Pathogen- and host-directed anti-inflammatory activities of macrolide antibiotics.

PubMed

Steel, Helen C; Theron, Annette J; Cockeran, Riana; Anderson, Ronald; Feldman, Charles

2012-01-01

Macrolide antibiotics possess several, beneficial, secondary properties which complement their primary antimicrobial activity. In addition to high levels of tissue penetration, which may counteract seemingly macrolide-resistant bacterial pathogens, these agents also possess anti-inflammatory properties, unrelated to their primary antimicrobial activity. Macrolides target cells of both the innate and adaptive immune systems, as well as structural cells, and are beneficial in controlling harmful inflammatory responses during acute and chronic bacterial infection. These secondary anti-inflammatory activities of macrolides appear to be particularly effective in attenuating neutrophil-mediated inflammation. This, in turn, may contribute to the usefulness of these agents in the treatment of acute and chronic inflammatory disorders of both microbial and nonmicrobial origin, predominantly of the airways. This paper is focused on the various mechanisms of macrolide-mediated anti-inflammatory activity which target both microbial pathogens and the cells of the innate and adaptive immune systems, with emphasis on their clinical relevance.

Pathogen- and Host-Directed Anti-Inflammatory Activities of Macrolide Antibiotics

PubMed Central

Steel, Helen C.; Theron, Annette J.; Cockeran, Riana; Anderson, Ronald; Feldman, Charles

2012-01-01

Macrolide antibiotics possess several, beneficial, secondary properties which complement their primary antimicrobial activity. In addition to high levels of tissue penetration, which may counteract seemingly macrolide-resistant bacterial pathogens, these agents also possess anti-inflammatory properties, unrelated to their primary antimicrobial activity. Macrolides target cells of both the innate and adaptive immune systems, as well as structural cells, and are beneficial in controlling harmful inflammatory responses during acute and chronic bacterial infection. These secondary anti-inflammatory activities of macrolides appear to be particularly effective in attenuating neutrophil-mediated inflammation. This, in turn, may contribute to the usefulness of these agents in the treatment of acute and chronic inflammatory disorders of both microbial and nonmicrobial origin, predominantly of the airways. This paper is focused on the various mechanisms of macrolide-mediated anti-inflammatory activity which target both microbial pathogens and the cells of the innate and adaptive immune systems, with emphasis on their clinical relevance. PMID:22778497

Nature nurtures the design of new semi-synthetic macrolide antibiotics.

PubMed

Fernandes, Prabhavathi; Martens, Evan; Pereira, David

2017-05-01

Erythromycin and its analogs are used to treat respiratory tract and other infections. The broad use of these antibiotics during the last 5 decades has led to resistance that can range from 20% to over 70% in certain parts of the world. Efforts to find macrolides that were active against macrolide-resistant strains led to the development of erythromycin analogs with alkyl-aryl side chains that mimicked the sugar side chain of 16-membered macrolides, such as tylosin. Further modifications were made to improve the potency of these molecules by removal of the cladinose sugar to obtain a smaller molecule, a modification that was learned from an older macrolide, pikromycin. A keto group was introduced after removal of the cladinose sugar to make the new ketolide subclass. Only one ketolide, telithromycin, received marketing authorization but because of severe adverse events, it is no longer widely used. Failure to identify the structure-relationship responsible for this clinical toxicity led to discontinuation of many ketolides that were in development. One that did complete clinical development, cethromycin, did not meet clinical efficacy criteria and therefore did not receive marketing approval. Work on developing new macrolides was re-initiated after showing that inhibition of nicotinic acetylcholine receptors by the imidazolyl-pyridine moiety on the side chain of telithromycin was likely responsible for the severe adverse events. Solithromycin is a fourth-generation macrolide that has a fluorine at the 2-position, and an alkyl-aryl side chain that is different from telithromycin. Solithromycin interacts at three sites on the bacterial ribosome, has activity against strains resistant to older macrolides (including telithromycin), and is mostly bactericidal. Pharmaceutical scientists involved in the development of macrolide antibiotics have learned from the teachings of Professor Satoshi Omura and progress in this field was not possible without his endeavors.

A platform for the discovery of new macrolide antibiotics

NASA Astrophysics Data System (ADS)

Seiple, Ian B.; Zhang, Ziyang; Jakubec, Pavol; Langlois-Mercier, Audrey; Wright, Peter M.; Hog, Daniel T.; Yabu, Kazuo; Allu, Senkara Rao; Fukuzaki, Takehiro; Carlsen, Peter N.; Kitamura, Yoshiaki; Zhou, Xiang; Condakes, Matthew L.; Szczypiński, Filip T.; Green, William D.; Myers, Andrew G.

2016-05-01

The chemical modification of structurally complex fermentation products, a process known as semisynthesis, has been an important tool in the discovery and manufacture of antibiotics for the treatment of various infectious diseases. However, many of the therapeutics obtained in this way are no longer effective, because bacterial resistance to these compounds has developed. Here we present a practical, fully synthetic route to macrolide antibiotics by the convergent assembly of simple chemical building blocks, enabling the synthesis of diverse structures not accessible by traditional semisynthetic approaches. More than 300 new macrolide antibiotic candidates, as well as the clinical candidate solithromycin, have been synthesized using our convergent approach. Evaluation of these compounds against a panel of pathogenic bacteria revealed that the majority of these structures had antibiotic activity, some efficacious against strains resistant to macrolides in current use. The chemistry we describe here provides a platform for the discovery of new macrolide antibiotics and may also serve as the basis for their manufacture.

A human health risk assessment for macrolide-resistant Campylobacter associated with the use of macrolides in Danish pig production.

PubMed

Alban, Lis; Nielsen, Elisabeth Okholm; Dahl, Jan

2008-02-01

In 2006, macrolides were withdrawn from the list of antibiotics recommended for veterinary treatment of diarrhoea in Danish pigs. The motive was to lower the antibiotic consumption in general and to mitigate the risk related to human infection with macrolide-resistant (Mres) Campylobacter. We subsequently conducted a risk assessment following international guidelines to address the risk for human health associated with usage of macrolides in Danish pigs. Data originated from surveillance programs, published papers, reports and statistics. Furthermore, an exposure model was built in @Risk. Mres Campylobacter is the hazard of interest. Data from different EU countries show that beef contains a very low prevalence (typically 0.1-1.1%) of Campylobacter; moreover, Mres is uncommon in Campylobacter isolates from cattle (between 0% and 6%). Beef was therefore left out of further analysis. For pork at retail, a high variation in the prevalence of Campylobacter has been reported within EU; but generally the prevalence is <10%, and the isolates are often Mres. EU data indicate that poultry meat harbor a high prevalence of Campylobacter (more more than 10%) with Mres at prevalence ranging from 0% to 8%. According to the exposure model - that included origin of meat as well as consumption patterns - most human cases of Mres campylobacteriosis (157 out of 186) was ascribed to imported meat. Only seven cases could be explained by veterinary usage of macrolides in Danish pigs. In general, human cases of campylobacteriosis are self-limiting, and it is questionable whether there is any excess risk related to infection with Mres Campylobacter compared to sensitive Campylobacter. In conclusion, the risk associated with veterinary use of macrolides in Danish pigs for the human health of Danes seemed to be low.

Macrolides versus azalides: a drug interaction update.

PubMed

Amsden, G W

1995-09-01

To describe the current drug interaction profiles for all approved and investigational macrolide and azalide antimicrobials, and to comment on the clinical impact of these interactions when appropriate. MEDLINE was searched to identify all pertinent studies, review articles, and case reports from 1975 to 1995. When appropriate information was not available in the literature, data were obtained from the product manufacturers. All available data were reviewed to give an unbiased account of possible drug interactions. Data for some of the interactions were not available from the literature, but were available from abstracts or from company-supplied materials. Although the data were not always entirely explicative, the best attempt was made to deliver the pertinent information that clinical practitioners would need to formulate practice opinions. When more in-depth information was supplied in the form of a review or study report, a thorough explanation of pertinent methodology was supplied. Since the introduction of erythromycin into clinical practice, there have been several clinically significant drug interactions identified throughout the literature associated with this drug. These interactions have been caused mostly by inhibition of the CYP3A subclass of hepatic enzymes, thereby decreasing the metabolism of any other agent given concurrently that is also cleared through this mechanism. With the development and marketing of several new macrolides, it was hoped that the drug interaction profile associated with this class would improve. This has been met with variable success. Although some of the extensions of the 14-membered ring macrolides have shown an incidence of interactions equal to that of erythromycin, others have shown improved profiles. In contrast, the 16-membered ring macrolides have demonstrated a much improved, though not absent, interaction profile. The most success in avoiding drug interactions through structure modification has been accomplished

Association Between the Order of Macrolide and Cephalosporin Treatment and Outcomes of Pneumonia

PubMed Central

Priya, Aruna; Mortensen, Eric M; Lindenauer, Peter K

2017-01-01

Abstract Background Many patients hospitalized with pneumonia are treated with combination macrolide/cephalosporin therapy. Macrolides have immunomodulatory effects and do not directly cause bacterial lysis. These effects suggest the possibility that initial treatment with a macrolide before a cephalosporin could improve patient outcomes by preventing the inflammatory response to rapid bacterial lysis that can be caused by cephalosporin treatment. This study explores whether initial treatment for pneumonia with a macrolide before a cephalosporin is associated with better patient outcomes than treatment with a cephalosporin before a macrolide. Methods This is a retrospective cohort study using a clinically rich database derived from electronic health records of 71 hospitals. We compared outcomes for pneumonia patients who received intravenous treatment with a macrolide at least 1 hour before a cephalosporin, versus patients who received a cephalosporin at least 1 hour before a macrolide. Propensity matching was performed for 527 patients in each group. Results Among the propensity-matched cohorts, for the macrolide first group, in-hospital mortality was 4.2% vs 5.5% for the cephalosporin first group (P = .31), combined in-hospital mortality/hospice discharge was 6.3% vs 9.3% (P = .06), median hospital length of stay was 101.5 hours vs 109.5 hours (P = .09), and 30-day readmission was 12.9% vs 10.6% (P = .27). Conclusions Treatment of pneumonia with a macrolide before a cephalosporin was not associated with significantly improved outcomes when compared with treatment with a cephalosporin first; however, the lower rate of mortality/discharge to hospice and the large confidence intervals allow for the possibility of a clinically significant benefit. PMID:28948176

Macrolide resistance in Legionella pneumophila: the role of LpeAB efflux pump.

PubMed

Massip, Clémence; Descours, Ghislaine; Ginevra, Christophe; Doublet, Patricia; Jarraud, Sophie; Gilbert, Christophe

2017-05-01

A previous study on 12 in vitro -selected azithromycin-resistant Legionella pneumophila lineages showed that ribosomal mutations were major macrolide resistance determinants. In addition to these mechanisms that have been well described in many species, mutations upstream of lpeAB operon, homologous to acrAB in Escherichia coli , were identified in two lineages. In this study, we investigated the role of LpeAB and of these mutations in macrolide resistance of L. pneumophila . The role of LpeAB was studied by testing the antibiotic susceptibility of WT, deleted and complemented L. pneumophila Paris strains. Translational fusion experiments using GFP as a reporter were conducted to investigate the consequences of the mutations observed in the upstream sequence of lpeAB operon. We demonstrated the involvement of LpeAB in an efflux pump responsible for a macrolide-specific reduced susceptibility of L. pneumophila Paris strain. Mutations in the upstream sequence of lpeAB operon were associated with an increased protein expression. Increased expression was also observed under sub-inhibitory macrolide concentrations in strains with both mutated and WT promoting regions. LpeAB are components of an efflux pump, which is a macrolide resistance determinant in L. pneumophila Paris strain. Mutations observed in the upstream sequence of lpeAB operon in resistant lineages led to an overexpression of this efflux pump. Sub-inhibitory concentrations of macrolides themselves participated in upregulating this efflux and could constitute a first step in the acquisition of a high macrolide resistance level. © 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.

Multiplex PCR To Identify Macrolide Resistance Determinants in Mannheimia haemolytica and Pasteurella multocida

PubMed Central

Rose, Simon; Desmolaize, Benoit; Jaju, Puneet; Wilhelm, Cornelia; Warrass, Ralf

2012-01-01

The bacterial pathogens Mannheimia haemolytica and Pasteurella multocida are major etiological agents in respiratory tract infections of cattle. Although these infections can generally be successfully treated with veterinary macrolide antibiotics, a few recent isolates have shown resistance to these drugs. Macrolide resistance in members of the family Pasteurellaceae is conferred by combinations of at least three genes: erm(42), which encodes a monomethyltransferase and confers a type I MLSB (macrolide, lincosamide, and streptogramin B) phenotype; msr(E), which encodes a macrolide efflux pump; and mph(E), which encodes a macrolide-inactivating phosphotransferase. Here, we describe a multiplex PCR assay that detects the presence of erm(42), msr(E), and mph(E) and differentiates between these genes. In addition, the assay distinguishes P. multocida from M. haemolytica by amplifying distinctive fragments of the 23S rRNA (rrl) genes. One rrl fragment acts as a general indicator of gammaproteobacterial species and confirms whether the PCR assay has functioned as intended on strains that are negative for erm(42), msr(E), and mph(E). The multiplex system has been tested on more than 40 selected isolates of P. multocida and M. haemolytica and correlated with MICs for the veterinary macrolides tulathromycin and tilmicosin, and the newer compounds gamithromycin and tildipirosin. The multiplex PCR system gives a rapid and robustly accurate determination of macrolide resistance genotypes and bacterial genus, matching results from microbiological methods and whole-genome sequencing. PMID:22564832

Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients.

PubMed

Simonis, Fabienne D; de Iudicibus, Gianfranco; Cremer, Olaf L; Ong, David S Y; van der Poll, Tom; Bos, Lieuwe D; Schultz, Marcus J

2018-01-01

Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1-4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43-0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39-0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS.

Macrolide therapy is associated with reduced mortality in acute respiratory distress syndrome (ARDS) patients

PubMed Central

de Iudicibus, Gianfranco; Cremer, Olaf L.; Ong, David S. Y.; van der Poll, Tom; Bos, Lieuwe D.; Schultz, Marcus J.

2018-01-01

Background Macrolides have been associated with favorable immunological effects in various inflammatory disease states. We investigated the association between macrolide therapy and mortality in patients with the acute respiratory distress syndrome (ARDS). Methods This was an unplanned secondary analysis of patients with ARDS within a large prospective observational study of critically ill patients in the intensive care units (ICUs) of two university-affiliated hospitals in the Netherlands. The exposure of interest was low-dose macrolide use prescribed for another reason than infection; we excluded patients who received high-dose macrolides for an infection. The primary endpoint was 30-day mortality. The association between macrolide therapy and mortality was determined in the whole cohort, as well as in a propensity score matched cohort; the association was compared between pulmonary versus non-pulmonary ARDS, and between two biological phenotypes based on plasma levels of 20 biomarkers. Results In total, 873 patients with ARDS were analyzed, of whom 158 patients (18%) received macrolide therapy during stay in ICU for a median duration of 3 (interquartile range, 1–4) days. Erythromycin was the most frequent prescribed macrolide (97%). Macrolide therapy was associated with reduced 30-day mortality in the whole cohort [22.8% vs. 31.6%; crude odds ratio (OR), 0.64 (interquartile range, 0.43–0.96), P=0.03]. The association in the propensity score matched cohort remained significant [22.8% vs. 32.9%; OR, 0.62 (interquartile range, 0.39–0.96), P=0.03]. Propensity matched associations with mortality were different in patients with non-pulmonary ARDS vs. pulmonary ARDS and also varied by biological phenotype. Conclusions These data together show that low-dose macrolide therapy prescribed for another reason than infection is associated with decreased mortality in patients with ARDS. PMID:29430441

Molecular characterization of macrolide resistant Streptococcus pyogenes isolates from pharyngitis patients in Serbia.

PubMed

Opavski, Natasa; Gajic, Ina; Borek, Anna L; Obszańska, Katarzyna; Stanojevic, Maja; Lazarevic, Ivana; Ranin, Lazar; Sitkiewicz, Izabela; Mijac, Vera

2015-07-01

A steady increase in macrolide resistance in Streptococcus pyogenes, group A streptococci (GAS) was reported in Serbia during 2004-2009 (9.9%). However, there are no data on the molecular epidemiology of pharyngeal macrolide resistance GAS (MRGAS) isolates. Therefore, the aims of this first nationwide study were to examine the prevalence of macrolide resistance in Serbian GAS and to determine their resistance phenotypes, genotypes and clonal relationships. Overall 3893 non-duplicate pharyngeal S. pyogenes isolates from outpatients with GAS infection were collected throughout country during 2008 and 2009. Among 486 macrolide resistant pharyngeal isolates collected, 103 were further characterized. Macrolide resistance phenotypes and genotypes were determined by double-disk diffusion test and PCR, respectively. Strain relatedness was determined by emm typing, multilocus sequence typing (MLST), multilocus variable tandem repeat analysis (MLVA), phage profiling (PP) and virulence factor profiling (VFP). Overall, macrolide resistance among GAS isolates in Serbia was 12.5%. M phenotype was the most common (71.8%), followed by iMLS (18.4%) and cMLS (9.7%). Three clonal complexes--emm75/mefA/ST49, emm12/mefA/ST36 and emm77/ermA/tetO/ST63 comprised over 90% of the tested strains. Although MLVA, PP and VFP distinguished 10, 20 and 12 different patterns, respectively, cluster analysis disclosed only small differences between strains which belonged to the same emm/ST type. Our data indicate dominance of three major internationally widely disseminated macrolide resistant clones and a high genetic homogeneity among the Serbian MRGAS population. Continued surveillance of macrolide resistance and clonal composition in MRGAS in Serbia in future is necessary to determine stability of MRGAS clones and to guide therapy strategies. Copyright © 2015 Elsevier B.V. All rights reserved.

Macrolide Hybrid Compounds: Drug Discovery Opportunities in Anti- Infective and Anti-inflammatory Area.

PubMed

Paljetak, Hana Cipcic; Tomaskovic, Linda; Matijasic, Mario; Bukvic, Mirjana; Fajdetic, Andrea; Verbanac, Donatella; Peric, Mihaela

2017-01-01

Macrolides, polyketide natural products, and their 15-membered semi-synthetic derivatives are composed of substituted macrocyclic lactone ring and used primarily as potent antibiotics. Recently their usefulness was extended to antimalarial and anti-inflammatory area. Hybrid macrolides presented in this article are the next generation semi-synthetic compounds that combine pharmacophores from antibacterial, antimalarial and anti-inflammatory area with 14- and 15-membered azalide scaffolds. Antibacterial azalide hybrids with sulphonamides showed improved activity against resistant streptococci while quinolone conjugates demonstrated full coverage of respiratory pathogens including macrolide resistant strains and their efficacy was confirmed in mouse pneumonia model. Antimalarial macrolide hybrids, mainly involving (chloro)quinoline pharmacophores, showed outstanding activity against chloroquine resistant strains, favourable pharmacokinetics, promising in vivo efficacy as well as encouraging developmental potential. Anti-inflammatory hybrids were obtained by combining macrolides with corticosteroid and non-steroidal anti-inflammatory drugs. They were found active in in vivo animal models of locally induced inflammation, asthma, inflammatory bowel disease and rheumatoid arthritis and demonstrated improved safety over parent steroid drugs. Overall, macrolide hybrids possess significant potential to be developed as potent novel medicines in therapeutic areas of utmost pharmaceutical interest. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Macrolide resistance mechanisms in Enterobacteriaceae: Focus on azithromycin.

PubMed

Gomes, Cláudia; Martínez-Puchol, Sandra; Palma, Noemí; Horna, Gertrudis; Ruiz-Roldán, Lidia; Pons, Maria J; Ruiz, Joaquim

2017-02-01

From its introduction in 1952 onwards, the clinical use of macrolides has been steadily increasing, both in human and veterinary medicine. Although initially designed to the treatment of Gram-positive microorganisms, this antimicrobial family has also been used to treat specific Gram-negative bacteria. Some of them, as azithromycin, are considered in the armamentarium against Enterobacteriaceae infections. However, the facility that this bacterial genus has to gain or develop mechanisms of antibiotic resistance may compromise the future usefulness of these antibiotics to fight against Enterobacteriaceae infections. The present review is focused on the mechanisms of macrolide resistance, currently described in Enterobacteriaceae.

Macrolides versus quinolones in Legionella pneumonia: results from the Community-Acquired Pneumonia Organization international study.

PubMed

Griffin, A T; Peyrani, P; Wiemken, T; Arnold, F

2010-04-01

Data supporting a quinolone or a macrolide as preferred therapy for community-acquired pneumonia (CAP) due to Legionella pneumophila are not firmly established. Some literature suggests a benefit of quinolones over macrolides. To compare time to clinical stability (TCS) and length of hospital stay (LOS) in patients with Legionella pneumonia who were treated with levofloxacin (LVX) compared to those treated with newer macrolides. An analysis of patients with Legionnaires' disease from the Community-Acquired Pneumonia Organization database was performed. Patients were diagnosed with CAP using radiographic and clinical criteria, while Legionella was detected by urinary antigen or sputum culture. All patients received a macrolide (azithromycin or clarithromycin) or LVX. TCS was defined as the time from hospital admission to candidacy for switch to oral therapy. A total of 39 patients were included for analysis. The mean TCS for the macrolide group was 5.1 days vs. 4.3 days for the LVX group (P = 0.43). The mean LOS for the macrolide group was 12.7 days vs. 8.9 days for the quinolone group (P = 0.10). LOS and TCS were not statistically different between the macrolide and the LVX groups in treating CAP due to Legionella, despite trends in both outcomes favoring LVX.

Toward the rational design of macrolide antibiotics to combat resistance

DOE PAGES

Pavlova, Anna; Parks, Jerry M.; Oyelere, Adegboyega K.; ...

2017-04-17

Here, macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from theirmore » crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.« less

Toward the rational design of macrolide antibiotics to combat resistance

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

Pavlova, Anna; Parks, Jerry M.; Oyelere, Adegboyega K.

Here, macrolides, one of the most prescribed classes of antibiotics, bind in the bacterial ribosome's polypeptide exit tunnel and inhibit translation. However, mutations and other ribosomal modifications, especially to the base A2058 of the 23S rRNA, have led to a growing resistance problem. Here, we have used molecular dynamics simulations to study the macrolides erythromycin and azithromycin in wild-type, A2058G-mutated, and singly or doubly A2058-methylated Escherichia coli ribosomes. We find that the ribosomal modifications result in less favorable interactions between the base 2058 and the desosamine sugar of the macrolides, as well as greater displacement of the macrolides from theirmore » crystal structure position, illuminating the causes of resistance. We have also examined four azithromycin derivatives containing aromatic indole-analog moieties, which were previously designed based on simulations of the stalling peptide SecM in the ribosome. Surprisingly, we found that the studied moieties could adopt very different geometries when interacting with a key base in the tunnel, A751, possibly explaining their distinct activities. Based on our simulations, we propose modifications to the indole-analog moieties that should increase their interactions with A751 and, consequently, enhance the potency of future azithromycin derivatives.« less

Association of macrolides with overall mortality and cardiac death among patients with various infections: A meta-analysis.

PubMed

Li, Xiang; Wang, Min; Liu, Guiyang; Ma, Jianli; Li, Chuntong

2016-03-01

A large body of evidences suggested that macrolide therapy could improve the survival of patients with various infections. While in the same time, macrolides are known to increase fatal arrhythmogenic risks and cause cardiac death. To assess the risks and benefits of macrolide therapy, we systematically reviewed all studies of macrolide use, cardiac death and mortality among patients with various infections. We searched Pubmed, Embase and Cochrane library and reviewed reference lists from 1980 through April 2015. Studies were included if they compared macrolides to other antibiotics in adults with various infections. The outcome measures were the overall mortality and the risk of cardiac death. Overall, macrolide use was associated with a statistically significant mortality reduction compared with nonmacrolide use (OR: 0.65, 95% CI: 0.46-0.92). There was no difference in the risk of cardiac death between macrolide and nonmacrolide regimes (OR: 1.43, 95% CI: 0.86-2.40). In subgroup analyses, macrolide use was found to be associated with the decreased risk of mortality in a population of older individuals (age>48 years, OR: 0.69; 95% CI: 0.66-0.72). While in a general population of young and middle-aged adults, the use of macrolide-based regimens could not decrease the risk of death from any cause (age<48 years, OR: 0.42; 95% CI: 0.02-11.01). As for cardiac death, macrolide use was found to be associated with increased risk of cardiac death in a population of older individuals (age>48 years, OR: 1.99; 95% CI: 1.53-2.59). Despite the potential cardiotoxic effects, there is a net benefit associated with macrolide use in older patients with various infections and macrolide use except roxithromycin was found to be associated with increased risk of cardiac death in a population of adults aged > 48 years. Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

High levels of macrolide-resistant Mycoplasma genitalium in Queensland, Australia.

PubMed

Trembizki, Ella; Buckley, Cameron; Bletchly, Cheryl; Nimmo, Graeme R; Whiley, David M

2017-10-01

The macrolide azithromycin is recommended for treatment of Mycoplasma genitalium infection; however, M. genitalium strains possessing macrolide resistance-mediating mutations (MRMMs) are increasingly being reported. Here, we used the SpeeDx ResistancePlus MG kit, which provides simultaneous detection of M. genitalium and MRMMs, to assess MRMM carriage among M. genitalium infections in Queensland, Australia. Performance characteristics of the ResistancePlus MG kit for M. genitalium detection were compared to in-house PCR. Available M. genitalium PCR-positive (n=67) and negative (n=281) samples from the years 2011 to 2017 were tested using the SpeeDx ResistancePlus MG kit. In total, 63.6 % M. genitalium-positive samples were indicated to harbour MRMMs. The ResistancePlus MG method provided sensitivity and specificity of 97 and 99.6 % respectively compared to in-house PCR for M. genitalium detection. Such high levels of macrolide-resistant M. genitalium raise further concerns over future use of azithromycin for treatment of M. genitalium infection.

Valosin containing protein (VCP) interacts with macrolide antibiotics without mediating their anti-inflammatory activities.

PubMed

Nujić, Krunoslav; Smith, Marjorie; Lee, Michael; Belamarić, Daniela; Tomašković, Linda; Alihodžić, Sulejman; Malnar, Ivica; Polančec, Denis; Schneider, Klaus; Eraković Haber, Vesna

2012-02-29

In addition to antibacterial activity, some macrolide antibiotics, such as azithromycin and clarithromycin, also exhibit anti-inflammatory properties in vitro and in vivo, although the targets and mechanism(s) of action remain unknown. The aim of the present study was to identify protein targets of azithromycin and clarithromycin which could potentially explain their anti-inflammatory effects. Using chemical proteomics approach, based on compound-immobilized affinity chromatography, valosin containing protein (VCP) was identified as a potential target of the macrolides. Validation studies confirmed the interaction of macrolides and VCP and gave some structural characteristics of this interaction. Cell based assays however, including the use of gene silencing and the study of VCP specific cellular functions in J774.A1 (murine macrophage) and IB3-1 (human cystic fibrotic epithelial) cell lines, failed to confirm an association between the binding of the macrolides to VCP and anti-inflammatory effects. These findings suggest the absence of an abundant high affinity protein target and the potential involvement of other biological molecules in the anti-inflammatory activity of macrolides. Copyright © 2011 Elsevier B.V. All rights reserved.

Inhibition of Protein Synthesis on the Ribosome by Tildipirosin Compared with Other Veterinary Macrolides

PubMed Central

Andersen, Niels Møller; Poehlsgaard, Jacob; Warrass, Ralf

2012-01-01

Tildipirosin is a 16-membered-ring macrolide developed to treat bacterial pathogens, including Mannheimia haemolytica and Pasteurella multocida, that cause respiratory tract infections in cattle and swine. Here we evaluated the efficacy of tildipirosin at inhibiting protein synthesis on the ribosome (50% inhibitory concentration [IC50], 0.23 ± 0.01 μM) and compared it with the established veterinary macrolides tylosin, tilmicosin, and tulathromycin. Mutation and methylation at key rRNA nucleotides revealed differences in the interactions of these macrolides within their common ribosomal binding site. PMID:22926570

History of macrolide use in pediatrics.

PubMed

Klein, J O

1997-04-01

Erythromycin, the prototypical macrolide, has been widely used since the 1950s in the management of pediatric infections. Erythromycin is the drug of choice for infants and children with Legionnaire's disease, pertussis, diphtheria, lower respiratory tract infections caused by Mycoplasma pneumoniae, Chlamydia pneumoniae and Chlamydia trachomatis and enteritis caused by Campylobacter jejuni. It is also indicated for treatment of syphilis; for streptococcal, staphylococcal and pneumococcal infections; genital infections caused by Ureaplasma urealyticum; and for the prevention of rheumatic fever and endocarditis in patients who are allergic to beta-lactam antibiotics. The new macrolides azithromycin and clarithromycin are also active against Borrelia burgdorferi, Helicobacter pylori, Mycobacterium avium-intracellulare complex, Cryptosporidium spp. and Toxoplasma gondii. Erythromycin is associated with a low risk of serious side effects, although gastric distress occurs in a significant proportion of patients. Drug interactions with theophylline, carbamazepine, warfarin, cyclosporine, terfenadine and digoxin limit erythromycin use. The newer macrolides azithromycin and clarithromycin are more stable, better absorbed and better tolerated than erythromycin. Azithromycin is more active than erythromycin against Haemophilus influenzae. Excellent tissue and intracellular penetration may contribute to their clinical efficacy. In children both azithromycin and clarithromycin are indicated for acute otitis media caused by Streptococcus pneumoniae, H. influenzae and Moraxella catarrhalis and for pharyngitis/tonsillitis caused by Streptococcus pyogenes. (As of December, 1996, azithromycin for oral suspension was approved for community-acquired pneumonia in children caused by C. pneumoniae, H. influenzae, M. pneumoniae and S. pneumoniae.) Claritromycin is also indicated for acute maxillary sinusitis, uncomplicated skin and skin structure infections, pneumonia and disseminated

Update on the combination effect of macrolide antibiotics in community-acquired pneumonia.

PubMed

Emmet O'Brien, M; Restrepo, Marcos I; Martin-Loeches, Ignacio

2015-09-01

Community-acquired pneumonia (CAP) is a leading cause of death from an infectious cause worldwide. Guideline-concordant antibiotic therapy initiated in a timely manner is associated with improved treatment responses and patient outcomes. In the post-antibiotic era, much of the morbidity and mortality of CAP is as a result of the interaction between bacterial virulence factors and host immune responses. In patients with severe CAP, or who are critically ill, there is a lot of emerging observational evidence demonstrating improved survival rates when treatment using combination therapy with a β-lactam and a macrolide is initiated, as compared to other antibiotic regimes without a macrolide. Macrolides in combination with a β-lactam antibiotic provide broader coverage for the atypical organisms implicated in CAP, and may contribute to antibacterial synergism. However, it has been postulated that the documented immunomodulatory effects of macrolides are the primary mechanism for improved patient outcomes through attenuation of bacterial virulence factors and host systemic inflammatory responses. Despite concerns regarding the limitations of observational evidence and the lack of confirmatory randomized controlled trials, the potential magnitude of mortality benefits estimated at 20-50% cannot be overlooked. In light of recent data from a number of trials showing that combination treatment with a macrolide and a suitable second agent is justified in all patients with severe CAP, such treatment should be obligatory for those admitted to an intensive care setting. Copyright © 2015 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Susceptibility of bacterial isolates from community-acquired infections in sub-Saharan Africa and Asia to macrolide antibiotics.

PubMed

Lubell, Yoel; Turner, Paul; Ashley, Elizabeth A; White, Nicholas J

2011-10-01

To review the literature on the susceptibility of common community pathogens in sub-Saharan Africa and Asia to the macrolide antibiotics. Inclusion criteria required that isolates were collected since 2004 to ensure results were of contemporary relevance. The data were aggregated by region, age group and sterility of site of culture sample. A total of 51 studies were identified, which reported the macrolide antimicrobial susceptibilities of common bacterial pathogens isolated since 2004. In general, there was less macrolide resistance in African than in Asian isolates. Most African studies reported high levels of macrolide susceptibility in Streptococcus pneumoniae, whereas most Chinese studies reported high levels of resistance. There was very little information available for Gram-negative organisms. Susceptibility of the pneumococcus to macrolides in SSA remains high in many areas, and good activity of azithromycin has been shown against Salmonellae spp. in Asia. In urban areas where high antibiotic consumption is prevalent, there was evidence of increased resistance to macrolides. However, there is no information on susceptibility from large areas in both continents. © 2011 Blackwell Publishing Ltd.

INVESTIGATING ENVIRONMENTAL SINKS OF MACROLIDE ANTIBIOTICS WITH ANALYTICAL CHEMISTRY

EPA Science Inventory

Possible environmental sinks (wastewater effluents, biosolids, sediments) of macrolide antibiotics (i.e., azithromycin, roxithromycin and clarithromycin)are investigated using state-of-the-art analytical chemistry techniques.

Whole Genome Sequence Analysis of Pig Respiratory Bacterial Pathogens with Elevated Minimum Inhibitory Concentrations for Macrolides.

PubMed

Dayao, Denise Ann Estarez; Seddon, Jennifer M; Gibson, Justine S; Blackall, Patrick J; Turni, Conny

2016-10-01

Macrolides are often used to treat and control bacterial pathogens causing respiratory disease in pigs. This study analyzed the whole genome sequences of one clinical isolate of Actinobacillus pleuropneumoniae, Haemophilus parasuis, Pasteurella multocida, and Bordetella bronchiseptica, all isolated from Australian pigs to identify the mechanism underlying the elevated minimum inhibitory concentrations (MICs) for erythromycin, tilmicosin, or tulathromycin. The H. parasuis assembled genome had a nucleotide transition at position 2059 (A to G) in the six copies of the 23S rRNA gene. This mutation has previously been associated with macrolide resistance but this is the first reported mechanism associated with elevated macrolide MICs in H. parasuis. There was no known macrolide resistance mechanism identified in the other three bacterial genomes. However, strA and sul2, aminoglycoside and sulfonamide resistance genes, respectively, were detected in one contiguous sequence (contig 1) of A. pleuropneumoniae assembled genome. This contig was identical to plasmids previously identified in Pasteurellaceae. This study has provided one possible explanation of elevated MICs to macrolides in H. parasuis. Further studies are necessary to clarify the mechanism causing the unexplained macrolide resistance in other Australian pig respiratory pathogens including the role of efflux systems, which were detected in all analyzed genomes.

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma

PubMed Central

Scholl, Ute I.; Abriola, Laura; Zhang, Chengbiao; Reimer, Esther N.; Plummer, Mark; Zhang, Junhui; Hoyer, Denton; Merkel, Jane S.; Wang, Wenhui; Lifton, Richard P.

2017-01-01

Aldosterone-producing adenomas (APAs) are benign tumors of the adrenal gland that constitutively produce the salt-retaining steroid hormone aldosterone and cause millions of cases of severe hypertension worldwide. Either of 2 somatic mutations in the potassium channel KCNJ5 (G151R and L168R, hereafter referred to as KCNJ5MUT) in adrenocortical cells account for half of APAs worldwide. These mutations alter channel selectivity to allow abnormal Na+ conductance, resulting in membrane depolarization, calcium influx, aldosterone production, and cell proliferation. Because APA diagnosis requires a difficult invasive procedure, patients often remain undiagnosed and inadequately treated. Inhibitors of KCNJ5MUT could allow noninvasive diagnosis and therapy of APAs carrying KCNJ5 mutations. Here, we developed a high-throughput screen for rescue of KCNJ5MUT-induced lethality and identified a series of macrolide antibiotics, including roxithromycin, that potently inhibit KCNJ5MUT, but not KCNJ5WT. Electrophysiology demonstrated direct KCNJ5MUT inhibition. In human aldosterone-producing adrenocortical cancer cell lines, roxithromycin inhibited KCNJ5MUT-induced induction of CYP11B2 (encoding aldosterone synthase) expression and aldosterone production. Further exploration of macrolides showed that KCNJ5MUT was similarly selectively inhibited by idremcinal, a macrolide motilin receptor agonist, and by synthesized macrolide derivatives lacking antibiotic or motilide activity. Macrolide-derived selective KCNJ5MUT inhibitors thus have the potential to advance the diagnosis and treatment of APAs harboring KCNJ5MUT. PMID:28604387

Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma.

PubMed

Scholl, Ute I; Abriola, Laura; Zhang, Chengbiao; Reimer, Esther N; Plummer, Mark; Kazmierczak, Barbara I; Zhang, Junhui; Hoyer, Denton; Merkel, Jane S; Wang, Wenhui; Lifton, Richard P

2017-06-30

Aldosterone-producing adenomas (APAs) are benign tumors of the adrenal gland that constitutively produce the salt-retaining steroid hormone aldosterone and cause millions of cases of severe hypertension worldwide. Either of 2 somatic mutations in the potassium channel KCNJ5 (G151R and L168R, hereafter referred to as KCNJ5MUT) in adrenocortical cells account for half of APAs worldwide. These mutations alter channel selectivity to allow abnormal Na+ conductance, resulting in membrane depolarization, calcium influx, aldosterone production, and cell proliferation. Because APA diagnosis requires a difficult invasive procedure, patients often remain undiagnosed and inadequately treated. Inhibitors of KCNJ5MUT could allow noninvasive diagnosis and therapy of APAs carrying KCNJ5 mutations. Here, we developed a high-throughput screen for rescue of KCNJ5MUT-induced lethality and identified a series of macrolide antibiotics, including roxithromycin, that potently inhibit KCNJ5MUT, but not KCNJ5WT. Electrophysiology demonstrated direct KCNJ5MUT inhibition. In human aldosterone-producing adrenocortical cancer cell lines, roxithromycin inhibited KCNJ5MUT-induced induction of CYP11B2 (encoding aldosterone synthase) expression and aldosterone production. Further exploration of macrolides showed that KCNJ5MUT was similarly selectively inhibited by idremcinal, a macrolide motilin receptor agonist, and by synthesized macrolide derivatives lacking antibiotic or motilide activity. Macrolide-derived selective KCNJ5MUT inhibitors thus have the potential to advance the diagnosis and treatment of APAs harboring KCNJ5MUT.

Predominant role of msr(D) over mef(A) in macrolide resistance in Streptococcus pyogenes.

PubMed

Zhang, Yan; Tatsuno, Ichiro; Okada, Ryo; Hata, Nanako; Matsumoto, Masakado; Isaka, Masanori; Isobe, Ken-ichi; Hasegawa, Tadao

2016-01-01

In Japan, the number of patients with streptococcal toxic shock syndrome is reported to be increasing. mef(A) gene-positive macrolide-resistant emm1 strains are thought to possibly contribute to the rise in the frequency of STSS. Although analyses of macrolide-resistant mechanisms, including mef(A) resistance, have been performed mainly in Streptococcus pneumoniae, the role of this gene in Streptococcus pyogenes has not been completely investigated. Therefore, to the best of our knowledge, we established the first mef(A)-knockout strain using an emm1-type S. pyogenes strain, and tested its susceptibility to erythromycin, clarithromycin and azithromycin. We found that the antimicrobial susceptibilities were almost identical to those of the parental strain. Hence, we established a knockout strain for another gene, msr(D), that is located immediately downstream of mef(A). The macrolide resistances of the resulting strain significantly decreased, and were further altered when both mef(A) and msr(D) were knocked out. The introduction of the msr(D) gene into a macrolide-sensitive strain conferred more resistance than the introduction of the mef(A) gene. The erythromycin susceptibilities of knockout strains were further dissected using two additional emm4- and emm75-type S. pyogenes strains. We found almost identical results for both strains except for the mef(A) knockout emm4 type, whose susceptibility was altered, although the change was less than that for the msr(D) knockout. These results suggest that both mef(A) and msr(D) are involved in macrolide resistance in S. pyogenes, and that the msr(D) gene plays a more predominant role in macrolide resistance than mef(A).

DNA Microarray for Detection of Macrolide Resistance Genes

PubMed Central

Cassone, Marco; D'Andrea, Marco M.; Iannelli, Francesco; Oggioni, Marco R.; Rossolini, Gian Maria; Pozzi, Gianni

2006-01-01

A DNA microarray was developed to detect bacterial genes conferring resistance to macrolides and related antibiotics. A database containing 65 nonredundant genes selected from publicly available DNA sequences was constructed and used to design 100 oligonucleotide probes that could specifically detect and discriminate all 65 genes. Probes were spotted on a glass slide, and the array was reacted with DNA templates extracted from 20 reference strains of eight different bacterial species (Streptococcus pneumoniae, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus haemolyticus, Escherichia coli, and Bacteroides fragilis) known to harbor 29 different macrolide resistance genes. Hybridization results showed that probes reacted with, and only with, the expected DNA templates and allowed discovery of three unexpected genes, including msr(SA) in B. fragilis, an efflux gene that has not yet been described for gram-negative bacteria. PMID:16723563

Macrolide antibiotics broadly and distinctively inhibit cytokine and chemokine production by COPD sputum cells in vitro.

PubMed

Marjanović, Nikola; Bosnar, Martina; Michielin, Francesca; Willé, David R; Anić-Milić, Tatjana; Culić, Ognjen; Popović-Grle, Sanja; Bogdan, Mile; Parnham, Michael J; Eraković Haber, Vesna

2011-05-01

Macrolide antibiotics are known to exert anti-inflammatory actions in vivo, including certain effects in COPD patients. In order to investigate the immunomodulatory profile of activity of macrolide antibiotics, we have studied the effects of azithromycin, clarithromycin, erythromycin and roxithromycin on the in vitro production of a panel of inflammatory mediators from cells isolated from human, steroid-naïve, COPD sputum samples. Macrolide effects were compared to three other commonly used anti-inflammatory compounds, the corticosteroid dexamethasone, the PDE4 inhibitor, roflumilast and the p38 kinase inhibitor, SB203580. Three of the four tested macrolides, azithromycin, clarithromycin and roxithromycin, exhibited pronounced, concentration-related reduction of IL-1β, IL-6, IL-10, TNF-α, CCL3, CCL5, CCL20, CCL22, CXCL1, CXCL5, and G-CSF release. Further slight inhibitory effects on IL-1α, CXCL8, GM-CSF, and PAI-1 production were also observed. Erythromycin was very weakly active. Qualitatively and quantitatively, macrolides exerted distinctive and, compared to other tested classes of compounds, more pronounced immunomodulatory effects, particularly in terms of chemokine (CCL3, CCL5, CCL20, CCL22, and CXCL5), IL-1β, G-CSF and PAI-1 release. The described modulation of inflammatory mediators could potentially contribute to further definition of biomarkers of macrolide anti-inflammatory activity in COPD. Copyright © 2011 Elsevier Ltd. All rights reserved.

Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion.

PubMed

Tarran, Robert; Sabater, Juan R; Clarke, Tainya C; Tan, Chong D; Davies, Catrin M; Liu, Jia; Yeung, Arthur; Garland, Alaina L; Stutts, M Jackson; Abraham, William M; Phillips, Gary; Baker, William R; Wright, Clifford D; Wilbert, Sibylle

2013-06-01

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2'-desoxy-9-(S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC₅₀ ~3.9 μM) and comparable to the antibacterial macrolide azithromycin (IC₅₀ ~2.4 μM). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance.

The crystal structure of two macrolide glycosyltransferases provides a blueprint for host cell antibiotic immunity

PubMed Central

Bolam, David N.; Roberts, Shirley; Proctor, Mark R.; Turkenburg, Johan P.; Dodson, Eleanor J.; Martinez-Fleites, Carlos; Yang, Min; Davis, Benjamin G.; Davies, Gideon J.; Gilbert, Harry J.

2007-01-01

Glycosylation of macrolide antibiotics confers host cell immunity from endogenous and exogenous agents. The Streptomyces antibioticus glycosyltransferases, OleI and OleD, glycosylate and inactivate oleandomycin and diverse macrolides including erythromycin, respectively. The structure of these enzyme–ligand complexes, in tandem with kinetic analysis of site-directed variants, provide insight into the interaction of macrolides with their synthetic apparatus. Erythromycin binds to OleD and the 23S RNA of its target ribosome in the same conformation and, although the antibiotic contains a large number of polar groups, its interaction with these macromolecules is primarily through hydrophobic contacts. Erythromycin and oleandomycin, when bound to OleD and OleI, respectively, adopt different conformations, reflecting a subtle effect on sugar positioning by virtue of a single change in the macrolide backbone. The data reported here provide structural insight into the mechanism of resistance to both endogenous and exogenous antibiotics, and will provide a platform for the future redesign of these catalysts for antibiotic remodelling. PMID:17376874

Nonantibiotic macrolides prevent human neutrophil elastase-induced mucus stasis and airway surface liquid volume depletion

PubMed Central

Sabater, Juan R.; Clarke, Tainya C.; Tan, Chong D.; Davies, Catrin M.; Liu, Jia; Yeung, Arthur; Garland, Alaina L.; Stutts, M. Jackson; Abraham, William M.; Phillips, Gary; Baker, William R.; Wright, Clifford D.; Wilbert, Sibylle

2013-01-01

Mucus clearance is an important component of the lung's innate defense system. A failure of this system brought on by mucus dehydration is common to both cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). Mucus clearance rates are regulated by the volume of airway surface liquid (ASL) and by ciliary beat frequency (CBF). Chronic treatment with macrolide antibiotics is known to be beneficial to both CF and COPD patients. However, chronic macrolide usage may induce bacterial resistance. We have developed a novel macrolide, 2′-desoxy-9-(S)-erythromycylamine (GS-459755), that has significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and Haemophilus influenzae. Since neutrophilia frequently occurs in chronic lung disease and human neutrophil elastase (HNE) induces mucus stasis by activating the epithelial sodium channel (ENaC), we tested the ability of GS-459755 to protect against HNE-induced mucus stasis. GS-459755 had no effect on HNE activity. However, GS-459755 pretreatment protected against HNE-induced ASL volume depletion in human bronchial epithelial cells (HBECs). The effect of GS-459755 on ASL volume was dose dependent (IC50 ∼3.9 μM) and comparable to the antibacterial macrolide azithromycin (IC50 ∼2.4 μM). Macrolides had no significant effect on CBF or on transepithelial water permeability. However, the amiloride-sensitive transepithelial voltage, a marker of ENaC activity, was diminished by macrolide pretreatment. We conclude that GS-459755 may limit HNE-induced activation of ENaC and may be useful for the treatment of mucus dehydration in CF and COPD without inducing bacterial resistance. PMID:23542952

Effect of subtherapeutic vs. therapeutic administration of macrolides on antimicrobial resistance in Mannheimia haemolytica and enterococci isolated from beef cattle

PubMed Central

Zaheer, Rahat; Cook, Shaun R.; Klima, Cassidy L.; Stanford, Kim; Alexander, Trevor; Topp, Edward; Read, Ron R.; McAllister, Tim A.

2013-01-01

Macrolides are the first-line treatment against bovine respiratory disease (BRD), and are also used to treat infections in humans. The macrolide, tylosin phosphate, is often included in the diet of cattle as a preventative for liver abscesses in many regions of the world outside of Europe. This study investigated the effects of administering macrolides to beef cattle either systemically through a single subcutaneous injection (therapeutic) or continuously in-feed (subtherapeutic), on the prevalence and antimicrobial resistance of Mannheimia haemolytica and Enterococcus spp. isolated from the nasopharynx and faeces, respectively. Nasopharyngeal and faecal samples were collected weekly over 28 days from untreated beef steers and from steers injected once with tilmicosin or tulathromycin or continuously fed tylosin phosphate at dosages recommended by manufacturers. Tilmicosin and tulathromycin were effective in lowering (P < 0.05) the prevalence of M. haemolytica, whereas subtherapeutic tylosin had no effect. M. haemolytica isolated from control- and macrolide-treated animals were susceptible to macrolides as well as to other antibiotics. Major bacteria co-isolated with M. haemolytica from the nasopharynx included Pasteurella multocida, Staphylococcus spp., Acinetobacter spp., Escherichia coli and Bacillus spp. With the exception of M. haemolytica and P. multocida, erythromycin resistance was frequently found in other isolated species. Both methods of macrolide administration increased (P < 0.05) the proportion of erythromycin resistant enterococci within the population, which was comprised almost exclusively of Enterococcus hirae. Injectable macrolides impacted both respiratory and enteric microbes, whereas orally administered macrolides only influenced enteric bacteria. PMID:23750157

Macrolides for treatment of Haemophilus ducreyi infection in sexually active adults.

PubMed

Romero, Laura; Huerfano, Cesar; Grillo-Ardila, Carlos F

2017-12-11

Chancroid is a genital ulcerative disease caused by Haemophilus ducreyi. This microorganism is endemic in Africa, where it can cause up to 10% of genital ulcers. Macrolides may be an effective alternative to treat chancroid and, based on their oral administration and duration of therapy, could be considered as first line therapy. To assess the effectiveness and safety of macrolides for treatment of H ducreyi infection in sexually active adults. We searched the Cochrane STI Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, WHO ICTRP, ClinicalTrials.gov and Web of Science to 30 October 2017. We also handsearched conference proceedings and reference lists of retrieved studies. Randomized controlled trials (RCTs) comparing macrolides in different regimens or with other therapeutic alternatives for chancroid. Two review authors independently assessed trials for inclusion, extracted data and assessed risk of bias. We resolved disagreements through consensus. We used the GRADE approach to assess the quality of the evidence. Seven RCTs (875 participants) met our inclusion criteria, of which four were funded by industry. Five studies (664 participants) compared macrolides with ceftriaxone, ciprofloxacin, spectinomycin or thiamphenicol. Low quality evidence suggested there was no difference between the groups after treatment in terms of clinical cure (risk ratio (RR) 1.09, 95% confidence interval (CI) 0.97 to 1.21; 2 studies, 340 participants with syndromic approach and RR 1.06, 95% CI 0.98 to 1.15; 5 studies, 348 participants with aetiological diagnosis) or improvement (RR 0.89, 95% CI 0.52 to 1.52; 2 studies, 340 participants with syndromic approach and RR 0.80, 95% CI 0.42 to 1.51; 3 studies, 187 participants with aetiological diagnosis). Based on low and very low quality evidence, there was no difference between macrolides and any other antibiotic treatments for microbiological cure (RR 0.93, 95% CI 0.74 to 1.16; 1 study, 45 participants) and minor adverse

Insights into resistance mechanism of the macrolide biosensor protein MphR(A) binding to macrolide antibiotic erythromycin by molecular dynamics simulation

NASA Astrophysics Data System (ADS)

Feng, Tingting; Zhang, Yanjun; Ding, Jing-Na; Fan, Song; Han, Ju-Guang

2015-12-01

Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and genetic expression regulating. MphR(A) protein binds to macrolide antibiotic erythromycin (Ery) and releases the gene operon, thus activates expression of the mphA gene and initiates Ery resistance. The two mutant amino acid residues (V66L and V126L) might potentially disrupt Ery binding to MphR(A). In these studies, the binding of macrolide antibiotic Ery to wild type (Wt) MphR(A) and double mutant (V66L/V126L) MphR(A) are explored by molecular dynamics simulations. Compared to the Apo-MphR(A) protein and Wt-MphR(A)-Ery complex, many interesting effects owing to the double mutant (V66L/V126L) are discovered. In the case of Ery, Helix I which plays an important role in transcription shows itself a right-hand α helix in Wt-MphR(A)-Ery, whereas the activated helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The calculated results exhibit that the double mutant V66L/V126L reduces the binding affinity of the V66L/V126L-MphR(A) to Ery, resulting in the block of Ery resistance. The binding free energy decomposition analysis reveals that the decrease of the binding affinity for the variant V66L/V126L-MphR(A)-Ery is mainly attributed to the gas phase electrostatic energies. The residue Leu66, Thr154, and Arg122 enhance the binding affinity of V66L/V126L-MphR(A) to Ery. The residues Tyr103 and His147 contributes mainly to binding energies in the Wt-MphR(A)-Ery complex, whereas the two residues have no contribution to the binding free energy inV66L/V126L-MphR(A)-Ery complex. Our study gives useful insights into the nature of amino acids mutation effect, the mechanism of blocking drug resistance at the atomic level and the characteristics in binding affinity for Ery to double mutant (V66L/V126L) MphR(A), which will contribute to the design of more effective macrolide antibiotics.

Combinations of Macrolide Resistance Determinants in Field Isolates of Mannheimia haemolytica and Pasteurella multocida▿

PubMed Central

Desmolaize, Benoit; Rose, Simon; Wilhelm, Cornelia; Warrass, Ralf; Douthwaite, Stephen

2011-01-01

Respiratory tract infections in cattle are commonly associated with the bacterial pathogens Mannheimia haemolytica and Pasteurella multocida. These infections can generally be successfully treated in the field with one of several groups of antibiotics, including macrolides. A few recent isolates of these species exhibit resistance to veterinary macrolides with phenotypes that fall into three distinct classes. The first class has type I macrolide, lincosamide, and streptogramin B antibiotic resistance and, consistent with this, the 23S rRNA nucleotide A2058 is monomethylated by the enzyme product of the erm(42) gene. The second class shows no lincosamide resistance and lacks erm(42) and concomitant 23S rRNA methylation. Sequencing of the genome of a representative strain from this class, P. multocida 3361, revealed macrolide efflux and phosphotransferase genes [respectively termed msr(E) and mph(E)] that are arranged in tandem and presumably expressed from the same promoter. The third class exhibits the most marked drug phenotype, with high resistance to all of the macrolides tested, and possesses all three resistance determinants. The combinations of erm(42), msr(E), and mph(E) are chromosomally encoded and intermingled with other exogenous genes, many of which appear to have been transferred from other members of the Pasteurellaceae. The presence of some of the exogenous genes explains recent reports of resistance to additional drug classes. We have expressed recombinant versions of the erm(42), msr(E), and mph(E) genes within an isogenic Escherichia coli background to assess their individually contributions to resistance. Our findings indicate what types of compounds might have driven the selection for these resistance determinants. PMID:21709086

Effects of macrolides on antigen-induced increases in cough reflex sensitivity in guinea pigs.

PubMed

Tokuda, Akira; Ohkura, Noriyuki; Fujimura, Masaki; Furusho, Shiho; Abo, Miki; Katayama, Nobuyuki

2010-02-01

Macrolides are antibiotics that have anti-inflammatory activities. Hence, they are used for both acute and chronic inflammatory airway diseases. However, the effects of these agents on allergic airway disorders presenting with an isolated chronic cough, such as non-asthmatic eosinophilic bronchitis and eosinophilic tracheobronchitis with cough hypersensitivity (atopic cough), still remain to be elucidated. To determine if macrolides are effective in the management of chronic cough caused by eosinophilic airway inflammation. The cough reflex sensitivity to inhaled capsaicin was measured at 48h after challenge with an aerosolized antigen in actively sensitized guinea pigs. The 14-, 15- or 16-membered macrolides (erythromycin, azythromycin, or josamycin, respectively) were given intraperitoneally every 12h after the antigen challenge. Bronchoalveolar lavage and the resection of the tracheal tissue were performed immediately after the measurement of the cough response to capsaicin. The antigen-induced increase in the number of coughs elicited by capsaicin inhalation was significantly reduced by treatments with erythromycin and azythromycin, but not with josamycin. Erythromycin dose-dependently inhibited the increases in the substance P, prostaglandin E(2) and leukotriene B(4) levels, but not the histamine levels, in the bronchoalveolar lavage fluid. However, erythromycin did not influence the antigen-induced decrease in the neutral endopeptidase (NEP) activity in the tracheal tissue. Both 14- and 15-membered, but not 16-membered, macrolides could reduce the antigen-induced cough reflex hypersensitivity by inhibiting the antigen-induced release of the afferent sensory nerve sensitizers. These macrolides may be therapeutically useful for the treatment of isolated chronic cough based on cough reflex hypersensitivity in allergic airway diseases such as non-asthmatic eosinophilic bronchitis and atopic cough. Copyright 2009 Elsevier Ltd. All rights reserved.

Molecular epidemiology, antimicrobial susceptibility, and characterization of macrolide-resistant Streptococcus pyogenes in Japan.

PubMed

Tanaka, Yuhei; Gotoh, Kenji; Teramachi, Mariko; Ishimoto, Kazuhisa; Tsumura, Naoki; Shindou, Shizuo; Yamashita, Yushiro

2016-11-01

Here we report the molecular epidemiology of macrolide-resistant Streptococcus pyogenes (group A streptococci, GAS) isolated from children with pharyngotonsillitis between 2011 and 2013 in Japan. In 299 isolates, 124 (41.5%) isolates were macrolide-resistant. We characterized the isolates by emm typing, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). Of 299 isolates, 124 (41.5%) were macrolide-resistant isolates, 76 (61.3%) possessed mefA and 46 (37.1%) possessed ermB. All 76 isolates with mefA possessed msrD. There were no isolates possessed ermTR in this study. Eight emm/MLST types were observed. The predominant type was emm1/ST28 (57 isolates, 46.0%), which possessed the mefA/msrD complex, presenting as the M phenotype. The second most predominant type was emm12/ST467, which possessed ermB, presenting as the cMLS B phenotype. Of the cMLS B phenotype isolates, types emm28/ST52 and emm12/ST36 had multiple genetic backgrounds. We found high proportions of macrolide-resistant GAS in the southwestern areas of Japan. Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Experimental pleurodesis induced by antibiotics (macrolides or quinolones).

PubMed

Teixeira, Lisete R; Vargas, Francisco S; Acencio, Milena M P; Bumlai, Renan U M; Antonangelo, Leila; Marchi, Evaldo

2006-12-01

Chemical pleurodesis is a therapeutic tool for the treatment of recurrent pleural effusions, mainly those of neoplastic etiology. In the past, tetracycline was the sclerosant agent of choice in clinical practice, but presently, there is no consensus about an ideal agent. The aim of this study was to evaluate the effectiveness of macrolides (azithromycin and clarithromycin) or quinolones (levofloxacin and gatifloxacin) in inducing experimental pleurodesis in rabbits. Forty New Zealand rabbits randomized into groups of 10 received (at a total volume of 2 mL for each animal) 1 of the 4 drugs by intrapleural injection. After 28 days, the animals were euthanized and the pleural cavity was evaluated macroscopically and microscopically. The intensity of the macroscopic adhesions was mild in all groups. On microscopic analysis, minimal pleural fibrosis and inflammation were observed in all animals. The macrolides (azithromycin or clarithromycin) and the quinolones (levofloxacin or gatifloxacin) when injected into the normal pleural space of rabbits are not effective in promoting pleurodesis. Additional research is required to identify sclerosing agents capable of inducing pleurodesis.

Characterization of in vivo-acquired resistance to macrolides of Mycoplasma gallisepticum strains isolated from poultry

PubMed Central

2011-01-01

The macrolide class of antibiotics, including tylosin and tilmicosin, is widely used in the veterinary field for prophylaxis and treatment of mycoplasmosis. In vitro susceptibility testing of 50 strains of M. gallisepticum isolated in Israel during the period 1997-2010 revealed that acquired resistance to tylosin as well as to tilmicosin was present in 50% of them. Moreover, 72% (13/18) of the strains isolated from clinical samples since 2006 showed acquired resistance to enrofloxacin, tylosin and tilmicosin. Molecular typing of the field isolates, performed by gene-target sequencing (GTS), detected 13 molecular types (I-XIII). Type II was the predominant type prior to 2006 whereas type X, first detected in 2008, is currently prevalent. All ten type X strains were resistant to both fluoroquinolones and macrolides, suggesting selective pressure leading to clonal dissemination of resistance. However, this was not a unique event since resistant strains with other GTS molecular types were also found. Concurrently, the molecular basis for macrolide resistance in M. gallisepticum was identified. Our results revealed a clear-cut correlation between single point mutations A2058G or A2059G in domain V of the gene encoding 23S rRNA (rrnA, MGA_01) and acquired macrolide resistance in M. gallisepticum. Indeed, all isolates with MIC ≥ 0.63 μg/mL to tylosin and with MIC ≥ 1.25 μg/mL to tilmicosin possess one of these mutations, suggesting an essential role in decreased susceptibility of M. gallisepticum to 16-membered macrolides. PMID:21810258

Macrolide antibiotic interaction and resistance on the bacterial ribosome.

PubMed

Poehlsgaard, Jacob; Douthwaite, Stephen

2003-02-01

Our understanding of the fine structure of many antibiotic target sites has reached a new level of enlightenment in the last couple of years due to the advent, by X-ray crystallography, of high-resolution structures of the bacterial ribosome. Many classes of clinically useful antibiotics bind to the ribosome to inhibit bacterial protein synthesis. Macrolide, lincosamide and streptogramin B (MLSB) antibiotics form one of the largest groups, and bind to the same site on the 50S ribosomal subunit. Here, we review the molecular details of the ribosomal MLSB site to put into perspective the main points from a wealth of biochemical and genetic data that have been collected over several decades. The information is now available to understand, at atomic resolution, how macrolide antibiotics interact with their ribosomal target, how the target is altered to confer resistance, and in which directions we need to look if we are to rationally design better drugs to overcome the extant resistance mechanisms.

New Fluorescent Macrolide Derivatives for Studying Interactions of Antibiotics and Their Analogs with the Ribosomal Exit Tunnel.

PubMed

Tereshchenkov, A G; Shishkina, A V; Karpenko, V V; Chertkov, V A; Konevega, A L; Kasatsky, P S; Bogdanov, A A; Sumbatyan, N V

2016-10-01

Novel fluorescent derivatives of macrolide antibiotics related to tylosin bearing rhodamine, fluorescein, Alexa Fluor 488, BODIPY FL, and nitrobenzoxadiazole (NBD) residues were synthesized. The formation of complexes of these compounds with 70S E. coli ribosomes was studied by measuring the fluorescence polarization depending on the ribosome amount at constant concentration of the fluorescent substance. With the synthesized fluorescent tylosin derivatives, the dissociation constants for ribosome complexes with several known antibiotics and macrolide analogs previously obtained were determined. It was found that the fluorescent tylosin derivatives containing BODIPY FL and NBD groups could be used to screen the binding of novel antibiotics to bacterial ribosomes in the macrolide-binding site.

Microbiological assay for the analysis of certain macrolides in pharmaceutical dosage forms.

PubMed

Mahmoudi, A; Fourar, R E-A; Boukhechem, M S; Zarkout, S

2015-08-01

Clarithromycin (CLA) and roxithromycin (ROX) are macrolide antibiotics with an expanded spectrum of activity that are commercially available as tablets. A microbiological assay, applying the cylinder-plate method and using a strain of Micrococcus luteus ATCC 9341 as test organism, has been used and validated for the quantification of two macrolide drugs; CLA and ROX in pure and pharmaceutical formulations. The validation of the proposed method was carried out for linearity, precision, accuracy and specificity. The linear dynamic ranges were from 0.1 to 0.5μg/mL for both compounds. Logarithmic calibration curve was obtained for each macrolide (r>0.989) with statistically equal slopes varying from 3.275 to 4.038, and a percentage relative standard deviation in the range of 0.24-0.92%. Moreover, the method was applied successfully for the assay of the studied drugs in pharmaceutical tablet dosage forms. Recovery from standard addition experiments in commercial products was 94.71-96.91% regarding clarithromycin and 93.94-98.12% regarding roxithromycin, with a precision (%RSD) 1.32-2.11%. Accordingly, this microbiological assay can be used for routine quality control analysis of titled drugs in tablet formulations. Copyright © 2015 Elsevier B.V. All rights reserved.

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.

Macrolones Are a Novel Class of Macrolide Antibiotics Active against Key Resistant Respiratory Pathogens In Vitro and In Vivo.

PubMed

Čipčić Paljetak, Hana; Verbanac, Donatella; Padovan, Jasna; Dominis-Kramarić, Miroslava; Kelnerić, Željko; Perić, Mihaela; Banjanac, Mihailo; Ergović, Gabrijela; Simon, Nerrisa; Broskey, John; Holmes, David J; Eraković Haber, Vesna

2016-09-01

As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Macrolones Are a Novel Class of Macrolide Antibiotics Active against Key Resistant Respiratory Pathogens In Vitro and In Vivo

PubMed Central

Verbanac, Donatella; Padovan, Jasna; Dominis-Kramarić, Miroslava; Kelnerić, Željko; Perić, Mihaela; Banjanac, Mihailo; Ergović, Gabrijela; Simon, Nerrisa; Broskey, John; Holmes, David J.; Eraković Haber, Vesna

2016-01-01

As we face an alarming increase in bacterial resistance to current antibacterial chemotherapeutics, expanding the available therapeutic arsenal in the fight against resistant bacterial pathogens causing respiratory tract infections is of high importance. The antibacterial potency of macrolones, a novel class of macrolide antibiotics, against key respiratory pathogens was evaluated in vitro and in vivo. MIC values against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, and Haemophilus influenzae strains sensitive to macrolide antibiotics and with defined macrolide resistance mechanisms were determined. The propensity of macrolones to induce the expression of inducible erm genes was tested by the triple-disk method and incubation in the presence of subinhibitory concentrations of compounds. In vivo efficacy was assessed in a murine model of S. pneumoniae-induced pneumonia, and pharmacokinetic (PK) profiles in mice were determined. The in vitro antibacterial profiles of macrolones were superior to those of marketed macrolide antibiotics, including the ketolide telithromycin, and the compounds did not induce the expression of inducible erm genes. They acted as typical protein synthesis inhibitors in an Escherichia coli transcription/translation assay. Macrolones were characterized by low to moderate systemic clearance, a large volume of distribution, a long half-life, and low oral bioavailability. They were highly efficacious in a murine model of pneumonia after intraperitoneal application even against an S. pneumoniae strain with constitutive resistance to macrolide-lincosamide-streptogramin B antibiotics. Macrolones are the class of macrolide antibiotics with an outstanding antibacterial profile and reasonable PK parameters resulting in good in vivo efficacy. PMID:27353268

Genetic and phenotypic characterization of resistance to macrolides in Streptococcus pyogenes from Argentina.

PubMed

Martínez, Silvia; Amoroso, Ana M; Famiglietti, Angela; de Mier, Carmen; Vay, Carlos; Gutkind, Gabriel O

2004-01-01

Five hundred and seventy-eight strains of group A streptococci (GAS) isolated mostly from paediatric pharyngeal swabs were tested to evaluate their susceptibility to erythromycin. Resistant strains were then tested for their MICs to erythromycin and clindamycin, their phenotype of resistance to macrolides-lincosamides-streptogramin (MLS(B)) and for the presence of macrolide resistance genes. The rate of resistance to erythromycin was 8.2%. Constitutive, inducible and M phenotypes of resistance were detected in 2.1, 2.1 and 95.8% of resistant strains, respectively. All M phenotypes harboured the mefA gene, whereas constitutive and inducible phenotypes had ermB and ermTR genes, respectively.

Macrolide-based regimens in absence of bacterial co-infection in critically ill H1N1 patients with primary viral pneumonia.

PubMed

Martín-Loeches, I; Bermejo-Martin, J F; Vallés, J; Granada, R; Vidaur, L; Vergara-Serrano, J C; Martín, M; Figueira, J C; Sirvent, J M; Blanquer, J; Suarez, D; Artigas, A; Torres, A; Diaz, E; Rodriguez, A

2013-04-01

To determine whether macrolide-based treatment is associated with mortality in critically ill H1N1 patients with primary viral pneumonia. Secondary analysis of a prospective, observational, multicenter study conducted across 148 Intensive Care Units (ICU) in Spain. Primary viral pneumonia was present in 733 ICU patients with pandemic influenza A (H1N1) virus infection with severe respiratory failure. Macrolide-based treatment was administered to 190 (25.9 %) patients. Patients who received macrolides had chronic obstructive pulmonary disease more often, lower severity on admission (APACHE II score on ICU admission (13.1 ± 6.8 vs. 14.4 ± 7.4 points, p < 0.05), and multiple organ dysfunction syndrome less often (23.4 vs. 30.1 %, p < 0.05). Length of ICU stay in survivors was not significantly different in patients who received macrolides compared to patients who did not (10 (IQR 4-20) vs. 10 (IQR 5-20), p = 0.9). ICU mortality was 24.1 % (n = 177). Patients with macrolide-based treatment had lower ICU mortality in the univariate analysis (19.2 vs. 28.1 %, p = 0.02); however, a propensity score analysis showed no effect of macrolide-based treatment on ICU mortality (OR = 0.87; 95 % CI 0.55-1.37, p = 0.5). Moreover, the sensitivity analysis revealed very similar results (OR = 0.91; 95 % CI 0.58-1.44, p = 0.7). A separate analysis of patients under mechanical ventilation yielded similar results (OR = 0.77; 95 % CI 0.44-1.35, p = 0.4). Our results suggest that macrolide-based treatment was not associated with improved survival in critically ill H1N1 patients with primary viral pneumonia.

Macrolide Therapy in Adults and Children with Non-Cystic Fibrosis Bronchiectasis: A Systematic Review and Meta-Analysis

PubMed Central

Tang, Yan; Gao, Yang; Lin, Zhi-ya; Lin, Zhi-min; Zhong, Nan-shan; Chen, Rong-chang

2014-01-01

Background A systematic review and meta-analysis was conducted to evaluate the efficacy and safety of macrolide therapy in adults and children with bronchiectasis. Methods We searched the PUBMED, EMBASE, CENTRAL databases to identify relevant studies. Two reviewers evaluated the studies and extracted data independently. The primary outcome was the number of bronchiectasis exacerbations. Secondary outcomes included exacerbation-related admissions, quality of life (QoL), spirometry, 6-minute walk test (6MWT) and adverse events. Results Nine eligible trials with 559 participants were included. Six were conducted on adults, and the remaining on children. Macrolide therapy significantly reduced the number of patients experiencing one or more exacerbation in adults [risk ratio (RR) = 0.59; 95% CI, 0.40 to 0.86; P = 0.006; I2 = 65%] and children [RR = 0.86; 95% CI, 0.75–0.99; P = 0.04; I2 = 0%], but not the number of patients with admissions for exacerbation. Macrolide therapy was also associated with reduced frequency of exacerbations in adults (RR = 0.42; 95% CI, 0.29 to 0.61; P<0.001; I2 = 64%) and children (RR = 0.50; 95% CI, 0.35 to 0.71; P<0.001). Pooled analyses suggested that spirometry, including FEV1 and FVC, were significantly improved in adults but not in children. Macrolide therapy improved the QoL (WMD, −6.56; 95% CI, −11.99 to −1.12; P = 0.02; I2 = 86%) but no significant difference in 6MWT (WMD, 4.15; 95% CI, −11.83 to 20.13; P = 0.61; I2 = 31%) and the overall adverse events (RR, 0.96; 95% CI, 0.82 to 1.13; P = 0.66; I2 = 0%) in adults. However, reports of diarrhea and abdominal discomforts were higher with macrolide therapy. Conclusions Macrolide maintenance therapy, both in adults and children, was effective and safe in reducing bronchiectasis exacerbations, but not the admissions for exacerbations. In addition, macrolide administration in adults was associated with improvement in Qo

Determination of macrolide antibiotics in chicken tissues by liquid chromatography-electrospray mass spectrometry

NASA Astrophysics Data System (ADS)

Salikin, Jamilah; Abdullah, Aminah

2013-11-01

A methodusingliquid chromatography-electrospray mass spectrometry (LC-(ESI)MS) for the simultaneous determination of three macrolides (tylosin, spiramycin and tilmicosin) in poultry muscle has been developed. The drugs were extracted with EDTA McIlvaine buffer, filter through celite 545 and the extracts were cleaned up by SPE Oasis HLB cartridge. Separation was carried out in end-capped silica-based C18 column and mobile phases containing trifluoroacetic acid-acetonitrile with a binary gradient system at a flow rate 0.5 ml/min. Detection was performed by single mass spectrometry with electrospray ionization in the positive mode. Several parameters affecting the mass spectra were studied. Chicken samples from the market were analyzed to check the residue of macrolide antibiotics.

Recombineering reveals a diverse collection of ribosomal proteins L4 and L22 that confer resistance to macrolide antibiotics

PubMed Central

Diner, Elie J.; Hayes, Christopher S.

2009-01-01

Summary Mutations in ribosomal proteins L4 and L22 confer resistance to erythromycin and other macrolide antibiotics in a variety of bacteria. L4 and L22 have elongated loops whose tips converge in the peptide exit tunnel near the macrolide binding site, and resistance mutations typically affect residues within these loops. Here, we use bacteriophage λ Red-mediated recombination, or “recombineering”, to uncover new L4 and L22 alleles that confer macrolide resistance in Escherichia coli. We randomized residues at the tips of the L4 and L22 loops using recombineered oligonucleotide libraries, and selected the mutagenized cells for erythromycin-resistant mutants. These experiments led to the identification of 341 different resistance mutations encoding 278 unique L4 and L22 proteins – the overwhelming majority of which are novel. Many resistance mutations were complex, involving multiple missense mutations, in-frame deletions, and insertions. Transfer of L4 and L22 mutations into wild-type cells by phage P1-mediated transduction demonstrated that each allele was sufficient to confer macrolide resistance. Although L4 and L22 mutants are typically resistant to most macrolides, selections carried out on different antibiotics revealed macrolide-specific resistance mutations. L22 Lys90Trp is one such allele, which confers resistance to erythromycin, but not tylosin or spiramycin. Purified L22 Lys90Trp ribosomes show reduced erythromycin binding, but have the same affinity for tylosin as wild-type ribosomes. Moreover, DMS methylation protection assays demonstrated that L22 Lys90Trp ribosomes bind tylosin more readily than erythromycin in vivo. This work underscores the exceptional functional plasticity of the L4 and L22 proteins, and highlights the utility of Red-mediated recombination in targeted genetic selections. PMID:19150357

[Activity of macrolides and fluoroquinolones against intracellular Legionella pneumophila].

PubMed

Yu, Ling-ling; Hu, Bi-jie; Huang, Sheng-lei; Zhou, Zhao-yan; Tao, Li-li

2011-06-01

To evaluate the activity of macrolides and fluoroquinolones against Legionella pneumophila by intracellular susceptibility testing. Minimum inhibitory concentration (MIC) was determined by standard agar dilution test according to the CLSI. For intracellular assays, legionella pneumonia was used to infect human monocytic cell line THP-1. Erythromycin, azithromycin, levofloxacin and moxifloxacin at 1 × MIC, 4 × MIC, 8 × MIC were added following phagocytosis. Number of viable bacteria was enumerated at 24 h on BCYE (buffered charcoal yeast extract) agar in duplicates using standard plate count method. The result was expressed as percentage inhibition. Mann-Whitney U test was used to determine the significant differences in mean percentage inhibition between agents. Percentage inhibition at 24 h were as follows: Erythromycin 1 × MIC (50.18 ± 27.29)%, 4 × MIC (79.48 ± 20.08)%, 8 × MIC (91.46 ± 8.70)%; Azithromycin 1 × MIC (66.77 ± 26.18)%, 4 × MIC (91.73 ± 8.72)%, 8 × MIC (97.10 ± 3.37)%; Levofloxacin 1 × MIC (99.84 ± 0.25)%, 4 × MIC (99.99 ± 0.02)%, 8 × MIC (99.99 ± 0.01)%; Moxifloxacin 1 × MIC (99.90 ± 0.10)%, 4 × MIC (99.99 ± 0.03)%, 8 × MIC (99.99 ± 0.03)%. The fluoroquinolones showed greater inhibitory activity than macrolides against legionella pneumophila(u = 1.0, 2.0, 5.0, P < 0.05). Levofloxacin and moxifloxacin had the same intracellular activity against legionella pneumophila (u = 190, 183, 217, P > 0.05). Azithromycin was more effective than erythromycin in inhibiting intracellular legionella pneumophila (u = 132, 125, 128, P < 0.05). The fluoroquinolones were more active than macrolides against legionella pneumophila. The intracellular activity of levofloxacin against legionella pneumophila appeared to be similar to moxifloxacin. Azithromycin was demonstrated to have superior activity against legionella pneumophila compared with erythromycin.

[Macrolide-resistant Streptococcus pneumoniae on the islands of Gran Canaria and Lanzarote (Spain): molecular mechanisms and serogroup relationships].

PubMed

Artiles, Fernando; Horcajada-Herrera, Iballa; Noguera-Catalán, Javier; Alamo-Antúnez, Isabel; Bordes-Benítez, Ana; Lafarga-Capuz, Bernardo

2007-11-01

Macrolide resistance in Streptococcus pneumoniae is coded by the ermB and mefA/E genes. The aim of this study was to determine the status of macrolide-resistance, the molecular mechanisms involved, the serogroup relationships, and the level of co-resistance in S. pneumoniae isolates from Gran Canaria and Lanzarote, in the Canary Islands, Spain. Macrolide resistance phenotypes were investigated in 261 S. pneumoniae clinical isolates over a two-year period (2004 and 2005). Genotypes were determined by PCR (detection of ermB and mefA/E genes). Overall macrolide resistance was 40.6% (106 isolates); 79.2% (84) of resistant isolates presented the MLSB phenotype (98.8% harbored the ermB gene), with a predominance of serogroup 19, and 20.8% (22) presented the M phenotype (77.3% displayed the mefA/E gene), all associated with serogroup 14. Worthy of note, the M phenotype was found in 8 invasive isolates from Lanzarote (80%) all from serogroup 14. The ermB and mefA/E genes were detected in 7 isolates belonging to serogroup 19. Absence of co-resistance was observed most frequently in serogroup 14 (66.7%). Co-resistance with penicillin G, tetracycline, and trimethoprim-sulfamethoxazole was associated with serogroup 19 (36.8%). Two isolates (0.8%) were resistant to telithromycin. The frequency of macrolide resistance mechanisms in the Canary Islands is different from that observed in the rest of Spain, particularly in Lanzarote, where 80% of isolates harbored the mefA/E gene and belonged to serogroup 14.

Comprehensive determination of macrolide antibiotics, their synthesis intermediates and transformation products in wastewater effluents and ambient waters by liquid chromatography-tandem mass spectrometry.

PubMed

Senta, Ivan; Krizman-Matasic, Ivona; Terzic, Senka; Ahel, Marijan

2017-08-04

Macrolide antibiotics are a prominent group of emerging contaminants frequently found in wastewater effluents and wastewater-impacted aquatic environments. In this work, a novel analytical method for simultaneous determination of parent macrolide antibiotics (azithromycin, erythromycin, clarithromycin and roxithromycin), along with their synthesis intermediates, byproducts, metabolites and transformation products in wastewater and surface water was developed and validated. Samples were enriched using solid-phase extraction on Oasis HLB cartridges and analyzed by reversed-phase liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The target macrolide compounds were separated on an ACE C18 PFP column and detected using multiple reaction monitoring in positive ionization polarity. The optimized method, which included an additional extract clean-up on strong anion-exchange cartridges (SAX), resulted in high recoveries and accuracies, low matrix effects and improved chromatographic separation of the target compounds, even in highly complex matrices, such as raw wastewater. The developed method was applied to the analysis of macrolide compounds in wastewater and river water samples from Croatia. In addition to parent antibiotics, several previously unreported macrolide transformation products and/or synthesis intermediates were detected in municipal wastewater, some of them reaching μg/L levels. Moreover, extremely high concentrations of macrolides up to mg/L level were found in pharmaceutical industry effluents, indicating possible importance of this source to the total loads into ambient waters. The results revealed a significant contribution of synthesis intermediates and transformation products to the overall mass balance of macrolides in the aquatic environment. Copyright © 2017. Published by Elsevier B.V.

Distribution of macrolide resistance mechanisms in Bulgarian clinical isolates of Streptococcus pyogenes during the years of 2013-2016.

PubMed

Muhtarova, Adile A; Gergova, Raina T; Mitov, Ivan G

2017-09-01

Streptococcus pyogenes, or group A streptococcus (GAS), is the main etiological agent of bacterial tonsillopharyngitis and a common cause of a wide variety of other mild to severe infections. Objectives of the present study was to determine and evaluate the distribution of genetic mechanisms associated with certain phenotypes of macrolide resistance in Bulgarian GAS isolated during the years of 2013-2016. All GAS strains were screened for the macrolide resistance genes erm(A), erm(B) and mef(A), using multiplex polymerase chain reaction (PCR). The minimal inhibitory concentrations (MICs) of erythromycin, azithromycin, clarithromycin, clindamycin were determined by E-tests. Almost 23% of GAS isolates obtained in 2013-2014 and near 40% of them in 2015-2016 contained various elements of resistance. The predominant gene was mef(A), which encodes an efflux pump (M-phenotype), identified in 57.84% of the macrolide-resistant strains. The next frequently prevalent mechanism was a combination of mef(A) and erm(B) in 22.55%, which determined high-level inducible or constitutive resistance to macrolides, lincosamides and streptogramins (iMLSB or cMLSB). The highest MIC value (>256mg/L) was detected in association with erm(B) (p<0.05). The MIC range was observed to be much higher in the isolates with combinations of resistance genes vs. those with mef genes alone (p<0.05). The data about the distribution and prevalence of macrolide resistance mechanisms obtained in this study can help in the treatment of persistent and recurrent GAS infections and in the correct choice of empiric therapy. Copyright © 2017 International Society for Chemotherapy of Infection and Cancer. Published by Elsevier Ltd. All rights reserved.

In vitro effects of four macrolides (roxithromycin, spiramycin, azithromycin (CP-62,993), and A-56268) on Toxoplasma gondii

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

Chang, H.R.; Pechere, J.C.

1988-04-01

The effect of four macrolides against intracellular Toxoplasma gondii was determined in three different in vitro systems. Unactivated murine peritoneal macrophages were infected with the virulent RH strain of T. gondii. The activity of the macrolides was first measured with (/sup 3/H)uracil, which is incorporated by the parasite but not the host cell. The 50% inhibitory concentrations (IC50s) and 95% confidence limits were calculated at 54 (38 to 73), 140 (98 to 201), 147 (101 to 214), and 246 (187 to 325) micron for roxithromycin, azithromycin (CP-62,993), A-56268, and spiramycin, respectively. Inhibition of Toxoplasma growth was confirmed by microscopic examinationmore » of the infected macrophages after treatment with roxithromycin. Compared with untreated controls, roxithromycin concentrations near the IC50s decreased the number of infected cells, the number of tachyzoites per vacuole, and the number of cells containing rosettes (i.e., clusters of more than eight tachyzoites). After treatment with the four macrolides, tachyzoites were released from the macrophages and subcultured in HeLa cells, which are nonprofessional phagocytes, to assess the viability of the remaining parasites. This showed that the macrolides at concentrations corresponding to four times their 90% inhibitory concentrations (IC90s) had no significant killing effect. At 8 times the IC90, roxithromycin showed an incomplete killing effect, similar to that of the combination of pyrimethamine (0.41 microM)-sulfadiazine (99.42 microM). All macrolides tested showed inhibitory effects against intracellular T. gondii, but amounts of azithromycin and A-56268 corresponding to the IC90 appeared to be toxic against the host macrophages, which might have had nonspecific activity against Toxoplasma metabolism.« less

Determination of Macrolide Antibiotics Using Dispersive Liquid-Liquid Microextraction Followed by Surface-Assisted Laser Desorption/Ionization Mass Spectrometry

NASA Astrophysics Data System (ADS)

Chen, Kuan-Yu; Yang, Thomas C.; Chang, Sarah Y.

2012-06-01

A novel method for the determination of macrolide antibiotics using dispersive liquid-liquid microextraction coupled to surface-assisted laser desorption/ionization mass spectrometric detection was developed. Acetone and dichloromethane were used as the disperser solvent and extraction solvent, respectively. A mixture of extraction solvent and disperser solvent were rapidly injected into a 1.0 mL aqueous sample to form a cloudy solution. After the extraction, macrolide antibiotics were detected using surface-assisted laser desorption/ionization mass spectrometry (SALDI/MS) with colloidal silver as the matrix. Under optimum conditions, the limits of detection (LODs) at a signal-to-noise ratio of 3 were 2, 3, 3, and 2 nM for erythromycin (ERY), spiramycin (SPI), tilmicosin (TILM), and tylosin (TYL), respectively. This developed method was successfully applied to the determination of macrolide antibiotics in human urine samples.

Antimicrobial susceptibility and molecular characterization of macrolide resistance of Mycoplasma bovis isolates from multiple provinces in China

PubMed Central

KONG, Ling-Cong; GAO, Duo; JIA, Bo-Yan; WANG, Zi; GAO, Yun-Hang; PEI, Zhi-Hua; LIU, Shu-Ming; XIN, Jiu-Qing; MA, Hong-Xia

2015-01-01

Mycoplasma bovis has spread widely throughout the world via animal movement and has become an important pathogen of bovine respiratory disease. However, the minimum inhibitory concentrations of antimicrobials for Mycoplasma bovis have not been studied in China. The objective of this study was to determine the prevalence and antibiotic resistance of Mycoplasma bovis isolated from young cattle with respiratory infection in China. Mycoplasma bovis was detected in 32/45 bovine respiratory infection outbreaks at beef farms in 8 provinces in China. The isolates were susceptible or had medium sensitivity to ciprofloxacin, enrofloxacin and doxycycline, but were frequently resistant to macrolides (13/32, 41%). An A2058G (Escherichia coli Numbering) mutation located in the rrnA operon in domain V of 23S rRNA was observed in strains that were resistant to macrolides. This single mutations at the rrnA operon in domain V of 23S rRNA may play an important role in the resistance of Mycoplasma bovis strains to macrolides. PMID:26346744

Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium.

PubMed

Porter, James D; Watson, Jennifer; Roberts, Lee R; Gill, Simren K; Groves, Helen; Dhariwal, Jaideep; Almond, Mark H; Wong, Ernie; Walton, Ross P; Jones, Lyn H; Tregoning, John; Kilty, Iain; Johnston, Sebastian L; Edwards, Michael R

2016-10-01

Exacerbations of asthma and COPD are triggered by rhinoviruses. Uncontrolled inflammatory pathways, pathogenic bacterial burden and impaired antiviral immunity are thought to be important factors in disease severity and duration. Macrolides including azithromycin are often used to treat the above diseases, but exhibit variable levels of efficacy. Inhaled corticosteroids are also readily used in treatment, but may lack specificity. Ideally, new treatment alternatives should suppress unwanted inflammation, but spare beneficial antiviral immunity. In the present study, we screened 225 novel macrolides and tested them for enhanced antiviral activity against rhinovirus, as well as anti-inflammatory activity and activity against Gram-positive and Gram-negative bacteria. Primary bronchial epithelial cells were grown from 10 asthmatic individuals and the effects of macrolides on rhinovirus replication were also examined. Another 30 structurally similar macrolides were also examined. The oleandomycin derivative Mac5, compared with azithromycin, showed superior induction (up to 5-fold, EC50 = 5-11 μM) of rhinovirus-induced type I IFNβ, type III IFNλ1 and type III IFNλ2/3 mRNA and the IFN-stimulated genes viperin and MxA, yet had no effect on IL-6 and IL-8 mRNA. Mac5 also suppressed rhinovirus replication at 48 h, proving antiviral activity. Mac5 showed antibacterial activity against Gram-positive Streptococcus pneumoniae; however, it did not have any antibacterial properties compared with azithromycin when used against Gram-negative Escherichia coli (as a model organism) and also the respiratory pathogens Pseudomonas aeruginosa and non-typeable Haemophilus influenzae. Further non-toxic Mac5 derivatives were identified with various anti-inflammatory, antiviral and antibacterial activities. The data support the idea that macrolides have antiviral properties through a mechanism that is yet to be ascertained. We also provide evidence that macrolides can be developed with

Separation analysis of macrolide antibiotics with good performance on a positively charged C18HCE column.

PubMed

Wei, Jie; Shen, Aijin; Yan, Jingyu; Jin, Gaowa; Yang, Bingcheng; Guo, Zhimou; Zhang, Feifang; Liang, Xinmiao

2016-03-01

The separation of basic macrolide antibiotics suffers from peak tailing and poor efficiency on traditional silica-based reversed-phase liquid chromatography columns. In this work, a C18HCE column with positively charged surface was applied to the separation of macrolides. Compared with an Acquity BEH C18 column, the C18HCE column exhibited superior performance in the aspect of peak shape and separation efficiency. The screening of mobile phase additives including formic acid, acetic acid and ammonium formate indicated that formic acid was preferable for providing symmetrical peak shapes. Moreover, the influence of formic acid content was investigated. Analysis speed and mass spectrometry compatibility were also taken into account when optimizing the separation conditions for liquid chromatography coupled with tandem mass spectrometry. The developed method was successfully utilized for the determination of macrolide residues in a honey sample. Azithromycin was chosen as the internal standard for the quantitation of spiramycin and tilmicosin, while roxithromycin was used for erythromycin, tylosin, clarithromycin, josamycin and acetylisovaleryltylosin. Good correlation coefficients (r(2) > 0.9938) for all macrolides were obtained. The intra-day and inter-day recoveries were 73.7-134.7% and 80.7-119.7% with relative standard deviations of 2.5-8.0% and 3.9-16.1%, respectively. Outstanding sensitivity with limits of quantitation (S/N ≥ 10) of 0.02-1 μg/kg and limits of detection (S/N ≥ 3) of 0.01-0.5 μg/kg were achieved. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The order of administration of macrolides and beta-lactams may impact the outcomes of hospitalized patients with community-acquired pneumonia: results from the community-acquired pneumonia organization.

PubMed

Peyrani, Paula; Wiemken, Timothy L; Metersky, Mark L; Arnold, Forest W; Mattingly, William A; Feldman, Charles; Cavallazzi, Rodrigo; Fernandez-Botran, Rafael; Bordon, Jose; Ramirez, Julio A

2018-01-01

The beneficial effect of macrolides for the treatment of community-acquired pneumonia (CAP) in combination with beta-lactams may be due to their anti-inflammatory activity. In patients with pneumococcal meningitis, the use of steroids improves outcomes only if they are administered before beta-lactams. The objective of this study was to compare outcomes in hospitalized patients with CAP when macrolides were administered before, simultaneously with, or after beta-lactams. Secondary data analysis of the Community-Acquired Pneumonia Organization (CAPO) International Cohort Study database. Study groups were defined based on the sequence of administration of macrolides and beta-lactams. The study outcomes were time to clinical stability (TCS), length of stay (LOS) and in-hospital mortality. Accelerated failure time models were used to evaluate the adjusted impact of sequential antibiotic administration and time-to-event outcomes, while a logistic regression model was used to evaluate their adjusted impact on mortality. A total of 99 patients were included in the macrolide before group and 305 in the macrolide after group. Administration of a macrolide before a beta-lactam compared to after a beta-lactam reduced TCS (3 vs. 4 days, p = .011), LOS (6 vs. 7 days, p = .002) and mortality (3 vs. 7.2%, p = .228). The administration of macrolides before beta-lactams was associated with a statistically significant decrease in TCS and LOS and a non-statistically significant decrease in mortality. The beneficial effect of macrolides in hospitalized patient with CAP may occur only if administered before beta-lactams.

Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.

PubMed

Matic, Vlatka; Kosowska, Klaudia; Bozdogan, Bulent; Kelly, Linda M; Smith, Kathy; Ednie, Lois M; Lin, Gengrong; Credito, Kim L; Clark, Catherine L; McGhee, Pamela; Pankuch, Glenn A; Jacobs, Michael R; Appelbaum, Peter C

2004-11-01

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for

Antipneumococcal Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Erythromycin, Azithromycin, Clarithromycin, Clindamycin, and Telithromycin

PubMed Central

Matic, Vlatka; Kosowska, Klaudia; Bozdogan, Bulent; Kelly, Linda M.; Smith, Kathy; Ednie, Lois M.; Lin, Gengrong; Credito, Kim L.; Clark, Catherine L.; McGhee, Pamela; Pankuch, Glenn A.; Jacobs, Michael R.; Appelbaum, Peter C.

2004-01-01

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were ≥0.5 μg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 μg/ml. Single-step studies showed mutation frequencies <5.0 × 10−10 to 3.5 × 10−7 for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 × 10−7 to >4.3 × 10−3 for

Pathological Studies on the Protective Effect of a Macrolide Antibiotic, Roxithromycin, against Sulfur Mustard Inhalation Toxicity in a Rat Model

DTIC Science & Technology

2011-01-01

placed in a water-jacketed (37C) glass vapor generator custom fabri - cated by Atmar Glass (Kennett Square, PA). Spontaneously breathing rats were...bronchiectasis, and pul- monary fibrosis (Emad and Rezaian 1997). Macrolide antibio- tics have shown effectiveness in a variety of chronic respiratory diseases ...observed in clinical studies of chronic inflammatory airway diseases (e.g., DPB) after long-term treatment with low dose of macrolides (Rubin 2004). For

High frequency of fluoroquinolone- and macrolide-resistant streptococci among clinically isolated group B streptococci with reduced penicillin susceptibility.

PubMed

Kimura, Kouji; Nagano, Noriyuki; Nagano, Yukiko; Suzuki, Satowa; Wachino, Jun-ichi; Shibayama, Keigo; Arakawa, Yoshichika

2013-03-01

Recently several clinical isolates of Streptococcus agalactiae [also known as group B Streptococcus (GBS)] that have acquired reduced penicillin susceptibility (PRGBS) by amino acid substitutions in the penicillin-binding protein 2X have emerged. The frequency of fluoroquinolone (FQ)- and macrolide-resistant streptococci among PRGBS is not yet known. Fifty-seven GBS [19 PRGBS and 38 penicillin-susceptible GBS (PSGBS)], isolated from different medical institutions in Japan, were studied. For GBS, the MICs of penicillin G, levofloxacin and erythromycin were determined using the agar dilution method. Nineteen PRGBS were previously confirmed as genetically diverse streptococci by PFGE. Further, the mechanisms underlying penicillin, FQ and macrolide non-susceptibility/resistance were analysed. The frequency of non-susceptibility to FQs among PSGBS was 18.4% (7/38), whereas that among PRGBS was 100% (19/19). The frequency of resistance to erythromycin among PSGBS was 7.9% (3/38), while that among PRGBS was 47.4% (9/19). Statistical significance was determined using Fisher's exact test between reduced penicillin susceptibility and FQ non-susceptibility (P ≤ 0.0001) and macrolide resistance (P=0.0012). The resistance/non-susceptibility mechanisms among PRGBS were diverse, suggesting that the PRGBS examined were not clonal. PRGBS isolates tend to show resistance to FQs and/or macrolides. Because the drug choice for treating these multidrug-resistant GBS is more limited than that for usual GBS, these strains may present future public health challenges.

Ultratrace analysis of nine macrolides, including tulathromycin A (Draxxin), in edible animal tissues with minicolumn liquid chromatography tandem mass spectrometry.

PubMed

Martos, Perry A; Lehotay, Steven J; Shurmer, Bryn

2008-10-08

The analysis of nine macrolides is presented, including tulathromycin A (Draxxin), in beef, poultry, and pork muscle with a simple multiresidue extraction and analysis method using high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The sample preparation method involves extraction with acetonitrile and defatting with hexane followed by dilution of the extracts for analysis. Separation of the nine macrolides was performed using an Atlantis dC 18, 3 mum, 3.9 mm x 20 mm minicolumn (guard column). Detection was carried out with two multiple reaction monitoring experiments per macrolide. The method detection limits (MDLs) were based on three times standard deviation of eight repeat spikes at 3.0 ng/g of a mix of the nine macrolides in the various tissues. The MDLs and retention times for the macrolides were as follows: lincomycin, 0.19 ng/g (t R = 5.00 min); tulathromycin, 0.46 ng/g (t R = 5.63 min); spiramycin, 0.21 ng/g (t R = 6.06 min); pirlimycin, 0.10 ng/g (t R = 6.04 min); clindamycin, 0.16 ng/g (t R = 6.20 min); tilmicosin, 0.29 ng/g (t R = 6.38 min); erythromycin, 0.19 ng/g (t R = 6.62 min); tylosin, 0.10 ng/g (t R = 6.72 min); and josamycin, 0.09 ng/g (t R = 6.98 min). Precision at 25 ng/g (n = 4) ranged from 2.3 to 9.4% for the compounds from beef muscle. Of interest is the detection of incurred residues of tulathromycin A in edible calf tissue at 0.10-7 mug/g, which is presented here for the first time.

Prevalence of macrolide and fluoroquinolone resistance-mediating mutations in Mycoplasma genitalium in five cities in Russia and Estonia

PubMed Central

Shipitsyna, Elena; Rumyantseva, Tatiana; Golparian, Daniel; Khayrullina, Guzel; Lagos, Amaya C.; Edelstein, Inna; Joers, Kai; Jensen, Jörgen S.; Savicheva, Alevtina; Rudneva, Natalia; Sukhanova, Larisa; Kozlov, Roman; Guschin, Alexander

2017-01-01

Background and objective Resistance in the sexually transmitted bacterium Mycoplasma genitalium to all recommended therapeutic antimicrobials have rapidly emerged. However, to date, internationally reported resistance surveillance data for M. genitalium strains circulating in Eastern Europe are entirely lacking. The aim of this study was to estimate the prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium in four cities in Russia and one in Estonia, 2013–2016. Materials and methods Consecutive urogenital samples found positive for M. genitalium during diagnostic testing were retrospectively analyzed for resistance-associated mutations in the 23S rRNA and parC genes using pyrosequencing and conventional Sanger sequencing, respectively. Results In total, 867 M. genitalium positive samples from 2013–2016 were analyzed. Macrolide resistance-associated mutations were detected in 4.6% of the samples from Russia (0.7–6.8% in different cities) and in 10% of the samples from Estonia. The mutations A2059G and A2058G were highly predominating in both Russia and Estonia, accounting together for 90.9% of the cases positive for nucleotide substitutions in the 23S rRNA gene. The rates of possible fluoroquinolone resistance-associated mutations were 6.2% in Russia (2.5–7.6% in different cities) and 5% in Estonia. The mutations S83I and S83N were the most frequent ones in Russia (24.4% each), whereas D87N highly predominated in Estonia (83.3% of all fluoroquinolone resistance-associated mutations). Approximately 1% of the samples in both countries harbored both macrolide and possible fluoroquinolone resistance-associated mutations, with A2058G and S83I being the most frequent combination (37.5%). Conclusions The prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium was 4.6% and 6.2%, respectively, in Russia, and 10% and 5%, respectively, in Estonia. Despite the relatively low rates of macrolide

Prevalence of macrolide and fluoroquinolone resistance-mediating mutations in Mycoplasma genitalium in five cities in Russia and Estonia.

PubMed

Shipitsyna, Elena; Rumyantseva, Tatiana; Golparian, Daniel; Khayrullina, Guzel; Lagos, Amaya C; Edelstein, Inna; Joers, Kai; Jensen, Jörgen S; Savicheva, Alevtina; Rudneva, Natalia; Sukhanova, Larisa; Kozlov, Roman; Guschin, Alexander; Unemo, Magnus

2017-01-01

Resistance in the sexually transmitted bacterium Mycoplasma genitalium to all recommended therapeutic antimicrobials have rapidly emerged. However, to date, internationally reported resistance surveillance data for M. genitalium strains circulating in Eastern Europe are entirely lacking. The aim of this study was to estimate the prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium in four cities in Russia and one in Estonia, 2013-2016. Consecutive urogenital samples found positive for M. genitalium during diagnostic testing were retrospectively analyzed for resistance-associated mutations in the 23S rRNA and parC genes using pyrosequencing and conventional Sanger sequencing, respectively. In total, 867 M. genitalium positive samples from 2013-2016 were analyzed. Macrolide resistance-associated mutations were detected in 4.6% of the samples from Russia (0.7-6.8% in different cities) and in 10% of the samples from Estonia. The mutations A2059G and A2058G were highly predominating in both Russia and Estonia, accounting together for 90.9% of the cases positive for nucleotide substitutions in the 23S rRNA gene. The rates of possible fluoroquinolone resistance-associated mutations were 6.2% in Russia (2.5-7.6% in different cities) and 5% in Estonia. The mutations S83I and S83N were the most frequent ones in Russia (24.4% each), whereas D87N highly predominated in Estonia (83.3% of all fluoroquinolone resistance-associated mutations). Approximately 1% of the samples in both countries harbored both macrolide and possible fluoroquinolone resistance-associated mutations, with A2058G and S83I being the most frequent combination (37.5%). The prevalence of macrolide and fluoroquinolone resistance-associated mutations in M. genitalium was 4.6% and 6.2%, respectively, in Russia, and 10% and 5%, respectively, in Estonia. Despite the relatively low rates of macrolide and fluoroquinolone resistance in these countries, antimicrobial resistance

Detection of macrolide resistance genes in culture-negative specimens from Bangladeshi children with invasive pneumococcal diseases.

PubMed

Hasanuzzaman, Md; Malaker, Roly; Islam, Maksuda; Baqui, Abdullah H; Darmstadt, Gary L; Whitney, Cynthia G; Saha, Samir K

2017-03-01

In recent years, an increasing prevalence of macrolide resistance among pneumococci in Bangladesh has been observed. However, the scenario remains incomplete, as few isolates (<1%) are available from pneumonia cases and most pneumococcal meningitis cases (>80%) are culture-negative. This study optimised a triplex PCR method to detect macrolide resistance genes (MRGs) (mefA and ermB) and cpsA from culture-negative pneumococcal cases to predict the prevalence and level of macrolide resistance. The presence of MRGs among pneumococcal strains (n=153) with a wide range of erythromycin MICs (<0.5 to ≥256mg/L) was determined by PCR. Triplex PCR was validated by simultaneous detection of MRG(s) and cpsA in culture-negative clinical specimens and corresponding isolates. The known impact of the presence of specific MRG(s) on MICs of strains was used to predict the MICs of non-culturable strains based on the presence/absence of MRG(s) in the specimens. None of the erythromycin-susceptible isolates possessed any of the MRGs, and all non-susceptible strains had ≥1 MRG. MICs were 2-16mg/L and ≥256mg/L for 93% of strains with mefA and ermB, respectively, whereas 100% of isolates with both genes had MICs≥256mg/L. PCR for body fluids showed 100% concordance with corresponding isolates when tested for MRG(s) in parallel. Erythromycin MICs can be predicted for non-culturable strains with 93-100% precision based on detection of ermB and/or mefA. This method will be useful for establishing comprehensive surveillance for macrolide resistance among pneumococci, specifically in the population with prior antibiotic use. Copyright © 2017. Published by Elsevier Ltd.

Cytotoxic macrolides from a new species of the deep-water marine sponge Leiodermatium.

PubMed

Sandler, Joel S; Colin, Patrick L; Kelly, Michelle; Fenical, William

2006-09-15

Chemical investigation of a new species of the deep-water marine sponge Leiodermatium, collected by manned submersible at a depth of 740 feet in Palau, resulted in the isolation of two cytotoxic macrolides, leiodolides A (1) and B (2). The leiodolides represent the first members of a new class of 19-membered ring macrolides, incorporating several unique functional groups including a conjugated oxazole ring, a bromine substituent, and an alpha-hydroxy-alpha-methyl carboxylic acid side-chain terminus. The structures of these new metabolites were established by spectroscopic analysis, chemical modification, and degradation. The relative and absolute stereochemistries at most chiral centers were assigned on detailed interpretation of spectroscopic data, coupled with chemical degradation and application of the modified Mosher ester method. Leiodolide A showed significant cytotoxicity (average GI(50) = 2.0 microM) in the National Cancer Institute's 60 cell line panel with enhanced activity against HL-60 leukemia and OVCAR-3 ovarian cancer cell lines.

A comparative uncertainty study of the calibration of macrolide antibiotic reference standards using quantitative nuclear magnetic resonance and mass balance methods.

PubMed

Liu, Shu-Yu; Hu, Chang-Qin

2007-10-17

This study introduces the general method of quantitative nuclear magnetic resonance (qNMR) for the calibration of reference standards of macrolide antibiotics. Several qNMR experimental conditions were optimized including delay, which is an important parameter of quantification. Three kinds of macrolide antibiotics were used to validate the accuracy of the qNMR method by comparison with the results obtained by the high performance liquid chromatography (HPLC) method. The purities of five common reference standards of macrolide antibiotics were measured by the 1H qNMR method and the mass balance method, respectively. The analysis results of the two methods were compared. The qNMR is quick and simple to use. In a new medicine research and development process, qNMR provides a new and reliable method for purity analysis of the reference standard.

Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition by Blocking Autophagy Flux in Head and Neck Squamous Cell Carcinoma Cell Lines

PubMed Central

Hirasawa, Kazuhiro; Moriya, Shota; Miyahara, Kana; Kazama, Hiromi; Hirota, Ayako; Takemura, Jun; Abe, Akihisa; Inazu, Masato; Hiramoto, Masaki; Tsukahara, Kiyoaki

2016-01-01

Autophagy, a self-digestive system for cytoplasmic components, is required to maintain the amino acid pool for cellular homeostasis. We previously reported that the macrolide antibiotics azithromycin (AZM) and clarithromycin (CAM) have an inhibitory effect on autophagy flux, and they potently enhance the cytocidal effect of various anticancer reagents in vitro. This suggests that macrolide antibiotics can be used as an adjuvant for cancer chemotherapy. Since cancer cells require a larger metabolic demand than normal cells because of their exuberant growth, upregulated autophagy in tumor cells has now become the target for cancer therapy. In the present study, we examined whether macrolides exhibit cytotoxic effect under an amino acid-starving condition in head and neck squamous cancer cell lines such as CAL 27 and Detroit 562 as models of solid tumors with an upregulated autophagy in the central region owing to hypovascularity. AZM and CAM induced cell death under the amino acid-depleted (AAD) culture condition in these cell lines along with CHOP upregulation, although they showed no cytotoxicity under the complete culture medium. CHOP knockdown by siRNA in the CAL 27 cells significantly suppressed macrolide-induced cell death under the AAD culture condition. CHOP-/- murine embryonic fibroblast (MEF) cell lines also attenuated AZM-induced cell death compared with CHOP+/+ MEF cell lines. Using a tet-off atg5 MEF cell line, knockout of atg5, an essential gene for autophagy, also induced cell death and CHOP in the AAD culture medium but not in the complete culture medium. This suggest that macrolide-induced cell death via CHOP induction is dependent on autophagy inhibition. The cytotoxicity of macrolide with CHOP induction was completely cancelled by the addition of amino acids in the culture medium, indicating that the cytotoxicity is due to the insufficient amino acid pool. These data suggest the possibility of using macrolides for “tumor-starving therapy”. PMID

Azithromycin is more allergenic than clarithromycin in children with suspected hypersensitivity reaction to macrolides.

PubMed

Barni, S; Butti, D; Mori, F; Pucci, N; Rossi, M E; Cianferoni, A; Novembre, E

2015-01-01

Macrolides are considered safe antibiotics with reduced allergenic activity. However, studies on the safety of macrolides are scarce, particularly in children. The aim of this study was to assess the frequency of hypersensitivity reactions to clarithromycin and azithromycin in a group of children referred to our allergy unit for suspected macrolide allergy. We retrospectively reviewed the charts of 90 children aged 1-17 years with symptoms suggestive of hypersensitivity reaction to clarithromycin or azithromycin between December 31, 2008 and December 31, 2013. The allergy workup included skin tests (ie, skin prick tests and/or intradermal tests), determination of serum specific IgE (sIgE) to clarithromycin and azithromycin, and, if necessary to reach a diagnosis, oral provocation tests. Seventy-seven children completed the allergy workup. A reaction to clarithromycin was recorded in 58 children (75.3%): 21 (36.2%) had a history of immediate reactions, and 37 (63.8%) had a history of nonimmediate reactions. A reaction to azithromycin was recorded in 19 children (24.6%): 6 (31.5%) had a history of immediate reaction, and 13 (68.42%) had a history of nonimmediate reaction. Positive results in skin tests and oral provocation tests with the suspect drug confirmed the diagnosis in 15.5% of reactions to clarithromycin (9 of 58) and in 47.3% of reactions to azithromycin (9 of 19) (P = .004). A complete allergy workup enabled us to confirm a diagnosis of clarithromycin and azithromycin allergy in 15.5% and 47.3% of cases, respectively. Azithromycin was more allergenic than clarithromycin in children.

Synergism between macrolide antibiotics and the azole fungicide ketoconazole in growth inhibition testing of the green alga Pseudokirchneriella subcapitata.

PubMed

Yamagishi, Takahiro; Horie, Yoshifumi; Tatarazako, Norihisa

2017-05-01

Macrolide antibiotics and azole fungicides are detected widely in the aquatic environment as a result of their increased use in humans and animal livestock disease and their incomplete removal by wastewater treatment plants. In most cases, ecotoxicological tests are performed by using individual chemical substances, but because of the coexistence of a number of chemicals in the environment, organisms are exposed to many chemicals simultaneously. Therefore, it is important to evaluate effects of chemical interactions, adding to potential hazards of individual chemical. Here, we investigated the synergetic effects of combined chemicals (the azole fungicide ketoconazole and either of two macrolide antibiotics, erythromycin and clarithromycin) in growth inhibition testing using Pseudokirchneriella subcapitata according to OECD Test guideline 201. Combination index plots, isobolograms, and curve-shift analyses revealed that the combination of macrolide antibiotic and ketoconazole at various ratios resulted in strong synergism that enhanced growth inhibition of P. subcapitata, suggesting the necessity of investigating potential hazard of combined chemicals for regulatory purposes. Copyright © 2017 Elsevier Ltd. All rights reserved.

Acquired resistance to the 16-membered macrolides tylosin and tilmicosin by Mycoplasma bovis.

PubMed

Lerner, Uri; Amram, Eytan; Ayling, Roger D; Mikula, Inna; Gerchman, Irena; Harrus, Shimon; Teff, Dina; Yogev, David; Lysnyansky, Inna

2014-01-31

The molecular mechanism of acquired resistance to the 16-membered macrolides tylosin (Ty) and tilmicosin (Tm) was investigated in Mycoplasma bovis field isolates. Sequence analysis of domains II and V of the two 23S rRNA alleles and ribosomal proteins L4 and L22 was performed on 54 M. bovis isolates showing different minimal inhibitory concentrations (MIC). The presence of any one of the point mutations G748A, C752T, A2058G, A2059G or A2059C (Escherichia coli numbering) in one or both alleles of the 23S rRNAs was correlated with decreased susceptibility to Ty (8-1024 μg/ml) and to Tm (32 to >256 μg/ml) in 27/27 and 27/31 M. bovis isolates, respectively. Although a single mutation in domain II or V could be sufficient to cause decreased susceptibility to Ty, our data imply that a combination of mutations in two domains is necessary to achieve higher MICs (≥ 128 μg/ml). The influence of a combination of mutations in two domains II and V on enhancement of resistance to Tm was less clear. In addition, the amino acid (aa) substitution L22-Q90H was found in 24/32 representative M. bovis isolates with different MICs, but no correlation with decreased susceptibility to Ty or Tm was identified. Multiple aa substitutions were also identified in the L4 protein, including at positions 185-186 (positions 64 and 65 in E. coli) which are adjacent to the macrolide-binding site. This is the first description of the molecular mechanism of acquired resistance to the 16-membered macrolides in M. bovis. Copyright © 2013 Elsevier B.V. All rights reserved.

A quantitative method for residues of macrolide antibiotics in porcine kidney by liquid chromatography/tandem mass spectrometry.

PubMed

Dickson, Leslie C; O'Byrne, Collin; Chan, Wayne

2012-01-01

An LC/MS/MS-based multiresidue quantitative method was developed for the macrolides erythromycin A, neospiramycin I, oleandomycin, spiramycin I, tilmicosin, and tylosin A in porcine kidney tissues. The Canadian Food Inspection Agency (CFIA) had as part of its analytical scope an LC/UV method for quantification of residues of two macrolide antibiotics, tilmicosin and tylosin A, in the kidney, liver, and muscle of cattle, swine, and poultry. The method could not reliably detect concentrations below 10 microg/kg. To increase the scope of the CFIA's analytical capabilities, a sensitive multiresidue quantitative method for macrolide residues in food animal tissues was required. Porcine kidney samples were extracted with acetonitrile and alkaline buffer and cleaned-up using silica-based C18 SPE cartridges. Sample extracts were analyzed using LC/MS/MS with positive electrospray ionization. Fitness for purpose was verified in a single-laboratory validation study using a second analyst. The working analytical range was 5 to 50 microg/kg. LOD and LOQ were 0.5 to 0.6 microg/kg and 1.5 to 3.0 microg/kg, respectively. Limits of identification were 0.5 to 2.0 microg/kg. Relative intermediate precisions were 8 to 17%. Average absolute recoveries were 68 to 76%.

Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases.

PubMed

Hodge, Sandra; Tran, Hai B; Hamon, Rhys; Roscioli, Eugene; Hodge, Greg; Jersmann, Hubertus; Ween, Miranda; Reynolds, Paul N; Yeung, Arthur; Treiberg, Jennifer; Wilbert, Sibylle

2017-05-01

We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides-2'-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2'-desoxy molecule (GS-560660)-with significantly diminished antibiotic activity against Staphylococcus aureus , Streptococcus pneumonia , Moraxella catarrhalis , and H. influenzae We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5-1 µg/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained >85% following 24 h exposure to either macrolide at concentrations up to 20 µg/ml. Secreted and intracellular-cleaved IL-1β was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll

The AcrAB-TolC pump is involved in macrolide resistance but not in telithromycin efflux in Enterobacter aerogenes and Escherichia coli.

PubMed

Chollet, Renaud; Chevalier, Jacqueline; Bryskier, André; Pagès, Jean-Marie

2004-09-01

The role of the AcrAB-TolC pump in macrolide and ketolide susceptibility in Escherichia coli and Enterobacter aerogenes was studied. Efflux pump inhibitor restored erythromycin, clarithromycin, and telithromycin susceptibilities to multidrug-resistant isolates. No modification of telithromycin accumulation was detected in E. aerogenes acrAB or tolC derivatives compared to that in the parental strain. Two independent efflux pumps, inhibited by phenylalanine arginine beta-naphthylamide, expel macrolides and telithromycin in E. aerogenes.

In vitro synergy testing of macrolide-quinolone combinations against 41 clinical isolates of Legionella.

PubMed Central

Martin, S J; Pendland, S L; Chen, C; Schreckenberger, P; Danziger, L H

1996-01-01

Combination antimicrobial therapy against Legionella species has not been well studied. Several quinolones have activity against Legionella strains, which prompted this in vitro search for a synergistic combination with the macrolides. By a checkerboard assay, erythromycin, clarithromycin, and azithromycin, each in combination with ciprofloxacin and levofloxacin, were tested for synergy against 46 isolates of Legionella. The agar dilution method was employed using buffered charcoal-yeast extract media. A final inoculum of 10(4) CFU per spot was prepared from 24-h growth of each isolate. Plates were incubated at 35 degrees C for 48 h. Synergy, partial synergy, additive effect, or indifference was observed for all combinations of antibiotics tested. There was no antagonism observed. Synergy occurred to a significantly greater extent for the clarithromycin-levofloxacin (P = 0.0001) and azithromycin-levofloxacin (P = 0.003) combinations versus erythromycin-levofloxacin. The azithromycin-ciprofloxacin combination demonstrated significantly greater synergy than did either erythromycin-ciprofloxacin (P = 0.003) or clarithromycin-ciprofloxacin (P = 0.001). The newer macrolides clarithromycin and azithromycin may be more active in combination with a fluoroquinolone than is erythromycin. PMID:8726012

Treatment failure rates and health care utilization and costs among patients with community-acquired pneumonia treated with levofloxacin or macrolides in an outpatient setting: a retrospective claims database analysis.

PubMed

Ye, Xin; Sikirica, Vanja; Schein, Jeffrey R; Grant, Richard; Zarotsky, Victoria; Doshi, Dilesh; Benson, Carmela Janagap; Riedel, Aylin A

2008-02-01

Macrolide antibiotics and fluoroquinolones are extensively used in the treatment of community-acquired pneumonia (CAP). This analysis was conducted to compare treatment failure rates and health care utilization and cost outcomes among patients with CAP treated with levo-floxacin (500 or 750 mg) or macrolides (azithromycin, clarithromycin, or erythromycin) in an outpatient setting. This was a retrospective analysis of claims data from a large US health plan. Patients were aged > or =18 years and had a primary diagnosis of CAP that was treated with oral levofloxacin or a macrolide in an outpatient setting (including physicians' offices, outpatient clinics, urgent care centers, and large ambulatory health centers). Patients were followed for 30 days after the index drug date to measure study outcomes. Multivariate regression analysis and a propensity score technique were used to compare rates of treatment failure and CAP-related health care utilization and costs. Two post hoc subgroup analyses were conducted in patients aged > or =50 and > or =65 years. Of the 7526 patients meeting the inclusion criteria, 2968 (39.4%) were treated with levofloxacin and 4558 (60.6%) with a macrolide. Unadjusted rates of treatment failure were 21.1% and 22.7% in the levofloxacin and macrolide cohorts, respectively. After adjustment for demographic characteristics, baseline comorbidities, and severity of illness, levofloxacin recipients were significantly less likely to experience treatment failure than macrolide recipients (odds ratio [OR] = 0.84; 95% CI, 0.75-0.94, P = 0.003). The likelihood of treatment failure was significantly lower in levofloxacin recipients aged > or =50 years (OR = 0.79; 95% CI, 0.66-0.94; P = 0.007) and > or =65 years (OR = 0.65; 95% CI, 0.43-1.00; P = 0.049) compared with the corresponding subgroups of macrolide recipients. The magnitude of this difference was greatest in the subgroup aged > or =65 years, which had a 35% reduced risk of treatment failure

Total synthesis and stereochemical assignment of the salicylate antitumor macrolide lobatamide C(1).

PubMed

Shen, Ruichao; Lin, Cheng Ting; Porco, John A

2002-05-22

The total synthesis and stereochemical assignment of the potent antitumor macrolide lobatamide C is reported. The synthesis involves Cu(I)-mediated enamide formation and Na(2)CO(3)-mediated esterification of a beta-hydroxy acid and a salicylate cyanomethyl ester. Macrolactonization was accomplished using a Mitsunobu protocol. The stereochemical assignment of lobatamide C was achieved by Mosher ester analysis and comparison with prepared stereoisomers.

The etiology of community-acquired pneumonia in Australia: why penicillin plus doxycycline or a macrolide is the most appropriate therapy.

PubMed

Charles, Patrick G P; Whitby, Michael; Fuller, Andrew J; Stirling, Robert; Wright, Alistair A; Korman, Tony M; Holmes, Peter W; Christiansen, Keryn J; Waterer, Grant W; Pierce, Robert J P; Mayall, Barrie C; Armstrong, John G; Catton, Michael G; Nimmo, Graeme R; Johnson, Barbara; Hooy, Michelle; Grayson, M L

2008-05-15

Available data on the etiology of community-acquired pneumonia (CAP) in Australia are very limited. Local treatment guidelines promote the use of combination therapy with agents such as penicillin or amoxycillin combined with either doxycycline or a macrolide. The Australian CAP Study (ACAPS) was a prospective, multicenter study of 885 episodes of CAP in which all patients underwent detailed assessment for bacterial and viral pathogens (cultures, urinary antigen testing, serological methods, and polymerase chain reaction). Antibiotic agents and relevant clinical outcomes were recorded. The etiology was identified in 404 (45.6%) of 885 episodes, with the most frequent causes being Streptococcus pneumoniae (14%), Mycoplasma pneumoniae (9%), and respiratory viruses (15%; influenza, picornavirus, respiratory syncytial virus, parainfluenza virus, and adenovirus). Antibiotic-resistant pathogens were rare: only 5.4% of patients had an infection for which therapy with penicillin plus doxycycline would potentially fail. Concordance with local antibiotic recommendations was high (82.4%), with the most commonly prescribed regimens being a penicillin plus either doxycycline or a macrolide (55.8%) or ceftriaxone plus either doxycycline or a macrolide (36.8%). The 30-day mortality rate was 5.6% (50 of 885 episodes), and mechanical ventilation or vasopressor support were required in 94 episodes (10.6%). Outcomes were not compromised by receipt of narrower-spectrum beta-lactams, and they did not differ on the basis of whether a pathogen was identified. The vast majority of patients with CAP can be treated successfully with narrow-spectrum beta-lactam treatment, such as penicillin combined with doxycycline or a macrolide. Greater use of such therapy could potentially reduce the emergence of antibiotic resistance among common bacterial pathogens.

In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients.

PubMed Central

Alcaide, F; Carratala, J; Liñares, J; Gudiol, F; Martin, R

1996-01-01

From January 1988 to December 1994, 66 consecutive blood culture isolates of viridans group streptococci collected from febrile neutropenic cancer patients were tested for antimicrobial susceptibilities by the agar dilution method. The antibiotics studied were erythromycin, clarithromycin, roxithromycin, dirithromycin, azithromycin, josamycin, diacetyl-midecamycin, spiramycin, and quinupristin-dalfopristin. A total of 26 (39.4%) strains were resistant to erythromycin with an MIC range of 0.5 to > 128 micrograms/ml. The strains were classified into three groups according to their penicillin susceptibility: 42 (63.6%) were susceptible, 8 (12.1%) were intermediately resistant, and 16 (24.3%) were highly resistant. The percentages of erythromycin-resistant strains in each group were 23.8, 62.5, and 68.8%, respectively. Streptococcus mitis was the species most frequently isolated (83.3%) and showed the highest rates of penicillin (40%) and erythromycin (43.6%) resistance. MICs of all macrolide antibiotics tested and of quinupristin-dalfopristin were higher for penicillin-resistant strains than for penicillin-susceptible strains. All macrolide antibiotics tested had cross-resistance to erythromycin, which was not observed with quinupristin-dalfopristin. Our study shows a high rate of macrolide resistance among viridans group streptococci isolated from blood samples of neutropenic cancer patients, especially those infected with penicillin-resistant strains. These findings make macrolides unsuitable prophylactic agents against viridans group streptococcal bacteremia in this patient population. PMID:8878591

Hydrolysis of amphenicol and macrolide antibiotics: Chloramphenicol, florfenicol, spiramycin, and tylosin.

PubMed

Mitchell, Shannon M; Ullman, Jeffrey L; Teel, Amy L; Watts, Richard J

2015-09-01

Antibiotics that enter the environment can present human and ecological health risks. An understanding of antibiotic hydrolysis rates is important for predicting their environmental persistence as biologically active contaminants. In this study, hydrolysis rates and Arrhenius constants were determined as a function of pH and temperature for two amphenicol (chloramphenicol and florfenicol) and two macrolide (spiramycin and tylosin) antibiotics. Antibiotic hydrolysis rates in pH 4-9 buffer solutions at 25°C, 50°C, and 60°C were quantified, and degradation products were characterized. All of the antibiotics tested remained stable and exhibited no observable hydrolysis under ambient conditions typical of aquatic ecosystems. Acid- and base-catalyzed hydrolysis occurred at elevated temperatures (50-60°C), and hydrolysis rates increased considerably below pH 5 and above pH 8. Hydrolysis rates also increased approximately 1.5- to 2.9-fold for each 10°C increase in temperature. Based on the degradation product masses found, the functional groups that underwent hydrolysis were alkyl fluoride, amide, and cyclic ester (lactone) moieties; some of the resultant degradation products may remain bioactive, but to a lesser extent than the parent compounds. The results of this research demonstrate that amphenicol and macrolide antibiotics persist in aquatic systems under ambient temperature and pH conditions typical of natural waters. Thus, these antibiotics may present a risk in aquatic ecosystems depending on the concentration present. Copyright © 2015. Published by Elsevier Ltd.

Molecular resistance mechanisms of Mycoplasma agalactiae to macrolides and lincomycin.

PubMed

Prats-van der Ham, Miranda; Tatay-Dualde, Juan; de la Fe, Christian; Paterna, Ana; Sánchez, Antonio; Corrales, Juan Carlos; Contreras, Antonio; Gómez-Martín, Ángel

2017-11-01

The extensive use of antimicrobials for disease control has caused a remarkable decrease in antimicrobial susceptibility of different animal mycoplasma species, including Mycoplasma agalactiae (M. agalactiae), the main causative agent of contagious agalactia. However, the molecular mechanisms behind M. agalactiae resistance to macrolides and lincomycin have not yet been elucidated. The aim of the present study was to investigate the association between minimum inhibitory concentration (MIC) values of different antimicrobials and mutations in the 23S rRNA gene and ribosomal proteins L4 and L22, analysing both field isolates (n=50) and in vitro selected resistant mutants of M. agalactiae. The obtained MIC results of the studied field isolates demonstrate an increasing development of tylosin resistance in this bacterium, in comparison to previous studies. Interestingly, predicted amino acid changes in L22 (Ser89Leu and Gln90Lys/His) were the first variations observed when MICs of M. agalactiae started to increase (tylosin MIC ≥0.8μg/ml), whereas mutations at positions 2058 or 2059 of domain V of the 23S rRNA gene appeared from MIC values of 1.6μg/ml. These results were consistent in both field isolates and in vitro selected mutants of M. agalactiae. Thus, although in other mycoplasma species resistance to macrolides and lincosamides had been mainly related to mutations in the 23S rRNA gene, this work demonstrates the role of alterations in ribosomal protein L22 in decreased susceptibility of M. agalactiae. Moreover, these mutations can be used as molecular markers to set an interpretative breakpoint of antimicrobial resistance for M. agalactiae. Copyright © 2017 Elsevier B.V. All rights reserved.

Molecularly imprinted solid-phase extraction for the determination of ten macrolide drugs residues in animal muscles by liquid chromatography-tandem mass spectrometry.

PubMed

Song, Xuqin; Zhou, Tong; Liu, Qingying; Zhang, Meiyu; Meng, Chenying; Li, Jiufeng; He, Limin

2016-10-01

A simple and sensitive method based on molecularly imprinted solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry was developed for the determination of the residues of ten macrolide drugs in swine, cattle and chicken muscles samples. The molecularly imprinted polymers (MIPs) were synthesized using tylosin as a template and methacrylic acid as a functional monomer. Samples were extracted with sodium borate buffer solution and ethyl acetate, and purified by the MIP cartridge. The results showed that the cartridge exhibited good recognition performance for macrolides, and better purification effect than the traditional solid-phase extraction cartridges. Recoveries of analytes at three spiking levels 1, 5 and 20μgkg(-1) ranged from 60.7% to 100.3% with the relative standard deviations less than 14%. The limits of detection of the method were between 0.1 and 0.4μgkg(-1). The method is useful for the routine monitoring of the residues of macrolide drugs in animal muscles. Copyright © 2016 Elsevier Ltd. All rights reserved.

Influence of macrolides, nutritional support and respiratory therapies in diabetes and normal glucose tolerance in cystic fibrosis. A retrospective analysis of a cohort of adult and younger patients.

PubMed

Megías, Marta Cano; Albarrán, Olga González; Vasco, Pablo Guisado; Ferreiro, Adelaida Lamas; Carro, Luis Maiz

2015-01-01

The development of cystic fibrosis related diabetes is associated with increased morbidity and mortality, worse nutritional status and lung function decline. It is known that patients with cystic fibrosis have a chronic inflammation status and that β pancreatic cells are very sensitive to oxidative stress. So these inflammatory mediators could contribute to the onset of progressive pancreatic fibrosis and, hence, to impair glucose metabolism. So, it could be hypothesized that the treatment with macrolides would protect and preserve β-cell function by decreasing pro-inflammatory cytokines and free oxidative radicals. We retrospectively analyzed a cohort of 64 patients affected of cystic fibrosis, older than 14 years, by using the first pathological 2-h oral glucose tolerance test; peripheral insulin resistance was calculated using the homeostasis model assessment for insulin resistance (HOMA - IR) and pancreatic β-cell function was estimated according to Wareham. The influence of macrolides, microbiological colonization, nutritional support and related clinical parameters were analyzed. Comparing CFRD without FPG and NGT, and after adjustment for microbial colonization, the significance of the use of macrolides was lost (p=0.1), as a risk or protective factor for any of the studied groups. Non-significative associations were found in the use of macrolides, inhaled corticosteroids and nutritional support therapies within the different disorders of carbohydrate metabolism. The anti-inflammatory and immunomodulating effect of macrolides did not seem to affect the β cell function or insulin resistance in patients with cystic fibrosis. The use of inhaled corticosteroids or nutritional supplements have not any influence in the carbohydrate metabolism. Further prospective studies are needed to analyze a potential protective role of macrolides in the development of carbohydrate metabolism alterations in cystic fibrosis. Copyright © 2014 Diabetes India. Published by

Mandelalides A-D, cytotoxic macrolides from a new Lissoclinum species of South African tunicate.

PubMed

Sikorska, Justyna; Hau, Andrew M; Anklin, Clemens; Parker-Nance, Shirley; Davies-Coleman, Michael T; Ishmael, Jane E; McPhail, Kerry L

2012-07-20

Mandelalides A-D are variously glycosylated, unusual polyketide macrolides isolated from a new species of Lissoclinum ascidian collected from South Africa, Algoa Bay near Port Elizabeth and the surrounding Nelson Mandela Metropole. Their planar structures were elucidated on submilligram samples by comprehensive analysis of 1D and 2D NMR data, supported by mass spectrometry. The assignment of relative configuration was accomplished by consideration of homonuclear and heteronuclear coupling constants in tandem with ROESY data. The absolute configuration was assigned for mandelalide A after chiral GC-MS analysis of the hydrolyzed monosaccharide (2-O-methyl-α-L-rhamnose) and consideration of ROESY correlations between the monosaccharide and aglycone in the intact natural product. The resultant absolute configuration of the mandelalide A macrolide was extrapolated to propose the absolute configurations of mandelalides B-D. Remarkably, mandelalide B contained the C-4' epimeric 2-O-methyl-6-dehydro-α-L-talose. Mandelalides A and B showed potent cytotoxicity to human NCI-H460 lung cancer cells (IC(50), 12 and 44 nM, respectively) and mouse Neuro-2A neuroblastoma cells (IC(50), 29 and 84 nM, respectively).

Lactimidomycin, Iso-migrastatin and Related Glutarimide-containing 12-membered Macrolides are Extremely Potent Inhibitors of Cell Migration

PubMed Central

Ju, Jianhua; Rajski, Scott R.; Lim, Si-Kyu; Seo, Jeong-Woo; Peters, Noël R.; Hoffmann, F. Michael; Shen, Ben

2009-01-01

Migrastatin (1), iso-migrastatin (5) and lactimidomycin (7) are all glutarimide-containing polyketides known for their unique structures and cytotoxic activities against human cancer cell lines. Migrastatin, a strong inhibitor of tumor cell migration, has been an important lead in the development of antimetastatic agents. Yet studies of the related 12-membered macrolides iso-migrastatin, lactimidomycin and related analogs have been hampered by their limited availability. We report here the production, isolation, structural characterization and biological activities of iso-migrastatin, lactimidomycin, and 23 related congeners. Our studies showed that, as a family, the glutarimide-containing 12-membered macrolides are extremely potent cell migration inhibitors with some members displaying activity on par or superior to that of migrastatin as exemplified by compounds 5, 7, and 9–12. On the basis of these findings, the structures and activity of this family of compounds as cell migration inhibitors are discussed. PMID:19132897

INVESTIGATING ENVIRONMENTAL SINKS OF MACROLIDE ...

EPA Pesticide Factsheets

Possible environmental sinks (wastewater effluents, biosolids, sediments) of macrolide antibiotics (i.e., azithromycin, roxithromycin and clarithromycin)are investigated using state-of-the-art analytical chemistry techniques. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analytical methodologies that can detect non-volatile, polar, water-soluble pharmaceuticals in source waters at levels that could be environmentally significant (at concentrations less than parts per billion, ppb). IAG with USGS ends in FY05. APM 20 due in FY05.Subtask 2: Coordination of interagency research and public outreach activities for PPCPs. Participate on NSTC Health and Environment subcommittee working group on PPCPs. Web site maintenance and expansion, invited technical presentations, invited articles for peer-reviewed journals, interviews

Production of macrolide antibiotics from a cytotoxic soil Streptomyces sp. strain ZDB.

PubMed

Dame, Zerihun T; Ruanpanun, Pornthip

2017-07-01

Crude extract from a culture of a soil Streptomyces sp. strain ZDB showed toxicity towards Artemia salina and antimicrobial activity against Escherichia coli, Bacillus subtilis, Staphylococcus aureus, Chlorella vulgaris, and Chlorella sorokiniana. Large scale fermentation of the strain led to the isolation of the macrolide antibiotics, bafilomycins A1 (1), B1 (2), and D (3) together with nonactic acid (4) and bostrycoidin-9-methyl ether (5). Structures of the antibiotics were determined based on spectral data analysis. We describe the isolation of the compounds and characterization of the producing strain.

Cytotoxic Halogenated Macrolides and Modified Peptides from the Apratoxin-Producing Marine Cyanobacterium Lyngbya bouillonii from Guam

PubMed Central

Matthew, Susan; Salvador, Lilibeth A.; Schupp, Peter J.; Paul, Valerie J.; Luesch, Hendrik

2010-01-01

Collections of the marine cyanobacterium Lyngbya bouillonii from shallow patch reefs in Apra Harbor, Guam, afforded three hitherto undescribed analogues of the glycosidic macrolide lyngbyaloside, namely 2-epi-lyngbyaloside (1) and the regioisomeric 18E- and 18Z–lyngbyalosides C (2 and 3). Concurrently we discovered two new analogues of the cytoskeletal actin-disrupting lyngbyabellins, 27-deoxylyngbyabellin A (4) and lyngbyabellin J (5), a novel macrolide of the laingolide family, laingolide B (6), and a linear modified peptide, lyngbyapeptin D (7), along with known lyngbyabellins A and B, lyngbyapeptin A, and lyngbyaloside. The structures of 1–7 were elucidated by a combination of NMR spectroscopic and mass spectrometric analysis. Compounds 1–6 were either brominated (1–3) or chlorinated (4–6), consistent with halogenation being a hallmark of many marine natural products. All extracts derived from these L. bouillonii collections were highly cytotoxic due to the presence of apratoxin A or also apratoxin C. Compounds 1–5 showed weak to moderate cytotoxicity to HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells. PMID:20704304

Clonal Spread of a Unique Strain of Macrolide-Resistant Mycoplasma Pneumoniae Within a Single Family in Italy.

PubMed

Chironna, Maria; Loconsole, Daniela; De Robertis, Anna Lisa; Morea, Anna; Scalini, Egidio; Quarto, Michele; Tafuri, Silvio; Germinario, Cinzia; Manzionna, Mariano

2016-03-01

Macrolide-resistant Mycoplasma pneumoniae (MR-MP) is an increasing problem worldwide. This study describes the clonal spread of a unique strain of MR-MP within a single family. On January 23, 2015, nasopharyngeal swabs and sputum samples were collected from the index case (a 9-year-old girl) in southern Italy. The patient had pneumonia and was initially treated with clarithromycin. MR-MP infection was suspected due to prolonged symptoms despite appropriate antibiotic therapy. Two further cases of pneumonia occurred in relatives (a 7-year-old cousin and the 36-year-old mother of the index case); therefore, respiratory samples were also collected from other family members. Sequence analysis identified mutations associated with resistance to macrolides. Both P1 major adhesion protein typing and multiple loci variable-number tandem repeat analysis (MLVA) typing were performed to assess the relatedness of the strains. The index case, the cousin, the mother, and another 4 family members (twin siblings of the index case, a 3-year-old cousin, and the grandmother) were positive for MR-MP. All strains harbored the mutation A2063G, had the same P1 subtype (1), and were MLVA (7/4/5/7/2) type Z. In addition, the index case's aunt (31 years of age and the probable source of infection) harbored an M pneumoniae strain with the same molecular profile; however, this strain was susceptible to macrolides. This cluster of MR-MP infection/carriage caused by a clonal strain suggests a high transmission rate within this family and highlights the need for increased awareness among clinicians regarding the circulation of MR-MP. Novel strategies for the treatment and prevention of M pneumoniae infections are required.

Total synthesis and structural revision of the marine macrolide neopeltolide.

PubMed

Custar, Daniel W; Zabawa, Thomas P; Scheidt, Karl A

2008-01-23

The total synthesis and structural revision of the marine natural product neopeltolide is reported. The key bond-forming step involves a Lewis acid-catalyzed intramolecular cyclization to install the tetrahydropyran ring and the macrocycle simultaneously. This type of cyclization is the first of its kind and assembles the carbon backbone of the natural product efficiently. The synthesis of the reported structure revealed differences in the data between the natural and synthetic material. After significant investigation, the diastereomeric molecule with the C11 and C13 configurations inverted was synthesized using the initial route. This compound matches the data reported for neopeltolide (1H, 13C, HRMS, IR, NOESY, [alpha]), thereby establishing the correct overall structure for this potent macrolide natural product, including the relative and absolute stereochemistry.

Synergistic anti-Campylobacter jejuni activity of fluoroquinolone and macrolide antibiotics with phenolic compounds

PubMed Central

Oh, Euna; Jeon, Byeonghwa

2015-01-01

The increasing resistance of Campylobacter to clinically important antibiotics, such as fluoroquinolones and macrolides, is a serious public health problem. The objective of this study is to investigate synergistic anti-Campylobacter jejuni activity of fluoroquinolones and macrolides in combination with phenolic compounds. Synergistic antimicrobial activity was measured by performing a checkerboard assay with ciprofloxacin and erythromycin in the presence of 21 phenolic compounds. Membrane permeability changes in C. jejuni by phenolic compounds were determined by measuring the level of intracellular uptake of 1-N-phenylnaphthylamine (NPN). Antibiotic accumulation assays were performed to evaluate the level of ciprofloxacin accumulation in C. jejuni. Six phenolic compounds, including p-coumaric acid, sinapic acid, caffeic acid, vanillic acid, gallic acid, and taxifolin, significantly increased the susceptibility to ciprofloxacin and erythromycin in several human and poultry isolates. The synergistic antimicrobial effect was also observed in ciprofloxacin- and erythromycin-resistant C. jejuni strains. The phenolic compounds also substantially increased membrane permeability and antibiotic accumulation in C. jejuni. Interestingly, some phenolic compounds, such as gallic acid and taxifolin, significantly reduced the expression of the CmeABC multidrug efflux pump. Phenolic compounds increased the NPN accumulation in the cmeB mutant, indicating phenolic compounds may affect the membrane permeability. In this study, we successfully demonstrated that combinational treatment of C. jejuni with antibiotics and phenolic compounds synergistically inhibits C. jejuni by impacting both antimicrobial influx and efflux. PMID:26528273

Identification and Characterization of Fluoroquinolone Non-susceptible Streptococcus pyogenes Clones Harboring Tetracycline and Macrolide Resistance in Shanghai, China

PubMed Central

Shen, Yinfang; Cai, Jiehao; Davies, Mark R.; Zhang, Chi; Gao, Kun; Qiao, Dan; Jiang, Haoqin; Yao, Weilei; Li, Yuefang; Zeng, Mei; Chen, Mingliang

2018-01-01

Streptococcus pyogenes, also known as group A Streptococcus (GAS), is one of the top 10 infectious causes of death worldwide. Macrolide and tetracycline resistant GAS has emerged as a major health concern in China coinciding with an ongoing scarlet fever epidemic. Furthermore, increasing rates of fluoroquinolone (FQ) non-susceptibility within GAS from geographical regions outside of China has also been reported. Fluoroquinolones are the third most commonly prescribed antibiotic in China and is an therapeutic alternative for multi-drug resistant GAS. The purpose of this study was to investigate the epidemiological and molecular features of GAS fluoroquinolone (FQ) non-susceptibility in Shanghai, China. GAS (n = 2,258) recovered between 2011 and 2016 from children and adults were tested for FQ-non-susceptibility. Efflux phenotype and mutations in parC, parE, gyrA, and gyrB were investigated and genetic relationships were determined by emm typing, pulsed-field gel electrophoresis and phylogenetic analysis. The frequency of GAS FQ-non-susceptibility was 1.3% (30/2,258), with the phenotype more prevalent in GAS isolated from adults (14.3%) than from children (1.2%). Eighty percent (24/30) of FQ-non-susceptible isolates were also resistant to both macrolides (ermB) and tetracycline (tetM) including the GAS sequence types emm12, emm6, emm11, and emm1. Genomic fingerprinting analysis of the 30 isolates revealed that non-susceptibility may arise in various genetic backgrounds even within a single emm type. No efflux phenotype was observed in FQ non-susceptible isolates, and molecular analysis of the quinolone resistance-determining regions (QRDRs) identified several sequence polymorphisms in ParC and ParE, and none in GyrA and GyrB. Expansion of this analysis to 152 publically available GAS whole genome sequences from Hong Kong predicted 7.9% (12/152) of Hong Kong isolates harbored a S79F ParC mutation, of which 66.7% (8/12) were macrolide and tetracycline resistant

Trends in penicillin and macrolide resistance among pneumococci in the UK and the Republic of Ireland in relation to antibiotic sales to pharmacies and dispensing doctors.

PubMed

Livermore, David M; Reynolds, Rosy; Stephens, Peter; Duckworth, Georgia; Felmingham, David; Johnson, Alan P; Murchan, Stephen; Murphy, Olive; Gungabissoon, Usha; Waight, Pauline; Pebody, Richard; Shackcloth, Jemma; Warner, Marina; Williams, Laura; George, Robert C

2006-10-01

It is widely believed that reducing antimicrobial usage should reduce resistance, although observational evidence is mixed. Pneumococci make ideal subjects to test this belief as they are widely surveyed and lack an animal reservoir. Accordingly, susceptibility data for pneumococci in the UK and Ireland were retrieved from the Health Protection Agency's LabBase/CoSurv system and from the European Antimicrobial Resistance Surveillance System (EARSS) and British Society for Antimicrobial Chemotherapy (BSAC) databases. The BSAC surveillance examines respiratory pneumococci; the other systems focus upon invasive organisms only, with the LabBase/CoSurv system being the most comprehensive, capturing data on most bacteraemias in England and Wales. National pharmacy sales data were obtained from the IMS Health MIDAS database and were modelled to the resistance data by logistic and linear regression analysis. All systems except for the BSAC respiratory surveillance data indicated that penicillin resistance has fallen significantly since 1999 in the UK, whereas macrolide resistance has been essentially stable, or has risen slightly. The data for Ireland were based on smaller sample sizes but suggested a fall in penicillin non-susceptibility from 1999 to 2004, with conflicting evidence for macrolide resistance. The recent decreasing trend in penicillin resistance is in contrast to a rising trend in England and Wales until (at least) 1997 and strongly rising macrolide resistance from 1989 to 1993. UK pharmacy sales of macrolides and oral beta-lactams fell by ca. 30% in the late 1990s following increased concern about resistance, before stabilising or rising weakly; sales in Ireland were stable or rose slightly in the study period. We conclude that falling penicillin resistance in pneumococci followed reduced sales of oral beta-lactams to pharmacies in the UK, but a similar fall in macrolide sales was not associated with any fall in resistance. Stabilisation or decline in

Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases

PubMed Central

Tran, Hai B.; Hamon, Rhys; Roscioli, Eugene; Hodge, Greg; Jersmann, Hubertus; Ween, Miranda; Reynolds, Paul N.; Yeung, Arthur; Treiberg, Jennifer; Wilbert, Sibylle

2017-01-01

We reported defective efferocytosis associated with cigarette smoking and/or airway inflammation in chronic lung diseases, including chronic obstructive pulmonary disease, severe asthma, and childhood bronchiectasis. We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides—2′-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2′-desoxy molecule (GS-560660)—with significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1β (cytometric bead array, immunofluorescence/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages ± 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5–1 µg/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained >85% following 24 h exposure to either macrolide at concentrations up to 20 µg/ml. Secreted and intracellular-cleaved IL-1β was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member

A CASE STUDY: CROP (LETTUCE, SPINACH, AND CARROTS) UPTAKE OF THREE MACROLIDE ANTIBIOTICS (AZITHROMYCIN, CLINDAMYCIN AND ROXITHROMYCIN) AND OTHER DRUGS

EPA Science Inventory

It has been shown that human-use macrolide antibiotics (azithromycin, clindamycin, and roxithromycin) are environmentally available in wastewaters, source waters, and biosolids. In order to better understand the fate of these compounds into food crops via root migration, we condu...

[Liquid chromatography-tandem mass spectrometry method for determination of 10 macrolide antibiotics in pork samples using on-line solid phase extraction purification].

PubMed

Zhang, Xiaoguang; Liu, Dong; Liu, Hongran; Li, Qiang; Li, Lili; Wang, Lixia; Zhang, Yan

2017-10-08

A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method based on-line solid phase extraction (SPE) purification was established to determine 10 macrolide antibiotics in pork samples. The samples were extracted with acetonitrile, and the extracts were dried with rotary evaporator at 40℃, then the analytes were dissolved with 2 mL phosphate buffer. The solutions were purified and concentrated by on-line SPE with HLB cartridges. The analytes were eluted with methanol, and then transferred to XBridge BEH C18 column, separated with the mobile phases of 10 mmol/L ammonium acetate aqueous solution and acetonitrile. Finally, the target analytes were detected by tandem mass spectrometry. The results showed that good linearity was obtained in the range of 0.1-200 μg/L for the 10 macrolide antibiotics with correlation coefficients better than 0.990. The limits of detection were in range of 0.05-0.30 μg/kg and the limits of quantitation were in range of 0.10-1.00 μg/kg. The recoveries of the method were in range of 69.6%-115.2% at the spiked levels of 0.10-10.0 μg/kg for all analytes, with the relative standard deviations less than 10%. The developed method can be used for the determination of the 10 macrolide antibiotics in pork samples.

Novel Tn916-like elements confer aminoglycoside/macrolide co-resistance in clinical isolates of Streptococcus gallolyticus ssp. gallolyticus.

PubMed

Kambarev, Stanimir; Pecorari, Frédéric; Corvec, Stéphane

2018-02-09

Streptococcus gallolyticus ssp. gallolyticus (Sgg) is a commensal bacterium and an opportunistic pathogen. In humans it has been clinically associated with the incidence of colorectal cancer (CRC) and epidemiologically recognized as an emerging cause of infective endocarditis (IE). The standard therapy of Sgg includes the administration of a penicillin in combination with an aminoglycoside. Even though penicillin-resistant isolates have still not been reported, epidemiological studies have shown that this microbe is a reservoir of multiple acquired genes, conferring resistance to tetracyclines, aminoglycosides, macrolides and glycopeptides. However, the underlying antibiotic resistance mobilome of Sgg remains poorly understood. To investigate the mobile genetic basis of antibiotic resistance in multiresistant clinical Sgg. Isolate NTS31106099 was recovered from a patient with IE and CRC at Nantes University Hospital, France and studied by Illumina WGS and comparative genomics. Molecular epidemiology of the identified mobile element(s) was performed using antibiotic susceptibility testing (AST), PCR, PFGE and WGS. Mobility was investigated by PCR and filter mating. Two novel conjugative transposons, Tn6263 and Tn6331, confer aminoglycoside/macrolide co-resistance in clinical Sgg. They display classical family Tn916/Tn1545 modular architecture and harbour an aph(3')-III→sat4→ant(6)-Ia→erm(B) multiresistance gene cluster, related to pRE25 of Enterococcus faecium. These and/or closely related elements are highly prevalent among genetically heterogeneous clinical isolates of Sgg. Previously unknown Tn916-like mobile genetic elements conferring aminoglycoside/macrolide co-resistance make Sgg, collectively with other gut Firmicutes such as enterococci and eubacteria, a potential laterally active reservoir of these antibiotic resistance determinants among the mammalian gastrointestinal microbiota. © The Author(s) 2018. Published by Oxford University Press on behalf

Public health consequences of macrolide use in food animals: a deterministic risk assessment.

PubMed

Hurd, H Scott; Doores, Stephanie; Hayes, Dermot; Mathew, Alan; Maurer, John; Silley, Peter; Singer, Randall S; Jones, Ronald N

2004-05-01

The potential impact on human health from antibiotic-resistant bacteria selected by use of antibiotics in food animals has resulted in many reports and recommended actions. The U.S. Food and Drug Administration Center for Veterinary Medicine has issued Guidance Document 152, which advises veterinary drug sponsors of one potential process for conducting a qualitative risk assessment of drug use in food animals. Using this guideline, we developed a deterministic model to assess the risk from two macrolide antibiotics, tylosin and tilmicosin. The scope of modeling included all label claim uses of both macrolides in poultry, swine, and beef cattle. The Guidance Document was followed to define the hazard, which is illness (i) caused by foodborne bacteria with a resistance determinant, (ii) attributed to a specified animal-derived meat commodity, and (iii) treated with a human use drug of the same class. Risk was defined as the probability of this hazard combined with the consequence of treatment failure due to resistant Campylobacter spp. or Enterococcus faecium. A binomial event model was applied to estimate the annual risk for the U.S. general population. Parameters were derived from industry drug use surveys, scientific literature, medical guidelines, and government documents. This unique farm-to-patient risk assessment demonstrated that use of tylosin and tilmicosin in food animals presents a very low risk of human treatment failure, with an approximate annual probability of less than 1 in 10 million Campylobacter-derived and approximately 1 in 3 billion E. faecium-derived risk.

Immunosuppressive macrolides of the type FK 506: a novel class of topical agents for treatment of skin diseases?

PubMed

Meingassner, J G; Stütz, A

1992-06-01

The immunosuppressive macrolide antibiotics FK 506 and rapamycin were tested for topical activity in experimental allergic contact dermatitis of farm pigs. This species was used because pig skin, in comparison to rodent skin, resembles human skin more closely. For comparison, cyclosporine A (CyA), which is orally but not topically active in patients with skin disease, dexamethasone, and clobetasol propionate were used. Treatment was performed twice, 30 min and 6 h after elicitation of challenge reaction. Topical application of 0.4 to 0.04% FK 506 caused a pronounced inhibition of inflammatory skin reactions of hypersensitivity to dinitrofluorobenzene. The treatment response was similar to the activity of 0.13% clobetasole. Dexamethasone (1.2%) was less active than clobetasol. In contrast, rapamycin and CyA were inactive at concentrations of 1.2 and 10%, respectively. Because the pig data on corticosteroids and cyclosporine A are in agreement with clinical findings, these studies indicate that immunosuppressive macrolides of the type FK 506 may be useful drugs for the topical treatment of human skin diseases that respond to local corticosteroids and oral treatment with cyclosporine A.

Use of Clindamycin Disks To Detect Macrolide Resistance Mediated by ermB and mefE in Streptococcus pneumoniae Isolates from Adults and Children

PubMed Central

Waites, Ken; Johnson, Crystal; Gray, Barry; Edwards, Kathryn; Crain, Marilyn; Benjamin, William

2000-01-01

We studied 198 macrolide-resistant S. pneumoniae isolates obtained from adults and children to evaluate whether 2-μg clindamycin disks can distinguish between isolates manifesting ermB- versus mefE-mediated resistance to clarithromycin and to determine the relative frequency with which each resistance mechanism occurred in these populations. The mefE gene was predominant among 109 isolates from children, occurring in 73.4% versus 50.6% of 89 isolates from adults. Three isolates (1.5%) did not amplify either gene. Among 125 mefE+ isolates, the MIC of clarithromycin at which 90% of the isolates tested were inhibited, determined by Etest, was 32 μg/ml versus >256 μg/ml in 70 ermB+ isolates. All ermB+ isolates were highly resistant to clindamycin (MICs >256 μg/ml), whereas all mefE+ isolates were susceptible to clindamycin using the 2-μg disk. Testing S. pneumoniae from the respiratory tract for susceptibility to clindamycin by agar disk diffusion is an easy and inexpensive method to estimate the frequency of resistance mediated by ermB in specific patient populations. Macrolide resistance mediated by ermB is usually of greater magnitude than that due to mefE. Clinical studies are needed to determine the significance of high- versus low-level macrolide resistance in S. pneumoniae. PMID:10790089

Ultra-Trace Analysis of Nine Macrolides, including Tulathromycin A (Draxxin), in Edible Animal Tissues with Mini-Column Liquid Chromatography Tandem Mass Spectrometry

USDA-ARS?s Scientific Manuscript database

Analysis of 9 macrolides is presented, including tulathromycin A (Draxxin), in beef, poultry and pork muscle with a simple multi-residue extraction and analysis method using high performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. The extraction method inv...

Simultaneous determination of five tetracycline and macrolide antibiotics in feeds using HPCE.

PubMed

Tong, Jing; Rao, Qinxiong; Zhu, Kui; Jiang, Zhigang; Ding, Shuangyang

2009-12-01

This work demonstrates the potential of HPCE in the analysis of antibiotics in a complex matrix such as feedstuffs. Using 20 mM citric acid-40 mM Na(2)HPO(4) buffer (pH 2.65), the five antibiotics, tetracycline, oxytetracycline, doxycycline, tilmicosin, and tylosin were successfully separated at 30 kV in a 64.5 cm x 75 microm id capillary. Good repeatability, stability, and reliability of the method were supported by <10% CV with mean recoveries of >70%, and the limit of detection of the five analytes was 0.5-1 mg/kg. It was for the first time that a capillary electrophoretic method was employed to simultaneously detect five tetracycline and macrolide antibiotics in animal feeds.

Macrolide antibiotics differentially influence human HepG2 cytotoxicity and modulate intrinsic/extrinsic apoptotic pathways in rat hepatocellular carcinoma model.

PubMed

Abdel-Hamid, Nagwa I; El-Azab, Mona F; Moustafa, Yasser M

2017-04-01

This study was designed to examine the potential antitumor effect of some macrolides: clarithromycin, azithromycin, and erythromycin on chemically induced hepatocellular carcinoma (HCC) in rats and on human hepatoma cells (HepG2) as well. The possible underlying antiapoptotic mechanisms were investigated. Antiproliferative activity was assessed in HepG2 using Sulforhodamine-B staining method. In vivo, HCC was induced in rats by initiation-selection-promotion protocol using diethylnitrosamine (200 mg/kg, single i.p. injection)/2-acetylaminofluorene (0.03% w/w supplemented-diet for 2 weeks)/carbon tetrachloride (2 ml/kg diluted in corn oil 1:1, single intra-gastric dose)/phenobarbitone sodium (0.05% w/w supplemented-diet for 28 weeks). Macrolides were administered once daily starting from the 3rd week until the 17th week at a dose of 100 mg/kg in the current 33-week study period. Clarithromycin showed a higher efficacy in the suppression of HepG2 proliferation with lower IC50 value than doxorubicin. In vivo, chemically-induced HCC rat model proved that clarithromycin suppressed HCC via induction of apoptosis through up-regulation of both extrinsic/intrinsic apoptotic pathways' proteins (TNFR1, cleaved caspase-3, and Bax with an increased Bax/Bcl-2 ratio) along with MMP-9 normalization. Similarly, azithromycin demonstrated antitumorigenic effect through both apoptotic pathways, however, to a lesser extent compared to clarithromycin. Moreover, azithromycin suppressed the proliferation of HepG2, however, at a higher IC50 than doxorubicin. Surprisingly, erythromycin increased HepG2 proliferation in vitro, along with worsened tumorigenic effect of the carcinogenic agents in the in vivo study with ineffective apoptotic outcome. Some macrolides represent potential antitumor agents; however, this evident anticancer activity is an individual effect rather than a group effect and involves modulation of both intrinsic and extrinsic apoptotic pathways.

A strategy for untargeted screening of macrolides and metabolites in bass by liquid chromatography coupled to quadrupole orbitrap mass spectrometry.

PubMed

Jia, Wei; Shi, Lin; Chu, Xiaogang; Chang, James; Chen, Ying; Zhang, Feng

2018-10-01

An analytical method for the non-target screening of macrolides and metabolites in bass (Lateolabrax) was developed using an automated on-line extraction procedure followed by ultrahigh-performance liquid chromatography coupled to electrospray ionization quadrupole Orbitrap high-resolution mass spectrometry (UHPLC Q-Orbitrap). The estimated performance characteristics were satisfied, complying with the requirements of the guidelines specified in European Commission Decision 2002/657/EC. The decision limit ranged from 0.12 μg kg -1 to 3.61 μg kg -1 , and detection capability ranged between 0.20 μg kg -1 and 6.02 μg kg -1 . Precision in terms of relative standard deviation (RSD) was under 14% for all compounds, and the extraction recoveries ranged from 81% to 107%. Finally, the method was applied to ten different commercially important bass species and confirmed the presence of ten macrolides and metabolites. Five non-target compounds of robenidine, lincomycin hydrochloride, thiacloprid, fenbendazole, and thiabendazole were elucidated in the untargeted screening. Copyright © 2018 Elsevier Ltd. All rights reserved.

Progress toward characterization of the group A Streptococcus metagenome: complete genome sequence of a macrolide-resistant serotype M6 strain.

PubMed

Banks, David J; Porcella, Stephen F; Barbian, Kent D; Beres, Stephen B; Philips, Lauren E; Voyich, Jovanka M; DeLeo, Frank R; Martin, Judith M; Somerville, Greg A; Musser, James M

2004-08-15

We describe the genome sequence of a macrolide-resistant strain (MGAS10394) of serotype M6 group A Streptococcus (GAS). The genome is 1,900,156 bp in length, and 8 prophage-like elements or remnants compose 12.4% of the chromosome. A 8.3-kb prophage remnant encodes the SpeA4 variant of streptococcal pyrogenic exotoxin A. The genome of strain MGAS10394 contains a chimeric genetic element composed of prophage genes and a transposon encoding the mefA gene conferring macrolide resistance. This chimeric element also has a gene encoding a novel surface-exposed protein (designated "R6 protein"), with an LPKTG cell-anchor motif located at the carboxyterminus. Surface expression of this protein was confirmed by flow cytometry. Humans with GAS pharyngitis caused by serotype M6 strains had antibody against the R6 protein present in convalescent, but not acute, serum samples. Our studies add to the theme that GAS prophage-encoded extracellular proteins contribute to host-pathogen interactions in a strain-specific fashion.

Syphilis epidemiology in 1994-2013, molecular epidemiological strain typing and determination of macrolide resistance in Treponema pallidum in 2013-2014 in Tuva Republic, Russia.

PubMed

Khairullin, Rafil; Vorobyev, Denis; Obukhov, Andrey; Kuular, Ural-Herel; Kubanova, Anna; Kubanov, Alexey; Unemo, Magnus

2016-07-01

The incidence of syphilis in the Tuva Republic (geographical centre of Asia), Russia has been exceedingly high historically. No detailed examinations and no molecular investigations of Treponema pallidum strains transmitted in the Tuva Republic, or in general, in Russia, were published internationally. We examined the syphilis epidemiology in 1994-2013, and the molecular epidemiology and macrolide resistance in T. pallidum strains in 2013-2014 in the Tuva Republic. Among 95 mainly primary or secondary syphilis patients, the arp, tpr, tp0548 and 23S rRNA genes in 85 polA gene-positive genital ulcer specimens were characterized. The syphilis incidence in Tuva Republic peaked in 1998 (1562), however declined to 177 in 2013. Among the 70 (82%) completely genotyped specimens, six molecular strain types were found. Strain type 14d/f accounted for 91%, but also 14c/f, 14d/g, 14b/f, 14i/f, 9d/f, and 4d/f were identified. Two (2.4%) specimens contained the 23S rRNA A2058G macrolide resistance mutation. This is the first internationally published typing study regarding T. pallidum in Russia, performed in the Tuva Republic with the highest syphilis incidence in Russia. The two molecular strain types 4d/f and 9d/f have previously been described only in Eastern and Northern China and for the first time, macrolide-resistant syphilis was described in Russia. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Occurrence and transport of tetracycline, sulfonamide, quinolone, and macrolide antibiotics in the Haihe River Basin, China.

PubMed

Luo, Yi; Xu, Lin; Rysz, Michal; Wang, Yuqiu; Zhang, Hao; Alvarez, Pedro J J

2011-03-01

The occurrence and transport of 12 antibiotics (from the tetracycline, sulfonamide, quinolone, and macrolide families) was studied in a 72-km stretch of the Haihe River, China, and in six of its tributaries. Aqueous and sediment samples were analyzed by HPLC-MS/MS. Sulfonamides were detected at the highest concentrations (24-385 ng/L) and highest frequencies (76-100%). Eight of the 12 antibiotics likely originated from veterinary applications in swine farms and fishponds, and concentrations at these sources (0.12-47 μg/L) were 1-2 orders of magnitude higher than in the effluent of local wastewater treatment plants. Sulfachloropyridazine (SCP) was detected in all swine farm and fishpond samples (maximum concentration 47 μg/L), which suggests its potential usefulness to indicate livestock source pollution in the Haihe River basin. Hydrological and chemical factors that may influence antibiotic distribution in the Haihe River were considered by multiple regression analysis. River flow rate exerted the most significant effect on the first-order attenuation coefficient (K) for sulfonamides, quinolones, and macrolides, with higher flow rates resulting in higher K, probably due to dilution. For tetracyclines, sediment total organic matter and cation exchange capacity exerted a greater impact on K than flow rate, indicating that adsorption to sediments plays an important role in attenuating tetracycline migration. Overall, the predominance of sulfonamides in the Haihe River underscores the need to consider regulating their veterinary use and improving the management and treatment of associated releases.

Comparison of charcoal- and starch-based media for testing susceptibilities of Legionella species to macrolides, azalides, and fluoroquinolones.

PubMed Central

Pendland, S L; Martin, S J; Chen, C; Schreckenberger, P C; Danziger, L H

1997-01-01

We compared growth characteristics of 46 Legionella strains grown on buffered charcoal yeast extract alpha (BCYE alpha) agar and buffered starch yeast extract (BSYE) agar and MICs of macrolides, azalides, and fluoroquinolones for these organisms. Growth was poor and not reproducible on BSYE agar. Growth was excellent on BCYE alpha, and MICs were easy to interpret. BCYE alpha is superior to BSYE for testing susceptibilities of Legionella species by agar dilution. PMID:9350781

Chemoenzymatic Total Synthesis and Structural Diversification of Tylactone-Based Macrolide Antibiotics through Late-Stage Polyketide Assembly, Tailoring, and C-H Functionalization.

PubMed

Lowell, Andrew N; DeMars, Matthew D; Slocum, Samuel T; Yu, Fengan; Anand, Krithika; Chemler, Joseph A; Korakavi, Nisha; Priessnitz, Jennifer K; Park, Sung Ryeol; Koch, Aaron A; Schultz, Pamela J; Sherman, David H

2017-06-14

Polyketide synthases (PKSs) represent a powerful catalytic platform capable of effecting multiple carbon-carbon bond forming reactions and oxidation state adjustments. We explored the functionality of two terminal PKS modules that produce the 16-membered tylosin macrocycle, using them as biocatalysts in the chemoenzymatic synthesis of tylactone and its subsequent elaboration to complete the first total synthesis of the juvenimicin, M-4365, and rosamicin classes of macrolide antibiotics via late-stage diversification. Synthetic chemistry was employed to generate the tylactone hexaketide chain elongation intermediate that was accepted by the juvenimicin (Juv) ketosynthase of the penultimate JuvEIV PKS module. The hexaketide is processed through two complete modules (JuvEIV and JuvEV) in vitro, which catalyze elongation and functionalization of two ketide units followed by cyclization of the resulting octaketide into tylactone. After macrolactonization, a combination of in vivo glycosylation, selective in vitro cytochrome P450-mediated oxidation, and chemical oxidation was used to complete the scalable construction of a series of macrolide natural products in as few as 15 linear steps (21 total) with an overall yield of 4.6%.

Selective activity of polyene macrolides produced by genetically modified Streptomyces on Trypanosoma cruzi.

PubMed

Rolón, Miriam; Seco, Elena M; Vega, Celeste; Nogal, Juan J; Escario, José A; Gómez-Barrio, Alicia; Malpartida, Francisco

2006-08-01

The growth inhibitory effects on Trypanosoma cruzi of several natural tetraene macrolides and their derivatives were studied and compared with that of amphotericin B. All tetraenes strongly inhibited in vitro multiplication. Proliferation of epimastigotes was arrested by all these drugs at < or =3.6 microM, which were also active on amastigotes proliferating in fibroblasts. Compared with amphotericin B, the compounds were less effective but also less toxic, showing no effect on the proliferation of J774 and NCTC 929 mammalian cells at concentrations active against the parasites. CE-108B (a polyene amide) appeared to be an especially potent trypanocidal compound, with strong in vivo trypanocidal activity and very low or no toxic side effects, and thus should be considered for further studies.

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.

MacA, a periplasmic membrane fusion protein of the macrolide transporter MacAB-TolC, binds lipopolysaccharide core specifically and with high affinity.

PubMed

Lu, Shuo; Zgurskaya, Helen I

2013-11-01

The Escherichia coli MacAB-TolC transporter has been implicated in efflux of macrolide antibiotics and secretion of enterotoxin STII. In this study, we found that purified MacA, a periplasmic membrane fusion protein, contains one tightly bound rough core lipopolysaccharide (R-LPS) molecule per MacA molecule. R-LPS was bound specifically to MacA protein with affinity exceeding that of polymyxin B. Sequence analyses showed that MacA contains two high-density clusters of positively charged amino acid residues located in the cytoplasmic N-terminal domain and the periplasmic C-terminal domain. Substitutions in the C-terminal cluster reducing the positive-charge density completely abolished binding of R-LPS. At the same time, these substitutions significantly reduced the functionality of MacA in the protection of E. coli against macrolides in vivo and in the in vitro MacB ATPase stimulation assays. Taken together, our results suggest that R-LPS or a similar glycolipid is a physiological substrate of MacAB-TolC.

DNA methylase activity as a marker for the presence of a family of phage-like elements conferring efflux-mediated macrolide resistance in streptococci.

PubMed

Figueiredo, T A; Aguiar, S I; Melo-Cristino, J; Ramirez, M

2006-11-01

Recently, two related chimeric genetic elements (Tn1207.3 and Phi10394.4) were shown to carry the macrolide efflux gene mef in Streptococcus pyogenes (group A streptococci [GAS]). The dissemination of elements belonging to the Tn1207.3/Phi10394.4 family in recent isolates of GAS, Streptococcus dysgalactiae subsp. equisimilis, Streptococcus pneumoniae, and Streptococcus agalactiae recovered in Portugal was surveyed. In total, 149 GAS, 18 S. pneumoniae, 4 S. dysgalactiae subsp. equisimilis, and 5 S. agalactiae isolates from infections, presenting the M phenotype of macrolide resistance and containing the mef gene, were screened for the presence of Tn1207.3/Phi10394.4 by PCR targeting open reading frames (ORFs) specific for these related elements. All the GAS isolates tested and one of the S. dysgalactiae subsp. equisimilis isolates carried Tn1207.3. However, neither of these elements was found in the isolates of the other streptococcal species. It was also noted that the DNAs of the isolates carrying Tn1207.3 were resistant to cleavage by the endonuclease SmaI. Cloning and expression of ORF12 of Tn1207.3 in Escherichia coli showed that it encoded a methyltransferase that rendered DNA refractory to cleavage by SmaI (M.Spy10394I). Using this characteristic as a marker for the presence of the Tn1207.3/Phi10394.4 family, we reviewed the literature and concluded that these genetic elements are widely distributed among tetracycline-susceptible GAS isolates presenting the M phenotype from diverse geographic origins and may have played an important role in the dissemination of macrolide resistance in this species.

Activities of two novel macrolides, GW 773546 and GW 708408, compared with those of telithromycin, erythromycin, azithromycin, and clarithromycin against Haemophilus influenzae.

PubMed

Kosowska, Klaudia; Credito, Kim; Pankuch, Glenn A; Hoellman, Dianne; Lin, Gengrong; Clark, Catherine; Dewasse, Bonifacio; McGhee, Pamela; Jacobs, Michael R; Appelbaum, Peter C

2004-11-01

The MIC at which 50% of strains are inhibited (MIC(50)) and the MIC(90) of GW 773546, a novel macrolide, were 1.0 and 2.0 microg/ml, respectively, for 223 beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC(50)s and MIC(90)s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 microg/ml, respectively, while the MIC(50) and MIC(90) of azithromycin were 1.0 and 2.0 microg/ml, respectively. The MIC(50) and MIC(90) of erythromycin were 4.0 and 8.0 microg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 microg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 x 10(-9) to 2.2 x 10(-6) with

Activities of Two Novel Macrolides, GW 773546 and GW 708408, Compared with Those of Telithromycin, Erythromycin, Azithromycin, and Clarithromycin against Haemophilus influenzae

PubMed Central

Kosowska, Klaudia; Credito, Kim; Pankuch, Glenn A.; Hoellman, Dianne; Lin, Gengrong; Clark, Catherine; Dewasse, Bonifacio; McGhee, Pamela; Jacobs, Michael R.; Appelbaum, Peter C.

2004-01-01

The MIC at which 50% of strains are inhibited (MIC50) and the MIC90 of GW 773546, a novel macrolide, were 1.0 and 2.0 μg/ml, respectively, for 223 β-lactamase-positive, β-lactamase-negative, and β-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC50s and MIC90s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 μg/ml, respectively, while the MIC50 and MIC90 of azithromycin were 1.0 and 2.0 μg/ml, respectively. The MIC50 and MIC90 of erythromycin were 4.0 and 8.0 μg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 μg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 × 10−9 to 2.2 × 10−6 with GW 773546, 1.5 × 10−9 to 6.0 �

Molecular Control of Polyene Macrolide Biosynthesis

PubMed Central

Santos-Aberturas, Javier; Vicente, Cláudia M.; Guerra, Susana M.; Payero, Tamara D.; Martín, Juan F.; Aparicio, Jesús F.

2011-01-01

Control of polyene macrolide production in Streptomyces natalensis is mediated by the transcriptional activator PimM. This regulator, which combines an N-terminal PAS domain with a C-terminal helix-turn-helix motif, is highly conserved among polyene biosynthetic gene clusters. PimM, truncated forms of the protein without the PAS domain (PimMΔPAS), and forms containing just the DNA-binding domain (DBD) (PimMDBD) were overexpressed in Escherichia coli as GST-fused proteins. GST-PimM binds directly to eight promoters of the pimaricin cluster, as demonstrated by electrophoretic mobility shift assays. Assays with truncated forms of the protein revealed that the PAS domain does not mediate specificity or the distinct recognition of target genes, which rely on the DBD domain, but significantly reduces binding affinity up to 500-fold. Transcription start points were identified by 5′-rapid amplification of cDNA ends, and the binding regions of PimMDBD were investigated by DNase I protection studies. In all cases, binding took place covering the −35 hexamer box of each promoter, suggesting an interaction of PimM and RNA polymerase to cause transcription activation. Information content analysis of the 16 sequences protected in target promoters was used to deduce the structure of the PimM-binding site. This site displays dyad symmetry, spans 14 nucleotides, and adjusts to the consensus TVGGGAWWTCCCBA. Experimental validation of this binding site was performed by using synthetic DNA duplexes. Binding of PimM to the promoter region of one of the polyketide synthase genes from the Streptomyces nodosus amphotericin cluster containing the consensus binding site was also observed, thus proving the applicability of the findings reported here to other antifungal polyketides. PMID:21187288

Contamination profiles and mass loadings of macrolide antibiotics and illicit drugs from a small urban wastewater treatment plant.

PubMed

Loganathan, Bommanna; Phillips, Malia; Mowery, Holly; Jones-Lepp, Tammy L

2009-03-01

Information is limited regarding sources, distribution, environmental behavior, and fate of prescribed and illicit drugs. Wastewater treatment plant (WWTP) effluents can be one of the sources of pharmaceutical and personal care products (PPCP) into streams, rivers and lakes. The objective of this study was to determine the contamination profiles and mass loadings of urobilin (a chemical marker of human waste), macrolide antibiotics (azithromycin, clarithromycin, roxithromycin), and two drugs of abuse (methamphetamine and ecstasy), from a small (<19 mega liters day(-1), equivalent to <5 million gallons per day) wastewater treatment plant in southwestern Kentucky. The concentrations of azithromycin, clarithromycin, methamphetamine and ecstasy in wastewater samples varied widely, ranging from non-detects to 300 ng L(-1). Among the macrolide antibiotics analyzed, azithromycin was consistently detected in influent and effluent samples. In general, influent samples contained relatively higher concentrations of the analytes than the effluents. Based on the daily flow rates and an average concentration of 17.5 ng L(-1) in the effluent, the estimated discharge of azithromycin was 200 mg day(-1) (range 63-400 mg day(-1)). Removal efficiency of the detected analytes from this WWTP were in the following order: urobilin>methamphetamine>azithromycin with percentages of removal of 99.9%, 54.5% and 47%, respectively, indicating that the azithromycin and methamphetamine are relatively more recalcitrant than others and have potential for entering receiving waters.

The novel conjugative transposon tn1207.3 carries the macrolide efflux gene mef(A) in Streptococcus pyogenes.

PubMed

Santagati, Maria; Iannelli, Francesco; Cascone, Carmela; Campanile, Floriana; Oggioni, Marco R; Stefani, Stefania; Pozzi, Gianni

2003-01-01

The macrolide efflux gene mef(A) of the Streptococcus pyogenes clinical strain 2812A was found to be carried by a 52-kb chromosomal genetic element that could be transferred by conjugation to the chromosome of other streptococcal species. The characteristics of this genetic element are typical of conjugative transposons and was named Tn1207.3. The size of Tn1207.3 was established by pulsed-field gel electrophoresis (PFGE), and DNA sequencing analysis showed that the 7,244 bp at the left end of Tn1207.3 were identical to those of the pneumococcal Tn1207.1 element. Tn1207.3-like genetic elements were found to be inserted at a single specific chromosomal site in 12 different clinical isolates S. pyogenes exhibiting the M phenotype of resistance to macrolides and carrying the mef(A) gene. Tn1207.3 was transferred from S. pyogenes 2812A to Streptococcus pneumoniae, and sequence analysis carried out on six independent transconjugants showed that insertion of Tn1207.3 in the pneumococcal genome always occurred at a single specific site as in Tn1207.1. Using MF2, a representative S. pneumoniae transconjugant, as a donor, Tn1207.3 was transferred again by conjugation to S. pyogenes and Streptococcus gordonii. The previously described nonconjugative element Tn1207.1 of S. pneumoniae appears to be a defective element, part of a longer conjugative transposon that carries mef(A) and is found in clinical isolates of S. pyogenes.

Serogroup 19 pneumococci containing both mef and erm macrolide resistance determinants in an American city.

PubMed

Toltzis, Philip; Dul, Michael; O'Riordan, Mary Ann; Jacobs, Michael R; Blumer, Jeffrey

2006-01-01

Asia has experienced a striking incidence of infection by highly resistant pneumococi containing both principal macrolide resistance determinants, namely, the mef efflux pump and the erm ribosomal methylase. mef/erm-containing pneumococci have not been identified in significant numbers in North America. Pneumococci were isolated as part of a larger study in Cleveland, OH examining colonization patterns among children randomized to 1 of 4 outpatient antibiotics for acute otitis media. Azithromycin-resistant organisms were tested for the presence of mef and erm sequences by polymerase chain reaction. The clonal relationship of pneumococci containing both genes was determined by pulsed field gel electrophoresis and multilocus sequence testing. Selected characteristics of children harboring mef/erm-containing organisms were compared with other participants of the larger study. Of 221 children colonized by pneumococci, 17 (7.7%) were colonized with an organism containing both determinants. All mef/erm-positive organisms demonstrated azithromycin minimum inhibitory concentrations > or =256 microg/mL and were coresistant to all other agents tested. The mef/erm-containing organisms were serotype 19A and 19F, all but 1 of which manifested similar pulsed field gel electrophoresis patterns. Multilocus sequence testing analysis indicated a relationship to the Taiwan-14 macrolide-resistant strain that has spread throughout Eastern Asia. More than one-third of children colonized by a mef/erm-containing organism had received > or =1 dose of conjugate pneumococcal vaccine, a significantly higher proportion than children carrying less resistant organisms (P< 0.01). No other characteristics distinguished children harboring a mef/erm-containing pneumococcus from other children enrolled in the larger study. Clonally related mef/erm-containing serogroup 19 pneumococci were prominent among otherwise healthy children in a North American metropolitan area. Our findings suggest that spread

Enhanced Molecular Typing of Treponema pallidum subspecies pallidum Strains From 4 Italian Hospitals Shows Geographical Differences in Strain Type Heterogeneity, Widespread Resistance to Macrolides, and Lack of Mutations Associated With Doxycycline Resistance.

PubMed

Giacani, Lorenzo; Ciccarese, Giulia; Puga-Salazar, Christian; Dal Conte, Ivano; Colli, Laura; Cusini, Marco; Ramoni, Stefano; Delmonte, Sergio; DʼAntuono, Antonietta; Gaspari, Valeria; Drago, Francesco

2018-04-01

Although syphilis rates have been relatively high in Italy for more than 15 years, no data on the molecular types of Treponema pallidum subspecies pallidum circulating in this country are yet available. Likewise, no data on how widespread is resistance to macrolide or tetracycline antibiotics in these strains exist. Such data would, however, promote comprehensive studies on the molecular epidemiology of syphilis infections in Italy and inform future interventions aiming at syphilis control in this and other European countries. Swabs from oral, genital, cutaneous, or anal lesions were obtained from 60 syphilis patients attending dermatology clinics in Milan, Turin, Genoa, and Bologna. Molecular typing of T. pallidum DNA was performed to provide a snapshot of the genetic diversity of strains circulating in Northern Italy. Samples were also screened for mutations conferring resistance to macrolides and tetracyclines. T. pallidum DNA was detected in 88.3% (53/60) of the specimens analyzed. Complete and partial T. pallidum typing data were obtained for 77.3% (41/53) and 15.0% (8/53) of samples, respectively, whereas 4 samples could not be typed despite T. pallidum DNA being detected. The highest strain type heterogeneity was seen in samples from Bologna and Milan, followed by Genoa. Minimal diversity was detected in samples from Turin, despite the highest number of typeable samples collected there. Resistance to macrolides was detected in 94.3% (50/53) of the strains, but no known mutations associated with tetracycline resistance were found. Genetic diversity among T. pallidum strains circulating in Northern Italy varies significantly among geographical areas regardless of physical distance. Resistance to macrolides is widespread.

MacA, a Periplasmic Membrane Fusion Protein of the Macrolide Transporter MacAB-TolC, Binds Lipopolysaccharide Core Specifically and with High Affinity

PubMed Central

Lu, Shuo

2013-01-01

The Escherichia coli MacAB-TolC transporter has been implicated in efflux of macrolide antibiotics and secretion of enterotoxin STII. In this study, we found that purified MacA, a periplasmic membrane fusion protein, contains one tightly bound rough core lipopolysaccharide (R-LPS) molecule per MacA molecule. R-LPS was bound specifically to MacA protein with affinity exceeding that of polymyxin B. Sequence analyses showed that MacA contains two high-density clusters of positively charged amino acid residues located in the cytoplasmic N-terminal domain and the periplasmic C-terminal domain. Substitutions in the C-terminal cluster reducing the positive-charge density completely abolished binding of R-LPS. At the same time, these substitutions significantly reduced the functionality of MacA in the protection of E. coli against macrolides in vivo and in the in vitro MacB ATPase stimulation assays. Taken together, our results suggest that R-LPS or a similar glycolipid is a physiological substrate of MacAB-TolC. PMID:23974027

Bacteriological Efficacies of Three Macrolides Compared with Those of Amoxicillin-Clavulanate against Streptococcus pneumoniae and Haemophilus influenzae

PubMed Central

Berry, Valerie; Thorburn, Christine E.; Knott, Sarah J.; Woodnutt, Gary

1998-01-01

Comparative antibacterial efficacies of erythromycin, clarithromycin, and azithromycin were examined against Streptococcus pneumoniae and Haemophilus influenzae, with amoxicillin-clavulanate used as the active control. In vitro, the macrolides at twice their MICs and at concentrations achieved in humans were bacteriostatic or reduced the numbers of viable S. pneumoniae slowly, whereas amoxicillin-clavulanate showed a rapid antibacterial effect. Against H. influenzae, erythromycin, clarithromycin, and clarithromycin plus 14-hydroxy clarithromycin at twice their MICs produced a slow reduction in bacterial numbers, whereas azithromycin was bactericidal. Azithromycin at the concentrations achieved in the serum of humans was bacteriostatic, whereas erythromycin and clarithromycin were ineffective. In experimental respiratory tract infections in rats, clarithromycin (equivalent to 250 mg twice daily [b.i.d.]) and amoxicillin-clavulanate (equivalent to 500 plus 125 mg b.i.d., respectively) were highly effective against S. pneumoniae, but azithromycin (equivalent to 500 and 250 mg once daily) was significantly less effective (P < 0.01). Against H. influenzae, clarithromycin treatment (equivalent to 250 or 500 mg b.i.d.) was similar to no treatment and was significantly less effective than amoxicillin-clavulanate treatment (P < 0.01). Azithromycin demonstrated significant in vivo activity (P < 0.05) but was significantly less effective than amoxicillin-clavulanate (P < 0.05). Overall, amoxicillin-clavulanate was effective in vitro and in vivo. Clarithromycin and erythromycin were ineffective in vitro and in vivo against H. influenzae, and azithromycin (at concentrations achieved in humans) showed unreliable activity against both pathogens. These results may have clinical implications for the utility of macrolides in the empiric therapy of respiratory tract infections. PMID:9835514

Solid phase microextraction of macrolide, trimethoprim, and sulfonamide antibiotics in wastewaters.

PubMed

McClure, Evelyn L; Wong, Charles S

2007-10-26

In this work, we optimize a solid phase microextraction (SPME) method for the simultaneous collection of antibiotics (sulfonamides, macrolides, and trimethoprim) present in wastewaters. The performance of the SPME method is compared to a solid phase extraction (SPE) method. Analytes in both cases were quantified by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) with electrospray ionization. The advantages offered by SPME in this application are: decreased sample volume requirements, ease of sample processing and extraction, decreased cost, and most importantly, elimination of electrospray matrix effects. Despite having higher limits of quantification (16-1380 ng/L in influent and 35-260 ng/L in effluent), nearly all of the compounds found to be present in Edmonton Gold Bar wastewater by SPE were measurable by SPME (i.e., sulfamethoxazole, trimethoprim, erythromycin, and clarithromycin), with values similar to those obtained using the former method. Limits of quantification for the SPE method for the measured compounds were 4.7-15 ng/L and 0.86-6.1 ng/L for influent and effluent, respectively.

Polysensitivity in delayed cutaneous adverse drug reactions to macrolides, clindamycin, and pristinamycin: clinical history and patch testing.

PubMed

El Khoury, M; Assier, H; Gener, G; Paul, M; Haddad, C; Chosidow, O; Wolkenstein, P; Ingen-Housz-Oro, S

2018-05-10

Although they have different biochemical structures, macrolides, lincosamides (including clindamycin) and streptogramins (including pristinamycin) share a similar mechanism of action on Gram-positive bacteria and are grouped into the MLS family. 1 Cross-allergies induced by drugs of similar mechanism of action but different chemical structure (polysensitivity) are poorly described. Our objectives were to investigate the possibility of polysensitivity among MLS antibiotics, and to compare the value of patch tests (PTs) in MLS-induced delayed-cutaneous adverse drug reactions (D-CADRs). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Trace analysis of trimethoprim and sulfonamide, macrolide, quinolone, and tetracycline antibiotics in chlorinated drinking water using liquid chromatography electrospray tandem mass spectrometry

USGS Publications Warehouse

Ye, Z.; Weinberg, H.S.; Meyer, M.T.

2007-01-01

A multirun analytical method has been developed and validated for trace determination of 24 antibiotics including 7 sulfonamides, 3 macrolides, 7 quinolones, 6 tetracyclines, and trimethoprim in chlorine-disinfected drinking water using a single solid-phase extraction method coupled to liquid chromatography with positive electrospray tandem mass spectrometry detection. The analytes were extracted by a hydrophilic-lipophilic balanced resin and eluted with acidified methanol (0.1% formic acid), resulting in analyte recoveries generally above 90%. The limits of quantitation were mostly below 10 ng/L in drinking water. Since the concentrated sample matrix typically caused ion suppression during electrospray ionization, the method of standard addition was used for quantitation. Chlorine residuals in drinking water can react with some antibiotics, but ascorbic acid was found to be an effective chlorine quenching agent without affecting the analysis and stability of the antibiotics in water. A preliminary occurrence study using this method revealed the presence of some antibiotics in drinking waters, including sulfamethoxazole (3.0-3.4 ng/L), macrolides (1.4-4.9 ng/L), and quinolones (1.2-4.0 ng/L). ?? 2007 American Chemical Society.

Comparative Treatment Failure Rates of Respiratory Fluoroquinolones or β-Lactam + Macrolide Versus β-Lactam Alone in the Treatment for Community-Acquired Pneumonia in Adult Outpatients

PubMed Central

Lee, Meng-Tse Gabriel; Lee, Shih-Hao; Chang, Shy-Shin; Chan, Ya-Lan; Pang, Laura; Hsu, Sue-Ming; Lee, Chien-Chang

2015-01-01

Abstract No comparative effectiveness study has been conducted for the following 3 antibiotics: respiratory fluoroquinolone, β-lactam, and β-lactam + advanced macrolide. To gain insights into the real-world clinical effectiveness of these antibiotics for community-acquired pneumonia in adult outpatients, our study investigated the treatment failure rates in 2 million representative participants from the National Health Informatics Project (NHIP) of Taiwan. A new-user cohort design was used to follow NHIP participants from January 2000 until December 2009. Treatment failure was defined by either one of the following events: a second antibiotic prescription, hospitalization due to CAP, an emergency department visit with a diagnosis of CAP, or 30-day nonaccident-related mortality. From 2006 to 2009, we identified 9256 newly diagnosed CAP outpatients, 1602 of whom were prescribed levofloxacin, 2100 were prescribed moxifloxacin, 5049 were prescribed β-lactam alone, and 505 were prescribed advanced macrolide + β-lactam. Compared with the β-lactam-based regimen, the propensity score-matched odds ratio for composite treatment failure was 0.81 (95% CI, 0.67–0.97) for moxifloxacin, 1.10 (95% CI, 0.90–1.35) for levofloxacin, and 0.95 (95% CI, 0.67–1.35) for macrolide +β-lactam. Moxifloxacin was associated with lower treatment failure rates compared with β-lactam alone, or levofloxacin in Taiwanese CAP outpatients. However, due to inherent limitations in our claims database, more randomized controlled trials are required before coming to a conclusion on which antibiotic is more effective for Taiwanese CAP outpatients. More population-based comparative effectiveness studies are also encouraged and should be considered as an integral piece of evidence in local CAP treatment guidelines. PMID:26426664

Determination of Ten Macrolide Drugs in Environmental Water Using Molecularly Imprinted Solid-Phase Extraction Coupled with Liquid Chromatography-Tandem Mass Spectrometry.

PubMed

Song, Xuqin; Zhou, Tong; Li, Jiufeng; Zhang, Meiyu; Xie, Jingmeng; He, Limin

2018-05-14

With the extensive application of antibiotics in livestock, their contamination of the aquatic environment has received more attention. Molecularly imprinted polymer (MIP), as an eco-friendly and durable solid-phase extraction material, has shown great potential for the separation and enrichment of antibiotics in water. This study aims at developing a practical and economical method based on molecularly imprinted solid phase extraction (MISPE) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneously detecting ten macrolide drugs in different sources of water samples. The MIP was synthesized by bulk polymerization using tylosin as the template and methacrylic acid as the functional monomer. The MIP exhibited a favorable load-bearing capacity for water (>90 mL), which is more than triple that of non-molecularly imprinted polymers (NIP). The mean recoveries of macrolides at four spiked concentration levels (limit of quantification, 40, 100, and 400 ng/L) were 62.6⁻100.9%, with intra-day and inter-day relative standard deviations below 12.6%. The limit of detection and limit of quantification were 1.0⁻15.0 ng/L and 3.0⁻40.0 ng/L, respectively. Finally, the proposed method was successfully applied to the analysis of real water samples.

Structural assignment of poecillastrins B and C, macrolide lactams from the deep-water Caribbean sponge Poecillastra species.

PubMed

Takada, Kentaro; Choi, Byoung W; Rashid, Mohammad A; Gamble, William R; Cardellina, John H; Van, Que N; Lloyd, John R; McMahon, James B; Gustafson, Kirk R

2007-03-01

Two new chondropsin-type macrolide lactams, poecillastrins B (1) and C (2), were isolated from aqueous extracts of the marine sponge Poecillastra sp. These trace metabolites were isolated in low yield (400-600 microg), and their structures were determined primarily by analysis of NMR data acquired using a cyrogenically cooled probe. High-quality 1D and 2D NMR data sets allowed complete assignment of the spectroscopic data and defined the new structures as 35-membered ring analogues of poecillastrin A (3). Compounds 1 and 2 showed potent cytotoxic activity against a human melanoma tumor cell line (LOX) with an IC50 value of less than 1 microg/mL.

Comparing two types of macrolide antibiotics for the purpose of assessing population-based drug interactions

PubMed Central

Fleet, Jamie L; Shariff, Salimah Z; Bailey, David G; Gandhi, Sonja; Juurlink, David N; Nash, Danielle M; Mamdani, Muhammad; Gomes, Tara; Patel, Amit M; Garg, Amit X

2013-01-01

Objective Clarithromycin strongly inhibits enzyme cytochrome P450 3A4, preventing the metabolism of some other drugs, while azithromycin is a weak inhibitor. Accordingly, blood concentrations of other drugs increase with clarithromycin coprescription leading to adverse events. These macrolide antibiotics also differ on other properties that may impact outcomes. In this study, we compared outcomes in two groups of macrolide antibiotic users in the absence of potentially interacting drugs. Design Population-based retrospective cohort study. Setting Ontario, Canada, from 2003 to 2010. Patients Patients (mean 74 years) prescribed clarithromycin (n=52 251) or azithromycin (referent group, n=46 618). Main outcomes The primary outcomes were hospital admission within 30 days of a new antibiotic prescription with any of the 12 conditions examined separately (acute kidney injury, acute myocardial infarction, neuroimaging (proxy for delirium), hypotension, syncope, hyperkalaemia, hyponatraemia, hyperglycaemia, arrhythmia, ischaemic stroke, gastrointestinal bleeding and sepsis). The secondary outcome was mortality. Results The baseline characteristics of the two groups, including patient demographics, comorbid conditions, infection type and prescribing physician specialty, were nearly identical. The median daily dose was 1000 mg for clarithromycin and 300 mg for azithromycin and the median duration of dispensing antibiotics was 10 and 5 days, respectively. There was no difference between the groups in the risk of hospitalisation for any condition studied (relative risk ranged from 0.67 to 1.23). Compared with azithromycin, clarithromycin was associated with a slightly higher risk of all-cause mortality (0.46% vs 0.37%, relative risk 1.25, 95% CI 1.03 to 1.52). Conclusions Clarithromycin can be used to assess drug interactions in population-based studies with azithromycin serving as a control group. However, any differences in mortality observed between the two

Sacrolide A, a new antimicrobial and cytotoxic oxylipin macrolide from the edible cyanobacterium Aphanothece sacrum

PubMed Central

Oku, Naoya; Matsumoto, Miyako; Yonejima, Kohsuke; Tansei, Keijiroh

2014-01-01

Summary Macroscopic gelatinous colonies of freshwater cyanobacterium Aphanothece sacrum, a luxury ingredient for Japanese cuisine, were found to contain a new oxylipin-derived macrolide, sacrolide A (1), as an antimicrobial component. The configuration of two chiral centers in 1 was determined by a combination of chiral anisotropy analysis and conformational analysis of different ring-opened derivatives. Compound 1 inhibited the growth of some species of Gram-positive bacteria, yeast Saccharomyces cerevisiae and fungus Penicillium chrysogenum, and was also cytotoxic to 3Y1 rat fibroblasts. Concern about potential food intoxication caused by accidental massive ingestion of A. sacrum was dispelled by the absence of 1 in commercial products. A manual procedure for degrading 1 in raw colonies was also developed, enabling a convenient on-site detoxification at restaurants or for personal consumption. PMID:25161741

Macrolide Resistance in Microorganisms at Antimicrobial-Free Swine Farms▿

PubMed Central

Zhou, Zhi; Raskin, Lutgarde; Zilles, Julie L.

2009-01-01

To investigate the relationship between agricultural antimicrobial use and resistance, a variety of methods for quantification of macrolide-lincosamide-streptogramin B (MLSB) resistance were applied to organic swine farm manure samples. Fluorescence in situ hybridization was used to indirectly quantify the specific rRNA methylation resulting in MLSB resistance. Using this method, an unexpectedly high prevalence of ribosomal methylation and, hence, predicted MLSB resistance was observed in manure samples from two swine finisher farms that reported no antimicrobial use (37.6% ± 6.3% and 40.5% ± 5.4%, respectively). A culture-based method targeting relatively abundant clostridia showed a lower but still unexpectedly high prevalence of resistance at both farms (27.7% ± 11.3% and 11.7% ± 8.6%, respectively), while the prevalence of resistance in cultured fecal streptococci was low at both farms (4.0%). These differences in the prevalence of resistance across microorganisms suggest the need for caution when extrapolating from data obtained with indicator organisms. A third antimicrobial-free swine farm, a breeder-to-finisher operation, had low levels of MLSB resistance in manure samples with all methods used (<9%). Tetracycline antimicrobials were detected in manure samples from one of the finisher farms and may provide a partial explanation for the high level of MLSB resistance. Taken together, these findings highlight the need for a more fundamental understanding of the relationship between antimicrobial use and the prevalence of antimicrobial resistance. PMID:19633121

Observations on macrolide resistance and susceptibility testing performance in field isolates collected from clinical bovine respiratory disease cases.

PubMed

DeDonder, Keith D; Harhay, Dayna M; Apley, Michael D; Lubbers, Brian V; Clawson, Michael L; Schuller, Gennie; Harhay, Gregory P; White, Brad J; Larson, Robert L; Capik, Sarah F; Riviere, Jim E; Kalbfleisch, Ted; Tessman, Ronald K

2016-08-30

The objectives of this study were; first, to describe gamithromycin susceptibility of Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni isolated from cattle diagnosed with bovine respiratory disease (BRD) and previously treated with either gamithromycin for control of BRD (mass medication=MM) or sham-saline injected (control=CON); second, to describe the macrolide resistance genes present in genetically typed M. haemolytica isolates; third, use whole-genome sequencing (WGS) to correlate the phenotypic resistance and genetic determinants for resistance among M. haemolytica isolates. M. haemolytica (n=276), P. multocida (n=253), and H. somni (n=78) were isolated from feedlot cattle diagnosed with BRD. Gamithromycin susceptibility was determined by broth microdilution. Whole-genome sequencing was utilized to determine the presence/absence of macrolide resistance genes and to genetically type M. haemolytica. Generalized linear mixed models were built for analysis. There was not a significant difference between MM and CON groups in regards to the likelihood of culturing a resistant isolate of M. haemolytica or P. multocida. The likelihood of culturing a resistant isolate of M. haemolytica differed significantly by state of origin in this study. A single M. haemolytica genetic subtype was associated with an over whelming majority of the observed resistance. H. somni isolation counts were low and statistical models would not converge. Phenotypic resistance was predicted with high sensitivity and specificity by WGS. Additional studies to elucidate the relationships between phenotypic expression of resistance/genetic determinants for resistance and clinical response to antimicrobials are necessary to inform judicious use of antimicrobials in the context of relieving animal disease and suffering. Copyright © 2016 Elsevier B.V. All rights reserved.

Visualizing the 16-membered ring macrolides tildipirosin and tilmicosin bound to their ribosomal site.

PubMed

Poehlsgaard, Jacob; Andersen, Niels M; Warrass, Ralf; Douthwaite, Stephen

2012-08-17

The veterinary antibiotic tildipirosin (20,23-dipiperidinyl-mycaminosyl-tylonolide, Zuprevo) was developed recently to treat bovine and swine respiratory tract infections caused by bacterial pathogens such as Pasteurella multocida. Tildipirosin is a derivative of the naturally occurring compound tylosin. Here, we define drug-target interactions by combining chemical footprinting with structure modeling and show that tildipirosin, tylosin, and an earlier tylosin derivative, tilmicosin (20-dimethylpiperidinyl-mycaminosyl-tylonolide, Micotil), bind to the same macrolide site within the large subunit of P. multocida and Escherichia coli ribosomes. The drugs nevertheless differ in how they occupy this site. Interactions of the two piperidine components, which are unique to tildipirosin, distinguish this drug from tylosin and tilmicosin. The 23-piperidine of tildipirosin contacts ribosomal residues on the tunnel wall while its 20-piperidine is oriented into the tunnel lumen and is positioned to interfere with the growing nascent peptide.

Macrolide resistance and genotypic characterization of Streptococcus pneumoniae in Asian countries: a study of the Asian Network for Surveillance of Resistant Pathogens (ANSORP).

PubMed

Song, Jae-Hoon; Chang, Hyun-Ha; Suh, Ji Yoeun; Ko, Kwan Soo; Jung, Sook-In; Oh, Won Sup; Peck, Kyong Ran; Lee, Nam Yong; Yang, Yonghong; Chongthaleong, Anan; Aswapokee, Nalinee; Chiu, Cheng-Hsun; Lalitha, M K; Perera, Jennifer; Yee, Ti Teow; Kumararasinghe, Gamini; Jamal, Farida; Kamarulazaman, Adeeba; Parasakthi, Navaratnam; Van, Pham Hung; So, Thomas; Ng, Tak Keung

2004-03-01

To characterize mechanisms of macrolide resistance among Streptococcus pneumoniae from 10 Asian countries during 1998-2001. Phenotypic and genotypic characterization of the isolates and their resistance mechanisms. Of 555 isolates studied, 216 (38.9%) were susceptible, 10 (1.8%) were intermediate and 329 (59.3%) were resistant to erythromycin. Vietnam had the highest prevalence of erythromycin resistance (88.3%), followed by Taiwan (87.2%), Korea (85.1%), Hong Kong (76.5%) and China (75.6%). Ribosomal methylation encoded by erm(B) was the most common mechanism of erythromycin resistance in China, Taiwan, Sri Lanka and Korea. In Hong Kong, Singapore, Thailand and Malaysia, efflux encoded by mef(A) was the more common in erythromycin-resistant isolates. In most Asian countries except Hong Kong, Malaysia and Singapore, erm(B) was found in >50% of pneumococcal isolates either alone or in combination with mef(A). The level of erythromycin resistance among pneumococcal isolates in most Asian countries except Thailand and India was very high with MIC(90)s of >128 mg/L. Molecular epidemiological studies suggest the horizontal transfer of the erm(B) gene and clonal dissemination of resistant strains in the Asian region. Data confirm that macrolide resistance in pneumococci is a serious problem in many Asian countries.

Three new 16-membered macrolide compounds from a genetically engineered strain S. avermitilis MHJ1011.

PubMed

Pan, Jun-Jie; Wan, Xu; Zhang, Shao-Yong; Huang, Jun; Zhang, Hui; Chen, An-Liang; Wang, Ji-Dong

2016-07-15

Three new 16-membered macrolide compounds, 13α-O-α-l-oleandrosyl milbemycin β3 (1), 13α-O-α-l-oleandrosyl-25-ethyl milbemycin β3 (2), 13α-O-α-l-oleandrosyl-25-isopropyl milbemycin β3 (3), were isolated from the genetically engineered strains Streptomyces avermitilis MHJ1011. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. Both compounds 1-3 displayed impressive acaricidal activity against larval mites with the IC50 values of 0.0327, 0.0276 and 0.0235mg/L, respectively, which are higher than those of 13α-hydroxy milbemycin β3 and 13α-hydroxy-25-ethyl milbemycin β3. Copyright © 2016 Elsevier Ltd. All rights reserved.

First Report of the 23S rRNA Gene A2058G Point Mutation Associated With Macrolide Resistance in Treponema pallidum From Syphilis Patients in Cuba.

PubMed

Noda, Angel A; Matos, Nelvis; Blanco, Orestes; Rodríguez, Islay; Stamm, Lola Virginia

2016-05-01

This study aimed to assess the presence of macrolide-resistant Treponema pallidum subtypes in Havana, Cuba. Samples from 41 syphilis patients were tested for T. pallidum 23S rRNA gene mutations. Twenty-five patients (61%) harbored T. pallidum with the A2058G mutation, which was present in all 8 subtypes that were identified. The A2059G mutation was not detected.

Cytotoxic 14-Membered Macrolides from a Mangrove-Derived Endophytic Fungus, Pestalotiopsis microspora.

PubMed

Liu, Shuai; Dai, Haofu; Makhloufi, Gamall; Heering, Christian; Janiak, Christoph; Hartmann, Rudolf; Mándi, Attila; Kurtán, Tibor; Müller, Werner E G; Kassack, Matthias U; Lin, Wenhan; Liu, Zhen; Proksch, Peter

2016-09-23

Seven new 14-membered macrolides, pestalotioprolides C (2), D-H (4-8), and 7-O-methylnigrosporolide (3), together with four known analogues, pestalotioprolide B (1), seiricuprolide (9), nigrosporolide (10), and 4,7-dihydroxy-13-tetradeca-2,5,8-trienolide (11), were isolated from the mangrove-derived endophytic fungus Pestalotiopsis microspora. Their structures were elucidated by analysis of NMR and MS data and by comparison with literature data. Single-crystal X-ray diffraction analysis was used to confirm the absolute configurations of 1, 2, and 10, while Mosher's method and the TDDFT-ECD approach were applied to determine the absolute configurations of 5 and 6. Compounds 3-6 showed significant cytotoxicity against the murine lymphoma cell line L5178Y with IC50 values of 0.7, 5.6, 3.4, and 3.9 μM, respectively, while compound 5 showed potent activity against the human ovarian cancer cell line A2780 with an IC50 value of 1.2 μM. Structure-activity relationships are discussed. Coculture of P. microspora with Streptomyces lividans caused a roughly 10-fold enhanced accumulation of compounds 5 and 6 compared to axenic fungal control.

Identification and quantification of five macrolide antibiotics in several tissues, eggs and milk by liquid chromatography-electrospray tandem mass spectrometry.

PubMed

Dubois, M; Fluchard, D; Sior, E; Delahaut, P

2001-04-05

We present an electrospray high-performance liquid chromatographic tandem mass spectrometric (HPLC-MS-MS) method capable of determining in several tissues (muscle, kidney, liver), eggs and milk the following five macrolides: tylosin, tilmicosin, spiramycin, josamycin, erythromycin. Roxithromycin was used as an internal standard. The method uses extraction in a Tris buffer at pH 10.5, followed by protein precipitation with sodium tungstate and clean-up on an Oasis solid-phase extraction column. The HPLC separation was performed on a Purospher C18 column (125 x 3 mm I.D.) protected by a guard column, with a gradient of aqueous 0.1 M ammonium acetate-acetonitrile as the mobile phase at a flow-rate of 0.7 ml min(-1). Protonated molecules served as precursor ions for electrospray ionisation in the positive ion mode and four product ions were chosen for each analyte for multiple reaction monitoring (MRM). A validation study was conducted to confirm the five macrolides by MRM HPLC-MS-MS analysis of a negative control and fortified samples. All of the samples analysed were confirmed with four ions. The ion ratio reproducibility limit ranged from 2.4 to 15%. All compounds could be detected and quantified at half-maximum residue limits (MRLs). The method is specific, quantitative and reproducible enough to conform to European Union recommendations within the concentration range 0.5 MRL-2 MRL (accuracy: 80 to 110%, relative standard deviation: 2 to 13%). This whole method allows extraction and analysis of up to 50 samples per day.

Application of silver ion in the separation of macrolide antibiotic components by high-speed counter-current chromatography.

PubMed

Wen, Yaoming; Wang, Jiaoyan; Chen, Xiuming; Le, Zhanxian; Chen, Yuxiang; Zheng, Wei

2009-05-29

Three macrolide antibiotic components - ascomycin, tacrolimus and dihydrotacrolimus - were separated and purified by silver ion high-speed counter-current chromatography (HSCCC). The solvent system consisted of n-hexane-tert-butyl methyl ether-methanol-water (1:3:6:5, v/v) and silver nitrate (0.10mol/l). The silver ion acted as a pi-complexing agent with tacrolimus because of its extra side double bond compared with ascomycin and dihydrotacrolimus. This complexation modified the partition coefficient values and the separation factors of the three components. As a result, ascomycin, tacrolimus and dihydrotacrolimus were purified from 150mg extracted crude sample with purities of 97.6%, 98.7% and 96.5%, respectively, and yields over 80% (including their tautomers). These results cannot be achieved with the same solvent system but without the addition of silver ion.

Genotypes of macrolide-resistant pneumococci from children in southwestern Japan: raised incidence of strains that have both erm(B) and mef(A) with serotype 6B clones.

PubMed

Ikenaga, Masaaki; Kosowska-Shick, Klaudia; Gotoh, Kenji; Hidaka, Hidenobu; Koga, Hiroyasu; Masunaga, Kenji; Nagai, Kensuke; Tsumura, Naoki; Appelbaum, Peter C; Matsuishi, Toyojiro

2008-09-01

MICs of penicillin G, erythromycin, clarithromycin, clindamycin, azithromycin, and telithromycin were tested for 189 clinical isolates collected during 2002 to 2005 from children in southwestern Japan. Serotyping and polymerase chain reaction for presence of erm(B) and mef(A) were performed. All strains with erm(B) + mef(A) were analyzed by pulsed-field gel electrophoresis (PFGE) and compared to 3 global clones: Spain(23F)-1; Spain(9V)-3 and its variant -14; a South Korean strain same as Taiwan (19F)-14 clone and 5 strains with erm(B) + mef(A) from other countries. Of the 173 macrolide-resistant (erythromycin MIC > or =0.5 microg/mL) strains, 104 (60.1%) had erm(B), 47 (27.2%) had mef(A), and 22 (12.7%) had erm(B) + mef(A). Strains expressing erm(B) or both erm(B) and mef(A) had high macrolide MIC(90)s (>64 microg/mL), except telithromycin (MIC(90), 0.25 microg/mL). Of the 22 erm(B) + mef(A) strains, 10 had 4 distinct PFGE patterns and were mainly serotype 6B clones, which differed from those described in previous reports; 5 other strains had unique profiles.

Macrolides for KCNJ5-mutated aldosterone-producing adenoma (MAPA): design of a study for personalized diagnosis of primary aldosteronism.

PubMed

Maiolino, Giuseppe; Ceolotto, Giulio; Battistel, Michele; Barbiero, Giulio; Cesari, Maurizio; Amar, Laurence; Caroccia, Brasilina; Padrini, Roberto; Azizi, Michel; Rossi, Gian Paolo

2018-02-06

Aldosterone-producing adenoma (APA) is the main curable cause of endocrine hypertension cause of primary aldosteronism (PA) and it is in up to 66% of all cases investigated with adrenal vein sampling (AVS). Mutations in the KCNJ5 potassium channel involve up to 70% of APA and cause the most florid PA phenotypes. The recent finding that macrolide antibiotics specifically inhibit in vitro the altered function of mutated KCNJ5 channels has opened new horizons for the diagnosis and treatment of APA with KCNJ5 mutations in that it can allow identification and target treatment of PA patients harbouring a mutated APA. Thus, we aimed at investigating if clarithromycin and roxithromycin, two macrolides that potently blunt mutated Kir3.4 channel function in vitro, affect plasma aldosterone concentration in adrenal vein blood during AVS and in peripheral blood, respectively, in PA patients with a mutated APA. We designed two proof of concept studies. In study A: consecutive patients with an unambiguous biochemical evidence of PA will be exposed to a single dose of 250 mg clarithromycin during AVS, to assess its effect on the relative aldosterone secretion index in adrenal vein blood from the gland with and without APA. In study B: consecutive hypertensive patients submitted to the work-up for hypertension will receive a single oral dose of 150 mg roxithromycin. The experimental endpoints will be the change induced by roxithromycin of plasma aldosterone concentration and other steroids, direct active renin concentration, serum K + , systolic and diastolic blood pressure. We expect to prove that: (i) clarithromycin allows identification of mutated APA before adrenalectomy and sequencing of tumour DNA; (ii) the acute changes of plasma aldosterone concentration, direct active renin concentration, and blood pressure in peripheral venous blood after roxithromycin can be a proxy for the presence of an APA with somatic mutations.

Structure and Function of the Macrolide Biosensor Protein, MphR(A), with and without Erythromycin

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

Zheng, Jianting; Sagar, Vatsala; Smolinsky, Adam

2009-09-02

The regulatory protein MphR(A) has recently seen extensive use in synthetic biological applications, such as metabolite sensing and exogenous control of gene expression. This protein negatively regulates the expression of a macrolide 2{prime}-phosphotransferase I resistance gene (mphA) via binding to a 35-bp DNA operator upstream of the start codon and is de-repressed by the presence of erythromycin. Here, we present the refined crystal structure of the MphR(A) protein free of erythromycin and that of the MphR(A) protein with bound erythromycin at 2.00- and 1.76-{angstrom} resolutions, respectively. We also studied the DNA binding properties of the protein and identified mutants ofmore » MphR(A) that are defective in gene repression and ligand binding in a cell-based reporter assay. The combination of these two structures illustrates the molecular basis of erythromycin-induced gene expression and provides a framework for additional applied uses of this protein in the isolation and engineered biosynthesis of polyketide natural products.« less

Thin-layer chromatographic determination of erythromycin and other macrolide antibiotics in livestock products.

PubMed

Petz, M; Solly, R; Lymburn, M; Clear, M H

1987-01-01

A method is described for determination of 4 macrolide antibiotics in livestock products. Erythromycin, tylosin, oleandomycin, and spiramycin were extracted from animal tissues, milk, and egg with acetonitrile at pH 8.5. Cleanup was done by adding sodium chloride and dichloromethane, evaporating the organic layer, and subsequent acid/base partitioning. After the antibiotics were separated by thin-layer chromatography (TLC), they were reacted with xanthydrol and could be detected as purple spots down to 0.02 mg/kg without interference by other commonly used therapeutic drugs (23 were tested). Anisaldehyde-sulfuric acid, cerium sulfate-molybdic acid, phosphomolybdic acid, and Dragendorff's reagent proved to be less sensitive as visualizing agents. For quantitation, TLC plates were scanned at 525 nm. Recoveries were between 71 and 96% for erythromycin and tylosin in liver, muscle, and egg at the 0.1-0.5 mg/kg level and 51% for erythromycin in milk at the 0.02 mg/kg level (coefficient of variation = 10-18%). Bioautography with Bacillus subtilis was used to confirm results, in addition to TLC analysis of derivatized antibiotics and liquid chromatography with electrochemical detection. Various derivatization procedures for erythromycin were investigated for improved ultra-violet or fluorescence detection in liquid chromatography.

Aquatic toxicity of the macrolide antibiotic clarithromycin and its metabolites.

PubMed

Baumann, Michaela; Weiss, Klaus; Maletzki, Dirk; Schüssler, Walter; Schudoma, Dieter; Kopf, Willi; Kühnen, Ute

2015-02-01

The human macrolide antibiotic clarithromycin is widespread in surface waters. Our study shows that its major metabolite 14-hydroxy(R)-clarithromycin is found in surface waters in comparable amounts. This metabolite is known to be pharmacologically active. Additionally, clarithromycin is partly metabolised to N-desmethyl-clarithromycin, which has no antimicrobial activity. For clarithromycin, some ecotoxicological studies on aquatic organisms have been published. However, many of them are not conform with the scientific principles as given in the "Technical guidance for deriving environmental quality standards" (TGD-EQS), because numerous studies were poorly documented and the methods did not contain analytical measurements confirming that the exposure concentrations were in the range of ± 20% of the nominal concentrations. Ecotoxicological effects of clarithromycin and its two metabolites on the zebrafish Danio rerio (embryo test), the microcrustacean Daphnia magna, the aquatic monocotyledonous macrophyte Lemna minor, the freshwater green alga Desmodesmus subspicatus (Chlorophyta) and the cyanobacterium Anabaena flosaquae were investigated in compliance with the TGD-EQS. Environmental risk assessment was performed using ErC10 values of Anabaena, the species most sensitive to clarithromycin and 14-hydroxy(R)-clarithromycin in our testing. Based oncomparable toxicity and similar concentrations of clarithromycin and its active metabolite 14-hydroxy(R)-clarithromycin in surface waters, an additional multiplication factor of 2 to the assessment factor of 10 on the ErC10 of clarithromycin should be used. Consequently, a freshwater quality standard of 0.130 μg L(-1) is proposed for clarithromycin as the "lead substance". Taking this additional multiplication factor of 2 into account, single monitoring of clarithromycin may be sufficient, in order to reduce the number of substances listed for routine monitoring programs. Copyright © 2014 Elsevier Ltd. All rights

Fluoroquinolones or macrolides in combination with β-lactams in adult patients hospitalized with community acquired pneumonia: a systematic review and meta-analysis.

PubMed

Vardakas, K Z; Trigkidis, K K; Falagas, M E

2017-04-01

The best treatment option for hospitalized patients with community-acquired pneumonia (CAP) has not been defined. The effectiveness of β-lactam/fluoroquinolone (BLFQ) versus β-lactam/macrolide (BLM) combinations for the treatment of patients with CAP was evaluated. PubMed, Scopus and the Cochrane Library were searched for observational cohort studies, non-randomized and randomized controlled trials providing data for patients with CAP receiving BLM or BLFQ. Mortality was the primary outcome. A meta-analysis was performed. MINORS and GRADE were used for data quality assessment. Seventeen studies (16 684 patients) were included. Randomized trials were not identified. A variety of β-lactams, fluoroquinolones and macrolides were used within and between the studies. Mortality was reported at different time points. The available body of evidence had very low quality. In the analysis of unadjusted data, mortality with BLFQ was higher than with BLM (risk ratio 1.33, 95% CI 1.15-1.54, I 2 28%). BLFQ was associated with higher mortality regardless of the study design, mortality recording time, study period and study BLM group mortality. BLFQ was associated with higher mortality in American but not European studies. No difference was observed in patients with bacteraemia and septic shock. In the meta-analysis of adjusted mortality data, a non-significant difference between the two regimens was observed (eight studies, adjusted risk ratio 1.26, 95% CI 0.95-1.67, I 2 43%). In the absence of data from randomized controlled trials recommendations cannot be made for or against either of the studied regimens in this group of hospitalized patients with CAP. Well designed randomized controlled trials comparing the two regimens are warranted. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

DOE PAGES

Pereira, Jose H.; Petchprayoon, Chutima; Hoepker, Alexander C.; ...

2014-07-22

The actin filament-binding and filament-severing activities of the aplyronine, kabiramide, and reidispongiolide families of marine macrolides are located within the hydrophobic tail region of the molecule. Two synthetic tail analogues of aplyronine C (SF-01 and GC-04) are shown to bind to G-actin with dissociation constants of (285±33) and (132±13) nM, respectively. The crystal structures of actin complexes with GC-04, SF-01, and kabiramide C reveal a conserved mode of tail binding within the cleft that forms between subdomains (SD) 1 and 3. Our studies support the view that filament severing is brought about by specific binding of the tail region tomore » the SD1/SD3 cleft on the upper protomer, which displaces loop-D from the lower protomer on the same half-filament. With previous studies showing that the GC-04 analogue can sever actin filaments, it is argued that the shorter complex lifetime of tail analogues with F-actin would make them more effective at severing filaments compared with plasma gelsolin. In conclusion, structure-based analyses are used to suggest more reactive or targetable forms of GC-04 and SF-01, which may serve to boost the capacity of the serum actin scavenging system, to generate antibody conjugates against tumor cell antigens, and to decrease sputum viscosity in children with cystic fibrosis.« less

Prevalence of methicillin resistance and macrolide-lincosamide-streptogramin B resistance in Staphylococcus haemolyticus among clinical strains at a tertiary-care hospital in Thailand.

PubMed

Teeraputon, S; Santanirand, P; Wongchai, T; Songjang, W; Lapsomthob, N; Jaikrasun, D; Toonkaew, S; Tophon, P

2017-09-01

Staphylococcus spp. is a major cause of nosocomial infection and sepsis. However, increasing drug resistance is becoming a challenge to microbiologists. The purpose of this study was to identify and determine antimicrobial resistance phenotypes and drug resistance genes of clinical coagulase-negative staphylococci (CoNS) isolates at Mae Sot Hospital in Tak province, Thailand. A total of 229 CoNS isolates were collected from clinical specimens during two periods in 2014 and in 2015. Staphylococcus haemolyticus was the most prevalent species (37.55%), followed by S. epidermidis (21.83%), S. saprophyticus (11.79%) and S. hominis (11.35%) respectively. The remaining 17.48% of the organisms comprised S. capitis, S. arlettae, S. cohnii, S. equorum, S. xylosus, S. warneri, S. sciuri, S. pettenkoferi, S. kloosii and S. lugdunensis. Methicillin-resistant CoNS (MRCoNS), containing the mec A gene, were detected in 145 of 229 isolates, mostly found in S. haemolyticus and S. epidermidis. In addition, the differentiation of their macrolide-lincosamide-streptogramin B (MLS B ) resistance phenotypes was determined by the D-test and corresponding resistance genes. Among 125 erythromycin-resistant CoNS, the prevalence of constitutive type of MLS B , inducible clindamycin resistance and macrolide-streptogramin B resistance phenotypes were 72, 13.60 and 14.40% respectively. These phenotypes were expressed in 80% of MRCoNS strains. In addition, the erm C gene (79.20%) was found to be more prevalent than the erm A gene (22.40%), especially among MRCoNS. These results indicate that CoNS may play an important role in spreading of drug resistance genes. More attention to these organisms in surveillance and monitoring programs is needed.

Rapid and selective extraction of multiple macrolide antibiotics in foodstuff samples based on magnetic molecularly imprinted polymers.

PubMed

Zhou, Yusun; Zhou, Tingting; Jin, Hua; Jing, Tao; Song, Bin; Zhou, Yikai; Mei, Surong; Lee, Yong-Ill

2015-05-01

Magnetic molecularly imprinted polymers (MMIPs) were prepared based on surface molecular imprinting using erythromycin (ERY) as template molecule and Fe3O4 nanoparticles as support substrate. The MMIPs possessed high adsorption capacity of 94.1 mg/g for ERY and the imprinting factor was 11.9 indicating good imprinted effect for ERY. Selective evaluation demonstrated favorable selectivity of MMIPs for multiple macrolide antibiotics (MACs). Using MMIPs as adsorptive material, a rapid and convenient magnetic solid-phase extraction (MSPE) procedure was established for simultaneous and selective separation of six MACs in pork, fish and shrimp samples, then the MACs was subjected to high-performance liquid chromatography-ultraviolet (HPLC-UV) analysis. At different fortified concentrations, the extraction recoveries could reach 89.1% and the relative standard deviations were lower than 12.4%. Chromatogram revealed the response signals of MACs in spiked samples were greatly enhanced and matrix interferences were effectively eliminated after treatment with MSPE. The proposed MSPE procedure coupled with HPLC-UV realized selective and sensitive determination of multiple MACs in foodstuff samples. Copyright © 2015 Elsevier B.V. All rights reserved.

Macrolide, lincosamide, and streptogramin B resistance in lipophilic Corynebacteria inhabiting healthy human skin.

PubMed

Szemraj, Magdalena; Kwaszewska, Anna; Pawlak, Renata; Szewczyk, Eligia M

2014-10-01

Corynebacteria exist as part of human skin microbiota. However, under some circumstances, they can cause opportunistic infections. The subject of the study was to examine the macrolide-lincosamide-streptogramin B (MLSB) antibiotic resistance in 99 lipophilic strains of Corynebacterium genus isolated from the skin of healthy men. Over 70% of the tested strains were resistant to erythromycin and clindamycin. All of which demonstrated a constitutive type of MLSB resistance mechanism. In all strains, there were being investigated the erm(A), erm(B), erm(C), erm(X), lin(A), msr(A), and mph(C) genes that could be responsible for the different types of resistance to marcolides, lincosamides, and streptogramin B. In all strains with the MLSB resistance phenotype, the erm(X) gene was detected. None of the other tested genes were discovered. Strains harboring the erm(X) gene were identified using a phenotypic method based on numerous biological and biochemical tests. Identification of the chosen strains was compared with the results of API Coryne, MALDI-TOF MS, and 16S rDNA sequencing methods. Only 7 out of the 23 investigated resistant strains provided successful results in all the used methods, showing that identification of this group of bacteria is still a great challenge. The MLSB resistance mechanism was common in most frequently isolated from healthy human skin Corynebacterium tuberculostearicum and Corynebacterium jeikeium strains. This represents a threat as these species are also commonly described as etiological factors of opportunistic infections.

Immunosuppressive Interactions among Calcium Channel Antagonists and Selected Corticosteroids and Macrolides Using Human whole Blood Lymphocytes

PubMed Central

Chow, Fung-Sing; Jusko, William J.

2014-01-01

Summary The immunosuppressive interactions of calcium channel antagonists [diltiazem (Dil), verapamil (Ver) and nifedipine (Nif)], with corticosteroids [methylprednisolone (Mpl), prednisolone (Prd)], and macrolides [tacrolimus (Tac) and sirolnnus (Sir)] were examined in human whole blood lymphocyte cultures. Gender-related differences in responses in the interactions between these drug classes were studied using blood from 6 males and 6 females. The nature and intensity of interactions were determined using an extended Loewe additivity model. All immunosuppressants exhibited higher potency than the calcium channel antagonists with mean IC50 values of: Dil (mM)Ver (mM)Nif (mM)Mpl (nM)Prd (nM)Tac (nM)Sir (nM)Male13541.921312.118.6150327Female11431.847.44.68.8111106 Gender-related differences in responses to Mpl and Prd were observed while the others were not significant. Additive interactions were found among calcium channel antagonists and corticosteroids. Significant synergistic interactions were observed between calcium channel antagonists and tacrolimus and sirolimus, although these are unlikely to be of clinical importance. These studies demonstrate diverse drug interactions in the examination of an important array of immunosuppressant drug combinations. PMID:15681895

Heat treatment effects on the antimicrobial activity of macrolide and lincosamide antibiotics in milk.

PubMed

Zorraquino, M A; Althaus, R L; Roca, M; Molina, M P

2011-02-01

Antibiotic residues in milk can cause serious problems for consumers and the dairy industry. Heat treatment of milk may diminish the antimicrobial activity of these antibiotic residues. This study analyzed the effect of milk processing (60 °C for 30 min, 120 °C for 20 min, and 140 °C for 10 s) on the antimicrobial activity of milk samples fortified with three concentrations of three macrolides (erythromycin: 20, 40 and 80 μg/liter; spiramycin: 100, 200, and 400 μg/liter; and tylosin: 500, 1,000, and 2,000 μg/liter) and one lincosamide (lincomycin: 1,000, 2,000, and 4,000 μg/liter). To measure the loss of antimicrobial activity, a bioassay based on the growth inhibition of Micrococcus luteus was done. The data were analyzed using a multiple linear regression model. The results indicate that treatment at 120 °C for 20 min produces inactivation percentages of 93% (erythromycin), 64% (spiramycin), 51% (tylosin), and 5% (lincomycin), while treatment at 140 °C for 10 s results in generally lower percentages (30% erythromycin, 35% spiramycin, 12% tylosin, and 5% lincomycin). The lowest loss or lowest reduction of antimicrobial activity (21% erythromycin and 13% spiramycin) was obtained by treatment at 60 °C for 30 min. Copyright ©, International Association for Food Protection

Assessing antibiotic sorption in soil: a literature review and new case studies on sulfonamides and macrolides

PubMed Central

2014-01-01

The increased use of veterinary antibiotics in modern agriculture for therapeutic uses and growth promotion has raised concern regarding the environmental impacts of antibiotic residues in soil and water. The mobility and transport of antibiotics in the environment depends on their sorption behavior, which is typically predicted by extrapolating from an experimentally determined soil-water distribution coefficient (Kd). Accurate determination of Kd values is important in order to better predict the environmental fate of antibiotics. In this paper, we examine different analytical approaches in assessing Kd of two major classes of veterinary antibiotics (sulfonamides and macrolides) and compare the existing literature data with experimental data obtained in our laboratory. While environmental parameters such as soil pH and organic matter content are the most significant factors that affect the sorption of antibiotics in soil, it is important to consider the concentrations used, the analytical method employed, and the transformations that can occur when determining Kd values. Application of solid phase extraction and liquid chromatography/mass spectrometry can facilitate accurate determination of Kd at environmentally relevant concentrations. Because the bioavailability of antibiotics in soil depends on their sorption behavior, it is important to examine current practices in assessing their mobility in soil. PMID:24438473

Chromatographic methods for determination of macrolide antibiotic residues in tissues and milk of food-producing animals.

PubMed

Moats, W A

1985-01-01

Tylosin, an antibiotic developed specifically for agricultural use, and erythromycin are the main macrolide antibiotics used in animal production. Two-dimensional thin layer chromatography has been used for detection of tylosin in poultry meat, eggs, and milk and for erythromycin in poultry meat. Detection limits reported are, for tylosin, 0.1 ppm in poultry meat, 0.05 ppm in egg, and 0.01 ppm in milk, and for erythromycin, 0.25 ppm in poultry meat. Liquid chromatography (LC) has also been used for determination of tylosin in milk, blood, and tissues of animals. Samples (milk, blood serum, or tissue homogenates in water or pH 2.2 buffer) were deproteinized with acetonitrile, tylosin was partitioned into methylene chloride, and the extracts were concentrated and dissolved in acetonitrile. Chromatography was done on a reverse phase end-capped C18 column using 0.002-0.005 M ammonium dihydrogen phosphate-acetonitrile-methanol (10 + 60 + 30-5 + 80 + 15). Solvent composition was varied with the type of sample analyzed. The method will detect 0.1 ppm tylosin in tissues and less in milk and blood serum. The LC method was more sensitive than microbiological assays for detection of tylosin in tissues of treated swine; recoveries of tylosin by the LC method were frequently several-fold higher.

Role of ATP binding and hydrolysis in assembly of MacAB-TolC macrolide transporter

PubMed Central

Lu, Shuo; Zgurskaya, Helen I.

2012-01-01

Summary MacB is a founding member of the Macrolide Exporter family of transporters belonging to the ATP-Binding Cassette superfamily. These proteins are broadly represented in genomes of both gram-positive and gram-negative bacteria and are implicated in virulence and protection against antibiotics and peptide toxins. MacB transporter functions together with MacA, a periplasmic membrane fusion protein, which stimulates MacB ATPase. In gram-negative bacteria, MacA is believed to couple ATP hydrolysis to transport of substrates across the outer membrane through a TolC-like channel. In this study, we report a real-time analysis of concurrent ATP hydrolysis and assembly of MacAB-TolC complex. MacB binds nucleotides with a low millimolar affinity and fast on- and off-rates. In contrast, MacA-MacB complex is formed with a nanomolar affinity, which further increases in the presence of ATP. Our results strongly suggest that association between MacA and MacB is stimulated by ATP binding to MacB but remains unchanged during ATP hydrolysis cycle. We also found that the large periplasmic loop of MacB plays the major role in coupling reactions separated in two different membranes. This loop is required for MacA-dependent stimulation of MacB ATPase and at the same time, contributes to recruitment of TolC into a trans-envelope complex. PMID:23057817

The suppression of enhanced bitterness intensity of macrolide dry syrup mixed with an acidic powder.

PubMed

Ishizaka, Toshihiko; Okada, Sachie; Takemoto, Eri; Tokuyama, Emi; Tsuji, Eriko; Mukai, Junji; Uchida, Takahiro

2007-10-01

The aim of the present study was to identify a medicine which strongly enhanced the bitterness of clarithromycin dry syrup (CAMD) when administered concomitantly and to develop a method to suppress this enhanced bitterness. The bitterness enhancement was evaluated not only by gustatory sensation tests but also using pH and taste sensor measurements of the mixed sample. A remarkable bitterness enhancement was found when CAMD was mixed with the acidic powder L-carbocysteine. The acidic pH (pH 3.40) of the suspension made from these two preparations, seemed to be due to enhanced release of clarithromycin caused by the dissolution of the alkaline polymer film-coating. Several methods for preventing this bitterness enhancement were investigated. Neither increasing the volume of water taken with the mixture, nor changing the ratio of CAMD:L-carbocysteine in the mixture, were effective in reducing the bitterness intensity of the CAMD/L-carbocysteine mixture. The best way to achieve taste masking was to first administer CAMD mixed with chocolate jelly, which has a neutral pH, followed by the L-carbocysteine suspension. Similar results were obtained for the bitterness suppression of azithromycin fine granules with L-carbocysteine. The chocolate jelly will be useful for taste masking of bitter macrolide drug formulations, when they need to be administered together with acidic drug formulations.

Miniaturized solid-phase extraction of macrolide antibiotics in honey and bovine milk using mesoporous MCM-41 silica as sorbent.

PubMed

Du, Li-Jing; Yi, Ling; Ye, Li-Hong; Chen, Yu-Bo; Cao, Jun; Peng, Li-Qing; Shi, Yu-Ting; Wang, Qiu-Yan; Hu, Yu-Han

2018-02-16

A simple and effective method of miniaturized solid-phase extraction (mini-SPE) was developed for the simultaneous purification and enrichment of macrolide antibiotics (MACs) (i.e. azithromycin, clarithromycin, erythromycin, lincomycin and roxithromycin) from honey and skim milk. Mesoporous MCM-41 silica was synthesized and used as sorbent in mini-SPE. Several key parameters affecting the performance of mini-SPE procedure were thoroughly investigated, including sorbent materials, amount of sorbent and elution solvents. Under the optimized condition, satisfactory linearity (r 2  > 0.99), acceptable precision (RSDs, 0.3-7.1%), high sensitivity (limit of detection in the range of 0.01-0.76 μg/kg), and good recoveries (83.21-105.34%) were obtained. With distinct advantages of simplicity, reliability and minimal sample requirement, the proposed mini-SPE procedure coupled with ultrahigh performance liquid chromatography and quadrupole time-of-flight tandem mass spectrometry could become an alternative tool to analyze the residues of MACs in complex food matrixes. Copyright © 2018 Elsevier B.V. All rights reserved.

Multiresidue chromatographic method for the determination of macrolide residues in muscle by high-performance liquid chromatography with UV detection.

PubMed

Juhel-Gaugain, M; Anger, B; Laurentie, M

1999-01-01

A high-performance liquid chromatographic (HPLC) method for the simultaneous determination of tilmicosin, tylosin, spiramycin, and its major metabolite neospiramycin was developed that is suitable for porcine, bovine, and poultry muscles. Macrolide residues were extracted from muscle with acetonitrile, fat was removed by liquid-liquid extraction with isooctane, and the extract was then cleaned on Bond Elut C18 cartridges. The HPLC separation was performed on an Inertsil ODS3 C18 column (150 x 4 mm) with 0.05% trifluoroacetic acid-acetonitrile in a gradient mode. Two different chromatographic gradients were used for tilmicosin-tylosin and spiramycin-neospiramycin, and the detection wavelengths were 287 and 232 nm, respectively. The method was validated from 1/2 the maximum residue limit (MRL) to 4 times the MRL with pork muscle samples. Mean recoveries were 60, 63.5, 51, and 42% for tilmicosin, tylosin, spiramycin, and neospiramycin, respectively. The detection limits are 15 micrograms/kg for tilmicosin and tylosin, 30 micrograms/kg for spiramycin, and 25 micrograms/kg for neospiramycin. Linearity, precision, and accuracy of the method were also tested.

Burkholderia pseudomallei isolates from Sarawak, Malaysian Borneo, are predominantly susceptible to aminoglycosides and macrolides.

PubMed

Podin, Yuwana; Sarovich, Derek S; Price, Erin P; Kaestli, Mirjam; Mayo, Mark; Hii, KingChing; Ngian, Hieung; Wong, SeeChang; Wong, IngTien; Wong, JinShyan; Mohan, Anand; Ooi, MongHow; Fam, TemLom; Wong, Jack; Tuanyok, Apichai; Keim, Paul; Giffard, Philip M; Currie, Bart J

2014-01-01

Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei. Resistance to gentamicin is generally a hallmark of B. pseudomallei, and gentamicin is a selective agent in media used for diagnosis of melioidosis. In this study, we determined the prevalence and mechanism of gentamicin susceptibility found in B. pseudomallei isolates from Sarawak, Malaysian Borneo. We performed multilocus sequence typing and antibiotic susceptibility testing on 44 B. pseudomallei clinical isolates from melioidosis patients in Sarawak district hospitals. Whole-genome sequencing was used to identify the mechanism of gentamicin susceptibility. A novel allelic-specific PCR was designed to differentiate gentamicin-sensitive isolates from wild-type B. pseudomallei. A reversion assay was performed to confirm the involvement of this mechanism in gentamicin susceptibility. A substantial proportion (86%) of B. pseudomallei clinical isolates in Sarawak, Malaysian Borneo, were found to be susceptible to the aminoglycoside gentamicin, a rare occurrence in other regions where B. pseudomallei is endemic. Gentamicin sensitivity was restricted to genetically related strains belonging to sequence type 881 or its single-locus variant, sequence type 997. Whole-genome sequencing identified a novel nonsynonymous mutation within amrB, encoding an essential component of the AmrAB-OprA multidrug efflux pump. We confirmed the role of this mutation in conferring aminoglycoside and macrolide sensitivity by reversion of this mutation to the wild-type sequence. Our study demonstrates that alternative B. pseudomallei selective media without gentamicin are needed for accurate melioidosis laboratory diagnosis in Sarawak. This finding may also have implications for environmental sampling of other locations to test for B. pseudomallei endemicity.

Analysis of macrolide antibiotics in water by magnetic solid-phase extraction and liquid chromatography-tandem mass spectrometry.

PubMed

Pérez, Rosa Ana; Albero, Beatriz; Férriz, Macarena; Tadeo, José Luis

2017-11-30

Macrolides are one of the most commonly used families of antibiotics employed in human and veterinary treatment. These compounds are considered emerging contaminants with potential ecological and human health risks that could be present in surface water. This paper describes the development and application of a simple and efficient extraction procedure for the determination of tilmicosin; erythromycin, tylosin and erythromycin-H 2 O from water samples. Sample extraction was carried out using magnetic solid-phase extraction using oleate functionalized magnetic nanoparticles followed by LC-MS/MS analysis. The effects of several parameters on the extraction efficiency of MLs from water were evaluated. The recovery results obtained were >84% for most of the compounds, except for erytromycin. The LOD and LOQ values ranged from 11.5 to 26ngL -1 and from 34 to 77ngL -1 , respectively. The selected method was applied to monitor these contaminants in water samples from different sources. Tilmicosin and tylosin were not detected in any of the samples, but erythromycin and erythromycin-H 2 O were found in 50% of the surface water samples at levels from

Molecular Typing of Treponema pallidum in the Czech Republic during 2011 to 2013: Increased Prevalence of Identified Genotypes and of Isolates with Macrolide Resistance

PubMed Central

Grillová, Linda; Pĕtrošová, Helena; Mikalová, Lenka; Strnadel, Radim; Dastychová, Eliška; Kuklová, Ivana; Kojanová, Martina; Kreidlová, Miluše; Vaňousová, Daniela; Hercogová, Jana; Procházka, Přemysl; Zákoucká, Hana; Krchňáková, Alena; Vašků, Vladimír

2014-01-01

From January 2011 to December 2013, a total of 262 samples, from 188 patients suspected of having syphilis were tested for the presence of treponemal DNA by PCR amplification of five chromosomal loci, including the polA (TP0105), tmpC (TP0319), TP0136, TP0548, and 23S rRNA genes. Altogether, 146 samples from 103 patients were PCR positive for treponemal DNA. A set of 81 samples from 62 PCR-positive patients were typeable, and among them, nine different genotypes were identified. Compared to a previous study in the Czech Republic during 2004 to 2010, the number of genotypes detected among syphilis patients in a particular year increased to six in both 2012 and 2013, although they were not the same six. The proportion of macrolide-resistant clinical isolates in this 3-year study was 66.7%. PMID:25100820

Burkholderia pseudomallei Isolates from Sarawak, Malaysian Borneo, Are Predominantly Susceptible to Aminoglycosides and Macrolides

PubMed Central

Podin, Yuwana; Sarovich, Derek S.; Price, Erin P.; Kaestli, Mirjam; Mayo, Mark; Hii, KingChing; Ngian, HieUng; Wong, SeeChang; Wong, IngTien; Wong, JinShyan; Mohan, Anand; Ooi, MongHow; Fam, TemLom; Wong, Jack; Tuanyok, Apichai; Keim, Paul; Giffard, Philip M.

2014-01-01

Melioidosis is a potentially fatal disease caused by the saprophytic bacterium Burkholderia pseudomallei. Resistance to gentamicin is generally a hallmark of B. pseudomallei, and gentamicin is a selective agent in media used for diagnosis of melioidosis. In this study, we determined the prevalence and mechanism of gentamicin susceptibility found in B. pseudomallei isolates from Sarawak, Malaysian Borneo. We performed multilocus sequence typing and antibiotic susceptibility testing on 44 B. pseudomallei clinical isolates from melioidosis patients in Sarawak district hospitals. Whole-genome sequencing was used to identify the mechanism of gentamicin susceptibility. A novel allelic-specific PCR was designed to differentiate gentamicin-sensitive isolates from wild-type B. pseudomallei. A reversion assay was performed to confirm the involvement of this mechanism in gentamicin susceptibility. A substantial proportion (86%) of B. pseudomallei clinical isolates in Sarawak, Malaysian Borneo, were found to be susceptible to the aminoglycoside gentamicin, a rare occurrence in other regions where B. pseudomallei is endemic. Gentamicin sensitivity was restricted to genetically related strains belonging to sequence type 881 or its single-locus variant, sequence type 997. Whole-genome sequencing identified a novel nonsynonymous mutation within amrB, encoding an essential component of the AmrAB-OprA multidrug efflux pump. We confirmed the role of this mutation in conferring aminoglycoside and macrolide sensitivity by reversion of this mutation to the wild-type sequence. Our study demonstrates that alternative B. pseudomallei selective media without gentamicin are needed for accurate melioidosis laboratory diagnosis in Sarawak. This finding may also have implications for environmental sampling of other locations to test for B. pseudomallei endemicity. PMID:24145517

Novel spectrophotometric method for determination of some macrolide antibiotics in pharmaceutical formulations using 1,2-naphthoquinone-4-sulphonate

NASA Astrophysics Data System (ADS)

Ashour, Safwan; Bayram, Roula

2012-12-01

New, simple and rapid spectrophotometric method has been developed and validated for the assay of two macrolide drugs, azithromycin (AZT) and erythromycin (ERY) in pure and pharmaceutical formulations. The proposed method was based on the reaction of AZT and ERY with sodium 1,2-naphthoquinone-4-sulphonate (NQS) in alkaline medium at 25 °C to form an orange-colored product of maximum absorption peak at 452 nm. All variables were studied to optimize the reaction conditions and the reaction mechanism was postulated. Beer's law was obeyed in the concentration range 1.5-33.0 and 0.92-8.0 μg mL-1 with limit of detection values of 0.026 and 0.063 μg mL-1 for AZT and ERY, respectively. The calculated molar absorptivity values are 4.3 × 104 and 12.3 × 104 L mol-1 cm-1 for AZT and ERY, respectively. The proposed methods were successfully applied to the determination of AZT and ERY in formulations and the results tallied well with the label claim. The results were statistically compared with those of an official method by applying the Student's t-test and F-test. No interference was observed from the concomitant substances normally added to preparations.

Macrolide resistance gene erm(TR) and erm(TR)-carrying genetic elements in Streptococcus agalactiae: characterization of ICESagTR7, a new composite element containing IMESp2907.

PubMed

Mingoia, Marina; Morici, Eleonora; Marini, Emanuela; Brenciani, Andrea; Giovanetti, Eleonora; Varaldo, Pietro E

2016-03-01

The objective of this study was to investigate macrolide-resistant Streptococcus agalactiae isolates harbouring erm(TR), an erm(A) gene subclass, with emphasis on their erm(TR)-carrying genetic elements. Four erm(TR)-carrying elements have been described to date: three closely related (ICE10750-RD.2, Tn1806 and ICESp1108) in Streptococcus pyogenes, Streptococcus pneumoniae and S. pyogenes, respectively; and one completely different (IMESp2907, embedded in ICESp2906 to form ICESp2905) in S. pyogenes. Seventeen macrolide-resistant erm(TR)-positive S. agalactiae isolates were phenotypically and genotypically characterized. Their erm(TR)-carrying elements were explored by analysing the distinctive recombination genes of known erm(TR)-carrying integrative and conjugative elements (ICEs) and by PCR mapping. The new genetic context and organization of IMESp2907 in S. agalactiae were explored using several experimental procedures and in silico analyses. Five isolates harboured ICE10750-RD.2/Tn1806, five isolates harboured ICESp1108 and five isolates bore unknown erm(TR)-carrying elements. The remaining two isolates, exhibiting identical serotypes and pulsotypes, harboured IMESp2907 in a new genetic environment, which was further investigated in one of the two isolates, SagTR7. IMESp2907 was circularizable in S. agalactiae, as described in S. pyogenes. The new IMESp2907 junctions were identified based on its site-specific integration; the att sites were almost identical to those in S. pyogenes. In strain SagTR7, erm(TR)-carrying IMESp2907 was embedded in an erm(TR)-less internal element related to ICE10750-RD.2/Tn1806, which, in turn, was embedded in an ICESde3396-like element. The resulting whole ICE, ICESagTR7 (∼129 kb), was integrated into the chromosome downstream of the rplL gene, and was excisable in circular form and transferable by conjugation. This is the first study exploring erm(TR)-carrying genetic elements in S. agalactiae. © The Author 2015. Published by

Occurrence of sulfonamide-, tetracycline-, plasmid-mediated quinolone- and macrolide-resistance genes in livestock feedlots in Northern China.

PubMed

Mu, Quanhua; Li, Jin; Sun, Yingxue; Mao, Daqing; Wang, Qing; Luo, Yi

2015-05-01

Antibiotic resistance genes (ARGs) in livestock feedlots deserve attention because they are prone to transfer to human pathogens and thus pose threats to human health. In this study, the occurrence of 21 ARGs, including tetracycline (tet)-, sulfonamide (sul)-, plasmid-mediated quinolone (PMQR)- and macrolide-resistance (erm) genes were investigated in feces and adjacent soils from chicken, swine, and cattle feedlots in Northern China. PMQR and sul ARGs were the most prevalent and account for over 90.0 % of the total ARGs in fecal samples. Specifically, PMQR genes were the most prevalent, accounting for 59.6 % of the total ARGs, followed by sul ARGs (34.2 %). The percentage of tet ARGs was 3.4 %, and erm ARGs accounted for only 1.9 %. Prevalence of PMQR and sul ARGs was also found in swine and cattle feces. The overall trend of ARG concentrations in feces of different feeding animals was chicken > swine > beef cattle in the studied area. In soils, sul ARGs had the highest concentration and account for 71.1 to 80.2 % of the total ARGs, which is possibly due to the widely distributed molecular carriers (i.e., class one integrons), facilitating sul ARG propagation. Overall, this study provides integrated profiles of various types of ARGs in livestock feedlots and thus provides a reference for the management of antibiotic use in livestock farming.

Discovery, Total Synthesis and Key Structural Elements for the Immunosuppressive Activity of Cocosolide, a Symmetrical Glycosylated Macrolide Dimer from Marine Cyanobacteria.

PubMed

Gunasekera, Sarath P; Li, Yang; Ratnayake, Ranjala; Luo, Danmeng; Lo, Jeannette; Reibenspies, Joseph H; Xu, Zhengshuang; Clare-Salzler, Michael J; Ye, Tao; Paul, Valerie J; Luesch, Hendrik

2016-06-06

A new dimeric macrolide xylopyranoside, cocosolide (1), was isolated from the marine cyanobacterium preliminarily identified as Symploca sp. from Guam. The structure was determined by a combination of NMR spectroscopy, HRMS, X-ray diffraction studies and Mosher's analysis of the base hydrolysis product. Its carbon skeleton closely resembles that of clavosolides A-D isolated from the sponge Myriastra clavosa, for which no bioactivity is known. We performed the first total synthesis of cocosolide (1) along with its [α,α]-anomer (26) and macrocyclic core (28), thus leading to the confirmation of the structure of natural 1. The convergent synthesis featured Wadsworth-Emmons cyclopropanation, Sakurai annulation, Yamaguchi macrocyclization/dimerization reaction, α-selective glycosidation and β-selective glycosidation. Compounds 1 and 26 potently inhibited IL-2 production in both T-cell receptor dependent and independent manners. Full activity requires the presence of the sugar moiety as well as the intact dimeric structure. Cocosolide also suppressed the proliferation of anti-CD3-stimulated T-cells in a dose-dependent manner. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Susceptibility of Legionella spp. to mycinamicin I and II and other macrolide antibiotics: effects of media composition and origin of organisms.

PubMed Central

Edelstein, P H; Pasiecznik, K A; Yasui, V K; Meyer, R D

1982-01-01

Thirty-three strains of Legionella spp., 29 of which were L. pneumophila, were tested for their susceptibilities to erythromycin (EM), rosaramicin, tylosin, mycinamicin I (Sch-27897), and mycinamicin II (Sch-27896). Testing was performed using an agar dilution method with two different types of media: buffered charcoal yeast extract medium supplemented with 0.1% alpha-ketoglutarate (BCYE alpha) and filter-sterilized yeast extract medium with 0.1% alpha-ketoglutarate (BYE alpha). The minimal inhibitory concentrations (MICs) of the drugs tested relative to the MICs of erythromycin were: rosaramicin, MIC approximately equal to 0.2 EM MIC; tylosin, MIC approximately equal to 2 EM MIC; mycinamicin I, MIC approximately equal to 0.5 EM MIC; and mycinamicin II, MIC approximately equal to EM MIC. Both types of media caused equivalent partial inactivation of the macrolides which was apparently due entirely to pH effect. MICs on BCYE alpha were one to five times more than those observed on BYE alpha; this may be due to poorer growth on BYE alpha. PMID:7125633

Multimodal biopanning of T7 phage-displayed peptides reveals angiomotin as a potential receptor of the anti-angiogenic macrolide Roxithromycin.

PubMed

Takakusagi, Kaori; Takakusagi, Yoichi; Suzuki, Takahiro; Toizaki, Aya; Suzuki, Aiko; Kawakatsu, Yaichi; Watanabe, Madoka; Saito, Yukihiro; Fukuda, Ryushi; Nakazaki, Atsuo; Kobayashi, Susumu; Sakaguchi, Kengo; Sugawara, Fumio

2015-01-27

Roxithromycin (RXM) is a semi-synthetic fourteen-membered macrolide antibiotic that shows anti-angiogenic activity in solid tumors. In the present study, we conducted biopanning of T7 phage-displayed peptides either on a 96-well formatted microplate, a flow injection-type quartz-crystal microbalance (QCM) biosensor, or a cuvette-type QCM. RXM-selected peptides of different sequence, length and number were obtained from each mode of screening. Subsequent bioinformatics analysis of the RXM-selected peptides consistently gave positive scores for the extracellular domain (E458-T596) of angiomotin (Amot), indicating that this may comprise a binding region for RXM. Bead pull down assay and QCM analysis confirmed that RXM directly interacts with Amot via the screen-guided region, which also corresponds to the binding site for the endogenous anti-angiogenic inhibitor angiostatin (Anst). Thus, multimodal biopanning of T7PD revealed that RXM binds to the extracellular domain on Amot as a common binding site with Anst, leading to inhibition of angiogenesis-dependent tumor growth and metastasis. These data might explain the molecular basis underlying the mechanism of action for the anti-angiogenic activity of RXM. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Molecular Typing and Macrolide Resistance of Syphilis Cases in Manitoba, Canada, From 2012 to 2016.

PubMed

Shuel, Michelle; Hayden, Kristy; Kadkhoda, Kamran; Tsang, Raymond S W

2018-04-01

The province of Manitoba, Canada, with a population of approximately 1.3 million, has been experiencing increased incidence of syphilis cases since 2015. In this study, we examined the detection of Treponema pallidum DNA in 354 clinical samples from 2012 to 2016, and determined molecular types and mutations conferring resistance to azithromycin in the polymerase chain reaction (PCR)-positive samples. T. pallidum DNA detection was done by PCR amplification of tpp47, bmp, and polA genes. Syphilis serology results were reviewed for the PCR-positive cases. Molecular typing of syphilis strains was done by analysis of the T, pallidum arp, tpr, and tp0548 gene targets as well as partial sequencing of the 23S rRNA gene for azithromycin resistance. Of the 354 samples tested, 74 individual cases were PCR positive. A result from the treponemal antibody chemiluminescent microparticle immunoassay test was positive in 72 of these cases and that from the Venereal Disease Research Laboratory testing was positive in 66. Mutations conferring resistance to azithromycin were found in all 74 PCR-positive samples. Molecular typing was completed on 57 PCR-positive samples, and 12 molecular types were identified with 14d/g found in 63.2%. Increased strain diversity was observed with 8 molecular types detected in 2016, whereas only 2 to 3 types were found in 2012 to 2014. A patient with 2 episodes of infection 9 months apart caused by different molecular strain types was also identified. The finding of an increase in genetic diversity in the strains in this study and an increase in macrolide resistance compared with previous Canadian reports highlighted the need for continued surveillance including strain characterization.

Haemophilus parasuis CpxRA two-component system confers bacterial tolerance to environmental stresses and macrolide resistance.

PubMed

Cao, Qi; Feng, Fenfen; Wang, Huan; Xu, Xiaojuan; Chen, Huanchun; Cai, Xuwang; Wang, Xiangru

2018-01-01

Haemophilus parasuis is an opportunistic pathogen localized in the upper respiratory tracts of pigs, its infection begins from bacterial survival under complex conditions, like hyperosmosis, oxidative stress, phagocytosis, and sometimes antibiotics as well. The two-component signal transduction (TCST) system serves as a common stimulus-response mechanism that allows microbes to sense and respond to diverse environmental conditions via a series of phosphorylation reactions. In this study, we investigated the role of TCST system CpxRA in H. parasuis in response to different environmental stimuli by constructing the ΔcpxA and ΔcpxR single deletion mutants as well as the ΔcpxRA double deletion mutant from H. parasuis serotype 4 isolate JS0135. We demonstrated that H. parasuis TCST system CpxRA confers bacterial tolerance to stresses and bactericidal antibiotics. The CpxR was found to play essential roles in mediating oxidative stress, osmotic stresses and alkaline pH stress tolerance, as well as macrolide resistance (i.e. erythromycin), but the CpxA deletion did not decrease bacterial resistance to abovementioned stresses. Moreover, we found via RT-qPCR approach that HAPS_RS00160 and HAPS_RS09425, both encoding multidrug efflux pumps, were significantly decreased in erythromycin challenged ΔcpxR and ΔcpxRA mutants compared with wild-type strain JS0135. These findings characterize the role of the TCST system CpxRA in H. parasuis conferring stress response tolerance and bactericidal resistance, which will deepen our understanding of the pathogenic mechanism in H. parasuis. Copyright © 2017 Elsevier GmbH. All rights reserved.

Critical 23S rRNA interactions for macrolide-dependent ribosome stalling on the ErmCL nascent peptide chain

PubMed Central

Koch, Miriam; Willi, Jessica; Pradère, Ugo; Hall, Jonathan

2017-01-01

Abstract The nascent peptide exit tunnel has recently been identified as a functional region of ribosomes contributing to translation regulation and co-translational protein folding. Inducible expression of the erm resistance genes depends on ribosome stalling at specific codons of an upstream open reading frame in the presence of an exit tunnel-bound macrolide antibiotic. The molecular basis for this translation arrest is still not fully understood. Here, we used a nucleotide analog interference approach to unravel important functional groups on 23S rRNA residues in the ribosomal exit tunnel for ribosome stalling on the ErmC leader peptide. By replacing single nucleobase functional groups or even single atoms we were able to demonstrate the importance of A2062, A2503 and U2586 for drug-dependent ribosome stalling. Our data show that the universally conserved A2062 and A2503 are capable of forming a non-Watson–Crick base pair that is critical for sensing and transmitting the stalling signal from the exit tunnel back to the peptidyl transferase center of the ribosome. The nucleobases of A2062, A2503 as well as U2586 do not contribute significantly to the overall mechanism of protein biosynthesis, yet their elaborate role for co-translational monitoring of nascent peptide chains inside the exit tunnel can explain their evolutionary conservation. PMID:28369621

Macrolides Blunt Aldosterone Biosynthesis: A Proof-of-Concept Study in KCNJ5 Mutated Adenoma Cells Ex Vivo.

PubMed

Caroccia, Brasilina; Prisco, Selene; Seccia, Teresa Maria; Piazza, Maria; Maiolino, Giuseppe; Rossi, Gian Paolo

2017-12-01

Aldosterone-producing adenoma (APA), a major subtype of primary hyperaldosteronism, the main curable cause of human endocrine hypertension, involves somatic mutations in the potassium channel Kir3.4 ( KCNJ5 ) in 30% to 70% of cases, typically the more florid phenotypes. Because KCNJ5 mutated channels were reported to be specifically sensitive to inhibition by macrolide antibiotics, which concentration dependently blunts aldosterone production in HAC15 transfected with the G151R and L168R mutated channel, we herein tested the effect of clarithromycin on aldosterone synthesis and secretion in a pure population of aldosterone-secreting cells obtained by immunoseparation (CD56 + cells) from APA tissues with/without the 2 most common KCNJ5 mutations. From a large cohort of patients with an unambiguous APA diagnosis, we recruited those who were wild type (n=3) or had G151R (n=2) and L168R (n=2) mutations. We found that clarithromycin concentration dependently lowered CYP11B2 gene expression (by 60%) and aldosterone secretion (by 70%; P <0.001 for both) in CD56 + cells isolated ex vivo from KCNJ5 mutated APAs, although it was ineffective in CD56 + cells from wild-type APAs. By proving the principle that the oversecretion of aldosterone can be specifically blunted in APA cells ex vivo with G151R and L168R mutations, these results provide compelling evidence of the possibility of specifically correcting aldosterone excess in patients with APA carrying the 2 most common KCNJ5 somatic mutations. © 2017 American Heart Association, Inc.

Critical 23S rRNA interactions for macrolide-dependent ribosome stalling on the ErmCL nascent peptide chain.

PubMed

Koch, Miriam; Willi, Jessica; Pradère, Ugo; Hall, Jonathan; Polacek, Norbert

2017-06-20

The nascent peptide exit tunnel has recently been identified as a functional region of ribosomes contributing to translation regulation and co-translational protein folding. Inducible expression of the erm resistance genes depends on ribosome stalling at specific codons of an upstream open reading frame in the presence of an exit tunnel-bound macrolide antibiotic. The molecular basis for this translation arrest is still not fully understood. Here, we used a nucleotide analog interference approach to unravel important functional groups on 23S rRNA residues in the ribosomal exit tunnel for ribosome stalling on the ErmC leader peptide. By replacing single nucleobase functional groups or even single atoms we were able to demonstrate the importance of A2062, A2503 and U2586 for drug-dependent ribosome stalling. Our data show that the universally conserved A2062 and A2503 are capable of forming a non-Watson-Crick base pair that is critical for sensing and transmitting the stalling signal from the exit tunnel back to the peptidyl transferase center of the ribosome. The nucleobases of A2062, A2503 as well as U2586 do not contribute significantly to the overall mechanism of protein biosynthesis, yet their elaborate role for co-translational monitoring of nascent peptide chains inside the exit tunnel can explain their evolutionary conservation. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

High Prevalence of Macrolide-resistance and Molecular Characterization of Streptococcus pyogenes Isolates Circulating in China from 2009 to 2016

PubMed Central

Lu, Binghuai; Fang, Yujie; Fan, Yanyan; Chen, Xingchun; Wang, Junrui; Zeng, Ji; Li, Yi; Zhang, Zhijun; Huang, Lei; Li, Hongxia; Li, Dong; Zhu, Fengxia; Cui, Yanchao; Wang, Duochun

2017-01-01

Streptococcus pyogenes, or group A Streptococcus, is a pathogen responsible for a wide range of clinical manifestations, from mild skin and soft tissue infections and pharyngitis to severe diseases. Its epidemiological characteristics should be comprehensively under surveillance for regulating the national prevention and treatment practice. Herein, a total of 140 S. pyogenes, including 38 invasive and 102 noninvasive isolates, were collected from infected patients in 10 tertiary general hospitals from 7 cities/provinces in China during the years 2009–2016. All strains were characterized by classical and molecular techniques for its emm types/subtypes, virulent factors and antibiotic resistance profiling. Of 140 isolates, 15 distinct emm types and 31 subtypes were detected, dominated by emm12 (60 isolates, 42.9%), emm1(43, 30.7%), and emm89 (10, 7.1%), and 8 new emm variant subtypes were identified. All strains, invasive or not, harbored the superantigenic genes, speB and slo. The other virulence genes, smeZ, speF, and speC accounted for 96.4, 91.4, and 87.1% of collected isolates, respectively. Further multilocus sequence typing (MLST) placed all strains into 22 individual sequence types (STs), including 4 newly-identified STs (11, 7.9%). All isolates were phenotypically susceptible to penicillin, ampicillin, cefotaxime, and vancomycin, whereas 131(93.5%), 132(94.2%), and 121(86.4%) were resistant to erythromycin, clindamycin, and tetracycline, respectively. Our study highlights high genotypic diversity and high prevalence of macrolide resistance of S. pyogenes among clinical isolates circulating in China. PMID:28642756

Bacteraemia due to Streptococcus gallolyticus subspecies pasteurianus is associated with digestive tract malignancies and resistance to macrolides and clindamycin.

PubMed

Sheng, Wang-Huei; Chuang, Yu-Chung; Teng, Lee-Jene; Hsueh, Po-Ren

2014-08-01

This study was intended to delineate the association between digestive tract malignancies and bacteraemia due to Streptococcus gallolyticus subspecies pasteurianus. We reviewed the medical records and microbiological results of patients with bacteraemia due to Streptococcus bovis during the period 2000-2012. Species and subspecies identification of isolates originally classified as S. bovis was confirmed by 16S rRNA sequencing and PCR restriction fragment length polymorphism (PCR-RFLP) assays. Minimum inhibitory concentrations of antimicrobial agents were determined by the broth microdilution method. Of the 172 S. bovis complex isolates obtained from 172 patients (age range, <1-94 years, median age, 66) with bacteraemia, 31 isolates were identified to be S. gallolyticus subspecies gallolyticus, 126 were S. gallolyticus subspecies pasteurianus, and 15 were shown to be Streptococcus infantarius. The majority (n = 104, 60%) of patients were male and had underlying malignancies (n = 87, 51%). Bacteraemia due to S. gallolyticus subspecies gallolyticus was significantly associated with endocarditis while S. gallolyticus subspecies pasteurianus was more likely to be associated with malignancies of the digestive tract, including gastric, pancreatic, hepatobiliary and colorectal cancers. Septic shock at presentation was the only factor associated with mortality among patients with bacteraemia due to either subspecies of S. bovis. Isolates of S. gallolyticus subspecies pasteurianus had higher rates of resistance to macrolides and clindamycin than isolates of S. gallolyticus subspecies gallolyticus. Extensive diagnostic work-up for digestive tract malignancies and trans-esophageal echocardiogram should be investigated in patients with bacteraemia caused by S. gallolyticus. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

The anti-biofilm effect of macrolides in a rat model of S. aureus foreign-body infection: Might it be of clinical relevance?

PubMed

El Haj, Cristina; Murillo, Oscar; Ribera, Alba; Garcia-Somoza, Dolors; Tubau, Fe; Cabellos, Carmen; Cabo, Javier; Ariza, Javier

2017-02-01

Using a tissue cage infection rat model, we test the anti-biofilm effect of clarithromycin on the efficacy of daptomycin and a daptomycin + rifampicin combination against methicillin-susceptible (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA). In vitro: kill curves, daptomycin exposure studies and clarithromycin activity against biofilm were studied. In vivo: the efficacies of clarithromycin, daptomycin or daptomycin + clarithromycin, daptomycin + rifampicin and daptomycin + rifampicin + clarithromycin combinations were evaluated. In vitro: the addition of clarithromycin to daptomycin improved its activity only against one MRSA strain. Changes in daptomycin MIC values appeared more quickly in MSSA than in MRSA strain, and this was not modified by clarithromycin. Clarithromycin prevented biofilm formation but did not eradicate it. In vivo: the daptomycin + rifampicin combination was the most effective treatment and was not improved by the addition of clarithromycin. Daptomycin and daptomycin + clarithromycin had similar effectiveness; the combination protected against the appearance of daptomycin resistance only in one MRSA strain. Using a staphylococcal foreign-body infection model, we observed a slight effect with the addition of clarithromycin to daptomycin, which resulted in protection against the appearance of daptomycin-resistant strains. However, efficacy was not improved. Overall, our findings do not support a relevant clinical role for macrolides in treating device-related staphylococcal infections based on their anti-biofilm effect.

Concentration of the macrolide antibiotic tulathromycin in broncho-alveolar cells is influenced by comedication of rifampicin in foals.

PubMed

Venner, Monica; Peters, Jette; Höhensteiger, Nina; Schock, Birthe; Bornhorst, Alexa; Grube, Markus; Adam, Ulrike; Scheuch, Eberhard; Weitschies, Werner; Rosskopf, Dieter; Kroemer, Heyo K; Siegmund, Werner

2010-02-01

Macrolide antibiotics penetrate in the lung against steep concentration gradients into the epithelial lining fluid (ELF) and broncho-alveolar cells (BAC). Since they interact with ABCB1, ABCC2, and organic anion transporting proteins (OATPs), which are localized to lung tissue, pulmonary concentration may be influenced by rifampicin (RIF), an inducer and modulator of efflux and uptake transporters. We measured concentrations of tulathromycin (TM) in plasma, ELF and BAC in 21 warm-blooded foals 24 and 192 h after first and last intramuscular injection of 2.5 mg/kg TM once weekly for 6 weeks. In 11 foals, TM was combined with RIF (10 mg/kg twice daily), and mRNA expression of ABCB1 and ABCC2 in BAC was assessed before and after RIF. Affinity of TM to ABCB1 and ABCC2 was measured by transport assays using cell monolayers and membrane vesicles of MDCKII and 2008 cells transfected with ABCB1 and ABCC2, respectively. At steady state, TM concentrated manifold in ELF and BAC. Comedication of RIF significantly decreased the AUC of TM (18.5 +/- 4.0 versus 24.4 +/- 3.7 microg x h/ml, p < 0.05) and lowered its concentrations in plasma (24 h, 0.17 +/- 0.05 versus 0.24 +/- 0.05 microg/ml; 192 h, 0.05 +/- 0.01 versus 0.06 +/- 0.01 microg/ml) and BAC (24 h, 0.84 +/- 0.36 versus 1.56 +/- 1.02 microg/ml; 192 h, 0.60 +/- 0.23 versus 1.23 +/- 0.90 microg/ml, all p < 0.05). Treatment with rifampicin did not markedly induce ABCB1 and ABCC2 expression. TM had no affinity to ABCB1 and ABCC2 in vitro. Concentration of TM in the lung of foals was significantly lowered by comedication of rifampicin most likely caused by extrapulmonary mechanisms leading to lower plasma concentrations.

Hierarchical Control on Polyene Macrolide Biosynthesis: PimR Modulates Pimaricin Production via the PAS-LuxR Transcriptional Activator PimM

PubMed Central

Santos-Aberturas, Javier; Vicente, Cláudia M.; Payero, Tamara D.; Martín-Sánchez, Lara; Cañibano, Carmen; Martín, Juan F.; Aparicio, Jesús F.

2012-01-01

Control of polyene macrolide production in Streptomyces natalensis is mediated by the transcriptional activator PimR. This regulator combines an N-terminal domain corresponding to the Streptomyces antibiotic regulatory protein (SARP) family of transcriptional activators with a C-terminal half homologous to guanylate cyclases and large ATP-binding regulators of the LuxR family. The PimR SARP domain (PimRSARP) was expressed in Escherichia coli as a glutathione S-transferase (GST)–fused protein. Electrophoretic mobility shift assays showed that GST-PimRSARP binds a single target, the intergenic region between the regulatory genes pimR and pimMs in the pimaricin cluster. The PimRSARP-binding site was investigated by DNaseI protection studies, revealing that it contains three heptameric direct repeats adjusting to the consensus 5′-CGGCAAG-3′. Transcription start points of pimM and pimR promoters were identified by 5′-RACE, revealing that unlike other SARPs, PimRSARP does not interact with the -35 region of its target promoter. Quantitative transcriptional analysis of these regulatory genes on mutants on each of them has allowed the identification of the pimM promoter as the transcriptional target for PimR. Furthermore, the constitutive expression of pimM restored pimaricin production in a pimaricin-deficient strain carrying a deletion mutant of pimR. These results reveal that PimR exerts its positive effect on pimaricin production by controlling pimM expression level, a regulator whose gene product activates transcription from eight different promoters of pimaricin structural genes directly. PMID:22693644

High prevalence of Streptococcus agalactiae from vaginas of women in Taiwan and its mechanisms of macrolide and quinolone resistance.

PubMed

Lee, Wen-Tsung; Lai, Mei-Chin

2015-10-01

Streptococcus agalactiae (GBS), is the most common pathogen causing infections among perinatal women and neonatal babies. Nonetheless, there are few studies on the occurrence of GBS among the pregnant women and the mechanisms of GBS resistance to quinolones and macrolides in Taiwan. GBS were isolated from vaginas of the pregnant and non-pregnant symptomatic women in Taiwan. The prevalence, antimicrobial susceptibility, and mechanisms of resistance against erythromycin and quinolone of total 188 isolates were studied. The isolation rate of GBS from pregnant women was significantly higher at 21.8% compare with the non-pregnant women of 13.2%. Antibiotic susceptibility test of the 188 GBS isolates revealed a high non-susceptible rate for erythromycin (50.0%) while the rate for levofloxacin was only 4.8%. Among 94 erythromycin non-susceptible GBS isolates, ermB gene was detected 83.1% (59/71) for those GBS that were non-susceptible to both clindamycin and tetracycline, which was significantly higher than GBS that are susceptible to clindamycin but resistant to tetracycline at 43.8% (7/16). No ermA or mef gene was detected in any isolate. Mutations were detected in the parC and gyrA genes in 14 out of 18 levofloxacin non-susceptible isolates. The predominant mutation type was the combination of Ser79Tyr in parC and Ser81Leu mutations in gyrA. GBS is the most common isolated pathogens in vaginal infections in Taiwan, resistance to tetracycline and erythromycin is higher than the rate observed for other regions of the world, while the resistance rate for levofloxacin was relatively lower in Taiwan. Copyright © 2014. Published by Elsevier B.V.

Functional implications of an intermeshing cogwheel-like interaction between TolC and MacA in the action of macrolide-specific efflux pump MacAB-TolC.

PubMed

Xu, Yongbin; Song, Saemee; Moeller, Arne; Kim, Nahee; Piao, Shunfu; Sim, Se-Hoon; Kang, Mooseok; Yu, Wookyung; Cho, Hyun-Soo; Chang, Iksoo; Lee, Kangseok; Ha, Nam-Chul

2011-04-15

Macrolide-specific efflux pump MacAB-TolC has been identified in diverse gram-negative bacteria including Escherichia coli. The inner membrane transporter MacB requires the outer membrane factor TolC and the periplasmic adaptor protein MacA to form a functional tripartite complex. In this study, we used a chimeric protein containing the tip region of the TolC α-barrel to investigate the role of the TolC α-barrel tip region with regard to its interaction with MacA. The chimeric protein formed a stable complex with MacA, and the complex formation was abolished by substitution at the functionally essential residues located at the MacA α-helical tip region. Electron microscopic study delineated that this complex was made by tip-to-tip interaction between the tip regions of the α-barrels of TolC and MacA, which correlated well with the TolC and MacA complex calculated by molecular dynamics. Taken together, our results demonstrate that the MacA hexamer interacts with TolC in a tip-to-tip manner, and implies the manner by which MacA induces opening of the TolC channel.

Functional Implications of an Intermeshing Cogwheel-like Interaction between TolC and MacA in the Action of Macrolide-specific Efflux Pump MacAB-TolC*

PubMed Central

Xu, Yongbin; Song, Saemee; Moeller, Arne; Kim, Nahee; Piao, Shunfu; Sim, Se-Hoon; Kang, Mooseok; Yu, Wookyung; Cho, Hyun-Soo; Chang, Iksoo; Lee, Kangseok; Ha, Nam-Chul

2011-01-01

Macrolide-specific efflux pump MacAB-TolC has been identified in diverse Gram-negative bacteria including Escherichia coli. The inner membrane transporter MacB requires the outer membrane factor TolC and the periplasmic adaptor protein MacA to form a functional tripartite complex. In this study, we used a chimeric protein containing the tip region of the TolC α-barrel to investigate the role of the TolC α-barrel tip region with regard to its interaction with MacA. The chimeric protein formed a stable complex with MacA, and the complex formation was abolished by substitution at the functionally essential residues located at the MacA α-helical tip region. Electron microscopic study delineated that this complex was made by tip-to-tip interaction between the tip regions of the α-barrels of TolC and MacA, which correlated well with the TolC and MacA complex calculated by molecular dynamics. Taken together, our results demonstrate that the MacA hexamer interacts with TolC in a tip-to-tip manner, and implies the manner by which MacA induces opening of the TolC channel. PMID:21325274

Stabilization Mechanism of Roxithromycin Tablets under Gastric pH Conditions.

PubMed

Inukai, Koki; Noguchi, Shuji; Kimura, Shin-Ichiro; Itai, Shigeru; Iwao, Yasunori

2018-05-31

Macrolide antibiotics are widely used at clinical sites. Clarithromycin (CAM), a 14-membered macrolide antibiotic, was reported to gelate under acidic conditions. Gelation allows oral administration of acid-sensitive CAM without enteric coating by hindering the penetration of gastric fluid into CAM tablets. However, it is unknown whether this phenomenon occurs in other macrolide antibiotics. In this study, we examined the gelation ability of three widely used macrolide antibiotics, roxithromycin (RXM), erythromycin A (EM), and azithromycin (AZM). The results indicated that not only CAM but also RXM gelated under acidic conditions. EM and AZM did not gelate under the same conditions. Gelation of RXM delayed the disintegration of the tablet and release of RXM from the tablet. Disintegration and release were also delayed in commercial RXM tablets containing disintegrants. This study showed that two of the four macrolides gelated, which affects tablet disintegration and dissolution and suggests that this phenomenon might also occur in other macrolides. Copyright © 2018. Published by Elsevier Inc.

Occurrence and distribution of sulfonamides, tetracyclines, quinolones, macrolides, and nitrofurans in livestock manure and amended soils of Northern China.

PubMed

Hou, Jie; Wan, Weining; Mao, Daqing; Wang, Chong; Mu, Quanhua; Qin, Songyan; Luo, Yi

2015-03-01

A feasible and rapid analysis for the simultaneous determination of sulfonamides (SAs), tetracyclines (TCs), fluoroquinolones (FQs), macrolides (MACs) and nitrofurans (NFs) in livestock manure and soils was established by solid-phase extraction (SPE)-ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). A total of 32 manure and 17 amended soil samples from the Liaoning and Tianjin areas in Northern China were collected for analysis. The largest detected frequencies and concentrations in manure samples were those of TCs (3326.6 ± 12,302.6 μg/kg), followed by FQs (411.3 ± 1453.4 μg/kg), SAs (170.6 ± 1060.2 μg/kg), NFs (85.1 ± 158.1 μg/kg), and MACs (1.4 ± 4.8 μg/kg). In general, veterinary antibiotics (VAs) were detected with higher concentrations in swine and chicken manure than in cattle manure, reflecting the heavy usage of VAs in swine and chicken husbandry in the studied area. Furthermore, higher residues of antibiotics were found in piglet and fattening swine manure than in sow manure. In addition, TCs were the most frequently (100%) detected antibiotics in amended soil with higher concentrations (up to 10,967.1 μg/kg) than any other VAs. The attenuation of SAs was more obvious than TCs in amended soil after fertilization, which can most likely be attributed to the stronger sorption of TCs than SAs to soil organic matter through cation exchange. This study illustrated the prevalence of TCs detected in both animal manure and fertilized agricultural soils in Northern China, which may increase the risk to human health through the food chain. Thus, TCs should be given more attention in the management of veterinary usage in livestock husbandry.

Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation.

PubMed

Niedrig, David; Maechler, Sarah; Hoppe, Liesa; Corti, Natascia; Kovari, Helen; Russmann, Stefan

2016-07-01

Some macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions. We conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records. Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7 %) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1 % had no ECG monitoring. Of all MQAB users, 547 (15.9 %) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions. In the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.

Decision and cost analysis of empirical antibiotic therapy of acute sinusitis in the era of increasing antimicrobial resistance: do we have an additional tool for antibiotic policy decisions?

PubMed

Babela, Robert; Jarcuska, Pavol; Uraz, Vladimir; Krčméry, Vladimír; Jadud, Branislav; Stevlik, Jan; Gould, Ian M

2017-11-01

No previous analyses have attempted to determine optimal therapy for upper respiratory tract infections on the basis of cost-minimization models and the prevalence of antimicrobial resistance among respiratory pathogens in Slovakia. This investigation compares macrolides and cephalosporines for empirical therapy and look at this new tool from the aspect of potential antibiotic policy decision-making process. We employed a decision tree model to determine the threshold level of macrolides and cephalosporines resistance among community respiratory pathogens that would make cephalosporines or macrolides cost-minimising. To obtain information on clinical outcomes and cost of URTIs, a systematic review of the literature was performed. The cost-minimization model of upper respiratory tract infections (URTIs) treatment was derived from the review of literature and published models. We found that the mean cost of empirical treatment with macrolides for an URTIs was €93.27 when the percentage of resistant Streptococcus pneumoniae in the community was 0%; at 5%, the mean cost was €96.45; at 10%, €99.63; at 20%, €105.99, and at 30%, €112.36. Our model demonstrated that when the percentage of macrolide resistant Streptococcus pneumoniae exceeds 13.8%, use of empirical cephalosporines rather than macrolides minimizes the treatment cost of URTIs. Empirical macrolide therapy is less expensive than cephalosporines therapy for URTIs unless macrolide resistance exceeds 13.8% in the community. Results have important antibiotic policy implications, since presented model can be use as an additional decision-making tool for new guidelines and reimbursement processes by local authorities in the era of continual increase in antibiotic resistance.

Enrofloxacin and Macrolides Alone or in Combination with Rifampicin as Antimicrobial Treatment in a Bovine Model of Acute Chlamydia psittaci Infection

PubMed Central

Prohl, Annette; Lohr, Markus; Ostermann, Carola; Liebler-Tenorio, Elisabeth; Berndt, Angela; Schroedl, Wieland; Rothe, Michael; Schubert, Evelyn; Sachse, Konrad; Reinhold, Petra

2015-01-01

Chlamydia psittaci is a zoonotic bacterium with a wide host range that can cause respiratory disease in humans and cattle. In the present study, effects of treatment with macrolides and quinolones applied alone or in combination with rifampicin were tested in a previously established bovine model of respiratory C. psittaci infection. Fifty animals were inoculated intrabronchially at the age of 6–8 weeks. Seven served as untreated controls, the others were assigned to seven treatment groups: (i) rifampicin, (ii) enrofloxacin, (iii) enrofloxacin + rifampicin, (iv) azithromycin, (v) azithromycin + rifampicin, (vi) erythromycin, and (vii) erythromycin + rifampicin. Treatment started 30 hours after inoculation and continued until 14 days after inoculation (dpi), when all animals were necropsied. The infection was successful in all animals and sufficient antibiotic levels were detected in blood plasma and tissue of the treated animals. Reisolation of the pathogen was achieved more often from untreated animals than from other groups. Nevertheless, pathogen detection by PCR was possible to the same extent in all animals and there were no significant differences between treated and untreated animals in terms of local (i.e. cell count and differentiation of BALF-cells) and systemic inflammation (i.e. white blood cells and concentration of acute phase protein LBP), clinical signs, and pathological findings at necropsy. Regardless of the reduced reisolation rate in treated animals, the treatment of experimentally induced respiratory C. psittaci infection with enrofloxacin, azithromycin or erythromycin alone or in combination with rifampicin was without obvious benefit for the host, since no significant differences in clinical and pathological findings or inflammatory parameters were detected and all animals recovered clinically within two weeks. PMID:25768665

High-throughput method for macrolides and lincosamides antibiotics residues analysis in milk and muscle using a simple liquid-liquid extraction technique and liquid chromatography-electrospray-tandem mass spectrometry analysis (LC-MS/MS).

PubMed

Jank, Louise; Martins, Magda Targa; Arsand, Juliana Bazzan; Campos Motta, Tanara Magalhães; Hoff, Rodrigo Barcellos; Barreto, Fabiano; Pizzolato, Tânia Mara

2015-11-01

A fast and simple method for residue analysis of the antibiotics classes of macrolides (erythromycin, azithromycin, tylosin, tilmicosin and spiramycin) and lincosamides (lincomycin and clindamycin) was developed and validated for cattle, swine and chicken muscle and for bovine milk. Sample preparation consists in a liquid-liquid extraction (LLE) with acetonitrile, followed by liquid chromatography-electrospray-tandem mass spectrometry analysis (LC-ESI-MS/MS), without the need of any additional clean-up steps. Chromatographic separation was achieved using a C18 column and a mobile phase composed by acidified acetonitrile and water. The method was fully validated according the criteria of the Commission Decision 2002/657/EC. Validation parameters such as limit of detection, limit of quantification, linearity, accuracy, repeatability, specificity, reproducibility, decision limit (CCα) and detection capability (CCβ) were evaluated. All calculated values met the established criteria. Reproducibility values, expressed as coefficient of variation, were all lower than 19.1%. Recoveries range from 60% to 107%. Limits of detection were from 5 to 25 µg kg(-1).The present method is able to be applied in routine analysis, with adequate time of analysis, low cost and a simple sample preparation protocol. Copyright © 2015. Published by Elsevier B.V.

High frequency of the 23S rRNA A2058G mutation of Treponema pallidum in Shanghai is associated with a current strategy for the treatment of syphilis.

PubMed

Lu, Haikong; Li, Kang; Gong, Weimin; Yan, Limeng; Gu, Xin; Chai, Ze; Guan, Zhifang; Zhou, Pingyu

2015-02-01

The preferred drugs for the treatment of syphilis, benzathine and procaine penicillin, have not been available in Shanghai for many years, and currently, the incidence of syphilis is increasing. Alternative antibiotics for patients with syphilis during the benzathine and procaine penicillin shortage include macrolides. The failure of macrolide treatment in syphilis patients has been reported in Shanghai, but the reason for this treatment failure remains unclear. We used polymerase chain reaction technology to detect a 23S rRNA A2058G mutation in Treponema pallidum in 109 specimens from syphilis patients. The use of azithromycin/erythromycin in the syphilis patients and the physicians' prescription habits were also assessed based on two questionnaires regarding the use of macrolides. A total of 104 specimens (95.4%) were positive for the A2058G mutation in both copies of the 23S rRNA gene, indicating macrolide resistance. A questionnaire provided to 122 dermatologists showed that during the penicillin shortage, they prescribed erythromycin and azithromycin for 8.24±13.95% and 3.21±6.37% of their patients, respectively, and in the case of penicillin allergy, erythromycin and azithromycin were prescribed 15.24±22.89% and 7.23±16.60% of the time, respectively. A second questionnaire provided to the syphilis patients showed that 150 (33.7%), 106 (23.8%) and 34 (7.6%) individuals had used azithromycin, erythromycin or both, respectively, although the majority did not use the drugs for syphilis treatment. Our findings suggest that macrolide resistance in Treponema pallidum is widespread in Shanghai. More than half of the syphilis patients had a history of macrolide use for other treatment purposes, which may have led to the high prevalence of macrolide resistance. Physicians in China are advised to not use azithromycin for early syphilis.

Seven-Year Surveillance of emm Types of Pediatric Group A Streptococcal Pharyngitis Isolates in Western Greece

PubMed Central

Syrogiannopoulos, George A.; Grivea, Ioanna N.; Al-Lahham, Adnan; Panagiotou, Maria; Tsantouli, Alexandra G.; Michoula Ralf René Reinert, Aspasia N.; van der Linden, Mark

2013-01-01

Background An experimental 26-valent M protein Group A streptococcal (GAS) vaccine has entered clinical studies. Pharyngeal GAS emm type surveillances in different areas and time-periods enhance the understanding of the epidemiology of GAS pharyngitis. Moreover, these surveillances, combined with the data on GAS invasive disease, can play a significant role in the formulation of multivalent type-specific vaccines. Methods During a 7-year period (1999–2005), 2408 GAS isolates were recovered from consecutive children with pharyngitis in Western Greece. The overall macrolide resistance rate was 22.8%. Along the study period we noted a tendency towards significantly decreased rates of resistance, with the lowest rates occurring in 2002 (15.3%), 2003 (15%) and 2004 (16.7%). A random sample of isolates from each year, 338 (61.7%) of the 548 macrolide-resistant and 205 (11%) of the macrolide-susceptible, underwent molecular analysis, including emm typing. Results The 543 typed isolates had 28 different emm types. A statistically significant association was found between macrolide resistance and emm4, emm22 and emm77, whereas emm1, emm3, emm6, emm12, emm87 and emm89 were associated with macrolide susceptibility. A significant yearly fluctuation was observed in emm4, emm28 and emm77. The most common macrolide-resistant GAS were emm77 isolates harboring erm(A), either alone or in combination with mef(A), emm4 carrying mef(A), emm28 possessing erm(B), emm75 carrying mef(A), emm12 harboring mef(A) and emm22 carrying erm(A). We estimated that 82.8% of the isolates belonged to emm types included in the novel 26-valent M protein vaccine. The vaccine coverage rate was determined mainly by the increased frequency of nonvaccine emm4 isolates. Conclusions A limited number of emm types dominated among macrolide-susceptible and macrolide-resistant GAS isolates. We observed seasonal fluctuations, which were significant for emm4, emm28 and emm77. This type of data can serve as baseline

A new mosaic integrative and conjugative element from Streptococcus agalactiae carrying resistance genes for chloramphenicol (catQ) and macrolides [mef(I) and erm(TR)].

PubMed

Morici, Eleonora; Simoni, Serena; Brenciani, Andrea; Giovanetti, Eleonora; Varaldo, Pietro E; Mingoia, Marina

2017-01-01

To investigate the genetic basis of catQ-mediated chloramphenicol resistance in Streptococcus agalactiae. Two clinical strains of catQ-positive chloramphenicol-resistant S. agalactiae (Sag236 and Sag403) were recently isolated, typed (MLST, PFGE pulsotypes, capsular types) and their antibiotic resistances investigated by phenotypic and genotypic approaches. Several molecular methods (PCR mapping, restriction assays, Southern blotting, sequencing and sequence analysis, conjugal transfer assays) were used to determine the genetic context of catQ and characterize a genetic element detected in the isolates. Sag236 and Sag403 shared the same ST (ST19), but exhibited a different capsular type (III and V, respectively) and pulsotype. Both harboured the macrolide resistance genes mef(I) and erm(TR) and the tetracycline resistance gene tet(M). Accordingly, they were resistant to chloramphenicol, erythromycin and tetracycline. catQ and mef(I) were associated in an IQ module that was indistinguishable in Sag236 and Sag403. In mating assays, chloramphenicol and erythromycin resistance proved transferable, at low frequency, only from Sag236. Transconjugants carried not only catQ and mef(I), but also erm(TR), suggesting a linkage of the three resistance genes in a mobile element, which, though seemingly non-mobile, was also detected in Sag403. The new element (designated ICESag236, ∼110 kb) results from recombination of two integrative and conjugative elements (ICEs) originally described in different streptococcal species: S. agalactiae ICESagTR7, carrying erm(TR); and Streptococcus pneumoniae ICESpn529IQ, carrying the prototype IQ module. These findings strengthen the notion that widespread streptococcal ICEs may form mosaics that enhance their diversity and spread, broaden their host range and carry new cargo genes. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions

Impact of Long-Term Erythromycin Therapy on the Oropharyngeal Microbiome and Resistance Gene Reservoir in Non-Cystic Fibrosis Bronchiectasis.

PubMed

Choo, Jocelyn M; Abell, Guy C J; Thomson, Rachel; Morgan, Lucy; Waterer, Grant; Gordon, David L; Taylor, Steven L; Leong, Lex E X; Wesselingh, Steve L; Burr, Lucy D; Rogers, Geraint B

2018-04-25

Long-term macrolide therapy reduces rates of pulmonary exacerbation in bronchiectasis. However, little is known about the potential for macrolide therapy to alter the composition and function of the oropharyngeal commensal microbiota or to increase the carriage of transmissible antimicrobial resistance. We assessed the effect of long-term erythromycin on oropharyngeal microbiota composition and the carriage of transmissible macrolide resistance genes in 84 adults with bronchiectasis, enrolled in the Bronchiectasis and Low-dose Erythromycin Study (BLESS) 48-week placebo-controlled trial of twice-daily erythromycin ethylsuccinate (400 mg). Oropharyngeal microbiota composition and macrolide resistance gene carriage were determined by 16S rRNA gene amplicon sequencing and quantitative PCR, respectively. Long-term erythromycin treatment was associated with a significant increase in the relative abundance of oropharyngeal Haemophilus parainfluenzae ( P = 0.041) and with significant decreases in the relative abundances of Streptococcus pseudopneumoniae ( P = 0.024) and Actinomyces odontolyticus ( P = 0.027). Validation of the sequencing results by quantitative PCR confirmed a significant decrease in the abundance of Actinomyces spp. ( P = 0.046). Erythromycin treatment did not result in a significant increase in the number of subjects who carried erm (A), erm (B), erm (C), erm (F), mef (A/E), and msrA macrolide resistance genes. However, the abundance of erm (B) and mef (A/E) gene copies within carriers who had received erythromycin increased significantly ( P < 0.05). Our findings indicate that changes in oropharyngeal microbiota composition resulting from long-term erythromycin treatment are modest and are limited to a discrete group of taxa. Associated increases in levels of transmissible antibiotic resistance genes within the oropharyngeal microbiota highlight the potential for this microbial system to act as a reservoir for resistance. IMPORTANCE Recent

Lack of evidence for erm(B) infiltration into erythromycin-resistant Campylobacter spp. from commercial turkey production in the southeastern United States

USDA-ARS?s Scientific Manuscript database

In Campylobacter spp., resistance to erythromycin and other macrolides has typically implicated ribosomal mutations, especially substitutions in the 23S rRNA gene. In 2014, the macrolide resistance gene erm(B) was reported for the first time in Campylobacter, and shown to be harbored in a multidrug ...

Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children.

PubMed

Korpela, Katri; Salonen, Anne; Virta, Lauri J; Kekkonen, Riina A; Forslund, Kristoffer; Bork, Peer; de Vos, Willem M

2016-01-26

Early-life antibiotic use is associated with increased risk for metabolic and immunological diseases, and mouse studies indicate a causal role of the disrupted microbiome. However, little is known about the impacts of antibiotics on the developing microbiome of children. Here we use phylogenetics, metagenomics and individual antibiotic purchase records to show that macrolide use in 2-7 year-old Finnish children (N=142; sampled at two time points) is associated with a long-lasting shift in microbiota composition and metabolism. The shift includes depletion of Actinobacteria, increase in Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase and increase in macrolide resistance. Furthermore, macrolide use in early life is associated with increased risk of asthma and predisposes to antibiotic-associated weight gain. Overweight and asthmatic children have distinct microbiota compositions. Penicillins leave a weaker mark on the microbiota than macrolides. Our results support the idea that, without compromising clinical practice, the impact on the intestinal microbiota should be considered when prescribing antibiotics.

Intestinal microbiome is related to lifetime antibiotic use in Finnish pre-school children

PubMed Central

Korpela, Katri; Salonen, Anne; Virta, Lauri J.; Kekkonen, Riina A.; Forslund, Kristoffer; Bork, Peer; de Vos, Willem M.

2016-01-01

Early-life antibiotic use is associated with increased risk for metabolic and immunological diseases, and mouse studies indicate a causal role of the disrupted microbiome. However, little is known about the impacts of antibiotics on the developing microbiome of children. Here we use phylogenetics, metagenomics and individual antibiotic purchase records to show that macrolide use in 2–7 year-old Finnish children (N=142; sampled at two time points) is associated with a long-lasting shift in microbiota composition and metabolism. The shift includes depletion of Actinobacteria, increase in Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase and increase in macrolide resistance. Furthermore, macrolide use in early life is associated with increased risk of asthma and predisposes to antibiotic-associated weight gain. Overweight and asthmatic children have distinct microbiota compositions. Penicillins leave a weaker mark on the microbiota than macrolides. Our results support the idea that, without compromising clinical practice, the impact on the intestinal microbiota should be considered when prescribing antibiotics. PMID:26811868

Seasonal variation, flux estimation, and source analysis of dissolved emerging organic contaminants in the Yangtze Estuary, China.

PubMed

Zhao, Heng; Cao, Zhen; Liu, Xue; Zhan, Yi; Zhang, Jing; Xiao, Xi; Yang, Yi; Zhou, Junliang; Xu, Jiang

2017-12-15

The occurrence and seasonal variation of 24 dissolved emerging organic contaminants in the Yangtze Estuary were studied, including 12 non-antibiotic pharmaceuticals, seven sulfonamides, two macrolides and three chloramphenicols. Sulfadiazine, erythromycin, thiamphenicol and paracetamol were the primary contaminants in sulfonamides, macrolides, chloramphenicols and non-antibiotic pharmaceutical groups, respectively. Compared to the concentrations at Datong, chloramphenicols at Xuliujing were significantly higher in autumn and winter, while macrolides were lower in spring. Based on the flux estimation, approximately 37.1 tons of sulfonamides, 17.4 tons of macrolides, 79.2 tons of chloramphenicols and 14.1 tons of non-antibiotic pharmaceuticals were discharged into the Yangtze Estuary from June 2013 to May 2014. However, the total flux from the Huangpu River only represented 5% of the total. The pharmaceutical sources were speculated on by analyzing the seasonal variations in pharmaceutical concentrations and fluxes at various sites. Both environmental and social factors might affect the fluxes. Copyright © 2017 Elsevier Ltd. All rights reserved.

How good is the evidence for the recommended empirical antimicrobial treatment of patients hospitalized because of community-acquired pneumonia? A systematic review.

PubMed

Oosterheert, J J; Bonten, M J M; Hak, E; Schneider, M M E; Hoepelman, I M

2003-10-01

For years, monotherapy with a beta-lactam antibiotic (penicillin, amoxicillin or second-generation cephalosporin) was recommended as empirical therapy for patients with community-acquired pneumonia (CAP). A combination of a beta-lactam and a macrolide antibiotic was only recommended for patients with severe CAP needing intensive care treatment or when atypical pathogens, i.e. Legionella pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae, were strongly suspected. However, new guidelines recommend a combination of a beta-lactam antibiotic plus a macrolide or monotherapy with a fluoroquinolone for all patients hospitalized with CAP. We evaluated whether treatment with a beta-lactam plus macrolide or quinolone monotherapy is truly superior to beta-lactam treatment alone. We systematically reviewed available studies, retrieved from MEDLINE and by hand-searching reference lists from recent reviews and guidelines on the effectiveness of recommended empirical antimicrobial treatment of patients hospitalized because of CAP. Eight relevant studies were selected. In six studies significant reductions in mortality were found, in one study a reduction in hospital length of stay was found and in one study no beneficial effects could be demonstrated for treatment regimens with fluoroquinolone monotherapy or combinations of beta-lactams and macrolides. The beneficial value of macrolides or fluoroquinolones might be the result of a large and mainly unrecognized role of atypical pathogens in the aetiology of CAP, anti-inflammatory effects of macrolides or resistance to beta-lactams of the most important pathogens. However, the studies supporting the recommended treatment regimen were designed as non-experimental cohort studies. As a consequence, the results may have been influenced by confounding by indication. In addition, the outcomes showed several inconsistencies. A randomized controlled trial is warranted to circumvent the methodological flaws in the designs of the

Role of long term antibiotics in chronic respiratory diseases.

PubMed

Suresh Babu, K; Kastelik, J; Morjaria, J B

2013-06-01

Antibiotics are commonly used in the management of respiratory disorders such as cystic fibrosis (CF), non-CF bronchiectasis, asthma and COPD. In those conditions long-term antibiotics can be delivered as nebulised aerosols or administered orally. In CF, nebulised colomycin or tobramycin improve lung function, reduce number of exacerbations and improve quality of life (QoL). Oral antibiotics, such as macrolides, have acquired wide use not only as anti-microbial agents but also due to their anti-inflammatory and pro-kinetic properties. In CF, macrolides such as azithromycin have been shown to improve the lung function and reduce frequency of infective exacerbations. Similarly macrolides have been shown to have some benefits in COPD including reduction in a number of exacerbations. In asthma, macrolides have been reported to improve some subjective parameters, bronchial hyperresponsiveness and airway inflammation; however have no benefits on lung function or overall asthma control. Macrolides have also been used with beneficial effects in less common disorders such as diffuse panbronchiolitis or post-transplant bronchiolitis obliterans syndrome. In this review we describe our current knowledge the use of long-term antibiotics in conditions such as CF, non-CF bronchiectasis, asthma and COPD together with up-to-date clinical and scientific evidence to support our understanding of the use of antibiotics in those conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Outcomes of resistance-guided sequential treatment of Mycoplasma genitalium infections: a prospective evaluation.

PubMed

Read, T R H; Fairley, C K; Murray, G L; Jensen, J S; Danielewski, J; Worthington, K; Doyle, M; Mokany, E; Tan, L; Chow, E P F; Garland, S M; Bradshaw, C S

2018-06-05

Rising macrolide and quinolone resistance in Mycoplasma genitalium necessitate new treatment approaches. We evaluated outcomes of sequential antimicrobial therapy for M.genitalium guided by a macrolide-resistance assay. In mid-2016 Melbourne Sexual Health Centre switched from azithromycin to doxycycline (100mg twice daily,7 days) for non-gonococcal urethritis/cervicitis/proctitis. Cases were tested for M. genitalium and macrolide-resistance mutations (MRM) by polymerase chain reaction (PCR). Directly after doxycycline, MRM-negative infections received 2.5g azithromycin (1g then 500mg daily for 3 days), and MRM-positive infections received sitafloxacin (100mg twice daily, 7 days). Assessment of test-of-cure and reinfection risk, occurred 14-90 days after the second antibiotic. Those reporting condomless sex with incompletely treated partners were excluded. Of 244 evaluable M. genitalium infections (52 women, 68 heterosexual men, 124 men who have sex with men) diagnosed from 20 June 2016 to 15 May 2017, MRM were detected in 167 [68.4% (95%confidence interval(CI):62.2%, 74.2%)]. Treatment with doxycycline decreased bacterial load by a mean 2.60 log10 (n=56, p<0.0001). Microbiologic cure occurred in: 73/77 MRM-negative infections [94.8% (95%CI:87.2%, 98.6%)] and in 154/167 MRM-positive infections [92.2% (95%CI:87.1%, 95.8%)]. Selection of macrolide-resistance occurred in only 2 [2.6% (95%CI: 0.3%, 9.2%)] of 76 macrolide-susceptible infections. Proportions reporting no missed doses and no adverse events, respectively, were: doxycycline 89.9% and 86.6%, sitafloxacin 90.8% and 80.5%, azithromycin 100% and 91.4%. In the context of high levels of antimicrobial resistance, switching from azithromycin to doxycycline for presumptive treatment of M. genitalium, followed by resistance-guided therapy, cured ≥92% of infections, with infrequent selection of macrolide resistance.

[A comparative evaluation of modern antibacterial preparations in the treatment of a severe degree of periodontitis at a stage of exacerbation].

PubMed

Dmitrieva, L A; Tsarev, V N; Romanov, A E; Filatova, N A; Chernyshova, S B; Sechko, O N

1998-01-01

Sensitivities of peptostreptococci, streptococci, Actinomyces, bacteroid, and fusobacterial strains pathogenic for the periodontium to wide-spectrum penicillines, cephalosporines, lincomycin, macrolides, metronidasole, and nitasole are compared. New macrolide antibiotics rulide. Macropene, gramicidin C, levomycetin, and rifampicin are highly effective. Some narrow-spectrum drugs, e.g. augmentin, cephalexin, and vancomycin (towards actinomycetes) were highly effective, too.

In Vitro Susceptibilities of Mycoplasma putrefaciens Field Isolates▿

PubMed Central

Antunes, N. T.; Tavío, M. M.; Mercier, P.; Ayling, R. D.; Al-Momani, W.; Assunção, P.; Rosales, R. S.; Poveda, J. B.

2007-01-01

MICs were determined for 15 antimicrobial agents against 37 Mycoplasma putrefaciens isolates. The most effective antimicrobial drug classes were the fluoroquinolones, the tetracyclines, the lincosamide lincomycin, and the macrolides. The susceptibility profile of the isolates correlated with the geographic origin. This is the first report of decreased susceptibility to the macrolides, lincomycin, and the tetracyclines in M. putrefaciens strains. PMID:17638695

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.

Cethromycin: A-195773, A-195773-0, A-1957730, Abbott-195773, ABT 773.

PubMed

2007-01-01

Cethromycin [ABT 773, A-195773, Abbott-195773, A-1957730, A-195773-0] is a once-daily ketolide antibiotic that originated from Abbott Laboratories' research into next-generation compounds to the macrolide antibacterial, clarithromycin. The aim of the research programme was to maintain the positive attributes of clarithromycin and to add the property of efficacy against macrolide-resistant organisms. Cethromycin acts by binding to the 23S molecule of the 50S ribosomal subunit. Advanced Life Sciences is conducting multinational, pivotal phase III trials of cethromycin for the treatment of mild-to-moderate community-acquired pneumonia, phase II/III trials for treatment of acute bacterial sinusitis, as well as preclinical trials for the treatment of anthrax. Advanced Life Sciences plans to advance discussions with prospective commercialisation partners for cethromycin during 2006. Abbott Laboratories and Taisho Pharmaceutical entered a collaboration to develop and commercialise new macrolide antibacterials in October 1997. Each company brought its existing macrolides into the collaboration and both companies were to jointly develop novel new macrolides. Abbott was to have exclusive marketing, manfacturing and supply rights worldwide (except in Japan) to any compounds resulting from this collaboration. Taisho was to receive royalties on Abbott's sales in consideration of granted rights. In Japan, the two companies were to co-market any resulting macrolide antibacterials. This agreement extended to the development of cethromycin; however, the agreement was suspended in April 2004 and appears to have been terminated. Abbott exclusively licensed cethromycin to Advanced Life Sciences worldwide excluding Japan in December 2004. Advanced Life Sciences initiated commercial manufacturing agreements for cethromycin with DSM and Cardinal Health in May 2006. In March 2006, Advanced Life Sciences completed private placement of $US36 million from which the net proceeds will be used

Phenotypic and molecular characterization of resistance to macrolides, lincosamides and type B streptogramin of clinical isolates of Staphylococcus spp. of a university hospital in Recife, Pernambuco, Brazil.

PubMed

Pereira, Jussyêgles Niedja da Paz; Rabelo, Marcelle Aquino; Lima, Jailton Lobo da Costa; Neto, Armando Monteiro Bezerra; Lopes, Ana Catarina de Souza; Maciel, Maria Amélia Vieira

2016-01-01

There is a mechanism of macrolide resistance in Staphylococcus spp. which also affects the lincosamides and type B streptogramins characterizing the so-called MLSB resistance, whose expression can be constitutive (cMLSB) or inducible (iMLSB) and is encoded mainly by ermA and ermC genes. The cMLSB resistance is easily detected by susceptibility testing used in the laboratory routine, but iMLSB resistance is not. Therapy with clindamycin in cases of infection with isolated iMLSB resistance may fail. To characterize the phenotypic (occurrence of cMLSB and iMLSB phenotypes) and molecular (occurrence of ermA and ermC genes) profiles of MLSB resistance of clinical isolates of susceptible and methicillin-resistant Staphylococcus aureus and CNS (coagulase-negative Staphylococcus) from patients of a university hospital, in Pernambuco. The antimicrobial susceptibility of 103 isolates was determined by the disk diffusion technique in Mueller-Hinton agar followed by oxacillin screening. The iMLSB phenotype was detected by D test. Isolates with cMLSB and iMLSB phenotypes were subjected to polymerase chain reaction (PCR) for the detection of ermA and ermC genes. The cMLSB and iMLSB phenotypes were respectively identified in 39 (37.9%) and five (4.9%) isolates. The iMLSB phenotype was found only in four (10.8%) methicillin-susceptible S. aureus and one (4.5%) methicillin-resistant S. aureus. In the 44 isolates subjected to PCR, four (9.1%) only ermA gene was detected, a lower frequency when compared to only ermC 17 (38.6%) gene and to one (2.3%) isolate presenting both genes. In the Staphylococcus spp. analyzed, the ermC gene was found more often than the ermA, although the iMLSB phenotype had been less frequent than the cMLSB. It was important to perform the D test for its detection to guide therapeutic approaches. Copyright © 2016 Elsevier Editora Ltda. All rights reserved.

Functional Repertoire of Antibiotic Resistance Genes in Antibiotic Manufacturing Effluents and Receiving Freshwater Sediments

PubMed Central

González-Plaza, Juan J.; Šimatović, Ana; Milaković, Milena; Bielen, Ana; Wichmann, Fabienne; Udiković-Kolić, Nikolina

2018-01-01

Environments polluted by direct discharges of effluents from antibiotic manufacturing are important reservoirs for antibiotic resistance genes (ARGs), which could potentially be transferred to human pathogens. However, our knowledge about the identity and diversity of ARGs in such polluted environments remains limited. We applied functional metagenomics to explore the resistome of two Croatian antibiotic manufacturing effluents and sediments collected upstream of and at the effluent discharge sites. Metagenomic libraries built from an azithromycin-production site were screened for resistance to macrolide antibiotics, whereas the libraries from a site producing veterinary antibiotics were screened for resistance to sulfonamides, tetracyclines, trimethoprim, and beta-lactams. Functional analysis of eight libraries identified a total of 82 unique, often clinically relevant ARGs, which were frequently found in clusters and flanked by mobile genetic elements. The majority of macrolide resistance genes identified from matrices exposed to high levels of macrolides were similar to known genes encoding ribosomal protection proteins, macrolide phosphotransferases, and transporters. Potentially novel macrolide resistance genes included one most similar to a 23S rRNA methyltransferase from Clostridium and another, derived from upstream unpolluted sediment, to a GTPase HflX from Emergencia. In libraries deriving from sediments exposed to lower levels of veterinary antibiotics, we found 8 potentially novel ARGs, including dihydrofolate reductases and beta-lactamases from classes A, B, and D. In addition, we detected 7 potentially novel ARGs in upstream sediment, including thymidylate synthases, dihydrofolate reductases, and class D beta-lactamase. Taken together, in addition to finding known gene types, we report the discovery of novel and diverse ARGs in antibiotic-polluted industrial effluents and sediments, providing a qualitative basis for monitoring the dispersal of ARGs

INVESTIGATING ENVIRONMENTAL SINKS OF MACROLIDE ...

EPA Pesticide Factsheets

There is no abstract available for this product. If further information is requested, please refer to the bibliographic citation and contact the person listed under the Contact Field. The research focused on in the subtasks is the development and application of state-of the-art technologies to meet the needs of the public, Office of Water, and ORD in the area of Water Quality. Located In the subtasks are the various research projects being performed in support of this Task and more in-depth coverage of each project. Briefly, each project's objective is stated below.Subtask 1: To integrate state-of-the-art technologies (polar organic chemical integrative samplers, advanced solid-phase extraction methodologies with liquid chromatography/electrospray/mass spectrometry) and apply them to studying the sources and fate of a select list of PPCPs. Application and improvement of analytical methodologies that can detect non-volatile, polar, water-soluble pharmaceuticals in source waters at levels that could be environmentally significant (at concentrations less than parts per billion, ppb). IAG with USGS ends in FY05. APM 20 due in FY05.Subtask 2: Coordination of interagency research and public outreach activities for PPCPs. Participate on NSTC Health and Environment subcommittee working group on PPCPs. Web site maintenance and expansion, invited technical presentations, invited articles for peer-reviewed journals, interviews for media, responding to public inquirie

Total synthesis and structure-activity investigation of the marine natural product neopeltolide.

PubMed

Custar, Daniel W; Zabawa, Thomas P; Hines, John; Crews, Craig M; Scheidt, Karl A

2009-09-02

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity.

Randomized, non-inferiority trial comparing a nitric oxide releasing solution with a macrolide antibiotic for control of bovine respiratory disease in beef feedlot calves at high-risk of developing respiratory tract disease.

PubMed

Crepieux, T; Miller, C; Regev-Shoshani, G; Schaefer, A; Dorin, C; Alexander, T; Timsit, E

2016-04-01

Nitric oxide, a molecule produced in most mammalian cells, has bactericidal and virucidal properties. Nasal instillation of a nitric oxide releasing solution (NORS) on arrival at the feedlot was recently reported as non-inferior to a parenteral injection of a macrolide antibiotic, tilmicosin, for control of bovine respiratory disease (BRD) in cattle at low-to-moderate risk of developing BRD. The objective of this study was to evaluate whether NORS was non-inferior to tilmicosin for control of BRD in cattle at high-risk of developing BRD (the target population for many BRD control programs). High-risk Angus-cross heifers (n=840) were randomly allocated to 2 treatment groups on arrival at a feedlot and received either NORS or tilmicosin for BRD control. Non-inferiority was assessed by calculating the difference in prevalence of heifers diagnosed with BRD during the first 40 d after arrival between NORS and tilmicosin treatment groups. The non-inferiority margin (δ) was set at 8.5%. Thirty-six and 19% of heifers were diagnosed with BRD in the NORS and tilmicosin groups, respectively. Because the lower bound of the 2-sided 95% confidence interval (CI) of the difference in BRD prevalence between the 2 treatment groups (17%; 95% CI=11-23%) was higher than δ, an inferiority of NORS was concluded. Although on-arrival nasal administration of NORS can be viewed as a more rational control strategy than parental injection of antibiotics, further research is needed to improve NORS efficacy before it can be recommended to prevent BRD in high-risk cattle. Copyright © 2016 Elsevier Ltd. All rights reserved.

Statin therapy in patients with community-acquired pneumonia.

PubMed

Grudzinska, Frances S; Dosanjh, Davinder Ps; Parekh, Dhruv; Dancer, Rachel Ca; Patel, Jaimin; Nightingale, Peter; Walton, Georgia M; Sapey, Elizabeth; Thickett, David R

2017-10-01

Community-acquired pneumonia (CAP) is the leading cause of death from infection in developed countries. There is evidence of an association between improved survival from infection and statin use. The possible beneficial effects of statins are complicated by the common use of macrolide antibiotics for pneumonia, with current guidance suggesting that concurrent macrolide and statin use is contraindicated.We conducted an observational study of statin use in patients with CAP. Of 2,067 patients with CAP, 30.4% were on statin therapy at admission. Statin users were more likely to survive the admission (p<0.001). In addition, we conducted a survey of doctors and found that knowledge regarding concurrent macrolide and statin use was lacking.These data suggest a potential role of statins in the management of CAP. Further research using high-dose statins is required to assess their safe use in subjects with mild to moderate infections. © Royal College of Physicians 2017. All rights reserved.

Total Synthesis and Structure-Activity Investigation of the Marine Natural Product Neopeltolide

PubMed Central

Custar, Daniel W.; Zabawa, Thomas P.; Hines, John; Crews, Craig M.; Scheidt, Karl A.

2009-01-01

The total synthesis and biological evaluation of neopeltolide and analogs are reported. The key bond-forming step utilizes a Lewis acid-catalyzed intramolecular macrocyclization that installs the tetrahydropyran ring and macrocycle simultaneously. Independent of each other, neither the macrolide nor the oxazole side chain substituents of neopeltolide can inhibit the growth of cancer cell lines. The biological data of the analogs indicate that alterations to either the ester side chain or the stereochemistry of the macrolide result in a loss of biological activity. PMID:19663512

SUSCEPTIBILITY OF RESPIRATORY ISOLATES OF STREPTOCOCCUS PNEUMONIAE ISOLATED FROM CHILDREN HOSPITALIZED IN THE CLINICAL CENTER NIS.

PubMed

Dinić, Marina M; Mladenović Antić, Snezana; Kocić, Branislava; Stanković Dordević, Dobrila; Vrbić, Miodrag; Bogdanović, Milena

2016-01-01

Streptococcus pneumoniae is one of the most common causes of respiratory infections. The aim was to study the susceptibility to antimicrobial agents of respiratory isolates ofStreptococcus pneumoniae obtained from hospitalized children. A total of 190 respiratory pneumococcal isolates obtained from children aged from 0 to 14 years were isolated and identified by using standard microbiological methods. Susceptibility to oxacillin, erythromycin, clindamycin, tetracycline, cotrimoxazole, ofloxacin and rifampicin was tested by disc diffusion method. Minimal inhibitory concentrations for amoxicillin and ceftriaxone were determined by means of E test. The macrolide-resistant phenotype was detected by double disc diffusion test. All tested isolates were susceptible to amoxicillin and ceftriaxone. The minimal amoxicillin concentration inhibiting the growth of 50% of isolates and of 90% of isolates was 0.50 microg/ml and 1.0 microg/ml, respectively and the minimal ceftriaxone concentration inhibiting the growth of 50% of isolates and of 90% of isolates was 0.25 microg/ml and 0.50 microg/ml, respectively. Susceptibility to erythromycin and clindamycin was observed in 21.6% and 29.47% of isolates, respectively. The resistence to macrolides-M phenotype was detected in 10.07% of isolates and constitutive macrolide-lincosamide-streptogramin phenotype (constitutive MLS phenotype) was found in 89.93% of isolates. All tested isolates were susceptible to ofloxacin and rifampicin. Amoxicillin could be the therapy of choice in pediatric practice. The macrolides should not be recommended for the empirical therapy of pneumococcal respiratory tract infection in our local area.

Microbiological toxicity of tilmicosin on human colonic microflora in chemostats.

PubMed

Hao, Haihong; Yao, Junping; Wu, Qinghua; Wei, Yajing; Dai, Menghong; Iqbal, Zahid; Wang, Xu; Wang, Yulian; Huang, Lingli; Chen, Dongmei; Tao, Yanfei; Liu, Zhenli; Yuan, Zonghui

2015-10-01

To evaluate the microbiological safety of tilmicosin on human intestinal microflora, four chemostat models of healthy human colonic ecosystems were exposed to tilmicosin (0, 0.436, 4.36, and 43.6 μg/mL) for 7 days. Prior to and during drug exposure, three microbiological endpoints were monitored daily including short-chain fatty acids, bacterial counts and macrolide susceptibility. Colonization resistance of each community was determined by 3 successive daily challenges of Salmonella typhimurium. Genes associated with virulence and macrolide resistance in Enterococcus faecalis were determined by PCR. Transcriptional expression of the virulence gene (gelE) in E. faecalis was determined by real-time RT-PCR. Our results showed that different concentrations of tilmicosin did not disrupt the colonization resistance in each chemostat. During exposure to 4.36 and 43.6 μg/mL tilmicosin, the Bacteroides fragilis population was significantly decreased while the proportion of resistant Enterococci increased. After long-term exposure to the highest concentration (43.6 μg/mL) of tilmicosin, the gelE gene was significantly up-regulated in the high-level macrolide resistant strains that also contained the ermB resistance gene. This study was the first of its kind to evaluate the microbiological toxicity of tilmicosin using a chemostat model. These findings also provide new insight into the co-occurrence of macrolide resistance and virulence in E. faecalis under tilmicosin selective pressure. Copyright © 2015 Elsevier Inc. All rights reserved.

Cellular accumulation of the new ketolide RU 64004 by human neutrophils: comparison with that of azithromycin and roxithromycin.

PubMed Central

Vazifeh, D; Abdelghaffar, H; Labro, M T

1997-01-01

We analyzed the uptake of RU 64004 by human neutrophils (polymorphonuclear leukocytes [PMNs]) relative to those of azithromycin and roxithromycin. RU 64004 was strongly and rapidly accumulated by PMNs, with a cellular concentration/extracellular concentration ratio (C/E) of greater than 200 in the first 5 min, and this was followed by a plateau at 120 to 180 min, with a C/E of 461 +/- 14.8 (10 experiments) at 180 min. RU 64004 uptake was moderately sensitive to external pH, and activation energy was also moderate (63 +/- 3.8 kJ/mol). RU 64004 was mainly located in PMN granules (about 70%) and egressed slowly from loaded cells, owing to avid reuptake. The possibility that PMN uptake of RU 64004 and other macrolides occurs through a carrier-mediated system was suggested by three key results. First, there existed a strong interindividual variability in uptake kinetics, suggesting variability in the numbers or activity of a transport protein. Second, macrolide uptake displayed saturation kinetics characteristic of that of a carrier-mediated transport system: RU 64004 had the highest Vmax value (3,846 ng/2.5 x 10(6) PMNs/5 min) and the lowest Km value (about 28 microM), indicating a high affinity for the transporter. Third, as observed previously with other erythromycin A derivatives, Ni2+ (a blocker of the Na+/Ca2+ exchanger which mediates Ca2+ influx in resting neutrophils) impaired RU 64004 uptake by PMNs, with a 50% inhibitory concentration of about 3.5 mM. In addition, we found that an active process is also involved in macrolide efflux, because verapamil significantly potentiated the release of all three macrolides tested. This effect of verapamil does not seem to be related to an inhibition of Ca2+ influx, because neither EGTA [ethylene glycol-bis (beta-aminoethyl ether)-N,N',N'-tetraacetic acid] nor Ni2+ modified macrolide efflux. The nature and characteristics of the entry- and efflux-mediating carrier systems are under investigation. PMID:9333032

Tilmicosin and tylosin have anti-inflammatory properties via modulation of COX-2 and iNOS gene expression and production of cytokines in LPS-induced macrophages and monocytes.

PubMed

Cao, Xing-Yuan; Dong, Mei; Shen, Jian-Zhong; Wu, Bei-Bei; Wu, Cong-Ming; Du, Xiang-Dang; Wang, Zhuo; Qi, Yi-Tao; Li, Bing-Yu

2006-05-01

Macrolides have been reported to modify the host immune and inflammatory responses both in vivo and in vitro. We examined the in vitro effect of the macrolides tilmicosin and tylosin, which are only used in the veterinary clinic, on the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)) and cytokines by lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and mouse peripheral blood mononuclear cells (PBMCs). Compared with 5 microg/mL, tilmicosin and tylosin concentrations of 10 microg/mL and 20 microg/mL significantly decreased the production of 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)), PGE(2), NO, tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta and IL-6, and increased IL-10 production. Cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) gene expression were also significantly reduced. These results support the opinion that macrolides may exert an anti-inflammatory effect through modulating the synthesis of several mediators and cytokines involved in the inflammatory process.

Group a streptococcus antibiotic resistance in southern Brazil: a 17-year surveillance study.

PubMed

Torres, Rosângela Stadnick Lauth de Almeida; Torres, Renato Pedro de Almeida; Smeesters, Pierre Robert; Palmeiro, Jussara Kasuko; de Messias-Reason, Iara José; Dalla-Costa, Libera M

2011-06-01

Scarce data are available about the antimicrobial resistance of Group A Streptococcus in South America. This study evaluated the antimicrobial susceptibility profile of 1,112 isolates of Group A Streptococcus during the period from 1993 to 2009 in Curitiba city, Brazil. Macrolide-resistant isolates were characterized by emm typing and pulsed-field gel electrophoresis. All isolates were susceptible to penicillin, vancomycin, and tigecycline. On the contrary, 18.6% of the isolates were resistant to tetracycline, presenting a minimum inhibitory concentration (MIC)(50)/MIC(90) of 32/64 mg/L. Erythromycin resistance rose from 1.9% before 2000 to 4% after 2000 and was associated with a marked increased of MIC levels. Simultaneously, both the phenotype and genotype of macrolide resistance were modified as the M phenotypes (mef(A) genotype) were replaced by the cMLS(B) phenotypes (erm(B) genotype). This polyclonal spreading of cMLS(B) macrolide resistance has not been previously observed in South America and should stimulate further epidemiological surveillance in this part of the world.

Cost-effectiveness of antibiotic treatment strategies for community-acquired pneumonia: results from a cluster randomized cross-over trial.

PubMed

van Werkhoven, Cornelis H; Postma, Douwe F; Mangen, Marie-Josee J; Oosterheert, Jan Jelrik; Bonten, Marc J M

2017-01-10

To determine the cost-effectiveness of strategies of preferred antibiotic treatment with beta-lactam/macrolide combination or fluoroquinolone monotherapy compared to beta-lactam monotherapy. Costs and effects were estimated using data from a cluster-randomized cross-over trial of antibiotic treatment strategies, primarily from the reduced third payer perspective (i.e. hospital admission costs). Cost-minimization analysis (CMA) and cost-effectiveness analysis (CEA) were performed using linear mixed models. CMA results were expressed as difference in costs per patient. CEA results were expressed as incremental cost-effectiveness ratios (ICER) showing additional costs per prevented death. A total of 2,283 patients were included. Crude average costs within 90 days from the reduced third payer perspective were €4,294, €4,392, and €4,002 per patient for the beta-lactam monotherapy, beta-lactam/macrolide combination, and fluoroquinolone monotherapy strategy, respectively. CMA results were €106 (95% CI €-697 to €754) for the beta-lactam/macrolide combination strategy and €-278 (95%CI €-991 to €396) for the fluoroquinolone monotherapy strategy, both compared to the beta-lactam monotherapy strategy. The ICER was not statistically significantly different between the strategies. Other perspectives yielded similar results. There were no significant differences in cost-effectiveness of strategies of preferred antibiotic treatment of CAP on non-ICU wards with either beta-lactam monotherapy, beta-lactam/macrolide combination therapy, or fluoroquinolone monotherapy. The trial was registered with ClinicalTrials.gov, number NCT01660204 , on May 2nd, 2012.

Solithromycin for the treatment of community-acquired bacterial pneumonia.

PubMed

Viasus, Diego; Ramos, Oscar; Ramos, Leidy; Simonetti, Antonella F; Carratalà, Jordi

2017-01-01

Community-acquired pneumonia is a major public health problem worldwide. In recent years, there has been an increase in the frequency of resistance to the antimicrobials such as β-lactams or macrolides which have habitually been used against the causative pathogens. Solithromycin, a next-generation macrolide, is the first fluoroketolide with activity against most of the frequently isolated bacteria in community-acquired pneumonia, including typical and atypical bacteria as well as macrolide-resistant Streptococcus pneumoniae. Areas covered: A detailed assessment of the literature relating to the antimicrobial activity, pharmacokinetic/pharmacodynamic properties, efficacy, tolerability and safety of solithromycin for the treatment of community-acquired bacterial pneumonia Expert commentary: Recent randomized controlled phase II/III trials have demonstrated the equivalent efficacy of oral and intravenous solithromycin compared with fluoroquinolones in patients with lower mild-to-moderate respiratory infections, and have shown that systemic adverse events are comparable between solithromycin and alternative treatments. However, studies of larger populations which are able to identify infrequent adverse events are now needed to confirm these findings. On balance, current data supports solithromycin as a promising therapy for empirical treatment in adults with community-acquired bacterial pneumonia.

Global antibiotic resistance in Streptococcus pneumoniae.

PubMed

Adam, Dieter

2002-07-01

The last two decades of the 20th century were marked by an increasing resistance rate among several bacteria. Threat of resistance is present in Staphylococcus spp., Enterococcus spp., Pseudomonas spp. and Enterobacteriaceae, which are the major pathogens in nosocomial infections. In the community, too, increasing resistance can be observed and is attributed mainly (but not exclusively) to Streptococcus pneumoniae and Haemophilus influenzae. To scrutinize this trend, resistance surveillance in the community was established about 10 years ago. One of the multinational, longitudinal surveillance programmes in place is the Alexander Project, which was established in 1992 to monitor the susceptibility of the major community-acquired lower respiratory tract pathogens to a range of antibacterial drugs. The Alexander Project has revealed a tendency towards increasing resistance of S. pneumoniae to penicillin and macrolide therapy. Within Europe, the prevalence of penicillin resistance among S. pneumoniae isolates is particularly high in France and Spain. Macrolide resistance in S. pneumoniae is also a growing problem in European countries such as France, Spain, Belgium and Italy, where the extent of macrolide resistance in S. pneumoniae now exceeds that of penicillin resistance.

Lipase-catalyzed ring-opening polymerization of lactones to polyesters and its mechanistic aspects.

PubMed

Namekawa, S; Suda, S; Uyama, H; Kobayashi, S

1999-01-01

Lipase catalysis induced a ring-opening polymerization of lactones with different ring-sizes. Small-size (four-membered) and medium-size lactones (six- and seven-membered) as well as macrolides (12-, 13-, 16-, and 17-membered) were subjected to lipase-catalyzed polymerization. The polymerization behaviors depended primarily on the lipase origin and the monomer structure. The macrolides showing much lower anionic polymerizability were enzymatically polymerized faster than epsilon-caprolactone. The granular immobilized lipase derived from Candida antartica showed extremely efficient catalysis in the polymerization of epsilon-caprolactone. Single-step terminal functionalization of the polyester was achieved by initiator and terminator methods. The enzymatic polymerizability of lactones was quantitatively evaluated by Michaelis-Menten kinetics.

Impact of antibiotic therapy in severe community-acquired pneumonia: Data from the Infauci study.

PubMed

Pereira, J M; Gonçalves-Pereira, J; Ribeiro, O; Baptista, J P; Froes, F; Paiva, J A

2018-02-01

Antibiotic therapy (AT) is the cornerstone of the management of severe community-acquired pneumonia (CAP). However, the best treatment strategy is far from being established. To evaluate the impact of different aspects of AT on the outcome of critically ill patients with CAP, we performed a post hoc analysis of all CAP patients enrolled in a prospective, observational, multicentre study. Of the 502 patients included, 76% received combination therapy, mainly a β-lactam with a macrolide (80%). AT was inappropriate in 16% of all microbiologically documented CAP (n=177). Hospital and 6months mortality were 34% and 35%. In adjusted multivariate logistic regression analysis, combination AT with a macrolide was independently associated with a reduction in hospital (OR 0.17, 95%CI 0.06-0.51) and 6months (OR 0.21, 95%CI 0.07-0.57) mortality. Prolonged AT (>7days) was associated with a longer ICU (14 vs. 7days; p<0.001) and hospital length of stay (LOS) (25 vs. 17days; p<0.001). Combination AT with a macrolide may be the most suitable AT strategy to improve both short and long term outcome of severe CAP patients. AT >7days had no survival benefit and was associated with a longer LOS. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of Antimicrobial Use in Agricultural Animals on Drug-resistant Foodborne Campylobacteriosis in Humans: A Systematic Literature Review.

PubMed

McCrackin, M A; Helke, Kristi L; Galloway, Ashley M; Poole, Ann Z; Salgado, Cassandra D; Marriott, Bernadette P

2016-10-02

Controversy continues concerning antimicrobial use in food animals and its relationship to drug-resistant infections in humans. We systematically reviewed published literature for evidence of a relationship between antimicrobial use in agricultural animals and drug-resistant foodborne campylobacteriosis in humans. Based on publications from the United States (U.S.), Canada and Denmark from 2010 to July 2014, 195 articles were retained for abstract review, 50 met study criteria for full article review with 36 retained for which data are presented. Two publications reported increase in macrolide resistance of Campylobacter coli isolated from feces of swine receiving macrolides in feed, and one of these described similar findings for tetracyclines and fluoroquinolones. A study in growing turkeys demonstrated increased macrolide resistance associated with therapeutic dosing with Tylan® in drinking water. One publication linked tetracycline-resistant C. jejuni clone SA in raw cow's milk to a foodborne outbreak in humans. No studies that identified farm antimicrobial use also traced antimicrobial-resistant Campylobacter from farm to fork. Recent literature confirms that on farm antibiotic selection pressure can increase colonization of animals with drug-resistant Campylobacter spp. but is inadequately detailed to establish a causal relationship between use of antimicrobials in agricultural animals and prevalence of drug-resistant foodborne campylobacteriosis in humans.

Treatment strategies for Legionella infection.

PubMed

Pedro-Botet, M Luisa; Yu, Victor L

2009-05-01

Given the nonspecific clinical manifestations of Legionnaires' disease and the high mortality of untreated Legionnaires' disease, we recommend routine use of Legionella testing, especially the Legionella urinary antigen test, for all patients with community-acquired pneumonia. This includes patients with ambulatory pneumonia and hospitalized children. Legionella cultures should be more widely available, especially in hospitals where the drinking water is colonized with Legionella. Azithromycin or levofloxacin can be considered as first-line therapy. Other antibiotics including tetracyclines, tigecycline, other fluoroquinolones and other macrolides (especially clarithromycin) are also effective. The clinical response of quinolones may be somewhat more favorable compared to macrolides, but the outcome is similar. If the Legionnaires' disease is hospital-acquired, culturing of the hospital drinking water for Legionella is indicated.

Immuno-modulation and anti-inflammatory benefits of antibiotics: the example of tilmicosin.

PubMed

Buret, André G

2010-01-01

Exaggerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects.

Susceptibility to antimicrobial agents among bovine mastitis pathogens isolated from North American dairy cattle, 2002-2010.

PubMed

Lindeman, Cynthia J; Portis, Ellen; Johansen, Lacie; Mullins, Lisa M; Stoltman, Gillian A

2013-09-01

Approximately 8,000 isolates of Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus uberis, Staphylococcus aureus, and Escherichia coli, isolated by 25 veterinary laboratories across North America between 2002 and 2010, were tested for in vitro susceptibility to beta-lactam, macrolide, and lincosamide drugs. The minimal inhibitory concentrations (MICs) of the beta-lactam drugs remained low against most of the Gram-positive strains tested, and no substantial changes in the MIC distributions were seen over time. Of the beta-lactam antimicrobial agents tested, only ceftiofur showed good in vitro activity against E. coli. The MICs of the macrolides and lincosamides also remained low against Gram-positive mastitis pathogens. While the MIC values given by 50% of isolates (MIC50) for erythromycin and pirlimycin and the streptococci were all low (≤0.5 µg/ml), the MIC values given by 90% of isolates (MIC90) were higher and more variable, but with no apparent increase over time. Staphylococcus aureus showed little change in erythromycin susceptibility over time, but there may be a small, numerical increase in pirlimycin MIC50 and MIC90 values. Overall, the results suggest that mastitis pathogens in the United States and Canada have not shown any substantial changes in the in vitro susceptibility to beta-lactam, macrolide, and lincosamide drugs tested over the 9 years of the study.

Bactericidal Effect and Pharmacodynamics of Cethromycin (ABT-773) in a Murine Pneumococcal Pneumonia Model

PubMed Central

Kim, Myo-Kyoung; Zhou, Wen; Tessier, Pamela R.; Xuan, Dawei; Ye, Min; Nightingale, Charles H.; Nicolau, David P.

2002-01-01

Cethromycin (ABT-773), a new ketolide, possesses potent in vitro activity against Streptococcus pneumoniae. The objective of this study was to investigate the in vivo bactericidal activity of cethromycin against macrolide-susceptible and -resistant S. pneumoniae in a murine pneumonia model and to describe the pharmacodynamic (PD) profile of cethromycin. Eight (two macrolide susceptible, six macrolide resistant) clinical isolates of S. pneumoniae were investigated. Cyclophosphamide administration rendered ICR mice transiently neutropenic prior to intratracheal inoculation with 0.05 ml of an S. pneumoniae suspension containing 107 to 108 CFU/ml. Oral cethromycin was initiated 12 to 14 h postinoculation over a dosage range of 0.1 to 800 mg/kg of body weight/day. Lungs from seven to eight mice per treatment and control groups were collected at 0 and 24 h posttherapy to assess bacterial density. The cumulative mortality (n = 12 to 13) was assessed at 120 h (end of therapy) and at 192 h (3 days posttherapy). Recovery of pneumococci from the lungs of infected animals prior to the initiation of therapy ranged from 4.6 to 7.2 log10 CFU. Growth in untreated control animals over a 24-h study period increased 0.3 to 2.7 log10 CFU. Cethromycin demonstrated a substantial bactericidal effect, regardless of macrolide susceptibility. Correlation between changes in bacterial density (24 h) and survival over both 120 and 192 h were statistically significant. All three PD parameters demonstrated a significant correlation with changes in log10 CFU/lung (Spearman's correlation coefficient, P < 0.001); however, the goodness of fit as assessed with the maximum effect (Emax) model revealed that the maximum concentration of free drug in serum (Cmax free)/MIC and the area under the free drug concentration-time curve (AUCfree)/MIC best explained the relationship between drug exposure and reductions in viable bacterial counts. These data reveal that an approximate cethromycin AUCfree/MIC of 50

Azithromycin 1.5g Over 5 Days Compared to 1g Single Dose in Urethral Mycoplasma genitalium: Impact on Treatment Outcome and Resistance.

PubMed

Read, Tim R H; Fairley, Christopher K; Tabrizi, Sepehr N; Bissessor, Melanie; Vodstrcil, Lenka; Chow, Eric P F; Grant, Mieken; Danielewski, Jennifer; Garland, Suzanne M; Hocking, Jane S; Chen, Marcus Y; Bradshaw, Catriona S

2017-02-01

We evaluated the impact of extended azithromycin (1.5g over 5 days) on selection of macrolide resistance and microbiological cure in men with Mycoplasma genitalium urethritis during 2013-2015 and compared this to cases treated with azithromycin 1g in 2012-2013. Microbiological cure was determined for men with M. genitalium urethritis treated with azithromycin 1.5g using quantitative polymerase chain reaction specific for M. genitalium DNA on samples 14-100 days post-treatment. Pre- and post-treatment macrolide resistance mutations were detected by sequencing the 23 S gene. There was no difference in proportions with microbiological cure between azithromycin 1.5g and 1g: 62/106 (58%; 95% confidence interval [CI], 49%, 68%) and 56/107 (52%; 95%CI 42-62%), P = .34, respectively. Also, there was no difference in the proportion of wild-type 23 S rRNA (presumed macrolide sensitive) infections cured after 1.5g and azithromycin 1g: 28/34 (82%; 95%CI 65-92%) and 49/60 (82%; 95%CI 70-90%), P=1.0, respectively. There was no difference between 1.5g and 1g in the proportions of wild-type infections with post-treatment resistance mutations: 4/34 (12%; 95%CI 3-27%) and 11/60 (18%; 95%CI 10-30%), respectively, P = .40. Pre-treatment resistance was present in 51/98 (52%; 95%CI 42-62%) cases in 2013-2015 compared to 47/107 (44%; 95%CI 34-54%) in 2012-2013, P = .25. Extended azithromycin 1.5g was no more effective than a single 1g dose at achieving cure of M. genitalium urethritis and importantly did not reduce the selection of macrolide resistance. Nonmacrolide and new approaches for the treatment of M. genitalium urethritis are required. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Fidaxomicin

MedlinePlus

... by Clostridium difficile (C. difficile; a type of bacteria that my cause severe or life-threatening diarrhea.) ... medications called macrolide antibiotics. It works by killing bacteria in the intestines.Fidaxomicin will not treat infections ...

Streptococcus agalactiae Causing Neonatal Infections in Portugal (2005-2015): Diversification and Emergence of a CC17/PI-2b Multidrug Resistant Sublineage.

PubMed

Martins, Elisabete R; Pedroso-Roussado, Cristiano; Melo-Cristino, José; Ramirez, Mário

2017-01-01

The molecular characterization of 218 GBS isolates recovered from neonatal invasive infections in Portugal in 2005-2015 revealed the existence of a small number of genetically distinct lineages that were present over a significant time-span. Serotypes III and Ia were dominant in the population, together accounting for >80% of the isolates. Clonal complex 17 included 50% of all isolates, highlighting the importance of the hypervirulent genetic lineage represented by serotype III ST17/ rib /PI-1+PI-2b. Serotype Ia was represented mainly by ST23, previously reported as dominant among invasive disease in non-pregnant adults in Portugal, but also by ST24, showing an increased frequency among late-onset disease. Overall erythromycin resistance was 16%, increasing during the study period ( p < 0.001). Macrolide resistance was overrepresented among CC1 and CC19 isolates ( p < 0.001 and p = 0.008, respectively). While representatives of the hypervirulent CC17 lineage were mostly susceptible to macrolides, we identified for the first time in Europe a recently emerging sublineage characterized by the loss of PI-1 (CC17/PI-2b), simultaneously resistant to macrolides, lincosamides, and tetracycline, also exhibiting high-level resistance to streptomycin and kanamycin. The stability and dominance of CC17 among neonatal invasive infections in the past decades indicates that it is extremely well adapted to its niche; however emerging resistance in this genetic background may have significant implications for the prevention and management of GBS disease.

Effects of tylosin, tilmicosin and tulathromycin on inflammatory mediators in bronchoalveolar lavage fluid of lipopolysaccharide-induced lung injury.

PubMed

Er, Ayse; Yazar, Enver

2012-12-01

The aim of this study was to determine the anti-inflammatory effects of macrolides through kinetic parameters in bronchoalveolar lavage fluid (BALF) of lipopolysaccharide-induced lung injury. Rats were divided into four groups: lipopolysaccharide (LPS), LPS + tylosin, LPS + tilmicosin and LPS + tulathromycin. BALF samples were collected at sampling times. TNF, IL-1β, IL-6, IL-10 and 13,14-dihydro-15-keto-prostaglandin F2α (PGM) and C-reactive protein (CRP) were analysed. Area under the curve (AUC) and maximum plasma concentration (Cmax) values of inflammatory mediators were determined by a pharmacokinetic computer programme. When inflammatory mediator concentrations were compared between the LPS group and other groups for each sampling time, the three macrolides had no pronounced depressor effect on cytokine levels, but they depressed PGM and CRP levels. In addition, tylosin and tilmicosin decreased the AUC0-24 level of TNF, while tilmicosin decreased the AUC0-24 level of IL-10. Tylosin and tulathromycin decreased the AUC0-24 of PGM, and all three macrolides decreased the AUC0-24 of CRP. Especially tylosin and tulathromycin may have more expressed anti-inflammatory effects than tilmicosin, via depressing the production of inflammatory mediators in the lung. The AUC may be used for determining the effects of drugs on inflammation. In this study, the antiinflammatory effects of these antibiotics were evaluated with kinetic parameters as a new and different approach.

Immuno-modulation and anti-inflammatory benefits of antibiotics: The example of tilmicosin

PubMed Central

Buret, André G.

2010-01-01

Exagerated immune responses, such as those implicated in severe inflammatory reactions, are costly to the metabolism. Inflammation and pro-inflammatory mediators negatively affect production in the food animal industry by reducing growth, feed intake, reproduction, milk production, and metabolic health. An ever-increasing number of findings have established that antibiotics, macrolides in particular, may generate anti-inflammatory effects, including the modulation of pro-inflammatory cytokines and the alteration of neutrophil function. The effects are time- and dose-dependent, and the mechanisms responsible for these phenomena remain incompletely understood. Recent studies, mostly using the veterinary macrolide tilmicosin, may have shed new light on the mode of action of some macrolides and their anti-inflammatory properties. Indeed, research findings demonstrate that this compound, amongst others, induces neutrophil apoptosis, which in turn provides anti-inflammatory benefits. Studies using tilmicosin model systems in vitro and in vivo demonstrate that this antibiotic has potent immunomodulatory effects that may explain why at least parts of its clinical benefits are independent of anti-microbial effects. More research is needed, using this antibiotic and others that may have similar properties, to clarify the biological mechanisms responsible for antibiotic-induced neutrophil apoptosis, and how this, in turn, may provide enhanced clinical benefits. Such studies may help establish a rational basis for the development of novel, efficacious, anti-microbial compounds that generate anti-inflammatory properties in addition to their antibacterial effects. PMID:20357951

13C and 15N CP/MAS, 1H-15N SCT CP/MAS and FTIR spectroscopy as tools for qualitative detection of the presence of zwitterionic and non-ionic forms of ansa-macrolide 3-formylrifamycin SV and its derivatives in solid state.

PubMed

Przybylski, Piotr; Pyta, Krystian; Klich, Katarzyna; Schilf, Wojciech; Kamieński, Bohdan

2014-01-01

(13)C, (15)N CP/MAS, including (1)H-(13)C and (1)H-(15)N short contact time CP/MAS experiments, and FTIR methods were applied for detailed structural characterization of ansa-macrolides as 3-formylrifamycin SV (1) and its derivatives (2-6) in crystal and in powder forms. Although HPLC chromatograms for 2/CH3 OH and 2/CH3 CCl3 were the same for rifampicin crystals dissolved in respective solvents, the UV-vis data recorded for them were different in 300-375 nm region. Detailed solid state (13)C and (15)N CP/MAS NMR and FTIR studies revealed that rifampicin (2), in contrast to 3-formylrifamycin SV (1) and its amino derivatives (3-6), can occur in pure non-ionic or zwitterionic forms in crystal and in pure these forms or a mixture of them in a powder. Multinuclear CP/MAS and FTIR studies demonstrated also that 3-6 derivatives were present exclusively in pure zwitterionic forms, both in powder and in crystal. On the basis of the solid state NMR and FTIR studies, two conformers of 3-formylrifamycin SV were detected in powder form due to the different orientations of carbonyl group of amide moiety. The PM6 molecular modeling at the semi-empirical level of theory, allowed visualization the most energetically favorable non-ionic and zwitterionic forms of 1-6 antibiotics, strongly stabilized via intramolecular H-bonds. FTIR studies indicated that the originally adopted forms of these type antibiotics in crystal or in powder are stable in standard laboratory conditions in time. The results presented point to the fact that because of a possible presence of two forms of rifampicin (compound 2), quantification of the content of this antibiotic in relevant pharmaceuticals needs caution. Copyright © 2013 John Wiley & Sons, Ltd.

Pharmaceuticals in Surface Waters and Potential Transfer to Irrigated Food Crops

EPA Science Inventory

A number of pharmaceuticals have been detected in surface waters across the United States. The objective of this study was to evaluate the presence of selected pharmaceuticals (macrolidic antibiotics and pseudoephedrine) and illicit drugs (methamphetamine, Ecstasy) in surface wat...

Development of an Analytical Method to Extract and Detect Pharmaceuticals in Plant Matrices

EPA Science Inventory

It has been shown that human-use macrolide antibiotics (azithromycin, clindamycin, and roxithromycin) are environmentally available in wastewaters, source waters, and biosolids. Since some water authorities use the treated wastewater effluent for non-potable water reuse such as f...

PHARMACEUTICALS IN WASTE STREAMS AND SURFACE WATERS OF THE COLORADO RIVER BASIN

EPA Science Inventory

A number of pharmaceuticals have been detected in surface waters across the United States. The objective of this study was to evaluate the presence of selected pharmaceuticals (macrolidic antibiotics and pseudoephedrine) and illicit drugs (methamphetamine and Ecstasy) in surface ...

Poecillastrin D: a new cytotoxin of the chondropsin class from marine sponge Jaspis serpentina.

PubMed

Takemoto, Daisaku; Takekawa, Yoshihiko; Soest, Rob W M van; Fusetani, Nobuhiro; Matsunaga, Shigeki

2007-11-01

Poecillastrin D (2) was isolated together with poecillastrin C (1) from the deep sea sponge, Japsis serpentina. Its structure was elucidated to be that of a macrolide lactam by spectroscopic methods. These compounds showed potent cytotoxicity against various tumor cell lines.

Tylosin sorption to diatomaceous earth described by Langmuir isotherm and Freundlich isotherm models

USDA-ARS?s Scientific Manuscript database

Tylosin, an antibiotic used for livestock, is a macrolide structurally similar to a number of important, often prescribed human antibiotics. Because of this relationship, tylosin presents a potential threat of antimicrobial resistance from environmental buildup. This work investigated tylosin sorpti...

Draft genome sequence analysis of eight streptogramin-resistant Enterococcus species isolated from animal and environmental sources in the US

USDA-ARS?s Scientific Manuscript database

Here, we present the draft genome sequences of eight streptogramin-resistant Enterococcus spp. (n=8) isolated from animals and an environmental source in the US from 2001-2004. Antimicrobial resistance genes were identified conferring resistance to the macrolide-lincosamide-streptogramins, aminoglyc...

Drug treatment of pneumococcal pneumonia in the elderly.

PubMed

Neralla, Sridhar; Meyer, Keith C

2004-01-01

Streptococcus pneumoniae has been recognised as a major cause of pneumonia since the time of Sir William Osler. Drug-resistant S. pneumoniae (DRSP), which have gradually become resistant to penicillins as well as more recently developed macrolides and fluoroquinolones, have emerged as a consequence of indiscriminate use of antibacterials coupled with the ability of the pneumococcus to adapt to a changing antibacterial milieu. Pneumococci use cell wall choline components to bind platelet-activating factor receptors, colonise mucosal surfaces and evade innate immune defenses. Numerous virulence factors that include hyaluronidase, neuraminidase, iron-binding proteins, pneumolysin and autolysin then facilitate cytolysis of host cells and allow tissue invasion and bloodstream dissemination. Changes in pneumococcal cell wall penicillin-binding proteins account for resistance to penicillins, mutations in the ermB gene cause high-level macrolide resistance and mutations in topoisomerase IV genes coupled with GyrA gene mutations alter DNA gyrase and lead to high-level fluoroquinolone resistance. Risk factors for lower respiratory tract infections in the elderly include age-associated changes in oral clearance, mucociliary clearance and immune function. Other risks for developing pneumonia include poor nutrition, hypoalbuminaemia, bedridden status, aspiration, recent viral infection, the presence of chronic organ dysfunction syndromes including parenchymal lung disease and recent antibacterial therapy. Although the incidence of infections caused by DRSP is rising, the effect of an increase in the prevalence of resistant pneumococci on mortality is not clear. When respiratory infections occur, rapid diagnosis and prompt, empirical administration of appropriate antibacterial therapy that ensures adequate coverage of DRSP is likely to increase the probability of a successful outcome when treating community-acquired pneumonia in elderly patients, particularly those with multiple

Effects of chlorophyll-derived efflux pump inhibitor pheophorbide a and pyropheophorbide a on erythromycin resistance of Staphylococcus aureus, Enterococcus faecalis, Salmonella Typhimurium and Escherichia coli

USDA-ARS?s Scientific Manuscript database

The purpose of this study was to validate the hypothesis that pheophorbide a and pyropheophorbide a reduce erythromycin resistance of reference strains of facultative anaerobic bacteria with multidrug or macrolide efflux pumps, as indicative of their effect on bacteria indigenous to anaerobic swine ...

Extended release amoxicillin/clavulanate: optimizing a product for respiratory infections based on pharmacodynamic principles.

PubMed

Jacobs, Michael R

2005-06-01

Acute bacterial respiratory tract infections cause a great deal of human morbidity and mortality. Treatment guidelines for these infections include macrolides, doxycycline, beta-lactams and beta-lactam/beta-lactamase inhibitor combinations such as amoxicillin/clavulanic acid to provide coverage for the common respiratory pathogens, including penicillin and macrolide nonsusceptible Streptococcus pneumoniae, as well as beta-lactamase-producing Haemophilus influenzae and Moraxella catarrhalis. In response to recent guidelines recommending higher dose amoxicillin to extend coverage to a higher percentage of S. pneumoniae, a new formulation of amoxicillin/clavulanic acid was developed. This formulation includes a higher amoxicillin dose, with part of the amoxicillin dose being in an extended release formulation, without increasing the clavulanate dose, for twice-daily oral treatment of these infections. Clinical studies of community-acquired pneumonia and acute rhinosinusitis have shown that the new formulation is well tolerated and highly efficacious, with clinical outcomes equivalent to comparators.

Drug-Sensing by the Ribosome Induces Translational Arrest via Active Site Perturbation

PubMed Central

Arenz, Stefan; Meydan, Sezen; Starosta, Agata L.; Berninghausen, Otto; Beckmann, Roland; Vázquez-Laslop, Nora; Wilson, Daniel N.

2014-01-01

SUMMARY During protein synthesis, nascent polypeptide chains within the ribosomal tunnel can act in cis to induce ribosome stalling and regulate expression of downstream genes. The Staphylococcus aureus ErmCL leader peptide induces stalling in the presence of clinically important macrolide antibiotics, such as erythromycin, leading to the induction of the downstream macrolide resistance methyltransferase ErmC. Here, we present a cryo-electron microscopy (EM) structure of the erythromycin-dependent ErmCL-stalled ribosome at 3.9 Å resolution. The structure reveals how the ErmCL nascent chain directly senses the presence of the tunnel-bound drug and thereby induces allosteric conformational rearrangements at the peptidyltransferase center (PTC) of the ribosome. ErmCL-induced perturbations of the PTC prevent stable binding and accommodation of the aminoacyl-tRNA at the A-site leading to inhibition of peptide bond formation and translation arrest. PMID:25306253

Predictors for individual patient antibiotic treatment effect in hospitalized community-acquired pneumonia patients.

PubMed

Simonetti, A F; van Werkhoven, C H; Schweitzer, V A; Viasus, D; Carratalà, J; Postma, D F; Oosterheert, J J; Bonten, M J M

2017-10-01

Our objective was to identify clinical predictors of antibiotic treatment effects in hospitalized patients with community-acquired pneumonia (CAP) who were not in the intensive care unit (ICU). Post-hoc analysis of three prospective cohorts (from the Netherlands and Spain) of adult patients with CAP admitted to a non-ICU ward having received either β-lactam monotherapy, β-lactam + macrolide, or a fluoroquinolone-based therapy as empirical antibiotic treatment. We evaluated candidate clinical predictors of treatment effects in multiple mixed-effects models by including interactions of the predictors with empirical antibiotic choice and using 30-day mortality, ICU admission and length of hospital stay as outcomes. Among 8562 patients, empirical treatment was β-lactam in 4399 (51.4%), fluoroquinolone in 3373 (39.4%), and β-lactam + macrolide in 790 (9.2%). Older age (interaction OR 1.67, 95% CI 1.23-2.29, p 0.034) and current smoking (interaction OR 2.36, 95% CI 1.34-4.17, p 0.046) were associated with lower effectiveness of fluoroquinolone on 30-day mortality. Older age was also associated with lower effectiveness of β-lactam + macrolide on length of hospital stay (interaction effect ratio 1.14, 95% CI 1.06-1.22, p 0.008). Older age and smoking could influence the response to specific antibiotic regimens. The effect modification of age and smoking should be considered hypothesis generating to be evaluated in future trials. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Community-Acquired Pneumonia in Adults: Diagnosis and Management.

PubMed

Kaysin, Alexander; Viera, Anthony J

2016-11-01

Community-acquired pneumonia is a leading cause of death. Risk factors include older age and medical comorbidities. Diagnosis is suggested by a history of cough, dyspnea, pleuritic pain, or acute functional or cognitive decline, with abnormal vital signs (e.g., fever, tachycardia) and lung examination findings. Diagnosis should be confirmed by chest radiography or ultrasonography. Validated prediction scores for pneumonia severity can guide the decision between outpatient and inpatient therapy. Using procalcitonin as a biomarker for severe infection may further assist with risk stratification. Most outpatients with community-acquired pneumonia do not require microbiologic testing of sputum or blood and can be treated empirically with a macrolide, doxycycline, or a respiratory fluoroquinolone. Patients requiring hospitalization should be treated with a fluoroquinolone or a combination of beta-lactam plus macrolide antibiotics. Patients with severe infection requiring admission to the intensive care unit require dual antibiotic therapy including a third-generation cephalosporin plus a macrolide alone or in combination with a fluoroquinolone. Treatment options for patients with risk factors for Pseudomonas species include administration of an antipseudomonal antibiotic and an aminoglycoside, plus azithromycin or a fluoroquinolone. Patients with risk factors for methicillin-resistant Staphylococcus aureus should be given vancomycin or linezolid, or ceftaroline in resistant cases. Administration of corticosteroids within 36 hours of hospital admission for patients with severe community-acquired pneumonia decreases the risk of adult respiratory distress syndrome and length of treatment. The 23-valent pneumococcal polysaccharide and 13-valent pneumococcal conjugate vaccinations are both recommended for adults 65 years and older to decrease the risk of invasive pneumococcal disease, including pneumonia.

Prophylactic Antibiotic Use in COPD and the Potential Anti-Inflammatory Activities of Antibiotics.

PubMed

Huckle, Anthony W; Fairclough, Lucy C; Todd, Ian

2018-05-01

Antibiotics have previously demonstrated anti-inflammatory properties, and they have been linked to therapeutic benefit in several pulmonary conditions that feature inflammation. Previous research suggests that these anti-inflammatory properties may be beneficial in the treatment of COPD. This review assesses the potential benefit of prophylactic, long-term, and low-dose antibiotic therapy in COPD, and whether any effects seen are anti-inflammatory in nature. Randomized, controlled trials comparing antibiotic therapy with placebo in subjects with stable COPD were evaluated. Twelve trials involving 3,784 participants and a range of antibiotics were included: azithromycin (6 studies, 1,972 participants), clarithromycin (1 study, 67 participants), erythromycin (3 studies, 254 participants), roxithromycin (1 study, 191 participants), and moxifloxacin (2 studies, 1,198 participants). In vitro, in vivo, and ex vivo experimental study designs exploring the mechanisms via which antibiotics may act in subjects with stable COPD were evaluated. Azithromycin and erythromycin showed the greatest effect in subjects with COPD, with evidence suggesting improvement in exacerbation-related outcomes and health status, as measured by the St George Respiratory Questionnaire. An increase in antibiotic resistance was reported in 2 studies. The macrolide class of antibiotics exhibited convincing anti-inflammatory properties with relevance to COPD, implicating several pathways as potential mechanisms of action. In conclusion, the therapeutic benefit of macrolide antibiotics in subjects with stable COPD is consistent with anti-inflammatory properties, and macrolides should be considered as a potential therapy in COPD. Safety concerns regarding antibiotic resistance need to be addressed before widespread use in clinical practice. Copyright © 2018 by Daedalus Enterprises.

Multicenter cross-sectional observational study of antibiotic resistance and the genotypes of Propionibacterium acnes isolated from Chinese patients with acne vulgaris.

PubMed

Fan, Yukun; Hao, Fei; Wang, Weizhen; Lu, Yonghong; He, Li; Wang, Gang; Chen, Wenchieh

2016-04-01

Antibiotics are widely applied in management of acne vulgaris, which raises the issue of antibiotic resistance. Due to improper application and supervision of antibiotics, antibiotic resistance has become a serious problem in China. So, the efficacy of antimicrobial therapy in acne is unclear without an objective monitor of antibiotic resistance of Propionibacterium acnes. This cross-sectional, multicenter observational study is aimed at understanding the status of antibiotic resistance in P. acnes, investigating the measures of acne management in China and analyzing the genotypes of antibiotic-resistant strains of P. acnes. Altogether, 312 strains of P. acnes were collected from patients in five medical centers across central China after reviewing the corresponding medical history in detail. The samples underwent antibiotic susceptibility assays by agar dilution method with a total of 11 classes of antibiotics being tested. The antibiotic-resistant strains were screened and further analyzed by investigation of the genotypes regarding 23S rRNA, 16S rRNA and erm(X). The predominant resistance occurred in macrolides and lincomycin with an overall resistance rate of 47.8%. The resistance to tetracyclines was scarce with only two cases identified. The emergence of minimum inhibitory concentration elevation for tetracyclines is associated with its application history (P < 0.005). The genotypes of the reported macrolide-lincosamide-streptogramin B resistance strains were also spotted in Chinese subjects while other resistance determinants may also exist. The tetracyclines have been proved to be vastly susceptible while macrolides and lincomycin face a serious resistance status in China. © 2015 Japanese Dermatological Association.

Chronic effects of air pollution on lung function after lung transplantation in the Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) study.

PubMed

Benmerad, Meriem; Slama, Rémy; Botturi, Karine; Claustre, Johanna; Roux, Antoine; Sage, Edouard; Reynaud-Gaubert, Martine; Gomez, Carine; Kessler, Romain; Brugière, Olivier; Mornex, Jean-François; Mussot, Sacha; Dahan, Marcel; Boussaud, Véronique; Danner-Boucher, Isabelle; Dromer, Claire; Knoop, Christiane; Auffray, Annick; Lepeule, Johanna; Malherbe, Laure; Meleux, Frederik; Nicod, Laurent; Magnan, Antoine; Pison, Christophe; Siroux, Valérie

2017-01-01

An irreversible loss in lung function limits the long-term success in lung transplantation. We evaluated the role of chronic exposure to ambient air pollution on lung function levels in lung transplant recipients (LTRs).The lung function of 520 LTRs from the Cohort in Lung Transplantation (COLT) study was measured every 6 months. The levels of air pollutants (nitrogen dioxide (NO 2 ), particulate matter with an aerodynamic cut-off diameter of x µm (PM x ) and ozone (O 3 )) at the patients' home address were averaged in the 12 months before each spirometry test. The effects of air pollutants on forced expiratory volume in 1 s (FEV 1 ) and forced vital capacity (FVC) in % predicted were estimated using mixed linear regressions. We assessed the effect modification of macrolide antibiotics in this relationship.Increased 12-month levels of pollutants were associated with lower levels of FVC % pred (-2.56%, 95% CI -3.86--1.25 for 5 µg·m -3 of PM 10 ; -0.75%, 95% CI -1.38--0.12 for 2 µg·m -3 of PM 2.5 and -2.58%, 95% CI -4.63--0.53 for 10 µg·m -3 of NO 2 ). In patients not taking macrolides, the deleterious association between PM and FVC tended to be stronger and PM 10 was associated with lower FEV 1 Our study suggests a deleterious effect of chronic exposure to air pollutants on lung function levels in LTRs, which might be modified with macrolides. Copyright ©ERS 2017.

Respiratory viral infections in infants with clinically suspected pertussis.

PubMed

Ferronato, Angela E; Gilio, Alfredo E; Vieira, Sandra E

2013-01-01

to evaluate the frequency of respiratory viral infections in hospitalized infants with clinical suspicion of pertussis, and to analyze their characteristics at hospital admission and clinical outcomes. a historical cohort study was performed in a reference service for pertussis, in which the research of respiratory viruses was also a routine for infants hospitalized with respiratory problems. All infants reported as suspected cases of pertussis were included. Tests for Bordetella pertussis (BP) (polymerase chain reaction/culture) and for respiratory viruses (RVs) (immunofluorescence) were performed. Patients who received macrolides before hospitalization were excluded. Clinical data were obtained from medical records. Among the 67 patients studied, BP tests were positive in 44%, and 26% were positive for RV. There was no etiological identification in 35%, and RV combined with BP was identified in 5%. All patients had similar demographic characteristics. Cough followed by inspiratory stridor or cyanosis was a strong predictor of pertussis, as well as prominent leukocytosis and lymphocytosis. Rhinorrhea and dyspnea were more frequent in viral infections. Macrolides were discontinued in 40% of patients who tested positive for RV and negative for BP. the results suggest that viral infection can be present in hospitalized infants with clinical suspicion of pertussis, and etiological tests may enable a reduction in the use of macrolides in some cases. However, the etiological diagnosis of respiratory virus infection, by itself, does not exclude the possibility of infection with BP. Copyright © 2013 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Ureaplasma parvum undergoes selection in utero resulting in genetically diverse isolates colonizing the chorioamnion of fetal sheep.

PubMed

Dando, Samantha J; Nitsos, Ilias; Polglase, Graeme R; Newnham, John P; Jobe, Alan H; Knox, Christine L

2014-02-01

Ureaplasmas are the microorganisms most frequently isolated from the amniotic fluid of pregnant women and can cause chronic intrauterine infections. These tiny bacteria are thought to undergo rapid evolution and exhibit a hypermutatable phenotype; however, little is known about how ureaplasmas respond to selective pressures in utero. Using an ovine model of chronic intraamniotic infection, we investigated if exposure of ureaplasmas to subinhibitory concentrations of erythromycin could induce phenotypic or genetic indicators of macrolide resistance. At 55 days gestation, 12 pregnant ewes received an intraamniotic injection of a nonclonal, clinical Ureaplasma parvum strain followed by (i) erythromycin treatment (intramuscularly, 30 mg/kg/day, n = 6) or (ii) saline (intramuscularly, n = 6) at 100 days gestation. Fetuses were then delivered surgically at 125 days gestation. Despite injecting the same inoculum into all the ewes, significant differences between amniotic fluid and chorioamnion ureaplasmas were detected following chronic intraamniotic infection. Numerous polymorphisms were observed in domain V of the 23S rRNA gene of ureaplasmas isolated from the chorioamnion (but not the amniotic fluid), resulting in a mosaiclike sequence. Chorioamnion isolates also harbored the macrolide resistance genes erm(B) and msr(D) and were associated with variable roxithromycin minimum inhibitory concentrations. Remarkably, this variability occurred independently of exposure of ureaplasmas to erythromycin, suggesting that low-level erythromycin exposure does not induce ureaplasmal macrolide resistance in utero. Rather, the significant differences observed between amniotic fluid and chorioamnion ureaplasmas suggest that different anatomical sites may select for ureaplasma subtypes within nonclonal, clinical strains. This may have implications for the treatment of intrauterine ureaplasma infections.

High Prevalence of Multidrug-Resistant Mycoplasma genitalium in Human Immunodeficiency Virus-Infected Men Who Have Sex With Men in Alabama.

PubMed

Dionne-Odom, Jodie; Geisler, William M; Aaron, Kristal J; Waites, Ken B; Westfall, Andrew O; Van Der Pol, Barbara; Xiao, Li

2018-02-10

We tested for Mycoplasma genitalium in 157 HIV-infected men. Urogenital and rectal prevalence were 10.8% and 6.4%. Macrolide resistance mutations were detected in 70.6% and 80% of urogenital and rectal samples, and fluoroquinolone resistance mutations in 26.7% and 40%, respectively.

Quantification of tylosin and tylosin antibiotic resistance genes in cattle waste

USDA-ARS?s Scientific Manuscript database

Presented is the development of a solid phase extraction (SPE) procedure and a liquid chromatography-mass spectrometry (LC-MS/MS) method for quantifying tylosin in cattle waste samples. Tylosin is a macrolide antibiotic found naturally as a fermentation product of Streptomyces fradiae and is mainly ...

Improving monitoring of erythromycin ribosome methylase genes in swine and cattle manures with gene targeted approaches

USDA-ARS?s Scientific Manuscript database

Macrolide antibiotics are often used in feed for animal industry to prevent diseases. Resistance to these antibiotics is associated with erythromycin ribosome methylase genes (erm genes), which were first discovered in Staphylococcus aureus. The erm gene confers resistance by methylating rRNA at the...

Are Sewage Treatment Plants Promoting Antibiotic Resistance?

EPA Science Inventory

1. Introduction 1.1. How bacteria exhibit resistance 1.1.1. Resistance to -lactams 1.1.2. Resistance to sulphonamides and trimethoprim 1.1.3. Resistance to macrolides 1.1.4. Resistance to fluoroquinolones 1.1.5. Resistance to tetracyclines 1.1.6. Resistance to nitroimidaz...

Campylobacter bacteremia in London: A 44-year single-center study.

PubMed

O'Hara, Geraldine A; Fitchett, Joseph R A; Klein, John L

2017-09-01

Campylobacter species are a well-recognized but rare cause of bloodstream infection. Here we reviewed 41 cases of Campylobacter bloodstream infection occurring at a single center in London over 44years, comprising 0.2% of all recorded episodes during this time period. Patients had a mean age of 46years and, contrasting with previous reports, nearly 50% of our patients did not have significant comorbidities. Ciprofloxacin resistance increased over the study period with 35% of isolates overall being resistant compared with only 3% exhibiting macrolide resistance. Despite a minority of patients receiving appropriate empirical antibiotic therapy, overall mortality was only 7%. Campylobacter bacteremia remains a rare but significant cause of morbidity with a low associated mortality. Underlying immunosuppressive conditions are common but by no means universal. In our setting, macrolides would be favored as empirical agents to treat suspected Campylobacter enteritis, including cases with associated bacteremia. Copyright © 2017 Elsevier Inc. All rights reserved.

Correlation of MIC value and disk inhibition zone diameters in clinical Legionella pneumophila serogroup 1 isolates.

PubMed

Bruin, Jacob P; Diederen, Bram M W; Ijzerman, Ed P F; Den Boer, Jeroen W; Mouton, Johan W

2013-07-01

Routine use of disk diffusion tests for detecting antibiotic resistance in Legionella pneumophila has not been described. The goal of this study was to determine the correlation of MIC values and inhibition zone diameter (MDcorr) in clinical L. pneumophila isolates. Inhibition zone diameter of 183 L. pneumophila clinical isolates were determined for ten antimicrobials. Disk diffusion results were correlated with MICs as determined earlier with E-tests. Overall the correlation of MIC values and inhibition zone diameters (MDcorr) of the tested antimicrobials is good, and all antimicrobials showed a WT distribution. Of the tested fluoroquinolones levofloxacin showed the best MDcorr. All macrolides showed a wide MIC distribution and good MDcorr. The MDcorr for cefotaxim, doxycycline and tigecycline was good, while for rifampicin and moxifloxacin, they were not. Overall good correlation between MIC value and disk inhibition zone were found for the fluoroquinolones, macrolides and cefotaxim. Copyright © 2013 Elsevier Inc. All rights reserved.

Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment

PubMed Central

Nobel, Yael R.; Cox, Laura M.; Kirigin, Francis F.; Bokulich, Nicholas A.; Yamanishi, Shingo; Teitler, Isabel; Chung, Jennifer; Sohn, Jiho; Barber, Cecily M.; Goldfarb, David S.; Raju, Kartik; Abubucker, Sahar; Zhou, Yanjiao; Ruiz, Victoria E.; Li, Huilin; Mitreva, Makedonka; Alekseyenko, Alexander V.; Weinstock, George M.; Sodergren, Erica; Blaser, Martin J.

2015-01-01

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment. PMID:26123276

Metabolic and metagenomic outcomes from early-life pulsed antibiotic treatment.

PubMed

Nobel, Yael R; Cox, Laura M; Kirigin, Francis F; Bokulich, Nicholas A; Yamanishi, Shingo; Teitler, Isabel; Chung, Jennifer; Sohn, Jiho; Barber, Cecily M; Goldfarb, David S; Raju, Kartik; Abubucker, Sahar; Zhou, Yanjiao; Ruiz, Victoria E; Li, Huilin; Mitreva, Makedonka; Alekseyenko, Alexander V; Weinstock, George M; Sodergren, Erica; Blaser, Martin J

2015-06-30

Mammalian species have co-evolved with intestinal microbial communities that can shape development and adapt to environmental changes, including antibiotic perturbation or nutrient flux. In humans, especially children, microbiota disruption is common, yet the dynamic microbiome recovery from early-life antibiotics is still uncharacterized. Here we use a mouse model mimicking paediatric antibiotic use and find that therapeutic-dose pulsed antibiotic treatment (PAT) with a beta-lactam or macrolide alters both host and microbiota development. Early-life PAT accelerates total mass and bone growth, and causes progressive changes in gut microbiome diversity, population structure and metagenomic content, with microbiome effects dependent on the number of courses and class of antibiotic. Whereas control microbiota rapidly adapts to a change in diet, PAT slows the ecological progression, with delays lasting several months with previous macrolide exposure. This study identifies key markers of disturbance and recovery, which may help provide therapeutic targets for microbiota restoration following antibiotic treatment.

Measurement of the Dissociation-Equilibrium Constants for Low Affinity Antibiotic Binding Interaction with Bacterial Ribosomes by the T2 (CPMG) and Line-Broadening Methods

NASA Astrophysics Data System (ADS)

Verdier, L.; Gharbi-Benarous, J.; Bertho, G.; Mauvais, P.; Girault, J.-P.

1999-10-01

In this study the dissociation constants of the low antibiotic-ribosomes interaction were determined by the T2 (CPMG), the Carr-Purcell-Meiboom-Gill spin-echo decay rate and the line-broadening methods. Three MLSB antibiotics were studied, a macrolide roxithromycin, a ketolide HMR 3647 and a lincosamide clindamycin for their weak interaction with three bacterial ribosomes, E. coli, Staphylococcus aureus sensitive and resistant to erythromycin. Nous avons mesuré la constante de dissociation, Kd correspondant à l'interaction faible antibiotique-ribosome bactérien pour des antibiotiques de différentes classes, un macrolide (roxithromycine), un kétolide (HMR 3647) et une lincosamide (clindamycine) avec des ribosomes de différentes souches bactériennes (E. coli, Staphylococcus aureus sensible ou résistant à l'erythromycin) par deux méthodes : l'une basée sur la variation des largeurs de raies et l'autre sur les temps de relaxation transversaux T2 en utilisant une séquence CPMG.

Hydroxylation and hydrolysis: two main metabolic ways of spiramycin I in anaerobic digestion.

PubMed

Zhu, Pei; Chen, Daijie; Liu, Wenbin; Zhang, Jianbin; Shao, Lei; Li, Ji-an; Chu, Ju

2014-02-01

The anaerobic degradation behaviors of five macrolides including spiramycin I, II, III, midecamycin and josamycin by sludge were investigated. Within 32days, 95% of spiramycin I, II or III was degraded, while the remove rate of midecamycin or josamycin was 75%. SPM I degradation was much higher in nutrition supplementation than that just in sludge. The degradation products and processes of spiramycin I were further characterized. Three molecules, designated P-1, P-2 and P-3 according to their order of occurrence, were obtained and purified. Structural determination was then performed by nuclear magnetic resonance and MS/MS spectra, and data indicated that hydroxylation and hydrolysis were main reactions during the anaerobic digestion of spiramycin I. P-1 is the intermediate of hydroxylation, and P-2 is the intermediate of hydrolysis. P-3 is the final product of the both reaction. This study revealed a hydroxylation and hydrolysis mechanism of macrolide in anaerobic digestion. Copyright © 2013 Elsevier Ltd. All rights reserved.

Calibration and controlled flume evaluation of polar organic chemical integrative samplers (POCIS) for tylosin

USDA-ARS?s Scientific Manuscript database

In recent years, the occurrence and fate of emerging contaminants such as antibiotics in the environment have become a concern. One of these is tylosin, a macrolide antibiotic that is used extensively in the swine industry as a growth promoter. The monitoring of these emerging contaminants for asses...

Drug-susceptibility of isolates of Brachyspira hyodysenteriae isolated from colonic mucosal specimens of pigs collected from slaughter houses in Japan in 2009

PubMed Central

KAJIWARA, Keita; KOZAWA, Midori; KANAZAWA, Takuya; UETSUKA, Kouji; NAKAJIMA, Hiromi; ADACHI, Yoshikazu

2015-01-01

Twenty nine isolates identified as Brachyspira hyodysenteriae were most susceptible to carbadox and metronidazole, whereas they were resistant to macrolides. The isolates showed intermediate susceptibility to tiamulin, lincomycin, penicillin G, ampicillin, chloramphenicol, tetracycline, enrofloxacin and valnemulin, with MIC50 values ranging from 0.39 to 3.13. PMID:26596637

Occurrence of antibiotics and their impacts to primary productivity in fishponds around Tai Lake, China.

PubMed

Song, Chao; Zhang, Cong; Fan, Limin; Qiu, Liping; Wu, Wei; Meng, Shunlong; Hu, Gengdong; Kamira, Barry; Chen, Jiazhang

2016-10-01

Antibiotics are widely used to improve the health and yields of farmed animals, including fish, but their use is accompanied by undesirable ecological effects. Relatively little is known about the water-body burden of antibiotics and their influence on primary productivity in aquaculture ecosystem. In this study, antibiotics usage within 24 fishponds, covering 4 areas, sampled 5 times, and having 5 fish species, was investigated surrounding Tai Lake in China. The study analyzed 15 antibiotics (including 5 sulfonamides, 2 quinolones, 3 β-lactams, 3 tetracyclines, 1 amphenicol, and 1 macrolide), and all of them were detected in water samples, with a detection frequency of 2-60%. Sulfonamides were the most prevalent, and concentrations of sulfamethoxazole, sulfamonomethoxine, and florfenicol being over 2000 ng L(-1) in some samples, while the other antibiotics levels ranged from ND (no detection) to 551.18 ng L(-1). Significant differences were observed in antibiotic burden among different regions for total antibiotics, sulfonamides, quinolones, and amphenicols; among time points for quinolones, β-lactams, and tetracyclines; and among species for quinolones and macrolides. Furthermore, basing on the risk quotient (RQ) method, the assessment revealed that florfenicol was of highest risk to algae with RQ values exceeding 0.1, while macrolide erythromycin posed the second highest risk. The partial correlation coefficient between total antibiotics and chlorophyll (a) was -0.035 that clearly indicated total antibiotics were detrimental to green algae growth, while the nutrient input and other physical - chemical factors were much more beneficial. Overall, holistic far-reaching measures of antibiotics control are recommended to preserve aquaculture ecosystem health. Copyright © 2016 Elsevier Ltd. All rights reserved.

Occurrence of antimicrobial agents, drug-resistant bacteria, and genes in the sewage-impacted Vistula River (Poland).

PubMed

Giebułtowicz, Joanna; Tyski, Stefan; Wolinowska, Renata; Grzybowska, Wanda; Zaręba, Tomasz; Drobniewska, Agata; Wroczyński, Piotr; Nałęcz-Jawecki, Grzegorz

2018-02-01

Antimicrobial agents (antimicrobials) are a group of therapeutic and hygienic agents that either kill microorganisms or inhibit their growth. Their occurrence in surface water may reveal harmful effects on aquatic biota and challenge microbial populations. Recently, there is a growing concern over the contamination of surface water with both antimicrobial agents and multidrug-resistant bacteria. The aim of the study was the determination of the presence of selected antimicrobials at specific locations of the Vistula River (Poland), as well as in tap water samples originating from the Warsaw region. Analysis was performed using the liquid chromatography-electrospray ionization-tandem mass spectrometry method. In addition, the occurrence of drug-resistant bacteria and resistance genes was determined using standard procedures. This 2-year study is the first investigation of the simultaneous presence of antimicrobial agents, drug-resistant bacteria, and genes in Polish surface water. In Poland, relatively high concentrations of macrolides are observed in both surface and tap water. Simultaneous to the high macrolide levels in the environment, the presence of the erm B gene, coding the resistance to macrolides, lincosamides, and streptogramin, was detected in almost all sampling sites. Another ubiquitous gene was int1, an element of the 5'-conserved segment of class 1 integrons that encode site-specific integrase. Also, resistant isolates of Enterococcus faecium and Enterococcus faecalis and Gram-negative bacteria were recovered. Multidrug-resistant bacteria isolates of Gram-negative and Enterococcus were also detected. The results show that wastewater treatment plants (WWTP) are the main source of most antimicrobials, resistant bacteria, and genes in the aquatic environment, probably due to partial purification during wastewater treatment processes.

In vitro activity of pazufloxacin, tosufloxacin and other quinolones against Legionella species.

PubMed

Higa, Futoshi; Akamine, Morikazu; Haranaga, Shusaku; Tohyama, Masato; Shinzato, Takashi; Tateyama, Masao; Koide, Michio; Saito, Atsushi; Fujita, Jiro

2005-12-01

The activities of pazufloxacin and tosufloxacin against Legionella spp. were evaluated in vitro and compared with those of other quinolones, macrolides and azithromycin. The conventional MICs were determined by the microbroth dilution method. Intracellular activities of drugs were evaluated by a cfu count. The minimal extracellular concentration inhibiting intracellular growth of bacteria (MIEC) was determined by a colorimetric cytopathic assay. MICs of pazuloxacin and tosufloxacin at which 90% (MIC90) of isolates are inhibited in 76 different Legionella spp. strains (38 ATCC strains and 38 clinical isolates) were 0.032 and 0.016 mg/L, whereas the MIC90s of levofloxacin, ciprofloxacin, garenoxacin, erythromycin, clarithromycin and azithromycin were 0.032, 0.032, 0.032, 2.0, 0.125 and 2.0 mg/L, respectively. Pazufloxacin and tosufloxacin at 4x MIC inhibited intracellular growth of Legionella pneumophila SG1 (80-045 strain), as did other quinolones, clarithromycin and azithromycin, whereas erythromycin at 4x MIC did not. MIECs of pazufloxacin, tosufloxacin, levofloxacin, ciprofloxacin and garenoxacin for the strain were 0.063, 0.004, 0.016, 0.032 and 0.008 mg/L respectively, which were superior to those of macrolides and azithromycin. Pazufloxacin showed potent activity against three additional clinical isolates of L. pneumophila SG1, one clinical isolate each of L. pneumophila SG3 and SG5, as well as Legionella micdadei, Legionella dumoffii and Legionella longbeachae SG1. Pazufloxacin and tosufloxacin, as well as other quinolones, were more potent than macrolides and an azalide. Present data warrant further study on the efficacy of these drugs in the treatment of Legionella infections.

Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia

PubMed Central

Fujii, Hideki; Yagi, Kazuma; Suzuki, Shoji; Hegab, Ahmed E.; Tasaka, Sadatomo; Nakamoto, Nobuhiro; Iwata, Satoshi; Honda, Kenya; Kanai, Takanori; Hasegawa, Naoki; Betsuyaku, Tomoko

2018-01-01

Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr-1+ cell populations in naïve mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post-influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-γ and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr-1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage−HLA-DR−CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides. PMID:29621339

Tilmicosin-induced bovine neutrophil apoptosis is cell-specific and downregulates spontaneous LTB4 synthesis without increasing Fas expression.

PubMed

Lee, Wilson D; Flynn, Andrew N; LeBlanc, Justin M; Merrill, John K; Dick, Paul; Morck, Douglas W; Buret, Andre G

2004-01-01

The pathology of bacterial pneumonia, such as seen in the bovine lung infected with Mannheimia haemolytica, is due to pathogen virulence factors and to inflammation initiated by the host. Tilmicosin is a macrolide effective in treating bacterial pneumonia and recent findings suggest that this antibiotic may provide anti-inflammatory benefits by inducing polymorphonuclear neutrophilic leukocyte (PMN) apoptosis. Using an in vitro bovine system, we examined the cell-specificity of tilmicosin, characterized the changes in spontaneous leukotriene B4 (LTB4) synthesis by PMN exposed to the macrolide, and assessed its effects on PMN Fas expression. Previous findings demonstrated that tilmicosin is able to induce PMN apoptosis. These results were confirmed in this study by the Annexin-V staining of externalized phosphatidylserine and the analysis with flow cytometry. The cell-specificity of tilmicosin was assessed by quantification of apoptosis in bovine PMN, mononuclear leukocytes, monocyte-derived macrophages, endothelial cells, epithelial cells, and fibroblasts cultured with the macrolide. The effect of tilmicosin on spontaneous LTB4 production by PMN was evaluated via an enzyme-linked immunosorbent assay. Finally, the mechanisms of tilmicosin-induced PMN apoptosis were examined by assessing the effects of tilmicosin on surface Fas expression on PMN. Tilmicosin-induced apoptosis was found to be at least partially cell-specific, as PMN were the only cell type tested to die via apoptosis in response to incubation with tilmicosin. PMN incubated with tilmicosin under conditions that induce apoptosis spontaneously produced less LTB4, but did not exhibit altered Fas expression. In conclusion, tilmicosin-induced apoptosis is specific to PMN, inhibits spontaneous LTB4 production, and occurs through a pathway independent of Fas upregulation.

Antimicrobial resistance genes in Actinobacillus pleuropneumoniae, Haemophilus parasuis and Pasteurella multocida isolated from Australian pigs.

PubMed

Dayao, Dae; Gibson, J S; Blackall, P J; Turni, C

2016-07-01

To identify genes associated with the observed antimicrobial resistance in Actinobacillus pleuropneumoniae, Haemophilus parasuis and Pasteurella multocida isolated from Australian pigs. Isolates with known phenotypic resistance to β-lactams, macrolides and tetracycline were screened for the presence of antimicrobial resistance genes. A total of 68 A. pleuropneumoniae, 62 H. parasuis and 20 P. multocida isolates exhibiting phenotypic antimicrobial resistance (A. pleuropneumoniae and P. multocida) or elevated minimal inhibitory concentrations (MICs) (H. parasuis) to any of the following antimicrobial agents - ampicillin, erythromycin, penicillin, tetracycline, tilmicosin and tulathromycin - were screened for a total of 19 associated antimicrobial resistance genes (ARGs) by PCR. The gene bla ROB-1 was found in all ampicillin- and penicillin-resistant isolates, but none harboured the bla TEM-1 gene. The tetB gene was found in 76% (74/97) of tetracycline-resistant isolates, 49/53 A. pleuropneumoniae, 17/30 H. parasuis and 8/14 P. multocida. One A. pleuropneumoniae isolate harboured the tetH gene, but none of the 97 isolates had tetA, tetC, tetD, tetE, tetL, tetM or tetO. A total of 92 isolates were screened for the presence of macrolide resistance genes. None was found to have ermA, ermB, ermC, erm42, mphE, mefA, msrA or msrE. The current study has provided a genetic explanation for the resistance or elevated MIC of the majority of isolates of Australian porcine respiratory pathogens to ampicillin, penicillin and tetracycline. However, the macrolide resistance observed by phenotypic testing remains genetically unexplained and further studies are required. © 2016 Australian Veterinary Association.

Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs

PubMed Central

SOARES, Geisla Mary Silva; FIGUEIREDO, Luciene Cristina; FAVERI, Marcelo; CORTELLI, Sheila Cavalca; DUARTE, Poliana Mendes; FERES, Magda

2012-01-01

Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole) and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of β-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections. PMID:22858695

Group A beta-hemolytic streptococcal pharyngitis and carriage rate among Egyptian children: a case-control study.

PubMed

Abd El-Ghany, Shereen Mohamed; Abdelmaksoud, Abeer Ahmed; Saber, Sally Mohamed; Abd El Hamid, Dalia Hosni

2015-01-01

Improper prescription of antibiotics for treatment of acute pharyngitis predisposes to emergence of a carrier state and antibiotic-resistant strains of group A streptococci (GAS). We sought to identify the frequency and antimicrobial susceptibility patterns of group A streptococci among Egyptian children with acute pharyngitis compared with asymptomatic children. Case-control study conducted from September 2013 to August 2014 at a pediatric outpatient clinic in Egypt. Throat swabs were collected from children with acute pharyngitis and from asymptomatic children. We evaluated the accuracy of McIsaac scores and the rapid antigen detection test (RADT) for diagnosis of GAS pharyngitis with throat culture as a reference test. Antimicrobial susceptibility testing of GAS isolates was done by the disc diffusion method. Of 142 children with acute pharyngitis (cases) and 300 asymptomatic children (controls) (age range, 4-16 years), GAS pharyngitis was diagnosed in 60/142 children (42.2%); 48/300 (16%) were found to be carriers. All GAS isolates in the case group were sensitive to penicillin; however, an MIC90 (0.12 micro g/mL) for penicillin is high and an alarming sign. The resistance rate to macrolides was 70% with the cMLSB phenotype in 65.1%. The sensitivities and specificities were 78.3% and 73.2% for McIsaac score of >=4 and 81.1% and 93.9% for RADT, respectively. GAS isolates in the control group were 100% sensitive to penicillin, while 12.5% and 37.5% were resistant to macrolides and tetracycline, respectively. An increased MIC90 for GAS isolates to penicillin is an alarming sign. A high frequency of resistance to macrolides was also observed.

Comparative in vitro activity of a pharmacokinetically enhanced oral formulation of amoxicillin/clavulanic acid (2000/125 mg twice daily) against 9172 respiratory isolates collected worldwide in 2000.

PubMed

Koeth, Laura M; Jacobs, Michael R; Good, Caryn E; Bajaksouzian, Saralee; Windau, Anne; Jakielaszek, Charles; Saunders, Kay A

2004-11-01

A new, pharmacokinetically enhanced, oral formulation of amoxicillin/clavulanic acid has been developed to overcome resistance in the major bacterial respiratory pathogen Streptococcus pneumoniae, while maintaining excellent activity against Haemophilus influenzae and Moraxella catarrhalis, including beta-lactamase producing strains. This study was conducted to provide in vitro susceptibility data for amoxicillin/clavulanic acid and 16 comparator agents against the key respiratory tract pathogens. Susceptibility testing was performed on 9172 isolates collected from 95 centers in North America, Europe, Australia, and Hong Kong by broth microdilution MIC determination, according to NCCLS methods, using amoxicillin/clavulanic acid and 16 comparator antimicrobial agents. Results were interpreted according to NCCLS breakpoints and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints based on oral dosing regimens. Overall, 93.5% of Streptococcus pneumoniae isolates were susceptible to amoxicillin/clavulanic acid at the current susceptible breakpoint of < or =2 microg/mL and 97.3% at the PK/PD susceptible breakpoint of < or =4 microg/mL for the extended release formulation. Proportions of isolates that were penicillin intermediate and resistant were 13% and 16.5%, respectively, while 25% were macrolide resistant and 21.8% trimethoprim/sulfamethoxazole resistant. 21.9% of Haemophilus influenzae were beta-lactamase producers and 16.8% trimethoprim/sulfamethoxazole resistant, >99% of isolates were susceptible to amoxicillin/clavulanic acid, cefixime, ciprofloxacin and levofloxacin at NCCLS breakpoints. The most active agents against Moraxella catarrhalis were amoxicillin/clavulanic acid, macrolides, cefixime, fluoroquinolones, and doxycycline. Overall, 13% of Streptococcus pyogenes were resistant to macrolides. The extended release formulation of amoxicillin/clavulanic acid has potential for empiric use against many respiratory tract infections worldwide due to its activity

A Compendium for Mycoplasma pneumoniae

PubMed Central

Parrott, Gretchen L.; Kinjo, Takeshi; Fujita, Jiro

2016-01-01

Historically, atypical pneumonia was a term used to describe an unusual presentation of pneumonia. Currently, it is used to describe the multitude of symptoms juxtaposing the classic symptoms found in cases of pneumococcal pneumonia. Specifically, atypical pneumonia is a syndrome resulting from a relatively common group of pathogens including Chlamydophila sp., and Mycoplasma pneumoniae. The incidence of M. pneumoniae pneumonia in adults is less than the burden experienced by children. Transmission rates among families indicate children may act as a reservoir and maintain contagiousness over a long period of time ranging from months to years. In adults, M. pneumoniae typically produces a mild, “walking” pneumonia and is considered to be one of the causes of persistent cough in patients. M. pneumoniae has also been shown to trigger the exacerbation of other lung diseases. It has been repeatedly detected in patients with bronchitis, asthma, chronic obstructive pulmonary disorder, and cystic fibrosis. Recent advances in technology allow for the rapid diagnosis of M. pneumoniae through the use of polymerase chain reaction or rapid antigen tests. With this, more effort has been afforded to identify the causative etiologic agent in all cases of pneumonia. However, previous practices, including the overprescribing of macrolide treatment in China and Japan, have created increased incidence of macrolide-resistant M. pneumoniae. Reports from these countries indicate that >85% of M. pneumoniae pneumonia pediatric cases are macrolide-resistant. Despite its extensively studied past, the smallest bacterial species still inspires some of the largest questions. The developments in microbiology, diagnostic features and techniques, epidemiology, treatment and vaccines, and upper respiratory conditions associated with M. pneumoniae in adult populations are included within this review. PMID:27148202

Impact of Intermittent Preventive Treatment in Pregnancy with Azithromycin-Containing Regimens on Maternal Nasopharyngeal Carriage and Antibiotic Sensitivity of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus: a Cross-Sectional Survey at Delivery

PubMed Central

Unger, Holger W.; Aho, Celestine; Ome-Kaius, Maria; Wangnapi, Regina A.; Umbers, Alexandra J.; Jack, Wanda; Lafana, Alice; Michael, Audrey; Hanieh, Sarah; Siba, Peter; Mueller, Ivo; Greenhill, Andrew R.

2015-01-01

Sulfadoxine-pyrimethamine (SP) plus azithromycin (AZ) (SPAZ) has the potential for intermittent preventive treatment of malaria in pregnancy (IPTp), but its use could increase circulation of antibiotic-resistant bacteria associated with severe pediatric infections. We evaluated the effect of monthly SPAZ-IPTp compared to a single course of SP plus chloroquine (SPCQ) on maternal nasopharyngeal carriage and antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus at delivery among 854 women participating in a randomized controlled trial in Papua New Guinea. Serotyping was performed, and antibiotic susceptibility was evaluated by disk diffusion and Etest. Potential risk factors for carriage were examined. Nasopharyngeal carriage at delivery of S. pneumoniae (SPAZ, 7.2% [30/418], versus SPCQ, 19.3% [84/436]; P < 0.001) and H. influenzae (2.9% [12/418] versus 6.0% [26/436], P = 0.028), but not S. aureus, was significantly reduced among women who had received SPAZ-IPTp. The number of macrolide-resistant pneumococcal isolates was small but increased in the SPAZ group (13.3% [4/30], versus SPCQ, 2.2% [2/91]; P = 0.033). The proportions of isolates with serotypes covered by the 13-valent pneumococcal conjugate vaccine were similar (SPAZ, 10.3% [3/29], versus SPCQ, 17.6% [16/91]; P = 0.352). Although macrolide-resistant isolates were rare, they were more commonly detected in women who had received SPAZ-IPTp, despite the significant reduction of maternal carriage of S. pneumoniae and H. influenzae observed in this group. Future studies on SPAZ-IPTp should evaluate carriage and persistence of macrolide-resistant S. pneumoniae and other pathogenic bacteria in both mothers and infants and assess the clinical significance of their circulation. PMID:25673788

Initial antibiotic selection and patient outcomes: observations from the National Pneumonia Project.

PubMed

Bratzler, Dale W; Ma, Allen; Nsa, Wato

2008-12-01

Guidelines for empirical treatment of hospitalized patients with pneumonia provide specific recommendations for antibiotic selection that are primarily based on findings from observational studies. We conducted a retrospective study of 27,330 community-dwelling, immunocompetent Medicare patients (age, >65 years) with pneumonia who were hospitalized in 1998-1999 and 2000-2001. Associations between initial antimicrobial regimens and risk-adjusted mortality were assessed, accounting for differences in patient characteristics, comorbidities, illness severity, geographic location, and processes of care. Treatment with nonpseudomonal third-generation cephalosporin monotherapy constituted the reference group for comparisons. For patients not in the intensive care unit, initial treatment with fluoroquinolone monotherapy was associated with reduced in-hospital mortality, 14-day mortality, and 30-day mortality rates (adjusted odds ratio [AOR] for 30-day mortality, 0.7; 95% confidence interval [CI], 0.6-0.9; P = .001). The combination of a cephalosporin plus a macrolide was associated with reduced 14-day and 30-day mortality rates (AOR for 30-day mortality, 0.7; 95% CI, 0.6-0.9; P < .001). For intensive care unit patients, the combination of a cephalosporin and a macrolide was associated with reduced in-hospital mortality (AOR, 0.6; 95% CI, 0.3-0.9; P = .018). Initial antimicrobial treatment with the combination of a second- or third-generation cephalosporin and a macrolide or initial treatment with a fluoroquinolone was associated with a reduced 30-day mortality rate, compared with treatment with third-generation cephalosporin monotherapy, among non-intensive care unit patients. Although our results are consistent with other observational studies, controversy continues to exist about the use of nonexperimental cohort studies to demonstrate associations between processes of care, such as antibiotic selection, and patient outcomes.

Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK1322322

PubMed Central

O'Dwyer, Karen; Hackel, Meredith; Hightower, Sarah; Hoban, Daryl; Bouchillon, Samuel; Qin, Donghui; Aubart, Kelly; Zalacain, Magdalena

2013-01-01

GSK1322322 is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (n = 2,370), Moraxella catarrhalis (n = 115), Streptococcus pneumoniae (n = 947), Streptococcus pyogenes (n = 617), and Staphylococcus aureus (n = 940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC90 of 1 μg/ml against M. catarrhalis and 4 μg/ml against H. influenzae, with 88.8% of β-lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by ≤4 μg/ml of GSK1322322, with an MIC90 of 2 μg/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC90 of 1 μg/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains, with an MIC90 of 0.5 μg/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC90 of 4 μg/ml in all cases. Time-kill studies showed that GSK1322322 had bactericidal activity against S. pneumoniae, H. influenzae, S. pyogenes, and S. aureus, demonstrating a ≥3-log10 decrease in the number of CFU/ml at 4× MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK1322322 represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens. PMID:23478958

Results from the Survey of Antibiotic Resistance (SOAR) 2011-13 in Ukraine.

PubMed

Feshchenko, Y; Dzyublik, A; Pertseva, T; Bratus, E; Dzyublik, Y; Gladka, G; Morrissey, I; Torumkuney, D

2016-05-01

To determine the antibiotic susceptibility of respiratory isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2011-13 from Ukraine. MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. A total of 134 isolates of S. pneumoniae and 67 of H. influenzae were collected from eight sites in Ukraine. Overall, 87.3% of S. pneumoniae were penicillin susceptible by CLSI oral breakpoints and 99.3% by CLSI iv breakpoints. Susceptibility to amoxicillin/clavulanic acid (amoxicillin), ceftriaxone and levofloxacin was 100% by CLSI and PK/PD breakpoints. Cephalosporin and macrolide susceptibility was ≥95.5% and 88.1%, respectively using CLSI breakpoints. Trimethoprim/sulfamethoxazole was essentially inactive against pneumococci. Of the 67 H. influenzae tested, 4.5% were β-lactamase positive and all H. influenzae were fully susceptible to amoxicillin/clavulanic acid, ceftriaxone, ciprofloxacin, cefixime and levofloxacin (all breakpoints). Cefuroxime susceptibility was 100% by CLSI but 73.1% by EUCAST and PK/PD breakpoints. A discrepancy was found in macrolide susceptibility between CLSI (∼100% susceptible), EUCAST (22%-43% susceptible) and PK/PD (0%-22% susceptible) breakpoints. Trimethoprim/sulfamethoxazole was poorly active (59.7% susceptible). Generally, antibiotic resistance was low in respiratory pathogens from Ukraine. However, only amoxicillin/clavulanic acid (amoxicillin), ceftriaxone and levofloxacin were fully active against both species. Trimethoprim/sulfamethoxazole was the least active, particularly against S. pneumoniae. Some susceptibility differences were apparent between CLSI, EUCAST and PK/PD breakpoints, especially with macrolides against H. influenzae. These data suggest that further efforts are required to harmonize these international breakpoints. Future studies are warranted to monitor continued low resistance levels in Ukraine

In vitro pharmacodynamics of gamithromycin against Mycoplasma mycoides subspecies mycoides Small Colony.

PubMed

Mitchell, John D; Goh, Shan; McKellar, Quintin A; McKeever, Declan J

2013-09-01

Mycoplasma mycoides mycoides Small Colony (MmmSC) is the causative agent of contagious bovine pleuropneumonia (CBPP), which is responsible for major economic losses in sub-Saharan Africa. Current control relies on live attenuated vaccines, which are of limited efficacy, and antimicrobials are now being assessed as an alternative or adjunct to vaccination. The objective of this study was to determine the in vitro effector kinetics of the macrolide antimicrobial, gamithromycin, against MmmSC in artificial medium and adult bovine serum. Furthermore, it was determined if any differences in gamithromycin activity between these two matrices were mirrored by the older macrolides, tylosin and tilmicosin. Minimum inhibitory concentrations (MICs) for gamithromycin, tylosin and tilmicosin against MmmSC strains B237 and Tan8 were determined in artificial medium and serum. Time-kill curves were constructed at concentrations corresponding to multiples of the MIC for all three macrolides in artificial medium and for gamithromycin in serum. Data were fitted to sigmoid Emax models. Post-antibiotic effects (PAE) were established by exposing strain B237 to antimicrobials at 10× MIC for 1h and monitoring mycoplasma growth thereafter. MICs for gamithromycin, tylosin and tilmicosin were 64-, 8- and 64-fold lower, respectively, in serum than in artificial medium at an inoculum size of 10(6)cfu/mL B237. A similar pattern emerged for Tan8. All three antimicrobials were mycoplasmastatic with maximum effects of -0.44, -0.32 and -0.49log10(cfu/mL) units for gamithromycin, tylosin and tilmicosin, respectively, against B237 in artificial medium. Tylosin and tilmicosin elicited longer PAEs than gamithromycin. In conclusion, gamithromycin, tylosin and tilmicosin all demonstrated in vitro efficacy against MmmSC and represent potential candidates for clinical studies to assess their therapeutic effect against CBPP. Copyright © 2013 Elsevier Ltd. All rights reserved.

Pneumococcal antimicrobial resistance: therapeutic strategy and management in community-acquired pneumonia.

PubMed

Aspa, Javier; Rajas, Olga; de Castro, Felipe Rodríguez

2008-02-01

Streptococcus pneumoniae has been consistently shown to represent the most frequent causative agent of community-acquired pneumonia (CAP) and pneumococcal antibiotic resistance towards different families of antibiotics continues to be a much-debated issue. Microbial resistance causes a great deal of confusion in choosing an empirical treatment for pneumonia and this makes it necessary to know which factors actually determine the real impact of antimicrobial resistance on the outcome of pneumococcal infections. Several different aspects have to be taken into account when analyzing this matter, such as the study design, the condition of the patient at the time of diagnosis, the choice of the initial antimicrobial regimen (combination or monotherapy) and the pharmacokinetic/pharmacodynamic variables of the chosen antibiotic. It is generally accepted that in the treatment of beta-lactam-resistant pneumococcal infections, the use of standard antipneumococcal beta-lactam agents is unlikely to impact negatively on the outcome of CAP when appropriate agents are given in sufficient doses. As a general rule, for infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will be effective; in the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment although higher dosages are recommended; finally, infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In areas of high prevalence of high-level macrolide resistance, empirical monotherapy with a macrolide is not optimal for the treatment of hospitalised patients with moderate or moderately-severe CAP. Fluoroquinolones are considered to be excellent antibiotics in the treatment of pneumococcal CAP in adults, but their general recommendation has been withheld due to fears of a widespread development

Association between Antibiotic Prescribing in Pregnancy and Cerebral Palsy or Epilepsy in Children Born at Term: A Cohort Study Using The Health Improvement Network

PubMed Central

Meeraus, Wilhelmine Hadler; Petersen, Irene; Gilbert, Ruth

2015-01-01

Background Between 19%-44% pregnant women are prescribed antibiotics during pregnancy. A single, large randomised-controlled-trial (ORACLE Childhood Study II) found an increased risk of childhood cerebral palsy and possibly epilepsy following prophylactic antibiotic use in pregnant women with spontaneous preterm labour. We ascertained whether this outcome could be reproduced across the population of babies delivered at term and prospectively followed in primary-care using data from The Health Improvement Network. Methods We determined the risk of cerebral palsy or epilepsy in children whose mothers were prescribed antibiotics during pregnancy using a cohort of 195,909 women linked to their live, term-born, singleton children. We compared the effect of antibiotic class, number of courses and timing of prescribing in pregnancy. Analyses were adjusted for maternal risk factors (e.g. recorded infection, age, chronic conditions, social deprivation, smoking status). Children were followed until age seven years or cessation of registration with the primary-care practitioner. Results In total, 64,623 (33.0%) women were prescribed antibiotics in pregnancy and 1,170 (0.60%) children had records indicating cerebral palsy or epilepsy. Adjusted analyses showed no association between prescribing of any antibiotic and cerebral palsy or epilepsy (adj.HR 1.04, 95%CI 0.91–1.19). However, compared with penicillins, macrolides were associated with an increased risk of cerebral palsy or epilepsy (adj.HR 1.78, 95%CI 1.18–2.69; number needed to harm 153, 95%CI 71–671). Conclusions We found no overall association between antibiotic prescribing in pregnancy and cerebral palsy and/or epilepsy in childhood. However, our finding of an increased risk of cerebral palsy or epilepsy associated with macrolide prescribing in pregnancy adds to evidence that macrolide use is associated with serious harm. PMID:25807115

Effect of in-feed administration and withdrawal of tylosin phosphate on antibiotic resistance in enterococci isolated from feedlot steers

PubMed Central

Beukers, Alicia G.; Zaheer, Rahat; Cook, Shaun R.; Stanford, Kim; Chaves, Alexandre V.; Ward, Michael P.; McAllister, Tim A.

2015-01-01

Tylosin phosphate is a macrolide commonly administered to cattle in North America for the control of liver abscesses. This study investigated the effect of in-feed administration of tylosin phosphate to cattle at subtherapeutic levels and its subsequent withdrawal on macrolide resistance using enterococci as an indicator bacterium. Fecal samples were collected from steers that received no antibiotics and steers administered tylosin phosphate (11 ppm) in-feed for 197 days and withdrawn 28 days before slaughter. Enterococcus species isolated from fecal samples were identified through sequencing the groES-EL intergenic spacer region and subject to antimicrobial susceptibility testing, identification of resistance determinants and pulsed-field gel electrophoresis profiling. Tylosin increased (P < 0.05) the proportion of eryR and tylR enterococci within the population. Just prior to its removal, the proportion of eryR and tylR resistant enterococci began decreasing and continued to decrease after tylosin was withdrawn from the diet until there was no difference (P > 0.05) between treatments on d 225. This suggests that antibiotic withdrawal prior to slaughter contributes to a reduction in the proportion of macrolide resistant enterococci entering the food chain. Among the 504 enterococci isolates characterized, Enterococcus hirae was found to predominate (n = 431), followed by Enterococcus villorum (n = 32), Enterococcus faecium (n = 21), Enterococcus durans (n = 7), Enterococcus casseliflavus (n = 4), Enterococcus mundtii (n = 4), Enterococcus gallinarum (n = 3), Enterococcus faecalis (n = 1), and Enterococcus thailandicus (n = 1). The diversity of enterococci was greater in steers at arrival than at exit from the feedlot. Erythromycin resistant isolates harbored the erm(B) and/or msrC gene. Similar PFGE profiles of eryR E. hirae pre- and post-antibiotic treatment suggest that increased abundance of eryR enterococci after administration of tylosin phosphate reflects

Bacteria evade immune recognition via TLR13 and binding of their 23S rRNA by MLS antibiotics by the same mechanisms

PubMed Central

Hochrein, Hubertus; Kirschning, Carsten J.

2013-01-01

The immune system recognizes pathogens and other danger by means of pattern recognition receptors. Recently, we have demonstrated that the orphan Toll-like receptor 13 (TLR13) senses a defined sequence of the bacterial rRNA and that bacteria use specific mechanisms to evade macrolide lincosamide streptogramin (MLS) antibiotics detection via TLR13. PMID:23802068

Regional Resistance Surveillance Program Results for 12 Asia-Pacific Nations (2011)

PubMed Central

Mendes, Rodrigo E.; Mendoza, Myrna; Banga Singh, Kirnpal K.; Castanheira, Mariana; Bell, Jan M.; Turnidge, John D.; Lin, Stephen S. F.

2013-01-01

The Regional Resistance Surveillance program monitored susceptibility rates and developing resistance by geographic region, including 12 Asia-Pacific (APAC) countries. Reference broth microdilution methods for susceptibility/interpretations were applied, processing 5,053 strains. Among Staphylococcus aureus isolates (37% methicillin-resistant S. aureus [MRSA], highest in South Korea [73%]), linezolid (LZD), tigecycline (TIG), and vancomycin were 100% active, but 33 and 34% of strains were levofloxacin (LEV) or macrolide resistant, respectively. Streptococcus pneumoniae was most resistant to β-lactams and macrolides (45%) but was LZD, LEV, and TIG susceptible (>98%). Extended-spectrum β-lactamase (ESBL) phenotype rates in Escherichia coli and Klebsiella spp. were 48 and 47%, respectively, and were highest in Taiwan, at 75 to 91%. The best anti-ESBL-phenotype agents were amikacin (81 to 96% susceptible), colistin (COL; >98%), TIG (>98%), and carbapenems (81 to 97%). Pseudomonas aeruginosa showed ≥20% resistance to all drugs except COL (99% susceptible). In conclusion, endemic evolving antimicrobial resistances in APAC nations show compromised roles for many commonly used antimicrobials. PMID:23959306

Fluorescent Probes of the Apoptolidins and their Utility in Cellular Localization Studies

PubMed Central

DeGuire, Sean M.; Earl, David C.; Du, Yu; Crews, Brenda A.; Jacobs, Aaron T.; Ustione, Alessandro; Daniel, Cristina; Chong, Katherine; Marnett, Lawrence J.; Piston, David W.; Bachmann, Brian O.; Sulikowski, Gary A.

2014-01-01

Apoptolidin A has been described as among the top 0.1% most cell selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties located at C9 and C27, respectively. In contrast to apoptolidin A, the aglycone (apoptolidinone) shows no cytotoxicity (>10 μM) when evaluated against several tumor cell lines. Apoptolidin H, the C27 deglycosylated analog of apoptolidin A, was produced by targeted glycosyl transferase gene deletion and displayed sub-micromolar activity against H292 lung carcinoma cells. Selective esterification of the C2′ hydroxyl group of apoptolidins A and H with 5-azidopentanoic acid afforded azido functionalized derivatives of potency equal to their parent macrolide. Azido apoptolidins readily underwent strain-promoted alkyne azido cycloaddition (SPAAC) reactions to provide access to fluorescent and biotin functionalized probes. Microscopy studies demonstrate apoptolidins A and H localize in the mitochondria of H292 human lung carcinoma cells. PMID:25430909

Multiclass determination and confirmation of antibiotic residues in honey using LC-MS/MS.

PubMed

Lopez, Mayda I; Pettis, Jeffery S; Smith, I Barton; Chu, Pak-Sin

2008-03-12

A multiclass method has been developed for the determination and confirmation in honey of tetracyclines (chlortetracycline, doxycycline, oxytetracycline, and tetracycline), fluoroquinolones (ciprofloxacin, danofloxacin, difloxacin, enrofloxacin, and sarafloxacin), macrolides (tylosin), lincosamides (lincomycin), aminoglycosides (streptomycin), sulfonamides (sulfathiazole), phenicols (chloramphenicol), and fumagillin residues using liquid chromatography tandem mass spectrometry (LC-MS/MS). Erythromycin (a macrolide) and monensin (an ionophore) can be detected and confirmed but not quantitated. Honey samples (approximately 2 g) are dissolved in 10 mL of water and centrifuged. An aliquot of the supernatant is used to determine streptomycin. The remaining supernatant is filtered through a fine-mesh nylon fabric and cleaned up by solid phase extraction. After solvent evaporation and sample reconstitution, 15 antibiotics are assayed by LC-MS/MS using electrospray ionization (ESI) in positive ion mode. Afterward, chloramphenicol is assayed using ESI in negative ion mode. The method has been validated at the low part per billion levels for most of the drugs with accuracies between 65 and 104% and coefficients of variation less than 17%. The evaluation of matrix effects caused by honey of different floral origin is presented.

Production and characterization of monoclonal antibodies against the antibiotic tilmicosin.

PubMed

Beier, Ross C; Creemer, Lawrence C; Ziprin, Richard L; Nisbet, David J

2005-12-14

Monoclonal antibodies (Mabs) were developed that specifically bind tilmicosin. Keyhole limpet hemocyanin (KLH) and bovine serum albumin (BSA) conjugates were used for the immunogen and plate coating antigen, respectively. The conjugates were synthesized by different methods, resulting in different linkages. Six hybridoma cell lines were isolated that produced Mabs that competed with tilmicosin, and have IgG1 isotype. The Til-1 and Til-5 Mabs had IC50 values for tilmicosin of 9.6 and 6.4 ng/well (48 and 32 ng/mL), respectively, and limits of detection at IC20 of 1.84 and 0.89 ng/well (9.2 and 4.45 ng/mL), respectively. The Mabs demonstrated high cross-reactivity to the macrolides containing 3,5-dimethylpiperidine at C20 and the amino sugar at C5. No cross-reactivity was observed for tylosin and other macrolides that did not contain 3,5-dimethylpiperidine. A competitive enzyme-linked immunosorbent assay (ELISA) was developed for the antibiotic tilmicosin by use of the developed Mabs. These Mabs may be excellent candidates for the determination and immunolocalization of tilmicosin.

Exploring the Role of CYP3A4 Mediated Drug Metabolism in the Pharmacological Modulation of Nitric Oxide Production

PubMed Central

Pérez-del Palacio, José; Díaz, Caridad; Vergara, Noemí; Algieri, Francesca; Rodríguez-Nogales, Alba; de Pedro, Nuria; Rodríguez-Cabezas, M. Elena; Genilloud, Olga; Gálvez, Julio; Vicente, Francisca

2017-01-01

Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide. In vitro systems based in human liver microsomes and activated mouse macrophages were developed for these purposes. Additionally in vitro production the hepatic metabolites of dual inhibitor, roxithromycin, was investigated achieving the identification and isolation of main hepatic biotransformation products. Our results suggested that for some macrolide compounds, the cytochrome P450 3A4 derived drug metabolites have an important effect on nitric oxide production and might critically contribute to the pharmacological immunomodulatory activity observed. PMID:28446877

Phenotypic and Genotypic Antimicrobial Resistance Profiles of Campylobacter jejuni Isolated from Cattle, Sheep, and Free-Range Poultry Faeces

PubMed Central

Oporto, Beatriz; Juste, Ramón A.; Hurtado, Ana

2009-01-01

Minimum inhibitory concentrations (MIC) of 13 antimicrobial agents were determined by broth microdilution for 72 Campylobacter jejuni strains from livestock. Twenty-three (31.9%) isolates were fully susceptible; all isolates were susceptible to erythromycin, chloramphenicol, streptomycin, gentamicin, sulfamethoxazole, and meropenem, and all but one to kanamycin. Resistance to quinolones was highest (52.8%), reaching similar values among poultry, dairy cattle, and sheep, but lower in beef cattle. Resistance to tetracyclines (48.6%) was mainly associated to dairy cattle and β-lactams (26.4%) to poultry. Multidrug resistance was mainly detected in dairy cattle (28.6%) and poultry (21.0%), whereas beef cattle had the highest percentage of fully susceptible isolates. Two real-time PCR assays to detect point mutations associated to quinolone (C257T in the gyrA gene) and macrolide (A2075G in the 23S rRNA genes) resistance were developed and validated on these strains. The analysis of a further set of 88 isolates by real-time PCR confirmed the absence of macrolide resistance and demonstrated the reproducibility and processability of the assay. PMID:20224816

World Health Organization Ranking of Antimicrobials According to Their Importance in Human Medicine: A Critical Step for Developing Risk Management Strategies to Control Antimicrobial Resistance From Food Animal Production.

PubMed

Collignon, Peter C; Conly, John M; Andremont, Antoine; McEwen, Scott A; Aidara-Kane, Awa; Agerso, Yvonne; Andremont, Antoine; Collignon, Peter; Conly, John; Dang Ninh, Tran; Donado-Godoy, Pilar; Fedorka-Cray, Paula; Fernandez, Heriberto; Galas, Marcelo; Irwin, Rebecca; Karp, Beth; Matar, Gassan; McDermott, Patrick; McEwen, Scott; Mitema, Eric; Reid-Smith, Richard; Scott, H Morgan; Singh, Ruby; DeWaal, Caroline Smith; Stelling, John; Toleman, Mark; Watanabe, Haruo; Woo, Gun-Jo

2016-10-15

Antimicrobial use in food animals selects for antimicrobial resistance in bacteria, which can spread to people. Reducing use of antimicrobials-particularly those deemed to be critically important for human medicine-in food production animals continues to be an important step for preserving the benefits of these antimicrobials for people. The World Health Organization ranking of antimicrobials according to their relative importance in human medicine was recently updated. Antimicrobials considered the highest priority among the critically important antimicrobials were quinolones, third- and fourth-generation cephalosporins, macrolides and ketolides, and glycopeptides. The updated ranking allows stakeholders in the agriculture sector and regulatory agencies to focus risk management efforts on drugs used in food animals that are the most important to human medicine. In particular, the current large-scale use of fluoroquinolones, macrolides, and third-generation cephalosporins and any potential use of glycopeptides and carbapenems need to be addressed urgently. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Effect of biochar amendment on tylosin adsorption-desorption and transport in two different soils

Treesearch

Chang Yoon Jeong; Jim J. Wang; Syam K. Dodla; Thomas L. Eberhardt; Les Groom

2012-01-01

The role of biochar as a soil amendment on the adsorption¨C desorption and transport of tylosin, a macrolide class of veterinary antibiotic, is little known. In this study, batch and column experiments were conducted to investigate the adsorption kinetics and transport of tylosin in forest and agricultural corn field soils amended with hardwood and softwood biochars....

In Vitro Capability of Faropenem To Select for Resistant Mutants of Streptococcus pneumoniae and Haemophilus influenzae▿ †

PubMed Central

Kosowska-Shick, Klaudia; Clark, Catherine; Credito, Kim; Dewasse, Bonifacio; Beachel, Linda; Ednie, Lois; Appelbaum, Peter C.

2008-01-01

When tested against nine strains of pneumococci and six of Haemophilus influenzae of various resistotypes, faropenem failed to select for resistant mutants after 50 days of consecutive subculture in subinhibitory concentrations. Faropenem also yielded low rates of spontaneous mutations against all organisms of both species. By comparison, resistant clones were obtained with macrolides, ketolides, and quinolones. PMID:18086853

In vitro capability of faropenem to select for resistant mutants of Streptococcus pneumoniae and Haemophilus influenzae.

PubMed

Kosowska-Shick, Klaudia; Clark, Catherine; Credito, Kim; Dewasse, Bonifacio; Beachel, Linda; Ednie, Lois; Appelbaum, Peter C

2008-02-01

When tested against nine strains of pneumococci and six of Haemophilus influenzae of various resistotypes, faropenem failed to select for resistant mutants after 50 days of consecutive subculture in subinhibitory concentrations. Faropenem also yielded low rates of spontaneous mutations against all organisms of both species. By comparison, resistant clones were obtained with macrolides, ketolides, and quinolones.

Draft Genome Sequence of a Canine Isolate of Methicillin-Resistant Staphylococcus haemolyticus

PubMed Central

Wigmore, Sarah M.; Wareham, David W.

2017-01-01

ABSTRACT Staphylococcus haemolyticus strain SW007 was isolated from a nasal swab taken from a healthy dog. The isolate is resistant to methicillin, mupirocin, macrolides, and sulfonamides. The SW007 draft genome is 2,325,410 bp and contains 2,277 coding sequences, including 60 tRNAs and nine complete rRNA-coding regions. PMID:28385855

Effects of national antibiotic stewardship and infection control strategies on hospital-associated and community-associated meticillin-resistant Staphylococcus aureus infections across a region of Scotland: a non-linear time-series study.

PubMed

Lawes, Timothy; Lopez-Lozano, José-María; Nebot, Cesar A; Macartney, Gillian; Subbarao-Sharma, Rashmi; Dare, Ceri Rj; Wares, Karen D; Gould, Ian M

2015-12-01

Restriction of antibiotic consumption to below predefined total use thresholds might remove the selection pressure that maintains antimicrobial resistance within populations. We assessed the effect of national antibiotic stewardship and infection prevention and control programmes on prevalence density of meticillin-resistant Staphylococcus aureus (MRSA) infections across a region of Scotland. This non-linear time-series analysis and quasi-experimental study explored ecological determinants of MRSA epidemiology among 1,289,929 hospital admissions and 455,508 adults registered in primary care in northeast Scotland. Interventions included antibiotic stewardship to restrict use of so-called 4C (cephalosporins, co-amoxiclav, clindamycin, and fluoroquinolones) and macrolide antibiotics; a hand hygiene campaign; hospital environment inspections; and MRSA admission screening. Total effects were defined as the difference between scenarios with intervention (observed) and without intervention (predicted from time-series models). The primary outcomes were prevalence density of MRSA infections per 1000 occupied bed days (OBDs) in hospitals or per 10,000 inhabitants per day (IDs) in the community. During antibiotic stewardship, use of 4C and macrolide antibiotics fell by 47% (mean decrease 224 defined daily doses [DDDs] per 1000 OBDs, 95% CI 154-305, p=0·008) in hospitals and 27% (mean decrease 2·52 DDDs per 1000 IDs, 0·65-4·55, p=0·031) in the community. Hospital prevalence densities of MRSA were inversely related to intensified infection prevention and control, but positively associated with MRSA rates in neighbouring hospitals, importation pressures, bed occupancy, and use of fluoroquinolones, co-amoxiclav, and third-generation cephalosporins, or macrolide antibiotics that exceeded hospital-specific thresholds. Community prevalence density was predicted by hospital MRSA rates and above-threshold use of macrolides, fluoroquinolones, and clindamycin. MRSA prevalence

Draft Genome Sequence of a Canine Isolate of Methicillin-Resistant Staphylococcus haemolyticus.

PubMed

Bean, David C; Wigmore, Sarah M; Wareham, David W

2017-04-06

Staphylococcus haemolyticus strain SW007 was isolated from a nasal swab taken from a healthy dog. The isolate is resistant to methicillin, mupirocin, macrolides, and sulfonamides. The SW007 draft genome is 2,325,410 bp and contains 2,277 coding sequences, including 60 tRNAs and nine complete rRNA-coding regions. Copyright © 2017 Bean et al.

Complete genome sequence of Streptomyces venezuelae ATCC 15439, a promising cell factory for production of secondary metabolites.

PubMed

Song, Ju Yeon; Yoo, Young Ji; Lim, Si-Kyu; Cha, Sun Ho; Kim, Ji-Eun; Roe, Jung-Hye; Kim, Jihyun F; Yoon, Yeo Joon

2016-02-10

Streptomyces venezuelae ATCC 15439, which produces 12- and 14-membered ring macrolide antibiotics, is a platform strain for heterologous expression of secondary metabolites. Its 9.05-Mb genome sequence revealed an abundance of genes involved in the biosynthesis of secondary metabolites and their precursors, which should be useful for the production of bioactive compounds. Copyright © 2015 Elsevier B.V. All rights reserved.

Azithromycin induced hepatocellular toxicity and hepatic encephalopathy in asymptomatic dilated cardiomyopathy

PubMed Central

Das, Bidyut Kumar

2011-01-01

Azithromycin is a widely used macrolide derivative and has generally been considered to be a very safe medication. Though gastrointestinal symptoms and reversible hearing loss are common, potentially serious side effects including angioedema and cholestatic jaundice occurred in less than one percent of patients. We report a case of asymptomatic dilated cardiomyopathy with Azithromycin induced severe hepatocellular toxicity and hepatic encephalopathy. PMID:22144789

Diversity-oriented synthesis leads to an effective class of bifunctional linchpins uniting anion relay chemistry (ARC) with benzyne reactivity

PubMed Central

Smith, Amos B.; Kim, Won-Suk

2011-01-01

In conjunction with the construction of a diversity-oriented synthesis library of 10-membered ring “natural product-like” macrolides, the design, synthesis, and validation of a unique class of bifunctional linchpins, uniting benzyne reactivity initiated by type II anion relay chemistry (ARC) has been achieved, permitting access to diverse [2+2], [3+2], and [4+2] cycloadducts. PMID:21245309

[Micromonospora resistence to definite antibiotics and their ability to produce structurally analogous antibiotics].

PubMed

Bibikova, M V; Ivanitskaia, L P; Tikhonova, A S

1980-01-01

Thirty six cultures of Micromonospora freshly isolated from soil samples were studied with respect to their sensitivity to a number of antibiotics of various structures and modes of action. It was found that all of them were highly sensitive to penicillin, ristomycin, tetracycline, rifampicin, streptomycin, olivomycin, carminomycin and dactinomycin. Significant differences in sensitivity of the Micromonospora cultures were revealed only with respect to gentamicin, tobramicin, erythromycin and lincomycin. Seven cultures were resistant to gentamicin and tobramicin and sensitive to all of the other antibiotics. Broad spectrum antibiotics were isolated from these cultures. The study of the antibiotic chemistry showed that they were 2-desoxystreptamine-containing aminoglycosides. Two cultures proved to be resistant to erythromycin and lincomycin. When identified with the use of antibiotic resistant staphylococcal strains, the crude antibiotic substances isolated from these cultures appeared to be not active against staphylococci resistant to erythromycin and lincomycin. By their chromatograpi- behaviour the antibiotics were close to macrolides. Therefore, it was found that production of aminoglycoside and macrolide antibiotics was most characteristic of Micromonospora. A certain correlation between resistance of Micromonospora to these 2 antibiotic groups and capacity for their production was shown.

Occurrence of antibiotics in water, sediments, aquatic plants, and animals from Baiyangdian Lake in North China.

PubMed

Li, Wenhui; Shi, Yali; Gao, Lihong; Liu, Jiemin; Cai, Yaqi

2012-11-01

This study investigated the presence and distribution of 22 antibiotics, including eight quinolones, nine sulfonamides and five macrolides, in the water, sediments, and biota samples from Baiyangdian Lake, China. A total of 132 samples were collected in 2008 and 2010, and laboratory analyses revealed that antibiotics were widely distributed in the lake. Sulfonamides were the dominant antibiotics in the water (0.86-1563 ng L(-1)), while quinolones were prominent in sediments (65.5-1166 μg kg(-1)) and aquatic plants (8.37-6532 μg kg(-1)). Quinolones (17.8-167 μg kg(-1)) and macrolides [from below detection limit (BDL) to 182 μg kg(-1)] were often found in aquatic animals and birds. Salvinia natans exhibited the highest bioaccumulation capability for quinolones among three species of aquatic plants. Geographical differences of antibiotic concentrations were greatly due to anthropogenic activities. Sewage discharged from Baoding City was likely the main source of antibiotics in the lake. Risk assessment of antibiotics on aquatic organisms suggested that algae and aquatic plants might be at risk in surface water, while animals were likely not at risk. Copyright © 2012 Elsevier Ltd. All rights reserved.

ABT-773 (Abbott Laboratories).

PubMed

Lawrence, L E

2001-06-01

ABT-773 is a macrolide antibacterial agent under development by Abbott Laboratories and Taisho Pharmaceutical Co Ltd for the potential treatment of bacterial infection [266579]. As of February 2001, ABT-773 had entered phase III trials in the US [398274]. Japanese phase II trials were expected to commence in June 2000 and a phase II trial is being designed for respiratory infections, with Abbott expecting filing in March 2002 [360455]. The bioavailability of ABT-773 in humans is unaffected by food [383228] and in a phase I, randomized, double-blind trial in healthy males only mild adverse effects, usually affecting the gastrointestinal system, were observed [383208]. Under an agreement, Abbott and Taisho are conducting joint research to discover new compounds; Abbott will have worldwide marketing, manufacturing and supply rights (except in Japan), and Taisho will receive royalties on Abbott's sales in consideration of granted rights. In Japan, the companies will co-market any resulting compounds [266579]. ABT-773 demonstrated good activity in vitro and in vivo against Streptococcus pneumoniae and Staphylococcus aureus [383229], [383231], and was highly potent even against macrolide-resistant [382149], [382150] and invasive [383782] S pneumoniae.

Role of rifampin-based combination therapy for severe community-acquired Legionella pneumophila pneumonia.

PubMed

Varner, Terra R; Bookstaver, P Brandon; Rudisill, Celeste N; Albrecht, Helmut

2011-07-01

To review the literature concerning the role of rifampin in the combination treatment of Legionella pneumophila pneumonia. A search of MEDLINE and Ovid databases was conducted (January 1970-May 2011) using the search terms Legionella pneumophila, pneumonia, Legionnaires' disease, rifampin or rifampicin, macrolide, fluoroquinolone, erythromycin, clarithromycin, levofloxacin, ciprofloxacin, and moxifloxacin In vivo studies published in English that compared antimicrobial therapies including rifampin for the treatment of Legionella pneumonia, as well as in vitro studies including an assessment of rifampin bioactivity, were included. Macrolides and fluoroquinolones have been effective as monotherapy in the treatment of L. pneumophila pneumonia. This review includes evidence summaries from 4 bioactivity evaluations, 6 clinical studies, and 6 reported cases of combination rifampin use. Combined with supporting evidence, the role of combination rifampin therapy is further delineated. Interpretation of the data is limited by the potential for selection bias and lack of consistent comparators. Rifampin therapy should be considered only for patients with severe disease or significant comorbid conditions (eg, uncontrolled diabetes, smoking, or obstructive lung disease) including immunocompromised hosts and those refractory to conventional monotherapy regimens. Caution for significant adverse drug events and drug-drug interactions should be taken with the addition of rifampin.

Emergence of scarlet fever Streptococcus pyogenes emm12 clones in Hong Kong is associated with toxin acquisition and multidrug resistance.

PubMed

Davies, Mark R; Holden, Matthew T; Coupland, Paul; Chen, Jonathan H K; Venturini, Carola; Barnett, Timothy C; Zakour, Nouri L Ben; Tse, Herman; Dougan, Gordon; Yuen, Kwok-Yung; Walker, Mark J

2015-01-01

A scarlet fever outbreak began in mainland China and Hong Kong in 2011 (refs. 1-6). Macrolide- and tetracycline-resistant Streptococcus pyogenes emm12 isolates represent the majority of clinical cases. Recently, we identified two mobile genetic elements that were closely associated with emm12 outbreak isolates: the integrative and conjugative element ICE-emm12, encoding genes for tetracycline and macrolide resistance, and prophage ΦHKU.vir, encoding the superantigens SSA and SpeC, as well as the DNase Spd1 (ref. 4). Here we sequenced the genomes of 141 emm12 isolates, including 132 isolated in Hong Kong between 2005 and 2011. We found that the introduction of several ICE-emm12 variants, ΦHKU.vir and a new prophage, ΦHKU.ssa, occurred in three distinct emm12 lineages late in the twentieth century. Acquisition of ssa and transposable elements encoding multidrug resistance genes triggered the expansion of scarlet fever-associated emm12 lineages in Hong Kong. The occurrence of multidrug-resistant ssa-harboring scarlet fever strains should prompt heightened surveillance within China and abroad for the dissemination of these mobile genetic elements.

Phytotoxic and Antifungal Metabolites from Curvularia crepinii QTYC-1 Isolated from the Gut of Pantala flavescens.

PubMed

Yin, Caiping; Jin, Liping; Sun, Feifei; Xu, Xiao; Shao, Mingwei; Zhang, Yinglao

2018-04-19

Four metabolites ( 1 ⁻ 4 ), including a new macrolide, O -demethylated-zeaenol ( 2 ), and three known compounds, zeaenol ( 1 ), adenosine ( 3 ), and ergosta-5,7,22-trien-3b-ol ( 4 ) were isolated and purified from Curvularia crepinii QTYC-1, a fungus residing in the gut of Pantala flavescens . The structures of isolated compounds were identified on the basis of extensive spectroscopic analysis and by comparison of the corresponding data with those reported in the literature previously. The new compound 2 showed good phytotoxic activity against Echinochloa crusgalli with an IC 50 value of less than 5 µg/mL, which was comparable to that of positive 2,4-dichlorophenoxyacetic acid (2,4-D). Compound 1 exhibited moderate herbicidal activity against E. crusgalli with an IC 50 value of 28.8 μg/mL. Furthermore, the new metabolite 2 was found to possess moderate antifungal activity against Valsa mali at the concentration of 100 µg/mL, with the inhibition rate of 50%. These results suggest that the new macrolide 2 and the known compound 1 have potential to be used as biocontrol agents in agriculture.

Effect of Erythromycin on Chronic Respiratory Infection Caused by Pseudomonas aeruginosa with Biofilm Formation in an Experimental Murine Model

PubMed Central

Nagata, Towako; Mukae, Hiroshi; Kadota, Junichi; Hayashi, Tomayoshi; Fujii, Takeshi; Kuroki, Misuzu; Shirai, Ryo; Yanagihara, Katsunori; Tomono, Kazunori; Koji, Takehiko; Kohno, Shigeru

2004-01-01

Diffuse panbronchiolitis (DPB) is a chronic lower respiratory tract infection commonly associated with persistent late-stage Pseudomonas aeruginosa infection. However, low-dose long-term therapy with certain macrolides is effective in most patients with DPB. The present study was designed to examine the effects of long-term erythromycin (ERY) therapy by using our established murine model of chronic respiratory P. aeruginosa infection. ERY or saline was administered from day 80 after intubation with a P. aeruginosa-precoated tube for the subsequent 10, 20, 40, and 80 days. Bacteriologic and histologic analyses of the murine lungs and electron microscopy of the intubated tube were performed. In the murine model, treatment with ERY for 80 days significantly reduced the number of viable P. aeruginosa organisms in the lungs (P < 0.05). The biofilm formed in situ by P. aeruginosa on the inner wall of the inoculation tube placed into the murine bronchus became significantly thinner after 80 days of ERY treatment. We conclude that the clinical efficacy of macrolides in DPB may be due at least in part to the reduction in P. aeruginosa biofilm formation. PMID:15155229

The association between measurements of antimicrobial use and resistance in the faeces microbiota of finisher batches.

PubMed

Andersen, V D; DE Knegt, L V; Munk, P; Jensen, M S; Agersø, Y; Aarestrup, F M; Vigre, H

2017-10-01

The objectives were to present three approaches for calculating antimicrobial (AM) use in pigs that take into account the rearing period and rearing site, and to study the association between these measurements and phenotypical resistance and abundance of resistance genes in faeces samples from 10 finisher batches. The AM use was calculated relative to the rearing period of the batches as (i) 'Finisher Unit Exposure' at unit level, (ii) 'Lifetime Exposure' at batch level and (iii) 'Herd Exposure' at herd level. A significant effect on the occurrence of tetracycline resistance measured by cultivation was identified for Lifetime Exposure for the AM class: tetracycline. Furthermore, for Lifetime Exposure for the AM classes: macrolide, broad-spectrum penicillin, sulfonamide and tetracycline use as well as Herd Unit Exposure for the AM classes: aminoglycoside, lincosamide and tetracycline use, a significant effect was observed on the occurrence of genes coding for the AM resistance classes: aminoglycoside, lincosamide, macrolide, β-lactam, sulfonamide and tetracycline. No effect was observed for Finisher Unit Exposure. Overall, the study shows that Lifetime Exposure is an efficient measurement of AM use in finisher batches, and has a significant effect on the occurrence of resistance, measured either by cultivation or metagenomics.

Antimicrobial resistance mechanisms among Campylobacter.

PubMed

Wieczorek, Kinga; Osek, Jacek

2013-01-01

Campylobacter jejuni and Campylobacter coli are recognized as the most common causative agents of bacterial gastroenteritis in the world. Humans most often become infected by ingesting contaminated food, especially undercooked chicken, but also other sources of bacteria have been described. Campylobacteriosis is normally a self-limiting disease. Antimicrobial treatment is needed only in patients with more severe disease and in those who are immunologically compromised. The most common antimicrobial agents used in the treatment of Campylobacter infections are macrolides, such as erythromycin, and fluoroquinolones, such as ciprofloxacin. Tetracyclines have been suggested as an alternative choice in the treatment of clinical campylobacteriosis but in practice are not often used. However, during the past few decades an increasing number of resistant Campylobacter isolates have developed resistance to fluoroquinolones and other antimicrobials such as macrolides, aminoglycosides, and beta-lactams. Trends in antimicrobial resistance have shown a clear correlation between use of antibiotics in the veterinary medicine and animal production and resistant isolates of Campylobacter in humans. In this review, the patterns of emerging resistance to the antimicrobial agents useful in treatment of the disease are presented and the mechanisms of resistance to these drugs in Campylobacter are discussed.

In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents.

PubMed Central

Sears, S D; O'Hare, J

1988-01-01

We determined the susceptibilities of five strains of Trichomonas vaginalis, one of which was metronidazole resistant, to 50 antimicrobial agents. For the metronidazole-susceptible strains, the most active agents were metronidazole, tinidazole, mebendazole, furazolidone, and anisomycin. Against the resistant strain mebendazole, furazolidone, and anisomycin were the most active. Antifungal agents, beta-lactams, macrolides, aminoglycosides, and folic acid antagonists were ineffective against all strains. PMID:3258142

Francisella tularensis Susceptibility to Antibiotics: A Comprehensive Review of the Data Obtained In vitro and in Animal Models

PubMed Central

Caspar, Yvan; Maurin, Max

2017-01-01

The antibiotic classes that are recommended for tularaemia treatment are the aminoglycosides, the fluoroquinolones and the tetracyclines. However, cure rates vary between 60 and 100% depending on the antibiotic used, the time to appropriate antibiotic therapy setup and its duration, and the presence of complications, such as lymph node suppuration. Thus, antibiotic susceptibility testing (AST) of F. tularensis strains remains of primary importance for detection of the emergence of antibiotic resistances to first-line drugs, and to test new therapeutic alternatives. However, the AST methods reported in the literature were poorly standardized between studies and AST data have not been previously evaluated in a comprehensive and comparative way. The aim of the present review was to summarize experimental data on antibiotic susceptibilities of F. tularensis obtained in acellular media, cell models and animal models since the introduction of fluoroquinolones in the treatment of tularaemia in 1989. We compiled MIC data of 33 antibiotics (including aminoglycosides, fluoroquinolones, tetracyclines, macrolides, β-lactams, chloramphenicol, rifampicin, and linezolid) against 900 F. tularensis strains (504 human strains), including 107 subsp. tularensis (type A), 789 subsp. holarctica (type B) and four subsp. mediasiatica strains, using various AST methods. Specific culture media were identified or confirmed as unsuitable for AST of F. tularensis. Overall, MICs were the lowest for ciprofloxacin (≤ 0.002–0.125 mg/L) and levofloxacin, and ranged from ≤ 0.016 to 2 mg/L for gentamicin, and 0.064 to 4 mg/L for doxycycline. No resistant strain to any of these antibiotics was reported. Fluoroquinolones also exhibited a bactericidal activity against intracellular F. tularensis and lower relapse rates in animal models when compared with the bacteriostatic compound doxycycline. As expected, lower MIC values were found for macrolides against type A and biovar I type B strains

Diagnosis and management of bronchiectasis.

PubMed

Smith, Maeve P

2017-06-19

KEY POINTS Following a diagnosis of bronchiectasis, it is important to investigate for an underlying cause. Goals of management are to suppress airway infection and inflammation, to improve symptoms and health-related quality of life. There are now validated scoring tools to help assess disease severity, which can help to stratify management. Good evidence supports the use of both exercise training and long-term macrolide therapy in long-term disease management.

[Legionnaire's disease in Italy: case list contribution].

PubMed

Scarlini, G; Carlino, G; Coletti, C; Parente, M; Orani, A M

1986-01-01

The authors describe two cases of Legionnaires disease brought to their attention and diagnosed through serological research utilizing two different methods: the indirect immunofluorescence and the microagglutination, in cooperation with the Higher Institute of Health. They conclude with some considerations upon the real necessity of circumscribed eziological research in all the cases of "hospitalized acute respiratory illness" and confirm the effectiveness of the treatment with macrolides in the Legionella Pneumophila infections.

Evaluation of a Microbiological Multi-Residue System on the detection of antibacterial substances in ewe milk.

PubMed

Althaus, Rafael; Berruga, Maria Isabel; Montero, Ana; Roca, Marta; Molina, Maria Pilar

2009-01-19

To protect both, public health and the dairy industry, from the presence of antibiotic residues in milk, control programmes have been established, which include the needed screening tests. This work focuses on the application of a Microbiological Multi-Residue System in ewe milk, a method based on the use of six different plates, each seeded with one of the following bacteria: Geobacillus stearothermophilus var. calidolactis (beta-lactams), Bacillus subtilis at pH 8.0 (aminoglycosides), Kocuria rhizophila (macrolides), Escherichia coli (quinolones), B. cereus (tetracyclines) and B. subtilis at pH 7.0 (sulphonamides), respectively. Twenty-three antimicrobial substances were analysed and a logistic regression was established for each substance assayed to relate the antibiotic concentration and the zone of microbial growth inhibition. Great linearity in the response was observed (regression coefficients of over 0.97). This fact suggests the possibility of establishing a decision level of antibiotic concentrations near to the Maximum Residue Limits (MRL). Zones of inhibition were suggested as proposed action levels for the different antimicrobial groups (diameters of inhibition of 18 mm for the aminoglycoside, beta-lactam and sulphonamide plates; 19 mm for the tetracycline plate, 21 mm for the macrolide plate, and 24 mm for the quinolone plate). Specificity and cross-reactivity were also assayed.

[Sensitivity of microbial associations of periodontal lesions to antibacterial agents].

PubMed

Makeeva, I M; Daurova, F Yu; Byakova, S F; Ippolitov, E V; Gostev, M S; Polikushina, A O; Shubin, E V

2016-01-01

The aim of the study was the development of approaches to improve the effectiveness of antibiotic therapy in dental practice on the basis of determining the sensitivity of pathogenic microorganisms to antibiotics of different groups. The study included determination of the sensitivity of the microbial complexes from wound exudate of periodontal pocket and apical abscess to macrolides, quinolones, penicillins, lincosamides and 5-nitroimidazole. A survey of dentists and dental clinics patients to identify the cause and frequency of use of antibiotics and to identify possible adverse reactions was also conducted. Dentists prefer macrolide antibiotics, protected penicillins, and fluoroquinolone combined with 5-nitroimidazole. All patients have taken antibiotics themselves at least once a year. Microbial complexes in patients with acute and exacerbated apical periodontitis in 79% of cases are susceptible to amoxicillin/clavulanic acid, to azithromycin - 52%, lincomycin - 36%, 5-nitroimidazole - 68%, ciprofloxacin - 73.7%. In patients with apical abscess high rates of resistance of microbial complexes to all types of antibiotics was revealed (33% for lincomycin 76,1% for ciprofloxacin, 28,6% for 5-nitroimidazole). Patients with moderate to severe periodontitis in 90.5% are sensitive to amoxicillin/clavulanic acid and azithromycin, in 62.4% to lincomycin. Sensitivity to ciprofloxacin was detected in 85.7% of patients, in 14.3% - moderate resistance.

Moxifloxacin in respiratory tract infections.

PubMed

Miravitlles, Marc

2005-02-01

Moxifloxacin is a fourth-generation fluoroquinolone that has been shown to be effective against respiratory pathogens, including Gram-positive (Streptococcus pneumoniae), Gram-negative (Haemophilus influenzae, Moraxella catarrhalis), and atypical strains (Chlamydia pneumoniae, Mycoplasma pneumoniae), as well as multi-drug resistant S. pneumoniae, including strains resistant to penicillin, macrolides, tetracyclines, trimethoprim/sulfamethoxazole and some fluoroquinolones. Moxifloxacin is highly concentrated in lung tissue, and has demonstrated rapid eradication rates. The bioavailability and half-life of moxifloxacin provides potent bactericidal effects at a dose of 400mg/day. The ratio of the area under the concentration-time curve to MIC of moxifloxacin is the highest among the fluoroquinolones against S. pneumoniae. The clinical efficacy of moxifloxacin has been shown in controlled studies of community-acquired pneumonia (CAP), exacerbations of chronic bronchitis (CB) and acute bacterial rhinosinusitis. Moxifloxacin has demonstrated a faster resolution of symptoms in CAP and exacerbations of CB patients compared with first-line therapy. It has also demonstrated better eradication in exacerbations of CB compared with standard therapy, in particular the macrolides. Treatment guidelines should take into account the results of clinical trials with moxifloxacin in order to establish the role of this antimicrobial in the therapeutic arsenal against respiratory tract infections.

Metabolism of tilmicosin by rabbit liver microsomes and hepatocytes.

PubMed

Montesissa, C; Capolongo, F; Santi, A; Biancotto, G; Dacasto, M

2004-01-01

We investigated tilmicosin (TIM) metabolism, at 25, 50 or 100 microM, in cultures of primary hepatocytes from rabbits bred commercially for food and in liver microsomes prepared from both untreated and rifampicin (RIF)-treated rabbits. RIF is a well-known cytochrome P4503A (CYP 3A) inducer in rabbits and most macrolides are known to be substrates of CYP 3A. No peaks in addition to those of the cis and trans forms of TIM were observed by high performance liquid chromatography (HPLC) in extracts of microsomes from untreated rabbits. When TIM was incubated with induced microsomes, at least two peaks were found by HPLC and an additional peak, eluting at shorter retention time was isolated from hepatocytes incubated for 24h with the macrolide. The structures of the metabolites were then estimated by liquid chromatography-mass spectrometry (LC-MS) in concentrated extracts from induced microsomes. Five metabolites were separated and putatively identified: cis and trans demethylated tilmicosin, tilmicosin N-oxide and cis and trans tilmicosin epoxide. The overall amount of metabolites produced in vitro using livers of untreated and RIF treated rabbits was very low, has also been observed in vivo and in vitro in cattle, chickens and pigs.

Associations of antimicrobial use with antimicrobial resistance in Campylobacter coli from grow-finish pigs in Japan.

PubMed

Ozawa, M; Makita, K; Tamura, Y; Asai, T

2012-10-01

To determine associations between antimicrobial use and antimicrobial resistance in Campylobacter coli, 155 isolates were obtained from the feces of apparently healthy grow-finish pigs in Japan. In addition, data on the use of antibiotics collected through the national antimicrobial resistance monitoring system in Japan were used for the analysis. Logistic regression was used to identify risk factors to antimicrobial resistance in C. coli in pigs for the following antimicrobials: ampicillin, dihydrostreptomycin, erythromycin, oxytetracycline, chloramphenicol, and enrofloxacin. The data suggested the involvement of several different mechanisms of resistance selection. The statistical relationships were suggestive of co-selection; use of macrolides was associated with enrofloxacin resistance (OR=2.94; CI(95%): 0.997, 8.68) and use of tetracyclines was associated with chloramphenicol resistance (OR=2.37; CI(95%): 1.08, 5.19). The statistical relationships were suggestive of cross-resistance: use of macrolides was associated with erythromycin resistance (OR=9.36; CI(95%): 2.96, 29.62) and the use of phenicols was associated with chloramphenicol resistance (OR=11.83; CI(95%): 1.41, 99.44). These data showed that the use of antimicrobials in pigs selects for resistance in C. coli within and between classes of antimicrobials. Copyright © 2012 Elsevier B.V. All rights reserved.

Studies of lysine cyclodeaminase from Streptomyces pristinaespiralis: Insights into the complex transition NAD+ state.

PubMed

Ying, Hanxiao; Wang, Jing; Shi, Ting; Zhao, Yilei; Wang, Xin; Ouyang, Pingkai; Chen, Kequan

2018-01-01

Lysine cyclodeaminase (LCD) catalyzes the piperidine ring formation in macrolide-pipecolate natural products metabolic pathways from a lysine substrate through a combination of cyclization and deamination. This enzyme belongs to a unique enzyme class, which uses NAD + as the catalytic prosthetic group instead of as the co-substrate. To understand the molecular details of NAD + functions in lysine cyclodeaminase, we have determined four ternary crystal structure complexes of LCD-NAD + with pipecolic acid (LCD-PA), lysine (LCD-LYS), and an intermediate (LCD-INT) as ligands at 2.26-, 2.00-, 2.17- and 1.80 Å resolutions, respectively. By combining computational studies, a NAD + -mediated "gate keeper" function involving NAD + /NADH and Arg49 that control the binding and entry of the ligand lysine was revealed, confirming the critical roles of NAD + in the substrate access process. Further, in the gate opening form, a substrate delivery tunnel between ε-carboxyl moiety of Glu264 and the α-carboxyl moiety of Asp236 was observed through a comparison of four structure complexes. The LCD structure details including NAD + -mediated "gate keeper" and substrate tunnel may assist in the exploration the NAD + function in this unique enzyme class, and in regulation of macrolide-pipecolate natural product synthesis. Copyright © 2017 Elsevier Inc. All rights reserved.

3D assembly based on 2D structure of Cellulose Nanofibril/Graphene Oxide Hybrid Aerogel for Adsorptive Removal of Antibiotics in Water

PubMed Central

Yao, Qiufang; Fan, Bitao; Xiong, Ye; Jin, Chunde; Sun, Qingfeng; Sheng, Chengmin

2017-01-01

Cellulose nanofibril/graphene oxide hybrid (CNF/GO) aerogel was fabricated via a one-step ultrasonication method for adsorptive removal of 21 kinds of antibiotics in water. The as-prepared CNF/GO aerogel possesses interconnected 3D network microstructure, in which GO nanosheets with 2D structure were intimately grown along CNF through hydrogen bonds. The aerogel exhibited superior adsorption capacity toward the antibiotics. The removal percentages (R%) of the antibiotics were more than 69% and the sequence of six categories antibiotics according to the adsorption efficiency was as follows: Tetracyclines > Quinolones > Sulfonamides > Chloramphenicols > β-Lactams > Macrolides. The adsorption mechanism was proposed to be electrostatic attraction, p-π interaction, π-π interaction and hydrogen bonds. In detail, the adsorption capacities of CNF/GO aerogel were 418.7 mg·g−1 for chloramphenicol, 291.8 mg·g−1 for macrolides, 128.3 mg·g−1 for quinolones, 230.7 mg·g−1 for β-Lactams, 227.3 mg·g−1 for sulfonamides, and 454.6 mg·g−1 for tetracyclines calculated by the Langmuir isotherm models. Furthermore, the regenerated aerogels still could be repeatedly used after ten cycles without obvious degradation of adsorption performance. PMID:28368045

Integrin-mediated targeting of protein polymer nanoparticles carrying a cytostatic macrolide

NASA Astrophysics Data System (ADS)

Shi, Pu

Cytotoxicity, low water solubility, rapid clearance from circulation, and offtarget side-effects are common drawbacks of conventional small-molecule drugs. To overcome these shortcomings, many multifunctional nanocarriers have been proposed to enhance drug delivery. In concept, multifunctional nanoparticles might carry multiple agents, control release rate, biodegrade, and utilize target-mediated drug delivery; however, the design of these particles presents many challenges at the stage of pharmaceutical development. An emerging solution to improve control over these particles is to turn to genetic engineering. Genetically engineered nanocarriers are precisely controlled in size and structure and can provide specific control over sites for chemical attachment of drugs. Genetically engineered drug carriers that assemble nanostructures including nanoparticles and nanofibers can be polymeric or nonpolymeric. This chapter summarizes the recent development of applications in drug and gene delivery utilizing nanostructures of polymeric genetically engineered drug carriers such as elastin-like polypeptides, silk-like polypeptides, and silk-elastin-like protein polymers, and non-polymeric genetically engineered drug carriers such as vault proteins and viral proteins. This chapter explores an alternative encapsulation strategy based on high-specificity avidity between a small molecule drug and its cognate protein target fused to the corona of protein polymer nanoparticles. With the new strategy, the drug associates tightly to the carrier and releases slowly, which may decrease toxicity and promote tumor accumulation via the enhanced permeability and retention effect. To test this hypothesis, the drug Rapamycin (Rapa) was selected for its potent anti-proliferative properties, which give it immunosuppressant and anti-tumor activity. Despite its potency, Rapa has low solubility, low oral bioavailability, and rapid systemic clearance, which make it an excellent candidate for nanoparticulate drug delivery. To explore this approach, genetically engineered diblock copolymers were constructed from elastin-like polypeptides (ELPs) that assemble small nanoparticles. ELPs are protein polymers of the sequence (Val-Pro-Gly-Xaa-Gly)n, where the identity of Xaa and n determine their assembly properties. Initially, a screening assay for model drug encapsulation in ELP nanoparticles was developed, which showed that Rose Bengal and Rapa have high non-specific encapsulation in the core of ELP nanoparticles with a sequence where Xaa = Ile or Phe. While excellent at entrapping these drugs, their release was relatively fast compared to their intended mean residence time in the human body. Having determined that Rapa can be non-specifically entrapped in the core of ELP nanoparticles, FK506 binding protein 12 (FKBP), which is the cognate protein target of Rapa, was genetically fused to the surface of these nanoparticles (FSI) to enhance their avidity towards Rapa. The fusion of FKBP to these nanoparticles slowed the terminal half-life of drug release to 57.8 h. To determine if this class of drug carriers has potential applications in vivo, FSI/Rapa was administered to mice carrying a human breast cancer model (MDA-MB-468). Compared to free drug, FSI encapsulation significantly decreased gross toxicity and enhanced the anti-cancer activity. In conclusion, protein polymer nanoparticles decorated with the cognate receptor of a high potency, low solubility drug (Rapa) efficiently improved drug loading capacity and its release. This approach has applications to the delivery of Rapa and its analogs; furthermore, this strategy has broader applications in the encapsulation, targeting, and release of other potent small molecules. Elastin-like polypeptides (ELPs) are genetically encoded protein polymers that reversibly phase separate in response to stimuli. They respond sharply to small shifts in temperature and form dense microdomains in the living eukaryotic cytosol. This chapter illustrates how to tune the ELP sequence and architecture for either coassembly or sorting of distinct proteins into microdomains within a living cell. Passive tumor targeting utilizing enhanced permeability and retention (EPR) effect has limited efficiency in targeting non-leaky tumors such as MDA-MB-468 breast tumor; however, an RGD tri-peptide decorated micelle nanoparticle can effectively accumulate in tumor site via integrin-mediated active tumor targeting. Different from inefficient and cytotoxic chemical linkage reactions, an elastin-based multi-functional nanocarrier can be assembled by genetic protein fusion and micelle co-assembly technology. The novel drug carrier contains the cognate Rapamycin (Rapa) receptor -- FK506 binding protein (FKBP) as the high-avidity drug binding domain and an RGD peptide as the active tumor targeting domain. Here we show that by co-assembling FKBP and RGD contained protein polymers into mixed micelle nanoparticles, they not only competently targeted endothelial and tumor cells in cell assays, but specifically delivered the drug with a slow release half-life of 38h. It was demonstrated that the active tumor targeting formulation of Rapa more effectively suppressed tumor growth compared to the passive tumor targeting formulation and free drug in tumor regression studies of mouse MDA-MB-468 xenografts. We believe that the exciting results will provide a new tool for the development of next-generation "smart" multi-functional drug carriers. (Abstract shortened by UMI.).

Turning the tide or riding the waves? Impacts of antibiotic stewardship and infection control on MRSA strain dynamics in a Scottish region over 16 years: non-linear time series analysis.

PubMed

Lawes, Timothy; López-Lozano, José-María; Nebot, César; Macartney, Gillian; Subbarao-Sharma, Rashmi; Dare, Ceri R J; Edwards, Giles F S; Gould, Ian M

2015-03-26

To explore temporal associations between planned antibiotic stewardship and infection control interventions and the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA). Retrospective ecological study and time-series analysis integrating typing data from the Scottish MRSA reference laboratory. Regional hospital and primary care in a Scottish Health Board. General adult (N=1,051,993) or intensive care (18,235) admissions and primary care registrations (460,000 inhabitants) between January 1997 and December 2012. Hand-hygiene campaign; MRSA admission screening; antibiotic stewardship limiting use of macrolides and '4Cs' (cephalosporins, coamoxiclav, clindamycin and fluoroquinolones). Prevalence density of MRSA clonal complexes CC22, CC30 and CC5/Other in hospital (isolates/1000 occupied bed days, OBDs) and community (isolates/10,000 inhabitant-days). 67% of all clinical MRSA isolates (10,707/15,947) were typed. Regional MRSA population structure was dominated by hospital epidemic strains CC30, CC22 and CC45. Following declines in overall MRSA prevalence density, CC5 and other strains of community origin became increasingly important. Reductions in use of '4Cs' and macrolides anticipated declines in sublineages with higher levels of associated resistances. In multivariate time-series models (R(2)=0.63-0.94) introduction of the hand-hygiene campaign, reductions in mean length of stay (when >4 days) and bed occupancy (when >74 to 78%) predicted declines in CC22 and CC30, but not CC5/other strains. Lower importation pressures, expanded MRSA admission screening, and reductions in macrolide and third generation cephalosporin use (thresholds for association: 135-141, and 48-81 defined daily doses/1000 OBDs, respectively) were followed by declines in all clonal complexes. Strain-specific associations with fluoroquinolones and clindamycin reflected resistance phenotypes of clonal complexes. Infection control measures and changes in population

Electronic structure of antibiotic erythromycin

NASA Astrophysics Data System (ADS)

Novak, Igor; Kovač, Branka

2015-03-01

The electronic structure of erythromycin A (ERYMA) molecule has been studied by UV photoelectron spectroscopy and assigned (in the low ionization energy region only) by empirical arguments. The two orbitals with highest energy (lowest ionization energy) are localized on the nitrogen of the desosamine sugar functional group and on the ester group of macrolide (lactone) ring. We discuss how these orbital energies can help to rationalize the known mode of binding of ERYMA to their biological receptors.

Effect of spiramycin and tulathromycin on abomasal emptying rate in milk-fed calves

PubMed Central

Rashnavadi, Mehdi; Nouri, Mohammad; Haji Hajikolaei, Mohammad R.; Najafzadeh, Housain; Constable, Peter D.

2014-01-01

Impaired abomasal motility is common in cattle with abomasal disorders. The macrolide erythromycin has been demonstrated to be an effective prokinetic agent in healthy calves and in adult cattle with abomasal volvulus or left displaced abomasum. We hypothesized that 2 structurally related macrolides, spiramycin and tulathromycin, would also be effective prokinetic agents in cattle. Six milk-fed, male, Holstein-Friesian calves were administered each of the following 4 treatments: spiramycin, 75 000 IU/kg BW, IM, this dose approximates 25 mg/kg BW, IM; tulathromycin, 2.5 mg/kg BW, SC; 2 mL of 0.9% NaCl (negative control); and erythromycin, 8.8 mg/kg BW, IM (positive control). Calves were fed 2 L of cow’s milk containing acetaminophen (50 mg/kg body weight) 30 min after each treatment was administered and jugular venous blood samples were obtained periodically after the start of sucking. Abomasal emptying rate was assessed by the time to maximal plasma acetaminophen concentration. Spiramycin, tulathromycin, and the positive control erythromycin increased abomasal emptying rate compared to the negative control. We conclude that the labeled antimicrobial dose of spiramycin and tulathromycin increases the abomasal emptying rate in healthy milk-fed calves. Additional studies investigating whether spiramycin and tulathromycin exert a prokinetic effect in adult cattle with abomasal hypomotility appear indicated. PMID:24396182

Antipneumococcal activity of ceftobiprole, a novel broad-spectrum cephalosporin.

PubMed

Kosowska, Klaudia; Hoellman, Dianne B; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C

2005-05-01

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC(50) and MIC(90) values (microg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1x and 2x the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2x the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2x the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole.

Antipneumococcal Activity of Ceftobiprole, a Novel Broad-Spectrum Cephalosporin

PubMed Central

Kosowska, Klaudia; Hoellman, Dianne B.; Lin, Gengrong; Clark, Catherine; Credito, Kim; McGhee, Pamela; Dewasse, Bonifacio; Bozdogan, Bülent; Shapiro, Stuart; Appelbaum, Peter C.

2005-01-01

Ceftobiprole (previously known as BAL9141), an anti-methicillin-resistant Staphylococcus aureus cephalosporin, was very highly active against a panel of 299 drug-susceptible and -resistant pneumococci, with MIC50 and MIC90 values (μg/ml) of 0.016 and 0.016 (penicillin susceptible), 0.06 and 0.5 (penicillin intermediate), and 0.5 and 1.0 (penicillin resistant). Ceftobiprole, imipenem, and ertapenem had lower MICs against all pneumococcal strains than amoxicillin, cefepime, ceftriaxone, cefotaxime, cefuroxime, or cefdinir. Macrolide and penicillin G MICs generally varied in parallel, whereas fluoroquinolone MICs did not correlate with penicillin or macrolide susceptibility or resistance. All strains were susceptible to linezolid, quinupristin-dalfopristin, daptomycin, vancomycin, and teicoplanin. Time-kill analyses showed that at 1× and 2× the MIC, ceftobiprole was bactericidal against 10/12 and 11/12 strains, respectively. Levofloxacin, moxifloxacin, vancomycin, and teicoplanin were each bactericidal against 10 to 12 strains at 2× the MIC. Azithromycin and clarithromycin were slowly bactericidal, and telithromycin was bactericidal against only 5/12 strains at 2× the MIC. Linezolid was mainly bacteriostatic, whereas quinupristin-dalfopristin and daptomycin showed marked killing at early time periods. Prolonged serial passage in the presence of subinhibitory concentrations of ceftobiprole failed to yield mutants with high MICs towards this cephalosporin, and single-passage selection showed very low frequencies of spontaneous mutants with breakthrough MICs towards ceftobiprole. PMID:15855516

Comparison of two treatments for the removal of selected organic micropollutants and bulk organic matter: conventional activated sludge followed by ultrafiltration versus membrane bioreactor.

PubMed

Sahar, E; Ernst, M; Godehardt, M; Hein, A; Herr, J; Kazner, C; Melin, T; Cikurel, H; Aharoni, A; Messalem, R; Brenner, A; Jekel, M

2011-01-01

The potential of membrane bioreactor (MBR) systems to remove organic micropollutants was investigated at different scales, operational conditions, and locations. The effluent quality of the MBR system was compared with that of a plant combining conventional activated sludge (CAS) followed by ultrafiltration (UF). The MBR and CAS-UF systems were operated and tested in parallel. An MBR pilot plant in Israel was operated for over a year at a mixed liquor suspended solids (MLSS) range of 2.8-10.6 g/L. The MBR achieved removal rates comparable to those of a CAS-UF plant at the Tel-Aviv wastewater treatment plant (WWTP) for macrolide antibiotics such as roxythromycin, clarithromycin, and erythromycin and slightly higher removal rates than the CAS-UF for sulfonamides. A laboratory scale MBR unit in Berlin - at an MLSS of 6-9 g/L - showed better removal rates for macrolide antibiotics, trimethoprim, and 5-tolyltriazole compared to the CAS process of the Ruhleben sewage treatment plant (STP) in Berlin when both were fed with identical quality raw wastewater. The Berlin CAS exhibited significantly better benzotriazole removal and slightly better sulfamethoxazole and 4-tolyltriazole removal than its MBR counterpart. Pilot MBR tests (MLSS of 12 g/L) in Aachen, Germany, showed that operating flux significantly affected the resulting membrane fouling rate, but the removal rates of dissolved organic matter and of bisphenol A were not affected.

The analysis of animal faeces as a tool to monitor antibiotic usage.

PubMed

Berendsen, Bjorn J A; Wegh, Robin S; Memelink, Joost; Zuidema, Tina; Stolker, Linda A M

2015-01-01

The analysis of antibiotics in animal faeces is important to obtain more insight in the possible formation of bacterial resistance in the animals׳ gut, to learn about the dissemination of antibiotics to the environment, to monitor trends in antibiotic usage and to detect the illegal and off-label use of antibiotics. To facilitate these studies a comprehensive method for the analysis of trace levels of 44 antibiotic compounds including tetracyclines, quinolones, macrolides and sulfonamides in animal faeces by liquid chromatography in combination with tandem mass spectrometric (LC-MS/MS) detection is reported. The method is fully validated according to European regulation and showed satisfactory quantitative performance according to the stringent criteria adopted, with the exception of some of the macrolide compounds, which can be analysed with somewhat high measurement uncertainty. A large survey was carried out monitoring swine and cattle faeces and the outcomes were striking. In 55% of the swines, originating from 80% of the swine farms and in 75% of the calves, originating from 95% of the cattle farms, antibiotics were detected. Oxytetracycline, doxycycline and sulfadiazine were the most detected antibiotics, followed by tetracycline, flumequine, lincomycin and tylosin. Over 34% of the faeces samples contained two or more different antibiotics with a maximum of eight. Possible explanations for these findings are given and the effects are discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of oral tilmicosin efficacy against severe cryptosporidiosis in neonatal kids under field conditions.

PubMed

Paraud, C; Pors, I; Chartier, C

2010-05-28

Many compounds have been screened for their potential anti-cryptosporidial activity in ruminants but none of them has been totally efficient in controlling the disease. Macrolide antibiotics have demonstrated some activity against Cryptosporidium spp. in humans. Tilmicosin is a macrolide antibiotic, available in France in an oral form (Pulmotil AC, Lilly France). The preventive efficacy of tilmicosin was evaluated in a goat farm experiencing severe clinical cryptosporidiosis in kids. Twenty-two kids were separated from their dams just after birth and placed in a separated pen. They were divided into 3 groups: an untreated group (10 kids), group 1 (6 kids) receiving tilmicosin at 25mg/kg BW/day and group 2 (6 kids) receiving tilmicosin at 50mg/kg BW/day. Tilmicosin was individually given by oral route from day 2 of age for 10 days. Three times a week, individual faecal samples were performed to assess the oocyst output. Clinical data, i.e. diarrhea and mortality, were recorded. In control kids, the highest prevalence and intensity of excretion were observed between day 6 and day 16 of age and mortality reached 90%. Excretion dynamic and clinical consequences were similar in both treated kid groups. Finally, tilmicosin did not demonstrate any activity against severe kid cryptosporidiosis in field conditions. (c) 2010 Elsevier B.V. All rights reserved.

Association of socioeconomic status with the use of chronic therapies and healthcare utilization in children with cystic fibrosis.

PubMed

Schechter, Michael S; McColley, Susanna A; Silva, Stefanie; Haselkorn, Tmirah; Konstan, Michael W; Wagener, Jeffrey S

2009-11-01

To determine whether previously reported socioeconomic status (SES)-related disparities in cystic fibrosis (CF) health outcomes vary by the indicator used (median household income by zip code [MIZ], maternal educational attainment [MEA], and state insurance coverage [MA]), and whether these disparities can be explained by differences in medical treatment. A cross-sectional analysis of data on patients age <18 years from the Epidemiologic Study of Cystic Fibrosis (ESCF). Disease severity showed a similar inverse correlation with all 3 SES measures. The number of stable clinic visits was unrelated to SES. Patients with MA had more sick outpatient visits and more courses of intravenous (IV) antibiotics for pulmonary exacerbations, and were more likely to be prescribed all chronic therapies. Low-MIZ patients had slightly fewer sick visits and more courses of IV antibiotics, and were more likely to receive oral nutrition supplements but less likely to receive macrolide prescriptions. Low-MEA patients were less likely to receive IV antibiotics at home, more likely to receive oral nutrition supplements, but less likely to receive macrolide prescriptions. CF health outcomes are correlated with the SES spectrum, but these disparities are not explained by differential use of health services or prescription of chronic therapy. Future investigations should focus on the possible impact of environmental exposures and differences in disease self-management.

Biosynthesis of the antifungal haterumalide, oocydin A, in Serratia, and its regulation by quorum sensing, RpoS and Hfq

PubMed Central

Matilla, Miguel A; Leeper, Finian J; Salmond, George P C

2015-01-01

Polyketides represent an important class of bioactive natural products with a broad range of biological activities. We identified recently a large trans-acyltransferase (AT) polyketide synthase gene cluster responsible for the biosynthesis of the antifungal, anti-oomycete and antitumor haterumalide, oocydin A (ooc). Using genome sequencing and comparative genomics, we show that the ooc gene cluster is widespread within biocontrol and phytopathogenic strains of the enterobacteria, Serratia and Dickeya. The analysis of in frame deletion mutants confirmed the role of a hydroxymethylglutaryl-coenzyme A synthase cassette, three flavin-dependent tailoring enzymes, a free-standing acyl carrier protein and two hypothetical proteins in oocydin A biosynthesis. The requirement of the three trans-acting AT domains for the biosynthesis of the macrolide was also demonstrated. Expression of the ooc gene cluster was shown to be positively regulated by an N-acyl-L-homoserine lactone-based quorum sensing system, but operating in a strain-dependent manner. At a post-transcriptional level, the RNA chaperone, Hfq, plays a key role in oocydin A biosynthesis. The Hfq-dependent regulation is partially mediated by the stationary phase sigma factor, RpoS, which was also shown to positively regulate the synthesis of the macrolide. Our results reveal differential regulation of the divergently transcribed ooc transcriptional units, highlighting the complexity of oocydin A production. PMID:25753587

The genetic diversity and phenotypic characterisation of Streptococcus agalactiae isolates from Rio de Janeiro, Brazil.

PubMed

Corrêa, Ana Beatriz de Almeida; Silva, Lígia Guedes da; Pinto, Tatiana de Castro Abreu; Oliveira, Ivi Cristina Menezes de; Fernandes, Flávio Gimenis; Costa, Natalia Silva da; Mattos, Marcos Corrêa de; Fracalanzza, Sergio Eduardo Longo; Benchetrit, Leslie Claude

2011-12-01

Streptococcus agalactiae isolates are more common among pregnant women, neonates and nonpregnant adults with underlying diseases compared to other demographic groups. In this study, we evaluate the genetic and phenotypic diversity in S. agalactiae strains from Rio de Janeiro (RJ) that were isolated from asymptomatic carriers. We analysed these S. agalactiae strains using pulsed-field gel electrophoresis (PFGE), serotyping and antimicrobial susceptibility testing, as well as by determining the macrolide resistance phenotype, and detecting the presence of the ermA/B, mefA/E and lnuB genes. The serotypes Ia, II, III and V were the most prevalent serotypes observed. The 60 strains analysed were susceptible to penicillin, vancomycin and levofloxacin. Resistance to clindamycin, chloramphenicol, erythromycin, rifampin and tetracycline was observed. Among the erythromycin and/or clindamycin resistant strains, the ermA, ermB and mefA/E genes were detected and the constitutive macrolides, lincosamides and streptogramin B-type resistance was the most prevalent phenotype observed. The lnuB gene was not detected in any of the strains studied. We found 56 PFGE electrophoretic profiles and only 22 of them were allocated in polymorphism patterns. This work presents data on the genetic diversity and prevalent capsular serotypes among RJ isolates. Approximately 85% of these strains came from pregnant women; therefore, these data may be helpful in developing future prophylaxis and treatment strategies for neonatal syndromes in RJ.

Serotypes, antibiotic susceptibilities, and multi-locus sequence type profiles of Streptococcus agalactiae isolates circulating in Beijing, China.

PubMed

Wang, Ping; Tong, Jing-jing; Ma, Xiu-hua; Song, Feng-li; Fan, Ling; Guo, Cui-mei; Shi, Wei; Yu, Sang-jie; Yao, Kai-hu; Yang, Yong-hong

2015-01-01

To investigate the serotypes, antibiotic susceptibilities, and multi-locus sequence type (MLST) profiles of Streptococcus agalactiae (S. agalactiae) in Beijing to provide references for the prevention and treatment of S. agalactiae infections. All isolates were identified using the CAMP test and the latex-agglutination assay and serotyped using a Strep-B-Latex kit, after which they were assessed for antibiotic susceptibility, macrolide-resistance genes, and MLST profiles. In total, 56 S. agalactiae isolates were identified in 863 pregnant women (6.5%). Serotypes Ia, Ib, II, III, and V were identified, among which types III (32.1%), Ia (17.9%), Ib (16.1%), and V (14.3%) were the predominant serotypes. All isolates were susceptible to penicillin and ceftriaxone. The nonsusceptiblity rates measured for erythromycin, clarithromycin, azithromycin, telithromycin, clindamycin, tetracycline, and levofloxacin were 85.7%, 92.9%, 98.2%, 30.4%, 73.2%, 91%, and 39.3%, respectively. We identified 14 sequence types (STs) for the 56 isolates, among which ST19 (30.4%) was predominant. The rate of fluoroquinolone resistance was higher in serotype III than in the other serotypes. Among the 44 erythromycin-resistant isolates, 32 (72.7%) carried ermB. S. agalactiae isolates of the serotypes Ia, Ib, III, and V are common in Beijing. Among the S. agalactiae isolates, the macrolide and clindamycin resistance rates are extremely high. Most of the erythromycin-resistant isolates carry ermB.

Polymerase chain reaction-based discrimination of viable from non-viable Mycoplasma gallisepticum.

PubMed

Tan, Ching Giap; Ideris, Aini; Omar, Abdul R; Yii, Chen Pei; Kleven, Stanley H

2014-09-02

The present study was based on the reverse transcription polymerase chain reaction (RT-PCR) of the 16S ribosomal nucleic acid (rRNA) of Mycoplasma for detection of viable Mycoplasma gallisepticum. To determine the stability of M. gallisepticum 16S rRNA in vitro, three inactivation methods were used and the suspensions were stored at different temperatures. The 16S rRNA of M. gallisepticum was detected up to approximately 20-25 h at 37 °C, 22-25 h at 16 °C, and 23-27 h at 4 °C. The test, therefore, could detect viable or recently dead M. gallisepticum (< 20 h). The RT-PCR method was applied during an in vivo study of drug efficacy under experimental conditions, where commercial broiler-breeder eggs were inoculated with M. gallisepticum into the yolk. Hatched chicks that had been inoculated in ovo were treated with Macrolide 1. The method was then applied in a flock of day 0 chicks with naturally acquired vertical transmission of M. gallisepticum, treated with Macrolide 2. Swabs of the respiratory tract were obtained for PCR and RT-PCR evaluations to determine the viability of M. gallisepticum. This study proved that the combination of both PCR and RT-PCR enables detection and differentiation of viable from non-viable M. gallisepticum.

Seeking key microorganisms for enhancing methane production in anaerobic digestion of waste sewage sludge.

PubMed

Mustapha, Nurul Asyifah; Hu, Anyi; Yu, Chang-Ping; Sharuddin, Siti Suhailah; Ramli, Norhayati; Shirai, Yoshihito; Maeda, Toshinari

2018-06-01

Efficient approaches for the utilization of waste sewage sludge have been widely studied. One of them is to use it for the bioenergy production, specifically methane gas which is well-known to be driven by complex bacterial interactions during the anaerobic digestion process. Therefore, it is important to understand not only microorganisms for producing methane but also those for controlling or regulating the process. In this study, azithromycin analogs belonging to macrolide, ketolide, and lincosamide groups were applied to investigate the mechanisms and dynamics of bacterial community in waste sewage sludge for methane production. The stages of anaerobic digestion process were evaluated by measuring the production of intermediate substrates, such as protease activity, organic acids, the quantification of bacteria and archaea, and its community dynamics. All azithromycin analogs used in this study achieved a high methane production compared to the control sample without any antibiotic due to the efficient hydrolysis process and the presence of important fermentative bacteria and archaea responsible in the methanogenesis stage. The key microorganisms contributing to the methane production may be Clostridia, Cladilinea, Planctomycetes, and Alphaproteobacteria as an accelerator whereas Nitrosomonadaceae and Nitrospiraceae may be suppressors for methane production. In conclusion, the utilization of antibiotic analogs of macrolide, ketolide, and lincosamide groups has a promising ability in finding the essential microorganisms and improving the methane production using waste sewage sludge.

Antibiotic sensitivity pattern from pregnant women with urinary tract infection in Bangalore, India.

PubMed

Sibi, G; Kumari, Pinki; Kabungulundabungi, Neema

2014-09-01

To determine the antibacterial profile of pregnant women with urinaty tract infections and analyze the antibiotic sensitivity pattern for the effective treatment. A total of 395 urine samples from pregnant women with different gestational age were processed for the isolation of uropathogens and tested against eight groups of antibiotics namely penicillins, cephalosporins, fluoroquinolones, aminoglycosides, macrolides, lincosamides, glycopeptides and sulfonamides. A positive culture percentage of 46.6% was obtained with the highest urinary tract infection in third trimester gestational age. Among the uropathogens isolated, 85.6% were Gram negative and 14.4% were Gram positive with Escherichia coli as the predominant bacteria (43.9%) followed by Klebsiella oxytoca (19.4%) and Klebsiella pneumoniae (13.3%). Antibiotic sensitivity assay revealed that amikacin had the highest overall sensitivity (n=136; 76.7%) and the subsequent highest sensitivity was observed with ciprofloxacin (n=132; 73.3%), clindamycin (n=124; 68.9%), cefotaxime (n=117; 65%) and nalidixic acid (n=115; 63.9%). The findings revealed that uropathogens were more resistant to penicillins, macrolides and glycopeptides which restrict their use in treating urinaty tract infections during pregnancy. In conclusion, common causative bacteria and their antibiotic sensitivity pattern are to be determined along with their safety to mother and fetus for the effective treatment of urinary tract infections during pregnancy. Copyright © 2014 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

In vitro activity of tylvalosin against Spanish field strains of Mycoplasma hyopneumoniae.

PubMed

Tavío, M M; Poveda, C; Assunção, P; Ramírez, A S; Poveda, J B

2014-11-29

Mycoplasma hyopneumoniae is involved in the porcine enzootic pneumonia and respiratory disease complex; therefore, the search for new treatment options that contribute to the control of this organism is relevant. The minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations of tylvalosin and 19 other antimicrobial agents against 20 Spanish field isolates of M. hyopneumoniae were determined using the broth microdilution method, with the type strain (J) as a control strain. Tylvalosin had MIC50 and MIC90 values of 0.016 and 0.06 µg/ml, respectively, and was the second-most effective of the assayed antibiotics, after valnemulin. Tiamulin, tylosin and lincomycin were also among the antibiotics with the lowest MIC50 and MIC90 values against the 20 field isolates (0.06-0.25 µg/ml). However, resistance to tylosin and spiramycin, which like tylvalosin, are 16-membered macrolides, was observed. The MIC50 and MIC90 values for ciprofloxacin and enrofloxacin ranged from 0.125 to 1 µg/ml; the corresponding values ranged from 2 to 4 µg/ml for oxytetracyline, which was the most active tetracycline. Furthermore, tylvalosin and valnemulin exhibited the highest bactericidal activities. In conclusion, the macrolide tylvalosin and the pleuromutilin valnemulin exhibited the highest in vitro antimicrobial activities against M. hyopneumoniae field isolates in comparison with the other tested antibiotics. British Veterinary Association.

Mutations Associated with Decreased Susceptibility to Seven Antimicrobial Families in Field and Laboratory-Derived Mycoplasma bovis Strains.

PubMed

Sulyok, Kinga M; Kreizinger, Zsuzsa; Wehmann, Enikő; Lysnyansky, Inna; Bányai, Krisztián; Marton, Szilvia; Jerzsele, Ákos; Rónai, Zsuzsanna; Turcsányi, Ibolya; Makrai, László; Jánosi, Szilárd; Nagy, Sára Ágnes; Gyuranecz, Miklós

2017-02-01

The molecular mechanisms of resistance to fluoroquinolones, tetracyclines, an aminocyclitol, macrolides, a lincosamide, a phenicol, and pleuromutilins were investigated in Mycoplasma bovis For the identification of mutations responsible for the high MICs of certain antibiotics, whole-genome sequencing of 35 M. bovis field isolates and 36 laboratory-derived antibiotic-resistant mutants was performed. In vitro resistant mutants were selected by serial passages of M. bovis in broth medium containing subinhibitory concentrations of the antibiotics. Mutations associated with high fluoroquinolones MICs were found at positions 244 to 260 and at positions 232 to 250 (according to Escherichia coli numbering) of the quinolone resistance-determining regions of the gyrA and parC genes, respectively. Alterations related to elevated tetracycline MICs were described at positions 962 to 967, 1058, 1195, 1196, and 1199 of genes encoding the 16S rRNA and forming the primary tetracycline binding site. Single transversion at position 1192 of the rrs1 gene resulted in a spectinomycin MIC of 256 μg/ml. Mutations responsible for high macrolide, lincomycin, florfenicol, and pleuromutilin antibiotic MICs were identified in genes encoding 23S rRNA. Understanding antibiotic resistance mechanisms is an important tool for future developments of genetic-based diagnostic assays for the rapid detection of resistant M. bovis strains. Copyright © 2017 American Society for Microbiology.

In Vitro Antibiotic Susceptibilities of Burkholderia mallei (Causative Agent of Glanders) Determined by Broth Microdilution and E-Test

PubMed Central

Heine, Henry S.; England, Marilyn J.; Waag, David M.; Byrne, W. Russell

2001-01-01

In vitro susceptibilities to 28 antibiotics were determined for 11 strains of Burkholderia mallei by the broth microdilution method. The B. mallei strains demonstrated susceptibility to aminoglycosides, macrolides, quinolones, doxycycline, piperacillin, ceftazidime, and imipenem. For comparison and evaluation, 17 antibiotic susceptibilities were also determined by the E-test. E-test values were always lower than the broth dilution values. Establishing and comparing antibiotic susceptibilities of specific B. mallei strains will provide reference information for assessing new antibiotic agents. PMID:11408233

Decreased Susceptibility to Ciprofloxacin among Shigella Isolates in the United States, 2006 to 2009▿

PubMed Central

Folster, Jason P.; Pecic, Gary; Bowen, Anna; Rickert, Regan; Carattoli, Alessandra; Whichard, Jean M.

2011-01-01

We characterized 20 Shigella isolates with decreased susceptibility to fluoroquinolones. Most patients (80%) from whom a travel history was obtained reported travel to South or Southeast Asia. Mutations within the quinolone resistance determining regions of gyrA and parC and plasmid-mediated resistance determinants (qnrB, qnrS, and aac(6′)-Ib-cr) were identified. The rise in antimicrobial resistance among Shigella isolates may necessitate the increased use of extended-spectrum cephalosporins or macrolides in some patients. PMID:21220535

[Legionnaires' disease: 21 cases observed over 2.5 years in a Parisian respiratory intensive care unit].

PubMed

Carette, M F; Mayaud, C; Dournon, E; Bure, A; Houacine, S; Morinière, B; Sicard, J F; Akoun, G

1985-01-01

The incidence of Legionnaire's disease is probably underestimated in France. Its clinical presentation is very suggestive, especially after the failure of a 48 hour therapeutic trial of beta-lactams, when a pneumococcal infection is initially suspected. This one sign is sufficient to orient the diagnostic survey and constitutes an indication for a therapeutic trial of macrolides for at least 72 hours. In fact, the delay in the diagnosis appears to be the determinant factor in the fatal outcome of the disease.

Phosphate Tether-Mediated Approach to the Formal Total Synthesis of (-)-Salicylihalamides A and B

PubMed Central

Chegondi, Rambabu; Tan, Mary M. L.; Hanson, Paul R.

2011-01-01

A concise formal synthesis of the cytotoxic macrolides (-)-salicylihalamides A and B is reported. Key features of the synthetic strategy include a chemoselective hydroboration, highly regio- and diastereoselective methyl cuprate addition, Pd-catalyzed formate reduction, and an E-selective ring-closing metathesis to construct the 12-membered macrocycle subunit. Overall, two routes have been developed from a readily prepared bicyclic phosphate (4-steps), a 13-step route and a more efficient 9-step sequence relying on regioselective esterification of a key diol. PMID:21504150

Concise synthesis and PTP1B inhibitory activity of (R)- and (S)-dihydroresorcylide.

PubMed

Jiang, Cheng-Shi; Zhang, Li; Gong, Jing-Xu; Li, Jing-Ya; Yao, Li-Gong; Li, Jia; Guo, Yue-Wei

2017-12-01

The present study was designed to develop a concise synthetic route for macrolide, with the purpose of confirming the absolute configuration of natural dihydroresorcylide (1) and making it more easily accessible for biological evaluation. The absolute configuration of C-3 in natural 1 was revised to be R by comparison of the rotation sign of synthetic (R)- and (S)-1. The synthetic (R)-1 was found to be a novel highly specific PTP1B inhibitor with an IC 50 value of 17.06 μM.

Jarisch-Herxheimer reaction among HIV-positive patients with early syphilis: azithromycin versus benzathine penicillin G therapy

PubMed Central

Tsai, Mao-Song; Yang, Chia-Jui; Lee, Nan-Yao; Hsieh, Szu-Min; Lin, Yu-Hui; Sun, Hsin-Yun; Sheng, Wang-Huei; Lee, Kuan-Yeh; Yang, Shan-Ping; Liu, Wen-Chun; Wu, Pei-Ying; Ko, Wen-Chien; Hung, Chien-Ching

2014-01-01

Introduction The Jarisch-Herxheimer reaction, a febrile inflammatory reaction that often occurs after the first dose of chemotherapy in spirochetal diseases, may result in deleterious effects to patients with neurosyphilis and to pregnant women. A single 2-g oral dose of azithromycin is an alternative treatment to benzathine penicillin G for early syphilis in areas with low macrolide resistance. With its potential anti-inflammatory activity, the impact of azithromycin on the incidence of the Jarisch-Herxheimer reaction in HIV-positive patients with early syphilis has rarely been investigated. Methods In HIV-positive patients with early syphilis, the Jarisch-Herxheimer reaction was prospectively investigated using the same data collection form in 119 patients who received benzathine penicillin G between 2007 and 2009 and 198 who received azithromycin between 2012 and 2013, when shortage of benzathine penicillin G occurred in Taiwan. Between 2012 and 2013, polymerase chain reaction (PCR) assay was performed to detect Treponema pallidum DNA in clinical specimens, and PCR restriction fragment length polymorphism of the 23S ribosomal RNA was performed to detect point mutations (2058G or A2059G) that are associated with macrolide resistance. Results The overall incidence of the Jarisch-Herxheimer reaction was significantly lower in patients receiving azithromycin than those receiving benzathine penicillin G (14.1% vs. 56.3%, p<0.001). The risk increased with higher rapid plasma reagin (RPR) titres (adjusted odds ratio [AOR] per 1-log2 increase, 1.21; confidence interval [CI], 1.04–1.41), but decreased with prior penicillin therapy for syphilis (AOR, 0.37; 95% CI, 0.19–0.71) and azithromycin treatment (AOR, 0.15; 95% CI, 0.08–0.29). During the study period, 310 specimens were obtained from 198 patients with syphilis for PCR assays, from whom T. pallidum was identified in 76 patients, one of whom (1.3%) was found to be infected with T. pallidum harbouring the

Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study.

PubMed

Aabenhus, Rune; Hansen, Malene Plejdrup; Saust, Laura Trolle; Bjerrum, Lars

2017-05-19

Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice. Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted. TRACKING THE OVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice. The over-use of antibiotics, particularly so

Efficacy of concurrent treatments in idiopathic pulmonary fibrosis patients with a rapid progression of respiratory failure: an analysis of a national administrative database in Japan.

PubMed

Oda, Keishi; Yatera, Kazuhiro; Fujino, Yoshihisa; Ishimoto, Hiroshi; Nakao, Hiroyuki; Hanaka, Tetsuya; Ogoshi, Takaaki; Kido, Takashi; Fushimi, Kiyohide; Matsuda, Shinya; Mukae, Hiroshi

2016-06-08

Some IPF patients show a rapid progression of respiratory failure. Most patients are treated with high-dose corticosteroids. However, no large clinical studies have investigated the prognosis or efficacy of combined treatments including high-dose corticosteroids in IPF patients with a rapid progression of respiratory failure. We enrolled IPF patients who received mechanical ventilation and high-dose corticosteroids between April 2010 and March 2013. Records were extracted from a Japanese nationwide inpatient database. We conducted a retrospective epidemiologic and prognostic analysis. Two hundred nine patients receiving an average of 12.8 days of ventilatory support were enrolled. There were 138 (66 %) fatal cases; the median survival was 21 days. The short-term (within 30 days) and long-term (within 90 days) survival rates were 44.6 and 24.6 %, respectively. The average monthly admission rate among the IPF patients with the rapid progression of respiratory failure in the winter was significantly higher than that in spring (p = 0.018). Survival did not differ to a statistically significant extent in the different geographic areas of Japan. Survivors were significantly younger (p = 0.002) with higher rates of mild dyspnea on admission (p = 0.012), they more frequently underwent bronchoscopy (p < 0.001), and received anticoagulants (p = 0.027), co-trimoxazole (p < 0.001) and macrolide (p = 0.02) more frequently than non-survivors. A multivariate logistic analysis demonstrated that two factors were significantly associated with a poor prognosis: >80 years of age (OR = 2.94, 95 % Cl 1.044-8.303; p = 0.041) and the intravenous administration of high-dose cyclophosphamide (OR = 3.17, 95 % Cl 1.101-9.148; p = 0.033). Undergoing bronchoscopy during intubation (OR = 0.25, 95 % Cl 0.079-0.798; p = 0.019) and the administration of co-trimoxazole (OR = 0.28, 95 % Cl 0.132-0.607; p = 0.001) and macrolides

NOVEL ANTIBIOTIC RESISTANCE DETERMINANTS FROM AGRICULTURAL SOIL EXPOSED TO ANTIBIOTICS WIDELY USED IN HUMAN MEDICINE AND ANIMAL FARMING.

PubMed

Lau, Calvin Ho-Fung; van Engelen, Kalene; Gordon, Stephen; Renaud, Justin; Topp, Edward

2017-06-16

Antibiotic resistance has emerged globally as one of the biggest threats to human and animal health. Although the excessive use of antibiotics is recognized for accelerating the selection for resistance, there is a growing body of evidence suggesting that natural environments are "hotspots" for the development of both ancient and contemporary resistance mechanisms. Given that pharmaceuticals can be entrained onto agricultural land through anthropogenic activities, this could be a potential driver for the emergence and dissemination of resistance in soil bacteria. Using functional metagenomics, we interrogated the "resistome" of bacterial communities found in a collection of Canadian agricultural soil, some of which had been receiving antibiotics widely used in human medicine (macrolides) or food animal production (sulfamethazine, chlortetracycline and tylosin) for up to 16 years. Of the 34 new antibiotic resistance genes (ARGs) recovered, the majority were predicted to encode for (multi)drug efflux systems, while a few share little to no homology with established resistance determinants. We characterized several novel gene products, including putative enzymes that can confer high-level resistance against aminoglycosides, sulfonamides, and broad range of beta-lactams, with respect to their resistance mechanisms and clinical significance. By coupling high-resolution proteomics analysis with functional metagenomics, we discovered an unusual peptide, PPP AZI 4 , encoded within an alternative open-reading frame not predicted by bioinformatics tools. Expression of the proline-rich PPP AZI 4 can promote resistance against different macrolides but not other ribosomal-targeting antibiotics, implicating a new macrolide-specific resistance mechanism that could be fundamentally linked to the evolutionary design of this peptide. IMPORTANCE Antibiotic resistance is a clinical phenomenon with an evolutionary link to the microbial pangenome. Genes and protogenes encoding for

Changes in Enterococcal Populations and Related Antibiotic Resistance along a Medical Center-Wastewater Treatment Plant-River Continuum

PubMed Central

Oberlé, Kenny; Galopin, Sébastien; Cattoir, Vincent; Budzinski, Hélène; Petit, Fabienne

2013-01-01

To determine if hospital effluent input has an ecological impact on downstream aquatic environment, antibiotic resistance in Enterococcus spp. along a medical center-retirement home-wastewater treatment plant-river continuum in France was determined using a culture-based method. Data on antibiotic consumption among hospitalized and general populations and levels of water contamination by antibiotics were collected. All isolated enterococci were genotypically identified to the species level, tested for in vitro antibiotic susceptibility, and typed by multilocus sequence typing. The erm(B) and mef(A) (macrolide resistance) and tet(M) (tetracycline resistance) genes were detected by PCR. Along the continuum, from 89 to 98% of enterococci, according to the sampled site, were identified as Enterococcus faecium. All E. faecium isolates from hospital and retirement home effluents were multiply resistant to antibiotics, contained erm(B) and mef(A) genes, and belonged to hospital-adapted clonal complex 17 (CC17). Even though this species remained dominant in the downstream continuum, the relative proportion of CC17 isolates progressively decreased in favor of other subpopulations of E. faecium that were more diverse, less resistant to antibiotics, and devoid of the classical macrolide resistance genes and that belonged to various sequence types. Antibiotic concentrations in waters were far below the MICs for susceptible isolates. CC17 E. faecium was probably selected in the gastrointestinal tract of patients under the pressure of administered antibiotics and then excreted together with the resistance genes in waters to progressively decrease along the continuum. PMID:23377946

The hospitalist perspective on treatment of community-acquired bacterial pneumonia.

PubMed

Amin, Alpesh N; Cerceo, Elizabeth A; Deitelzweig, Steven B; Pile, James C; Rosenberg, David J; Sherman, Bradley M

2014-03-01

Community-acquired bacterial pneumonia (CABP) is an important health care concern in the United States and worldwide, and is associated with significant morbidity, mortality, and health care expenditure. Streptococcus pneumoniae is the most frequent causative pathogen of CABP. Other common pathogens include Staphylococcus aureus, Haemophilus influenzae, Enterobacteriaceae, Legionella pneumophila, Mycoplasma pneumoniae, and Chlamydophila pneumoniae. However, in clinical practice, the causative pathogen of CABP is most often not identified. Therefore, a common treatment approach for patients hospitalized with CABP is empiric antibiotic therapy with a β-lactam in combination with a macrolide, respiratory fluoroquinolones, or tetracyclines. An increase in the incidence of S. pneumoniae that is resistant to frequently used antibiotics, including β-lactams, macrolides, and tetracyclines, provides a challenge for the physician when selecting empiric antimicrobial therapy. When patients with CABP do not respond to initial therapy, they must be adequately reevaluated with further diagnostic testing, change in antimicrobial regimen, and/or transfer of the patient to a higher level of care. The role of hospital medicine physicians is crucial in treating patients who are hospitalized with CABP. An important focus of hospitalists is to provide care improvement in a way that addresses both patient and hospital needs. It is essential that the hospitalist provides best possible patient care, including adherence to quality measures, optimizing the patient's hospital length of stay, and arranging adequate post-discharge care in an effort to prevent readmission and provide appropriate ongoing outpatient care.

In vitro antimicrobial susceptibility of Mycoplasma bovis isolated in Israel from local and imported cattle.

PubMed

Gerchman, Irena; Levisohn, Sharon; Mikula, Inna; Lysnyansky, Inna

2009-06-12

Monitoring of susceptibility to antibiotics in field isolates of pathogenic bovine mycoplasmas is important for appropriate choice of treatment. Our study compared in vitro susceptibility profiles of Mycoplasma bovis clinical strains, isolated during 2005-2007 from Israeli and imported calves. Minimal inhibitory concentration (MIC) values were determined for macrolides by the microbroth dilution test, for aminoglycosides by commercial Etest, and for fluoroquinolones and tetracyclines by both methods. Notably, although correlation between the methods was generally good, it was not possible to determine the MIC endpoint for enrofloxacin-resistant strains (MIC > or =2.5 microg/ml in the microtest) by Etest. Comparison of antibiotic susceptibility profiles between local and imported M. bovis strains revealed that local strains were significantly more resistant to macrolides than most isolates from imported animals, with MIC(50) of 128 microg/ml vs. 2 microg/ml for tilmicosin and 8 microg/ml vs. 1 microg/ml for tylosin, respectively. However, local strains were more susceptible than most imported strains to fluoroquinolones and spectinomycin. Difference in susceptibility to tetracycline, doxycycline and oxytetracycline between local and imported strains was expressed in MIC(90) values for imported strains in the susceptible range compared to intermediate susceptibility for local strains. The marked difference in susceptibility profiles of M. bovis strains isolated from different geographical regions seen in this study emphasizes the necessity for performing of the antimicrobial susceptibility testing periodically and on a regional basis.

Afebrile pneumonia (whooping cough) syndrome in infants at Hospital Universitario del Valle, Cali, 2001-2007

PubMed Central

Villegas, Dolly; Echandía-Villegas, Connie Alejandra

2012-01-01

Introduction: Afebrile pneumonia syndrome in infants, also called infant pneumonitis, pneumonia caused by atypical pathogens or whooping cough syndrome is a major cause of severe lower respiratory infection in young infants, both in developing countries and in developed countries. Objective: To describe children with afebrile pneumonia syndrome. Methods: Through a cross-sectional study, we reviewed the medical records of children diagnosed with afebrile pneumonia treated at Hospital Universitario del Valle, a reference center in southwestern Colombia, between June 2001 and December 2007. We obtained data on maternal age and origin, prenatal care, the childs birth, breastfeeding, vaccination status, symptoms, signs, diagnosis, treatment, and complications. Results: We evaluated 101 children with this entity, noting a stationary presentation: June-August and November- December. A total of 73% of the children were under 4 months of age; the most common symptoms were: cyanotic and spasmodic cough (100%), respiratory distress (70%), and unquantified fever (68%). The most common findings: rales (crackles) (50%), wheezing and expiratory stridor (37%); 66% were classified as mild and of the remaining 33%, half of them required attention in the intensive care unit. In all, there was clinical diagnosis of afebrile pneumonia syndrome in infants, but no etiologic diagnosis was made and despite this, 94% of the children received macrolides. Conclusions: These data support the hypothesis that most of these patients acquired the disease by airway, possibly caused by viral infection and did not require the indiscriminate use of macrolides. PMID:24893051

Analysis of resistance genes of clinical Pannonibacter phragmitetus strain 31801 by complete genome sequencing.

PubMed

Ming, De-Song; Chen, Qing-Qing; Chen, Xiao-Tin

2018-05-14

To clarify the resistance mechanisms of Pannonibacter phragmitetus 31801, isolated from the blood of a liver abscess patient, at the genomic level, we performed whole genomic sequencing using a PacBio RS II single-molecule real-time long-read sequencer. Bioinformatic analysis of the resulting sequence was then carried out to identify any possible resistance genes. Analyses included Basic Local Alignment Search Tool searches against the Antibiotic Resistance Genes Database, ResFinder analysis of the genome sequence, and Resistance Gene Identifier analysis within the Comprehensive Antibiotic Resistance Database. Prophages, clustered regularly interspaced short palindromic repeats (CRISPR), and other putative virulence factors were also identified using PHAST, CRISPRfinder, and the Virulence Factors Database, respectively. The circular chromosome and single plasmid of P. phragmitetus 31801 contained multiple antibiotic resistance genes, including those coding for three different types of β-lactamase [NPS β-lactamase (EC 3.5.2.6), β-lactamase class C, and a metal-dependent hydrolase of β-lactamase superfamily I]. In addition, genes coding for subunits of several multidrug-resistance efflux pumps were identified, including those targeting macrolides (adeJ, cmeB), tetracycline (acrB, adeAB), fluoroquinolones (acrF, ceoB), and aminoglycosides (acrD, amrB, ceoB, mexY, smeB). However, apart from the tripartite macrolide efflux pump macAB-tolC, the genome did not appear to contain the complete complement of subunit genes required for production of most of the major multidrug-resistance efflux pumps.

Use of microbial cultures and antibiotics in the prevention of infection-associated preterm birth.

PubMed

Klein, Laura L; Gibbs, Ronald S

2004-06-01

The purpose of this study was to summarize recent evidence regarding infection-associated preterm birth and to make appropriate recommendations. Antepartum treatment of lower genital tract infection or bacterial colonization has been found to reduce the incidence of preterm birth in the case of asymptomatic bacteriuria and bacterial vaginosis in selected patients but has been proved to be ineffective for vaginal colonization with organisms such as Ureaplasma urealyticum and group B streptococcus. This is a clinical opinion based on a review of recent data related to 1) the association between lower genital tract infection and preterm birth and 2) antibiotic trials to prevent preterm birth. Antepartum treatment of lower genital tract infection or bacterial colonization has been found to reduce the incidence of preterm birth in the case of asymptomatic bacteriuria and bacterial vaginosis in selected patients, but has been proven to be ineffective for vaginal colonization with organisms such as Ureaplasma urealyticum and group B streptococcus. Large well-designed trials have shown that the routine administration of antibiotics to women with preterm labor and intact membranes is not beneficial; however, antibiotic regimens including macrolides are recommended for preterm premature rupture of the membranes. Large well-designed trials have shown that the routine administration of antibiotics to women with preterm labor and intact membranes is not beneficial; however, antibiotic regimens that include macrolides are recommended for preterm premature rupture of the membranes.

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.

Afebrile pneumonia (whooping cough) syndrome in infants at Hospital Universitario del Valle, Cali, 2001-2007.

PubMed

Villegas, Dolly; Echandía-Villegas, Connie Alejandra; Echandía, Carlos Armando

2012-04-01

Afebrile pneumonia syndrome in infants, also called infant pneumonitis, pneumonia caused by atypical pathogens or whooping cough syndrome is a major cause of severe lower respiratory infection in young infants, both in developing countries and in developed countries. To describe children with afebrile pneumonia syndrome. Through a cross-sectional study, we reviewed the medical records of children diagnosed with afebrile pneumonia treated at Hospital Universitario del Valle, a reference center in southwestern Colombia, between June 2001 and December 2007. We obtained data on maternal age and origin, prenatal care, the childs birth, breastfeeding, vaccination status, symptoms, signs, diagnosis, treatment, and complications. We evaluated 101 children with this entity, noting a stationary presentation: June-August and November- December. A total of 73% of the children were under 4 months of age; the most common symptoms were: cyanotic and spasmodic cough (100%), respiratory distress (70%), and unquantified fever (68%). The most common findings: rales (crackles) (50%), wheezing and expiratory stridor (37%); 66% were classified as mild and of the remaining 33%, half of them required attention in the intensive care unit. In all, there was clinical diagnosis of afebrile pneumonia syndrome in infants, but no etiologic diagnosis was made and despite this, 94% of the children received macrolides. These data support the hypothesis that most of these patients acquired the disease by airway, possibly caused by viral infection and did not require the indiscriminate use of macrolides.

Serotypes, Antibiotic Susceptibilities, and Multi-Locus Sequence Type Profiles of Streptococcus agalactiae Isolates Circulating in Beijing, China

PubMed Central

Ma, Xiu-hua; Song, Feng-li; Fan, Ling; Guo, Cui-mei; Shi, Wei; Yu, Sang-jie; Yao, Kai-hu; Yang, Yong-hong

2015-01-01

Background To investigate the serotypes, antibiotic susceptibilities, and multi-locus sequence type (MLST) profiles of Streptococcus agalactiae (S. agalactiae) in Beijing to provide references for the prevention and treatment of S. agalactiae infections. Methods All isolates were identified using the CAMP test and the latex-agglutination assay and serotyped using a Strep-B-Latex kit, after which they were assessed for antibiotic susceptibility, macrolide-resistance genes, and MLST profiles. Results In total, 56 S. agalactiae isolates were identified in 863 pregnant women (6.5%). Serotypes Ia, Ib, II, III, and V were identified, among which types III (32.1%), Ia (17.9%), Ib (16.1%), and V (14.3%) were the predominant serotypes. All isolates were susceptible to penicillin and ceftriaxone. The nonsusceptiblity rates measured for erythromycin, clarithromycin, azithromycin, telithromycin, clindamycin, tetracycline, and levofloxacin were 85.7%, 92.9%, 98.2%, 30.4%, 73.2%, 91%, and 39.3%, respectively. We identified 14 sequence types (STs) for the 56 isolates, among which ST19 (30.4%) was predominant. The rate of fluoroquinolone resistance was higher in serotype III than in the other serotypes. Among the 44 erythromycin-resistant isolates, 32 (72.7%) carried ermB. Conclusion S. agalactiae isolates of the serotypes Ia, Ib, III, and V are common in Beijing. Among the S. agalactiae isolates, the macrolide and clindamycin resistance rates are extremely high. Most of the erythromycin-resistant isolates carry ermB. PMID:25781346

Application of passive sampling in assessing the occurrence and risk of antibiotics and endocrine disrupting chemicals in the Yangtze Estuary, China.

PubMed

Shi, X; Zhou, J L; Zhao, H; Hou, L; Yang, Y

2014-09-01

Polar organic chemical integrative sampler (POCIS) was used in assessing the occurrence and risk of 12 widely used antibiotics and 5 most potent endocrine disrupting chemicals (EDCs) in the Yangtze Estuary, China. During laboratory validation, the kinetics of pollutant uptake by POCIS were linear, and the sampling rates of most compounds were raised by flow rate and salinity, reaching the highest values at salinity 14‰. The sampling rates varied with the target compounds with the EDCs showing the highest values (overall average=0.123Ld(-1)), followed by chloramphenicols (0.100Ld(-1)), macrolides (0.089Ld(-1)), and finally sulfonamides (0.056Ld(-1)). Validation in the Yangtze Estuary in 2013 showed that the field sampling rates were significantly greater for all compounds except bisphenol A, in comparison to laboratory results, and high-frequency spot sampling is critical for fully validating the passive sampler. The field studies show that antibiotics were widely detected in the Yangtze Estuary, with concentrations varying from below quantification to 1613ngL(-1), suggesting their widespread use and persistence in estuarine waters. The dominating pollutants in July were sulfonamides with a total concentration of 258ngL(-1) and in October were macrolides with a total concentration of 350ngL(-1). The calculation of risk quotient suggested that sulfapyridine, sulfaquinoxaline and erythromycin-H2O may have caused medium damage to sensitive organisms such as fish. Copyright © 2014. Published by Elsevier Ltd.

The generalizability of bronchiectasis randomized controlled trials: A multicentre cohort study.

PubMed

Chalmers, James D; McDonnell, Melissa J; Rutherford, Robert; Davidson, John; Finch, Simon; Crichton, Megan; Dupont, Lieven; Hill, Adam T; Fardon, Thomas C; De Soyza, Anthony; Aliberti, Stefano; Goeminne, Pieter

2016-03-01

Randomized controlled trials (RCTs) for bronchiectasis have experienced difficulties with recruitment and in reaching their efficacy end-points. To estimate the generalizability of such studies we applied the eligibility criteria for major RCTs in bronchiectasis to 6 representative observational European Bronchiectasis cohorts. Inclusion and exclusion criteria from 10 major RCTs were applied in each cohort. Demographics and outcomes were compared between patients eligible and ineligible for RCTs. 1672 patients were included. On average 33.0% were eligible for macrolide trials, 15.0% were eligible for inhaled antibiotic trials, 15.9% for the DNAse study and 47.7% were eligible for a study of dry powder mannitol. Within these groups, some trials were highly selective with only 1-9% of patients eligible. Eligible patients were generally more severe with higher mortality during follow-up (mean 17.2 vs 9.0% for macrolide studies, 19.2%% vs 10.7% for inhaled antibiotic studies), and a higher frequency of exacerbations than ineligible patients. As up to 93% of patients were ineligible for studies, however, numerically more deaths and exacerbations occurred in ineligible patient across studies (mean 56% of deaths occurred in ineligible patients across all studies). Our data suggest that patients enrolled in RCT's in bronchiectasis are only partially representative of patients in clinical practice. The majority of mortality and morbidity in bronchiectasis occurs in patients ineligible for many current trials. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

AFNOR validation of Premi Test, a microbiological-based screening tube-test for the detection of antimicrobial residues in animal muscle tissue.

PubMed

Gaudin, Valerie; Juhel-Gaugain, Murielle; Morétain, Jean-Pierre; Sanders, Pascal

2008-12-01

Premi Test contains viable spores of a strain of Bacillus stearothermophilus which is sensitive to antimicrobial residues, such as beta-lactams, tetracyclines, macrolides and sulphonamides. The growth of the strain is inhibited by the presence of antimicrobial residues in muscle tissue samples. Premi Test was validated according to AFNOR rules (French Association for Normalisation). The AFNOR validation was based on the comparison of reference methods (French Official method, i.e. four plate test (FPT) and the STAR protocol (five plate test)) with the alternative method (Premi Test). A preliminary study was conducted in an expert laboratory (Community Reference Laboratory, CRL) on both spiked and incurred samples (field samples). Several method performance criteria (sensitivity, specificity, relative accuracy) were estimated and are discussed, in addition to detection capabilities. Adequate agreement was found between the alternative method and the reference methods. However, Premi Test was more sensitive to beta-lactams and sulphonamides than the FPT. Subsequently, a collaborative study with 11 laboratories was organised by the CRL. Blank and spiked meat juice samples were sent to participants. The expert laboratory (CRL) statistically analysed the results. It was concluded that Premi Test could be used for the routine determination of antimicrobial residues in muscle of different animal origin with acceptable analytical performance. The detection capabilities of Premi Test for beta-lactams (amoxicillin, ceftiofur), one macrolide (tylosin) and tetracycline were at the level of the respective maximum residue limits (MRL) in muscle samples or even lower.

Antimicrobial Use and Resistance in Swine Waste Treatment Systems▿

PubMed Central

Jindal, Archana; Kocherginskaya, Svetlana; Mehboob, Asma; Robert, Matthew; Mackie, Roderick I.; Raskin, Lutgarde; Zilles, Julie L.

2006-01-01

Chlortetracycline and the macrolide tylosin were identified as commonly used antimicrobials for growth promotion and prophylaxis in swine production. Resistance to these antimicrobials was measured throughout the waste treatment processes at five swine farms by culture-based and molecular methods. Conventional farm samples had the highest levels of resistance with both culture-based and molecular methods and had similar levels of resistance despite differences in antimicrobial usage. The levels of resistance in organic farm samples, where no antimicrobials were used, were very low by a culture-based method targeting fecal streptococci. However, when the same samples were analyzed with a molecular method detecting methylation of a specific nucleotide in the 23S rRNA that results in resistance to macrolides, lincosamides, and streptogramin B (MLSB), an unexpectedly high level of resistant rRNA (approximately 50%) was observed, suggesting that the fecal streptococci were not an appropriate target group to evaluate resistance in the overall microbial community and that background levels of MLSB resistance may be substantial. All of the feed samples tested, including those from the organic farm, contained tetracycline resistance genes. Generally, the same tetracycline resistance genes and frequency of detection were found in the manure and lagoon samples for each commercial farm. The levels of tetracycline and MLSB resistance remained high throughout the waste treatment systems, suggesting that the potential impact of land application of treated wastes and waste treatment by-products on environmental levels of resistance should be investigated further. PMID:17041160

Insights into the metabolic mechanism of rapamycin overproduction in the shikimate-resistant Streptomyces hygroscopicus strain UV-II using comparative metabolomics.

PubMed

Geng, Huiyan; Liu, Huanhuan; Liu, Jiao; Wang, Cheng; Wen, Jianping

2017-06-01

Rapamycin is a polyketide with a 31-membered macrolide ring that possesses powerful immunosuppressant activity. In this study, we firstly obtained a mutant, shikimate-resistant Streptomyces hygroscopicus strain UV-II, which displayed about 3.20-fold higher rapamycin production (305.9 mg/L) than the wild-type S. hygroscopicus ATCC29253 (95.5 mg/L). Under optimal conditions, with the addition of 2 g/L shikimic acid, the strain's rapamycin production was further increased by approximately 34.9%, to 412.6 mg/L. To gain deeper insights into the effects of shikimic acid resistance and supplementation, the fermentation properties, metabolite concentrations, and transcriptional levels of relevant genes were analyzed and evaluated for differences between this improved mutant and its parental strain. The results showed that most of the metabolic modules involved in rapamycin biosynthesis were upregulated in the mutant strain. Analysis of metabolic pathways and gene expression levels further revealed that shikimic acid metabolism plays a crucial role in the synthesis of rapamycin, and identified the rapK gene as a potential target for genetic manipulation to obtain rapamycin-producing strains with improved product yield. Consequently, the rapK gene was overexpressed in the UV-II strain, which to our delight further improved rapamycin production to 457.3 mg/L. These findings thus provide a theoretical basis for further improvements in the production of not only rapamycin, but also of other, analogous macrolide compounds.

Trends and patterns of antibiotic consumption in China's tertiary hospitals: Based on a 5 year surveillance with sales records, 2011-2015.

PubMed

Wushouer, Haishaerjiang; Tian, Ye; Guan, Xiao-Dong; Han, Sheng; Shi, Lu-Wen

2017-01-01

The consumption of antibiotics is a major driver in the development of antimicrobial resistance. This study aims to identify the trends and patterns of the total antibiotic consumption in China's tertiary hospitals from 2011 to 2015 by retrospectively analyzing aggregated monthly surveillance data on antibiotic sales made to 468 hospitals from 28 provinces. Antibiotic consumption was expressed in DDD per 1,000 inhabitants per day (DID). We compared population weighted antibiotic consumption patterns in China with European countries using indicators from the European Surveillance of Antimicrobial Consumption (ESAC). Total antibiotic consumption, including all the specific antibiotic class except for aminoglycoside antibacterials, were significantly increased during the study period from an average of 7.97 DID in 2011 to 10.08 DID in 2015. In 2015, the eastern regions of China consumed the most antibiotics using population denominator while the western regions consumed the most using inpatient denominator. Cephalosporins accounted for 28.6% of total DID, followed by beta-lactam-beta-lactamase inhibitor combinations (20.0%), macrolides (17.4%), and fluoroquinolones (10.5%). Antibiotic in parenteral form accounted for nearly half of all antibiotics. Although over the past few years major efforts had been made to reduce the risks of excessive antibiotic use through antibiotic stewardship, total antibiotic consumption showed a significant upward trend during the study period. A consistent preference for cephalosporins, macrolides, beta-lactam-beta-lactamase inhibitor combinations, as well as parenteral preparations was observed.

Diagnosis and Treatment of Nontuberculous Mycobacterial Lung Disease.

PubMed

Kwon, Yong-Soo; Koh, Won-Jung

2016-05-01

Nontuberculous mycobacteria (NTM) are ubiquitous organisms; their isolation from clinical specimens does not always indicate clinical disease. The incidence of NTM lung diseases has been increasing worldwide. Although the geographic diversity of NTM species is well known, Mycobacterium avium complex (MAC), M. abscessus complex (MABC), and M. kansasii are the most commonly encountered and important etiologic organisms. Two distinct types of NTM lung diseases have been reported, namely fibrocavitary and nodular bronchiectatic forms. For laboratory diagnosis of NTM lung diseases, both liquid and solid media cultures and species-level identification are strongly recommended to enhance growth detection and determine the clinical relevance of isolates. Treatment for NTM lung diseases consists of a multidrug regimen and a long course of therapy, lasting more than 12 months after negative sputum conversion. For MAC lung disease, several new macrolide-based regimens are now recommended. For nodular bronchiectatic forms of MAC lung diseases, an intermittent three-time-weekly regimen produces outcomes similar to those of daily therapy. Treatment of MABC lung disease is very difficult, requiring long-term use of parenteral agents in combination with new macrolides. Treatment outcomes are much better for M. massiliense lung disease than for M. abscessus lung disease. Thus, precise identification of species in MABC infection is needed for the prediction of antibiotic response. Likewise, increased efforts to improve treatment outcomes and develop new agents for NTM lung disease are needed.

Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3).

PubMed

Hattori, Hiromu; Kaufmann, Elias; Miyatake-Ondozabal, Hideki; Berg, Regina; Gademann, Karl

2018-04-12

The commercial macrolide antibiotic fidaxomicin was synthesized in a highly convergent manner. Salient features of this synthesis include a β-selective noviosylation, a β-selective rhamnosylation, a ring-closing metathesis, a Suzuki coupling, and a vinylogous Mukaiyama aldol reaction. Careful choice of protecting groups and fine-tuning of the glycosylation reactions led to the first total synthesis of fidaxomicin. In addition, a relay synthesis of fidaxomicin was established, which gives access to a conveniently protected intermediate from the natural material for derivatization. The first total synthesis of a related congener, tiacumicin A, is presented.

Update on bacterial pneumonia in the foal and weanling.

PubMed

Reuss, Sarah M; Cohen, Noah D

2015-04-01

Bacterial pneumonia is a common cause of disease in both neonatal and weanling foals. The causal organism or organisms differ with the age of the foal, should be identified via microbiologic culture, and will ultimately dictate appropriate treatment. Initial treatment in neonates should be broad spectrum and bactericidal, whereas weanling age foals may receive more targeted treatment. The combination of a macrolide antibiotic and rifampin remains the gold standard for treatment of Rhodococcus equi pneumonia; however, resistance to these antimicrobials is a concern. Copyright © 2015 Elsevier Inc. All rights reserved.

Oxidation of brefeldin A.

PubMed

Proksa, B; Uhrin, D; Adamcová, J; Fuska, J

1992-08-01

Oxidation of the macrolide antibiotic brefeldin A with pyridinium chlorochromate adsorbed on alumina afforded [6S, 10E, 11aS, 14E]-6-methyl-2,3,6,7,8,9,11a,12-octahydro-4 H-cyclopent[f]oxacyclotridecin-1,4,13-trione together with 13-oxobrefeldin. These compounds showed higher cytotoxic activity on P388 leukemia cells than brefeldin A, brefeldin A-1,13-diacetate, brefeldin A-13-acetate, tetrahydrobrefeldin or tetrahydrobrefeldin-1,13-dione. 13-Oxobrefeldin exceeded brefeldin A in antifungal activity on Candida albicans.

[Streptococcus pyogenes or group A streptococcal infections in child: French national reference center data].

PubMed

Bidet, P; Plainvert, C; Doit, C; Mariani-Kurkdjian, P; Bonacorsi, S; Lepoutre, A; Bouvet, A; Poyart, C; Bingen, E

2010-02-01

Since the 1980s, infections due to Streptococcus pyogenes or group A streptococci (GAS) were marked by the increase in invasive infections and the emergence of clones which were resistant to macrolides. Those challenges led the French national reference center for streptococci to enhance the epidemiological survey and the characterization of GAS strains, in collaboration with the National Institute for Public Health Surveillance. Active surveillance is of major importance for implementation of therapeutic and prophylactic guidelines and for evaluation of future streptococcal vaccines. Copyright 2009 Elsevier Masson SAS. All rights reserved.

Antibiotics for the treatment of rheumatoid arthritis

PubMed Central

Ogrendik, Mesut

2014-01-01

Antibiotic treatment for rheumatoid arthritis (RA) commenced in the 1930s with the use of sulfasalazine. Later, tetracyclines were successfully used for the treatment of RA. In double-blind and randomized studies, levofloxacin and macrolide antibiotics (including clarithromycin and roxithromycin) were also shown to be effective in the treatment of RA. There have been several reports in the literature indicating that periodontal pathogens are a possible cause of RA. Oral bacteria are one possible cause of RA. In this review, we aimed to investigate the effects of different antibiotics in RA treatment. PMID:24403843

Macrolide Antibiotics Improve Phagocytic Capacity and Reduce Inflammation In Sulfur Mustard-Exposed Monocytes

DTIC Science & Technology

2008-12-01

phagocytotic function and on inflammatory cytokines/mediators production in vitro using SM-exposed monocyte THP - 1 cells. Using flow cytometry we found...in vitro using SM-exposed monocyte THP - 1 cells. 2. MATERIALS AND METHODS 2.1 Reagents Sulfur mustard (2,2’-dichlorodiethyl sulfide; 4 mM) was...monocyte THP - 1 cells were obtained from ATCC (Manassas, VA). Cells were grown as suspension in the optimized media as formulated by the manufacturer and

Mass loading and emission of thirty-seven pharmaceuticals in a typical municipal wastewater treatment plant in Hunan Province, Southern China.

PubMed

Lin, Huiju; Li, Haipu; Chen, Leilei; Li, Lei; Yin, Ling; Lee, Hsiaowan; Yang, Zhaoguang

2018-01-01

The occurrence, fate, mass loading and environmental emission of 37 pharmaceuticals were studied through an integrated approach involving both dissolved and adsorbed phase at a typical wastewater treatment plant in Hunan Province, Southern China. The results displayed the prevalence of 24 and 23 compounds in dissolved phase of influent and effluent, respectively. Fourteen compounds were found adsorbed onto sludge with a mean concentration ranging from 0.85 to 2900μg/kg dry weight. Twelve compounds exhibited high adsorption potential onto suspended particulate matter (SPM) with a mean fraction ranging from 8.8% (trimethoprim) to 97% (tetracycline). Furthermore, SPM showed a diverse absorbability in influent and effluent water circumstance. The overall elimination varied from -16% for lincomycin to 99% for paracetamol, while macrolides were able to withstand the whole treatment process. Mass balance analysis indicated that degradation was the predominant removal pathway for most compounds, and adsorption onto sludge combined with a minor portion of degradation explained for the reduction of tetracyclines and fluoroquinolones, whereas macrolides were recalcitrant to both two processes. The total mass loading was estimated to be up to 2800mg/d/1000 inhabitants and most compounds exhibited lower or comparable level comparing to the global published data. The total environmental emission was estimated up to be 1000mg/d/1000 inhabitants, and a value of 650mg/d/1000 inhabitants was obtained when considering merely the dissolved phase. This work would be helpful for the better understanding of ultimate fate and real pollution of pharmaceuticals in the water environment. Copyright © 2017 Elsevier Inc. All rights reserved.

Distribution, mass load and environmental impact of multiple-class pharmaceuticals in conventional and upgraded municipal wastewater treatment plants in East China.

PubMed

Yuan, Xiangjuan; Qiang, Zhimin; Ben, Weiwei; Zhu, Bing; Qu, Jiuhui

2015-03-01

The occurrence, fate and environmental impact of 30 pharmaceuticals including sulfonamides, fluoroquinolones, tetracyclines, macrolides, dihydrofolate reductase inhibitors, β-blockers, antiepileptics, lipid regulators, and stimulants were studied in two municipal wastewater treatment plants (WWTPs) located in Wuxi City, East China. A total of 23 pharmaceuticals were detected in wastewater samples, with a maximum concentration of 16.1 μg L(-1) (caffeine) in the influent and 615.5 ng L(-1) (azithromycin) in the effluent; 19 pharmaceuticals were detected in sludge samples at concentrations up to 12.13 mg kg(-1), with ofloxacin, azithromycin and norfloxacin being the predominant species. Mass balance analysis showed that biodegradation primarily accounted for the removal of sulfonamides, most of the macrolides, and other miscellaneous pharmaceuticals, while adsorption onto the sludge was the primary removal pathway for fluoroquinolones, tetracylines, and azithromycin during biological treatment. The total mass loads of target pharmaceuticals per capita in the two WWTPs were in the ranges of 2681.8-4333.3, 248.0-416.6 and 214.6-374.5 μg per day per inhabitant in the influent, effluent and dewatered sludge, respectively. The upgraded Plant A adopting the combined anaerobic/anoxic/oxic and moving bed biofilm process exhibited a much higher removal of target pharmaceuticals than the conventional Plant B adopting the C-Orbal oxidation ditch process. The concentration levels of sulfamethoxazole, ofloxacin, ciprofloxacin and clarithromycin in the effluent, ofloxacin in the sludge, and the mixture of all target pharmaceuticals in both effluent and sludge posed a high risk to algae in aquatic environments.

Improved detection of multiple environmental antibiotics through an optimized sample extraction strategy in liquid chromatography-mass spectrometry analysis.

PubMed

Yi, Xinzhu; Bayen, Stéphane; Kelly, Barry C; Li, Xu; Zhou, Zhi

2015-12-01

A solid-phase extraction/liquid chromatography/electrospray ionization/multi-stage mass spectrometry (SPE-LC-ESI-MS/MS) method was optimized in this study for sensitive and simultaneous detection of multiple antibiotics in urban surface waters and soils. Among the seven classes of tested antibiotics, extraction efficiencies of macrolides, lincosamide, chloramphenicol, and polyether antibiotics were significantly improved under optimized sample extraction pH. Instead of only using acidic extraction in many existing studies, the results indicated that antibiotics with low pK a values (<7) were extracted more efficiently under acidic conditions and antibiotics with high pK a values (>7) were extracted more efficiently under neutral conditions. The effects of pH were more obvious on polar compounds than those on non-polar compounds. Optimization of extraction pH resulted in significantly improved sample recovery and better detection limits. Compared with reported values in the literature, the average reduction of minimal detection limits obtained in this study was 87.6% in surface waters (0.06-2.28 ng/L) and 67.1% in soils (0.01-18.16 ng/g dry wt). This method was subsequently applied to detect antibiotics in environmental samples in a heavily populated urban city, and macrolides, sulfonamides, and lincomycin were frequently detected. Antibiotics with highest detected concentrations were sulfamethazine (82.5 ng/L) in surface waters and erythromycin (6.6 ng/g dry wt) in soils. The optimized sample extraction strategy can be used to improve the detection of a variety of antibiotics in environmental surface waters and soils.

Isolation of a new broad spectrum antifungal polyene from Streptomyces sp. MTCC 5680.

PubMed

Vartak, A; Mutalik, V; Parab, R R; Shanbhag, P; Bhave, S; Mishra, P D; Mahajan, G B

2014-06-01

A new polyene macrolide antibiotic PN00053 was isolated from the fermentation broth of Streptomyces sp. wild-type strain MTCC-5680. The producer strain was isolated from fertile mountain soil of Naldehra region, Himachal Pradesh, India. The compound PN00053 was purified through various steps of chromatographic techniques and bio-activity guided fractionation followed by its characterization using physiochemical properties, spectral data ((1) H-NMR, (13) C-NMR, HMBC, HSQC, and COSY) and MS analysis. PN00053 exhibited broad spectrum in vitro antifungal activity against strains of Aspergillus fumigatus (HMR), A. fumigatus ATCC 16424, Candida albicans (I.V.), C. albicans ATCC 14503, C. krusei GO6, C. glabrata HO4, Cryptococcus neoformans, Trichophyton sp. as well as fluconazole resistant strains C. krusei GO3 and C. glabrata HO5. It did not inhibit growth of gram positive and gram-negative bacteria, displaying its specificity against fungi. PN00053 is a novel polyene macrolide isolated from a wild strain of Streptomyces sp. PM0727240 (MTCC5680), an isolate from the mountainous rocky regions of Himachal Pradesh, India. The compound is a new derivative of the antibiotic Roflamycoin [32, 33-didehydroroflamycoin (DDHR)]. It displayed broad spectrum antifungal activity against yeast and filamentous fungi. However, it did not show any antibacterial activity. The in vitro study revealed that PN00053 has better potency as compared to clinical gold standard fluconazole. The development of pathogenic resistance against the polyenes has been seldom reported. Hence, we envisage PN00053 could be a potential antifungal lead. © 2014 The Society for Applied Microbiology.

Effects of pre-transplant azithromycin administration on kidney graft function: study protocol for a double-blind randomized clinical trial.

PubMed

Mokhtari, Gholamreza; Teimoori, Mojtaba

2018-06-28

Kidney transplantation is the best strategy for the management of end-stage renal disease; however, the outcomes need to improve further. Macrolides show antimicrobial and anti-inflammatory properties in chronic diseases and intraoperatively, and can accumulate in tissues for extended periods. Therefore, theoretically, when administered to a donor and because of accumulation in the donor kidney, macrolides can cause graft immunomodulation and improve kidney transplantation outcomes. This study is a single-center, randomized clinical trial. A total of 60 kidney donors will be randomly allocated to the azithromycin or placebo group and treated with a single dose (1 g) of azithromycin or placebo, respectively, 1 day before surgery. Recruitment commenced in September 2016 and is expected to be completed by March 2018. The primary outcome is kidney graft function. The secondary outcomes include rejection rate, urinary tract infections in graft recipients, pain and systemic inflammatory response syndrome in live donors, and complications in both donors and recipients. Outcomes will be evaluated at baseline and every day in the first week after transplantation, as well as at 1 and 3 months post transplantation. Adverse reactions will be documented. If the efficacy of azithromycin in reducing adverse outcomes is confirmed, it would serve as an easy to use, economic intervention able to lower post-transplantation risks. Short and mid-term analyses of blood and urine samples as well as immunological assays will facilitate a more in-depth analysis of the effects of azithromycin on transplantation outcomes. Iranian Clinical Trial Registry, IRCT201606141853N11 , registered on September 5, 2016.

Reduction in outpatient antibiotic sales for pre-school children: interrupted time series analysis of weekly antibiotic sales data in Sweden 1992-2002.

PubMed

Högberg, Liselotte; Oke, Thimothy; Geli, Patricia; Lundborg, Cecilia Stålsby; Cars, Otto; Ekdahl, Karl

2005-07-01

The aim of this study was to use detailed weekly data on outpatient antibiotic sales for pre-school children in Sweden to test for the significance of trends during 1992-2002. We also report on the special features found in weekly antibiotic data, and how the interrupted time series (ITS) design can adjust for this. Weekly data on the total number of dispensed outpatient antibiotic prescriptions to pre-school children were studied, as well as the individual subgroups commonly used to treat respiratory tract infections in children: narrow-spectrum penicillins, broad-spectrum penicillins and macrolides. In parallel, monthly data of paracetamol sales of paediatric dosages were analysed to reflect trends in symptomatic treatment. An ITS model controlling for seasonality and autocorrelation was used to examine the datasets for significant level and trend shifts. A significant increase in mean and change in level could be found in the total antibiotic data in 1997, also reflected in broad-spectrum penicillin data where a similar trend break occurred in 1996. For macrolides, a trend break with a decrease in mean was noted in 1996, but no trend breaks were found in narrow-spectrum penicillin data. In contrast to the general decreasing trends in antibiotic sales, the yearly over-the-counter sales of paracetamol in paediatric preparations increased during the same period, with no identified trend breaks. The overall decrease in antibiotic sales and increase in paediatric paracetamol sales might suggest that symptomatic treatment in the home has increased, as antibiotics are less commonly prescribed.

Premedication with Clarithromycin Is Effective against Secondary Bacterial Pneumonia during Influenza Virus Infection in a Pulmonary Emphysema Mouse Model.

PubMed

Harada, Tatsuhiko; Ishimatsu, Yuji; Hara, Atsuko; Morita, Towako; Nakashima, Shota; Kakugawa, Tomoyuki; Sakamoto, Noriho; Kosai, Kosuke; Izumikawa, Koichi; Yanagihara, Katsunori; Mukae, Hiroshi; Kohno, Shigeru

2016-09-01

Secondary bacterial pneumonia (SBP) during influenza increases the severity of chronic obstructive pulmonary disease (COPD) and its associated mortality. Macrolide antibiotics, including clarithromycin (CAM), are potential treatments for a variety of chronic respiratory diseases owing to their pharmacological activities, in addition to antimicrobial action. We examined the efficacy of CAM for the treatment of SBP after influenza infection in COPD. Specifically, we evaluated the effect of CAM in elastase-induced emphysema mice that were inoculated with influenza virus (strain A/PR8/34) and subsequently infected with macrolide-resistant Streptococcus pneumoniae CAM was administered to the emphysema mice 4 days prior to influenza virus inoculation. Premedication with CAM improved pathologic responses and bacterial load 2 days after S. pneumoniae inoculation. Survival rates were higher in emphysema mice than control mice. While CAM premedication did not affect viral titers or exert antibacterial activity against S. pneumoniae in the lungs, it enhanced host defense and reduced inflammation, as evidenced by the significant reductions in total cell and neutrophil counts and interferon (IFN)-γ levels in bronchoalveolar lavage fluid and lung homogenates. These results suggest that CAM protects against SBP during influenza in elastase-induced emphysema mice by reducing IFN-γ production, thus enhancing immunity to SBP, and by decreasing neutrophil infiltration into the lung to prevent injury. Accordingly, CAM may be an effective strategy to prevent secondary bacterial pneumonia in COPD patients in areas in which vaccines are inaccessible or limited. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

[Urinary pneumococcal or Legionella antigen detection tests and low-spectrum antibiotic therapy for community-acquired pneumonia].

PubMed

Roger, P-M; Risso, K; Hyvernat, H; Landraud, L; Vassallo, M; Dellamonica, J; de Salvador, F; Cua, E; Bernardin, G

2010-06-01

We performed urinary antigen tests for pneumococcus and Legionella for patients with community-acquired pneumonia (CAP), to prescribe a documented antibiotic therapy. We report the efficiency of low-spectrum antibiotic treatment, illustrating the inappropriateness of bacteriological respiratory sampling. Patients with CAP were enrolled from three different units; the pneumonia severity index was used to assess the disease. Respiratory samples were also listed. Low-spectrum antibiotic therapy was amoxicillin for pneumococcal infection, and macrolides or non-anti-pneumococcal fluoroquinolone for legionellosis. Six hundred and seventy-five CAP were diagnosed during the study period,, 150 with positive urinary antigen tests (23%), among which 108 pneumococcal infections (73%), 40 legionellosis (26%), and two mixed infections. The pneumonia severity index was 106+/-38. Amoxicillin was prescribed in 108 cases, fluoroquinolone in 24 cases, macrolide in 18 cases. The outcome was favourable for 138 patients (92%). Eighty three respiratory samples allowed identification of a bacterium for 58 patients (39%), among which 24 strains were not in the antibiotic spectrum: Haemophilus influenzae and Pseudmomonas aeruginosa in six cases, Staphylococcus aureus in five cases, Klebsiella pneumoniae in two cases, and another Gram negative bacillus in five cases. These strains were resistant in vitro to the prescribed treatment in 19/24 cases (79%). One out of 12 patients who died had a respiratory sample positive for Enterobacter spp strain resistant to the ongoing antibiotic treatment. The low-spectrum antibiotic therapy based on urinary antigen tests is efficient, and demonstrates respiratory tract colonisation with bacteriological strains usually considered as pathogenic.

Simplified Quantitative Assay System for Measuring Activities of Drugs against Intracellular Legionella pneumophila

PubMed Central

Higa, Futoshi; Kusano, Nobuchika; Tateyama, Masao; Shinzato, Takashi; Arakaki, Noriko; Kawakami, Kazuyoshi; Saito, Atsushi

1998-01-01

We developed a new simple assay for the quantitation of the activities of drugs against intracellular Legionella pneumophila. The cells of a murine macrophage-like cell line (J774.1 cells) allowed the intracellular growth and replication of the bacteria, which ultimately resulted in cell death. The infected J774.1 cell monolayers in 96-well microplates were first treated with antibiotics and were further cultured for 72 h. The number of viable J774.1 cells in each well was quantified by a colorimetric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and an enzyme-linked immunosorbent assay reader. The number of growing bacteria in each well was also determined by counting the numbers of CFU on buffered charcoal yeast extract-α agar plates. Viable J774.1 cell counts, determined by the colorimetric assay, were inversely proportional to the number of intracellular replicating bacteria. The minimum extracellular concentrations (MIECs) of 24 antibiotics causing inhibition of intracellular growth of L. pneumophila were determined by the colorimetric assay system. The MIECs of beta-lactams and aminoglycosides were markedly higher than the MICs in buffered yeast extract-α broth. The MIECs of macrolides, fluoroquinolones, rifampin, and minocycline were similar to the respective MICs. According to their intracellular activities, clarithromycin and sparfloxacin were the most potent among the macrolides or fluoroquinolones tested in this study. Our results indicated that the MTT assay system allows comparative and quantitative evaluations of the intracellular activities of antibiotics and efficient processing of a large number of samples. PMID:9574712

Autoinflammatory disease in the lung.

PubMed

Scambler, Thomas; Holbrook, Jonathan; Savic, Sinisa; McDermott, Michael F; Peckham, Daniel

2018-04-19

Ascertaining the dominant cell type driving an immunological disease is essential to understanding the causal pathology and, therefore, selecting or developing an effective treatment. Classifying immunological diseases in this way has led to successful treatment regimens for many monogenic diseases; however, when the dominant cell type is unclear and there is no obvious causal genetic mutation, then identifying the correct disease classification and appropriate therapy can be challenging. In this review we focus on pulmonary immunological diseases where an innate immune signature has been identified as a predominant aspect of the immunopathology. We describe the molecular pathology of 'autoinflammatory diseases of the lung' and propose that small molecule and biological therapies, including recombinant interleukin-1 receptor antagonist, that target key innate immune pathways, are likely be beneficial in the control of pulmonary and systemic inflammation in these conditions. In addition, the successful use of macrolide antibiotics to treat lung infections in these conditions further confirms that the innate immune system is the key conductor of inflammation in these pulmonary diseases, as there is a strong body of evidence that macrolides are able to modulate the NLRP3 inflammasome and interleukin-1β and interleukin-18 secretion, both of which are central players in the innate immune response. Throughout this review we highlight the published evidence of autoinflammatory disease in chronic obstructive pulmonary disease, bronchiectasis, cystic fibrosis and rheumatoid lung disease and suggest that the fundamental pathology of these diseases places them towards the autoinflammatory pole of the immunological disease continuum. © 2018 John Wiley & Sons Ltd.

Influence of livestock activities on residue antibiotic levels of rivers in Hong Kong.

PubMed

Selvam, Ammaiyappan; Kwok, Katrina; Chen, Yumei; Cheung, Anna; Leung, Kelvin S Y; Wong, Jonathan W C

2017-04-01

Occurrence of 10 antibiotics in the Yuen Long (YLR), Kam Tin (KTR), and Shing Mun (SMR) rivers of Hong Kong and possible influence of livestock activities on the concentrations of antibiotics were investigated. Tetracycline (30-497 ng/L), sulfadiazine (2-80 ng/L), sulfamethoxazole (2-152 ng/L), ofloxacin (5-227 ng/L), and erythromycin (1-315 ng/L) were detected in all the three rivers; chlortetracycline (23-227 ng/L), oxytetracycline (7-104 ng/L), ciprofloxacin (12-68 ng/L), and roxithromycin (1-105 ng/L) were detected in YLR and KTR, whereas norfloxacin (3-34 ng/L) was detected in KTR only. Significant correlation between livestock population and antibiotic contamination was observed in YLR only, indicating the influences of other sources in KTR and SMR. Among the antibiotics, significant correlation was observed between tetracyclines and sulfonamides indicating the major influence of livestock farms, whereas tetracyclines/sulfonamides were negatively correlated with fluoroquinolones/macrolides implying the differential origin of the latter class of antibiotics. Water quality of KTR and YLR were highly influenced by the non-point source pollutions, while of SMR was relatively good. Particularly, Escherichia coli populations of the YLR and KTR were 3-4 logs higher than those of the SMR indicating the involvement of livestock farms and sewerages. Good correlation between tetracyclines (TCs)/sulfonamides (SAs) and number of livestock farms and a negative correlation between TCs/SAs and fluoroquinolones (FQs)/macrolides (MLs) could be used as an indicator to trace the possible source of pollution.

High isolation rate and multidrug resistance tendency of penicillin-susceptible group B Streptococcus with reduced ceftibuten susceptibility in Japan.

PubMed

Banno, Hirotsugu; Kimura, Kouji; Seki, Tomomi; Jin, Wanchun; Wachino, Jun-Ichi; Yamada, Keiko; Nagano, Noriyuki; Arakawa, Yoshichika

2018-05-17

Group B Streptococcus (GBS) clinical isolates with reduced penicillin susceptibility (PRGBS) have emerged through acquisition of amino acid substitutions in penicillin-binding protein 2X (PBP2X). Moreover, we also reported the emergence of penicillin-susceptible GBS clinical isolates with reduced ceftibuten susceptibility (CTB r PSGBS) due to amino acid substitutions in PBPs. However, whether or not these amino acid substitutions are responsible for the reduced ceftibuten susceptibility (RCTBS) profile remains unclear. Furthermore, the rate of CTB r PSGBS isolation and their multidrug resistance tendency remain uncertain. Therefore, we collected 377 clinical GBS isolates from multiple regions in Japan between August 2013 and August 2015. These isolates were characterized by determining MICs and sequencing the pbp2x gene. The isolation rate of CTB r PSGBS was 7.2% (27/377). CTB r PSGBS isolate harbor two types of amino acid substitutions in PBP2X [(T394A type) and (I377V, G398A, Q412L, and H438H type)]. The relevance of the amino acid substitutions found to the RCTBS was confirmed with allelic exchange techniques. Allelic exchange recombinant clones acquired two types of amino acid substitutions in PBP2X showed RCTBS. Furthermore, total ratio of resistance and non-susceptibility to both macrolides and fluoroquinolones in CTB r PSGBS was 51.9% (14/27). The isolation rate of CTB r PSGBS is non-negligibly high and the CTB r PSGBS tends to exhibit resistance and non-susceptible profile to both macrolides and fluoroquinolones.

Uptake of antibiotics by human polymorphonuclear leukocyte cytoplasts

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

Hand, W.L.; King-Thompson, N.L.

Enucleated human polymorphonuclear leukocytes (PMN cytoplasts), which have no nuclei and only a few granules, retain many of the functions of intact neutrophils. To better define the mechanisms and intracellular sites of antimicrobial agent accumulation in human neutrophils, we studied the antibiotic uptake process in PMN cytoplasts. Entry of eight radiolabeled antibiotics into PMN cytoplasts was determined by means of a velocity gradient centrifugation technique. Uptakes of these antibiotics by cytoplasts were compared with our findings in intact PMN. Penicillin entered both intact PMN and cytoplasts poorly. Metronidazole achieved a concentration in cytoplasts (and PMN) equal to or somewhat lessmore » than the extracellular concentration. Chloramphenicol, a lipid-soluble drug, and trimethoprim were concentrated three- to fourfold by cytoplasts. An unusual finding was that trimethroprim, unlike other tested antibiotics, was accumulated by cytoplasts more readily at 25 degrees C than at 37 degrees C. After an initial rapid association with cytoplasts, cell-associated imipenem declined progressively with time. Clindamycin and two macrolide antibiotics (roxithromycin, erythromycin) were concentrated 7- to 14-fold by cytoplasts. This indicates that cytoplasmic granules are not essential for accumulation of these drugs. Adenosine inhibited cytoplast uptake of clindamycin, which enters intact phagocytic cells by the membrane nucleoside transport system. Roxithromycin uptake by cytoplasts was inhibited by phagocytosis, which may reduce the number of cell membrane sites available for the transport of macrolides. These studies have added to our understanding of uptake mechanisms for antibiotics which are highly concentrated in phagocytes.« less

Trends in antibiotic utilization in eight Latin American countries, 1997-2007.

PubMed

Wirtz, Veronika J; Dreser, Anahí; Gonzales, Ralph

2010-03-01

To describe the trends in antibiotic utilization in eight Latin American countries between 1997-2007 We analyzed retail sales data of oral and injectable antibiotics (World Health Organization (WHO) Anatomic Therapeutic Chemical (ATC) code J01) between 1997 and 2007 for Argentina, Brazil, Chile, Colombia, Mexico, Peru, Uruguay, and Venezuela. Antibiotics were aggregated and utilization was calculated for all antibiotics (J01); for macrolides, lincosamindes, and streptogramins (J01 F); and for quinolones (J01 M). The kilogram sales of each antibiotic were converted into defined daily dose per 1 000 inhabitants per day (DID) according to the WHO ATC classification system. We calculated the absolute change in DID and relative change expressed in percent of DID variation, using 1997 as a reference Total antibiotic utilization has increased in Peru, Venezuela, Uruguay, and Brazil, with the largest relative increases observed in Peru (5.58 DID, +70.6%) and Venezuela (4.81 DID, +43.0%). For Mexico (-2.43 DID; -15.5%) and Colombia (-4.10; -33.7%), utilization decreased. Argentina and Chile showed major reductions in antibiotic utilization during the middle of this period. In all countries, quinolone use increased, particularly sharply in Venezuela (1.86 DID, +282%). The increase in macrolide, lincosaminde, and streptogramin use was greatest in Peru (0.76 DID, +82.1%), followed by Brazil, Argentina, and Chile Analyzing antibiotic utilization in Latin America presents a series of challenges. Creating policy-relevant evidence based on antimicrobial consumption patterns is needed in order to foster policies aimed at improving appropriate use of antibiotics in the region.

Synthesis and Biological Evaluation of Neopeltolide and Analogs

PubMed Central

Cui, Yubo; Balachandran, Raghavan

2012-01-01

The synthesis of neopeltolide analogs that contain variations in the oxazole-containing side chain and in the macrolide core are reported along with the GI50 values for these compounds against MCF7, HCT-116, and p53 knockout HCT-116 cell lines. Although biological activity is sensitive to changes in the macrocycle and the side chain, several analogs displayed GI50 values of <25 nM. Neopeltolide and several of the more potent analogs were significantly less potent against p53 knockout cells, suggesting that p53 plays an auxiliary role in the activity of these compounds. PMID:22329423

Short communication: In vitro antimicrobial susceptibility of Mycoplasma bovis isolates identified in milk from dairy cattle in Belgium, Germany, and Italy.

PubMed

Barberio, A; Flaminio, B; De Vliegher, S; Supré, K; Kromker, V; Garbarino, C; Arrigoni, N; Zanardi, G; Bertocchi, L; Gobbo, F; Catania, S; Moroni, P

2016-08-01

The objective of this study was to assess the in vitro antimicrobial susceptibility of 73 isolates of Mycoplasma bovis isolated from milk of dairy cattle herds of Belgium, Germany, and Italy. Minimal inhibitory concentration (MIC) values were determined by the microbroth dilution method for the following antimicrobials: erythromycin, spiramycin, tilmicosin, tylosin, lincomycin, enrofloxacin, doxycycline, oxytetracycline, florfenicol, and tiamulin. Macrolides, florfenicol, oxytetracycline, and enrofloxacin, were chosen because they represent antimicrobials families commonly used in several countries for treatment of M. bovis, and their MIC values in cattle population are reported in several studies, allowing a comparison with previous data. Doxycycline and tiamulin were selected to assess the susceptibility of M. bovis to new antimicrobials, because they are not registered in the European Union for the treatment of dairy cattle. Among the agents of the different antimicrobial classes, the macrolides showed the highest concentration to inhibit 90% of isolates (MIC90), all above the highest concentration tested: >8μg/mL for erythromycin, >16μg/mL for spiramycin, and >32μg/mL for tilmicosin and tylosin. Also the MIC90 of lincomycin was above the highest concentration tested (>32μg/mL), but the distribution of the MIC values was almost perfectly bimodal: 41 isolates had a MIC ≤0.5μg/mL and 30 isolates >32μg/mL. Oxytetracycline had a 2-fold higher concentration to inhibit 50% of isolates (2 vs. 0.5μg/mL) and 1-fold higher MIC90 (4 vs. 2μg/mL) than doxycycline. Enrofloxacin and florfenicol had both a MIC90 of 2μg/mL, whereas tiamulin had a MIC90 of 0.5μg/mL. Significant differences on the MIC values were found among the 3 countries for several antimicrobials: compared with Germany, Belgium and Italy showed significantly higher MIC for lincomycin, spiramycin, and tylosin, and lower for oxytetracycline and florfenicol. The Belgian isolates showed the lowest MIC

Antibiotic prescribing practice for acute, uncomplicated respiratory tract infections in primary care settings in New Delhi, India.

PubMed

Kotwani, Anita; Holloway, Kathleen

2014-07-01

To obtain information on prescribing rates and choice of antibiotics for acute, uncomplicated respiratory tract infections (RTIs) in the community. Antibiotic use in acute, uncomplicated RTIs consisting of common cold/sore throat/cough for not more than five days was surveyed in the community (December 2007-November 2008) using patient exit interviews at public and private facilities from four localities in New Delhi. Data were collected from 10 public sector facilities and 20 private clinics over one year. The percentage of acute, uncomplicated RTIs patients receiving antibiotics in general and using the Anatomical Therapeutic Chemical classification and the Defined Daily Dose (ATS/DDD) were analysed. At public and private facilities, 45% (746/1646) and 57% (259/457) of acute, uncomplicated RTI patients were prescribed at least one antibiotic, respectively. The main antibiotic class calculated as percentage of total antibiotics DDDs/1000 prescribed to acute, uncomplicated RTI patients at private clinics was cephalosporins, J01DA (39%), followed by fluoroquinolones, J01MA (24%), penicillins, J01C (19%) and macrolides, J01FA (15%). Newer members from each class were prescribed; older antibiotics such as co-trimoxazole or tetracyclines were rarely prescribed. At public facilities, the main class of antibiotic prescribed was penicillins (31%), followed by macrolides (25%), fluoroquinolones (20%) and cephalosporins (10%). Study clearly shows overuse and inappropriate choice of antibiotics for the treatment of acute, uncomplicated RTIs which are mainly due to virus and do not require antibiotic treatment. Results of the study warrant interventional strategies to promote rational use of antibiotics to decrease the overgrowing threat of antibiotic resistance. © 2014 John Wiley & Sons Ltd.

Results from the Survey of Antibiotic Resistance (SOAR) 2012–14 in Thailand, India, South Korea and Singapore

PubMed Central

Torumkuney, D.; Chaiwarith, R.; Reechaipichitkul, W.; Malatham, K.; Chareonphaibul, V.; Rodrigues, C.; Chitins, D. S.; Dias, M.; Anandan, S.; Kanakapura, S.; Park, Y. J.; Lee, K.; Lee, H.; Kim, J. Y.; Lee, Y.; Lee, H. K.; Kim, J. H.; Tan, T. Y.; Heng, Y. X.; Mukherjee, P.; Morrissey, I.

2016-01-01

Objectives To provide susceptibility data for community-acquired respiratory tract isolates of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis collected in 2012–14 from four Asian countries. Methods MICs were determined using Etest® for all antibiotics except erythromycin, which was evaluated by disc diffusion. Susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. For macrolide/clindamycin interpretation, breakpoints were adjusted for incubation in CO2 where available. Results Susceptibility of S. pneumoniae was generally lower in South Korea than in other countries. Penicillin susceptibility assessed using CLSI oral or EUCAST breakpoints ranged from 21.2% in South Korea to 63.8% in Singapore. In contrast, susceptibility using CLSI intravenous breakpoints was much higher, at 79% in South Korea and ∼95% or higher elsewhere. Macrolide susceptibility was ∼20% in South Korea and ∼50%–60% elsewhere. Among S. pyogenes isolates (India only), erythromycin susceptibility (∼20%) was lowest of the antibiotics tested. In H. influenzae antibiotic susceptibility was high except for ampicillin, where susceptibility ranged from 16.7% in South Korea to 91.1% in India. South Korea also had a high percentage (18.1%) of β-lactamase-negative ampicillin-resistant isolates. Amoxicillin/clavulanic acid susceptibility for each pathogen (PK/PD high dose) was between 93% and 100% in all countries except for H. influenzae in South Korea (62.5%). Conclusions Use of EUCAST versus CLSI breakpoints had profound differences for cefaclor, cefuroxime and ofloxacin, with EUCAST showing lower susceptibility. There was considerable variability in susceptibility among countries in the same region. Thus, continued surveillance is necessary to track future changes in antibiotic resistance. PMID:27048580

Production of rosamicin derivatives in Micromonospora rosaria by introduction of D-mycinose biosynthetic gene with PhiC31-derived integration vector pSET152.

PubMed

Anzai, Yojiro; Iizaka, Yohei; Li, Wei; Idemoto, Naoki; Tsukada, Shu-ichi; Koike, Kazuo; Kinoshita, Kenji; Kato, Fumio

2009-08-01

Some of the polyketide-derived bioactive compounds contain sugars attached to the aglycone core, and these sugars often impart specific biological activity to the molecule or enhance this activity. Mycinamicin II, a 16-member macrolide antibiotic produced by Micromonospora griseorubida A11725, contains a branched lactone and two different deoxyhexose sugars, D-desosamine and D-mycinose, at the C-5 and C-21 positions, respectively. The D-mycinose biosynthesis genes, mycCI, mycCII, mycD, mycE, mycF, mydH, and mydI, present in the M. griseorubida A11725 chromosome were introduced into pSET152 under the regulation of the promoter of the apramycin-resistance gene aac(3)IV. The resulting plasmid pSETmycinose was introduced into Micromonospora rosaria IFO13697 cells, which produce the 16-membered macrolide antibiotic rosamicin containing a branched lactone and D-desosamine at the C-5 position. Although the M. rosaria TPMA0001 transconjugant exhibited low rosamicin productivity, two new compounds, IZI and IZII, were detected in the ethylacetate extract from the culture broth. IZI was identified as a mycinosyl rosamicin derivative, 23-O-mycinosyl-20-deoxo-20-dihydro-12,13-deepoxyrosamicin (MW 741), which has previously been synthesized by a bioconversion technique. This is the first report on production of mycinosyl rosamicin-derivatives by a engineered biosynthesis approach. The integration site PhiC31attB was identified on M. rosaria IFO13697 chromosome, and the site lay within an ORF coding a pirin homolog protein. The pSETmycinose could be useful for stimulating the production of "unnatural" natural mycinosyl compounds by various actinomycete strains using the bacteriophage PhiC31 att/int system.

Revisiting the structures of several antibiotics bound to the bacterial ribosome

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

Bulkley, David; Innis, C. Axel; Blaha, Gregor

2010-10-08

The increasing prevalence of antibiotic-resistant pathogens reinforces the need for structures of antibiotic-ribosome complexes that are accurate enough to enable the rational design of novel ribosome-targeting therapeutics. Structures of many antibiotics in complex with both archaeal and eubacterial ribosomes have been determined, yet discrepancies between several of these models have raised the question of whether these differences arise from species-specific variations or from experimental problems. Our structure of chloramphenicol in complex with the 70S ribosome from Thermus thermophilus suggests a model for chloramphenicol bound to the large subunit of the bacterial ribosome that is radically different from the prevailing model.more » Further, our structures of the macrolide antibiotics erythromycin and azithromycin in complex with a bacterial ribosome are indistinguishable from those determined of complexes with the 50S subunit of Haloarcula marismortui, but differ significantly from the models that have been published for 50S subunit complexes of the eubacterium Deinococcus radiodurans. Our structure of the antibiotic telithromycin bound to the T. thermophilus ribosome reveals a lactone ring with a conformation similar to that observed in the H. marismortui and D. radiodurans complexes. However, the alkyl-aryl moiety is oriented differently in all three organisms, and the contacts observed with the T. thermophilus ribosome are consistent with biochemical studies performed on the Escherichia coli ribosome. Thus, our results support a mode of macrolide binding that is largely conserved across species, suggesting that the quality and interpretation of electron density, rather than species specificity, may be responsible for many of the discrepancies between the models.« less

Revisiting the Structures of Several Antibiotics Bound to the Bacterial Ribosome

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

D Bulkley; C Innis; G Blaha

2011-12-31

The increasing prevalence of antibiotic-resistant pathogens reinforces the need for structures of antibiotic-ribosome complexes that are accurate enough to enable the rational design of novel ribosome-targeting therapeutics. Structures of many antibiotics in complex with both archaeal and eubacterial ribosomes have been determined, yet discrepancies between several of these models have raised the question of whether these differences arise from species-specific variations or from experimental problems. Our structure of chloramphenicol in complex with the 70S ribosome from Thermus thermophilus suggests a model for chloramphenicol bound to the large subunit of the bacterial ribosome that is radically different from the prevailing model.more » Further, our structures of the macrolide antibiotics erythromycin and azithromycin in complex with a bacterial ribosome are indistinguishable from those determined of complexes with the 50S subunit of Haloarcula marismortui, but differ significantly from the models that have been published for 50S subunit complexes of the eubacterium Deinococcus radiodurans. Our structure of the antibiotic telithromycin bound to the T. thermophilus ribosome reveals a lactone ring with a conformation similar to that observed in the H. marismortui and D. radiodurans complexes. However, the alkyl-aryl moiety is oriented differently in all three organisms, and the contacts observed with the T. thermophilus ribosome are consistent with biochemical studies performed on the Escherichia coli ribosome. Thus, our results support a mode of macrolide binding that is largely conserved across species, suggesting that the quality and interpretation of electron density, rather than species specificity, may be responsible for many of the discrepancies between the models.« less

Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages.

PubMed

Lemaire, Sandrine; Van Bambeke, Françoise; Tulkens, Paul M

2009-09-01

CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of < or = 6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (Emax; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here.

Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection.

PubMed

Brown, Kevin A; Khanafer, Nagham; Daneman, Nick; Fisman, David N

2013-05-01

The rising incidence of Clostridium difficile infection (CDI) could be reduced by lowering exposure to high-risk antibiotics. The objective of this study was to determine the association between antibiotic class and the risk of CDI in the community setting. The EMBASE and PubMed databases were queried without restriction to time period or language. Comparative observational studies and randomized controlled trials (RCTs) considering the impact of exposure to antibiotics on CDI risk among nonhospitalized populations were considered. We estimated pooled odds ratios (OR) for antibiotic classes using random-effect meta-analysis. Our search criteria identified 465 articles, of which 7 met inclusion criteria; all were observational studies. Five studies considered antibiotic risk relative to no antibiotic exposure: clindamycin (OR = 16.80; 95% confidence interval [95% CI], 7.48 to 37.76), fluoroquinolones (OR = 5.50; 95% CI, 4.26 to 7.11), and cephalosporins, monobactams, and carbapenems (CMCs) (OR = 5.68; 95% CI, 2.12 to 15.23) had the largest effects, while macrolides (OR = 2.65; 95% CI, 1.92 to 3.64), sulfonamides and trimethoprim (OR = 1.81; 95% CI, 1.34 to 2.43), and penicillins (OR = 2.71; 95% CI, 1.75 to 4.21) had lower associations with CDI. We noted no effect of tetracyclines on CDI risk (OR = 0.92; 95% CI, 0.61 to 1.40). In the community setting, there is substantial variation in the risk of CDI associated with different antimicrobial classes. Avoidance of high-risk antibiotics (such as clindamycin, CMCs, and fluoroquinolones) in favor of lower-risk antibiotics (such as penicillins, macrolides, and tetracyclines) may help reduce the incidence of CDI.

Occurrence, species distribution, antimicrobial resistance and clonality of methicillin- and erythromycin-resistant staphylococci in the nasal cavity of domestic animals.

PubMed

Bagcigil, Funda A; Moodley, Arshnee; Baptiste, Keith E; Jensen, Vibeke F; Guardabassi, Luca

2007-04-15

beta-Lactams and macrolides are important antibiotics for treatment of staphylococcal infections in both humans and animals. The aim of the study was to investigate the occurrence, species distribution and clonality of methicillin- and erythromycin-resistant staphylococci in the nasal cavity of dogs, horses, pigs, and cattle in Denmark. Nasal swabs were collected from a total of 400 animals, including 100 individuals of each species. Methicillin- and erythromycin-resistant staphylococci were isolated on selective media, identified by 16S rDNA sequencing, and typed by pulsed field gel electrophoresis (PFGE). Methicillin-resistant coagulase-negative staphylococci (MRCoNS) harbouring mecA were isolated from horses (50%) and dogs (13%), but not from food animals. The species identified were S. haemolyticus (n=21), S. vitulinus (n=19), S. sciuri (n=13), S. epidermidis (n=8), and S. warneri (n=2). mecA-mediated methicillin resistance in S. vitulinus was described for the first time. Methicillin-resistant S. aureus was not detected. PFGE analysis revealed the presence of specific MRCoNS clones in samples originating from the same veterinary hospital or equine farm. Erythromycin-resistant S. aureus (ERSA) was detected in 38% of pigs and all isolates harboured a constitutively expressed erm(C) gene. The vast majority (37/38) of pigs carrying ERSA originated from a farm characterized by frequent use of macrolides. Most ERSA isolates (28/38) displayed indistinguishable or closely related PFGE patterns, indicating clonal distribution within the farm. Based on the analysis of data on antimicrobial consumption, the occurrence of MRCoNS in companion animals and that of ERSA in pigs reflected national and local patterns of antimicrobial usage.

Antimicrobial Susceptibility Patterns of Brachyspira Species Isolated in Taiwan.

PubMed

Yeh, Jih-Ching; Lo, Dan-Yuan; Chang, Shao-Kuang; Kuo, Hung-Chih

2018-03-13

Some members of the Brachyspira genus cause diseases such as swine dysentery (SD) and porcine intestinal (or colonic) spirochetosis. Severe economic losses are caused by decreased feed intake and increased feed conversion ratio, as well as costs associated with treatment and death. A loss of clinical efficacy of some antimicrobial agents authorized for treating SD has been observed in many countries. The aim of this study was to analyze the antimicrobial susceptibility of Brachyspira isolated from Taiwan and to investigate the mechanism of decreased susceptibility to macrolides. A total of 55 Brachyspira isolates obtained from the grower-finisher period were evaluated in this study. These isolates included B. hyodysenteriae (n = 37), B. murdochii (n = 11), B. pilosicoli (n = 5), B. intermedia (n = 1), and B. innocens (n = 1). Antimicrobial susceptibility testing was performed to examine 12 selected antimicrobial agents. The results showed that the 50% and 90% minimum inhibitory concentration (MIC) values of the tested macrolides were all >256 μg/ml. The MIC 50 of lincomycin, tiamulin, carbadox, olaquindox, ampicillin, amoxicillin, doxycycline, oxytetracycline, and gentamicin were 32, 1, ≤0.125, ≤0.125, 0.5, 0.25, 2, 2, and 2 μg/ml. The genetic basis of the decreased susceptibility to tylosin and lincomycin in Brachyspira spp. was investigated and the results showed a possible connection to the mutations at position A2058 and G2032 of the 23S rRNA gene. These findings demonstrated that, in Taiwan, there may be a decrease in susceptibility of Brachyspira spp. to antimicrobials commonly used for the treatment of SD.

Trends in broad-spectrum antibiotic prescribing for children with acute otitis media in the United States, 1998–2004

PubMed Central

Coco, Andrew S; Horst, Michael A; Gambler, Angela S

2009-01-01

Background Overuse of broad-spectrum antibiotics is associated with antibiotic resistance. Acute otitis media (AOM) is responsible for a large proportion of antibiotics prescribed for US children. Rates of broad-spectrum antibiotic prescribing for AOM are unknown. Methods Analysis of the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey, 1998 to 2004 (N = 6,878). Setting is office-based physicians, hospital outpatient departments, and emergency departments. Patients are children aged 12 years and younger prescribed antibiotics for acute otitis media. Main outcome measure is percentage of broad-spectrum antibiotics, defined as amoxicillin/clavulanate, macrolides, cephalosporins and quinolones. Results Broad-spectrum prescribing for acute otitis media increased from 34% of visits in 1998 to 45% of visits in 2004 (P < .001 for trend). The trend was primarily attributable to an increase in prescribing of amoxicillin/clavulanate (8% to 15%; P < .001 for trend) and macrolides (9% to 15%; P < .001 for trend). Prescribing remained stable for amoxicillin and cephalosporins while decreasing for narrow-spectrum agents (12% to 3%; P < .001 for trend) over the study period. Independent predictors of broad-spectrum antibiotic prescribing were ear pain, non-white race, public and other insurance (compared to private), hospital outpatient department setting, emergency department setting, and West region (compared to South and Midwest regions), each of which was associated with lower rates of broad-spectrum prescribing. Age and fever were not associated with prescribing choice. Conclusion Prescribing of broad-spectrum antibiotics for acute otitis media has steadily increased from 1998 to 2004. Associations with non-clinical factors suggest potential for improvement in prescribing practice. PMID:19552819

A Multicenter Collaborative to Improve Care of Community Acquired Pneumonia in Hospitalized Children.

PubMed

Parikh, Kavita; Biondi, Eric; Nazif, Joanne; Wasif, Faiza; Williams, Derek J; Nichols, Elizabeth; Ralston, Shawn

2017-03-01

The Value in Inpatient Pediatrics Network sponsored the Improving Care in Community Acquired Pneumonia collaborative with the goal of increasing evidence-based management of children hospitalized with community acquired pneumonia (CAP). Project aims included: increasing use of narrow-spectrum antibiotics, decreasing use of macrolides, and decreasing concurrent treatment of pneumonia and asthma. Data were collected through chart review across emergency department (ED), inpatient, and discharge settings. Sites reviewed up to 20 charts in each of 6 3-month cycles. Analysis of means with 3-σ control limits was the primary method of assessment for change. The expert panel developed project measures, goals, and interventions. A change package of evidence-based tools to promote judicious use of antibiotics and raise awareness of asthma and pneumonia codiagnosis was disseminated through webinars. Peer coaching and periodic benchmarking were used to motivate change. Fifty-three hospitals enrolled and 48 (91%) completed the 1-year project (July 2014-June 2015). A total of 3802 charts were reviewed for the project; 1842 during baseline cycles and 1960 during postintervention cycles. The median before and after use of narrow-spectrum antibiotics in the collaborative increased by 67% in the ED, 43% in the inpatient setting, and 25% at discharge. Median before and after use of macrolides decreased by 22% in the ED and 27% in the inpatient setting. A decrease in asthma and CAP codiagnosis was noted, but the change was not sustained. Low-cost strategies, including collaborative sharing, peer benchmarking, and coaching, increased judicious use of antibiotics in a diverse range of hospitals for pediatric CAP. Copyright © 2017 by the American Academy of Pediatrics.

ICESpy009, a Conjugative Genetic Element Carrying mef(E) in Streptococcus pyogenes

PubMed Central

Camilli, Romina; Rizzi, Ermanno; Pietrelli, Alessandro; De Bellis, Gianluca; Pantosti, Annalisa

2016-01-01

Efflux-mediated macrolide resistance due to mef(E) and mel, carried by the mega element, is common in Streptococcus pneumoniae, for which it was originally characterized, but it is rare in Streptococcus pyogenes. In S. pyogenes, mega was previously found to be enclosed in Tn2009, a composite genetic element of the Tn916 family containing tet(M) and conferring erythromycin and tetracycline resistance. In this study, S. pyogenes isolates containing mef(E), apparently not associated with other resistance determinants, were examined to characterize the genetic context of mega. By whole-genome sequencing of one isolate, MB56Spyo009, we identified a novel composite integrative and conjugative element (ICE) carrying mega, designated ICESpy009, belonging to the ICESa2603 family. ICESpy009 was 55 kb long, contained 61 putative open reading frames (ORFs), and was found to be integrated into hylA, a novel integration site for the ICESa2603 family. The modular organization of the ICE was similar to that of members of the ICESa2603 family carried by different streptococcal species. In addition, a novel cluster of accessory resistance genes was found inside a region that encloses mega. PCR mapping targeting ICESpy009 revealed the presence of a similar ICE in five other isolates under study. While in three isolates the integration site was the same as that of ICESpy009, in two isolates the ICE was integrated into rplL, the typical integration site of the ICESa2603 family. ICESpy009 was able to transfer macrolide resistance by conjugation to both S. pyogenes and S. pneumoniae, showing the first evidence of the transferability of mega from S. pyogenes. PMID:27067338

Metagenomic profiles of antibiotic resistance genes (ARGs) between human impacted estuary and deep ocean sediments.

PubMed

Chen, Baowei; Yang, Ying; Liang, Ximei; Yu, Ke; Zhang, Tong; Li, Xiangdong

2013-11-19

Knowledge of the origins and dissemination of antibiotic resistance genes (ARGs) is essential for understanding modern resistomes in the environment. The mechanisms of the dissemination of ARGs can be revealed through comparative studies on the metagenomic profiling of ARGs between relatively pristine and human-impacted environments. The deep ocean bed of the South China Sea (SCS) is considered to be largely devoid of anthropogenic impacts, while the Pearl River Estuary (PRE) in south China has been highly impacted by intensive human activities. Commonly used antibiotics (sulfamethazine, norfloxacin, ofloxacin, tetracycline, and erythromycin) have been detected through chemical analysis in the PRE sediments, but not in the SCS sediments. In the relatively pristine SCS sediments, the most prevalent and abundant ARGs are those related to resistance to macrolides and polypeptides, with efflux pumps as the predominant mechanism. In the contaminated PRE sediments, the typical ARG profiles suggest a prevailing resistance to antibiotics commonly used in human health and animal farming (including sulfonamides, fluoroquinolones, and aminoglycosides), and higher diversity in both genotype and resistance mechanism than those in the SCS. In particular, antibiotic inactivation significantly contributed to the resistance to aminoglycosides, β-lactams, and macrolides observed in the PRE sediments. There was a significant correlation in the levels of abundance of ARGs and those of mobile genetic elements (including integrons and plasmids), which serve as carriers in the dissemination of ARGs in the aquatic environment. The metagenomic results from the current study support the view that ARGs naturally originate in pristine environments, while human activities accelerate the dissemination of ARGs so that microbes would be able to tolerate selective environmental stress in response to anthropogenic impacts.

Fidaxomicin Inhibits Clostridium difficile Toxin A-Mediated Enteritis in the Mouse Ileum

PubMed Central

Koon, Hon Wai; Ho, Samantha; Hing, Tressia C.; Cheng, Michelle; Chen, Xinhua; Ichikawa, Yoshi; Kelly, Ciarán P.

2014-01-01

Clostridium difficile infection (CDI) is a common, debilitating infection with high morbidity and mortality. C. difficile causes diarrhea and intestinal inflammation by releasing two toxins, toxin A and toxin B. The macrolide antibiotic fidaxomicin was recently shown to be effective in treating CDI, and its beneficial effect was associated with fewer recurrent infections in CDI patients. Since other macrolides possess anti-inflammatory properties, we examined the possibility that fidaxomicin alters C. difficile toxin A-induced ileal inflammation in mice. The ileal loops of anesthetized mice were injected with fidaxomicin (5, 10, or 20 μM), and after 30 min, the loops were injected with purified C. difficile toxin A or phosphate-buffered saline alone. Four hours after toxin A administration, ileal tissues were processed for histological evaluation (epithelial cell damage, neutrophil infiltration, congestion, and edema) and cytokine measurements. C. difficile toxin A caused histologic damage, evidenced by increased mean histologic score and ileal interleukin-1β (IL-1β) protein and mRNA expression. Treatment with fidaxomicin (20 μM) or its primary metabolite, OP-1118 (120 μM), significantly inhibited toxin A-mediated histologic damage and reduced the mean histology score and ileal IL-1β protein and mRNA expression. Both fidaxomicin and OP-1118 reduced toxin A-induced cell rounding in human colonic CCD-18Co fibroblasts. Treatment of ileal loops with vancomycin (20 μM) and metronidazole (20 μM) did not alter toxin A-induced histologic damage and IL-1β protein expression. In addition to its well known antibacterial effects against C. difficile, fidaxomicin may possess anti-inflammatory activity directed against the intestinal effects of C. difficile toxins. PMID:24890583

Results from the Survey of Antibiotic Resistance (SOAR) 2014-16 in the Czech Republic.

PubMed

Torumkuney, D; Zemlickova, H; Maruscak, M; Morrissey, I

2018-04-01

To determine the antibiotic susceptibility of isolates of Streptococcus pneumoniae and Haemophilus influenzae collected in 2014-16 from patients with community-acquired respiratory infections in the Czech Republic. MICs were determined by CLSI broth microdilution and susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. S. pneumoniae isolates (n = 200) showed high rates of susceptibility (>95%) to amoxicillin, amoxicillin/clavulanic acid, penicillin [intravenous (iv) non-meningitis], ceftriaxone, cefuroxime and the fluoroquinolones using CLSI breakpoints. Susceptibility to cefaclor and trimethoprim/sulfamethoxazole was 94%-94.5%, to penicillin (oral) 91.5% and to the macrolides 89.5%. Susceptibility of H. influenzae (n = 197) to amoxicillin/clavulanic acid, ceftriaxone, cefuroxime, azithromycin and the fluoroquinolones was ≥98% by CLSI criteria. Rates of susceptibility to the remaining agents were ≥75% except for clarithromycin at 37.1%. Great variability was seen across breakpoints, especially for the macrolides, cefaclor and cefuroxime (oral), 98.0% of H. influenzae showing susceptibility to the latter by CLSI criteria, 69.5% by PK/PD and 1.5% by EUCAST standards. The β-lactamase rate was 13.7% with no β-lactamase-negative-ampicillin-resistant (BLNAR) isolates by CLSI criteria. Antibiotic resistance among the two major respiratory pathogens remained low in the Czech Republic. These findings support local clinicians in continuing the historically restrictive use of antibiotics in the Czech Republic, with selection of narrower-spectrum agents for the empirical therapy of community-acquired respiratory tract infections. This highlights one of the great benefits of continuous surveillance of antimicrobial resistance: knowledge of current local resistance patterns reduces the need to choose broad-spectrum agents that contribute to increasing resistance worldwide.

The suppository form of antibiotic administration: pharmacokinetics and clinical application.

PubMed

Bergogne-Bérézin, E; Bryskier, A

1999-02-01

The rectal route of antibiotic administration might be used effectively when other routes of administration are inadequate or unsuitable. With the use of various adjuvants, the rectal route can provide satisfactory pharmacokinetics and acceptable local tolerance. Experiments in animals have demonstrated the influence of the pharmaceutical formulation of suppositories on the rectal absorption and systemic distribution of beta-lactams and aminoglycosides. In healthy volunteers and in children under treatment, similar adjuvants--mainly glyceride mixtures or non-ionic surface agents--have increased the rectal absorption of aminopenicillins, cephalosporins and macrolides. Other antibiotics, including metronidazole and cotrimoxazole, have been investigated in respect of their potential rectal administration.

Chronic toxicity of diphenhydramine hydrochloride and erythromycin thiocyanate to Daphnia, Daphnia magna, in a continuous exposure test system

USGS Publications Warehouse

Meinertz, Jeffery R.; Schreier, Theresa M.; Bernardy, Jeffry A.; Franz, Jeanne L.

2011-01-01

Diphenhydramine hydrochloride (DH; Benadryl(TM), an over-the-counter antihistamine) and erythromycin thiocyanate (ET; a commonly used macrolide antibiotic) are pharmaceutical compounds whose chronic toxicity to Daphnia magna had not been characterized. Continuous exposure to DH concentrations about 5 times greater than the maximum reported environmental concentration of 0.023 μg/L for 21 days or to ET concentrations about 40 times the maximum reported environmental concentration of 6 μg/L for 21 days did not significantly impact D. magna survival and production. In this study the no observable effect concentration for DH was 0.12 μg/L and for ET was 248 μg/L.

Total Synthesis of Bryostatins. Development of Methodology for Atom-Economic and Stereoselective Synthesis of the C-ring Subunit

PubMed Central

Trost, Barry M.; Frontier, Alison J.; Thiel, Oliver R.; Yang, Hanbiao; Dong, Guangbin

2012-01-01

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for stereoselective assembly of the C-ring subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the C-ring subunit of bryostatins. PMID:21793057

Pneumonia Updates on Legionella, Chlamydophila, and Mycoplasma Pneumonia

PubMed Central

Sharma, Lokesh; Losier, Ashley; Tolbert, Thomas; Dela Cruz, Charles S.; Marion, Chad R.

2017-01-01

SUMMARY CAP due to Legionella, Chlamydophyla, or Mycoplasma continues to be a diagnostic challenge due to the nonspecific clinical and radiographic presentations. The vague clinical presentations of atypical CAP contribute to its underdiagnosis and under-reporting. Advancements in diagnostic techniques bring hope to rapid and accurate diagnosis of atypical CAP. Macrolides and respiratory fluoroquinolones are currently the antibiotics of choice, but this may change in the near future as more antibiotics resistance patterns emerge for atypical CAP. Several controversies still exist in atypical CAP, underscoring the need for continued investigation of preventing atypical CAP and determine its association with chronic lung diseases. PMID:28159161

MRSA: status and prospects for therapy? An evaluation of key papers on the topic of MRSA and antibiotic resistance.

PubMed

Barrett, John F

2004-12-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a serious nosocomial pathogen, and a related community-sourced MRSA is emerging. MRSA has evolved to become the major S. aureus phenotype in the hospital, emerging from just 30 to over 60% of the S. aureus population over the past 15 years. Together with its beta-lactam resistance, MRSA possesses multi-drug resistance genotype, including quinolones, macrolides and sulfonamides. MRSA has now emerged as the predominant nosocomial Gram-positive pathogen, and it has a high rate of mortality. Action must be taken to contain and eradicate MRSA through a combination of infection control and the development of novel anti-MRSA agents and vaccines.

Seasonal variation of macrolide resistance gene abundances in the South Fork Iowa River Watershed

USDA-ARS?s Scientific Manuscript database

The Midwestern United States is dominated by agricultural production with high concentrations of swine, leading to application of swine manure onto lands with artificial subsurface drainage. Previous reports have indicated elevated levels of antibiotic resistance genes (ARGs) in surface water and gr...

Impact of “Raised without Antibiotics” Beef Cattle Production Practices on Occurrences of Antimicrobial Resistance

PubMed Central

Vikram, Amit; Rovira, Pablo; Agga, Getahun E.; Arthur, Terrance M.; Bosilevac, Joseph M.; Wheeler, Tommy L.; Morley, Paul S.; Belk, Keith E.

2017-01-01

ABSTRACT The specific antimicrobial resistance (AMR) decreases that can be expected from reducing antimicrobial (AM) use in U.S. beef production have not been defined. To address this data gap, feces were recovered from 36 lots of “raised without antibiotics” (RWA) and 36 lots of “conventional” (CONV) beef cattle. Samples (n = 719) were collected during harvest and distributed over a year. AMR was assessed by (i) the culture of six AM-resistant bacteria (ARB), (ii) quantitative PCR (qPCR) for 10 AMR genes (ARGs), (iii) a qPCR array of 84 ARGs, and (iv) metagenomic sequencing. Generally, AMR levels were similar, but some were higher in CONV beef cattle. The prevalence of third-generation cephalosporin-resistant (3GCr) Escherichia coli was marginally different between production systems (CONV, 47.5%; RWA, 34.8%; P = 0.04), but the seasonal effect (summer, 92.8%; winter, 48.3%; P < 0.01) was greater. Erythromycin-resistant (ERYr) Enterococcus sp. concentrations significantly differed between production systems (CONV, 1.91 log10 CFU/g; RWA, 0.73 log10 CFU/g; P < 0.01). Levels of aadA1, ant(6)-I, blaACI, erm(A), erm(B), erm(C), erm(F), erm(Q), tet(A), tet(B), tet(M), and tet(X) ARGs were higher (P < 0.05) in the CONV system. Aggregate abundances of all 43 ARGs detected by metagenomic sequencing and the aggregate abundances of ARGs in the aminoglycoside, β-lactam, macrolide-lincosamide-streptogramin B (MLS), and tetracycline AM classes did not differ (log2 fold change < 1.0) between CONV and RWA systems. These results suggest that further reductions of AM use in U.S. beef cattle production may not yield significant AMR reductions beyond MLS and tetracycline resistance. IMPORTANCE The majority of antimicrobial (AM) use in the United States is for food-animal production, leading to concerns that typical AM use patterns during “conventional” (CONV) beef cattle production in the United States contribute broadly to antimicrobial resistance (AMR) occurrence. In

Molecular epidemiology and distribution of serotypes, genotypes, and antibiotic resistance genes of Streptococcus agalactiae clinical isolates from Guelma, Algeria and Marseille, France.

PubMed

Bergal, A; Loucif, L; Benouareth, D E; Bentorki, A A; Abat, C; Rolain, J-M

2015-12-01

This study describes, for the first time, the genetic and phenotypic diversity among 93 Streptococcus agalactiae (group B Streptococcus, GBS) isolates collected from Guelma, Algeria and Marseille, France. All strains were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). The molecular support of antibiotic resistance and serotyping were investigated by polymerase chain reaction (PCR). The phylogenetic lineage of each GBS isolate was determined by multilocus sequence typing (MLST) and grouped into clonal complexes (CCs) using eBURST. The isolates represented 37 sequence types (STs), 16 of which were novel, grouped into five CCs, and belonging to seven serotypes. Serotype V was the most prevalent serotype in our collection (44.1%). GBS isolates of each serotype were distributed among multiple CCs, including cps III/CC19, cps V/CC1, cps Ia/CC23, cps II/CC10, and cps III/CC17. All isolates presented susceptibility to penicillin, whereas resistance to erythromycin was detected in 40% and tetracycline in 82.2% of isolates. Of the 37 erythromycin-resistant isolates, 75.7% showed the macrolide-lincosamide-streptogramin B (MLSB)-resistant phenotype and 24.3% exhibited the macrolide (M)-resistant phenotype. Constitutive MLSB resistance (46%) mediated by the ermB gene was significantly associated with the Guelma isolates, whereas the M resistance phenotype (24.3%) mediated by the mefA/E gene dominated among the Marseille isolates and belonged to ST-23. Tetracycline resistance was predominantly due to tetM, which was detected alone (95.1%) or associated with tetO (3.7%). These results provide epidemiological data in these regions that establish a basis for monitoring increased resistance to erythromycin and also provide insight into correlations among clones, serotypes, and resistance genes.

Coagulase-negative staphylococci (CoNS) isolated from ready-to-eat food of animal origin--phenotypic and genotypic antibiotic resistance.

PubMed

Chajęcka-Wierzchowska, Wioleta; Zadernowska, Anna; Nalepa, Beata; Sierpińska, Magda; Łaniewska-Trokenheim, Łucja

2015-04-01

The aim of this work was to study the pheno- and genotypical antimicrobial resistance profile of coagulase negative staphylococci (CoNS) isolated from 146 ready-to-eat food of animal origin (cheeses, cured meats, sausages, smoked fishes). 58 strains were isolated, they were classified as Staphylococcus xylosus (n = 29), Staphylococcus epidermidis (n = 16); Staphylococcus lentus (n = 7); Staphylococcus saprophyticus (n = 4); Staphylococcus hyicus (n = 1) and Staphylococcus simulans (n = 1) by phenotypic and genotypic methods. Isolates were tested for resistance to erythromycin, clindamycin, gentamicin, cefoxitin, norfloxacin, ciprofloxacin, tetracycline, tigecycline, rifampicin, nitrofurantoin, linezolid, trimetoprim, sulphamethoxazole/trimethoprim, chloramphenicol, quinupristin/dalfopristin by the disk diffusion method. PCR was used for the detection of antibiotic resistance genes encoding: methicillin resistance--mecA; macrolide resistance--erm(A), erm(B), erm(C), mrs(A/B); efflux proteins tet(K) and tet(L) and ribosomal protection proteins tet(M). For all the tet(M)-positive isolates the presence of conjugative transposons of the Tn916-Tn1545 family was determined. Most of the isolates were resistant to cefoxitin (41.3%) followed by clindamycin (36.2%), tigecycline (24.1%), rifampicin (17.2%) and erythromycin (13.8%). 32.2% staphylococcal isolates were multidrug resistant (MDR). All methicillin resistant staphylococci harboured mecA gene. Isolates, phenotypic resistant to tetracycline, harboured at least one tetracycline resistance determinant on which tet(M) was most frequent. All of the isolates positive for tet(M) genes were positive for the Tn916-Tn1545 -like integrase family gene. In the erythromycin-resistant isolates, the macrolide resistance genes erm(C) or msr(A/B) were present. Although coagulase-negative staphylococci are not classical food poisoning bacteria, its presence in food could be of public health significance due to the possible spread of

[An outbreak of legionellosis in a nursery].

PubMed

Sakai, Hideaki; Akaihata, Mitsuko; Niitsuma, Katsunao; Hosoya, Mitsuaki

2004-05-01

We experienced an outbreak of legionellosis in infants for the first time in Japan. In Fukushima Prefecture Wakamatsu Nursery, the patients who had respiratory symptoms of cough, wheeze and fever appeared one after another from the middle of June, 2002. We suspected that an outbreak of legionellosis had occurred and then carried out urinary antigen detection of Legionella pneumophila. As a result, 8 patients were positive. They consisted of 5 boys and 3 girls, and ranged in age from 11 months to 1 year 10 months. Underlying disease was observed in one patient, and 6 patients were hospitalized. All 8 patients had rhinorrhea, cough, fever and 7 patients had wheeze. The average duration of cough was 9.9 days and that of fever was 4.5 days. In the admitted 6 patients, WBC ranged in count from 7,500/microliter to 15,300/microliter and CRP ranged from 0.2 mg/dl to 2.5 mg/dl. Chest X-rays showed infiltrative shadows (right lower lobe, left lower lobe) in 2 patients. With regard to the treatment, macrolide or tetracycline antibiotics were administered in 4 of 8 patients, and beta-lactams were administered in others. Water samples were obtained from 12 locations at the nursery, including the shower head of the bathroom, the bathtub, the taps, the laundry and so on. But cultures of water samples failed to grow legionella. We suspected that the source of infection was the humidifiers or the nebulizer used for disinfection. Through this outbreak, it became obvious that the mild case of legionellosis really existed. Furthermore, we suggested that it was possible for the patient with mild legionellosis to cure without administration of macrolide or tetracycline antibiotics.

Smart strategies for doctors and doctors-in-training: heuristics in medicine.

PubMed

Wegwarth, Odette; Gaissmaier, Wolfgang; Gigerenzer, Gerd

2009-08-01

How do doctors make sound decisions when confronted with probabilistic data, time pressures and a heavy workload? One theory that has been embraced by many researchers is based on optimisation, which emphasises the need to integrate all information in order to arrive at sound decisions. This notion makes heuristics, which use less than complete information, appear as second-best strategies. In this article, we challenge this pessimistic view of heuristics. We introduce two medical problems that involve decision making to the reader: one concerns coronary care issues and the other macrolide prescriptions. In both settings, decision-making tools grounded in the principles of optimisation and heuristics, respectively, have been developed to assist doctors in making decisions. We explain the structure of each of these tools and compare their performance in terms of their facilitation of correct predictions. For decisions concerning both the coronary care unit and the prescribing of macrolides, we demonstrate that sacrificing information does not necessarily imply a forfeiting of predictive accuracy, but can sometimes even lead to better decisions. Subsequently, we discuss common misconceptions about heuristics and explain when and why ignoring parts of the available information can lead to the making of more robust predictions. Heuristics are neither good nor bad per se, but, if applied in situations to which they have been adapted, can be helpful companions for doctors and doctors-in-training. This, however, requires that heuristics in medicine be openly discussed, criticised, refined and then taught to doctors-in-training rather than being simply dismissed as harmful or irrelevant. A more uniform use of explicit and accepted heuristics has the potential to reduce variations in diagnoses and to improve medical care for patients.

Results from the Survey of Antibiotic Resistance (SOAR) 2012-14 in Thailand, India, South Korea and Singapore.

PubMed

Torumkuney, D; Chaiwarith, R; Reechaipichitkul, W; Malatham, K; Chareonphaibul, V; Rodrigues, C; Chitins, D S; Dias, M; Anandan, S; Kanakapura, S; Park, Y J; Lee, K; Lee, H; Kim, J Y; Lee, Y; Lee, H K; Kim, J H; Tan, T Y; Heng, Y X; Mukherjee, P; Morrissey, I

2016-05-01

To provide susceptibility data for community-acquired respiratory tract isolates of Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae and Moraxella catarrhalis collected in 2012-14 from four Asian countries. MICs were determined using Etest(®) for all antibiotics except erythromycin, which was evaluated by disc diffusion. Susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. For macrolide/clindamycin interpretation, breakpoints were adjusted for incubation in CO2 where available. Susceptibility of S. pneumoniae was generally lower in South Korea than in other countries. Penicillin susceptibility assessed using CLSI oral or EUCAST breakpoints ranged from 21.2% in South Korea to 63.8% in Singapore. In contrast, susceptibility using CLSI intravenous breakpoints was much higher, at 79% in South Korea and ∼95% or higher elsewhere. Macrolide susceptibility was ∼20% in South Korea and ∼50%-60% elsewhere. Among S. pyogenes isolates (India only), erythromycin susceptibility (∼20%) was lowest of the antibiotics tested. In H. influenzae antibiotic susceptibility was high except for ampicillin, where susceptibility ranged from 16.7% in South Korea to 91.1% in India. South Korea also had a high percentage (18.1%) of β-lactamase-negative ampicillin-resistant isolates. Amoxicillin/clavulanic acid susceptibility for each pathogen (PK/PD high dose) was between 93% and 100% in all countries except for H. influenzae in South Korea (62.5%). Use of EUCAST versus CLSI breakpoints had profound differences for cefaclor, cefuroxime and ofloxacin, with EUCAST showing lower susceptibility. There was considerable variability in susceptibility among countries in the same region. Thus, continued surveillance is necessary to track future changes in antibiotic resistance. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved

Comparative genomics of transport proteins in developmental bacteria: Myxococcus xanthus and Streptomyces coelicolor

PubMed Central

2013-01-01

Background Two of the largest fully sequenced prokaryotic genomes are those of the actinobacterium, Streptomyces coelicolor (Sco), and the δ-proteobacterium, Myxococcus xanthus (Mxa), both differentiating, sporulating, antibiotic producing, soil microbes. Although the genomes of Sco and Mxa are the same size (~9 Mbp), Sco has 10% more genes that are on average 10% smaller than those in Mxa. Results Surprisingly, Sco has 93% more identifiable transport proteins than Mxa. This is because Sco has amplified several specific types of its transport protein genes, while Mxa has done so to a much lesser extent. Amplification is substrate- and family-specific. For example, Sco but not Mxa has amplified its voltage-gated ion channels but not its aquaporins and mechano-sensitive channels. Sco but not Mxa has also amplified drug efflux pumps of the DHA2 Family of the Major Facilitator Superfamily (MFS) (49 versus 6), amino acid transporters of the APC Family (17 versus 2), ABC-type sugar transport proteins (85 versus 6), and organic anion transporters of several families. Sco has not amplified most other types of transporters. Mxa has selectively amplified one family of macrolid exporters relative to Sco (16 versus 1), consistent with the observation that Mxa makes more macrolids than does Sco. Conclusions Except for electron transport carriers, there is a poor correlation between the types of transporters found in these two organisms, suggesting that their solutions to differentiative and metabolic needs evolved independently. A number of unexpected and surprising observations are presented, and predictions are made regarding the physiological functions of recognizable transporters as well as the existence of yet to be discovered transport systems in these two important model organisms and their relatives. The results provide insight into the evolutionary processes by which two dissimilar prokaryotes evolved complexity, particularly through selective chromosomal gene

Characterisation of a collection of Streptococcus pneumoniae isolates from patients suffering from acute exacerbations of chronic bronchitis: in vitro susceptibility to antibiotics and biofilm formation in relation to antibiotic efflux and serotypes/serogroups.

PubMed

Vandevelde, Nathalie M; Tulkens, Paul M; Diaz Iglesias, Yvan; Verhaegen, Jan; Rodriguez-Villalobos, Hector; Philippart, Ivan; Cadrobbi, Julie; Coppens, Nathalie; Boel, An; Van Vaerenbergh, Kristien; Francart, Hugo; Vanhoof, Raymond; Liistro, Giuseppe; Jordens, Paul; d'Odemont, Jean-Paul; Valcke, Yvan; Verschuren, Franck; Van Bambeke, Françoise

2014-09-01

The correlation between Streptococcus pneumoniae serotypes, biofilm production, antibiotic susceptibility and drug efflux in isolates from patients suffering from acute exacerbations of chronic bronchitis (AECB) remains largely unexplored. Using 101 isolates collected from AECB patients for whom partial (n=51) or full (n=50) medical details were available, we determined serotypes (ST)/serogroups (SG) (Quellung reaction), antibiotic susceptibility patterns [MIC (microdilution) using EUCAST and CLSI criteria] and ability to produce biofilm in vitro (10-day model; crystal violet staining). The majority of patients were 55-75 years old and <5% were vaccinated against S. pneumoniae. Moreover, 54% showed high severity scores (GOLD 3-4), and comorbidities were frequent including hypertension (60%), cancer (24%) and diabetes (20%). Alcohol and/or tobacco dependence was >30%. Isolates of SG6-11-15-23, known for large biofilm production and causing chronic infections, were the most prevalent (>15% each), but other isolates also produced biofilm (SG9-18-22-27 and ST8-20 being most productive), except SG7, SG29 and ST5 (<2% of isolates each). Resistance (EUCAST breakpoints) was 8-13% for amoxicillin and cefuroxime, 35-39% for macrolides, 2-8% for fluoroquinolones and 2% for telithromycin. ST19A isolates showed resistance to all antibiotics, ST14 to all except moxifloxacin, and SG9 and SG19 to all except telithromycin, moxifloxacin and ceftriaxone (SG19 only). Solithromycin and telithromycin MICs were similar. No correlation was observed between biofilm production and MIC or efflux (macrolides, fluoroquinolones). S. pneumoniae serotyping may improve AECB treatment by avoiding antibiotics with predictable low activity, but it is not predictive of biofilm production. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Randomized, Double-Blind, Multicenter Phase 2 Study Comparing the Efficacy and Safety of Oral Solithromycin (CEM-101) to Those of Oral Levofloxacin in the Treatment of Patients with Community-Acquired Bacterial Pneumonia

PubMed Central

Oldach, David; Clark, Kay; Schranz, Jennifer; Das, Anita; Craft, J Carl; Scott, Drusilla; Jamieson, Brian D.

2013-01-01

Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.) PMID:23507282

Randomized, double-blind, multicenter phase 2 study comparing the efficacy and safety of oral solithromycin (CEM-101) to those of oral levofloxacin in the treatment of patients with community-acquired bacterial pneumonia.

PubMed

Oldach, David; Clark, Kay; Schranz, Jennifer; Das, Anita; Craft, J Carl; Scott, Drusilla; Jamieson, Brian D; Fernandes, Prabhavathi

2013-06-01

Solithromycin, a new macrolide, and the first fluoroketolide in clinical development, with activity against macrolide-resistant bacteria, was tested in 132 patients with moderate to moderately severe community-acquired bacterial pneumonia (CABP) in a multicenter, double-blind, randomized phase 2 study. Patients were enrolled and randomized (1:1) to either 800 mg solithromycin orally (PO) on day 1, followed by 400 mg PO daily on days 2 to 5, or 750 mg levofloxacin PO daily on days 1 to 5. Efficacy outcome rates of clinical success at the test-of-cure visit 4 to 11 days after the last dose of study drug were comparable in the intent-to-treat (ITT) (84.6% for solithromycin versus 86.6% for levofloxacin) and microbiological-intent-to-treat (micro-ITT) (77.8% for solithromycin versus 71.4% for levofloxacin) populations. Early response success rates at day 3, defined as improvement in at least two cardinal symptoms of pneumonia, were also comparable (72.3% for solithromycin versus 71.6% for levofloxacin). More patients treated with levofloxacin than with solithromycin experienced treatment-emergent adverse events (TEAEs) during the study (45.6% versus 29.7%). The majority of TEAEs were mild or moderate gastrointestinal symptoms and included nausea (1.6% for solithromycin; 10.3% for levofloxacin), diarrhea (7.8% for solithromycin; 5.9% for levofloxacin), and vomiting (0% for solithromycin; 4.4% for levofloxacin). Six patients, all of whom received levofloxacin, discontinued the study drug due to an adverse event. Solithromycin demonstrated comparable efficacy and favorable safety relative to levofloxacin. These findings support a phase 3 study of solithromycin for the treatment of CABP. (This study has been registered at ClinicalTrials.gov under registration no. NCT01168713.).

The Primary Resistance of Helicobacter pylori in Taiwan after the National Policy to Restrict Antibiotic Consumption and Its Relation to Virulence Factors—A Nationwide Study

PubMed Central

Chen, Mei-Jyh; Chen, Chieh-Chang; Fang, Yu-Jen; Lee, Ji-Yuh; Wu, Jeng-Yih; Luo, Jiing-Chyuan; Liou, Tai-Cherng; Chang, Wen-Hsiung; Tseng, Cheng-Hao; Wu, Chun-Ying; Yang, Tsung-Hua; Chang, Chun-Chao; Wang, Hsiu‐Po; Sheu, Bor-Shyang; Lin, Jaw-Town; Bair, Ming-Jong; Wu, Ming-Shiang

2015-01-01

Objective The Taiwan Government issued a policy to restrict antimicrobial usage since 2001. We aimed to assess the changes in the antibiotic consumption and the primary resistance of H. pylori after this policy and the impact of virulence factors on resistance. Methods The defined daily dose (DDD) of antibiotics was analyzed using the Taiwan National Health Insurance (NHI) research database. H. pylori strains isolated from treatment naïve (N=1395) and failure from prior eradication therapies (N=360) from 9 hospitals between 2000 and 2012 were used for analysis. The minimum inhibitory concentration was determined by agar dilution test. Genotyping for CagA and VacA was determined by PCR method. Results The DDD per 1000 persons per day of macrolides reduced from 1.12 in 1997 to 0.19 in 2008, whereas that of fluoroquinolones increased from 0.12 in 1997 to 0.35 in 2008. The primary resistance of amoxicillin, clarithromycin, metronidazole, and tetracycline remained as low as 2.2%, 7.9%, 23.7%, and 1.9% respectively. However, the primary levofloxacin resistance rose from 4.9% in 2000–2007 to 8.3% in 2008–2010 and 13.4% in 2011–2012 (p=0.001). The primary resistance of metronidazole was higher in females than males (33.1% vs. 18.8%, p<0.001), which was probably attributed to the higher consumption of nitroimidazole. Neither CagA nor VacA was associated with antibiotic resistance. Conclusions The low primary clarithromycin and metronidazole resistance of H. pylori in Taiwan might be attributed to the reduced consumption of macrolides and nitroimidazole after the national policy to restrict antimicrobial usage. Yet, further strategies are needed to restrict the consumption of fluoroquinolones in the face of rising levofloxacin resistance. PMID:25942450

Antibiotic prescriptions for outpatient acute rhinosinusitis in Canada, 2007-2013

PubMed Central

Weese, Scott; Glass-Kaastra, Shiona; McIsaac, Warren

2017-01-01

Introduction Acute rhinosinusitis (ARS) is a respiratory disease commonly caused by viral infections. Physicians regularly prescribe antibiotics despite bacterial etiologies being uncommon. This is of concern, as this use adds to the selection pressure for resistance. Here we present the descriptive epidemiology of acute rhinosinusitis and corresponding antibiotic prescribing practices by Canadian outpatient physicians from 2007–2013. Materials/Methods Diagnosis and antibiotic prescription data for ARS were extracted from the Canadian Disease and Therapeutic Index for 2007 to 2013, and population data were acquired from Statistics Canada. ARS diagnosis and antibiotic prescription rates and frequencies of antibiotic classes were calculated. Results Eighty-eight percent of patients diagnosed with ARS in 2013 were adults, with a greater rate of antibiotic prescriptions observed among the adults relative to the pediatric patients (1632.9 and 468.6 antibiotic prescriptions per 10,000 inhabitants). Between 2007 and 2013, the ARS diagnosis rate decreased from 596 to 464 diagnoses per 10,000 inhabitants, while the percentage of diagnoses with antibiotic prescriptions at the national level remained stable (87% to 84%). From 2007 to 2013, prescription rates for macrolides decreased from 203.5 to 105.4 prescriptions per 10,000 inhabitants. In 2013, penicillins with extended spectrum were more commonly prescribed compared to macrolides among adult patients (153.5 and 105.4 prescriptions per 10,000 inhabitants, respectively). Conclusion This study is the first to describe physician antibiotic prescribing practices for treatment of ARS in Canada. Results show that antibiotic treatment for ARS represents an area for implementing antimicrobial stewardship, and through it, managing antibiotic resistance. Further work is required to better understand diagnosing practices and treatment criteria for ARS, and use this information to further assist physicians to limit unnecessary

Cellular Accumulation and Pharmacodynamic Evaluation of the Intracellular Activity of CEM-101, a Novel Fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in Human THP-1 Macrophages ▿ †

PubMed Central

Lemaire, Sandrine; Van Bambeke, Françoise; Tulkens, Paul M.

2009-01-01

CEM-101 is a novel fluoroketolide with lower MICs than those of telithromycin and macrolides. Our aim was to assess the cellular accumulation and intracellular activity of CEM-101 using models developed for analyzing the pharmacokinetics and pharmacological properties of antibiotics against phagocytized bacteria. We used THP-1 macrophages and Staphylococcus aureus (ATCC 25923 [methicillin (meticillin) sensitive]), Listeria monocytogenes (strain EGD), and Legionella pneumophila (ATCC 33153). CEM-101 reached cellular-to-extracellular-concentration ratios of about 350 within 24 h (versus approximately 20, 30, and 160 for telithromycin, clarithromycin, and azithromycin, respectively). This intracellular accumulation was suppressed by incubation at a pH of ≤6 and by monensin (proton ionophore) and was unaffected by verapamil (P-glycoprotein inhibitor; twofold accumulation increase for azithromycin) or gemfibrozil. While keeping with the general properties of the macrolide antibiotics in terms of maximal efficacy (Emax; approximately 1-log10-CFU decrease compared to the postphagocytosis inoculum after a 24-h incubation), CEM-101 showed significantly greater potency against phagocytized S. aureus than telithromycin, clarithromycin, and azithromycin (for which the 50% effective concentration [EC50] and static concentrations were about 3-, 6-, and 15-fold lower, respectively). CEM-101 was also about 50-fold and 100-fold more potent than azithromycin against phagocytized L. monocytogenes and L. pneumophila, respectively. These differences in EC50s and static concentrations between drugs were minimized when data were expressed as multiples of the MIC, demonstrating the critical role of intrinsic drug activity (MIC) in eliciting the antibacterial intracellular effects, whereas accumulation per se was unimportant. CEM-101 should show enhanced in vivo potency if used at doses similar to those of the comparators tested here. PMID:19564365

Culture methods impact recovery of antibiotic-resistant Enterococci including Enterococcus cecorum from pre- and postharvest chicken.

PubMed

Suyemoto, M M; Barnes, H J; Borst, L B

2017-03-01

Pathogenic strains of Enterococcus cecorum (EC) expressing multidrug resistance have emerged. In National Antimicrobial Resistance Monitoring System (NARMS) data, EC is rarely recovered from chickens. Two NARMS methodologies (FDA and USDA) were compared with standard culture (SC) techniques for recovery of EC. NARMS methods failed to detect EC in 58 caecal samples, 20 chicken breast or six whole broiler samples. EC was recovered from 1 of 38 (2·6%) and 2 of 38 (5·2%) preharvest spinal lesions (USDA and FDA method, respectively). In contrast, using the SC method, EC was recovered from 44 of 53 (83%) caecal samples, all 38 (100%) spinal lesions, 14 of 20 (70%) chicken breast samples, and all three spinal lesions identified in whole carcasses. Compared with other Enterococcus spp., EC isolates had a higher prevalence of resistance to macrolides. The NARMS methods significantly affected recovery of enterococcal species other than EC. When the postharvest FDA method was applied to preharvest caecal samples, isolates of Enterococcus faecium were preferentially recovered. All 11 E. faecium isolates were multidrug resistant, including resistance to penicillin, daptomycin and linezolid. These findings confirm that current methodologies may not accurately identify the amount and range of antimicrobial resistance of enterococci from chicken sources. Enterococci are an important reservoir for antimicrobial resistance. This study demonstrates how current culture methods underreport resistance to macrolides in enterococci by selecting against strains of Enterococcus cecorum in pre- and postharvest chicken. Further, the application of postharvest surveillance methods to preharvest samples resulted in selective recovery of Enterococcus faecium over Enterococcus faecalis. Isolates of E. faecium recovered exhibited multidrug resistance including penicillin, daptomycin and linezolid resistance. These findings suggest that culture methodology significantly impacts the range and

Does variation among provincial drug formulary antimicrobial listings in Canada influence prescribing rates?

PubMed

Glass-Kaastra, Shiona K; Finley, Rita; Hutchinson, Jim; Patrick, David M; Weiss, Karl; Conly, John

2014-01-01

The financial accessibility of antimicrobial drugs to the outpatient community in Canada is governed at the provincial level through formularies. Each province may choose to list particular drugs or impose restriction criteria on products in order to guide prescribing and/or curtail costs. Although changes to formularies have been shown to change patterns in the use of individual products and alter costs, no comparison has been made among the provincial antimicrobial formularies with regards to flexibility/stringency, or an assessment of how these formularies impact overall antimicrobial use in the provinces. To summarize provincial antimicrobial formularies and assess whether their relative flexibility/stringency had a statistical impact upon provincial prescription volume during a one year period. Provincial drug plan formularies were accessed and summarized for all prescribed antimicrobials in Canada during 2010. The number of general and restricted benefits for each plan was compiled by antimicrobial classification. Population-adjusted prescription rates for all individual antimicrobials and by antimicrobial class were obtained from the Canadian Integrated Program for Antimicrobial Resistance Surveillance. Correlations between the number of general benefits, restricted benefits, and total benefits with the prescription rate in the provinces were assessed by Spearman rank correlation coefficients. Formularies varied considerably among the Canadian provinces. Quebec had the most flexible formulary, offering the greatest number of general benefits and fewest restrictions. In contrast, Saskatchewan's formulary displayed the lowest number of general benefits and most restrictions. Correlation analyses detected a single significant result; macrolide prescription rates decreased as the number of general macrolide benefits increased. All other rates of provincial antimicrobial prescribing and measures of flexibility/stringency revealed no significant correlations

Trends and patterns of antibiotic consumption in Shanghai municipality, China: a 6 year surveillance with sales records, 2009-14.

PubMed

Lin, Hai; Dyar, Oliver James; Rosales-Klintz, Senia; Zhang, Jianzhong; Tomson, Göran; Hao, Mo; Stålsby Lundborg, Cecilia

2016-06-01

The objective of this study was to identify the trends and patterns of total antibiotic use in Shanghai from 2009 to 2014. Sales records were collected from a minimum of 160 hospitals and 241 primary healthcare settings and used as a proxy for consumption. Antibiotic sales expressed in DDD per 1000 inhabitants per day (DID) were calculated. We compared patterns of antibiotic use in the Shanghai municipality, populated by 24 million inhabitants, with European countries using indicators from the European Surveillance of Antimicrobial Consumption (ESAC). Total antibiotic use was highest at 25.9 DID in 2010, fell to 17.8 DID in 2012 and remained stable thereafter. The majority of this reduction occurred over 6 months in 2011. In 2014, two-thirds of the antibiotic sales were to hospitals (serving both inpatients and outpatients) and one-third to primary healthcare institutions. Cephalosporins accounted for 50.2% of total DID, followed by macrolides (18.2%), quinolones (16.0%) and penicillins (7.3%). A fifth of all antibiotics were used in parenteral form. We have successfully used aggregated sales data to monitor antibiotic usage across a large urban population over a 6 year period. A rapid, substantial and sustained reduction in antibiotic usage across the entire health system occurred. This coincided with several interventions across hierarchies in the health sector, including a national campaign. The patterns of antibiotic use indicate persistent preferences for cephalosporins, macrolides, quinolones and parenteral preparations. Further efforts are needed to investigate and improve the quality of antibiotic use. © The Author 2016. 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.

Antibiotic prescriptions for outpatient acute rhinosinusitis in Canada, 2007-2013.

PubMed

Sharma, Prateek; Finley, Rita; Weese, Scott; Glass-Kaastra, Shiona; McIsaac, Warren

2017-01-01

Acute rhinosinusitis (ARS) is a respiratory disease commonly caused by viral infections. Physicians regularly prescribe antibiotics despite bacterial etiologies being uncommon. This is of concern, as this use adds to the selection pressure for resistance. Here we present the descriptive epidemiology of acute rhinosinusitis and corresponding antibiotic prescribing practices by Canadian outpatient physicians from 2007-2013. Diagnosis and antibiotic prescription data for ARS were extracted from the Canadian Disease and Therapeutic Index for 2007 to 2013, and population data were acquired from Statistics Canada. ARS diagnosis and antibiotic prescription rates and frequencies of antibiotic classes were calculated. Eighty-eight percent of patients diagnosed with ARS in 2013 were adults, with a greater rate of antibiotic prescriptions observed among the adults relative to the pediatric patients (1632.9 and 468.6 antibiotic prescriptions per 10,000 inhabitants). Between 2007 and 2013, the ARS diagnosis rate decreased from 596 to 464 diagnoses per 10,000 inhabitants, while the percentage of diagnoses with antibiotic prescriptions at the national level remained stable (87% to 84%). From 2007 to 2013, prescription rates for macrolides decreased from 203.5 to 105.4 prescriptions per 10,000 inhabitants. In 2013, penicillins with extended spectrum were more commonly prescribed compared to macrolides among adult patients (153.5 and 105.4 prescriptions per 10,000 inhabitants, respectively). This study is the first to describe physician antibiotic prescribing practices for treatment of ARS in Canada. Results show that antibiotic treatment for ARS represents an area for implementing antimicrobial stewardship, and through it, managing antibiotic resistance. Further work is required to better understand diagnosing practices and treatment criteria for ARS, and use this information to further assist physicians to limit unnecessary antibiotic prescribing practices.

Antibiotic resistance among Ureaplasma spp. isolates: cause for concern?

PubMed

Beeton, M L; Spiller, O B

2017-02-01

There is growing global concern regarding the rise of antibiotic-resistant organisms. Many of these reports have focused on various Gram-positive and Gram-negative pathogens, with little attention to the genus Ureaplasma. Ureaplasma spp. are associated with numerous infectious diseases affecting pregnant women, neonates and the immunocompromised. Treatment options are extremely limited due to high levels of intrinsic resistance resulting from the unique physiology of these organisms and further restricted in cases of the developing fetus or neonate, often limiting therapeutic options to predominantly macrolides or rarely fluoroquinolones. The increasing presence of macrolide- and fluoroquinolone-resistant strains among neonatal infections may result in pan-drug resistance and potentially untreatable conditions. Here, we review the requirements for accurate measurement of antimicrobial susceptibility, provide a comprehensive review of the antimicrobial resistance (AMR) for Ureaplasma species in the literature and contextualize these results relative to some investigators' reliance on commercial kits that are not CLSI compliant when determining AMR. The dramatic variation in the resistance patterns and impact of high levels of AMR amongst neonatal populations suggests the need for continued surveillance. Commercial kits represent an excellent tool for initial antibiotic susceptibility determination and screening. However, AMR reporting must utilize internationally standardized methods, as high-titre samples, or Mycoplasma hominis-contaminated samples routinely give false AMR results. Furthermore, there is a requirement for future reports to determine the underlying AMR mechanisms and determine whether expanding AMR is due to spontaneous mutation, transmission of resistance genes on mobile elements or selection and expansion of resistant clones. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy

Negative environmental impacts of antibiotic-contaminated effluents from pharmaceutical industries.

PubMed

Bielen, Ana; Šimatović, Ana; Kosić-Vukšić, Josipa; Senta, Ivan; Ahel, Marijan; Babić, Sanja; Jurina, Tamara; González Plaza, Juan José; Milaković, Milena; Udiković-Kolić, Nikolina

2017-12-01

Effluents from pharmaceutical industries are recognized as significant contributors to aquatic pollution with antibiotics. Although such pollution has been mostly reported in Asia, knowledge on industrial discharges in other regions of the world, including Europe, and on the effects associated with such exposures is still limited. Thus, we performed chemical, microbiological and ecotoxicological analyses of effluents from two Croatian pharmaceutical industries during four seasons. In treated effluents of the company synthesizing macrolide antibiotic azithromycin (AZI), the total concentration of AZI and two macrolide by-products from its synthesis was 1-3 orders of magnitude higher in winter and springtime (up to 10.5 mg/L) than during the other two seasons (up to 638 μg/L). Accordingly, the highest total concentrations (up to 30 μg/L) in the recipient river were measured in winter and spring. Effluents from second company formulating veterinary antibiotics contained fluoroquinolones, trimethoprim, sulfonamides and tetracyclines ranging from low μg/L to approx. 200 μg/L. Low concentrations of these antibiotics, from below the limit of quantification to approx. few μg/L, have also been measured in the recipient stream. High frequency of culturable bacteria resistant to AZI (up to 83%) or sulfamethazine (up to 90%) and oxytetracycline (up to 50%) were also found in studied effluents. Finally, we demonstrated that toxicity to algae and water fleas often exceeded the permitted values. Most highly contaminated effluents induced multiple abnormalities in zebrafish embryos. In conclusion, using a wide array of analyses we have demonstrated that discharges from pharmaceutical industries can pose a significant ecological and public health concern due to their toxicity to aquatic organisms and risks for promoting development and spread of antibiotic resistance. Copyright © 2017 Elsevier Ltd. All rights reserved.

An automated on-line turbulent flow liquid-chromatography technology coupled to a high resolution mass spectrometer LTQ-Orbitrap for suspect screening of antibiotic transformation products during microalgae wastewater treatment.

PubMed

Jaén-Gil, Adrián; Hom-Diaz, Andrea; Llorca, Marta; Vicent, Teresa; Blánquez, Paqui; Barceló, Damià; Rodríguez-Mozaz, Sara

2018-06-11

The evaluation of wastewater treatment capabilities in terms of removal of water pollutants is crucial when assessing water mitigation issues. Not only the monitoring of target pollutants becomes a critical point, but also the transformation products (TPs) generated. Since these TPs are very often unknown compounds, their study in both wastewater and natural environment is currently recognized as a tedious task and challenging research field. In this study, a novel automated suspect screening methodology was developed for a comprehensive assessment of the TPs generated from nine antibiotics during microalgae water treatment. Three macrolides (azithromycin, erythromycin, clarithromycin), three fluoroquinolones (ofloxacin, ciprofloxacin, norfloxacin) and three additional antibiotics (trimethoprim, pipemidic acid, sulfapyridine) were selected as target pollutants. The analysis of samples was carried out by direct injection in an on-line turbulent flow liquid chromatography-high resolution mass spectrometry (TFC-LC-LTQ-Orbitrap-MS/MS) system, followed by automatic data processing for compound identification. The screening methodology allowed the identification of 40 tentative TPs from a list of software predicted intermediates created automatically. Once known and unknown TPs were identified, degradation pathways were suggested considering the different mechanisms involved on their formation (biotic and abiotic). Results reveal microalgae ability for macrolide biotransformation, but not for other antibiotics such as for fluoroquinolones. Finally, the intermediates detected were included into an in-house library and applied to the identification of tentative TPs in real toilet wastewater treated in a microalgae based photobioreactor (PBR). The overall approach allowed a comprehensive overview of the performance of microalgae water treatment in a fast and reliable manner: it represents a useful tool for the rapid screening of wide range of compounds, reducing time

Pharmacodynamic Evaluation of the Intracellular Activities of Antibiotics against Staphylococcus aureus in a Model of THP-1 Macrophages

PubMed Central

Barcia-Macay, Maritza; Seral, Cristina; Mingeot-Leclercq, Marie-Paule; Tulkens, Paul M.; Van Bambeke, Françoise

2006-01-01

The pharmacodynamic properties governing the activities of antibiotics against intracellular Staphylococcus aureus are still largely undetermined. Sixteen antibiotics of seven different pharmacological classes (azithromycin and telithromycin [macrolides]; gentamicin [an aminoglycoside]; linezolid [an oxazolidinone]; penicillin V, nafcillin, ampicillin, and oxacillin [β-lactams]; teicoplanin, vancomycin, and oritavancin [glycopeptides]; rifampin [an ansamycin]; and ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin [quinolones]) have been examined for their activities against S. aureus (ATCC 25923) in human THP-1 macrophages (intracellular) versus that in culture medium (extracellular) by using a 0- to 24-h exposure time and a wide range of extracellular concentrations (including the range of the MIC to the maximum concentration in serum [Cmax; total drug] of humans). All molecules except the macrolides caused a net reduction in bacterial counts that was time and concentration/MIC ratio dependent (four molecules tested in detail [gentamicin, oxacillin, moxifloxacin, and oritavancin] showed typical sigmoidal dose-response curves at 24 h). Maximal intracellular activities remained consistently lower than extracellular activities, irrespective of the level of drug accumulation and of the pharmacological class. Relative potencies (50% effective concentration or at a fixed extracellular concentration/MIC ratio) were also decreased, but to different extents. At an extracellular concentration corresponding to their Cmaxs (total drug) in humans, only oxacillin, levofloxacin, garenoxacin, moxifloxacin, and oritavancin had truly intracellular bactericidal effects (2-log decrease or more, as defined by the Clinical and Laboratory Standards Institute guidelines). The intracellular activities of antibiotics against S. aureus (i) are critically dependent upon their extracellular concentrations and the duration of cell exposure (within the 0- to 24-h time frame) to

Pharmacokinetics and Pharmacodynamics of Tildipirosin Against Pasteurella multocida in a Murine Lung Infection Model

PubMed Central

Zeng, Dongping; Sun, Meizhen; Lin, Zhoumeng; Li, Miao; Gehring, Ronette; Zeng, Zhenling

2018-01-01

Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle. PMID:29867911

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.

Large-area burns with pandrug-resistant Pseudomonas aeruginosa infection and respiratory failure.

PubMed

Ning, Fang-Gang; Zhao, Xiao-Zhuo; Bian, Jing; Zhang, Guo-An

2011-02-01

Infection due to pandrug-resistant Pseudomonas aeruginosa (PDRPA) has become a challenge in clinical practice. The aim of this research was to summarize the treatment of large-area burns (60% - 80%) with PDRPA infection and respiratory failure in our hospital over the last two years, and to explore a feasible treatment protocol for such patients. We retrospectively analyzed the treatment of five patients with large-area burns accompanied by PDRPA infection and respiratory failure transferred to our hospital from burn units in hospitals in other Chinese cities from January 2008 to February 2010. Before PDRPA infection occurred, all five patients had open wounds with large areas of granulation because of the failure of surgery and dissolving of scar tissue; they had also undergone long-term administration of carbapenems. This therapy included ventilatory support, rigorous repair of wounds, and combined antibiotic therapy targeted at drug-resistance mechanisms, including carbapenems, ciprofloxacin, macrolide antibiotics and β-lactamase inhibitors. Four patients recovered from burns and one died after therapy. First, compromised immunity caused by delayed healing of burn wounds in patients with large-area burns and long-term administration of carbapenems may be the important factors in the initiation and progression of PDRPA infection. Second, if targeted at drug-resistance mechanisms, combined antibiotic therapy using carbapenems, ciprofloxacin, macrolide antibiotics and β-lactamase inhibitors could effectively control PDRPA infection. Third, although patients with large-area burns suffered respiratory failure and had high risks from anesthesia and surgery, only aggressive skin grafting with ventilatory support could control the infection and save lives. Patients may not be able to tolerate a long surgical procedure, so the duration of surgery should be minimized, and the frequency of surgery increased.

Mycoplasma Pneumoniae among Children Hospitalized with Community-acquired Pneumonia.

PubMed

Kutty, Preeta K; Jain, Seema; Taylor, Thomas H; Bramley, Anna M; Diaz, Maureen H; Ampofo, Krow; Arnold, Sandra R; Williams, Derek J; Edwards, Kathryn M; McCullers, Jonathan A; Pavia, Andrew T; Winchell, Jonas M; Schrag, Stephanie J; Hicks, Lauri A

2018-05-17

The burden and epidemiology of Mycoplasma pneumoniae (Mp) among U.S. children (<18 years) hospitalized with community-acquired pneumonia (CAP) are poorly understood. In the Etiology of Pneumonia in the Community (EPIC) study, we prospectively enrolled 2254 children hospitalized with radiographically-confirmed pneumonia from January 2010-June 2012 and tested nasopharyngeal/oropharyngeal swabs for Mp using real-time polymerase chain reaction (PCR). Clinical and epidemiological features of Mp-PCR-positive and -negative children were compared using logistic regression. Macrolide susceptibility was assessed by genotyping isolates. In the EPIC study, 182(8%) children were Mp-PCR-positive (median age: 7 years); 12% required intensive care and 26% had pleural effusion. No in-hospital deaths occurred. Macrolide resistance was found in 6/169(4%) isolates. Of 178(98%) Mp-PCR-positive children tested for co-pathogens, 50(28%) had ≥1 co-pathogen detected. Variables significantly associated with higher odds of Mp detection included age {10-17 years [adjusted odds ratio (aOR): 7.9 (95% confidence interval (CI): 4.5-13.6)] and 5-9 years [aOR: 4.8 (CI: 2.9-7.8)] vs. 2-4 years}, outpatient antibiotics ≤5 days pre-admission [aOR: 2.3 (CI: 1.5-3.4)], and co-pathogen detection [aOR: 2.1 (CI: 1.3-3.1)]. Clinical characteristics often seen included hilar lymphadenopathy, rales, headache, sore throat, and decreased breath sounds. Usually considered as a mild respiratory infection, M. pneumoniae was the most commonly detected bacteria among children ≥5 years hospitalized with CAP; one-quarter of whom had co-detections. Although associated with clinically non-specific symptoms, there was a need for intensive care support in some cases. M. pneumoniae should be included in the differential diagnosis for school-aged children hospitalized with CAP.

Decline in extractable antibiotics in manure-based composts during composting.

PubMed

Kim, K-R; Owens, G; Ok, Y S; Park, W-K; Lee, D B; Kwon, S-I

2012-01-01

A wide variety of antibiotics have been detected in natural water samples and this is of potential concern because of the adverse environmental effects of such antibiotic residues. One of the main sources of antibiotics effluence to the surrounding environment is livestock manures which often contain elevated concentrations of veterinary antibiotics (VAs) which survive digestion in the animal stomach following application in animal husbandry practices. In Korea, livestock manures are normally used for compost production indicating that there is potential for antibiotic release to the environment through compost application to agricultural lands. Therefore, reduction of the amount of VAs in composts is crucial. The purpose of this study was to understand the influence of the composting process and the components of the compost on the levels of three common classes of antibiotics (tetracyclines, sulfonamides, and macrolides). Composted materials at different stages of composting were collected from compost manufacturing plants and the variation in antibiotic concentrations was determined. Three different antibiotics, chlortetracycline (CTC), sulfamethazine (SMZ), and tylosin (TYL) at three different concentrations (2, 10, and 20mgkg(-1)) were also applied to a mixture of pig manure and sawdust and the mixtures incubated using a laboratory scale composting apparatus to monitor the changes in antibiotic concentrations during composting together with the physicochemical properties of the composts. During composting, in both field and lab-scale investigations, the concentrations of all three different antibiotics declined below the relevant Korean guideline values (0.8mgkg(-1) for tetracyclines, 0.2mgkg(-1) for sulfonamides and 1.0mgkg(-1) for macrolides). The decline of tetracycline and sulfonamide concentrations was highly dependent on the presence of sawdust while there was no influence of sawdust on TYL decline. Copyright © 2011 Elsevier Ltd. All rights reserved.

ICESpy009, a Conjugative Genetic Element Carrying mef(E) in Streptococcus pyogenes.

PubMed

Del Grosso, Maria; Camilli, Romina; Rizzi, Ermanno; Pietrelli, Alessandro; De Bellis, Gianluca; Pantosti, Annalisa

2016-07-01

Efflux-mediated macrolide resistance due to mef(E) and mel, carried by the mega element, is common in Streptococcus pneumoniae, for which it was originally characterized, but it is rare in Streptococcus pyogenes In S. pyogenes, mega was previously found to be enclosed in Tn2009, a composite genetic element of the Tn916 family containing tet(M) and conferring erythromycin and tetracycline resistance. In this study, S. pyogenes isolates containing mef(E), apparently not associated with other resistance determinants, were examined to characterize the genetic context of mega. By whole-genome sequencing of one isolate, MB56Spyo009, we identified a novel composite integrative and conjugative element (ICE) carrying mega, designated ICESpy009, belonging to the ICESa2603 family. ICESpy009 was 55 kb long, contained 61 putative open reading frames (ORFs), and was found to be integrated into hylA, a novel integration site for the ICESa2603 family. The modular organization of the ICE was similar to that of members of the ICESa2603 family carried by different streptococcal species. In addition, a novel cluster of accessory resistance genes was found inside a region that encloses mega. PCR mapping targeting ICESpy009 revealed the presence of a similar ICE in five other isolates under study. While in three isolates the integration site was the same as that of ICESpy009, in two isolates the ICE was integrated into rplL, the typical integration site of the ICESa2603 family. ICESpy009 was able to transfer macrolide resistance by conjugation to both S. pyogenes and S. pneumoniae, showing the first evidence of the transferability of mega from S. pyogenes. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Risk factors for persistent Aspergillus respiratory isolation in cystic fibrosis.

PubMed

Hong, Gina; Psoter, Kevin J; Jennings, Mark T; Merlo, Christian A; Boyle, Michael P; Hadjiliadis, Denis; Kawut, Steven M; Lechtzin, Noah

2018-02-12

Aspergillus species are increasingly detected in the respiratory tracts of individuals with cystic fibrosis (CF), and chronic Aspergillus fumigatus is associated with more frequent hospitalizations for pulmonary exacerbations. However, patient and clinical factors that may contribute to the acquisition of persistent Aspergillus infection have yet to be identified. The objective of this study was to identify risk factors for development of Aspergillus respiratory isolation in CF. A retrospective cohort study of participants in the CF Foundation Patient Registry between 2006 and 2012 was conducted. Generalized estimating equation models were used to evaluate the association between the development of persistent Aspergillus respiratory isolation and individual level demographic and clinical characteristics. Among 16,095 individuals with CF followed from 2006 to 2012, 1541 (9.6%) subjects developed persistent Aspergillus isolation. White race (Odds Ratio [OR] 1.74, 95% confidence interval 1.23, 2.48, p<0.001) and pancreatic insufficiency (OR 1.50, 95% CI 1.09, 2.06, p<0.001) were found to be risk factors for persistent Aspergillus isolation. Chronic therapies, including inhaled antibiotics (OR 1.33; 95% CI 1.21, 1.46), macrolides (OR 1.23, 95% CI 1.14, 1.32, p<0.001), and inhaled corticosteroids (OR 1.13, 95% CI 1.04, 1.20, p<0.001) were also independently associated with an increased risk for persistent Aspergillus isolation. We identified macrolides and inhaled antibiotics, which individually have been shown to improve CF outcomes, and inhaled corticosteroids as risk factors for developing persistent Aspergillus isolation. Further work is needed to determine whether these associations are causal or due to confounding by other factors. Copyright © 2018 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Occurrence of transferable antibiotic resistances in commercialized ready-to-eat mealworms (Tenebrio molitor L.).

PubMed

Osimani, Andrea; Cardinali, Federica; Aquilanti, Lucia; Garofalo, Cristiana; Roncolini, Andrea; Milanović, Vesna; Pasquini, Marina; Tavoletti, Stefano; Clementi, Francesca

2017-12-18

The present study aimed to assess the occurrence of transferable determinants conferring resistance to tetracyclines, macrolide-lincosamide-streptogramin B, vancomycin, beta-lactams, and aminoglycosides in 40 samples of commercialized edible mealworms (Tenebrio molitor L.) purchased from European Union (EU) and non-EU producers. A high prevalence of tet(K) was observed in all of the samples assayed, with percentages of PCR-based positivity that ranged from 80% (samples from Thailand) to 100% (samples from the Netherlands, Belgium and France). For macrolides, erm(B) prevailed, being detected in 57.5% of the samples assayed, whereas erm(A) and erm(C) were detected with lower frequencies. Genes for resistance to vancomycin were only detected in samples produced in France and Belgium, with 90% and 10% of the samples being positive for vanA, respectively. Beta-lactamase genes were found with low occurrence, whereas the gene aac-aph, conferring high resistance to aminoglycosides, was found in 40% of the samples produced in the Netherlands and Belgium and 20% of the samples produced in Thailand. The results of Principal Coordinate Analysis and Principal Component Analysis depicted a clean separation of the samples collected from the four producers based on the distribution of the 12 AR determinants considered. Given the growing interest on the use of mealworms as a novel protein source, AR detection frequencies found in the present study suggest further investigation into the use of antibiotics during rearing of this insect species and more extensive studies focused on the factors that can affect the diffusion of transferable ARs in the production chain. Until such studies are completed, prudent use of antibiotics during rearing of edible insects is recommended. Copyright © 2017 Elsevier B.V. All rights reserved.

Structure-activity relations of successful pharmacologic chaperones for rescue of naturally occurring and manufactured mutants of the gonadotropin-releasing hormone receptor.

PubMed

Janovick, Jo Ann; Goulet, Mark; Bush, Eugene; Greer, Jonathan; Wettlaufer, David G; Conn, P Michael

2003-05-01

We expressed a test system of wild-type (WT) rat (r) and human (h) gonadotropin-releasing hormone (GnRH) receptors (GnRHRs), including naturally occurring (13) and manufactured (five) "loss-of-function" mutants of the GnRHR. These were used to assess the ability of different GnRH peptidomimetics to rescue defective GnRHR mutants and determine their effect on the level of membrane expression of the WT receptors. Among the manufactured mutants were the shortest rGnRHR C-terminal truncation mutant that resulted in receptor loss-of-function (des(325-327)-rGnRHR), two nonfunctional deletion mutants (des(237-241)-rGnRHR and des(260-265)-rGnRHR), two nonfunctional Cys mutants (C(229)A-rGnRHR and C(278)A-rGnRHR); the naturally occurring mutants included all 13 full-length GnRHR point mutations reported to date that result in full or partial human hypogonadotropic hypogonadism. The 10 peptidomimetics assessed as potential rescue molecules ("pharmacoperones") are from three differing chemical pedigrees (indoles, quinolones, and erythromycin-derived macrolides) and were originally developed as GnRH peptidomimetic antagonists. These structures were selected for this study because of their predicted ability to permeate the cell membrane and interact with a defined affinity with the GnRH receptor. All peptidomimetics studied with an IC(50) value (for hGnRHR) macrolides with IC(50) values as high as 669.5 nM showed efficacy as rescue compounds. The ability to rescue a particular receptor was a reasonable predictor of the ability to rescue others, even across species lines, although particular mutants could not be rescued by any of the drugs tested.

Results from the Survey of Antibiotic Resistance (SOAR) 2011–14 in the Democratic Republic of Congo, Ivory Coast, Republic of Senegal and Kenya

PubMed Central

Kacou-Ndouba, A.; Revathi, G.; Mwathi, P.; Seck, A.; Diop, A.; Kabedi-Bajani, M. J.; Mwiti, W.; Anguibi-Pokou, M. J.; Morrissey, I.; Torumkuney, D.

2016-01-01

Objectives To assess antibiotic susceptibility of community-acquired respiratory tract isolates from Ivory Coast, Kenya, Democratic Republic of Congo (DRC) and Senegal in 2011–14. Methods Bacterial isolates were collected and MICs determined using Etest® for all antibiotics except erythromycin, for which testing was by disc diffusion. Susceptibility was assessed using CLSI, EUCAST and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. For macrolide interpretation, CLSI breakpoints were adjusted for incubation in CO2. Results Susceptibility to penicillin (using CLSI oral or EUCAST breakpoints) was low among isolates of Streptococcus pneumoniae from the DRC and Kenya (17.4% and 19%, respectively) but higher among isolates from the Ivory Coast (70%) and Senegal (85.7%). Penicillin susceptibility using CLSI iv breakpoints was higher in all countries, but still only 69.6% in the DRC. Macrolide susceptibility (based on CLSI erythromycin disc diffusion breakpoints) was also low in Kenya (∼65%) but 87%–100% elsewhere. Haemophilus influenzae were only collected in the DRC and Senegal, with β-lactamase prevalence of 39% and 4%, respectively. Furthermore, β-lactamase-negative ampicillin-resistant (BLNAR) isolates were found in DRC (four isolates, 17%), but only two isolates were found in Senegal (by EUCAST definition). Amoxicillin/clavulanic acid in vitro susceptibility was 73.9% in the DRC and 100% in Senegal based on CLSI breakpoints, but this reduced to 65.2% in the DRC when BLNAR rates were considered. Clarithromycin susceptibility was >95% in both countries. Conclusions There was considerable variability in antibiotic susceptibility among the African countries participating in the surveillance programme. Thus, continued surveillance is necessary to track future changes in antibiotic resistance. Use of EUCAST versus CLSI breakpoints showed profound differences for cefaclor and ofloxacin against S. pneumoniae, with EUCAST showing lower susceptibility. PMID

[New drugs for horses and production animals in 2017].

PubMed

Emmerich, Ilka Ute

2018-04-01

In 2017, no new active pharmaceutical ingredients were released on the German market for horses or food-producing animals. Four established veterinary active pharmaceutical ingredients became available for additional species: the ectoparasitic Fluralaner (Exzolt®) of the isoxazoline group was additionally authorized for chickens, the macrolide antibiotics Gamithromycin (Zactran®) and Tulathromycin (Draxxin®) for sheep and the nonsteroidal anti-inflammatory drug Tolfenamic Acid (Tolfedol®) from the fenamate group for cattle and pigs. Additionally, one drug with a new combination of active ingredients, one drug with a new pharmaceutical form and one drug with a new mode of administration have been launched on the market for horses and food-producing animals. Schattauer GmbH.

Infective endocarditis caused by multidrug-resistant Streptococcus mitis in a combined immunocompromised patient: an autopsy case report.

PubMed

Matsui, Natsuko; Ito, Makoto; Kuramae, Hitoshi; Inukai, Tomomi; Sakai, Akiyoshi; Okugawa, Masaru

2013-04-01

An autopsy case of infective endocarditis caused by multidrug-resistant Streptococcus mitis was described in a patient with a combination of factors that compromised immune status, including autoimmune hemolytic anemia, post-splenectomy state, prolonged steroid treatment, and IgA deficiency. The isolated S. mitis strain from blood culture was broadly resistant to penicillin, cephalosporins, carbapenem, macrolides, and fluoroquinolone. Recurrent episodes of bacterial infections and therapeutic use of several antibiotics may underlie the development of multidrug resistance for S. mitis. Because clinically isolated S. mitis strains from chronically immunocompromised patients have become resistant to a wide spectrum of antibiotics, appropriate antibiotic regimens should be selected when treating invasive S. mitis infections in these compromised patients.

Total synthesis of bryostatins: the development of methodology for the atom-economic and stereoselective synthesis of the ring C subunit.

PubMed

Trost, Barry M; Frontier, Alison J; Thiel, Oliver R; Yang, Hanbiao; Dong, Guangbin

2011-08-22

Bryostatins, a family of structurally complicated macrolides, exhibit an exceptional range of biological activities. The limited availability and structural complexity of these molecules makes development of an efficient total synthesis particularly important. This article describes our initial efforts towards the total synthesis of bryostatins, in which chemoselective and atom-economical methods for the stereoselective assembly of the ring C subunit were developed. A Pd-catalyzed tandem alkyne-alkyne coupling/6-endo-dig cyclization sequence was explored and successfully pursued in the synthesis of a dihydropyran ring system. Elaboration of this methodology ultimately led to a concise synthesis of the ring C subunit of bryostatins. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Determination of tylosin residues in pig tissues using high-performance liquid chromatography.

PubMed

De Liguoro, M; Anfossi, P; Angeletti, R; Montesissa, C

1998-06-01

In accordance with the maximum residue limit of 100 micrograms kg-1 established by EU legislation, a simple and sensitive high-performance liquid chromatographic (HPLC) method was developed for the measurement of tylosin residues in pig tissues (fat, kidney, liver and muscle). Tylosin, a macrolide antibiotic, is extracted with water-methanol and cleaned-up by solid-phase extraction (SPE) on cation-exchange cartridges using methanol elution. Tylosin was determined by reversed-phase HPLC with UV detection at 280 nm and the mean recovery from pig tissues fortified in the range 50-200 micrograms kg-1 was 70-85%, with intra- and inter-day RSDs in the ranges 3.4-9.1 and 3.9-10.1% respectively.

Neutrophils alter the inflammatory milieu by signal-dependent translation of constitutive messenger RNAs

NASA Astrophysics Data System (ADS)

Lindemann, Stephan W.; Yost, Christian C.; Denis, Melvin M.; McIntyre, Thomas M.; Weyrich, Andrew S.; Zimmerman, Guy A.

2004-05-01

The mechanisms by which neutrophils, key effector cells of the innate immune system, express new gene products in inflammation are largely uncharacterized. We found that they rapidly translate constitutive mRNAs when activated, a previously unrecognized response. One of the proteins synthesized without a requirement for transcription is the soluble IL-6 receptor , which translocates to endothelial cells and induces a temporal switch to mononuclear leukocyte recruitment. Its synthesis is regulated by a specialized translational control pathway that is inhibited by rapamycin, a bacterial macrolide with therapeutic efficacy in transplantation, inflammatory syndromes, and neoplasia. Signal-dependent translation in activated neutrophils may be a critical mechanism for alteration of the inflammatory milieu and a therapeutic target.

Pyrilamine-induced prolonged QT interval in adolescent with drug overdose.

PubMed

Paudel, Govinda; Syed, Muhammad; Kalantre, Sarika; Sharma, Jayendra

2011-10-01

The widespread availability of antihistamines in many over-the-counter preparations can lead to significant hazard to the public because of their possible link to potential ventricular arrhythmias secondary to prolongation of QT interval. The effect can be further compounded by the use of other commonly used medications such as macrolides, antifungal agents, antipsychotics, and other antihistamine-containing preparations. The effect of antihistamines on QT interval is not a class effect but is unique to certain medications. Pyrilamine, a first-generation antihistaminic agent, is considered safe as there are no reports regarding its cardiac toxicity available in literature. We report a case of an adolescent with prolonged QT interval after an overdose of pyrilamine.

Clonal Expansion of the Macrolide Resistant ST386 within Pneumococcal Serotype 6C in France

PubMed Central

Janoir, Claire; Cohen, Robert; Levy, Corinne; Bingen, Edouard; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle

2014-01-01

In France, the use of the 7-valent pneumococcal conjugate vaccine (PCV7) lead to an overall significant decrease in PCV7 invasive pneumococcal disease (IPD) incidence. However, the decrease in vaccine serotype prevalence was partially counterbalanced by the serotype replacement phenomenon. In this study, we analyzed the role of the newly described serotype 6C as one of the replacement serotypes. This work was conducted on a large time scale from the early PCV7 era (2002–2003) to the PCV13 era (2010–2011), both on IPD strains recovered from the whole population and nasopharyngeal colonizing strains isolated in infant less than two years, who are known to be the main reservoir for pneumococci. Serotype 6C took advantage over 6A and 6B serotypes, which both decreased over time. A continuous and significant increase in 6C IPD was observed in adults along the study period; in contrast, in children less than two years, only an increase in 6C nasopharyngeal carriage was found, the prevalence of serotype 6C in IPD remaining very low over time. Among 101 6C invasive and colonizing strains studied by MLST, 24 STs were found to be related to three major clonal complexes, CC395, CC176, and CC315. STs related to CC176 tend to disappear after 2009 and were essentially replaced by ST386 (CC315), which dramatically increased over time. This clonal expansion may be explained by the erythromycin and tetracycline resistances associated with this clone. Finally, the decrease observed in nasopharyngeal 6C carriage since 2010, likely related to the PCV13 introduction in the French immunization schedule, is expected to lead to a decrease in 6C IPD in adults thereafter. PMID:24603763

Tracing the Sources of Macrolide Antibiotics and Illicit Drugs into the Lower Colorado River Basin

EPA Science Inventory

A number of pharmaceuticals have been detected in surface waters across the United States. Antibiotics present in the environment can produce resistance in microorganisms, which could potentially have adverse effects on human health. In addition, while the ecotoxicological signif...

Around the macrolide - Impact of 3D structure of macrocycles on lipophilicity and cellular accumulation.

PubMed

Koštrun, Sanja; Munic Kos, Vesna; Matanović Škugor, Maja; Palej Jakopović, Ivana; Malnar, Ivica; Dragojević, Snježana; Ralić, Jovica; Alihodžić, Sulejman

2017-06-16

The aim of this study was to investigate lipophilicity and cellular accumulation of rationally designed azithromycin and clarithromycin derivatives at the molecular level. The effect of substitution site and substituent properties on a global physico-chemical profile and cellular accumulation of investigated compounds was studied using calculated structural parameters as well as experimentally determined lipophilicity. In silico models based on the 3D structure of molecules were generated to investigate conformational effect on studied properties and to enable prediction of lipophilicity and cellular accumulation for this class of molecules based on non-empirical parameters. The applicability of developed models was explored on a validation and test sets and compared with previously developed empirical models. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Epoch-making milestones in antibiotic exploratory researches in Japan.

PubMed

Hotta, Kunimoto

2017-01-01

Professor Satoshi Ōmura was awarded the 2015 Nobel Prize in Physiology or Medicine. He is the third to win the award for research on antibiotic, following Fleming' (UK, 1945, discovery of penicillin) and Waksman (USA, 1952, discovery of streptomycin), and the second person after Waksman to receive the award for research on actinomycetes. By focusing his research on macrolides stemming from leucomycin research rather than β-lactams like penicillin or aminoglycosides like streptomycin, Prof. Ōmura realized many scientific achievements. These efforts finally led to the discovery of avermectin and its semi-synthetic derivative, ivermectin, considered a monumental contribution to the human race. In this manuscript, I will outline the chronicles of the epoch-making antibiotic exploratory researches preceding Prof. Ōmura.

Antimicrobial Drug Prescription and Neisseria gonorrhoeae Susceptibility, United States, 2005–2013

PubMed Central

Bartoces, Monina G.; Soge, Olusegun O.; Riedel, Stefan; Kubin, Grace; Del Rio, Carlos; Papp, John R.; Hook, Edward W.; Hicks, Lauri A.

2017-01-01

We investigated whether outpatient antimicrobial drug prescribing is associated with Neisseria gonorrhoeae antimicrobial drug susceptibility in the United States. Using susceptibility data from the Gonococcal Isolate Surveillance Project during 2005–2013 and QuintilesIMS data on outpatient cephalosporin, macrolide, and fluoroquinolone prescribing, we constructed multivariable linear mixed models for each antimicrobial agent with 1-year lagged annual prescribing per 1,000 persons as the exposure and geometric mean MIC as the outcome of interest. Multivariable models did not demonstrate associations between antimicrobial drug prescribing and N. gonorrhoeae susceptibility for any of the studied antimicrobial drugs during 2005–2013. Elucidation of epidemiologic factors contributing to resistance, including further investigation of the potential role of antimicrobial drug use, is needed. PMID:28930001

[A case of Legionella pneumonia with multiple organ failure].

PubMed

Li, Jiali; Wen, Rui; Deng, Hong; Li, Qian

2016-06-28

Legionella pneumonia (LP) is a rare systemic infectious disease, which is often misdiagnosed by clinicians due to the atypical symptoms. A middle-aged man who suffered from fever and dyspnea was diagnosed as community acquired pneumonia (CAP) in Changsha Central Hospital in March 2015. The treatment was unsatisfied firstly. The patients showed further symptoms of rhabdomyolysis, acute liver and renal failure, and impaired neural functions, who was diagnosed as LP with multiple organ failure based on a positive test for Legionella antibody. The patient was recovered after treated with moxifloxacin combined with azithromycin and continuous renal replacement therapy. LP should be paid attention when patient was diagnosed as CAP and failed to be treated. The satisfied outcome is achieved after application of macrolide, quinolones and comprehensive treatments.

Antibiotic sensitivity and resistance in Ornithobacterium rhinotracheale strains from Belgian broiler chickens.

PubMed

Devriese, L A; De Herdt, P; Haesebrouck, F

2001-06-01

Establishing the antibiotic sensitivity of the avian respiratory pathogen Ornithobacterium rhinotracheale is difficult because of the organism's complex growth requirements and the unusually frequent occurrence of resistance. The minimal inhibitory concentrations of 10 antibiotics were determined for 45 strains of O. rhinotracheale from Belgian broiler chickens collected from 45 farms between 1995 and 1998. They were compared with the type strain, which was isolated from a turkey, and a strain isolated from a rook. All the broiler strains were resistant to lincomycin and to the beta-lactams ampicillin and ceftiofur. Less than 10% of the strains were sensitive to the macrolides tylosin and spiramycin, tilmicosin and flumequine. A few strains were sensitive to enrofloxacin and doxycycline. All strains were sensitive to tiamulin.

Proposed quality control guidelines for antimicrobial susceptibility tests using tilmicosin.

PubMed Central

Shryock, T R; White, D W; Werner, C S; Staples, J M

1995-01-01

Quality control guidelines for tilmicosin, a novel veterinary-use-only macrolide, were developed in a multi-laboratory study according to established National Committee for Clinical Laboratory Standards (NCCLS) procedures (M23-T2). Tilmicosin was incorporated into Sensititre plates for broth microdilution endpoint testing and into two lots of 15-micrograms disks for Kirby-Bauer agar disk diffusion testing. One common lot and five unique lots of Mueller-Hinton media were used. (Broth was cation adjusted, and agar was supplemented with 5% defibrinated sheep blood.) Bacteria used for reference strains included Pasteurella haemolytica 128K, Pasteurella multocida ATCC 43137, and Staphylococcus aureus ATCC 29213 (microdilution) and ATCC 25923 (disk). Replicate tests were conducted. Disk diffusion and broth microdilution quality control ranges are proposed. PMID:7714188

Epidemiology, clinical features, diagnosis and treatment of Haemophilus ducreyi - a disappearing pathogen?

PubMed

Lewis, David A

2014-06-01

Chancroid, caused by Haemophilus ducreyi, has declined in importance as a sexually transmitted pathogen in most countries where it was previously endemic. The global prevalence of chancroid is unknown as most countries lack the required laboratory diagnostic capacity and surveillance systems to determine this. H. ducreyi has recently emerged as a cause of chronic skin ulceration in some South Pacific islands. Although no antimicrobial susceptibility data for H. ducreyi have been published for two decades, it is still assumed that the infection will respond successfully to treatment with recommended cephalosporin, macrolide or fluoroquinolone-based regimens. HIV-1-infected patients require careful follow-up due to reports of treatment failure with single dose regimens. Buboes may need additional treatment with either aspiration or excision and drainage.

The crystal structure of P450-TT heme-domain provides the first structural insights into the versatile class VII P450s.

PubMed

Tavanti, Michele; Porter, Joanne L; Levy, Colin W; Gómez Castellanos, J Rubén; Flitsch, Sabine L; Turner, Nicholas J

2018-07-02

The first crystal structure of a class VII P450, CYP116B46 from Tepidiphilus thermophilus, has been solved at 1.9 Å resolution. The structure reveals overall conservation of the P450-fold and a water conduit around the I-helix. Active site residues have been identified and sequence comparisons have been made with other class VII enzymes. A structure similarity search demonstrated that the P450-TT structure is similar to enzymes capable of oxy-functionalization of fatty acids, terpenes, macrolides, steroids and statins. The insight gained from solving this structure will provide a guideline for future engineering and modelling studies on this catalytically promiscuous class of enzymes. Copyright © 2018 Elsevier Inc. All rights reserved.

Bronchiectasis in the Last Five Years: New Developments

PubMed Central

Khoo, Jun Keng; Venning, Victoria; Wong, Conroy; Jayaram, Lata

2016-01-01

Bronchiectasis, a chronic lung disease characterised by cough and purulent sputum, recurrent infections, and airway damage, is associated with considerable morbidity and mortality. To date, treatment options have been limited to physiotherapy to clear sputum and antibiotics to treat acute infections. Over the last decade, there has been significant progress in understanding the epidemiology, pathophysiology, and microbiology of this disorder. Over the last five years, methods of assessing severity have been developed, the role of macrolide antibiotic therapy in reducing exacerbations cemented, and inhaled antibiotic therapies show promise in the treatment of chronic Pseudomonas aeruginosa infection. Novel therapies are currently undergoing Phase 1 and 2 trials. This review aims to address the major developments within the field of bronchiectasis over this time. PMID:27941638

Immunology-Based Techniques for the Detection of Veterinary Drug Residues in Foods

NASA Astrophysics Data System (ADS)

Reig, Milagro; Toldrá, Fidel

Veterinary drugs are used in farm animals, via the feed or the drinking water, to prevent the outbreak of diseases or even for the treatment of diseases. However, the growth of animals may be promoted through the use of hormones and antibiotics. Depending on the type of residue and the application and washing conditions, these substances or its metabolites may remain in meat and other foods of animal origin and may cause adverse effects on consumers’ health. This is the main reason why its use is strictly regulated or even banned (case of the European Union) in different countries. Antibiotics typically used for growth promotion include chloramphenicol, nitrofurans, and enrofloxacin but others like sulphonamides, macrolides etc. may also be used (Reig & Toldrá, 2007).

Lung abscess in a child secondary to Mycoplasma pneumoniae infection.

PubMed

Ruffini, E; De Petris, L; Candelotti, P; Tulli, M; Sabatini, M R; Luciani, L; Carlucci, A

2014-01-01

We present a case of a lung abscess in a child 6-year-old admitted with a history of right hemithorax pain lasting for 15 days and the onset of mild fever in the last two days. Etiological research showed positivity of IgM antibodies to Mycoplasma pneumoniae after seven days of admission. The child has been successfully treated with antibiotic therapy, without the use of macrolides, for a duration of 4 weeks. Our study suggests that the Mycoplasma pneumoniae infection may predispose to severe infections, such as lung abscess, caused by typical respiratory pathogens. The reported case of lung abscess is one of the few reported in the literature in the modern antibiotic era and is the first preceded by Mycoplasma pneumoniae infection.

Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad-Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium.

PubMed

Salvador-Reyes, Lilibeth A; Sneed, Jennifer; Paul, Valerie J; Luesch, Hendrik

2015-08-28

Cytotoxicity-guided fractionation of a Guamanian cyanobacterial collection yielded the new compounds amantelides A (1) and B (2). These polyketides are characterized by a 40-membered macrolactone ring consisting of a 1,3-diol and contiguous 1,5-diol units and a tert-butyl substituent. Amantelide A (1) displayed potent cytotoxicity with submicromolar IC₅₀ against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Acetylation of the hydroxy group at C-33 in 2 caused a close to 10-fold decrease in potency. Exhaustive acetylation of the hydroxy groups abrogated the antiproliferative activity of amantelide A (1) by 20-67-fold. Further bioactivity assessment of 1 against bacterial pathogens and marine fungi indicated a broad spectrum of bioactivity.

Amantelides A and B, Polyhydroxylated Macrolides with Differential Broad Spectrum Cytotoxicity from a Guamanian Marine Cyanobacterium

PubMed Central

Salvador-Reyes, Lilibeth A.; Sneed, Jennifer; Paul, Valerie J.; Luesch, Hendrik

2016-01-01

Cytotoxicity-guided fractionation of a Guamanian cyanobacterial collection yielded the new compounds amantelides A (1) and B (2). These polyketides are characterized by a 40-membered macrolactone ring consisting of a 1,3-diol and contiguous 1,5-diol units and a tert-butyl substituent. Amantelide A (1) displayed potent cytotoxicity with sub-micromolar IC50 against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cell lines. Acetylation of the hydroxy group at C-33 in 2 caused a close to 10-fold decrease in potency. Exhaustive acetylation of the hydroxy groups abrogated the antiproliferative activity of amantelide A (1) by 20–67-fold. Further bioactivity assessment of 1 against bacterial pathogens and marine fungi indicated a broad spectrum of bioactivity. PMID:26204500

Fate and transport of tylosin and macrolide-resistance genes following manure applications in tile-drained landscapes

USDA-ARS?s Scientific Manuscript database

The use of antibiotics in swine production leads to antibiotic-resistance in gastrointestinal bacteria. Application of swine manure to drained agricultural fields introduces elevated levels of antibiotic-resistant bacteria and residual antibiotics. The persistence and transport of these agents are g...

Antitumour polyether macrolides: four new halichondrins from the New Zealand deep-water marine sponge Lissodendoryx sp.

PubMed

Hickford, Sarah J H; Blunt, John W; Munro, Murray H G

2009-03-15

The isolation is reported of four new variants of the halichondrin B skeleton, very minor potently bioactive components from the Poecilosclerid sponge Lissodendoryx sp. These compounds were isolated in microgram quantities only from a collection of 1tonne of sponge. The structural elucidations relied heavily on the use of capillary NMR spectroscopy and the application of an HSQC-DEPT overlay technique.

Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens

PubMed Central

Fyfe, Corey; O’Brien, William; Hackel, Meredith; Minyard, Mary Beth; Waites, Ken B.; Dubois, Jacques; Murphy, Timothy M.; Slee, Andrew M.; Weiss, William J.; Sutcliffe, Joyce A.

2017-01-01

ABSTRACT TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 µg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 µg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 µg/ml), Streptococcus pyogenes (MIC90 = 0.03 µg/ml), Haemophilus influenzae (MIC90 = 0.12 µg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 µg/ml). TP-271 showed activity (MIC90 = 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising

Activity of Telithromycin (HMR 3647) against Anaerobic Bacteria Compared to Those of Eight Other Agents by Time-Kill Methodology†

PubMed Central

Credito, Kim L.; Ednie, Lois M.; Jacobs, Michael R.; Appelbaum, Peter C.

1999-01-01

Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria. Time-kill studies were carried out with the addition of Oxyrase in order to prevent the introduction of CO2. Macrolide-azalide-ketolide MICs were 0.004 to 32.0 μg/ml. Of the latter group, telithromycin had the lowest MICs, especially against non-Bacteroides fragilis group strains, followed by azithromycin, clarithromycin, erythromycin A, and roxithromycin. Clindamycin was active (MIC ≤ 2.0 μg/ml) against all anaerobes except Peptostreptococcus magnus and Bacteroides thetaiotaomicron, while pristinamycin MICs were 0.06 to 4.0 μg/ml. Amoxicillin-clavulanate had MICs of ≤1.0 μg/ml, while metronidazole was active (MICs, 0.03 to 2.0 μg/ml) against all except Propionibacterium acnes. After 48 h at twice the MIC, telithromycin was bactericidal (≥99.9% killing) against 6 strains, with 99% killing of 9 strains and 90% killing of 10 strains. After 24 h at twice the MIC, 90, 99, and 99.9% killing of nine, six, and three strains, respectively, occurred. Lower rates of killing were seen at earlier times. Similar kill kinetics relative to the MIC were seen with other macrolides. After 48 h at the MIC, clindamycin was bactericidal against 8 strains, with 99 and 90% killing of 9 and 10 strains, respectively. After 24 h, 90% killing of 10 strains occurred at the MIC. The kinetics of clindamycin were similar to those of pristinamycin. After 48 h at the MIC, amoxicillin-clavulanate showed 99.9% killing of seven strains, with 99% killing of eight strains and 90% killing of nine strains. At four times the MIC, metronidazole was bactericidal against 8 of 10 strains tested after 48 h and against all 10 strains after 24 h; after 12 h, 99% killing of all 10 strains occurred. PMID:10428930

Activity of telithromycin (HMR 3647) against anaerobic bacteria compared to those of eight other agents by time-kill methodology.

PubMed

Credito, K L; Ednie, L M; Jacobs, M R; Appelbaum, P C

1999-08-01

Time-kill studies examined the activities of telithromycin (HMR 3647), erythromycin A, azithromycin, clarithromycin, roxithromycin, clindamycin, pristinamycin, amoxicillin-clavulanate, and metronidazole against 11 gram-positive and gram-negative anaerobic bacteria. Time-kill studies were carried out with the addition of Oxyrase in order to prevent the introduction of CO(2). Macrolide-azalide-ketolide MICs were 0.004 to 32.0 microg/ml. Of the latter group, telithromycin had the lowest MICs, especially against non-Bacteroides fragilis group strains, followed by azithromycin, clarithromycin, erythromycin A, and roxithromycin. Clindamycin was active (MIC /=99.9% killing) against 6 strains, with 99% killing of 9 strains and 90% killing of 10 strains. After 24 h at twice the MIC, 90, 99, and 99.9% killing of nine, six, and three strains, respectively, occurred. Lower rates of killing were seen at earlier times. Similar kill kinetics relative to the MIC were seen with other macrolides. After 48 h at the MIC, clindamycin was bactericidal against 8 strains, with 99 and 90% killing of 9 and 10 strains, respectively. After 24 h, 90% killing of 10 strains occurred at the MIC. The kinetics of clindamycin were similar to those of pristinamycin. After 48 h at the MIC, amoxicillin-clavulanate showed 99.9% killing of seven strains, with 99% killing of eight strains and 90% killing of nine strains. At four times the MIC, metronidazole was bactericidal against 8 of 10 strains tested after 48 h and against all 10 strains after 24 h; after 12 h, 99% killing of all 10 strains occurred.

[Clinical features of four atypical pediatric cases of endemic typhus with pneumonia].

PubMed

Liu, Jin-rong; Xu, Bao-ping; Li, Shao-gang; Liu, Jun; Tian, Bao-lin; Zhao, Shun-ying

2013-10-01

To analyze clinical manifestations, treatment and prognosis of 4 cases with endemic typhus. The clinical data of four endemic typhus patients in prognosis were retrospectively analyzed. These four atypical cases of endemic typhus with pneumonia were treated in our department from October 2011 to March 2012. They were all male, with an age range of 15 months to 7 years. The four patients had long history, mild respiratory symptom and no improvement was found after treatment with cephalosporins. There were no evidences of bacterial, viral, or fungal infections and we thought they might have infection with other pathogen. Three were from rural areas. Routine blood tests, Weil-Felix reaction, blood smear (Giemsa staining) , and indirect immunofluorescence assay were performed. Blood smear and IFA tests showed evidences for endemic typhus. The clinical presentations were atypical, the patients had no headache, but all had fever, rash, and pneumonia of varying severity. None of the patients had a severe cough, but bronchial casts were observed in one case. Recurrent fever was reported in three cases. Physical examinations showed no eschars, but one patient had a subconjunctival hemorrhage, and one had skin scratches, cervical lymphadenopathy, pleural effusion, pericardial effusion, and cardiac dilatation. Two patients had remarkably increased peripheral blood leukocyte counts; both these patients also had high alanine aminotransferase (ALT) levels and one had a high C-reactive protein (CRP) level. Weil-Felix testing was negative or the OX19 titer was low. The peripheral blood smear (Giemsa stain) showed intracellular pathogens in all four cases. After combined therapy with doxycycline and macrolide antibiotics, all four patients recovered well. The endemic typhus children often come from rural areas. The clinical presentations were atypical, they usually have no headache, but have fever (often Periodic fever) , rash, and pneumonia of varying severity in these four cases

Mass flow of antibiotics in a wastewater treatment plant focusing on removal variations due to operational parameters.

PubMed

Marx, Conrad; Günther, Norbert; Schubert, Sara; Oertel, Reinhard; Ahnert, Markus; Krebs, Peter; Kuehn, Volker

2015-12-15

Wastewater treatment plants (WWTPs) are not designed to purposefully eliminate antibiotics and therefore many previous investigations have been carried out to assess their fate in biological wastewater treatment processes. In order to consolidate previous findings regarding influencing factors like the solid and hydraulic retention time an intensive monitoring was carried out in a municipal WWTP in Germany. Over a period of 12months daily samples were taken from the in- and effluent as well as diverse sludge streams. The 14 selected antibiotics and one metabolite cover the following classes: cephalosporins, diaminopyrimidines, fluoroquinolones, lincosamide, macrolides, penicillins, sulfonamides and tetracyclines. Out of the 15 investigated substances, the removal of only clindamycin and ciprofloxacin show significant correlations to SRT, temperature, HRT and nitrogen removal. The dependency of clindamycin's removal could be related to the significant negative removal (i.e. production) of clindamycin in the treatment process and was corrected using the human metabolite clindamycin-sulfoxide. The average elimination was adjusted from -225% to 3% which suggests that clindamycin can be considered as an inert substance during the wastewater treatment process. Based on the presented data, the mass flow analysis revealed that macrolides, clindamycin/clindamycin-sulfoxide and trimethoprim were mainly released with the effluent, while penicillins, cephalosporins as well as sulfamethoxazole were partly degraded in the studied WWTP. Furthermore, levofloxacin and ciprofloxacin are the only antibiotics under investigation with a significant mass fraction bound to primary, excess and digested sludge. Nevertheless, the sludge concentrations are highly inconsistent which leads to questionable results. It remains unclear whether the inconsistencies are due to insufficiencies in sampling and/or analytical determination or if the fluctuations can be considered reasonable for

Pneumonia acquired in the community through drug-resistant Streptococcus pneumoniae.

PubMed

Ewig, S; Ruiz, M; Torres, A; Marco, F; Martinez, J A; Sanchez, M; Mensa, J

1999-06-01

The aim of the study was to determine the incidence of and risk factors for drug resistance of Streptococcus pneumoniae, and its impact on the outcome among hospitalized patients of pneumococcal pneumonia acquired in the community. Consecutive patients with culture-proven pneumococcal pneumonia were prospectively studied with regard to the incidence of pneumococcal drug resistance, potential risk factors, and in-hospital outcome variables. A total of 101 patients were studied. Drug resistance to penicillin, cephalosporin, or a macrolide drug was found in pneumococci from 52 of the 101 (52%) patients; 49% of these isolates were resistant to penicillin (16% intermediate resistance, 33% high resistance), 31% to cephalosporin (22% intermediate and 9% high resistance), and 27% to a macrolide drug. In immunocompetent patients, age > 65 yr was significantly associated with resistance to cephalosporin (odds ratio [OR]: 5.0; 95% confidence interval [CI]: 1.3 to 18.8, p = 0. 01), and with the presence of > 2 comorbidities with resistance to penicillin (OR: 4.7; 95% CI: 1.2 to 19.1; p < 0.05). In immunosuppressed patients, bacteremia was inversely associated with resistance to penicillin and cephalosporin (OR: 0.04; 95% CI: 0.003 to 0.45; p < 0.005; and OR: 0.46; 95% CI: 0.23 to 0.93; p < 0.05, respectively). Length of hospital stay, severity of pneumonia, and complications were not significantly affected by drug resistance. Mortality was 15% in patients with any drug resistance, as compared with 6% in those without resistance. However, any drug resistance was not significantly associated with death (relative risk [RR]: 2. 5; 95% CI: 0.7 to 8.9; p = 0.14). Moreover, attributable mortality in the presence of discordant antimicrobial treatment was 12%, as compared with 10% (RR: 1.2; 95% CI: 0.3 to 5.3; p = 0.67) in the absence of such treatment. We conclude that the incidence of drug-resistant pneumococci was high. Risk factors for drug resistance included advanced age

Antibiofilm and antibacterial effects of specific chitosan molecules on Staphylococcus aureus isolates associated with bovine mastitis

PubMed Central

Asli, Abdelhamid; Brouillette, Eric; Ster, Céline; Ghinet, Mariana Gabriela; Brzezinski, Ryszard; Lacasse, Pierre; Jacques, Mario

2017-01-01

Staphylococcus aureus is one of the major pathogens causing bovine intramammary infections (IMIs) and mastitis. Mastitis is the primary cause for the use of antibiotics in dairy farms but therapeutic failure is often observed. One of the reasons for the lack of effectiveness of antibiotic therapy despite the observed susceptibility of bacterial isolates in vitro are bacterial biofilms. In this study, we used chitosan of well-defined molecular weight (0.4–0.6, 1.3, 2.6 and 4.0 kDa) and investigated their antibiofilm and antibacterial activities in in vitro and in vivo models related to S. aureus IMIs. A chitosan of at least 6 units of glucosamine was necessary for maximum antibacterial activity. The 2.6 and 4.0 kDa forms were able to prevent biofilm production by the biofilm hyperproducer strain S. aureus 2117 and a bovine MRSA (methicillin-resistant S. aureus). The intramammary administration of the 2.6 kDa chitosan showed no adverse effects in mice or in cows, as opposed to the slight inflammatory effect observed in mammary glands with the 4.0 kDa derivative. The 2.6 kDa chitosan killed bacteria embedded in pre-established biofilms in a dose-dependent manner with a >3 log10 reduction in CFU at 4 mg/ml. Also, the 2.6 kDa chitosan could prevent the persistence of the internalized MRSA into the mammary epithelial cell line MAC-T. An in vitro checkerboard assay showed that the 2.6 kDa chitosan produced a synergy with the macrolide class of antibiotics (e.g., tilmicosin) and reduced the MIC of both molecules by 2–8 times. Finally, the intramammary administration of the 2.6 kDa chitosan alone (P<0.01) or in combination with tilmicosin (P<0.0001) reduced the colonization of mammary glands in a murine IMI model. Our results suggest that the use of chitosan alone or in combination with a low dose of a macrolide could help reduce antibiotic use in dairy farms. PMID:28486482

Novel Structure of Enterococcus faecium-Originated ermB-Positive Tn1546-Like Element in Staphylococcus aureus.

PubMed

Wan, Tsai-Wen; Hung, Wei-Chun; Tsai, Jui-Chang; Lin, Yu-Tzu; Lee, Hao; Hsueh, Po-Ren; Lee, Tai-Fen; Teng, Lee-Jene

2016-10-01

We determined the resistance determinants in 274 erythromycin-resistant methicillin-susceptible Staphylococcus aureus (MSSA) isolates during a 13-year period, 2000 to 2012. The resistance phenotypes, inducible macrolide-lincosamide-streptogramin (iMLS), constitutive MLS (cMLS), and macrolide-streptogramin (MS) resistance phenotypes, were examined by a double-disk diffusion D test. The ermB gene was more frequent (35%; 97/274) than ermC (27%; 75/274) or ermA (21%; 58/274). All 97 ermB-positive isolates harbored Tn551 and IS1216V The majority (89/97) of ermB-positive isolates displayed the cMLS phenotype and carried mobile element structure (MES)-like structures, which has been previously reported in sequence type 59 (ST59) methicillin-resistant S. aureus (MRSA). The remaining 8 ermB-carrying isolates, belonging to ST7 (n = 4), ST5 (n = 3), and ST59 (n = 1), were sasK intact and did not carry MES-like structures. Unlike a MES-like structure that was located on the chromosome, the ermB elements on sasK-intact isolates were located on plasmids by S1 nuclease pulsed-field gel electrophoresis (PFGE) analysis and conjugation tests. Sequence data for the ermB-containing region (14,566 bp) from ST59 NTUH_3874 revealed that the best match was a Tn1546-like element in plasmid pMCCL2 DNA (GenBank accession number AP009486) of Macrococcus caseolyticus Tn1546 is recognized as an enterococcal transposon and was known from the vancomycin resistance gene cluster in vancomycin-resistant Enterococcus (VRE). So far, acquisitions of Tn1546 in S. aureus have occurred in clonal complex 5 (CC5) MRSA, but not in MSSA. This is the first report that MSSA harbors an Enterococcus faecium-originated ermB-positive Tn1546-like element located on a plasmid. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Efficacy of concomitant administration of clarithromycin and acetylcysteine in bronchiolitis obliterans in seventeen sulfur mustard—exposed patients: An open-label study

PubMed Central

Ghanei, Mostafa; Abolmaali, Kamran; Aslani, Jafar

2004-01-01

Background: Victims of sulfur mustard (SM) gas exposure experience different types of chronic pulmonary disease, manifested as cough, sputum production, and dyspnea. Conventional therapies (eg, immunosuppressive drugs, corticosteroids) have not been effective in these patients. Objective: This study was carried out to determine the efficacy of concomitant administration of the macrolide clarithromycin and the mucolytic agent acetylcysteine in the treatment of bronchiolitis obliterans in SM-exposed patients. Methods: This open-label clinical study was conducted at the Research Center of Chemical Injuries, Baqiyatallah Medical Sciences University, Tehran, Iran. Clarithromycin and acetylcysteine were administered concomitantly for 6 months to male SM-exposed patients with chronic bronchitis and bronchiolitis obliterans who were nonresponsive to conventional treatments. Efficacy analysis included symptom assessment and pulmonary function tests (forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) using spirometry, performed at baseline and after 2 and 6 months of treatment. Results: Seventeen male patients (mean [SD] age, 38.3 [5.3] years [range, 31–50 years]; mean [SD] body weight, 77.9 [15.7] kg) were included in the study. Cough and sputum production were each found in 10 of 17 patients (58.8%) at baseline and were improved in all 10 patients after the administration of clarithromycin and acetylcysteine. FEV1 and FVC also were improved, by mean (SD) 10.6% (9.7%) (P < 0.001 vs baseline) and 12.9% (13.6%) (P = 0.001 vs baseline). No significant change in FEV1/FVC ratio was found. Conclusions: In this study of concomitant administration of clarithromycin and acetylcysteine for the treatment of bronchiolitis obliterans in SM-exposed patients, symptoms and pulmonary function were improved. These results may have been related to the therapeutic effects of a macrolide antibiotic on chronic bronchitis and bronchiolitis obliterans

A seventeen-year observation of the antimicrobial susceptibility of clinical Campylobacter jejuni and the molecular mechanisms of erythromycin-resistant isolates in Beijing, China.

PubMed

Zhou, Jiyuan; Zhang, Maojun; Yang, Wanna; Fang, Yuqing; Wang, Guiqiang; Hou, Fengqin

2016-01-01

To investigate the dynamic development of the antimicrobial resistance of Campylobacter jejuni isolated from human diarrhea in Beijing, China, between 1994 and 2010, and to further analyze the molecular mechanisms of erythromycin-resistant strains. Susceptibility tests were performed on 203 non-duplicate clinical C. jejuni strains against eight common antibiotics using the standard agar dilution method. The molecular determinants were further studied in the erythromycin (ERY) non-susceptible strains. The analysis focused on the 23S rRNA gene, the rplD and rplV ribosomal genes, the ermB gene, and the regulatory region of the CmeABC efflux pump. The rates of resistance of C. jejuni to ciprofloxacin (CIP), nalidixic acid (NAL), doxycycline (DOX), tetracycline (TET), florfenicol (FFC), and chloramphenicol (CHL) increased significantly over the period studied (all p<0.05). Similarly, the proportions of resistant patterns (CIP-NAL-DOX-TET, CIP-NAL-DOX-TET-FFC, and CIP-NAL-DOX-TET-CHL) increased remarkably. In this study, 4.4% (9/203) of C. jejuni strains were ERY non-susceptible. The A2075G mutation in the 23S rRNA was found in all of the resistant strains except cj8091, which harbored the ermB gene. Interestingly, the ermB gene was also detected in intermediately resistant isolates, and the earliest ermB-positive strain cj94473 was derived in 1994. Moreover, none of the ribosomal rplD or rplV genes harbored mutations that have been described to confer resistance to macrolides. Different mutations affecting the regulatory region of the CmeABC efflux pump were also found. This is the first comprehensive study on the recent trend in antimicrobial resistance and the molecular mechanisms of macrolide resistance in clinical C. jejuni strains isolated in China. More stringent monitoring and regulation of human and animal antimicrobial use are warranted. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Investigating antibiotics, antibiotic resistance genes, and microbial contaminants in groundwater in relation to the proximity of urban areas.

PubMed

Szekeres, Edina; Chiriac, Cecilia Maria; Baricz, Andreea; Szőke-Nagy, Tiberiu; Lung, Ildiko; Soran, Maria-Loredana; Rudi, Knut; Dragos, Nicolae; Coman, Cristian

2018-05-01

Groundwater is an essential public and drinking water supply and its protection is a goal for global policies. Here, we investigated the presence and prevalence of antibiotic residues, antibiotic resistance genes (ARGs), mobile genetic elements (MGEs), and microbial contamination in groundwater environments at various distances from urban areas. Antibiotic concentrations ranged from below detection limit to 917 ng/L, being trimethoprim, macrolide, and sulfonamide the most abundant antibiotic classes. A total of eleven ARGs (aminoglycoside, β-lactam, chloramphenicol, Macrolide-Lincosamide-Streptogramin B - MLSB, sulfonamide, and tetracycline), one antiseptic resistance gene, and two MGEs were detected by qPCR with relative abundances ranging from 6.61 × 10 -7 to 2.30 × 10 -1 copies/16S rRNA gene copies. ARGs and MGEs were widespread in the investigated groundwater environments, with increased abundances not only in urban, but also in remote areas. Distinct bacterial community profiles were observed, with a higher prevalence of Betaproteobacteria and Bacteroidetes in the less-impacted areas, and that of Firmicutes in the contaminated groundwater. The combined characteristics of increased species diversity, distinct phylogenetic composition, and the possible presence of fecal and/or pathogenic bacteria could indicate different types of contamination. Significant correlations between ARGs, MGEs and specific taxa within the groundwater bacterial community were identified, revealing the potential hosts of resistance types. Although no universal marker gene could be determined, a co-selection of int1, qacEΔ1 and sulI genes, a proxy group for anthropogenic pollution, with the tetC, tetO, tetW resistance genes was identified. As the tet group was observed to follow the pattern of environmental contamination for the groundwater samples investigated in this study, our results strongly support the proposal of this group of genes as an environmental tracer of

Risk factors for extended-spectrum β-lactamase-producing Escherichia coli urinary tract infection in the community in Denmark: a case-control study.

PubMed

Søgaard, M; Heide-Jørgensen, U; Vandenbroucke, J P; Schønheyder, H C; Vandenbroucke-Grauls, C M J E

2017-12-01

To verify the role of proton pump inhibitors (PPI) and nitrofurantoin, which have appeared as novel risk factors for carriage of extended-spectrum β-lactamase (ESBL) -producing Escherichia coli, as risk factors for ESBL E. coli urinary tract infection (UTI). We included known risk factors to ascertain whether our findings are comparable with those of previous studies. Population-based case-control study including 339 cases with community-onset ESBL E. coli UTI in 2007-2012, 3390 non-ESBL E. coli UTI controls and 3390 population controls. We investigated potential risk factors by estimating ORs and 95% CIs adjusting for sex, age and co-morbidity. Comparing cases with non-ESBL E. coli UTI, PPI use yielded an OR of 1.6 (95% CI 1.2-2.0) and antibiotic exposure gave an OR of 1.4 (95% CI 1.1-1.8); these were driven by nitrofurantoin (OR 1.8; 95% CI 1.3-2.6) and macrolides (OR 1.7; 95% CI 1.2-2.3). Other risk factors included previous hospitalization with one or two and more than two hospitalizations versus none yielding ORs of 1.9 (95% CI 1.4-2.5) and 4.6 (95% CI 3.2-6.8), recent surgery (OR 2.0; 95% CI 1.5-2.8), renal disease (OR 2.2; 95% CI 1.4-3.4), chronic pulmonary disease (OR 1.4; 95% CI 1.0-2.0) and cancer (OR 1.5; 95% CI 1.1-2.1). Comparing cases with population controls, we found that most risk factors were also risk factors for non-ESBL UTI. ESBL E. coli UTI were associated with previous hospitalization and surgery. Nitrofurantoin and macrolides augmented the risk. PPIs had a moderate effect but may be important facilitators of ESBL carriage due to their widespread use. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Gatifloxacin phase IV surveillance trial (TeqCES study) utilizing 5000 primary care physician practices: report of pathogens isolated and susceptibility patterns in community-acquired respiratory tract infections.

PubMed

Pfaller, Michael A; Jones, Ronald N

2002-09-01

Recently FDA-approved fluoroquinolones like gatifloxacin possess enhanced activity against Gram-positive pathogens such as Streptococcus pneumoniae. However, experience with adverse events among previously used fluoroquinolones has led to expanded post-marketing investigations of clinical efficacy and safety. An open-label gatifloxacin trial was initiated in early 2000, using 2795 (>15000 enrolled cases) primary care providers for treatment of community-acquired respiratory tract infections (CARTI) such as community-acquired pneumonia (CAP), acute bacterial exacerbation of chronic bronchitis (ABECB), acute sinusitis. Microbiology specimens and sputum slides were referred to a reference laboratory, pathogens identified and reference antimicrobial susceptibility tests performed. Results were classified by infection site, geographic census region and patient profile/demographics. The most frequent pathogens were: for CAP (n = 384)-S. pneumoniae (37%) > Hemophilus influenzae (31%) > Moraxella catarrhalis (13%); for ABECB (528)-H. influenzae (37%) > M. catarrhalis (26%) > S. pneumoniae (17%); and for sinusitis (2691)-M. catarrhalis (29%) > H. influenzae (24%) > S. pneumoniae (17%). H. parainfluenzae (ABECB) and S. aureus (sinusitis) were also commonly isolated. CAP S. pneumoniae isolates had significantly less high-level resistance (5% at > or =2 micro g/ml) than those isolates from ABECB or sinusitis (13-15%). United States census zone differences in S. pneumoniae resistance were identified (greatest in West or East South Central, South Atlantic). S. pneumoniae macrolide resistance was high (23-33%) and H. influenzae clarithromycin susceptibility was only 56-62%. beta-lactamase rates in H. influenzae and M. catarrhalis were 21-29% and 88-92%, respectively. Only one S. pneumoniae was not susceptible to gatifloxacin, and this new fluoroquinolone was fourfold more potent than levofloxacin (MIC(50,) 0.25 vs. 1 micro g/ml). This Phase IV surveillance trial (Teq

A Comprehensive Analysis on Spread and Distribution Characteristic of Antibiotic Resistance Genes in Livestock Farms of Southeastern China.

PubMed

Wang, Na; Guo, Xinyan; Yan, Zheng; Wang, Wei; Chen, Biao; Ge, Feng; Ye, Boping

2016-01-01

The pollution of antibiotic resistance genes (ARGs) in livestock farms is a problem which need to be paid more attention to, due to the severe resistance dissemination and the further human health risk. In this study, all the relevant exposure matrices (manure, soil and water) of sixteen animal farms in Southeastern China were sampled to determine twenty-two ARGs conferring resistance to five major classes of antibiotics including tetracyclines, sulfonamides, quinolones, aminoglycosides, and macrolides. The results showed that the spread property of sul genes was most extensive and strong, followed by tet and erm genes. The abundance of tet genes expressing ribosomal protection proteins (tetM, tetO, tetQ, tetT and tetW) was higher than that expressing efflux pump proteins (tetA, tetC, tetE and tetG) in each type of samples. The high abundance and frequency of ermB gene in the matrices should be paid more attention, because macrolides is a major medicine for human use. For manures, it was found that the similar ARGs distribution rules were existing in poultry manure or porcine manure samples, despite of the different origins of these two types of livestock farms. Meanwhile, it was interesting that the distribution rule of tet genes in animal manure was nearly the same as all the ARGs. For soils, the result of nonmetric multi-dimensional scaling (NMDS) analysis showed that the pollution of ARGs in the soils fertilized by poultry and cattle manures were more substantial in northern Jiangsu, but no significant ARGs diversity was observed among porcine manured soils of five different regions. Furthermore, most ARGs showed significant positive relationships with environmental variables such as concentration of sulfonamides, tetracyclines, Cu, Zn and total organic carbon (TOC). The pollution profile and characteristics of so many ARGs in livestock farms can provide significative foundation for the regulation and legislation of antibiotics in China.

Antibiotic susceptibility in Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes in Pakistan: a review of results from the Survey of Antibiotic Resistance (SOAR) 2002-15.

PubMed

Zafar, A; Hasan, R; Nizamuddin, S; Mahmood, N; Mukhtar, S; Ali, F; Morrissey, I; Barker, K; Torumkuney, D

2016-05-01

To investigate changes in the antibiotic susceptibility of Streptococcus pneumoniae, Haemophilus influenzae and Streptococcus pyogenes from the Survey of Antibiotic Resistance (SOAR) in community-acquired respiratory tract infections (CA-RTIs) between 2002 and 2015 in Pakistan. This is a review based on previously published studies from 2002-03, 2004-06 and 2007-09 and also new data from 2014-15. Susceptibility was determined by Etest(®) or disc diffusion according to CLSI and pharmacokinetic/pharmacodynamic (PK/PD) breakpoints. A total of 706 isolates from CA-RTIs comprising 381 S. pneumoniae, 230 H. influenzae and 95 S. pyogenes were collected between 2002 and 2015 and tested against a range of antibiotics. Antibiotic resistance in S. pneumoniae rose steeply from 2002 to 2009, with isolates non-susceptible to penicillin and macrolides increasing from 10% to 34.1% and from 13%-14% to 29.7%, respectively. Susceptibility to amoxicillin/clavulanic acid (and by inference amoxicillin) remained between 99.4% and 100% from 2002 to 2015. Over the years, the prevalence of susceptibility to cefuroxime was 98%-100% among S. pneumoniae. Resistance in S. pneumoniae to some older antibiotics between 2007 and 2009 was high (86.8% for trimethoprim/sulfamethoxazole and 57.2% for tetracycline). Between 2002 and 2015, ampicillin resistance (β-lactamase-positive strains) among H. influenzae has remained low (between 2.6% and 3.2%) and almost unchanged over the years (H. influenzae was not tested during 2004-06). For S. pyogenes isolates, macrolide resistance reached 22%; however, susceptibility to penicillin, amoxicillin/clavulanic acid and cefuroxime remained stable at 100%. In S. pneumoniae from Pakistan, there has been a clear reduction in susceptibility to key antibiotics since 2002, but not to amoxicillin/clavulanic acid (amoxicillin) or cefuroxime. However, susceptibility in H. influenzae has remained stable. Local antibiotic susceptibility/resistance data are essential to

Newer Antibacterials in Therapy and Clinical Trials

PubMed Central

Paknikar, Simi S; Narayana, Sarala

2012-01-01

In order to deal with the rising problem of antibiotic resistance, newer antibacterials are being discovered and added to existing pool. Since the year 2000, however, only four new classes of antibacterials have been discovered. These include the oxazolidinones, glycolipopeptides, glycolipodepepsipeptide and pleuromutilins. Newer drugs were added to existing classes of antibiotics, such as streptogramins, quinolones, beta-lactam antibiotics, and macrolide-, tetracycline- and trimethoprim-related drugs. Most of the antibacterials are directed against resistant S. aureus infections, with very few against resistant gram-negative infections. The following article reviews the antibacterials approved by the FDA after the year 2000 as well as some of those in clinical trials. Data was obtained through a literature search via Pubmed and google as well as a detailed search of our library database. PMID:23181224

[New antibacterial agents on the market and in the pipeline].

PubMed

Kern, W V

2015-11-01

After some years of stagnation there have been several new successful developments in the field of antibacterial agents. Most of these new developments have been in conventional antibacterial classes. New drugs among the beta-lactam agents are methicillin-resistant Staphylococcus aureus (MRSA) active cephalosporins (ceftaroline and ceftobiprole) and new combinations of beta-lactam with beta-lactamase inhibitors (ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/relebactam and meropenem/RPX7009). New developments can also be observed among oxazolidinones (tedizolid, radezolid, cadazolid and MRX-I), macrolides/ketolides (modithromycin and solithromycin), aminoglycosides (plazomicin), quinolones (nemonoxacin, delafloxacin and avarofloxacin), tetracyclines (omadacycline and eravacycline) as well as among glycopeptides and lipopeptides (oritavancin, telavancin, dalbavancin and surotomycin). New agents in a very early developmental phase are FabI inhibitors, endolysines, peptidomimetics, lipid A inhibitors, methionyl-tRNA synthetase inhibitors and teixobactin.

Legionella spp. and Legionnaires' disease.

PubMed

Diederen, B M W

2008-01-01

Infection with Legionella spp. is an important cause of community- and hospital-acquired pneumonia, occurring both sporadically and in outbreaks. Infection with Legionella spp. ranks among the three most common causes of severe pneumonia in the community setting, and is isolated in 1-40% of cases of hospital-acquired pneumonia. There are no clinical features unique to Legionnaires' disease. Macrolides and fluoroquinolones are the most widely used drugs in treatment. The availability of a good diagnostic repertoire, suitable for accurately diagnosing LD, constitutes the basis for the early recognition and treatment of the individual patient as well as for effective measures for prevention and control. This review summarizes the available information regarding the microbiology, clinical presentation, diagnosis and treatment of LD, with an emphasis on the laboratory diagnosis of infection with Legionella spp.

Unintentional human exposure to tilmicosin (Micotil 300).

PubMed

Von Essen, Susanna; Spencer, Jonathan; Hass, Brian; List, Pam; Seifert, Steven A

2003-01-01

Tilmicosin phosphate is a macrolide antibiotic that is used to treat cattle for pathogens that cause Bovine Respiratory Disease. A 28-year-old man with no prior history of heart disease developed severe chest pain, inverted T waves, and intraventricular conduction delay on EKG and mild elevation of cardiac enzymes 5 hours after unintentional injection of less than half of a 12cc syringe filled with Micotil 300 (tilmicosin phosphate 300 mg/mL, propylene glycol 25%, phosphoric acid, water for injection). The patient made an uneventful recovery after hospitalization. This case provides evidence that unintentional injection of tilmicosin can cause cardiac symptoms and laboratory evidence of myocardial injury. Tilmicosin should always be administered by properly trained personnel who are using techniques designed to reduce the risk of accidental self-injection.

Minimum inhibitory concentration breakpoints and disk diffusion inhibitory zone interpretive criteria for tilmicosin susceptibility testing against Pasteurella multocida and Actinobacillus pleuropneumoniae associated with porcine respiratory disease.

PubMed

Shryock, Thomas R; Staples, J Mitchell; DeRosa, David C

2002-09-01

Tilmicosin is a novel macrolide antibiotic developed for exclusive use in veterinary medicine. Tilmicosin has been approved as a feed premix to control porcine respiratory disease associated with Pasteurella multocida and Actinobacillus pleuropneumoniae. The development of antimicrobial susceptibility testing guidelines for tilmicosin was predicated on the relationship of clinical efficacy studies that demonstrated a favorable therapeutic outcome, on pharmacokinetic data, and on in vitro test data, as recommended by the National Committee for Clinical Laboratory Standards (NCCLS). The approved breakpoints for the minimum inhibitory concentration dilution testing for both species are resistant, > or = 32 microg/ml, and susceptible, < or = 16 microg/ml. The zone of inhibition interpretive criteria for disk diffusion testing with a 15-microg tilmicosin disk are resistant, < or = 10 mm, and susceptible, > or = 11 mm.