomyces coelicolor A3(2) as a model system to determine the genome-wide transcriptional response following exposure to three antibiotics (vancomycin, moenomycin A and bacitracin) that target distinct stages of cell wall biosynthesis. Results A generalised response to all three antibiotics was identified which involves activation of transcription of the cell envelope stress sigma factor σE, together with elements of the stringent response, and of the heat, osmotic and oxidative stress regulons. Attenuation of this system by deletion of genes encoding the osmotic stress sigma factor σB or the ppGpp synthetase RelA reduced resistance to both vancomycin and bacitracin. Many antibiotic-specific transcriptional changes were identified, representing cellular processes potentially important for tolerance to each antibiotic. Sensitivity studies using mutants constructed on the basis of the transcriptome profiling confirmed a role for several such genes in antibiotic resistance, validating the usefulness of the approach. Conclusions Antibiotic inhibition of bacterial cell wall biosynthesis induces both common and compound-specific transcriptional responses. Both can be exploited to increase antibiotic susceptibility. Regulatory networks known to govern responses to environmental and nutritional stresses are also at the core of the common antibiotic response, and likely help cells survive until any specific resistance mechanisms are fully functional. PMID:21569315

Investigation of the sensitising and cross-sensitising potential of textile dyes and beta-lactam antibiotics using a biphasic mice local lymph node assay.

PubMed

Ahuja, Varun; Schreiber, Clemens; Platzek, Thomas; Stahlmann, Ralf

2009-07-01

We used a modified protocol of the murine local lymph node assay (LLNA) to study the cross-sensitising potential of (a) textile dye disperse yellow 3 and its metabolite 2-amino-p-cresol, (b) two antibiotics, penicillin G and cefotiam. The test substances were applied in a biphasic manner, i.e. first on the shaved skin of the back followed by application on the dorsal side of the ears after 2 weeks. The end-points analysed included thickness and weight of an ear-biopsy, weight and cell number of the draining lymph node, and lymphocyte cell surface markers analysed by flow-cytometry. Disperse yellow 3 and its metabolite significantly altered the various end-points at both the tested concentrations (0.5 and 1%), thus demonstrating the sensitising potential of the two substances. The cross-sensitisation study showed significant modulation in the tested variables in the treated group as compared to the control, signifying cross-sensitisation potential of the two substances. Penicillin G and cefotiam showed significant changes in various end-points, pointing towards their sensitising potential. However, even at 50% concentration of the beta-lactams no significant change in any end-point indicating absence of cross-reactivity of the antibiotics was noticed. We conclude that a biphasic, modified protocol of the LLNA is a suitable approach to test for a cross-reactivity potential of two related compounds.

Thiopeptide antibiotics stimulate biofilm formation in Bacillus subtilis

PubMed Central

Bleich, Rachel; Watrous, Jeramie D.; Dorrestein, Pieter C.; Bowers, Albert A.; Shank, Elizabeth A.

2015-01-01

Bacteria have evolved the ability to produce a wide range of structurally complex natural products historically called “secondary” metabolites. Although some of these compounds have been identified as bacterial communication cues, more frequently natural products are scrutinized for antibiotic activities that are relevant to human health. However, there has been little regard for how these compounds might otherwise impact the physiology of neighboring microbes present in complex communities. Bacillus cereus secretes molecules that activate expression of biofilm genes in Bacillus subtilis. Here, we use imaging mass spectrometry to identify the thiocillins, a group of thiazolyl peptide antibiotics, as biofilm matrix-inducing compounds produced by B. cereus. We found that thiocillin increased the population of matrix-producing B. subtilis cells and that this activity could be abolished by multiple structural alterations. Importantly, a mutation that eliminated thiocillin’s antibiotic activity did not affect its ability to induce biofilm gene expression in B. subtilis. We go on to show that biofilm induction appears to be a general phenomenon of multiple structurally diverse thiazolyl peptides and use this activity to confirm the presence of thiazolyl peptide gene clusters in other bacterial species. Our results indicate that the roles of secondary metabolites initially identified as antibiotics may have more complex effects—acting not only as killing agents, but also as specific modulators of microbial cellular phenotypes. PMID:25713360

Unexpected Biotransformation of the HDAC Inhibitor Vorinostat Yields Aniline-Containing Fungal Metabolites.

PubMed

Adpressa, Donovon A; Stalheim, Kayla J; Proteau, Philip J; Loesgen, Sandra

2017-07-21

The diversity of genetically encoded small molecules produced by filamentous fungi remains largely unexplored, which makes these fungi an attractive source for the discovery of new compounds. However, accessing their full chemical repertoire under common laboratory culture conditions is a challenge. Epigenetic manipulation of gene expression has become a well-established tool for overcoming this obstacle. Here, we report that perturbation of the endophytic ascomycete Chalara sp. 6661, producer of the isofusidienol class of antibiotics, with the HDAC inhibitor vorinostat resulted in the production of four new modified xanthones. The structures of chalanilines A (1) and B (2) and adenosine-coupled xanthones A (3) and B (4) were determined by extensive NMR spectroscopic analyses, and the bioactivities of 1-4 were tested in antibiotic and cytotoxicity assays. Incorporation studies with deuterium-labeled vorinostat indicate that the aniline moiety in chalalanine A is derived from vorinostat itself. Our study shows that Chalara sp. is able to metabolize the HDAC inhibitor vorinostat to release aniline. This is a rare report of fungal biotransformation of the popular epigenetic modifier vorinostat into aniline-containing polyketides.

Antibacterial activity of exogenous glutathione and its synergism on antibiotics sensitize carbapenem-associated multidrug resistant clinical isolates of Acinetobacter baumannii.

PubMed

Alharbe, Roaa; Almansour, Ayidh; Kwon, Dong H

2017-10-01

A major clinical impact of A. baumannii is hospital-acquired infections including ventilator-associated pneumonia. The treatment of this pathogen is often difficult due to its innate and acquired resistance to almost all commercially available antibiotics. Infections with carbapenem-associated multidrug resistant A. baumannii is the most problematic. Glutathione is a tripeptide thiol-antioxidant and antibacterial activity of exogenous glutathione was reported in some bacteria. However, clinical relevance and molecular details of the antibacterial activity of glutathione are currently unclear. Seventy clinical isolates of A. baumannii including 63 carbapenem-associated multidrug resistant isolates and a type strain A. baumannii ATCC 19606 were used to determine minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Fractional inhibitory concentration (FIC) and time-killing activity with meropenem and/or glutathione were also determined in the carbapenem-associated multidrug resistant isolates. In addition, the roles of exogenous glutathione in multidrug efflux pumps and β-lactamase production were examined. Levels of MIC and MBC were ranged from 10 to 15mM of exogenous glutathione. All tested carbapenem-associated multidrug resistant isolates were sensitized by all tested antibiotics in combination with subinhibitory concentrations of glutathione. FIC levels of glutathione with carbapenem (meropenem) were all<0.5 and the carbapenem-associated multidrug resistant isolates were killed by subinhibitory concentrations of both glutathione and meropenem at>2log10 within 12h, suggesting glutathione synergistically interacts with meropenem. The roles of multidrug efflux pumps and β-lactamase production were excluded for the glutathione-mediated antibiotic susceptibility. Overall results demonstrate that the antibacterial activity of glutathione is clinically relevant and its synergism on antibiotics sensitizes clinical isolates of A. baumannii regardless of their resistance or susceptibility to antibiotics. This finding suggests that exogenous glutathione alone and/or in combination with existing antibiotics may be applicable to treat infections with carbapenem-associated multidrug resistant A. baumannii. Copyright © 2017 Elsevier GmbH. All rights reserved.

A combination of silver nanoparticles and visible blue light enhances the antibacterial efficacy of ineffective antibiotics against methicillin-resistant Staphylococcus aureus (MRSA).

PubMed

Akram, Fatma Elzahraa; El-Tayeb, Tarek; Abou-Aisha, Khaled; El-Azizi, Mohamed

2016-08-17

Silver nanoparticles (AgNPs) are potential antimicrobials agents, which can be considered as an alternative to antibiotics for the treatment of infections caused by multi-drug resistant bacteria. The antimicrobial effects of double and triple combinations of AgNPs, visible blue light, and the conventional antibiotics amoxicillin, azithromycin, clarithromycin, linezolid, and vancomycin, against ten clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) were investigated. The antimicrobial activity of AgNPs, applied in combination with blue light, against selected isolates of MRSA was investigated at 1/2-1/128 of its minimal inhibitory concentration (MIC) in 24-well plates. The wells were exposed to blue light source at 460 nm and 250 mW for 1 h using a photon emitting diode. Samples were taken at different time intervals, and viable bacterial counts were determined. The double combinations of AgNPs and each of the antibiotics were assessed by the checkerboard method. The killing assay was used to test possible synergistic effects when blue light was further combined to AgNPs and each antibiotic at a time against selected isolates of MRSA. The bactericidal activity of AgNPs, at sub-MIC, and blue light was significantly (p < 0.001) enhanced when both agents were applied in combination compared to each agent alone. Similarly, synergistic interactions were observed when AgNPs were combined with amoxicillin, azithromycin, clarithromycin or linezolid in 30-40 % of the double combinations with no observed antagonistic interaction against the tested isolates. Combination of the AgNPs with vancomycin did not result in enhanced killing against all isolates tested. The antimicrobial activity against MRSA isolates was significantly enhanced in triple combinations of AgNPs, blue light and antibiotic, compared to treatments involving one or two agents. The bactericidal activities were highest when azithromycin or clarithromycin was included in the triple therapy compared to the other antibiotics tested. A new strategy can be used to combat serious infections caused by MRSA by combining AgNPs, blue light, and antibiotics. This triple therapy may include antibiotics, which have been proven to be ineffective against MRSA. The suggested approach would be useful to face the fast-growing drug-resistance with the slow development of new antimicrobial agents, and to preserve last resort antibiotics such as vancomycin.

Mechanisms of the post-antibiotic effects induced by rifampicin and gentamicin in Escherichia coli.

PubMed

Stubbings, William; Bostock, Julieanne; Ingham, Eileen; Chopra, Ian

2006-08-01

The mechanisms by which antibiotics induce a post-antibiotic effect in susceptible bacteria are poorly understood. To explore the mechanisms more fully we examined the recovery of macromolecular synthesis in Escherichia coli during gentamicin- and rifampicin-induced post-antibiotic effects. E. coli ATCC 25922 was exposed to rifampicin and to gentamicin at 5x MIC for 60 min to induce post-antibiotic effects. The antibiotics were then removed from the culture medium by washing the cells. The rates of DNA, RNA and protein synthesis during the post-antibiotic effect and recovery periods were subsequently determined by measuring the incorporation of radiolabelled uridine, thymidine and leucine into trichloroacetic acid precipitable material. Recovery of E. coli ATCC 25922 from the rifampicin-induced post-antibiotic effect coincided with the recovery of RNA and protein synthesis. Recovery from the gentamicin-induced post-antibiotic effect coincided with the recovery of protein synthesis. These data support the hypothesis that antibiotic molecules retained in the cell mediate the post-antibiotic effect by suppressing the biochemical activity of their molecular targets.

The Challenge of Antibiotic-Resistant Staphylococcus: Lessons from Hospital Nurseries in the mid-20th Century

PubMed Central

Shaffer, Robyn Kroop

2013-01-01

In the late 1940s, epidemics of antibiotic-resistant strains of Staphylococcus aureus began to plague postpartum nurseries in hospitals across the United States. Exacerbated by overcrowding and nursing shortages, resistant S. aureus outbreaks posed a novel challenge to physicians and nurses heavily reliant on antibiotics as both prophylaxis and treatment. This paper explores the investigation of the reservoir, mode of transmission, and virulence of S. aureus during major hospital outbreaks and the subsequent implementation of novel infection control measures from the late 1940s through the early 1960s. The exploration of these measures reveals a shift in infection control policy as hospitals, faced with the failure of antibiotics to slow S. aureus outbreaks, implemented laboratory culture routines, modified nursery structure and layout, and altered nursing staff procedures to counter various forms of S. aureus transmission. Showcasing the need for widespread epidemiologic surveillance, ultimately manifesting itself in specialized “hospital epidemiology” training promoted in the 1970s, the challenges faced by hospital nurses in the 1950s prove highly relevant to the continued struggle with methicillin-resistant Staphylococcus aureus (MRSA) and other resistant nosocomial infections. PMID:23766746

The challenge of antibiotic-resistant Staphylococcus: lessons from hospital nurseries in the mid-20th century.

PubMed

Shaffer, Robyn Kroop

2013-06-01

In the late 1940s, epidemics of antibiotic-resistant strains of Staphylococcus aureus began to plague postpartum nurseries in hospitals across the United States. Exacerbated by overcrowding and nursing shortages, resistant S. aureus outbreaks posed a novel challenge to physicians and nurses heavily reliant on antibiotics as both prophylaxis and treatment. This paper explores the investigation of the reservoir, mode of transmission, and virulence of S. aureus during major hospital outbreaks and the subsequent implementation of novel infection control measures from the late 1940s through the early 1960s. The exploration of these measures reveals a shift in infection control policy as hospitals, faced with the failure of antibiotics to slow S. aureus outbreaks, implemented laboratory culture routines, modified nursery structure and layout, and altered nursing staff procedures to counter various forms of S. aureus transmission. Showcasing the need for widespread epidemiologic surveillance, ultimately manifesting itself in specialized "hospital epidemiology" training promoted in the 1970s, the challenges faced by hospital nurses in the 1950s prove highly relevant to the continued struggle with methicillin-resistant Staphylococcus aureus (MRSA) and other resistant nosocomial infections.

Ciprofloxacin induces oxidative stress in duckweed (Lemna minor L.): Implications for energy metabolism and antibiotic-uptake ability.

PubMed

Gomes, Marcelo Pedrosa; Gonçalves, Cíntia Almeida; de Brito, Júlio César Moreira; Souza, Amanda Miranda; da Silva Cruz, Fernanda Vieira; Bicalho, Elisa Monteze; Figueredo, Cleber Cunha; Garcia, Queila Souza

2017-04-15

We investigate the physiological responses and antibiotic-uptake capacity of Lemna minor exposed to ciprofloxacin. Ciprofloxacin (Cipro) induced toxic effects and hormesis in plants by significantly modifying photosynthesis and respiration pathways. A toxic effect was induced by a concentration ≥1.05mg ciprofloxacin l -1 while hormesis occurs at the lowest concentration studied (0.75mg ciprofloxacin l -1 ). By impairing normal electron flow in the respiratory electron transport chain, ciprofloxacin induces hydrogen peroxide (H 2 O 2 ) production. The ability of plants to cope with H 2 O 2 accumulation using antioxidant systems resulted in stimulation/deleterious effects to photosynthesis by Cipro. Cipro-induced oxidative stress was also associated with the ability of L. minor plants to uptake the antibiotic and, therefore, with plant-uptake capacity. Our results indicate that instead of being a photosystem II binding molecule, Cipro induces oxidative stress by targeting the mitochondrial ETC, which would explain the observed effects of the antibiotic on non-target eukaryotic organisms. The selection of plants species with a high capacity to tolerate oxidative stress may constitute a strategy to be used in Cipro-remediation programs. Copyright © 2017 Elsevier B.V. All rights reserved.

Antibiotic Resistance in Burkholderia Species

PubMed Central

Rhodes, Katherine A.; Schweizer, Herbert P.

2016-01-01

The genus Burkholderia comprises metabolically diverse and adaptable Gram-negative bacteria, which thrive in often adversarial environments. A few members of the genus are prominent opportunistic pathogens. These include B. mallei and B. pseudomallei of the B. pseudomallei complex, which cause glanders and melioidosis, respectively. B. cenocepacia, B. multivorans, and B. vietnamiensis belong to the B. cepacia complex and affect mostly cystic fibrosis patients. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. The first line of defense against antimicrobials in Burkholderia species is the outer membrane penetration barrier. Most Burkholderia contain a modified lipopolysaccharide that causes intrinsic polymyxin resistance. Contributing to reduced drug penetration are restrictive porin proteins. Efflux pumps of the resistance nodulation cell division family are major players in Burkholderia multidrug resistance. Third and fourth generation β-lactam antibiotics are seminal for treatment of Burkholderia infections, but therapeutic efficacy is compromised by expression of several β-lactamases and ceftazidime target mutations. Altered DNA gyrase and dihydrofolate reductase targets cause fluoroquinolone and trimethoprim resistance, respectively. Although antibiotic resistance hampers therapy of Burkholderia infections, the characterization of resistance mechanisms lags behind other non-enteric Gram-negative pathogens, especially ESKAPE bacteria such as Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. PMID:27620956

Self-Assessment of Antimicrobial Stewardship in Primary Care: Self-Reported Practice Using the TARGET Primary Care Self-Assessment Tool

PubMed Central

Owens, Rebecca; Moore, Michael; Pilat, Dirk; McNulty, Cliodna

2017-01-01

Multifaceted antimicrobial stewardship (AMS) interventions including: antibiotic guidance, reviews of antibiotic use using audits, education, patient facing materials, and self-assessment, are successful in improving antimicrobial use. We aimed to measure the self-reported AMS activity of staff completing a self-assessment tool (SAT). The Royal College of General Practitioners (RCGP)/Public Health England (PHE) SAT enables participants considering an AMS eLearning course to answer 12 short questions about their AMS activities. Questions cover guidance, audit, and reflection about antibiotic use, patient facing materials, and education. Responses are recorded digitally. Data were collated, anonymised, and exported into Microsoft Excel. Between November 2014 and June 2016, 1415 users completed the SAT. Ninety eight percent reported that they used antibiotic guidance for treating common infections and 63% knew this was available to all prescribers. Ninety four percent of GP respondents reported having used delayed prescribing when appropriate, 25% were not using Read codes, and 62% reported undertaking a practice-wide antibiotic audit in the last two years, of which, 77% developed an audit action plan. Twenty nine percent had undertaken other antibiotic-related clinical courses. Fifty six percent reported sharing patient leaflets covering infection. Many prescribers reported undertaking a range of AMS activities. GP practice managers should ensure that all clinicians have access to prescribing guidance. Antibiotic audits should be encouraged to enable GP staff to understand their prescribing behaviour and address gaps in good practice. Prescribers are not making full use of antibiotic prescribing-related training opportunities. Read coding facilitates more accurate auditing and its use by all clinicians should be encouraged. PMID:28813003

Self-Assessment of Antimicrobial Stewardship in Primary Care: Self-Reported Practice Using the TARGET Primary Care Self-Assessment Tool.

PubMed

Owens, Rebecca; Jones, Leah Ffion; Moore, Michael; Pilat, Dirk; McNulty, Cliodna

2017-08-16

Multifaceted antimicrobial stewardship (AMS) interventions including: antibiotic guidance, reviews of antibiotic use using audits, education, patient facing materials, and self-assessment, are successful in improving antimicrobial use. We aimed to measure the self-reported AMS activity of staff completing a self-assessment tool (SAT). The Royal College of General Practitioners (RCGP)/Public Health England (PHE) SAT enables participants considering an AMS eLearning course to answer 12 short questions about their AMS activities. Questions cover guidance, audit, and reflection about antibiotic use, patient facing materials, and education. Responses are recorded digitally. Data were collated, anonymised, and exported into Microsoft Excel. Between November 2014 and June 2016, 1415 users completed the SAT. Ninety eight percent reported that they used antibiotic guidance for treating common infections and 63% knew this was available to all prescribers. Ninety four percent of GP respondents reported having used delayed prescribing when appropriate, 25% were not using Read codes, and 62% reported undertaking a practice-wide antibiotic audit in the last two years, of which, 77% developed an audit action plan. Twenty nine percent had undertaken other antibiotic-related clinical courses. Fifty six percent reported sharing patient leaflets covering infection. Many prescribers reported undertaking a range of AMS activities. GP practice managers should ensure that all clinicians have access to prescribing guidance. Antibiotic audits should be encouraged to enable GP staff to understand their prescribing behaviour and address gaps in good practice. Prescribers are not making full use of antibiotic prescribing-related training opportunities. Read coding facilitates more accurate auditing and its use by all clinicians should be encouraged.

The effect of systemic antibiotics administered during the active phase of non-surgical periodontal therapy or after the healing phase: a systematic review.

PubMed

Fritoli, Aretuza; Gonçalves, Cristiane; Faveri, Marcelo; Figueiredo, Luciene Cristina; Pérez-Chaparro, Paula Juliana; Fermiano, Daiane; Feres, Magda

2015-01-01

The aim of this systematic review was to compare the clinical effectiveness of systemic antibiotics administered in the active stage of periodontal treatment or after the healing phase. An electronic search was performed in the databases EMBASE, MEDLINE and Cochrane Central Register of Controlled Trials (CENTRAL), in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement. A manual search of the reference list of selected studies and of review articles was also performed up to November 2013. Randomized Clinical Trials (RCT) that evaluated the systemic administration of antibiotics as adjuvants to scaling and root planning (SRP) at different phases of periodontal treatment were included. Systematic reviews and studies that evaluated subjects with systemic diseases and those that used subantimicrobial doses of antibiotics were excluded. The initial search identified 1,039 articles, of which seven were selected, and only one met the inclusion criteria. This study showed that subjects taking metronidazole and amoxicillin at the initial phase of treatment exhibited statistically significantly greater reduction in pocket depth and gain in clinical attachment level in initially deep sites (PD≥7 mm) than subjects taking antibiotics after healing (p<0.05). This comparison was conducted 2 months after antibiotic intake, at the healing phase. To date, only one short-term RCT has directly compared different moments of systemic antibiotics administration, as adjuncts to SRP, in the treatment of periodontitis. Although the results of this study suggested some benefits for antibiotics intake during the active phase of therapy, these findings need to be confirmed by larger placebo-controlled randomized clinical trials with longer follow-up periods.

[Development of arbekacin and synthesis of new derivatives stable to enzymatic modifications by methicillin-resistant Staphylococcus aureus].

PubMed

Kondo, S

1994-06-01

Our studies on the resistance mechanisms and chemical modifications of aminoglycoside antibiotics led to the synthesis of arbekacin (ABK), which was refractory to most aminoglycoside-modifying enzymes in resistant bacteria. In 1990, ABK was launched into clinical uses in Japan as a chemotherapeutic agent for the treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA). By 1993 only a few MRSA strains moderately resistant to ABK (MIC, 6.25-12.5 micrograms/ml) had clinically been isolated. ABK was modified by the reaction with an excess of an enzyme preparation extracted from an ABK-resistant strain (12.5 micrograms/ml) and three inactivated products were produced, consisting mainly of ABK 2''-phosphate along with small amounts of 6'-N-acetyl-ABK and the doubly modified ABK. Based on these results, replacement of the 2''-hydroxyl by amino group in dibekacin (DKB) or in ABK was designed to obtain potent active derivatives against MRSA. Conversion of the 2''-hydroxyl group by DMSO-DCC oxidation followed by reductive amination with NH4OAc-NaBH3CN gave 2''-amino-2''-deoxy-DKB (D1) and -ABK (A1). Their 5-deoxy (D2 and A2), 5-epifluoro (D3 and A3) and 5-epiamino (D4 and A4) derivatives were also synthesized. All 2''-amino-2''-deoxy-ABK derivatives (A1, A2, A3 and A4) showed excellent activities against MRSA and Gram-negative bacteria, as expected. Among them, A4 having low acute toxicity and nephrotoxicity was selected as a new candidate for anti-MRSA agent.

Fragments of the Bacterial Toxin Microcin B17 as Gyrase Poisons

PubMed Central

Collin, Frédéric; Thompson, Robert E.; Jolliffe, Katrina A.; Payne, Richard J.; Maxwell, Anthony

2013-01-01

Fluoroquinolones are very important drugs in the clinical antibacterial arsenal; their success is principally due to their mode of action: the stabilisation of a gyrase-DNA intermediate (the cleavage complex), which triggers a chain of events leading to cell death. Microcin B17 (MccB17) is a modified peptide bacterial toxin that acts by a similar mode of action, but is unfortunately unsuitable as a therapeutic drug. However, its structure and mechanism could inspire the design of new antibacterial compounds that are needed to circumvent the rise in bacterial resistance to current antibiotics. Here we describe the investigation of the structural features responsible for MccB17 activity and the identification of fragments of the toxin that retain the ability to stabilise the cleavage complex. PMID:23593482

Fragments of the bacterial toxin microcin B17 as gyrase poisons.

PubMed

Collin, Frédéric; Thompson, Robert E; Jolliffe, Katrina A; Payne, Richard J; Maxwell, Anthony

2013-01-01

Fluoroquinolones are very important drugs in the clinical antibacterial arsenal; their success is principally due to their mode of action: the stabilisation of a gyrase-DNA intermediate (the cleavage complex), which triggers a chain of events leading to cell death. Microcin B17 (MccB17) is a modified peptide bacterial toxin that acts by a similar mode of action, but is unfortunately unsuitable as a therapeutic drug. However, its structure and mechanism could inspire the design of new antibacterial compounds that are needed to circumvent the rise in bacterial resistance to current antibiotics. Here we describe the investigation of the structural features responsible for MccB17 activity and the identification of fragments of the toxin that retain the ability to stabilise the cleavage complex.

Borrelidins C-E: New Antibacterial Macrolides from a Saltern-Derived Halophilic Nocardiopsis sp.

PubMed

Kim, Jungwoo; Shin, Daniel; Kim, Seong-Hwan; Park, Wanki; Shin, Yoonho; Kim, Won Kyung; Lee, Sang Kook; Oh, Ki-Bong; Shin, Jongheon; Oh, Dong-Chan

2017-06-06

Chemical investigation of a halophilic actinomycete strain belonging to the genus Nocardiopsis inhabiting a hypersaline saltern led to the discovery of new 18-membered macrolides with nitrile functionality, borrelidins C-E ( 1 - 3 ), along with a previously reported borrelidin ( 4 ). The planar structures of borrelidins C-E, which are new members of the rare borrelidin class of antibiotics, were elucidated by NMR, mass, IR, and UV spectroscopic analyses. The configurations of borrelidines C-E were determined by the interpretation of ROESY NMR spectra, J-based configuration analysis, a modified Mosher's method, and CD spectroscopic analysis. Borrelidins C and D displayed inhibitory activity, particularly against the Gram-negative pathogen Salmonella enterica , and moderate cytotoxicity against the SNU638 and K562 carcinoma cell lines.

Antimalarial Activities of Peptide Antibiotics Isolated from Fungi

PubMed Central

Nagaraj, G.; Uma, M. V.; Shivayogi, M. S.; Balaram, Hemalatha

2001-01-01

Malaria caused by Plasmodium falciparum is a major public health problem in the developing countries of the world. Clinical treatment of malaria has become complicated due to the occurrence of infections caused by drug resistant parasites. Secondary metabolites from fungi are an attractive source of chemotherapeutic agents. This work reports the isolation and in vitro antiplasmodial activities of peptide antibiotics of fungal origin. The three peptide antibiotics used in this study were efrapeptins, zervamicins, and antiamoebin. The high-performance liquid chromatography-purified peptides were characterized by nuclear magnetic resonance and mass spectral analysis. All three fungal peptides kill P. falciparum in culture with 50% inhibitory concentrations in the micromolar range. A possible mode of action of these peptide antibiotics on P. falciparum is presented. PMID:11120957

Bu-2470, a new peptide antibiotic complex. I. Production, isolation and properties of Bu-2470 A, B1 and B2.

PubMed

Konishi, M; Sugawara, K; Tomita, K; Matsumoto, K; Miyaki, T; Fujisawa, K; Tsukiura, H; Kawaguchi, H

1983-06-01

A strain of Bacillus circulans produced a complex of basic peptide antibiotics designated Bu-2470, which was found to contain four active components, A, B1, B2a and B2b. Bu-2470 A specifically inhibited various Pseudomonas species including P. aeruginosa, P. maltophilia and P. putida, but otherwise its antibacterial spectrum was limited to certain Gram-negative organisms. Bu-2470 B1 and B2 (B2a + B2b) showed broad antibiotic activity against Gram-positive and Gram-negative bacteria including Pseudomonas species. The physicochemical and biological properties of Bu-2470 B1 and B2 are very similar to those of the octapeptin group of antibiotics.

Impact of different antibiotics on methane production using waste-activated sludge: mechanisms and microbial community dynamics.

PubMed

Mustapha, Nurul Asyifah; Sakai, Kenji; Shirai, Yoshihito; Maeda, Toshinari

2016-11-01

Anaerobic digestion is an effective method for reducing the by-product of waste-activated sludge (WAS) from wastewater treatment plants and for producing bioenergy from WAS. However, only a limited number of studies have attempted to improve anaerobic digestion by targeting the microbial interactions in WAS. In this study, we examined whether different antibiotics positively, negatively, or neutrally influence methane fermentation by evaluating changes in the microbial community and functions in WAS. Addition of azithromycin promoted the microbial communities related to the acidogenic and acetogenic stages, and a high concentration of soluble proteins and a high activity of methanogens were detected. Chloramphenicol inhibited methane production but did not affect the bacteria that contribute to the hydrolysis, acidogenesis, and acetogenesis digestion stages. The addition of kanamycin, which exhibits the same methane productivity as a control (antibiotic-free WAS), did not affect all of the microbial communities during anaerobic digestion. This study demonstrates the simultaneous functions and interactions of diverse bacteria and methanogenic Archaea in different stages of the anaerobic digestion of WAS. The ratio of Caldilinea, Methanosarcina, and Clostridium may correspond closely to the trend of methane production in each antibiotic. The changes in microbial activities and function by antibiotics facilitate a better understanding of bioenergy production.

The fate of antibiotic resistance genes and class 1 integrons following the application of swine and dairy manure to soils.

PubMed

Sandberg, Kyle D; LaPara, Timothy M

2016-02-01

The goal of this study was to determine the fate of antibiotic resistance genes (ARGs) and class 1 integrons following the application of swine and dairy manure to soil. Soil microcosms were amended with either manure from swine fed subtherapeutic levels of antibiotics or manure from dairy cows that were given antibiotics only rarely and strictly for veterinary purposes. Microcosms were monitored for 6 months using quantitative PCR targeting 16S rRNA genes (a measure of bacterial biomass), intI1, erm(B), tet(A), tet(W) and tet(X). Swine manure had 10- to 100-fold higher levels of ARGs than the dairy manure, all of which decayed over time after being applied to soil. A modified Collins-Selleck model described the decay of ARGs in the soil microcosms well, particularly the characteristic in which the decay rate declined over time. By the completion of the soil microcosm experiments, ARGs in the dairy manure-amended soils returned to background levels, whereas the ARGs in swine manure remained elevated compared to control microcosms. Our research suggests that the use of subtherapeutic use of antibiotics in animal feed could lead to the accumulation of ARGs in soils to which manure is applied. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Towards the discovery of drug-like RNA ligands?

PubMed

Foloppe, Nicolas; Matassova, Natalia; Aboul-Ela, Fareed

2006-11-01

Targeting RNA with small molecule drugs is an area of great potential for therapeutic treatment of infections and possibly genetic and autoimmune diseases. However, a mature set of precedents and established methodology is lacking. The physicochemical properties of RNA raise specific issues and obstacles to development, and contribute to explain the distinct characteristics of natural RNA ligands, including antibiotics. Yet, RNA-targeting strategies are being implemented to reinvigorate antibacterial discovery by using the ribosomal X-ray structures to modify known antibiotics. To exploit further these structures, we suggest the use of existing protein kinase-directed libraries of drug-like compounds to target the A-site of the bacterial ribosome, on the basis of a specific structural hypothesis.

Effect of three lactobacilli with strain-specific activities on the growth performance, faecal microbiota and ileum mucosa proteomics of piglets.

PubMed

Su, Yating; Chen, Xingjie; Liu, Ming; Guo, Xiaohua

2017-01-01

The beneficial effects of Lactobacillus probiotics in animal production are often strain-related. Different strains from the same species may exert different weight-gain effect on hosts in vivo. Most lactobacilli are selected based on their in vitro activities, and their metabolism and regulation on the intestine based on strain-related characters are largely unexplored. The objective of the present study was to study the in vivo effects of the three lactobacilli on growth performance and to compare the differential effects of the strains on the faecal microbiota and ileum mucosa proteomics of piglets. Three hundred and sixty piglets were assigned to one of four treatments, which included an antibiotics-treated control and three experimental groups supplemented with the three lactobacilli, L. salivarius G1-1, L. reuteri G8-5 and L. reuteri G22-2, respectively. Piglets were weighed and the feed intake was recorded to compare the growth performance. The faecal lactobacilli and coliform was quantified using quantitative PCR and the faecal microbiota was profiled by denaturing gradient gel electrophoresis (DGGE). The proteomic approach was applied to compare the differential expression of proteins in the ileum mucosa. No statistical difference was found among the three Lactobacillus -treated groups in animal growth performance compared with the antibiotics-treated group ( P  > 0.05). Supplementation of lactobacilli in diets significantly increased the relative 16S rRNA gene copies of Lactobacillus genus on both d 14 and d 28 ( P  < 0.05)., and the bacterial community profiles based on DGGE from the lactobacilli-treated groups were distinctly different from the antibiotics-treated group ( P  < 0.05). The ileum mucosa of piglets responded to all Lactobacillus supplementation by producing more newly expressed proteins and the identified proteins were all associated with the functions beneficial for stabilization of cell structure. Besides, some other up-regulated and down-regulated proteins in different Lactobacillus -treated groups showed the expression of proteins were partly strain-related. All the three lactobacilli in this study show comparable effects to antibiotics on piglets growth performance. The three lactobacilli were found able to modify intestinal microbiota and mucosa proteomics. The regulation of protein expression in the intestinal mucosa are partly associated with the strains administrated in feed.

Oral versus intravenous antibiotics for patients with Klebsiella pneumoniae liver abscess: study protocol for a randomized controlled trial.

PubMed

Molton, James; Phillips, Rachel; Gandhi, Mihir; Yoong, Joanne; Lye, David; Tan, Thuan Tong; Fisher, Dale; Archuleta, Sophia

2013-10-31

Klebsiella pneumoniae liver abscess is the most common etiology of liver abscess in Singapore and much of Asia, and its incidence is increasing. Current management includes prolonged intravenous antibiotic therapy, but there is limited evidence to guide oral conversion. The implicated K1/K2 capsule strain of Klebsiella pneumoniae is almost universally susceptible to ciprofloxacin, an antibiotic with high oral bioavailability. Our primary aim is to compare the efficacy of early (< one week) step-down to oral antibiotics, to continuing four weeks of intravenous antibiotics, in patients with Klebsiella liver abscess. The study is designed as a multi-center randomized open-label active comparator-controlled non-inferiority trial, with a non-inferiority margin of 12%. Eligible participants will be inpatients over the age of 21 with a CT or ultrasound scan suggestive of a liver abscess, and Klebsiella pneumoniae isolated from abscess fluid or blood. Randomization into intervention or active control arms will be performed with a 1:1 allocation ratio. Participants randomized to active control will receive IV ceftriaxone 2 grams daily to complete a total of four weeks of IV antibiotics. Participants randomized to intervention will be immediately converted to oral ciprofloxacin 750 mg twice daily. At Week four, all participants will undergo abdominal imaging and be assessed for clinical response (CRP < 20 mg/l, absence of fever, plus scan showing that the maximal diameter of the abscess has reduced). If criteria are met, antibiotics are stopped; if not, oral antibiotics are continued, with reassessment for clinical response fortnightly. If criteria for clinical response are met by Week 12, the primary endpoint of clinical cure is met. A cost analysis will be performed to assess the cost saving of early conversion to oral antibiotics, and a quality of life analysis will be performed to assess whether treatment with oral antibiotics is less burdensome than prolonged IV antibiotics. Our results would help inform local and international practice guidelines regarding the optimal antibiotic management of Klebsiella liver abscess. A finding of non-inferiority may translate to the wider adoption of a more cost-effective strategy that reduces hospital length of stay and improves patient-centered outcomes and satisfaction. Clinical trials gov NCT01723150.

The Antibiotic Resistance Problem Revisited

ERIC Educational Resources Information Center

Lawson, Michael A.

2008-01-01

The term "antibiotic" was first proposed by Vuillemin in 1889 but was first used in the current sense by Walksman in 1941. An antibiotic is defined as a "derivative produced by the metabolism of microorganisms that possess antibacterial activity at low concentrations and is not toxic to the host." In this article, the author describes how…

Platensimycin and platencin: promising antibiotics for future application in human medicine.

PubMed

Martens, Evan; Demain, Arnold L

2011-11-01

Platensimycin and platencin are novel antibiotics produced by Streptomyces platensis. They are potent and non-toxic natural products active against Gram-positive pathogens, including antibiotic-resistant strains and Mycobacterium tuberculosis. They were isolated using an intriguing target-based whole-cell antisense differential sensitivity assay as inhibitors of fatty acid biosynthesis of type II. This type of biosynthesis is not present in humans. Platensimycin inhibits the elongation-condensing enzyme FabF, whereas platencin inhibits both FabF and FabH. For these antibiotics to become successful drugs, their pharmacokinetics must be improved. They have too high a rate of clearance in the body, yielding a low degree of systematic exposure. They work well when administered by continuous infusion, but this is not a useful method of delivery to patients. The two antibiotics and many analogs have been prepared by chemical synthesis. Natural congeners have also been obtained from the producing actinomycete. However, none of these molecules are as active as platensimycin and platencin. Using tools of rational metabolic engineering, superior strains have been produced making hundreds of times more antibiotic than the natural strains.

Berberine enhances the antibacterial activity of selected antibiotics against coagulase-negative Staphylococcus strains in vitro.

PubMed

Wojtyczka, Robert D; Dziedzic, Arkadiusz; Kępa, Małgorzata; Kubina, Robert; Kabała-Dzik, Agata; Mularz, Tomasz; Idzik, Danuta

2014-05-22

Synergistic interactions between commonly used antibiotics and natural bioactive compounds may exhibit therapeutic benefits in a clinical setting. Berberine, an isoquinoline-type alkaloid isolated from many kinds of medicinal plants, has proven efficacy against a broad spectrum of microorganisms. The aim of the presented work was to assess the antibacterial activity of berberine chloride in light of the effect exerted by common antibiotics on fourteen reference strains of Staphylococccus spp., and to evaluate the magnitude of interactions of berberine with these antistaphylococcal antibiotics. In our study minimum inhibitory concentrations (MIC) of berberine chloride against CoNS ranged from 16 to 512 µg/mL. The most noticeable effects were observed for S. haemolyticus ATCC 29970, S. epidermidis ATCC 12228, S. capitis subsp. capitis ATCC 35661, S. galinarium ATCC 700401, S. hominis subsp. hominis ATCC 27844, S. intermedius ATCC 29663 and S. lugdunensis ATCC 49576. The most significant synergistic effect was noticed for berberine in combination with linezolid, cefoxitin and erythromycin. The synergy between berberine and antibiotics demonstrates the potential application of compound combinations as an efficient, novel therapeutic tool for antibiotic-resistant bacterial infections.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

PubMed

Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

2016-01-01

The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

PubMed Central

Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark

2016-01-01

ABSTRACT The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment. PMID:27536734

Controlled release of moxifloxacin from intraocular lenses modified by Ar plasma-assisted grafting with AMPS or SBMA: An in vitro study.

PubMed

Pimenta, A F R; Vieira, A P; Colaço, R; Saramago, B; Gil, M H; Coimbra, P; Alves, P; Bozukova, D; Correia, T R; Correia, I J; Guiomar, A J; Serro, A P

2017-08-01

Intraocular lenses (IOLs) present an alternative for extended, local drug delivery in the prevention of post-operative acute endophthalmitis. In the present work, we modified the surface of a hydrophilic acrylic material, used for manufacturing of IOLs, through plasma-assisted grafting copolymerization of 2-acrylamido-2-methylpropane sulfonic acid (AMPS) or [2-(methacryloyloxy)ethyl]dimethyl-(3-sulfopropyl)ammonium hydroxide (SBMA), with the aim of achieving a controlled and effective drug release. The material was loaded with moxifloxacin (MFX), a commonly used antibiotic for endophthalmitis prevention. The characterization of the modified material showed that relevant properties, like swelling capacity, wettability, refractive index and transmittance, were not affected by the surface modification. Concerning the drug release profiles, the most promising result was obtained when AMPS grafting was done in the presence of MFX. This modification led to a higher amount of drug being released for a longer period of time, which is a requirement for the prevention of endophthalmitis. The material was found to be non-cytotoxic for rabbit corneal endothelial cells. In a second step, prototype IOLs were modified with AMPS and loaded with MFX as previously and, after sterilization and storage (30days), they were tested under dynamic conditions, in a microfluidic cell with volume and renovation rate similar to the eye aqueous humour. MFX solutions collected in this assay were tested against Staphylococcus aureus and Staphylococcus epidermidis and the released antibiotic proved to be effective against both bacteria until the 12th day of release. Copyright © 2017 Elsevier B.V. All rights reserved.

Toward a new focus in antibiotic and drug discovery from the Streptomyces arsenal

PubMed Central

Antoraz, Sergio; Santamaría, Ramón I.; Díaz, Margarita; Sanz, David; Rodríguez, Héctor

2015-01-01

Emergence of antibiotic resistant pathogens is changing the way scientists look for new antibiotic compounds. This race against the increased prevalence of multi-resistant strains makes it necessary to expedite the search for new compounds with antibiotic activity and to increase the production of the known. Here, we review a variety of new scientific approaches aiming to enhance antibiotic production in Streptomyces. These include: (i) elucidation of the signals that trigger the antibiotic biosynthetic pathways to improve culture media, (ii) bacterial hormone studies aiming to reproduce intra and interspecific communications resulting in antibiotic burst, (iii) co-cultures to mimic competition-collaboration scenarios in nature, and (iv) the very recent in situ search for antibiotics that might be applied in Streptomyces natural habitats. These new research strategies combined with new analytical and molecular techniques should accelerate the discovery process when the urgency for new compounds is higher than ever. PMID:26029195

The distribution and partitioning of common antibiotics in water and sediment of the Pearl River Estuary, South China.

PubMed

Liang, Ximei; Chen, Baowei; Nie, Xiangping; Shi, Zhen; Huang, Xiaoping; Li, Xiangdong

2013-09-01

Antibiotics released into the aquatic environment play an important role in the spread of antibiotic resistance. In the Pearl River Estuary (PRE) and the coastal zone, the concentrations of antibiotics decreased from the Pearl River to the estuary, suggesting that antibiotics primarily originated from river tributaries and terrigenous sources. Within the PRE area, the concentrations of antibiotics in water were higher in the west coast than the east side, reflecting the high density of anthropogenic activities and hydraulic conditions along the west riverbank. Seasonal variations were also observed for most of detected antibiotics in water. The pseudo-partitioning coefficient of norfloxacin had a good correlation with the TOC content of sediments, as did erythromycin-H2O with the pH of water. The results suggest that environmental conditions can significantly affect the distribution of antibiotics between water and sediment. Copyright © 2013 Elsevier Ltd. All rights reserved.

A combined pharmacodynamic quantitative and qualitative model reveals the potent activity of daptomycin and delafloxacin against Staphylococcus aureus biofilms.

PubMed

Bauer, Julia; Siala, Wafi; Tulkens, Paul M; Van Bambeke, Françoise

2013-06-01

Biofilms are associated with persistence of Staphylococcus aureus infections and therapeutic failures. Our aim was to set up a pharmacodynamic model comparing antibiotic activities against biofilms and examining in parallel their effects on viability and biofilm mass. Biofilms of S. aureus ATCC 25923 (methicillin-sensitive S. aureus [MSSA]) or ATCC 33591 (methicillin-resistant S. aureus [MRSA]) were obtained by culture in 96-well plates for 6 h/24 h. Antibiotic activities were assessed after 24/48 h of exposure to concentrations ranging from 0.5 to 512 times the MIC. Biofilm mass and bacterial viability were quantified using crystal violet and the redox indicator resazurin. Biofilms stained with Live/Dead probes were observed by using confocal microscopy. Concentration-effect curves fitted sigmoidal regressions, with a 50% reduction toward both matrix and viability obtained at sub-MIC or low multiples of MICs against young biofilms for all antibiotics tested. Against mature biofilms, maximal efficacies and potencies were reduced, with none of the antibiotics being able to completely destroy the matrix. Delafloxacin and daptomycin were the most potent, reducing viability by more than 50% at clinically achievable concentrations against both strains, as well as reducing biofilm depth, as observed in confocal microscopy. Rifampin, tigecycline, and moxifloxacin were effective against mature MRSA biofilms, while oxacillin demonstrated activity against MSSA. Fusidic acid, vancomycin, and linezolid were less potent overall. Antibiotic activity depends on biofilm maturity and bacterial strain. The pharmacodynamic model developed allows ranking of antibiotics with respect to efficacy and potency at clinically achievable concentrations and highlights the potential utility of daptomycin and delafloxacin for the treatment of biofilm-related infections.

A Combined Pharmacodynamic Quantitative and Qualitative Model Reveals the Potent Activity of Daptomycin and Delafloxacin against Staphylococcus aureus Biofilms

PubMed Central

Bauer, Julia; Siala, Wafi; Tulkens, Paul M.

2013-01-01

Biofilms are associated with persistence of Staphylococcus aureus infections and therapeutic failures. Our aim was to set up a pharmacodynamic model comparing antibiotic activities against biofilms and examining in parallel their effects on viability and biofilm mass. Biofilms of S. aureus ATCC 25923 (methicillin-sensitive S. aureus [MSSA]) or ATCC 33591 (methicillin-resistant S. aureus [MRSA]) were obtained by culture in 96-well plates for 6 h/24 h. Antibiotic activities were assessed after 24/48 h of exposure to concentrations ranging from 0.5 to 512 times the MIC. Biofilm mass and bacterial viability were quantified using crystal violet and the redox indicator resazurin. Biofilms stained with Live/Dead probes were observed by using confocal microscopy. Concentration-effect curves fitted sigmoidal regressions, with a 50% reduction toward both matrix and viability obtained at sub-MIC or low multiples of MICs against young biofilms for all antibiotics tested. Against mature biofilms, maximal efficacies and potencies were reduced, with none of the antibiotics being able to completely destroy the matrix. Delafloxacin and daptomycin were the most potent, reducing viability by more than 50% at clinically achievable concentrations against both strains, as well as reducing biofilm depth, as observed in confocal microscopy. Rifampin, tigecycline, and moxifloxacin were effective against mature MRSA biofilms, while oxacillin demonstrated activity against MSSA. Fusidic acid, vancomycin, and linezolid were less potent overall. Antibiotic activity depends on biofilm maturity and bacterial strain. The pharmacodynamic model developed allows ranking of antibiotics with respect to efficacy and potency at clinically achievable concentrations and highlights the potential utility of daptomycin and delafloxacin for the treatment of biofilm-related infections. PMID:23571532

Underlying Mechanism of Antimicrobial Activity of Chitosan Microparticles and Implications for the Treatment of Infectious Diseases

PubMed Central

Jeon, Soo Jin; Oh, Manhwan; Yeo, Won-Sik; Galvão, Klibs N.; Jeong, Kwang Cheol

2014-01-01

The emergence of antibiotic resistant microorganisms is a great public health concern and has triggered an urgent need to develop alternative antibiotics. Chitosan microparticles (CM), derived from chitosan, have been shown to reduce E. coli O157:H7 shedding in a cattle model, indicating potential use as an alternative antimicrobial agent. However, the underlying mechanism of CM on reducing the shedding of this pathogen remains unclear. To understand the mode of action, we studied molecular mechanisms of antimicrobial activity of CM using in vitro and in vivo methods. We report that CM are an effective bactericidal agent with capability to disrupt cell membranes. Binding assays and genetic studies with an ompA mutant strain demonstrated that outer membrane protein OmpA of E. coli O157:H7 is critical for CM binding, and this binding activity is coupled with a bactericidal effect of CM. This activity was also demonstrated in an animal model using cows with uterine diseases. CM treatment effectively reduced shedding of intrauterine pathogenic E. coli (IUPEC) in the uterus compared to antibiotic treatment. Since Shiga-toxins encoded in the genome of bacteriophage is often overexpressed during antibiotic treatment, antibiotic therapy is generally not recommended because of high risk of hemolytic uremic syndrome. However, CM treatment did not induce bacteriophage or Shiga-toxins in E. coli O157:H7; suggesting that CM can be a potential candidate to treat infections caused by this pathogen. This work establishes an underlying mechanism whereby CM exert antimicrobial activity in vitro and in vivo, providing significant insight for the treatment of diseases caused by a broad spectrum of pathogens including antibiotic resistant microorganisms. PMID:24658463