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1

An approach to identifying drug resistance associated mutations in bacterial strains  

PubMed Central

Background Drug resistance in bacterial pathogens is an increasing problem, which stimulates research. However, our understanding of drug resistance mechanisms remains incomplete. Fortunately, the fast-growing number of fully sequenced bacterial strains now enables us to develop new methods to identify mutations associated with drug resistance. Results We present a new comparative approach to identify genes and mutations that are likely to be associated with drug resistance mechanisms. In order to test the approach, we collected genotype and phenotype data of 100 fully sequenced strains of S. aureus and 10 commonly used drugs. Then, applying the method, we re-discovered the most common genetic determinants of drug resistance and identified some novel putative associations. Conclusions Firstly, the collected data may help other researchers to develop and verify similar techniques. Secondly, the proposed method is successful in identifying drug resistance determinants. Thirdly, the in-silico identified genetic mutations, which are putatively involved in drug resistance mechanisms, may increase our understanding of the drug resistance mechanisms.

2012-01-01

2

Exploiting bacterial drug resistance: a single construct for the diagnosis and treatment of drug resistant infections  

NASA Astrophysics Data System (ADS)

?-lactamase enzyme-activated photosensitizer (?-LEAP). We aim to exploit drug resistance mechanisms to selectively release photosensitizers (PSs) for a specific photodynamic antimicrobial effect and reduced host tissue damage. Consequently, the fluorescence emission intensity of the PSs increases and allows for the detection of enzyme activity. In this work we sought to evaluate ?-LEAP for use as a sensitive molecular probe. We have reported the enzyme specific antibacterial action of ?-LEAP. Here we report the use of ?-LEAP for the rapid functional definition of a ?-lactamase.

Sallum, Ulysses W.; Zheng, Xiang; Verma, Sarika; Hasan, Tayyaba

2009-06-01

3

An analogy between the evolution of drug resistance in bacterial communities and malignant tissues  

PubMed Central

Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance in bacterial communities. We propose that this evolution is the result of a programmed and collective stress response performed by interacting cells, and that, given this fundamental connection, studying bacterial communities can provide deeper insights into the dynamics of adaptation and the evolution of cells within tumours.

Lambert, Guillaume; Estevez-Salmeron, Luis; Oh, Steve; Liao, David; Emerson, Beverly M.; Tlsty, Thea D.; Austin, Robert H.

2012-01-01

4

Antibacterial activity of two limonoids from Swietenia mahagoni against multiple-drug-resistant (MDR) bacterial strains  

Microsoft Academic Search

Solvent partitioning followed by column chromatography of the MeOH extract of the seeds of Swietenia mahagoni afforded two limonoids, swietenolide (1) and 2-hydroxy-3-O-tigloylswietenolide (2). The compounds were identified by spectroscopic means. The antibacterial activity of these compounds was assessed against\\u000a eight multiple-drug-resistant bacterial strains (clinical isolates) by the conventional disc diffusion method. While both\\u000a compounds were active against all test

A. K. M. Shahidur Rahman; A. K. Azad Chowdhury; Husne-Ara Ali; Sheikh Z. Raihan; Mohammad S. Ali; Lutfun Nahar; Satyajit D. Sarker

2009-01-01

5

75 FR 33317 - Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial...  

Federal Register 2010, 2011, 2012, 2013

...and antibacterial drug development. The workshop will address antibacterial drug resistance, mechanisms of resistance, epidemiology of resistance, and issues in the development of rapid diagnostic devices and antibacterial drugs for the diagnosis and...

2010-06-11

6

Building a Morbidostat: An automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition  

PubMed Central

We present a protocol for building and operating an automated fluidic system for continuous culture that we call the “morbidostat”. The morbidostat is used to follow evolution of microbial drug resistance in real time. Instead of exposing bacteria to predetermined drug environments, the morbidostat constantly measures the growth rates of evolving microbial populations and dynamically adjusts drug concentrations inside culture vials in order to maintain a constant drug induced inhibition. The growth rate measurements are done using an optical detection system that is based on measuring the intensity of back-scattered light from bacterial cells suspended in the liquid culture. The morbidostat can additionally be used as a chemostat or a turbidostat. The whole system can be built from readily available components within two to three weeks, by biologists with some electronics experience or engineers familiar with basic microbiology.

Toprak, Erdal; Veres, Adrian; Yildiz, Sadik; Pedraza, Juan M.; Chait, Remy; Paulsson, Johan; Kishony, Roy

2013-01-01

7

Interactions of Antibiotics and Methanolic Crude Extracts of Afzelia Africana (Smith.) Against Drug Resistance Bacterial Isolates  

PubMed Central

Infection due to multidrug resistance pathogens is difficult to manage due to bacterial virulence factors and because of a relatively limited choice of antimicrobial agents. Thus, it is imperative to discover fresh antimicrobials or new practices that are effective for the treatment of infectious diseases caused by drug-resistant microorganisms. The objective of this experiment is to investigate for synergistic outcomes when crude methanolic extract of the stem bark of Afzelia africana and antibiotics were combined against a panel of antibiotic resistant bacterial strains that have been implicated in infections. Standard microbiological protocols were used to determine the minimum inhibitory concentrations (MICs) of the extract and antibiotics, as well as to investigate the effect of combinations of the methanolic extract of A. africana stem bark and selected antibiotics using the time-kill assay method. The extract of Afzelia africana exhibited antibacterial activities against both Gram-negative and Gram-positive bacteria made up of environmental and standard strains at a screening concentration of 5 mg/mL. The MICs of the crude extracts and the antibiotics varied between 1 ?g/mL and 5.0 mg/mL. Overall, synergistic response constituted about 63.79% of all manner of combinations of extract and antibiotics against all test organisms; antagonism was not detected among the 176 tests carried out. The extract from A. africana stem bark showed potentials of synergy in combination with antibiotics against strains of pathogenic bacteria. The detection of synergy between the extract and antibiotics demonstrates the potential of this plant as a source of antibiotic resistance modulating compounds.

Aiyegoro, Olayinka; Adewusi, Adekanmi; Oyedemi, Sunday; Akinpelu, David; Okoh, Anthony

2011-01-01

8

Novel Bacterial Metabolite Merochlorin A Demonstrates in vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus  

PubMed Central

Background We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics. Methods Merochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines. Results The structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum. Conclusions The unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum.

Sakoulas, George; Nam, Sang-Jip; Loesgen, Sandra; Fenical, William; Jensen, Paul R.; Nizet, Victor; Hensler, Mary

2012-01-01

9

Bacterial Resistance in Acne  

Microsoft Academic Search

Antibiotics play a major role in acne therapy. Physicians base treatment choices on personal perceptions of efficacy, cost-effectiveness or risk-benefit ratios and rarely take bacterial resistance into account. It is well documented that resistant strains of coagulase-negative staphylococci within the resident skin flora increase in both prevalence and population density as duration of therapy increases. Acne patients represent a considerable

E. A. Eady

1998-01-01

10

Globally dispersed mobile drug-resistance genes in Gram-negative bacterial isolates from patients with bloodstream infections in a US urban general hospital  

PubMed Central

Mobile drug-resistance genes with identical nucleic acid sequences carried by multidrug-resistant Escherichia coli strains that cause community-acquired infections are becomingly increasingly dispersed worldwide. Over a 2-year period, we analysed Gram-negative bacterial (GNB) pathogens from the blood of inpatients at an urban public hospital to determine what proportion of these isolates carried such globally dispersed drug-resistance genes. Of 376 GNB isolates, 167 (44?%) were Escherichia coli, 50 (13?%) were Klebsiella pneumoniae, 25 (7?%) were Pseudomonas aeruginosa, 25 (7?%) were Proteus mirabilis and 20 (5?%) were Enterobacter cloacae; the remainder (24?%) comprised 26 different GNB species. Among E. coli isolates, class 1 integrons were detected in 64 (38?%). The most common integron gene cassette configuration was dfrA17-aadA5, found in 30 (25?%) of 119 drug-resistant E. coli isolates and in one isolate of Moraxella morganii. Extended-spectrum ?-lactamase (ESBL) genes were found in 16 E. coli isolates (10?%). These genes with identical sequences were found in nearly 40?% of bloodstream E. coli isolates in the study hospital, as well as in a variety of bacterial species from clinical and non-clinical sources worldwide. Thus, a substantial proportion of bloodstream infections among hospitalized patients were caused by E. coli strains carrying drug-resistance genes that are dispersed globally in a wide variety of bacterial species.

Adams-Sapper, S.; Sergeevna-Selezneva, J.; Tartof, S.; Raphael, E.; Diep, B. An; Perdreau-Remington, F.

2012-01-01

11

Bacterial endotoxins and nonspecific resistance.  

PubMed

The stress situations, including medical intervention (e.g. operations, antitumor drugs, irradiation, etc.) decrease the nonspecific resistance of the body. In these situations patients people have greater chance to get an opportunistic infection than healthy ones. The restoration or elevation of the activity of immune system in injured patients is a very important task of medicine. Minute amounts of bacterial endotoxin (LPS)--given parenterally--can elevate the nonspecific resistance. Unfortunately this beneficial influence is associated with noxious properties. Irradiation (60 Co-gamma; 150 kGy) is a good technique for the detoxification of LPS. The radiodetoxified endotoxin (RD-LPS) preparation (so-called TOLERIN) is less toxic but its beneficial properties is preserved. On the basis of animal experiments and clinical trials TOLERIN could be a suitable preparation for regeneration of the lymphoreticular-immune system and elevation of nonspecific resistance. PMID:9554170

Bertók, L

1997-01-01

12

Synthetic Interaction between the TipN Polarity Factor and an AcrAB-Family Efflux Pump Implicates Cell Polarity in Bacterial Drug Resistance.  

PubMed

Quinolone antibiotics are clinically important drugs that target bacterial DNA replication and chromosome segregation. Although the AcrAB-family efflux pumps generally protect bacteria from such drugs, the physiological role of these efflux systems and their interplay with other cellular events are poorly explored. Here, we report an intricate relationship between antibiotic resistance and cell polarity in the model bacterium Caulobacter crescentus. We show that a polarity landmark protein, TipN, identified by virtue of its ability to direct flagellum placement to the new cell pole, protects cells from toxic misregulation of an AcrAB efflux pump through a cis-encoded nalidixic acid-responsive transcriptional repressor. Alongside the importance of polarity in promoting the inheritance and activity of virulence functions including motility, we can now ascribe to it an additional role in drug resistance that is distinct from classical efflux mechanisms. PMID:24726830

Kirkpatrick, Clare L; Viollier, Patrick H

2014-05-22

13

Evolution and Impact of Bacterial Drug Resistance in the Context of Cystic Fibrosis Disease and Nosocomial Settings  

PubMed Central

The use of antibiotics is unavoidable in trying to treat acute infections and in the prevention and control of chronic infections. Over the years, an ever increasing number of infections has escalated the use of antibiotics, which has necessitated action against an emerging bacterial resistance. There seems to be a continuous acquisition of new resistance mechanisms among bacteria that switch niches between human, animals, and the environment. An antibiotic resistant strain emerges when it acquires the DNA that confers the added capacity needed to survive in an unusual niche. Once acquired, a new resistance mechanism evolves according to the dynamics of the microenvironment; there is then a high probability that it is transferred to other species or to an avirulent strain of the same species. A well understood model for studying emerging antibiotic resistance and its impact is Pseudomonas aeruginosa, an opportunistic pathogen which is able to cause acute and chronic infections in nosocomial settings. This bacterium has a huge genetic repertoire consisting of genes that encode both innate and acquired antibiotic resistance traits. Besides acute infections, chronic colonization of P. aeruginosa in the lungs of cystic fibrosis (CF) patients plays a significant role in morbidity and mortality. Antibiotics used in the treatment of such infections has increased the longevity of patients over the last several decades. However, emerging multidrug resistant strains and the eventual increase in the dosage of antibiotic(s) is of major concern. Though there are various infections that are treated by single/combined antibiotics, the particular case of P. aeruginosa infection in CF patients serves as a reference for understanding the impact of overuse of antibiotics and emerging antibiotic resistant strains. This mini review presents the need for judicious use of antibiotics to treat various types of infections, protecting patients and the environment, as well as achieving a better treatment outcome.

Sriramulu, Dinesh

2013-01-01

14

A case report of a multi-drug resistant bacterial infection in a diabetic patient treated in northeast Brazil  

PubMed Central

Diabetes mellitus is one of the most critical health conditions around the world, not only in terms of the number of affected people, disability, and premature mortality, but also in regards to the health care costs involved in controlling and treating its complications. Among the most constant ailments the diabetic patient suffers is the diabetic foot, defined as any infection, ulceration, and/or necrosis of deep tissues associated with neurological abnormalities and various degrees of peripheral vascular disease of the lower limbs. Diabetic foot ulcerations have become a major and increasing public health concern and its associated morbidities, impairment of the patients’ quality of life, and the implied costs for management have attracted the attention of numerous health care providers. In this case report, the authors review a unique presentation of a polymicrobial infection of a multi-drug resistant character species formed by oxacillin-resistant Staphylococcus aureus, Acinetobacter baumannii and Acinetobacter lwoffii.

Neto, Renato Motta; Ansaldi, Miguel Angel; da Costa, Maria Eduarda S.M.; da Silva, Samuel Oliveira; Luz, Victor Hugo F.

2012-01-01

15

The Functional Resistance of Bacterial Biofilms  

Microsoft Academic Search

There is intellectual coherence when a physician must tell patients that the bacteria causing their infection have tested\\u000a resistant to the empiric antibiotic therapy, and that an alternative drug must be used. In this chapter, we will concern ourselves\\u000a with the growing number of bacterial infections in which antibiograms of the causative organism show sensitivity to standard\\u000a antibiotics in readily

Christoph A. Fux; Paul Stoodley; Mark Shirtliff; J. William Costerton

16

Drug Resistance in Leishmaniasis  

PubMed Central

The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sbv). Widespread misuse has led to the emergence of Sbv resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance.

Chakravarty, Jaya; Sundar, Shyam

2010-01-01

17

Drug Resistant Diseases.  

National Technical Information Service (NTIS)

The collection of abstracts provides information on Malaria, Japanese B Encephalitis and Melioidosis in the Soviet Union, China and Vietnam obtained from publications dated 1 January 1964 to date. Searches were concentrated on resistance to therapy, drug ...

L. Perkins

1968-01-01

18

PCR amplification on a microarray of gel-immobilized oligonucleotides: detection of bacterial toxin- and drug-resistant genes and their mutations.  

PubMed

PCR amplification on a microarray of gel-immobilized primers (microchip) has been developed. One of a pair of PCR primers was immobilized inside a separate microchip polyacrylamide porous gel pad of 0.1 x 0.1 x 0.02 (or 0.04) micron in size and 0.2 (or 0.4) nL in volume. The amplification was carried out simultaneously both in solution covering the microchip array and inside gel pads. Each gel pad contained the immobilized forward primers, while the fluorescently labeled reverse primers, as well as all components of the amplification reaction, diffused into the gel pads from the solution. To increase the amplification efficiency, the forward primers were also added into the solution. The kinetics of amplification was measured in real time in parallel for all gel pads with a fluorescent microscope equipped with a charge-coupled device (CCD) camera. The accuracy of the amplification was assessed by using the melting curves obtained for the duplexes formed by the labeled amplification product and the gel-immobilized primers during the amplification process; alternatively, the duplexes were produced by hybridization of the extended immobilized primers with labeled oligonucleotide probes. The on-chip amplification was applied to detect the anthrax toxin genes and the plasmid-borne beta-lactamase gene responsible for bacterial ampicillin resistance. The allele-specific type of PCR amplification was used to identify the Shiga toxin gene and discriminate it from the Shiga-like one. The genomic mutations responsible for rifampicin resistance of the Mycobacterium tuberculosis strains were detected by the same type of PCR amplification of the rpoB gene fragment isolated from sputum of tuberculosis patients. The on-chip PCR amplification has been shown to be a rapid, inexpensive and powerful tool to test genes responsible for bacterial toxin production and drug resistance, as well as to reveal point nucleotide mutations. PMID:11056816

Strizhkov, B N; Drobyshev, A L; Mikhailovich, V M; Mirzabekov, A D

2000-10-01

19

Mechanisms of bacterial biocide and antibiotic resistance.  

PubMed

Resistance to antibiotics is increasingly commonplace amongst important human pathogens. Although the mechanism(s) of resistance vary from agent to agent they typically involve one or more of: alteration of the drug target in the bacterial cell, enzymatic modification or destruction of the drug itself, or limitation of drug accumulation as a result of drug exclusion or active drug efflux. While most of these are agent specific, providing resistance to a single antimicrobial or class of antimicrobial, there are currently numerous examples of efflux systems that accommodate and, thus, provide resistance to a broad range of structurally unrelated antimicrobials -- so-called multidrug efflux systems. Resistance to biocides is less common and likely reflects the multiplicity of targets within the cell as well as the general lack of known detoxifying enzymes. Resistance typically results from cellular changes that impact on biocide accumulation, including cell envelope changes that limit uptake, or expression of efflux mechanisms. Still, target site mutations leading to biocide resistance, though rare, are known. Intriguingly, many multidrug efflux systems also accommodate biocides (e.g. triclosan) such that strains expressing these are both antibiotic- and biocide-resistant. Indeed, concern has been expressed regarding the potential for agents such as triclosan to select for strains resistant to multiple clinically-relevant antibiotics. Some of the better characterized examples of such multidrug efflux systems can be found in the opportunistic pathogen Pseudomonas aeruginosa where they play an important role in the noted intrinsic and acquired resistance of this organism to antibiotics and triclosan. These tripartite pumps include an integral inner membrane drug-proton antiporter, an outer membrane- and periplasm-spanning channel-forming protein and a periplasmic link protein that joins these two. Expression of efflux genes is governed minimally by the product of a linked regulatory gene that is in most cases the target for mutation in multidrug resistant strains hyperexpressing these efflux systems. Issues for consideration include the natural function of these efflux systems and the therapeutic potential of targeting these systems in combating acquired multidrug resistance. PMID:12000613

Poole, K

2002-01-01

20

Mechanisms of bacterial biocide and antibiotic resistance.  

PubMed

Resistance to antibiotics is increasingly commonplace amongst important human pathogens. Although the mechanism(s) of resistance vary from agent to agent they typically involve one or more of: alteration of the drug target in the bacterial cell, enzymatic modification or destruction of the drug itself, or limitation of drug accumulation as a result of drug exclusion or active drug efflux. While most of these are agent specific, providing resistance to a single antimicrobial or class of antimicrobial, there are currently numerous examples of efflux systems that accommodate and, thus, provide resistance to a broad range of structurally unrelated antimicrobials--so-called multidrug efflux systems. Resistance to biocides is less common and likely reflects the multiplicity of targets within the cell as well as the general lack of known detoxifying enzymes. Resistance typically results from cellular changes that impact on biocide accumulation, including cell envelope changes that limit uptake, or expression of efflux mechanisms. Still, target site mutations leading to biocide resistance, though rare, are known. Intriguingly, many multidrug efflux systems also accommodate biocides (e.g. triclosan) such that strains expressing these are both antibiotic- and biocide-resistant. Indeed, concern has been expressed regarding the potential for agents such as triclosan to select for strains resistant to multiple clinically-relevant antibiotics. Some of the better characterized examples of such multidrug efflux systems can be found in the opportunistic pathogen Pseudomonas aeruginosa where they play an important role in the noted intrinsic and acquired resistance of this organism to antibiotics and triclosan. These tripartite pumps include an integral inner membrane drug-proton antiporter, an outer membrane- and periplasm-spanning channel-forming protein and a periplasmic link protein that joins these two. Expression of efflux genes is governed minimally by the product of a linked regulatory gene that is in most cases the target for mutation in multidrug resistant strains hyperexpressing these efflux systems. Issues for consideration include the natural function of these efflux systems and the therapeutic potential of targeting these systems in combating acquired multidrug resistance. PMID:12481829

Poole, K

2002-01-01

21

Development of bacterial transglycosylase inhibitors as new antibiotics: Moenomycin A treatment for drug-resistant Helicobacter pylori.  

PubMed

The problem of multidrug-resistant Helicobacter pylori requires new antibiotics development. We have evaluated a potential antibiotics, moenomycin A, which is classified as a phosphoglycolipid antibiotics that targets transglycosylase and is previously thought to be limited in Gram-positive bacteria. Herein, we report the activity of moenomycin A against multidrug-resistant H. pylori and the isolates from patients with different gastrointestinal diseases. PMID:24775303

Tseng, Yen-Yu; Liou, Jyh-Ming; Hsu, Tsui-Ling; Cheng, Wei-Chieh; Wu, Ming-Shiang; Wong, Chi-Huey

2014-06-01

22

Drug Resistance in Leishmaniasis  

PubMed Central

Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy.

Croft, Simon L.; Sundar, Shyam; Fairlamb, Alan H.

2006-01-01

23

Isoniazid Resistance and the Future of Drug-Resistant Tuberculosis  

PubMed Central

Bacterial chromosomal mutations that confer antibiotic resistance often have deleterious effects that impose costs on reproductive fitness. This observation has led to the generalization that in the absence of the selection pressure exerted through treatment, the frequency of resistance will decrease. This model implies that the prudent use of antibiotics will eventually result in a decline in the prevalence of drug resistance. Recent work, however, suggests that some resistance-conferring mutations may not significantly impair fitness and that others may be accompanied by compensatory mutations that restore the organisms’ reproductive potential. Thus drug resistance, once introduced, may persist unless specific measures are implemented to target prevalent drug-resistant cases. Here we present ecological evidence to support the hypothesis that mutations at the 315 position of katG confer isoniazid resistance for Mycobacterium tuberculosis without diminishing virulence or transmissibility.

COHEN, TED; BECERRA, MERCEDES C.; MURRAY, MEGAN B.

2009-01-01

24

Combination Approaches to Combat Multi-Drug Resistant Bacteria  

PubMed Central

The increasing prevalence of infections caused by multi-drug resistant bacteria is a global health problem that is exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein we describe recent developments toward combination therapies for the treatment of multi-drug resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of ?-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems. We also discuss screening of libraries of previously approved drugs to identify non-obvious antimicrobial adjuvants.

Worthington, Roberta J.; Melander, Christian

2013-01-01

25

In vitro antibiotic resistance in bacterial keratitis in London  

PubMed Central

AIM—To document changes in the profile of bacterial isolates from cases of keratitis and changes in their susceptibility to first line antibiotic therapies.?METHODS—A retrospective review was performed of all bacterial isolates from cases of keratitis seen between 1984 and 1999. In vitro laboratory susceptibilities to antibiotics were determined by the Kirby-Bauer disc diffusion method. The number of isolates, changes in the proportion of bacterial types, and the number that were fully resistant to monotherapy (ofloxacin), dual therapy (gentamicin and cefuroxime), and prophylactic treatment (chloramphenicol) were calculated.?RESULTS—There were 1312 bacterial isolates over 16 years. Gram positive bacteria accounted for 54.7% of isolates and Staphylococcus species (33.4%) were the most frequently isolated organisms. During the study period there has been an increase in the proportion of Pseudomonas species isolates but no overall increase in the proportion of Gram negative isolates. There has not been an increase in the proportion of isolates resistant to ofloxacin since 1995 or an increase in resistance to the combination of gentamicin and cefuroxime. However, since 1984 there has been a significant increase in proportion of Gram negative organisms resistant to chloramphenicol (p=0.0019).?CONCLUSIONS—An increase in the in vitro resistance of organisms to first line therapies for bacterial keratitis has not been observed. An increased resistance to chloramphenicol indicates that this drug is unlikely to provide prophylactic cover when Gram negative infection is a risk. Continued monitoring for the emergence of antibiotic resistance is recommended.??

Tuft, S.; Matheson, M.

2000-01-01

26

Drug Resistance in HIV-1  

PubMed Central

Purpose of the review Changing antiretroviral regimens and the introduction of new antiretroviral drugs have altered drug resistance patterns in resistance human immunodeficiency virus type 1 (HIV-1). This review summarizes recent information on antiretroviral drug resistance. Recent findings As tenofovir and abacavir have replaced zidovudine and stavudine in antiretroviral regimens, thymidine analog resistance mutations have become less common in patients failing antiretroviral therapy in developed countries. Similarly, the near universal use of ritonavir-boosted protease inhibitors (PI) in place of unboosted PIs has made the selection of PI resistance mutations uncommon in patients failing a first- or second-line PI regimen. The challenge of treating patients with multidrug-resistant HIV-1 has largely been addressed by the advent of newer PIs, second-generation non-nucleoside reverse transcriptase inhibitors and drugs in novel classes, including integrase inhibitors and CCR5 antagonists. Resistance to these newer agents can emerge, however, resulting in the appearance of novel drug resistance mutations in the HIV-1 polymerase, integrase and envelope genes. Summary New drugs make possible the effective treatment of multidrug-resistant HIV-1, but the activity of these drugs may be limited by the appearance of novel drug resistance mutations.

Kuritzkes, Daniel R.

2011-01-01

27

Resistance to antimicrobial drugs in Ghana  

PubMed Central

Background Antimicrobial drug resistance is a global issue that affects health, economic, and social development. The problem has been attributed to misuse of antimicrobial agents. Purpose To identify the agents of bacterial infection in Ghana, determine their antibiogram, and the possibility of setting up a surveillance program. Patients and methods A prospective quantitative study set in various hospitals including two teaching hospitals, seven regional hospitals, and two district hospitals in Ghana. A total of 5099 bacterial isolates from various clinical specimens were collected over a period of 1 year, including data related to the patients. Susceptibility of the isolates was determined by the Kirby–Bauer method. In addition, the minimum inhibitory concentration (MIC) of multidrug-resistant isolates of epidemiological significance was also determined using the E-test. Results A wide range of bacterial isolates were identified in both teaching and regional hospitals. High percentage of resistance was observed for tetracycline (82%), cotrimoxazole (73%), ampicillin (76%), and chloramphenicol (75%). Multidrug resistance was observed to a combination of ampicillin, tetracycline, chloramphenicol, and cotrimoxazole. On the other hand, a lower percentage of resistance was observed for ceftriaxone (6.3%), ciprofloxacin (11%), and amikacin (9.9%). Conclusion Generally, the prevalence of multidrug resistance was widespread among the various isolates. Some multidrug-resistant strains of Staphylococcus aureus, Salmonella typhi, and non-typhoidal Salmonella (NTS) had high MIC to cefuroxime (>256), gentamicin (>256), and ciprofloxacin (>32).

Newman, Mercy J; Frimpong, Enoch; Donkor, Eric S; Opintan, Japheth A; Asamoah-Adu, Alex

2011-01-01

28

[Travellers and multi-drug resistance bacteria].  

PubMed

The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers. PMID:22413540

Takeshita, Nozomi

2012-02-01

29

Antibacterial Cleaning Products and Drug Resistance  

PubMed Central

We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug–resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug resistance after 1 year (odds ratio 1.33, 95% confidence interval 0.74–2.41), nor did it have an effect on bacterial susceptibility to triclosan. However, more extensive and longer term use of triclosan might provide a suitable environment for emergence of resistant species. Further research on this issue is needed.

Marshall, Bonnie; Levy, Stuart B.; Della-Latta, Phyllis; Lin, Susan X.; Larson, Elaine

2005-01-01

30

Communicating trends in resistance using a drug resistance index  

PubMed Central

Background Antibiotic resistance is a growing problem worldwide, but communicating this challenge to policymakers and non-experts is complicated by the multiplicity of bacterial pathogens and the distinct classes of antibiotics used to treat them. It is difficult, even for experts aware of the pharmacodynamics of antibiotics, to infer the seriousness of resistance without information on how commonly the antibiotic is being used and whether alternative antibiotics are available. Difficulty in aggregating resistance to multiple drugs to assess trends poses a further challenge to quantifying and communicating changes in resistance over time and across locations. Methods We developed a method for aggregating bacterial resistance to multiple antibiotics, creating an index comparable to the composite economic indices that measure consumer prices and stock market values. The resulting drug resistance index (DRI) and various subindices show antibiotic resistance and consumption trends in the USA but can be applied at any geographical level. Findings The DRI based on use patterns in 1999 for Escherichia coli rose from 0.25 (95% CI 0.23 to 0.26) to 0.30 (95% CI 0.29 to 0.32) between 1999 and 2006. However, the adaptive DRI, which includes treatment of baseline resistant strains with alternative agents, climbed from 0.25 to 0.27 (95% CI 0.25 to 0.28) during that period. In contrast, both the static-use and the adaptive DRIs for Acinetobacter spp. rose from 0.41 (95% CI 0.4 to 0.42) to 0.48 (95% CI 0.46 to 0.49) between 1999 and 2006. Interpretation Divergence between the static-use and the adaptive-use DRIs for E coli reflects the ability of physicians to adapt to increasing resistance. However, antibiotic use patterns did not change much in response to growing resistance to Acinetobacter spp. because physicians were unable to adapt; new drugs for Acinetobacter spp. are therefore needed. Composite indices that aggregate resistance to various drugs can be useful for assessing changes in drug resistance across time and space.

Klugman, Keith P

2011-01-01

31

Bacterial vaccines and antibiotic resistance  

PubMed Central

Spread of antibiotic resistance is mediated by clonal lineages of bacteria that besides being resistant also possess other properties promoting their success. Some vaccines already in use, such as the pneumococcal conjugate vaccines, have had an effect on these successful clones, but at the same time have allowed for the expansion and resistance evolution of previously minor clones not covered by the vaccine. Since resistance frequently is horizontally transferred it will be difficult to generate a vaccine that covers all possible genetic lineages prone to develop resistance unless the vaccine target(s) is absolutely necessary for spread and/or disease development. Targeting the resistance mechanism itself by a vaccine is an interesting but hitherto unexplored approach.

Normark, Staffan

2014-01-01

32

Bacterial vaccines and antibiotic resistance.  

PubMed

Abstract Spread of antibiotic resistance is mediated by clonal lineages of bacteria that besides being resistant also possess other properties promoting their success. Some vaccines already in use, such as the pneumococcal conjugate vaccines, have had an effect on these successful clones, but at the same time have allowed for the expansion and resistance evolution of previously minor clones not covered by the vaccine. Since resistance frequently is horizontally transferred it will be difficult to generate a vaccine that covers all possible genetic lineages prone to develop resistance unless the vaccine target(s) is absolutely necessary for spread and/or disease development. Targeting the resistance mechanism itself by a vaccine is an interesting but hitherto unexplored approach. PMID:24694025

Henriques-Normark, Birgitta; Normark, Staffan

2014-05-01

33

Membrane active vancomycin analogues: a strategy to combat bacterial resistance.  

PubMed

The alarming growth of antibiotic resistant superbugs such as vancomycin-resistant Enterococci and Staphylococci has become a major global health hazard. To address this issue, we report the development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compounds were shown to be bactericidal at low concentrations and did not induce bacterial resistance. An optimized compound in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no observed toxicity. The remarkable activity of these compounds is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics. PMID:24846441

Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B; Haldar, Jayanta

2014-06-12

34

Molecular mechanisms that confer antibacterial drug resistance.  

PubMed

Antibiotics--compounds that are literally 'against life'--are typically antibacterial drugs, interfering with some structure or process that is essential to bacterial growth or survival without harm to the eukaryotic host harbouring the infecting bacteria. We live in an era when antibiotic resistance has spread at an alarming rate and when dire predictions concerning the lack of effective antibacterial drugs occur with increasing frequency. In this context it is apposite to ask a few simple questions about these life-saving molecules. What are antibiotics? Where do they come from? How do they work? Why do they stop being effective? How do we find new antibiotics? And can we slow down the development of antibiotic-resistant superbugs? PMID:10963607

Walsh, C

2000-08-17

35

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance  

PubMed Central

The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

Ghannoum, Mahmoud A.; Rice, Louis B.

1999-01-01

36

Bacterial gold sensing and resistance  

Microsoft Academic Search

Gold ions are mobilized and disseminated through the environment and enter into the cells by non-specific intake. To avoid\\u000a deleterious effect that occurs even at very low concentrations, bacteria such as Salmonella enterica and Cupriavidus metallidurans use Au-specific MerR-type transcriptional regulators to detect the presence of these toxic ions, and control the expression\\u000a of specific resistance factors. In contrast to

Susana K. Checa; Fernando C. Soncini

2011-01-01

37

Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence.  

PubMed

Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed. PMID:23859207

Worthington, Roberta J; Blackledge, Meghan S; Melander, Christian

2013-07-01

38

Drug Resistance in African Trypanosomiasis  

Microsoft Academic Search

\\u000a African trypanosomes include the causative agents of sleeping sickness in humans and those affecting live stock. Vaccination\\u000a being jeopardized by the ever-changing surface coats of bloodstream-form trypanosomes, chemotherapy is the mainstay in the\\u000a control of infections. However, the drugs in use are old, cause severe side effects, and their efficacy is undermined by the\\u000a emergence of drug-resistant trypanosomes. Reliable supply

Enock Matovu; Pascal Mäser

39

Bacterial resistance to silver in wound care.  

PubMed

Ionic silver exhibits antimicrobial activity against a broad range of micro-organisms. As a consequence, silver is included in many commercially available healthcare products. The use of silver is increasing rapidly in the field of wound care, and a wide variety of silver-containing dressings are now commonplace (e.g. Hydrofiber dressing, polyurethane foams and gauzes). However, concerns associated with the overuse of silver and the consequent emergence of bacterial resistance are being raised. The current understanding of the biochemical and molecular basis behind silver resistance has been documented since 1998. Despite the sporadic evidence of bacterial resistance to silver, there have been very few studies undertaken and documented to ascertain its prevalence. The risks of antibacterial resistance developing from the use of biocides may well have been overstated. It is proposed that hygiene should be emphasized and targeted towards those applications that have demonstrable benefits in wound care. It is the purpose of this review to assess the likelihood of widespread resistance to silver and the potential for silver to induce cross-resistance to antibiotics, in light of its increasing usage within the healthcare setting. PMID:15823649

Percival, S L; Bowler, P G; Russell, D

2005-05-01

40

Bacterial mercury resistance from atoms to ecosystems  

Microsoft Academic Search

Bacterial resistance to inorganic and organic mercury compounds (HgR) is one of the most widely observed phenotypes in eubacteria. Loci conferring HgR in Gram-positive or Gram-negative bacteria typically have at minimum a mercuric reductase enzyme (MerA) that reduces reactive ionic Hg(II) to volatile, relatively inert, monoatomic Hg(0) vapor and a membrane-bound protein (MerT) for uptake of Hg(II) arranged in an

Tamar Barkay; Susan M Miller; Anne O Summers

2003-01-01

41

Colourful parrot feathers resist bacterial degradation  

PubMed Central

The brilliant red, orange and yellow colours of parrot feathers are the product of psittacofulvins, which are synthetic pigments known only from parrots. Recent evidence suggests that some pigments in bird feathers function not just as colour generators, but also preserve plumage integrity by increasing the resistance of feather keratin to bacterial degradation. We exposed a variety of colourful parrot feathers to feather-degrading Bacillus licheniformis and found that feathers with red psittacofulvins degraded at about the same rate as those with melanin and more slowly than white feathers, which lack pigments. Blue feathers, in which colour is based on the microstructural arrangement of keratin, air and melanin granules, and green feathers, which combine structural blue with yellow psittacofulvins, degraded at a rate similar to that of red and black feathers. These differences in resistance to bacterial degradation of differently coloured feathers suggest that colour patterns within the Psittaciformes may have evolved to resist bacterial degradation, in addition to their role in communication and camouflage.

Burtt, Edward H.; Schroeder, Max R.; Smith, Lauren A.; Sroka, Jenna E.; McGraw, Kevin J.

2011-01-01

42

Proteome studies of bacterial antibiotic resistance mechanisms.  

PubMed

Ever since antibiotics were used to help humanity battle infectious diseases, microorganisms straight away fought back. Antibiotic resistance mechanisms indeed provide microbes with possibilities to by-pass and survive the action of antibiotic drugs. Several methods have been employed to identify these microbial resistance mechanisms in an ongoing effort to reduce the steadily increasing number of treatment failures due to multi-drug-resistant microbes. Proteomics has evolved to an important tool for this area of research. Following rapid advances in whole genome sequencing, proteomic technologies have been widely used to investigate microbial gene expression. This review highlights the contribution of proteomics in identifying microbial drug resistance mechanisms. It summarizes different proteomic studies on bacteria resistant to different antibiotic drugs. The review further includes an overview of the methodologies used, as well as lists key proteins identified, thus providing the reader not only a summary of research already done, but also directions for future research. This article is part of a Special Issue entitled: Trends in Microbial Proteomics. PMID:24184230

Vranakis, Iosif; Goniotakis, Ioannis; Psaroulaki, Anna; Sandalakis, Vassilios; Tselentis, Yannis; Gevaert, Kris; Tsiotis, Georgios

2014-01-31

43

Increasing Drug Resistance in Extensively Drug-Resistant Tuberculosis, South Africa  

PubMed Central

We expanded second-line tuberculosis (TB) drug susceptibility testing for extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa. Of 19 patients with extensively drug-resistant TB identified during February 2008–April 2009, 13 (68%) had isolates resistant to all 8 drugs tested. This resistance leaves no effective treatment with available drugs in South Africa.

Richardson, Jessica; Moodley, Prashini; Moodley, Salona; Babaria, Palav; Ramtahal, Melissa; Heysell, Scott K.; Li, Xuan; Moll, Anthony P.; Friedland, Gerald; Sturm, A. Willem; Gandhi, Neel R.

2011-01-01

44

Genetic dissection of bacterial speck disease resistance in tomato  

Microsoft Academic Search

The bacterial speck disease of tomato has been developed as a model system to elucidate the molecular basis of specificity in plant-bacterial interactions and to study signal transduction events involved in the expression of plant disease resistance. We have employed a mutagenic approach to define the steps involved in the expression of disease resistance to the bacterial pathogen, Pseudomonas syringae

John Salmeron; Caius Rommens; Susan Barker; Francine Carland; Giles Oldroyd; Anand Mehta; Douglas Dahlbeck; Brian Staskawicz

1994-01-01

45

Pseudomonas aeruginosa - a phenomenon of bacterial resistance.  

PubMed

Pseudomonas aeruginosa is one of the leading nosocomial pathogens worldwide. Nosocomial infections caused by this organism are often hard to treat because of both the intrinsic resistance of the species (it has constitutive expression of AmpC beta-lactamase and efflux pumps, combined with a low permeability of the outer membrane), and its remarkable ability to acquire further resistance mechanisms to multiple groups of antimicrobial agents, including beta-lactams, aminoglycosides and fluoroquinolones. P. aeruginosa represents a phenomenon of bacterial resistance, since practically all known mechanisms of antimicrobial resistance can be seen in it: derepression of chromosomal AmpC cephalosporinase; production of plasmid or integron-mediated beta-lactamases from different molecular classes (carbenicillinases and extended-spectrum beta-lactamases belonging to class A, class D oxacillinases and class B carbapenem-hydrolysing enzymes); diminished outer membrane permeability (loss of OprD proteins); overexpression of active efflux systems with wide substrate profiles; synthesis of aminoglycoside-modifying enzymes (phosphoryltransferases, acetyltransferases and adenylyltransferases); and structural alterations of topoisomerases II and IV determining quinolone resistance. Worryingly, these mechanisms are often present simultaneously, thereby conferring multiresistant phenotypes. This review describes the known resistance mechanisms in P. aeruginosa to the most frequently administrated antipseudomonal antibiotics: beta-lactams, aminoglycosides and fluoroquinolones. PMID:19528173

Strateva, Tanya; Yordanov, Daniel

2009-09-01

46

Socioeconomic and Behavioral Factors Leading to Acquired Bacterial Resistance to Antibiotics in Developing Countries  

Microsoft Academic Search

In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread

Iruka N. Okeke; Adebayo Lamikanra; Robert EdelmanÜ

1999-01-01

47

Mechanisms of anticancer drug resistance.  

PubMed

Chemotherapy agents are extremely important in the treatment of liquid malignancies, such as lymphoma, myeloma, and chronic lymphocytic leukemia. In addition, chemotherapy agents have proven effective in the adjuvant treatment of solid tumors, such as osteosarcoma, hemangiosarcoma, transitional cell carcinoma, and others. Unfortunately, chemotherapy resistance in these situations is the most significant cause of treatment failure. Therefore, the ability to predict, treat, or circumvent resistance is extremely likely to improve clinical outcomes. This article has reviewed the most widely investigated forms of chemotherapy resistance, such as reduced drug accumulation, increased DNA damage repair, decreased apoptosis, and others; however, new mechanisms are being found at an alarming pace. In addition, investigations to date have routinely centered on single-cell mechanisms of drug resistance, and cancer is truly a three dimensional disease. The elucidation of mechanisms surrounding (1) how tumors interact with their normal microenvironment, (2) how tumors interact in a three-dimensional environment, and (3) a better understanding of basic tumor physiology and biology may supersede in importance those previously elucidated single-cell mechanisms of chemoresistance. PMID:12852241

Bergman, Philip J

2003-05-01

48

Microevolution of extensively drug-resistant tuberculosis in Russia  

PubMed Central

Extensively drug-resistant (XDR) tuberculosis (TB), which is resistant to both first- and second-line antibiotics, is an escalating problem, particularly in the Russian Federation. Molecular fingerprinting of 2348 Mycobacterium tuberculosis isolates collected in Samara Oblast, Russia, revealed that 72% belonged to the Beijing lineage, a genotype associated with enhanced acquisition of drug resistance and increased virulence. Whole-genome sequencing of 34 Samaran isolates, plus 25 isolates representing global M. tuberculosis complex diversity, revealed that Beijing isolates originating in Eastern Europe formed a monophyletic group. Homoplasic polymorphisms within this clade were almost invariably associated with antibiotic resistance, indicating that the evolution of this population is primarily driven by drug therapy. Resistance genotypes showed a strong correlation with drug susceptibility phenotypes. A novel homoplasic mutation in rpoC, found only in isolates carrying a common rpoB rifampicin-resistance mutation, may play a role in fitness compensation. Most multidrug-resistant (MDR) isolates also had mutations in the promoter of a virulence gene, eis, which increase its expression and confer kanamycin resistance. Kanamycin therapy may thus select for mutants with increased virulence, helping preserve bacterial fitness and promoting transmission of drug-resistant TB strains. The East European clade was dominated by two MDR clusters, each disseminated across Samara. Polymorphisms conferring fluoroquinolone resistance were independently acquired multiple times within each cluster, indicating that XDR TB is currently not widely transmitted.

Casali, Nicola; Nikolayevskyy, Vladyslav; Balabanova, Yanina; Ignatyeva, Olga; Kontsevaya, Irina; Harris, Simon R.; Bentley, Stephen D.; Parkhill, Julian; Nejentsev, Sergey; Hoffner, Sven E.; Horstmann, Rolf D.; Brown, Timothy; Drobniewski, Francis

2012-01-01

49

Drug-resistant and multidrug-resistant tubercle bacilli  

Microsoft Academic Search

Drug resistant (DR) and multidrug resistant (MDR) tuberculosis (TB) is a consequence of human activity and did not exist before chemotherapeutic drugs were introduced. Monotherapy with various drugs in sequence or other inadequate drug regimens have strongly contributed to the creation of MDR-TB. Such TB strains are mainly prevalent in regions with weak national TB programmes or poor socio-economic environments.

Björn Petrini; Sven Hoffner

1999-01-01

50

Genetic Mechanisms of Transfer of Drug Resistance  

Microsoft Academic Search

Resistance to antibiotics in clinical bacteria has closely followed the introduction of each antibiotic. Resistance to sulfa\\u000a drugs and penicillin was known in the 1940s, and the transmissibility of resistance to sulfa drugs, streptomycin, chloramphenicol,\\u000a and tetracycline became known during the following decade. In the course of studies on bacillary dysentery in Japan, it was\\u000a found that drug resistances could

Paul H. Roy

51

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance  

Microsoft Academic Search

BACKGROUND: Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated

Stacey L Hembruff; Monique L Laberge; David J Villeneuve; Baoqing Guo; Zachary Veitch; Melanie Cecchetto; Amadeo M Parissenti

2008-01-01

52

Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics?  

PubMed Central

Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the ?-, ?-, and/or ?-CA families. In the last decade, the ?-CAs from Neisseria spp. and Helicobacter pylori as well as the ?-class enzymes from Escherichia coli, H. pylori, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and characterized in detail. For some of these enzymes the X-ray crystal structures were determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates reported. Although efficient inhibitors have been reported for many such enzymes, only for Neisseria spp., H. pylori, B. suis, and S. pneumoniae enzymes it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs represent promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets.

Supuran, Claudiu T.

2011-01-01

53

Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries.  

PubMed Central

In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance.

Okeke, I. N.; Lamikanra, A.; Edelman, R.

1999-01-01

54

77 FR 60126 - Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability  

Federal Register 2010, 2011, 2012, 2013

...for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability...industry entitled ``Acute Bacterial Otitis Media: Developing Drugs for Treatment...the treatment of acute bacterial otitis media (ABOM). This guidance finalizes...

2012-10-02

55

Bacterial resistance to disinfectants: present knowledge and future problems  

Microsoft Academic Search

Bacterial resistance to antibiotics is a long-established, widely-studied problem. Increasingly, attention is being directed to the responses of various types of microbes to biocides (antiseptics, disinfectants and preservatives). Different groups of bacteria vary in their susceptibility to biocides, with bacterial spores being the most resistant, followed by mycobacteria, then Gramnegative organisms, with cocci generally being the most sensitive. There are

A. D. Russell

1999-01-01

56

Drug Abuse Resistance Education. Administrative Orientation. Revised.  

ERIC Educational Resources Information Center

The goal of the Drug Abuse Resistance Education (DARE) Program is to prevent drug abuse among school children, by targeting children at an age (K-6) when they are most receptive to drug prevention education and before they are likely to have been led by their peers to experiment with tobacco, alcohol, and other drugs. Project DARE seeks to prevent…

North Carolina State Dept. of Justice, Raleigh.

57

Surgery for drug-resistant focal epilepsy  

PubMed Central

During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy.

Rao, Malla Bhaskara; Arivazhagan, Arimappamagan; Sinha, Sanjib; Bharath, Rose Dawn; Mahadevan, Anita; Bhat, Maya; Satishchandra, Parthasarthy

2014-01-01

58

Leishmania donovani Develops Resistance to Drug Combinations  

PubMed Central

Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance to the different drugs used in such combinations. As a result, this study was designed to elucidate the ability of Leishmania donovani to develop experimental resistance to anti-leishmanial drug combinations. The induction of resistance to amphotericin B/miltefosine, amphotericin B/paromomycin, amphotericin B/SbIII, miltefosine/paromomycin, and SbIII/paromomycin was determined using a step-wise adaptation process to increasing drug concentrations. Intracellular amastigotes resistant to these drug combinations were obtained from resistant L. donovani promastigote forms, and the thiol and ATP levels and the mitochondrial membrane potential of the resistant lines were analysed. Resistance to drug combinations was obtained after 10 weeks and remained in the intracellular amastigotes. Additionally, this resistance proved to be unstable. More importantly, we observed that promastigotes/amastigotes resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs. Additionally, the thiol levels increased in resistant lines that remained protected against the drug-induced loss of ATP and mitochondrial membrane potential. We have therefore demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used. Resistance to the combinations miltefosine/paromomycin and SbIII/paromomycin is easily obtained experimentally. These results have been validated in intracellular amastigotes, and have important relevance for ensuring the long-term efficacy of drug combinations.

Garcia-Hernandez, Raquel; Manzano, Jose Ignacio

2012-01-01

59

Clinical Management of HIV Drug Resistance  

PubMed Central

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Cortez, Karoll J.; Maldarelli, Frank

2011-01-01

60

New approaches to combating antimicrobial drug resistance  

Microsoft Academic Search

Recent work shows that the inhibition of the SOS stress response in Escherichia coli reduces the development of resistance to the antibiotics ciprofloxacin and rifampicin. This finding may help in the battle against the rise of resistance to antimicrobial drugs.

Matthew B Avison

2005-01-01

61

Bacterial and archaeal resistance to ionizing radiation  

NASA Astrophysics Data System (ADS)

Organisms living in extreme environments must cope with large fluctuations of temperature, high levels of radiation and/or desiccation, conditions that can induce DNA damage ranging from base modifications to DNA double-strand breaks. The bacterium Deinococcus radiodurans is known for its resistance to extremely high doses of ionizing radiation and for its ability to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Recently, extreme ionizing radiation resistance was also generated by directed evolution of an apparently radiation-sensitive bacterial species, Escherichia coli. Radioresistant organisms are not only found among the Eubacteria but also among the Archaea that represent the third kingdom of life. They present a set of particular features that differentiate them from the Eubacteria and eukaryotes. Moreover, Archaea are often isolated from extreme environments where they live under severe conditions of temperature, pressure, pH, salts or toxic compounds that are lethal for the large majority of living organisms. Thus, Archaea offer the opportunity to understand how cells are able to cope with such harsh conditions. Among them, the halophilic archaeon Halobacterium sp and several Pyrococcus or Thermococcus species, such as Thermococcus gammatolerans, were also shown to display high level of radiation resistance. The dispersion, in the phylogenetic tree, of radioresistant prokaryotes suggests that they have independently acquired radioresistance. Different strategies were selected during evolution including several mechanisms of radiation byproduct detoxification and subtle cellular metabolism modifications to help cells recover from radiation-induced injuries, protection of proteins against oxidation, an efficient DNA repair tool box, an original pathway of DNA double-strand break repair, a condensed nucleoid that may prevent the dispersion of the DNA fragments and specific radiation-induced proteins involved in radioresistance. Here, we compare mechanisms and discuss hypotheses suggested to contribute to radioresistance in several Archaea and Eubacteria.

Confalonieri, F.; Sommer, S.

2011-01-01

62

Drug resistance mutations for surveillance of transmitted HIV1 drug-resistance: 2009 update  

Microsoft Academic Search

Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January

Diane E. Bennett; Ricardo J. Camacho; Dan Otelea; Daniel R. Kuritzkes; Hervé Fleury; Mark Kiuchi; Walid Heneine; Rami Kantor; Michael R. Jordan; Jonathan M. Schapiro; Anne-Mieke Vandamme; Paul Sandstrom; Charles A. B. Boucher; Vijver van de D. A. M. C; Soo-Yon Rhee; Tommy F. Liu; Deenan Pillay; Robert W. Shafer

2009-01-01

63

Population Mobility, Globalization, and Antimicrobial Drug Resistance  

Microsoft Academic Search

Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new

Douglas W. MacPherson; Brian D. Gushulak; William B. Baine; Shukal Bala; Paul O. Gubbins; Paul Holtom; Marisel Segarra-Newnham

2009-01-01

64

Types and drug susceptibility patterns of bacterial isolates from eye discharge samples at Gondar University Hospital, Northwest Ethiopia  

PubMed Central

Background The type and pattern of organisms that cause ocular infection changes over time. Moreover, the causative organisms have developed increased drug resistance. Therefore, the aim of this study was to determine the prevalent bacterial agents of eye discharge and their drug susceptibility patterns to commonly used antimicrobial agents. Methods A retrospective study was conducted at Gondar University Hospital, Northwest Ethiopia from September, 2009 to August, 2012. Culture and drug susceptibility test results of patients who had eye infections were taken for analysis. Eye discharge samples were cultured on MacConkey agar, blood agar and chocolate agar plates. A standard biochemical procedure was used for full identification of bacterial isolates. Antimicrobial susceptibility tests were done on Mueller-Hinton agar by using disk diffusion method. Data was entered and analyzed by using SPSS version 16 software. Result A total of 102 eye discharges were submitted for microbiological evaluation, of which (60.8%) had bacterial growth. The most frequently isolated bacterial isolates were gram-positive bacteria (74.2%). The predominant bacterial species isolated was Coagulase-negative staphylococci (27.4%) followed by S. aureus (21%). Within the age group of 1 day-2 years old, (66.1%) of bacteria were isolated. Most of the bacterial isolates were resistance to ampicilin (71%), amoxicilin (62.9%), erythromycin (43.5%), gentamicin (45.2%), penicillin (71%), trimethoprim-sulphamethoxazole (58.1%), and tetracycline (64.6%) while Ceftriaxon and Ciprofloxacin showed (75.8%) and (80%) susceptibility respectively. From the total bacterial isolates, (87.1%) were showed multi drug resistance (MDR) to two or more drugs. Conclusion The prevalence of bacterial isolates in eye discharge was high in the study area and majority of isolates were gram-positive bacteria. Most of the bacterial isolates were resistant to frequently used antimicrobials. Therefore, drug susceptibility test is necessary before prescribing any antimicrobials.

2014-01-01

65

Bacterial mercury resistance from atoms to ecosystems.  

PubMed

Bacterial resistance to inorganic and organic mercury compounds (HgR) is one of the most widely observed phenotypes in eubacteria. Loci conferring HgR in Gram-positive or Gram-negative bacteria typically have at minimum a mercuric reductase enzyme (MerA) that reduces reactive ionic Hg(II) to volatile, relatively inert, monoatomic Hg(0) vapor and a membrane-bound protein (MerT) for uptake of Hg(II) arranged in an operon under control of MerR, a novel metal-responsive regulator. Many HgR loci encode an additional enzyme, MerB, that degrades organomercurials by protonolysis, and one or more additional proteins apparently involved in transport. Genes conferring HgR occur on chromosomes, plasmids, and transposons and their operon arrangements can be quite diverse, frequently involving duplications of the above noted structural genes, several of which are modular themselves. How this very mobile and plastic suite of proteins protects host cells from this pervasive toxic metal, what roles it has in the biogeochemical cycling of Hg, and how it has been employed in ameliorating environmental contamination are the subjects of this review. PMID:12829275

Barkay, Tamar; Miller, Susan M; Summers, Anne O

2003-06-01

66

Molecular diagnosis of tuberculosis and drug resistance.  

PubMed

Molecular drug susceptibility testing (MDST) provides rapid diagnosis of tuberculosis (TB) and detection of drug resistance with commendable sensitivity and specificity. MDST reduces unnecessary isolation or treatment, when a negative result for TB is obtained. Because of the possibility of false detection of rifampin resistance by probe-based MDST, confirmation by sequencing is recommended, especially in regions where the prevalence of resistance is low. Revealing mutation identity by sequencing offers opportunities to study drug minimum inhibitory concentrations for each mutation. Such information enables prediction of resistance levels, and may be helpful in formulating optimal regimens, when treatment options are limited. PMID:24856529

Lin, Shou-Yean Grace; Desmond, Edward P

2014-06-01

67

Structural insights into bacterial resistance to cerulenin.  

PubMed

Cerulenin is a fungal toxin that inhibits both eukaryotic and prokaryotic ketoacyl-acyl carrier protein synthases or condensing enzymes. It has been used experimentally to treat cancer and obesity, and is a potent inhibitor of bacterial growth. Understanding the molecular mechanisms of resistance to cerulenin and similar compounds is thus highly relevant for human health. We have previously described a Bacillus subtilis cerulenin-resistant strain, expressing a point-mutated condensing enzyme FabF (FabF[I108F]) (i.e. FabF with isoleucine 108 substituted by phenylalanine). We now report the crystal structures of wild-type FabF from B. subtilis, both alone and in complex with cerulenin, as well as of the FabF[I108F] mutant protein. The three-dimensional structure of FabF[I108F] constitutes the first atomic model of a condensing enzyme that remains active in the presence of the inhibitor. Soaking the mycotoxin into preformed wild-type FabF crystals allowed for noncovalent binding into its specific pocket within the FabF core. Interestingly, only co-crystallization experiments allowed us to trap the covalent complex. Our structure shows that the covalent bond between Cys163 and cerulenin, in contrast to that previously proposed, implicates carbon C3 of the inhibitor. The similarities between Escherichia coli and B. subtilis FabF structures did not explain the reported inability of ecFabF[I108F] (i.e. FabF from Escherichia coli with isoleucine 108 substituted by phenylalanine) to elongate medium and long-chain acyl-ACPs. We now demonstrate that the E. coli modified enzyme efficiently catalyzes the synthesis of medium and long-chain ketoacyl-ACPs. We also characterized another cerulenin-insensitive form of FabF, conferring a different phenotype in B. subtilis. The structural, biochemical and physiological data presented, shed light on the mechanisms of FabF catalysis and resistance to cerulenin. Database: Crystallographic data (including atomic coordinates and structure factors) have been deposited in the Protein Data Bank under accession codes 4LS5, 4LS6, 4LS7 and 4LS8. PMID:24641521

Trajtenberg, Felipe; Altabe, Silvia; Larrieux, Nicole; Ficarra, Florencia; de Mendoza, Diego; Buschiazzo, Alejandro; Schujman, Gustavo E

2014-05-01

68

Marker Assisted Selection of Bacterial Blight Resistance Genes in Rice  

Microsoft Academic Search

Bacterial leaf blight caused by Xanthomonas oryzae pv. oryzae is one of the most important diseases affecting rice production in Asia. We were interested in surveying rice genotypes that are popularly used in the Indian breeding program for conferring resistance to bacterial blight, using 11 STMS and 6 STS markers. The basis of selection of these DNA markers was their

A. P. Davierwala; A. P. K. Reddy; M. D. Lagu; P. K. Ranjekar; V. S. Gupta

2001-01-01

69

Anomalous high native resistance to athymic mice to bacterial pathogens.  

PubMed Central

Congenitally athymic (nude) mice exhibited an anomalous high resistance against infections with the facultative intracellular parasite Listeria monocytogenes and other bacterial pathogens. Protection against lethal infection was demonstrated to result from the presence of naturally occurring activated macrophages in the reticuloendothelial organs of the nude mice. This was exemplified after intravenous challenge by enhanced bacterial clearance from the blood and augmented bacterial killing in the spleens and livers of nude mice as compared with immunologically competent control mice. Resident peritoneal macrophages of nude mice were not activated in terms of phagocytic, bactericidal, or tumoricidal potential. The development of activated fixed tissue macrophages appears to arise as a result of the T-lymphocyte deficiency since thymus implantation abrogated the enhanced resistance of nude mice. Antibiotic elimination of intestinal bacteria also modified resistance to bacterial infection, indicating a role of environmental factors on macrophage activation. Several possible mechanisms leading to macrophage activation and heightened resistance to infection in nude mice are offered.

Nickol, A D; Bonventre, P F

1977-01-01

70

Plasmids and evolutionary rescue by drug resistance.  

PubMed

Antibiotic resistance provides evolutionary rescue for bacterial populations under the threat of extinction through antibiotics. It can arise de novo through mutation in the population, or be obtained from other bacterial populations via the transfer of a resistance-conferring plasmid. We use stochastic modeling methods to establish whether the most likely source of rescue is via a plasmid or via the chromosome, and show that contrary to what is assumed plasmids are not necessarily beneficial locations for resistance genes. Competition at the plasmid level of selection is of great importance-the spread of a resistant plasmid in the population can be slowed or entirely stopped by a nonresistant version of the same plasmid. We suggest that future studies on antibiotic-resistant plasmids should explicitly consider competition at this level of selection. PMID:24749717

Tazzyman, Samuel J; Bonhoeffer, Sebastian

2014-07-01

71

Emergence and mechanisms of bacterial resistance in surgical infections.  

PubMed

Antimicrobial resistance is commonplace among bacteria involved in surgical infections, including Staphylococcus aureus, enterococci, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Bacteroides species. Resistance traits can be encoded on chromosomes or transmissible plasmids. The basic mechanisms of resistance are alteration of drug target, prevention of drug access to target, and drug inactivation. Examples include alteration of penicillin-binding proteins in resistance to penicillinase-resistant penicillins, ribosomal binding site protection in tetracycline resistance, and beta-lactamase destruction of beta-lactam compounds. Resistance due to the many types of beta-lactamases that have thus far been identified is wide-spread among common pathogens; use of beta-lactam/beta-lactamase inhibitor combinations has proved effective as one means of counteracting such resistance. Contending with resistance involves appropriate use of available antimicrobials, development of novel agents or modification of existing agents, and measures to forestall emergence and spread of resistant organisms. PMID:7755162

Neu, H C

1995-05-01

72

Emerging pathogens: Dynamics, mutation and drug resistance  

SciTech Connect

This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others

1997-10-01

73

Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options.  

PubMed

Gram-negative bacterial infections constitute an emerging threat because of the development of multidrug-resistant organisms. There is a relative shortage of new drugs in the antimicrobial development pipeline that have been tested in vitro and evaluated in clinical studies. Antibiotics that are in the pipeline for the treatment of serious Gram-negative bacterial infections include the cephalosporins, ceftobiprole, ceftarolin and FR-264205. Tigecycline is the first drug approved from a new class of antibiotics called glycylcyclines, and there has been renewed interest in this drug for the treatment of some multidrug-resistant Gram-negative organisms. Carbapenems in the pipeline include tomopenem, with the approved drugs doripenem and faropenem, an oral agent, under evaluation for activity against multidrug-resistant Gram-negative bacterial infections. Polymyxins are old antibiotics traditionally considered to be toxic, but which are being used because of their activity against resistant Gram-negative organisms. New pharmacokinetic and pharmacodynamic data are available regarding the use of these agents. Finally, antimicrobial peptides and efflux pump inhibitors are two new classes of agents under development. This review of investigational antibiotics shows that several new agents will become available in the coming years, even though the pace of antimicrobial research is far from ideal. PMID:18246520

Vergidis, Paschalis I; Falagas, Matthew E

2008-02-01

74

[Quorum sensing of genes expression--perspective drug target against bacterial pathogenicity].  

PubMed

Bacteria are capable to sense an increase of cell density population and to reply quickly and coordinately by the induction of special sets of genes. This type of the regulation was named Quorum Sensing (QS); it is based on the effect of low-molecular-weight signaling molecules of different nature (autoinducers) which accumulate in the culture at high density of bacterial population and interact with receptor regulatory proteins. QS systems are the global regulators of bacterial genes expression and play a key role in the control of many metabolic processes in cell including the regulation of virulence of bacteria. Here we review the molecular mechanisms of QS systems functioning in bacteria belonging to different taxonomic groups and discuss the potential of QS regulation as a new drug target for the treatment of bacterial infections. At present this approach is accounted as a new alternative strategy of antimicrobial therapy directed on the development of drugs inhibiting QS regulation and active just against pathogenicity of bacteria (antipathogenic drugs). Such a strategy allows to avoid a wide dissemination of resistant forms of pathogenic bacteria and the formation of biofilms increasing in many times the resistance of bacteria to drug preparations. PMID:16637260

Khmel', I A; Metlitskaia, A Z

2006-01-01

75

Evolutionary paths to antibiotic resistance under dynamically sustained drug stress  

PubMed Central

Antibiotic resistance can evolve through sequential accumulation of multiple mutations1. To study such gradual evolution, we developed a selection device, the morbidostat, which continuously monitors bacterial growth and dynamically regulates drug concentrations such that the evolving population is constantly challenged. We analyzed evolutionary trajectories of Escherichia coli populations towards resistance to chloramphenicol, doxycycline, and trimethoprim. Over a period of ~20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing revealed both drug-specific and drug-general genetic changes. Chloramphenicol and doxycycline resistance evolved through diverse combinations of mutations in genes involved in translation, transcription, and transport2. In contrast, trimethoprim resistance evolved in a stepwise manner1,3, through mutations restricted to the target enzyme dihydrofolate reductase (DHFR)4,5. Sequencing DHFR over time revealed that parallel populations not only evolved similar mutations, but also acquired them in similar order6. Uncovering such recurrent genotypic pathways may help the spread of resistance.

Toprak, Erdal; Veres, Adrian; Michel, Jean-Baptiste; Chait, Remy; Hartl, Daniel L.; Kishony, Roy

2012-01-01

76

Mechanisms of Drug Resistance in Plasmodium falciparum.  

National Technical Information Service (NTIS)

Drug resistance has emerged as a major problem in the treatment of all microbial agents and in many cancer chemotherapies. This has necessitated the continuous development of new chemotherapeutic agents both for treatment of infectious agents and for canc...

D. F. Wirth

1992-01-01

77

Synthetic lethality to overcome cancer drug resistance.  

PubMed

A large body of evidence point out that the onset of synthetic lethality may provide a useful tool for amplifying the efficacy of drugs in anticancer regimens, to uncover interdependence between genes and to identify predictive factors that would be extremely useful to guide in the selection of more effective targeted drugs and drug combinations for each patient. Here, we provide an overview on the exploitation of synthetic lethality to overcome drug resistance to conventional chemotherapy in several types of solid tumors. We report recent findings on cellular markers and gene mutations which are specifically essential for the viability of cancer cells and for resistance to chemotherapeutics. In addition, new molecularly targeted strategies to overcome drug resistance are suggested. PMID:22788762

Porcelli, L; Quatrale, A E; Mantuano, P; Silvestris, N; Brunetti, A E; Calvert, H; Paradiso, A; Azzariti, A

2012-01-01

78

Resistance to antituberculosis drugs in Japan  

Microsoft Academic Search

Setting: Five years after the last survey of drug-resistant tuberculosis in Japan, a serious new phenomenon has gradually begun to appear. A nationwide survey was conducted by the Tuberculosis Research Committee.Objective: To determine resistance patterns to five anti-tuberculosis drugs and risk factors.Design: Cultures were obtained from patients hospitalized at 38 hospitals in various districts of Japan throughout 6 months, from

K. Hirano; Y. Kazumi; C. Abe; T. Mori; M. Aoki; T. Aoyagi

1996-01-01

79

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance  

PubMed Central

Background Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2), epirubicin (MCF-7EPI), paclitaxel (MCF-7TAX-2), or docetaxel (MCF-7TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters. Results In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance. Conclusion This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.

Hembruff, Stacey L; Laberge, Monique L; Villeneuve, David J; Guo, Baoqing; Veitch, Zachary; Cecchetto, Melanie; Parissenti, Amadeo M

2008-01-01

80

Dissemination of bacterial fluoroquinolone resistance in two multidrug-resistant enterobacteriaceae.  

PubMed

Bacterial resistance to antimicrobials has become one of the greatest challenges for clinical microbiologists and healthcare practitioners worldwide. Acquisition of resistance genes has proven to be difficult to characterize and is largely uncontrollable in the environment. Here we sought to characterize conjugal horizontal gene transfer of plasmid-encoded fluoroquinolone resistance genes from two strains of Enterobacteriaceae, one clinical and one from a municipal wastewater treatment plant environment. Conjugation was dissimilar between the two strains. Escherichia coli strain LR09, containing a plasmid with the aac(6')-Ib-cr fluoroquinolone resistance gene, did not conjugate with any of the 15 strains tested, while Enterobacter aerogenes strain YS11 conjugated with two strains of E. coli. The resultant transconjugants were also dissimilar in their stability and potential persistence. The observations presented herein exemplify the difficulties in understanding and controlling the spread of antimicrobial resistance. Thus, it may be prudent to address drug disposal and destruction, incorporating a life-cycle assessment plan 'from cradle to grave', treating antimicrobials as chemical or environmental contaminants. © 2014 S. Karger AG, Basel. PMID:24862457

Jung, Carina M

2014-01-01

81

Expression of cytokeratin confers multiple drug resistance  

SciTech Connect

The cytokeratin network is an extensive filamentous structure in the cytoplasm whose biological function(s) is unknown. Based upon previous data showing the modification of cytokeratin by mitoxantrone, the authors investigated the ability of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. They have compared the survival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence of chemotherapeutic drugs. The expression of cytokeratins 8 and 18 conferred a multiple drug resistance phenotype on cells exposed to mitoxantrone, doxorubicin, methotrexate, melphalan, Colcemid, and vincristine. The degree of drug resistance was 5-454 times that of parental cells, depending upon the agent used. Drug resistance could not be attributed to altered growth characteristics, altered drug accumulation, or an altered drug efflux in the transfected cells. Cytokeratin does not confer resistance to ionizing radiation, which damages DNA independently on intracellular transport mechanisms. These data suggest a role for cytokeratin networks in conferring a drug resistance phenotype.

Bauman, P.A.; Dalton, W.S.; Anderson, J.M.; Cress, A.E. (Univ. of Arizona, Tucson, AZ (United States))

1994-06-07

82

Infectious Multiple Drug Resistance in the Enterobacteriaceae.  

National Technical Information Service (NTIS)

Tobramycin-resistant burn wound isolates from five different bacterial genera contained a common 68 x 10 to the 6th power dalton R plasmid that could be transmitted by conjugation to Escherichia coli K-12. It was possible by a variety of newly developed m...

S. Falkow

1977-01-01

83

Ion efflux systems involved in bacterial metal resistances  

Microsoft Academic Search

Summary Studying metal ion resistances gives us important insights into environmental processes and provides an understanding of basic living processes. This review concentrates on bacterial efflux systems for inorganic metal cations and anions, which have generally been found as resistance systems from bacteria isolated from metal-polluted environments. The protein products of the genes involved are sometimes prototypes of new families

Dietrich H. Nies; Simon Silver

1995-01-01

84

[Treatment of drug-resistant depression].  

PubMed

Depression is drug-resistant, if the severity of the symptoms has not decreased to half of the starting situation, despite appropriately conducted treatment with two antidepressants belonging to two different pharmacological categories. The incidence of drug-resistant depression in Finland is approximately 1%, and it is being treated too passively, whereby the number of disability pensions is rising. Current treatments include combinations of antidepressants, additional drugs for depression, psychotherapy, electrotherapy and serial magnetic stimulation. Ketamine infusions are also an effective, yet still experimental form of treatment. PMID:24340715

Taiminen, Tero

2013-01-01

85

NOTE: Dielectrophoretic assay of bacterial resistance to antibiotics  

NASA Astrophysics Data System (ADS)

The dielectrophoretic collection spectra of antibiotic-sensitive and antibiotic-resistant strains of Staphylococcus epidermidis have been determined. These indicate that in the absence of antibiotic treatment there is a strong similarity between the dielectric properties of sensitive and resistant strains, and that there is a significant difference between the sensitive strains before and after treatment with the antibiotic streptomycin after 24 h exposure. This method offers possibilities for the assessment of bacterial resistance to antibiotics.

Johari, Juliana; Hübner, Yvonne; Hull, Judith C.; Dale, Jeremy W.; Hughes, Michael P.

2003-07-01

86

The Prevalence of Resistant Bacterial Colonization in Chronic Hemodialysis Patients  

Microsoft Academic Search

Backgound: Hospitalized dialysis patients are at increased risk for colonization and infection with resistant bacterial strains. Methods: We performed a cross-sectional analysis of the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) colonization in 198 hemodialysis outpatients, 75 of whom had longitudinal screening data from prior hospitalization. Nasal specimens for MRSA, perirectal specimens for VRE, and permanent catheter

Alexander C. Hadley; Tobi B. Karchmer; Gregory B. Russell; Debra G. McBride; Barry I. Freedman

2007-01-01

87

Mechanisms of Drug-Resistance in Kinases  

PubMed Central

Introduction Because of their important roles in disease and excellent “druggability”, kinases have become the second-largest drug target family. The great success of the BCR-ABL inhibitor imatinib in treating CML illustrates the high potential of kinase inhibitor (KI) therapeutics, but also unveiled a major limitation: the development of drug-resistance. This is a significant concern as KIs reach large patient populations for an expanding array of indications. Areas covered We provide an up-to-date understanding of the mechanisms through which KIs function, and through which cells can become KI-resistant. We review current and future approaches to overcome KI-resistance, focussing on currently approved KIs and KIs in clinical trials. We then discuss approaches to improve KI efficacy and overcome drug-resistance and novel approaches to develop less drug-resistance prone KI-therapeutics. Expert opinion Although drug-resistance is a concern for current KI-therapeutics, recent progress in our understanding of the underlying mechanisms and promising technological advances may overcome this limitation and provide powerful new therapeutics.

Barouch-Bentov, Rina; Sauer, Karsten

2010-01-01

88

Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis  

PubMed Central

In March 2012, in response to reports of tuberculosis (TB) resistant to all anti-TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug-resistant TB. Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB. Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB.

Nunn, Paul; Kurbatova, Ekaterina V.; Weyer, Karin; Dalton, Tracy L.; Wares, Douglas F.; Iademarco, Michael F.; Castro, Kenneth G.; Raviglione, Mario

2012-01-01

89

Transporters involved in resistance to antimalarial drugs  

PubMed Central

The ability to treat and control Plasmodium falciparum infection through chemotherapy has been compromised by the advent and spread of resistance to antimalarial drugs. Research in this area has identified the P. falciparum chloroquine resistance transporter (PfCRT) and the multidrug resistance-1 (PfMDR1) transporter as key determinants of decreased in vitro susceptibility to several principal antimalarial drugs. Transfection-based in vitro studies are consistent with clinical findings of an association between mutations in the pfcrt gene and failure of chloroquine treatment, and between amplification of the pfmdr1 gene and failure of mefloquine treatment. Many countries are now switching to arte-misinin-based combination therapies. These incorporate partner drugs of which some have an in vitro efficacy that can be modulated by changes in pfcrt or pfmdr1. Here, we summarize investigations of these and other recently identified P. falciparum transporters in the context of antimalarial mode of action and mechanisms of resistance.

Valderramos, Stephanie G.; Fidock, David A.

2010-01-01

90

CancerDR: Cancer Drug Resistance Database  

PubMed Central

Cancer therapies are limited by the development of drug resistance, and mutations in drug targets is one of the main reasons for developing acquired resistance. The adequate knowledge of these mutations in drug targets would help to design effective personalized therapies. Keeping this in mind, we have developed a database “CancerDR”, which provides information of 148 anti-cancer drugs, and their pharmacological profiling across 952 cancer cell lines. CancerDR provides comprehensive information about each drug target that includes; (i) sequence of natural variants, (ii) mutations, (iii) tertiary structure, and (iv) alignment profile of mutants/variants. A number of web-based tools have been integrated in CancerDR. This database will be very useful for identification of genetic alterations in genes encoding drug targets, and in turn the residues responsible for drug resistance. CancerDR allows user to identify promiscuous drug molecules that can kill wide range of cancer cells. CancerDR is freely accessible at http://crdd.osdd.net/raghava/cancerdr/

Kumar, Rahul; Chaudhary, Kumardeep; Gupta, Sudheer; Singh, Harinder; Kumar, Shailesh; Gautam, Ankur; Kapoor, Pallavi; Raghava, Gajendra P. S.

2013-01-01

91

Drug-resistant tuberculosis: emerging treatment options.  

PubMed

Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug-drug interactions in patients coinfected with human immunodeficiency virus (HIV), inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drugsusceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO) has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and markers for adequacy of treatment and an integrative approach to fulfill WHO goals. However, regulatory control over the drug market, as well as public-private partnership to use health program facilities to track patients and ensure completion of adequate therapy will be necessary to exploit fully the potential of the newer regimens to eliminate tuberculosis. PMID:22287857

Adhvaryu, Meghna; Vakharia, Bhasker

2011-01-01

92

Drug-resistant tuberculosis: emerging treatment options  

PubMed Central

Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV), inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drugsusceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO) has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and markers for adequacy of treatment and an integrative approach to fulfill WHO goals. However, regulatory control over the drug market, as well as public-private partnership to use health program facilities to track patients and ensure completion of adequate therapy will be necessary to exploit fully the potential of the newer regimens to eliminate tuberculosis.

Adhvaryu, Meghna; Vakharia, Bhasker

2011-01-01

93

Prevalence and antimicrobial resistance pattern of bacterial meningitis in Egypt  

PubMed Central

Infectious diseases are the leading cause of morbidity and mortality in the developing world. In Egypt bacterial diseases constitute a great burden, with several particular bacteria sustaining the leading role of multiple serious infections. This article addresses profound bacterial agents causing a wide array of infections including but not limited to pneumonia and meningitis. The epidemiology of such infectious diseases and the prevalence of Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae are reviewed in the context of bacterial meningitis. We address prevalent serotypes in Egypt, antimicrobial resistance patterns and efficacy of vaccines to emphasize the importance of periodic surveillance for appropriate preventive and treatment strategies.

Shaban, Lamyaa; Siam, Rania

2009-01-01

94

Volatilization of mercury by resting mercury-resistant bacterial cells  

SciTech Connect

The mercuric ion reduction systems encoded by the Hg{sup 2+}inducible mer operon confers bacterial resistance to mercuric ion. The mer A gene product which is a FAD-containing enzyme catalyzes the reduction of Hg{sup 2+} to volatile elemental mercury with the helo of intracellular thiols and NADP as a cofactor Our earlier studies have shown that growing cells of different mercury-resistant bacteria reduce Hg{sup 2+} compounds to Ha(O). We have also shown the effect of thiol compounds and flavins on mercury-degrading enzyme activities in mercury-resistant bacteria. Here we report that resting cells of mercury-resistant bacteria survive in a buffer system for several hours, synthesize inducible mercury-degrading enzymes and volatilize mercury from a mercury-containing buffer system. We know of no information regarding studies of mercury-degrading enzymes in resting mercury-resistant bacterial cells.

Ghosh, S.; Sadhukhan, P.C.; Ghosh, D.K. [Univ. College of Science, Calcutta (India)] [and others] [Univ. College of Science, Calcutta (India); and others

1996-02-01

95

Antimalarial drug resistance and combination chemotherapy.  

PubMed Central

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives.

White, N

1999-01-01

96

Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections.  

PubMed

Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis. PMID:23859208

Labby, Kristin J; Garneau-Tsodikova, Sylvie

2013-07-01

97

Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections  

PubMed Central

Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis.

Labby, Kristin J; Garneau-Tsodikova, Sylvie

2013-01-01

98

HCV drug resistance and DAA agents.  

PubMed

New treatment options for HCV infection with Direct-Acting Antivirals (DAAs) increased SVR rate in treated patients but on the other hand drew attention to the problem of HCV drug resistance. Drug-resistant HCV mutants are present in all infected patients even before the treatment initiation and their number grows significantly over the first few days of DAAs therapy. But HCV has no known genetic form of intra-cellular persistence (does not integrate with host's genome and cannot produce episomal forms) which enables its total eradication. It is likely that the effective interferon-free, based on all-oral DAAs drug combination will be available within the next few years. This paper reviews HCV resistance mechanisms and their significance in treatment. I also presents results of recent DAAs trials. PMID:24340550

Szymanek, Anna; Krzysztof, Simon

2013-01-01

99

Predicting drug sensitivity and resistance  

Microsoft Academic Search

For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the

Gergely Szakács; Jean-Philippe Annereau; Samir Lababidi; Uma Shankavaram; Angela Arciello; Kimberly J. Bussey; William Reinhold; Yanping Guo; Gary D. Kruh; Mark Reimers; John N. Weinstein; Michael M. Gottesman

2004-01-01

100

Topiramate for drug-resistant epilepsies  

Microsoft Academic Search

Topiramate is a new anti-epileptic drug with proven efficacy against partial seizures in adults. A retrospective assessment of the use of topiramate in drug-resistant childhood epilepsy was undertaken. Thirty-four children (median age of 10 years; range 2–18 years) were treated for a median of 9 months (range 6–18 months). The starting dose was 0.25–2.0mg\\/kg\\/day increasing to a maximum of 13mg\\/kg\\/day.

Stella Yeung; Colin D. Ferrie; Deborah G. Murdoch-Eaton; John H. Livingston

2000-01-01

101

[Investigation of extensive drug resistance in multidrug resistance tuberculosis isolates].  

PubMed

Increasing number of drug resistant tuberculosis (TB) cases, observed in recent years, is an important public health problem. Extensively drug resistant TB (XDR-TB) is the development of resistance against any fluoroquinolones and at least one of the injectable second line anti-TB drugs in addition to resistance against isoniazide and rifampicin which are the first line anti-TB drugs [definition of multidrug resistant TB (MDR-TB)]. Anti-TB therapy failed with first-line anti-TB drugs due to MDR-TB cases is being planned according to second-line anti-TB drug susceptibility test results if available and if not, standart treatment protocols are used. Although it is recommended that individual anti-TB therapy should be designed according to the isolate's susceptibility test results, standart therapeutic protocols are always needed since second-line anti-TB drug susceptibility testing generally could not be performed in developing countries like Turkey. For this reason, nationwide and regional surveillance studies to determine the resistance patterns are always needed to make decisions about the standard therapy algorithms. In this study, it was aimed to investigate the presence of extensive drug resistance among 81 MDR-TB isolates obtained from various health care facilities from Istanbul, Izmir and Manisa and to determine the XDR-TB incidence in Marmara and Aegean regions. Furthermore, we aimed to provide epidemiological data to clinicians to support their choice of second-line anti-TB drugs for MDR-TB infections. Susceptibility testing of isolates for the first and the second-line anti-TB drugs were performed by using modified Middlebrook 7H9 broth in fluorometric BACTEC MGIT 960 system (Becton Dickinson, USA). Eighty-one MDR-TB isolates included in this study were isolated from 43 (53.1%) patients residing in Istanbul, 26 (32.1%) in Izmir and 12 (14.8%) in Manisa provinces. We could not find any isolate consistent with XDR-TB definition in this study. Second-line drug resistance rates of MDR-TB isolates to amikacin and kanamycin were 1.2%, ofloxacin and levofloxacin were 2.5%, capreomycin was 14.8%, ethionamide was 37% whereas linezolid resistance was not detected. Statistically significant correlation was detected between resistance rates of these antibiotic pairs; levofloxacin-ofloxacin (p< 0.01), amikacin-kanamycin (p= 0.01) and streptomycin-ethionamide (p= 0.04). In our study, extensive drug resistance was not encountered in any MDR-TB isolates while high resistance rates was observed against ethionamide and capreomycin. It can be concluded that parenteral aminoglycosides amikasin and kanamycin, fluoroquinolones and linezolid seemed to be reliable anti-TB agents in MDR-TB treatment, however, further larger scale studies are needed. PMID:23390903

Bektöre, Bayhan; Haznedaro?lu, Tunçer; Baylan, Orhan; Ozyurt, Mustafa; Ozkütük, Nuri; Satana, Dilek; Cavu?o?lu, Cengiz; Seber, Engin

2013-01-01

102

[Staphylococcuses and their drug-resistance in inflammations of submandibular lymph nodes in children].  

PubMed

Analysis of bacteriological examination results in 46 children with submandibular lymph nodes inflammation has been presented in the paper. The examinations have been carried out from the point of view of observation of bacterial flora variation and its drug--resistance. The analysis of examination results has revealed existence of strains such as: S. aureus, S. albus, S. epidermidis. The attention has been called to the necessity of bacterial flora examinations considering substantial changes in the frequency of particular strains occurrence and their drug resistance. PMID:3270600

Gruszewska-Lewczuk, L; Zó?kowski, K

1988-10-01

103

Drug resistance confounding prion therapeutics  

PubMed Central

There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and Creutzfeldt–Jakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of Creutzfeldt–Jakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration.

Berry, David B.; Lu, Duo; Geva, Michal; Watts, Joel C.; Bhardwaj, Sumita; Oehler, Abby; Renslo, Adam R.; DeArmond, Stephen J.; Prusiner, Stanley B.; Giles, Kurt

2013-01-01

104

Resistance of bacterial spores to ultraviolet light  

SciTech Connect

Dormant spores of gram-positive bacteria, such as the various Bacillus species, usually are more resistant to killing by ultraviolet light than are growing cells. During the first minutes of spore germination, the spore's UV resistance rises significantly before dropping to the decreased value of the vegetative cell. For all strains of all species that have been tested, the spores are considerably more UV-resistant than their corresponding growing cells. Since the killing of cells or spores by UV-radiation is due to the presence of UV-induced photoproducts in DNA, there are two major factors that might be expected to influence UV resistance. (1) the UV photochemistry of the DNA in vivo, i.e., the type of photoproducts formed in DNA by UV radiation, the quantum efficiency of their formation, and their lethality; and (2) the efficiency of the repair or removal of these photoproducts. The DNA in the dormant spores has a different UV photochemistry than does the DNA in the growing cell, while the young germinated spore's DNA may exhibit a third type of UV photochemistry. There is at least one repair system which is specific for UV photoproducts produced in the dormant spore, as well as repair systems that act on UV photoproducts formed in other stages of growth.

Setlow, P.

1988-01-01

105

Detection of bacterial blight resistance genes in basmati rice landraces.  

PubMed

Aromatic basmati rice is vulnerable to bacterial blight disease. Genes conferring resistance to bacterial blight have been identified in coarse rice; however, their incorporation into basmati varieties compromises the prized basmati aroma. We identified bacterial blight resistance genes Xa4, xa5, Xa7, and xa13 in 52 basmati landraces and five basmati cultivars using PCR markers. The Xa7 gene was found to be the most prevalent among the cultivars and landraces. The cultivars Basmati-385 and Basmati-2000 also contained the Xa4 gene; however, xa5 and xa13 were confined to landraces only. Ten landraces were found to have multiple resistance genes. Landraces Basmati-106, Basmati-189 and Basmati-208 contained Xa4 and Xa7 genes. Whereas, landraces Basmati-122, Basmati-427, Basmati-433 were observed to have xa5 and Xa7 genes. Landraces Basmati-48, Basmati-51A, Basmati-334, and Basmati-370A possessed Xa7 and xa13 genes. The use of landraces containing recessive genes xa5 and xa13 as donor parents in hybridization with cultivars Basmati-385 and Basmati-2000, which contain the genes Xa4 and Xa7, will expedite efforts to develop bacterial blight-resistant basmati rice cultivars through marker assisted selection, based on a pyramiding approach, without compromising aroma and grain quality. PMID:22869552

Ullah, I; Jamil, S; Iqbal, M Z; Shaheen, H L; Hasni, S M; Jabeen, S; Mehmood, A; Akhter, M

2012-01-01

106

Mechanisms of Candida biofilm drug resistance.  

PubMed

Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, ?-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

2013-10-01

107

[The bacterial cell wall and penicillin resistance: facts, questions and hopes].  

PubMed

The simplest conceivable event at the level of the gene can result in the emergence of antibiotic-resistant determinants. The bacterial world behaves as an enormous organism the cells of which exchange their genes with great ease and, likewise, the opportunities for the exchange of genetic material in nature is, probably, limitless. This knowledge cannot be ignored. It leads to the important conclusion that the antibiotics are societal drugs. A resistance gene which has appeared somewhere in the world can travel far and fast. PMID:9887589

Ghuysen, J M

1998-01-01

108

DRUG RESISTANCE OF ENTERIC BACTERIA II.  

PubMed Central

Harada, Kenji (Gunma University, Maebashi, Japan), Mitsuo Kameda, Mitsue Suzuki, and Susumu Mitsuhashi. Drug resistance of enteric bacteria. II. Transduction of transmissible drug-resistance (R) factors with phage epsilon. J. Bacteriol. 86:1332–1338. 1963.—Transmissible drug-resistance (R) factors, which transfer resistance to tetracycline (TC), chloramphenicol, streptomycin, and sulfonamide by cell-to-cell contact, were found to be transduced in the system of Salmonella E group with phage epsilon (?15 and ?34). The R+ transductants of S. newington (S-84) and S. chittagong (S-224) were all found to be unable to transfer their R factors by conjugation, and their R factors were not eliminated by treatment with acridine dyes so far as tested. The R factors containing TC resistance were consistently segregated when transduced. At low multiplicities of infection, the R+ transductants with ?15 were all nonlysogenic and unable to produce normal ?15 phage particles; among the R+ transductants with ?34, 34% were lysogenic and 66% were sensitive to ?34.

Harada, Kenji; Kameda, Mitsuo; Suzuki, Mitsue; Mitsuhashi, Susumu

1963-01-01

109

Update on tamper-resistant drug formulations.  

PubMed

An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes. PMID:23415386

Romach, M K; Schoedel, K A; Sellers, E M

2013-06-01

110

Biofilms as a mechanism of bacterial resistance.  

PubMed

Inside the biofilm, antimicrobial agents must overcome high cell density, an increased number of resistant mutants, substance delivery, molecular exchanges, such as high levels of beta-lactamases or inducers of efflux pump expression, and specific adaptive cells, so-called persisters. The environment within the biofilm modulates the response to antibiotics, especially when the SOS response or DNA repair systems are involved. Exposure to subinhibitory concentrations of antibiotics can enhance biofilm formation and mutagenesis. Thus, a global response to cell stress seems to be responsible for antibiotic-induced biofilm formation. PMID:24847653

Jolivet-Gougeon, Anne; Bonnaure-Mallet, Martine

2014-03-01

111

Drug resistance reversal activity of anticancer drug loaded solid lipid nanoparticles in multi-drug resistant cancer cells.  

PubMed

The aim of our study was to enhance the cytotoxicity of anticancer drugs by reversing the resistance of multi-drug resistant cancer cells. The cytotoxicities of paclitaxel (PTX) and doxorubicin (DOX), either as single agents or loaded in solid lipid nanoparticles (SLN) by a solvent diffusion method, were examined using drug sensitive cancer cells and drug resistant cells by measuring the drug concentration required for 50% growth inhibition (IC50). Compared to Taxol and DOX·HCl solution, both PTX and DOX loaded in SLN exhibited higher cytotoxicities in human breast tumor drug sensitive MCF-7 and drug resistant MCF-7/ADR cells. The ability of PTX loaded SLN and DOX loaded SLN to reverse the drug resistance of MCF-7 cells compared to MCF-7/ADR cells was 31.0 and 4.3 fold, respectively. Both PTX and DOX loaded SLN showed the same trends of enhanced cytotoxicity against a second wild type/drug resistant human ovarian cancer cell pair SKOV3 and SKOV3-TR30 cells. The reversal powers were 3.8 and 1.9 fold for PTX loaded SLN and DOX loaded SLN, respectively. PMID:23711779

Miao, Jing; Du, Yong-Zhong; Yuan, Hong; Zhang, Xing-Guo; Hu, Fu-Qiang

2013-10-01

112

PARAMETERS OF TREATED STAINLESS STEEL SURFACES IMPORTANT FOR RESISTANCE TO BACTERIAL CONTAMINATION  

EPA Science Inventory

Use of materials that are resistant to bacterial contamination could enhance food safety during processing. Common finishing treatments of stainless steel surfaces used for components of poultry processing equipment were tested for resistance to bacterial attachment. Surface char...

113

Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants.  

PubMed

Control of bacterial diseases has, for many years, been dependent on the use of antibiotics. Due to the high levels of efficacy of antibiotics in the past other disease control options have, to a large extent, been neglected. Mankind is now facing an increasing problem with antibiotic resistance. In an effort to retain some antibiotics for human use, there are moves afoot to limit or even ban the use of antibiotics in animal production. The use of antibiotics as growth promoters have been banned in the European Union and the USA. The potential ban on the use of antibiotics to treat diseases in production animals creates a dilemma for man-suffer significant problem with bacterial infection or suffer from a severe shortage of food! There are other options for the control of bacterial diseases. These include vaccine development, bacteriophage therapy, and improved biosecurity. Vaccine development against bacterial pathogens, particularly opportunistic pathogens, is often very challenging, as in many cases the molecular basis of the virulence is not always clearly understood. This is particularly true for Escherichia coli. Biosecurity (disinfection) has been a highly neglected area in disease control. With the ever-increasing problems with antibiotic resistance-the focus should return to improvements in biosecurity. As with antibiotics, bacteria also have mechanisms for resistance to disinfectants. To ensure that we do not replace one set of problems (increasing antibiotic resistance) with another (increasing resistance to disinfectants) we need to fully understand the modes of action of disinfectants and how the bacteria develop resistance to these disinfectants. Molecular studies have been undertaken to relate the presence of QAC resistance genes in bacteria to their levels of sensitivity to different generations of QAC-based products. The mode of action of QAC on bacteria has been studied using NanoSAM technology, where it was revealed that the QAC causes disruption of the bacterial cell wall and leaking of the cytoplasm out of the cells. Our main focus is on the control of bacterial and viral diseases in the poultry industry in a post-antibiotic era, but the principles remain similar for disease control in any veterinary field as well as in human medicine. PMID:24595606

Bragg, Robert; Jansen, Arina; Coetzee, Marisa; van der Westhuizen, Wouter; Boucher, Charlotte

2014-01-01

114

The Culturable Soil Antibiotic Resistome: A Community of Multi-Drug Resistant Bacteria  

PubMed Central

Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16–23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, blaNDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family.

Walsh, Fiona; Duffy, Brion

2013-01-01

115

The culturable soil antibiotic resistome: a community of multi-drug resistant bacteria.  

PubMed

Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16-23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, bla NDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family. PMID:23776501

Walsh, Fiona; Duffy, Brion

2013-01-01

116

Heavy metals in liquid pig manure in light of bacterial antimicrobial resistance  

SciTech Connect

Heavy metals are regularly found in liquid pig manure, and might interact with bacterial antimicrobial resistance. Concentrations of heavy metals were determined by atomic spectroscopic methods in 305 pig manure samples and were connected to the phenotypic resistance of Escherichia coli (n=613) against 29 antimicrobial drugs. Concentrations of heavy metals (/kg dry matter) were 0.08-5.30 mg cadmium, 1.1-32.0 mg chrome, 22.4-3387.6 mg copper, <2.0-26.7 mg lead, <0.01-0.11 mg mercury, 3.1-97.3 mg nickel and 93.0-8239.0 mg zinc. Associated with the detection of copper and zinc, resistance rates against {beta}-lactams were significantly elevated. By contrast, the presence of mercury was significantly associated with low antimicrobial resistance rates of Escherichia coli against {beta}-lactams, aminoglycosides and other antibiotics. Effects of subinhibitory concentrations of mercury on bacterial resistance against penicillins, cephalosporins, aminoglycosides and doxycycline were also demonstrated in a laboratory trial. Antimicrobial resistance in the porcine microflora might be increased by copper and zinc. By contrast, the occurrence of mercury in the environment might, due to co-toxicity, act counter-selective against antimicrobial resistant strains.

Hoelzel, Christina S., E-mail: Christina.Hoelzel@wzw.tum.de [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany); Mueller, Christa [Institute for Agroecology, Organic Farming and Soil Protection, Bavarian State Research Center for Agriculture (LfL), Lange Point 12, 85354 Freising (Germany)] [Institute for Agroecology, Organic Farming and Soil Protection, Bavarian State Research Center for Agriculture (LfL), Lange Point 12, 85354 Freising (Germany); Harms, Katrin S. [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)] [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany); Mikolajewski, Sabine [Department for Quality Assurance and Analytics, Bavarian State Research Center for Agriculture (LfL), Lange Point 4, 85354 Freising (Germany)] [Department for Quality Assurance and Analytics, Bavarian State Research Center for Agriculture (LfL), Lange Point 4, 85354 Freising (Germany); Schaefer, Stefanie; Schwaiger, Karin; Bauer, Johann [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)] [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)

2012-02-15

117

Drug interactions modulate the potential for evolution of resistance.  

PubMed

Antimicrobial treatments increasingly rely on multidrug combinations, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially on the frequency with which multidrug resistance arises. Yet, it is unknown how this propensity for resistance depends on cross-resistance and on epistatic interactions-ranging from synergy to antagonism-between the drugs. Here, we analyzed how interactions between pairs of drugs affect the spontaneous emergence of resistance in the medically important pathogen Staphylococcus aureus. Resistance is selected for within a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant mutants to grow. Introducing an experimental method for high-throughput colony imaging, we counted resistant colonies arising across a two-dimensional matrix of drug concentrations for each of three drug pairs. Our data show that these different drug combinations have significantly different impacts on the size of the window of drug concentrations where resistance is selected for. We framed these results in a mathematical model in which the frequencies of resistance to single drugs, cross-resistance, and epistasis combine to determine the propensity for multidrug resistance. The theory suggests that drug pairs which interact synergistically, preferred for their immediate efficacy, may in fact favor the future evolution of resistance. This framework reveals the central role of drug epistasis in the evolution of resistance and points to new strategies for combating the emergence of drug-resistant bacteria. PMID:18815368

Michel, Jean-Baptiste; Yeh, Pamela J; Chait, Remy; Moellering, Robert C; Kishony, Roy

2008-09-30

118

Antimicrobial Drug Resistance in Pathogens Causing Nosocomial Infections at a University Hospital in Taiwan, 1981-1999  

Microsoft Academic Search

To determine the distribution and antimicrobial drug resistance in bacterial pathogens causing nosocomial infections, surveillance data on nosocomial infections documented from 1981 to 1999 at National Taiwan Uni- versity Hospital were analyzed. During this period, 35,580 bacterial pathogens causing nosocomial infections were identified. Candida species increased considerably, ranking first by 1999 in the incidence of pathogens causing all nosocomial infections,

Po-Ren Hsueh; Mei-Ling Chen; Chun-Chuan Sun; Wen-Hwei Chen; Hui-Ju Pan; Li-Seh Yang; Shan-Chwen Chang; Shen-Wu Ho; Chin-Yu Lee; Wei-Chuan Hsieh; Kwen-Tay Luh

2002-01-01

119

Differential resistance of drinking water bacterial populations to monochloramine disinfection.  

PubMed

The impact of monochloramine disinfection on the complex bacterial community structure in drinking water systems was investigated using culture-dependent and culture-independent methods. Changes in viable bacterial diversity were monitored using culture-independent methods that distinguish between live and dead cells based on membrane integrity, providing a highly conservative measure of viability. Samples were collected from lab-scale and full-scale drinking water filters exposed to monochloramine for a range of contact times. Culture-independent detection of live cells was based on propidium monoazide (PMA) treatment to selectively remove DNA from membrane-compromised cells. Quantitative PCR (qPCR) and pyrosequencing of 16S rRNA genes was used to quantify the DNA of live bacteria and characterize the bacterial communities, respectively. The inactivation rate determined by the culture-independent PMA-qPCR method (1.5-log removal at 664 mg·min/L) was lower than the inactivation rate measured by the culture-based methods (4-log removal at 66 mg·min/L). Moreover, drastic changes in the live bacterial community structure were detected during monochloramine disinfection using PMA-pyrosequencing, while the community structure appeared to remain stable when pyrosequencing was performed on samples that were not subject to PMA treatment. Genera that increased in relative abundance during monochloramine treatment include Legionella, Escherichia, and Geobacter in the lab-scale system and Mycobacterium, Sphingomonas, and Coxiella in the full-scale system. These results demonstrate that bacterial populations in drinking water exhibit differential resistance to monochloramine, and that the disinfection process selects for resistant bacterial populations. PMID:24625288

Chiao, Tzu-Hsin; Clancy, Tara M; Pinto, Ameet; Xi, Chuanwu; Raskin, Lutgarde

2014-04-01

120

DDTRP: Database of Drug Targets for Resistant Pathogens  

PubMed Central

Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called ‘Database of Drug Targets for Resistant Pathogens’ (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP.

Sundaramurthi, Jagadish Chandrabose; Ramanandan, Prabhakaran; Brindha, Sridharan; Subhasree, Chelladurai Ramarathnam; Prasad, Abhimanyu; Kumaraswami, Vasanthapuram; Hanna, Luke Elizabeth

2011-01-01

121

Development of bacterially resistant polyurethane for coating medical devices.  

PubMed

Polyurethanes have been widely used in medicine for coating and packaging implantable and other medical devices. Polyether-urethanes, in particular, have superior mechanical properties and are biocompatible, but in common with other medical materials they are susceptible to microbial film formation. In this study, polyether-urethane was end-capped with silver lactate and silver sulfadiazine functional groups to produce a bacterially resistant polymer without sacrificing the useful mechanical properties of the polyether-polyurethane. The silver ions were covalently incorporated into the polymer during chain extension of the prepolymer. The functionalized polymers were structurally characterized by light scattering, electron microscopy, NMR, FTIR and Raman spectroscopy. Mechanical properties, hydrophilicity, in vitro stability and antibacterial action of polymers were also investigated. Results indicate that both silver salts were successfully incorporated into the polymer structure without significant effect on mechanical properties, whilst conferring acceptable bacterial resistance. PMID:22287552

Roohpour, Nima; Moshaverinia, Alireza; Wasikiewicz, Jaroslaw M; Paul, Deepen; Wilks, Mark; Millar, Michael; Vadgama, Pankaj

2012-02-01

122

Multi-drug resistant Ewingella americana.  

PubMed

We report a case of pneumonia due to multi-drug resistant Ewingella americana in a young patient admitted in the Intensive Care Unit of Hera General Hospital, Makkah, Saudi Arabia with severe head injury in a road traffic accident. He was an Indonesian pilgrim who had traveled to the Kingdom of Saudi Arabia to perform Hajj in December 2007. Ewingella americana was identified to be the pathogen of pneumonia with clinical signs and symptoms along with positive radiological findings. PMID:18626541

Bukhari, Syed Z; Hussain, Waleed M; Fatani, Mohammad I; Ashshi, Ahmad M

2008-07-01

123

Current Management of HBV Antiviral Drug Resistance  

Microsoft Academic Search

Long-term administration of oral anti-hepatitis B virus (HBV) nucleoside or nucleotide analogues therapy (NUC) is the first-line\\u000a treatment option for most patients with chronic hepatitis B infection. Although NUC rapidly inhibits HBV replication in most\\u000a patients, in the long term, this therapeutic regimen is challenged by the emergence of drug-resistant mutant virions, ultimately\\u000a leading to treatment failure and liver disease

Pietro Lampertico; Mauro Viganò; Massimo Colombo

2011-01-01

124

Overcoming drug resistance in multi-drug resistant cancers and microorganisms  

PubMed Central

Resistance development against multiple drugs is a common feature among many pathogens—including bacteria such as Pseudomonas aeruginosa, viruses, and parasites—and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their large size and are often released only on contact with the perceived competitor. Thus, multi-domain proteins are missed during traditional methods of looking for growth zone inhibition of susceptible bacteria as demonstrated by antibiotics, but may represent the weapons of the future in the fights against both drug-resistant cancers and pathogens such as P. aeruginosa.

Avner, Benjamin S.; Fialho, Arsenio M.; Chakrabarty, Ananda M.

2012-01-01

125

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.  

PubMed

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB. PMID:23060633

Migliori, Giovanni Battista; Sotgiu, Giovanni; Gandhi, Neel R; Falzon, Dennis; DeRiemer, Kathryn; Centis, Rosella; Hollm-Delgado, Maria-Graciela; Palmero, Domingo; Pérez-Guzmán, Carlos; Vargas, Mario H; D'Ambrosio, Lia; Spanevello, Antonio; Bauer, Melissa; Chan, Edward D; Schaaf, H Simon; Keshavjee, Salmaan; Holtz, Timothy H; Menzies, Dick

2013-07-01

126

HIV-1 Reverse Transcriptase and Antiviral Drug Resistance. Part 2  

PubMed Central

Structures of RT and its complexes combined with biochemical and clinical data help in illuminating the molecular mechanisms of different drug-resistance mutations. The NRTI drugs that are used in combinations have different primary mutation sites. RT mutations that confer resistance to one drug can be hypersensitive to another RT drug. Structure of an RT-DNA-nevirapine complex revealed how NNRTI binding forbids RT from forming a polymerase competent complex. Collective knowledge about various mechanisms of drug resistance by RT has broader implications for understanding and targeting drug resistance in general.

Das, Kalyan; Arnold, Eddy

2014-01-01

127

Chemical Communication of Antibiotic Resistance by a Highly Resistant Subpopulation of Bacterial Cells  

PubMed Central

The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species.

El-Halfawy, Omar M.; Valvano, Miguel A.

2013-01-01

128

Exploiting nanotechnology to overcome tumor drug resistance: Challenges and opportunities.  

PubMed

Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. PMID:24036273

Kirtane, Ameya R; Kalscheuer, Stephen M; Panyam, Jayanth

2013-11-01

129

Breast Cancer-Targeted Nuclear Drug Delivery Overcoming Drug Resistance for Breast Cancer Chemotherapy.  

National Technical Information Service (NTIS)

Breast cancer cells drug resistance mechanisms are the major factors to reduce the cytotoxic effects and even the chemotherapeutic efficacy of anti- cancer drugs. Nanocarriers for drug delivery based on the EPR effect targeted to cell cytosol subject to v...

M. Radosz W. J. Murdoch Y. Shen

2013-01-01

130

Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates.  

PubMed

Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2'-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB-TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes. PMID:12959639

Malléa, Monique; Mahamoud, Abdallah; Chevalier, Jacqueline; Alibert-Franco, Sandrine; Brouant, Pierre; Barbe, Jacques; Pagès, Jean-Marie

2003-12-15

131

Personalized HIV therapy to control drug resistance.  

PubMed

The therapy of HIV patients is characterized by both the high genomic diversity of the virus population harbored by the patient and a substantial volume of therapy options. The virus population is unique for each patient and time point. The large number of therapy options makes it difficult to select an optimal or near optimal therapy, especially with therapy-experienced patients. In the past decade, computer-based support for therapy selection, which assesses the level of viral resistance against drugs has become a mainstay for HIV patients. We discuss the properties of available systems and the perspectives of the field. PMID:24847654

Lengauer, Thomas; Pfeifer, Nico; Kaiser, Rolf

2014-03-01

132

Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin.  

PubMed

Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) of sensitive strains of Escherichia coli. The aim of this study was to investigate the effect of proanthocyanidin on adherence of uropathogenic multi-drug resistant E. coli to uroepithelial cells, which has not yet been investigated so far. Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. Purity and structural assignment of proanthocyanidin was assessed using high performance liquid chromatography and (13)C nuclear magnetic resonance spectroscopy, respectively. Subsequently, its affect on multi-drug resistant bacteria as well as quantification of anti-adherence bioactivity on human vaginal and bladder epithelial cells was appraised. Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 µg/ml with significant bacteriuria. Probable proanthocyanidin through A-type linkages either combines to P-fimbriae of bacterial cells or modifies the structural entity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. The proanthocyanidin exhibited anti-adherence property with multi-drug resistant strains of uropathogenic P-fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells. PMID:21688109

Gupta, Ashish; Dwivedi, Mayank; Mahdi, Abbas Ali; Nagana Gowda, G A; Khetrapal, Chunni Lal; Bhandari, Mahendra

2012-04-01

133

Drug resistance in Indian visceral leishmaniasis.  

PubMed

Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost. PMID:11703838

Sundar, S

2001-11-01

134

Bacterial pathogens.  

PubMed

Bacterial infections are frequent complications among patients treated for cancer. The type, severity, and treatment of bacterial infections vary and depend upon the specific malignancy, associated chemotherapies, and transplantation. This chapter discusses commonly encountered bacterial pathogens as well as Nocardia and mycobacteria in patients with cancer and addresses the clinical syndromes and management. Drug-resistant bacteria are becoming an increasingly recognized problem in patients with cancer. Antimicrobial resistance in select gram-positive and gram-negative bacteria are discussed along with the mechanisms of resistance and recommended therapies. PMID:24706222

Wilson, John W

2014-01-01

135

Aberrant DNA methylation and drug resistance of tumor cells.  

PubMed

Drug resistance is one of the major obstacles limiting the success of cancer chemotherapy. The underlying mechanisms are complex. In recent years, the contribution of epigenetic changes to drug resistance has drawn increasing attention. DNA methylation is an important epigenetic modification that plays an important role in regulating gene expression and maintaining genome stability. Primary or acquired resistance of tumor cells is usually accompanied by aberrant DNA methylation. Accumulating evidence has shown that aberrant DNA methylation is involved in drug resistance of tumor cells. In this review, we briefly review the relationship between DNA methylation and drug resistance of tumor cells as well as the underlying mechanisms. PMID:24846990

Xinxin, Si; Yujie, Sun

2014-05-20

136

Evaluation of Idaho's DARE "Drug Abuse Resistance Education" Projects.  

ERIC Educational Resources Information Center

The DARE (Drug Abuse Resistance Education) program teaches students decision-making skills, shows them how to resist peer pressure to experiment with drugs and alcohol, and provides positive alternatives to drug use. This report looks at one state's DARE programs. Included are an overview of the implementation process, a program appraisal with…

Silva, Roberta K.

137

Evaluation of Idaho's DARE "Drug Abuse Resistance Education Projects."  

ERIC Educational Resources Information Center

The goal of DARE (Drug Abuse Resistance Education) is not to completely eliminate the drug and alcohol problems of society. It is a proactive prevention program designed to equip youth (focusing on elementary school) with skills for resisting peer pressure to experiment with drugs, and to manage anger without resorting to violence or the use of…

Silva, Roberta K.

138

Bacteriocin from Bacillus subtilis as a novel drug against diabetic foot ulcer bacterial pathogens  

PubMed Central

Objective To isolate and identify Bacillus subtilis (B. subtilis) from soil and to characterize and partially purify the bacteriocin. To evaluate the antimicrobial activity against four diabetic foot ulcer bacterial pathogens. Methods Genotypic identification was done based on Bergey's manual of systemic bacteriology. Antimicrobial susceptibility test was done by Kirby-Bauer disc diffusion method. Colonies were identified by colony morphology and biochemical characterization and also compared with MTCC 121 strain. Further identification was done by 16S rRNA sequencing. Inhibitory activities of partially purified bacteriocin on all the DFU isolates were done by agar well diffusion method. The strain was identified to produce bacteriocin by stab overlay assay. Bacteriocin was extracted by organic solvent extraction using chloroform, further purified by HPLC and physical, and chemical characterization was performed. Results The four isolates showed high level of resistance to amoxyclav and sensitivity to ciprofloxacin. HPLC purification revealed that the extracts are bacteriocin. The phylogenetic tree analysis results showed that the isolate was 99% related to B. subtilis BSF01. The results reveled activity to all the four isolates and high level of activity was seen in case of Klebsiella sp. Conclusions Partially purified bacteriocin was found to have antimicrobial activity against the four diabetic foot ulcer bacterial pathogens, which can thus be applied as a better drug molecule on further studies. The strain B. subtilis are found to be safe for use and these antimicrobial peptides can be used as an antimicrobial in humans to treat DFU bacterial pathogens.

Joseph, Baby; Dhas, Berlina; Hena, Vimalin; Raj, Justin

2013-01-01

139

Heat stable antimicrobial activity of Burkholderia gladioli OR1 against clinical drug resistant isolates  

PubMed Central

Background & objectives: Drug resistant microbes are a serious challenge to human health. During the search for novel antibiotics/inhibitors from the agricultural soil, a bacterial colony was found to inhibit the growth of clinical isolates including Staphylococcus (resistant to amikacin, ciprofloxacin, clindamycin, clinafloxacin, erythromycin, gentamicin and methicillin) and Candida (resistant to fluconazole and itraconazole). The culture was identified as Burkholderia gladioli and produced at least five different antimicrobial compounds which were highly stable at high temperature (121°C) and in the broad pH range (3.0-11.0). We report here the antimicrobial activity of B. gladioli against drug resistant bacterial pathogens. Methods: The bacterial culture was identified using morphological, biochemical and 16S rRNA gene sequencing techniques. The antimicrobial activity of the identified organism against a range of microbial pathogens was checked by Kirby-Bauer's disc diffusion method. The antimicrobial compounds in the cell free supernatant were chloroform-extracted and separated by thin layer chromatography (TLC). Results: B. gladioli OR1 exhibited broad spectrum antimicrobial activity against drug resistant clinical isolates belonging to various genera of bacteria (Staphylococcus, Enterobacter, Enterococcus, Acinetobacter and Citrobacter) and a fungus (Candida). Based on TLC profile and bioautography studies, the chloroform extract of B. gladioli OR1 consisted of at least three anti-staphylococcal and two anti-Candida metabolites. The antimicrobial activity was heat stable (121°C/20 min) as well as pH stable (3.0-11.0). Interpretation & conclusions: The bacterial soil isolate, B. gladioli OR1 possessed the ability to kill various drug resistant bacteria and a fungus. This organism produced many antimicrobial metabolites which might have the potential to be used as antibiotics in future.

Bharti, Pratibha; Anand, Vivek; Chander, Jagdish; Singh, Inder Pal; Singh, Tej Vir; Tewari, Rupinder

2012-01-01

140

Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug resistant tuberculosis  

PubMed Central

A critical question in tuberculosis control is why some strains of Mycobacterium tuberculosis are preferentially associated with multiple drug resistances. We demonstrate that M. tuberculosis strains from Lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from Lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug susceptible Lineage 2 strain will harbor multidrug resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug resistant tuberculosis should target bacterial as well as treatment-related risk factors.

Ford, Christopher B.; Shah, Rupal R.; Maeda, Midori Kato; Gagneux, Sebastien; Murray, Megan B.; Cohen, Ted; Johnston, James C.; Gardy, Jennifer; Lipsitch, Marc; Fortune, Sarah M.

2013-01-01

141

Gene Expression and Evolution of Antifungal Drug Resistance  

Microsoft Academic Search

Permanent changes in gene expression result from certain forms of antifungal resistance. In this study, we asked whether any changes in gene expression are required for the evolution of a drug-resistant phenotype in populations. We examined the changes in gene expression resulting from the evolution of resistance in exper- imental populations of the yeast Saccharomyces cerevisiae with two antifungal drugs,

James B. Anderson; Caroline Sirjusingh; Nazia Syed; Shantelle Lafayette

2009-01-01

142

Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance  

PubMed Central

Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms.

Fernandez, Lucia

2012-01-01

143

Newer systems for bacterial resistances to toxic heavy metals.  

PubMed

Bacterial plasmids contain specific genes for resistances to toxic heavy metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, and Zn2+. Recent progress with plasmid copper-resistance systems in Escherichia coli and Pseudomonas syringae show a system of four gene products, an inner membrane protein (PcoD), an outer membrane protein (PcoB), and two periplasmic Cu(2+)-binding proteins (PcoA and PcoC). Synthesis of this system is governed by two regulatory proteins (the membrane sensor PcoS and the soluble responder PcoR, probably a DNA-binding protein), homologous to other bacterial two-component regulatory systems. Chromosomally encoded Cu2+ P-type ATPases have recently been recognized in Enterococcus hirae and these are closely homologous to the bacterial cadmium efflux ATPase and the human copper-deficiency disease Menkes gene product. The Cd(2+)-efflux ATPase of gram-positive bacteria is a large P-type ATPase, homologous to the muscle Ca2+ ATPase and the Na+/K+ ATPases of animals. The arsenic-resistance system of gram-negative bacteria functions as an oxyanion efflux ATPase for arsenite and presumably antimonite. However, the structure of the arsenic ATPase is fundamentally different from that of P-type ATPases. The absence of the arsA gene (for the ATPase subunit) in gram-positive bacteria raises questions of energy-coupling for arsenite efflux. The ArsC protein product of the arsenic-resistance operons of both gram-positive and gram-negative bacteria is an intracellular enzyme that reduces arsenate [As(V)] to arsenite [As(III)], the substrate for the transport pump. Newly studied cation efflux systems for Cd2+, Zn2+, and Co2+ (Czc) or Co2+ and Ni2+ resistance (Cnr) lack ATPase motifs in their predicted polypeptide sequences. Therefore, not all plasmid-resistance systems that function through toxic ion efflux are ATPases. The first well-defined bacterial metallothionein was found in the cyanobacterium Synechococcus. Bacterial metallothionein is encoded by the smtA gene and contains 56 amino acids, including nine cysteine residues (fewer than animal metallothioneins). The synthesis of Synechococcus metallothionein is regulated by a repressor protein, the product of the adjacent but separately transcribed smtB gene. Regulation of metallothionein synthesis occurs at different levels; quickly by derepression of repressor activity, or over a longer time by deletion of the repressor gene at fixed positions and by amplification of the metallothionein DNA region leading to multiple copies of the gene. PMID:7843081

Silver, S; Ji, G

1994-09-01

144

Structure and function of efflux pumps that confer resistance to drugs.  

PubMed Central

Resistance to therapeutic drugs encompasses a diverse range of biological systems, which all have a human impact. From the relative simplicity of bacterial cells, fungi and protozoa to the complexity of human cancer cells, resistance has become problematic. Stated in its simplest terms, drug resistance decreases the chance of providing successful treatment against a plethora of diseases. Worryingly, it is a problem that is increasing, and consequently there is a pressing need to develop new and effective classes of drugs. This has provided a powerful stimulus in promoting research on drug resistance and, ultimately, it is hoped that this research will provide novel approaches that will allow the deliberate circumvention of well understood resistance mechanisms. A major mechanism of resistance in both microbes and cancer cells is the membrane protein-catalysed extrusion of drugs from the cell. Resistant cells exploit proton-driven antiporters and/or ATP-driven ABC (ATP-binding cassette) transporters to extrude cytotoxic drugs that usually enter the cell by passive diffusion. Although some of these drug efflux pumps transport specific substrates, many are transporters of multiple substrates. These multidrug pumps can often transport a variety of structurally unrelated hydrophobic compounds, ranging from dyes to lipids. If we are to nullify the effects of efflux-mediated drug resistance, we must first of all understand how these efflux pumps can accommodate a diverse range of compounds and, secondly, how conformational changes in these proteins are coupled to substrate translocation. These are key questions that must be addressed. In this review we report on the advances that have been made in understanding the structure and function of drug efflux pumps.

Borges-Walmsley, M Ines; McKeegan, Kenneth S; Walmsley, Adrian R

2003-01-01

145

Bacterial enterotoxins are associated with resistance to colon cancer  

PubMed Central

One half million patients suffer from colorectal cancer in industrialized nations, yet this disease exhibits a low incidence in under-developed countries. This geographic imbalance suggests an environmental contribution to the resistance of endemic populations to intestinal neoplasia. A common epidemiological characteristic of these colon cancer-spared regions is the prevalence of enterotoxigenic bacteria associated with diarrheal disease. Here, a bacterial heat-stable enterotoxin was demonstrated to suppress colon cancer cell proliferation by a guanylyl cyclase C-mediated signaling cascade. The heat-stable enterotoxin suppressed proliferation by increasing intracellular cGMP, an effect mimicked by the cell-permeant analog 8-br-cGMP. The antiproliferative effects of the enterotoxin and 8-br-cGMP were reversed by L-cis-diltiazem, a cyclic nucleotide-gated channel inhibitor, as well as by removal of extracellular Ca2+, or chelation of intracellular Ca2+. In fact, both the enterotoxin and 8-br-cGMP induced an L-cis-diltiazem-sensitive conductance, promoting Ca2+ influx and inhibition of DNA synthesis in colon cancer cells. Induction of this previously unrecognized antiproliferative signaling pathway by bacterial enterotoxin could contribute to the resistance of endemic populations to intestinal neoplasia, and offers a paradigm for targeted prevention and therapy of primary and metastatic colorectal cancer.

Pitari, G. M.; Zingman, L. V.; Hodgson, D. M.; Alekseev, A. E.; Kazerounian, S.; Bienengraeber, M.; Hajnoczky, G.; Terzic, A.; Waldman, S. A.

2003-01-01

146

Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells  

NASA Astrophysics Data System (ADS)

Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anticancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a nonuniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combating the emergence of resistance.

Greulich, Philip; Waclaw, Bart?omiej; Allen, Rosalind J.

2012-08-01

147

Resistance to antimalarial drugs: molecular, pharmacological and clinical considerations  

PubMed Central

One of the greatest obstacles to the control of malaria has been the spread of resistance to drugs used on a large scale. This review provides an update of the current understanding of the molecular basis for antimalarial drug resistance. Parasite intrinsic resistance is just one component that determines the in vivo efficacy of a drug. Human immune responses and pharmacological properties play important roles in determining the clinical outcome of treatment. The emergence and spread of resistance also results from an interplay of these factors. Current efforts to characterize and deter resistance to new combination therapy are also discussed.

Travassos, Mark A.; Laufer, Miriam K.

2009-01-01

148

Mycobacterium tuberculosis interactome analysis unravels potential pathways to drug resistance  

PubMed Central

Background Emergence of drug resistant varieties of tuberculosis is posing a major threat to global tuberculosis eradication programmes. Although several approaches have been explored to counter resistance, there has been limited success due to a lack of understanding of how resistance emerges in bacteria upon drug treatment. A systems level analysis of the proteins involved is essential to gain insights into the routes required for emergence of drug resistance. Results We derive a genome-scale protein-protein interaction network for Mycobacterium tuberculosis H37Rv from the STRING database, with proteins as nodes and interactions as edges. A set of proteins involved in both intrinsic and extrinsic drug resistance mechanisms are identified from literature. We then compute shortest paths from different drug targets to the set of resistance proteins in the protein-protein interactome, to derive a sub-network relevant to study emergence of drug resistance. The shortest paths are then scored and ranked based on a new scheme that considers (a) drug-induced gene upregulation data, from microarray experiments reported in literature, for the individual nodes and (b) edge-hubness, a network parameter which signifies centrality of a given edge in the network. High-scoring paths identified from this analysis indicate most plausible pathways for the emergence of drug resistance. Different targets appear to have different propensities for four drug resistance mechanisms. A new concept of 'co-targets' has been proposed to counter drug resistance, co-targets being defined as protein(s) that need to be simultaneously inhibited along with the intended target(s), to check emergence of resistance to a given drug. Conclusion The study leads to the identification of possible pathways for drug resistance, providing novel insights into the problem of resistance. Knowledge of important proteins in such pathways enables identification of appropriate 'co-targets', best examples being RecA, Rv0823c, Rv0892 and DnaE1, for drugs targeting the mycolic acid pathway. Insights obtained about the propensity of a drug to trigger resistance will be useful both for more careful identification of drug targets as well as to identify target-co-target pairs, both implementable in early stages of drug discovery itself. This approach is also inherently generic, likely to significantly impact drug discovery.

Raman, Karthik; Chandra, Nagasuma

2008-01-01

149

Klebsiella pneumoniae Antimicrobial Drug Resistance, United States, 1998-2010  

PubMed Central

We studied antimicrobial-resistant Klebsiella pneumoniae for 1998–2010 by using data from The Surveillance Network. Susceptibility results (n = 3,132,354) demonstrated significant increases in resistance to all antimicrobial drugs studied, except tetracycline. Cross-resistance among carbapenem-resistant K. pneumoniae was lower for tetracycline and amikacin.

Sanchez, Guillermo V.; Master, Ronald N.; Clark, Richard B.; Fyyaz, Madiha; Duvvuri, Padmaraj; Ekta, Gupta

2013-01-01

150

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles  

PubMed Central

Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug–gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development.

Rickardson, L; Fryknas, M; Dhar, S; Lovborg, H; Gullbo, J; Rydaker, M; Nygren, P; Gustafsson, M G; Larsson, R; Isaksson, A

2005-01-01

151

Beijing/W Genotype Mycobacterium tuberculosis and Drug Resistance  

PubMed Central

Beijing/W genotype Mycobacterium tuberculosis is widespread, may be increasing, and may have a predilection for drug resistance. Individual-level data on >29,000 patients from 49 studies in 35 countries were combined to assess the Beijing genotype’s prevalence worldwide, trends over time and with age, and associations with drug resistance. We found 4 patterns for Beijing/W genotype tuberculosis (TB): 1) endemic, not associated with drug resistance (high level in most of East Asia, lower level in parts of the United States); 2) epidemic, associated with drug resistance (high level in Cuba, the former Soviet Union, Vietnam, and South Africa, lower level in parts of Western Europe); 3) epidemic but drug sensitive (Malawi, Argentina); and 4) very low level or absent (parts of Europe, Africa). This study confirms that Beijing/W genotype TB is an emerging pathogen in several areas and a predominant endemic strain in others; it is frequently associated with drug resistance.

2006-01-01

152

New approaches for understanding mechanisms of drug resistance in schistosomes  

PubMed Central

SUMMARY Schistosomes are parasitic flatworms that cause schistosomiasis, a neglected tropical disease that affects hundreds of millions worldwide. Treatment and control of schistosomiasis relies almost entirely on the single drug praziquantel (PZQ), making the prospect of emerging drug resistance particularly worrisome. This review will survey reports of PZQ (and other drug) resistance in schistosomes and other platyhelminths, and explore mechanisms by which drug resistance might develop. Newer genomic and post-genomic strategies that offer the promise of better understanding of how drug resistance might arise in these organisms will be discussed. These approaches could also lead to insights into the mode of action of these drugs and potentially provide markers for monitoring the emergence of resistance.

GREENBERG, ROBERT M.

2013-01-01

153

Engaging Resistant Adolescents in Drug Abuse Treatment  

PubMed Central

In the first phase of a two-part treatment development study, families with a treatment-resistant, drug-abusing adolescent (n=42) were offered 12 sessions of Community Reinforcement and Family Training (CRAFT). This parent-focused intervention was designed to help parents facilitate their adolescents' entry in treatment and support adolescents' subsequent behavior change and to improve parent and family functioning. In the second phase, successfully engaged adolescents (n=30) were offered 12 sessions of a multicomponent individual cognitive behavioral therapy (CBT) targeting substance use and related problem behaviors. Measures were collected at pre- and post-treatment for parents and adolescents, with an additional follow-up assessment for parents at 3-months post-treatment. Parents in the CRAFT intervention experienced a significant reduction in negative symptoms and 71% of parents were successful in engaging their resistant youth in treatment. The CBT intervention for the engaged youth was associated with a statistically significant, but not clinically significant, reduction in marijuana use.

Waldron, Holly Barrett; Kern-Jones, Sheryl; Turner, Charles W.; Peterson, Thomas R.; Ozechowski, Timothy J.

2007-01-01

154

Drug resistance in brain diseases and the role of drug efflux transporters  

Microsoft Academic Search

Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders.

Heidrun Potschka; Wolfgang Löscher

2005-01-01

155

Significance of antibiotics resistance amongst clinical bacterial isolates in Lagos.  

PubMed

In vitro susceptibility of several strains of six different species of clinical facultative pathogens involved in nosocomial infections in our hospital was investigated by a series of disc diffusion, broth dilution and Chequerboard titration testing. With disc diffusion method all the test strains, except Streptococcus pyogenes, were resistant to penicillin. 46% of the Klebsiella aerogenes and 73% of the Pseudomonas strains were generally resistant to cefotaxime. The minimum inhibitory concentration (MIC) of the antibiotics correlated well with the results of the disc diffusion tests. Synergistic effects were demonstrated by various combinations of gentamicin, ampicillin, clindamycin, colistin, cefoxitin, and ceftriazone against resistant strains of S. aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella aerogenes. Against S. aureus the effect of gentamicin/clindamycin demonstrated indifference. The need for stringent caution is strongly advocated in the selection of combination therapy for serious infections caused by some hospital bacterial strains particularly in acute care units. The clinical microbiologist should be consulted at all times during the process of selection of an appropriate combined therapy for expert guidance. PMID:7803333

Rotimi, V O; Onyenefa, P I; Banjo, T O; Ogunsola, F T; Adenuga, A

1994-01-01

156

Death by design: where curcumin sensitizes drug-resistant tumours.  

PubMed

Chemotherapy remains the core of anticancer treatment. However, despite the tremendous strides made in the development of targeted anticancer therapies, emergence of resistance to chemotherapeutic drugs is still a major obstacle in the successful management of resistant tumours. Therefore, profound investigation into the in-depth molecular mechanisms of drug resistance is essential and may hopefully translate into effective therapies that can flip the switch from drug resistance to susceptibility. Mechanistically, resistance phenomena may be explained by (i) overexpression of drug efflux pumps, (ii) enhanced drug detoxification, (iii) rapid DNA repair efficiency, (iv) defects in apoptosis regulation, and (v) active cell survival signals. Several adverse effects associated with multidrug resistance and the need for safe multi-targeted anticancer drugs instigated the use of the phytochemical, curcumin, the yellow pigment of the spice turmeric, which has pleotropic activities. We performed a structured literature review using PubMed and Medline searches with secondary review of cited publications, identifying studies on the role of curcumin in conquering drug resistance in cancer. This review describes how curcumin sensitizes cancer cells through regulation of multiple multidrug resistance pathways, thus employing one drug for multiple targets. Curcumin helps the cancer cells to regain their 'forgotten' apoptosis, modulates drug-target interaction at different levels, restrains survival pathways when their proteins are overexpressed, and finds an alternate way to carry forward the process of sensitization of different resistant tumours. Additionally, the review dissects the role of curcumin, if any, in targeting the major culprit of drug resistance, cancer stem cells (CSC), thereby circumventing resistance. Taken together, this review strongly suggests that curcumin is a promising chemosensitizing agent and that the unique properties of curcumin may be exploited for successful management of resistant tumours. PMID:22753715

Saha, Shilpi; Adhikary, Arghya; Bhattacharyya, Pushpak; DAS, Tanya; Sa, Gaurisankar

2012-07-01

157

Pyramiding of bacterial blight resistance genes in rice: marker-assisted selection using RFLP and PCR  

Microsoft Academic Search

DNA marker-assisted selection was used to pyramid four bacterial blight resistance genes, Xa-4, xa-5, xa-13 and Xa-21. Breeding lines with two, three and four resistance genes were developed and tested for resistance to the bacterial blight\\u000a pathogen (Xanthomonas oryzae pv. oryzae). The pyramid lines showed a wider spectrum and a higher level of resistance than lines with only a single

N. Huang; E. R. Angeles; J. Domingo; G. Magpantay; S. Singh; G. Zhang; N. Kumaravadivel; J. Bennett; G. S. Khush

1997-01-01

158

The Drug Resistance Strategies Project as Translational Research  

ERIC Educational Resources Information Center

This paper tells the story of the multi-layered translational process of the Drug Resistance Strategies Project. The Drug Resistance Strategies Project provides an exemplar of translational scholarship, translating adolescent narratives about their substance use experiences into an efficacious, substance abuse prevention middle school curriculum.…

Hecht, Michael L.; Miller-Day, Michelle

2007-01-01

159

Hsp90 Governs Dispersion and Drug Resistance of Fungal Biofilms  

Microsoft Academic Search

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We

Nicole Robbins; Priya Uppuluri; Jeniel Nett; Ranjith Rajendran; Gordon Ramage; Jose L. Lopez-Ribot; David Andes; Leah E. Cowen

2011-01-01

160

The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance.  

PubMed

Chemotherapy in cancer patients is still not satisfactory because of drug resistance. The main mechanism of drug resistance results from the ability of cancer cells to actively expel therapeutic agents via transport proteins of the ABC family. ABCB1 and ABCG2 are the two main proteins responsible for drug resistance in cancers. Recent investigations indicate that aldehyde dehydrogenase (ALDH) can also be involved in drug resistance. Expression of the ABC transporters and ALDH enzymes is observed in normal stem cells, cancer stem cells and drug resistant cancers. Current chemotherapy regimens remove the bulk of the tumour but are usually not effective against cancer stem cells (CSCs) expressing ALDH. As a result, the number of ALDH positive drug resistant CSCs increases after chemotherapy. This indicates that therapies targeting drug resistant CSCs should be developed. A number of therapies targeting CSCs are currently under investigation. These therapies include differentiation therapy using different retinoic acids (RA) as simple agents or in combination with DNA methyltransferase inhibitors (DNMTi) and/or histone deacetylase inhibitors (HDACi). Therapies that target cancer stem cell signaling pathways are also under investigation. A number of natural compounds are effective against cancer stem cells and lead to decreasing numbers of ALDH positive cells and downregulation of the ABC proteins. Combinations of differentiation therapies or therapies targeting CSC signaling pathways with classical cytostatics seem promising. This review discusses the role of ALDH and ABC proteins in the development of drug resistance in cancer and current therapies designed to target CSCs. PMID:23721823

Januchowski, Rados?aw; Wojtowicz, Karolina; Zabel, Maciej

2013-09-01

161

The medicinal chemistry of multidrug resistance (MDR) reversing drugs  

Microsoft Academic Search

Multidrug resistance (MDR) is a kind of resistance of cancer cells to multiple classes of chemotherapic drugs that can be structurally and mechanistically unrelated. Classical MDR regards altered membrane transport that results in lower cell concentrations of cytotoxic drug and is related to the over expression of a variety of proteins that act as ATP-dependent extrusion pumps. P-glycoprotein (Pgp) and

E. Teodori; S. Dei; S. Scapecchi; F. Gualtieri

2002-01-01

162

Standardization of antituberculosis drug resistance surveillance in Europe  

Microsoft Academic Search

ABSTRACT: Surveillance of antituberculosis drug,resistance is an essential tool for evaluating,the,quality,of,tuberculosis,control,programmes.,Consensus-based recommendations,on uniform,reporting,of antituberculosis drug,resistance surveil- lance data in Europe have been developed,by a Working,Group of the World Health Organization,(WHO) and,the International Union Against Tuberculosis and,Lung Disease (IUATLD). Laboratories should use standardized,methods,for testing drug susceptibility with a quality assurance,programme,including national and international proficiency test- ing. The proportion of drug resistance,

V. Schwœbel; Ml. Moro; F. Drobniewski; S. e. Hoffner; M. c. Raviglione; H. l. Rieder; Lambregts-van Weezenbeek

163

The de novo selection of drug-resistant malaria parasites.  

PubMed Central

Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired from others, and not by selecting resistance de novo. The de novo emergence of resistance can be prevented by use of antimalarial combinations. Artemisinin derivative combinations are particularly effective. Ensuring adequate treatment of the relatively few heavily infected patients would slow the emergence of resistance.

White, N J; Pongtavornpinyo, W

2003-01-01

164

DRUG RESISTANCE OF ENTERIC BACTERIA IV.  

PubMed Central

Kondo, Eiko (Gunma University, Maebashi, Japan), and Susumu Mitsuhashi. Drug resistance of enteric bacteria. IV. Active transducing phage P1 CM produced by the combination of R factor with phage P1. J. Bacteriol. 88:1266–1276. 1964.—During an investigation of the transduction of R factors with phage P1, a phage lysate capable of transducing the character of chloramphenicol resistance (CMr) in extremely high frequency was obtained. The transduction of the CMr character with the lysate was consistently accompanied by lysogenization with the phage used for transduction. This lysate exhibits no beneficial effect with normal P1, and no effect is produced by decreasing the multiplicity of infection. A single infection with the phage allows the formation of plaques as well as CMr lysogenic cells at the center of the plaque. Both the transducing and plaque-forming activities of the lysate were lost by neutralization with anti-P1 phage serum, and its absorption to the host bacteria was enhanced by the addition of Ca++. Thus, it was concluded that a derivative of P1 phage (P1 CM) was isolated which had not only the ability to transduce the CMr character but also the capacity to form plaques; i.e., the CMr gene of R factor is specifically associated with the genome of phage P1. No detectable differences were noted between P1 CM and normal P1 phage in density-gradient analyses in CsCl, in stability of lysogenization, in ability to transduce chromosomal markers, and in the mode of induction from lysogenic cells by ultraviolet irradiation. The instance of transduction of the CMr character described here may also be considered as an example of lysogenic conversion, in the sense that the alteration in CMr character is inseparable from lysogenicity.

Kondo, Eiko; Mitsuhashi, Susumu

1964-01-01

165

Mechanisms and insights into drug resistance in cancer  

PubMed Central

Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.

Zahreddine, Hiba; Borden, Katherine L. B.

2013-01-01

166

Antimalarial drugs clear resistant parasites from partially immune hosts.  

PubMed

Circumstantial evidence in human malaria suggests that elimination of parasites by drug treatment meets higher success rates in individuals having some background immunity. In this study, using the rodent malaria model Plasmodium chabaudi, we show that drug-resistant parasites can be cleared by drugs when the host is partially immune. PMID:11557487

Cravo, P; Culleton, R; Hunt, P; Walliker, D; Mackinnon, M J

2001-10-01

167

Antimalarial Drugs Clear Resistant Parasites from Partially Immune Hosts  

Microsoft Academic Search

Circumstantial evidence in human malaria suggests that elimination of parasites by drug treatment meets higher success rates in individuals having some background immunity. In this study, using the rodent malaria model Plasmodium chabaudi, we show that drug-resistant parasites can be cleared by drugs when the host is partially immune. Malaria due to Plasmodium falciparum is still a major cause of

PEDRO CRAVO; RICHARD CULLETON; PAUL HUNT; DAVID WALLIKER; MARGARET J. MACKINNON

2001-01-01

168

Transport Mechanisms of Resistance to Drugs and Toxic Metals  

Microsoft Academic Search

This chapter discusses the types of transport systems that confer resistance to antibiotics, antimicrobial drugs, and toxic\\u000a metals. A number of these are discussed in detail in other chapters, so here we focus on the ways in which microorganisms\\u000a have evolved to use transporters to evade the toxic effects of drugs and metals.\\u000a \\u000a Resistance to therapeutic drugs and toxic metals

Adrian R. Walmsley; Barry P. Rosen

169

Cancer stem cells and drug resistance: the potential of nanomedicine  

PubMed Central

Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs.

Vinogradov, Serguei; Wei, Xin

2012-01-01

170

Systematic review of HIV drug resistance in Southeast Asia.  

PubMed

In 2010, 3.5 million people were living with HIV in the World Health Organization Southeast Asia Region (SEAR), giving this region the greatest burden of HIV after Africa. Scale-up of antiretroviral therapy has resulted in over 717,000 benefitting from it by the end of 2010. A systematic review of studies of HIV drug resistance in the SEAR published between 2000 and 2011 was performed. Of 10 studies of transmitted HIV drug resistance in recently infected patients, all but two reported low levels (< 5%) of transmitted resistance. Of 23 studies of HIV drug resistance in pretreatment populations initiating antiretroviral therapy, three reported moderate levels (5-15%) of HIV drug resistance and 20 reported low levels. Amongst 17 studies of acquired HIV drug resistance, levels of nucleoside reverse transcriptase inhibitor and nonnucleoside reverse transcriptase inhibitor resistance ranged from 52 to 92% and 43 to 100%, respectively, amongst those with virological failure. Overall, data included in this review suggest that currently recommended first- and second-line regimens are appropriate for the cohorts studied. However, data were only available from two of 11 Southeast Asia Region countries and studies largely examined urban populations. Results are unlikely to be representative of the region. Studies lacked standardized methods, which greatly limits comparability of data and their use for public health and antiretroviral therapy program planning. Routine, standardized, and nationally representative HIV drug resistance surveillance should be strongly encouraged in the Southeast Asia Region countries to best characterize population-level HIV drug resistance. National-level HIV drug resistance surveillance data may be used to optimize delivery of HIV care and treatment and minimize emergence of population-level HIV drug resistance, thus promoting the long-term efficacy and durability of available first- and second-line antiretroviral therapy regimens. PMID:24002200

Trotter, Andrew B; Hong, Steven Y; Srikantiah, Padmini; Abeyewickreme, Iyanthi; Bertagnolio, Silvia; Jordan, Michael R

2013-01-01

171

Mycobacterium tuberculosis interactome analysis unravels potential pathways to drug resistance  

Microsoft Academic Search

Background  Emergence of drug resistant varieties of tuberculosis is posing a major threat to global tuberculosis eradication programmes.\\u000a Although several approaches have been explored to counter resistance, there has been limited success due to a lack of understanding\\u000a of how resistance emerges in bacteria upon drug treatment. A systems level analysis of the proteins involved is essential\\u000a to gain insights into

Karthik Raman; Nagasuma Chandra

2008-01-01

172

Antitubercular Drug Resistance in Four Healthcare Facilities in North India  

PubMed Central

Tuberculosis (TB) is a major public-health problem in India, having the highest number of incident and multidrug-resistant (MDR) TB cases. The study was carried out to appraise the prevalence of first-line anti-TB drug resistance in Mycobacterium tuberculosis (MTB) and its patterns among different types of TB patients from different settings in a province of North India. Of 3,704 clinical specimens, 345 (9.3%) were culture-positive, and drug-susceptibility testing was carried out for 301 MTB strains. A high level of primary and acquired drug resistance of MTB was observed in the region studied, with weighted mean of 10.5% and 28.08%, 12.81% and 29.72%, 17.12% and 29.94%, 11.97% and 27.84%, and 10.74% and 23.54% for rifampicin, isoniazid, streptomycin, ethambutol-resistant and MDR cases respectively. Drug resistance was significantly higher in pulmonary (p=0.014) and acquired drug-resistant TB cases (p<0.001). Any drug resistance (p=0.002) and MDR TB were significantly (p=0.009) associated with HIV-seropositive cases. An urgent plan is needed to continuously monitor the transmission trends of drug-resistant strains, especially MDR-TB strains, in the region.

Gupta, Anamika; Mathuria, Jitendra Prasad; Singh, Surya Kumar; Gulati, Anil Kumar

2011-01-01

173

Mycobacterium tuberculosis resistance to antituberculosis drugs in Mozambique*, **  

PubMed Central

OBJECTIVE: To determine the drug resistance profile of Mycobacterium tuberculosis in Mozambique. METHODS: We analyzed secondary data from the National Tuberculosis Referral Laboratory, in the city of Maputo, Mozambique, and from the Beira Regional Tuberculosis Referral Laboratory, in the city of Beira, Mozambique. The data were based on culture-positive samples submitted to first-line drug susceptibility testing (DST) between January and December of 2011. We attempted to determine whether the frequency of DST positivity was associated with patient type or provenance. RESULTS: During the study period, 641 strains were isolated in culture and submitted to DST. We found that 374 (58.3%) were resistant to at least one antituberculosis drug and 280 (43.7%) were resistant to multiple antituberculosis drugs. Of the 280 multidrug-resistant tuberculosis cases, 184 (65.7%) were in previously treated patients, most of whom were from southern Mozambique. Two (0.71%) of the cases of multidrug-resistant tuberculosis were confirmed to be cases of extensively drug-resistant tuberculosis. Multidrug-resistant tuberculosis was most common in males, particularly those in the 21-40 year age bracket. CONCLUSIONS: M. tuberculosis resistance to antituberculosis drugs is high in Mozambique, especially in previously treated patients. The frequency of M. tuberculosis strains that were resistant to isoniazid, rifampin, and streptomycin in combination was found to be high, particularly in samples from previously treated patients.

Pires, Germano Manuel; Folgosa, Elena; Nquobile, Ndlovu; Gitta, Sheba; Cadir, Nureisha

2014-01-01

174

The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance  

PubMed Central

In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria.

Sarathy, Jansy Passiflora; Dartois, Veronique; Lee, Edmund Jon Deoon

2012-01-01

175

Artificial bacterial flagella for remote-controlled targeted single-cell drug delivery.  

PubMed

An approach for batch preparation of liposome-functionalized microdevices is demonstrated for remotely controlled single-cell drug delivery. The liposome functionalized artificial bacterial flagella exhibit corkscrew swimming in 3D with micrometer positioning precision by applying an external rotating magnetic field. The devices are also capable of delivering water-soluble drugs to single cells in vitro. PMID:24616145

Mhanna, Rami; Qiu, Famin; Zhang, Li; Ding, Yun; Sugihara, Kaori; Zenobi-Wong, Marcy; Nelson, Bradley J

2014-05-01

176

Epidemiological control of drug resistance and compensatory mutation under resistance testing and second-line therapy.  

PubMed

The fitness cost of antibiotic resistance in the absence of treatment raises the possibility that prudent use of drugs may slow or reverse the rise of resistance. Unfortunately, compensatory mutations that lower this cost may lead to entrenched resistance. Here, we develop a mathematical model of resistance evolution and compensatory mutation to determine whether reversion to sensitivity can occur, and how disease control might be facilitated by a second-line therapy. When only a single antibiotic is available, sensitive bacteria reach fixation only under treatment rates so low that hardly any cases are treated. We model a scenario in which drug sensitivity can be accurately tested so that a second-line therapy is administered to resistant cases. Before the rise of resistance to the second drug, disease eradication is possible if resistance testing and second-line treatment are conducted at a high enough rate. However, if double drug resistance arises, the possibility of disease eradication is greatly reduced and compensated resistance prevails in most of the parameter space. The boundary separating eradication from fixation of compensated resistance is strongly influenced by the underlying basic reproductive number of the pathogen and drug efficacy in sensitive cases, but depends less on the resistance cost and compensation. When double resistance is possible, the boundary is affected by the relative strengths of resistance against the two drugs in the double-resistant-compensated strain. PMID:24267872

Saddler, Clare A; Wu, Yue; Valckenborgh, Frank; Tanaka, Mark M

2013-12-01

177

Structural pharmacogenomics, drug resistance and the design of anti-infective super-drugs  

Microsoft Academic Search

Large-scale comparative analysis of drug-target polymorphism structures enables the rational design of next generation ‘super drugs’ – drugs that are less prone to development of drug resistance or that work for the largest possible fraction of the patient population. Furthermore, knowledge of the drug-target-shape repertoire that exists within the patient population enables predictions of likely clinical trial outcomes and response

Edward T. Maggio; Mark Shenderovich; Ron Kagan; Dean Goddette; Kal Ramnarayan

2002-01-01

178

Multidrug-resistant bacterial infections after liver transplantation: An ever-growing challenge  

PubMed Central

Bacterial infections are a leading cause of morbidity and mortality among solid organ transplant recipients. Over the last two decades, various multidrug-resistant (MDR) pathogens have emerged as relevant causes of infection in this population. Although this fact reflects the spread of MDR pathogens in health care facilities worldwide, several factors relating to the care of transplant donor candidates and recipients render these patients particularly prone to the acquisition of MDR bacteria and increase the likelihood of MDR infectious outbreaks in transplant units. The awareness of this high vulnerability of transplant recipients to infection leads to the more frequent use of broad-spectrum empiric antibiotic therapy, which further contributes to the selection of drug resistance. This vicious cycle is difficult to avoid and leads to a scenario of increased complexity and narrowed therapeutic options. Infection by MDR pathogens is more frequently associated with a failure to start appropriate empiric antimicrobial therapy. The lack of appropriate treatment may contribute to the high mortality occurring in transplant recipients with MDR infections. Furthermore, high therapeutic failure rates have been observed in patients infected with extensively-resistant pathogens, such as carbapenem-resistant Enterobacteriaceae, for which optimal treatment remains undefined. In such a context, the careful implementation of preventive strategies is of utmost importance to minimize the negative impact that MDR infections may have on the outcome of liver transplant recipients. This article reviews the current literature regarding the incidence and outcome of MDR infections in liver transplant recipients, and summarizes current preventive and therapeutic recommendations.

Santoro-Lopes, Guilherme; de Gouvea, Erika Ferraz

2014-01-01

179

Genetic and functional characterization of the rice bacterial blight disease resistance gene xa5.  

PubMed

Xanthomonas oryzae pv. oryzae is the causal agent of rice bacterial blight, a destructive rice disease worldwide. The gene xa5 provides race-specific resistance to X. oryzae pv. oryzae, and encodes the small subunit of transcription factor IIA. How xa5 functions in bacterial blight resistance is not well understood, and its recessive gene action is disputed. Here we show that xa5 is inherited in a completely recessive manner and the susceptible allele Xa5 is fully dominant. In accordance with this, bacterial growth in heterozygous and homozygous susceptible lines is not significantly different. Further, one allele of Xa5 is sufficient to promote disease in previously resistant plants; additional copies are not predictive of increased lesion length. Surprisingly, a resistant nearly isogenic line (NIL) of an indica variety sustains high levels of bacterial populations compared to the susceptible NIL, yet the resistant plants restrict symptom expression. In contrast, in japonica NILs, bacterial population dynamics differ in resistant and susceptible genotypes. However, both resistant indica and japonica plants delay bacterial movement down the leaf. These results support a model in which xa5-mediated recessive resistance is the result of restricted bacterial movement, but not restricted multiplication. PMID:18944079

Iyer-Pascuzzi, A S; Jiang, H; Huang, L; McCouch, S R

2008-03-01

180

Drug Resistance among Pulmonary Tuberculosis Patients in Calabar, Nigeria.  

PubMed

Background. This study aimed to determine the pattern of drug susceptibility to first-line drugs among pulmonary TB patients in two hospitals in Calabar, Nigeria. Methods. This was a descriptive cross-sectional study carried out between February 2011 and April 2012. Sputum samples from consecutive TB patients in Calabar were subjected to culture on Lowenstein-Jensen (LJ) slopes followed by drug susceptibility testing (DST). The DST was performed on LJ medium by the proportion method. Results. Forty-two of the 100 Mycobacterium tuberculosis strains were found to be resistant to at least one drug. Resistance to only one drug (monoresistance) was found in 17 patients. No strains with monoresistance to rifampicin were found. Resistance to two drugs was found in 22 patients, while one patient was resistant to both three and four drugs. MDR TB was seen in 4% (4/100). The independent variables of HIV serology and sex were not significantly associated with resistance (P > 0.05). Conclusion. There was a high prevalence of anti-TB drug resistance in Calabar. PMID:24078872

Otu, Akaninyene; Umoh, Victor; Habib, Abdulrazak; Ameh, Soter; Lawson, Lovett; Ansa, Victor

2013-01-01

181

What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?  

PubMed Central

The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance.

Colijn, Caroline; Cohen, Ted; Fraser, Christophe; Hanage, William; Goldstein, Edward; Givon-Lavi, Noga; Dagan, Ron; Lipsitch, Marc

2010-01-01

182

[New tuberculosis drugs in resistant and multiresistant tuberculosis].  

PubMed

Drug-resistant tuberculosis is a globally emerging problem with a rising incidence. According to the WHO in 2008, 17% of strains of Mycobacterium tuberculosis, in untreated cases were resistant to at least one drug and 3.6% were resistant to rifampicin and isoniazid, which is called multidrug-resistant tuberculosis. The problem is greater in patients previously treated and in some countries, where rates of multidrug resistance reach 60%. Approximately 5% of multidrug-resistant tuberculosis patients are also resistant to any fluoroquinolone and at least one injectable drug, being called extensively drug-resistant tuberculosis. The treatment of these forms of tuberculosis requires the use of second-line drugs, which causes higher cost, higher toxicity and a longer duration of treatment. There is a need for new compounds with efficacy and safety profiles better than those currently used to treat these forms of tuberculosis. In the last decade different drugs have being reassessed and appeared, which are at different stages of development. PMID:23540388

Ramírez Lapausa, Marta; Pascual Pareja, José Francisco; Noguerado Asensio, Arturo

2013-10-01

183

Prevalence of tuberculosis drug resistance in 10 provinces of China  

PubMed Central

Background The emergence of drug-resistant tuberculosis (TB) hampers TB control. Ten provinces in China performed drug resistance surveys among tuberculosis (TB) patients in 1996–2004 to assess levels of drug resistance. Methods Provincial drug resistance surveys included all isolates from newly diagnosed, smear-positive TB patients. Drug susceptibility testing (DST) against isoniazid, rifampicin, streptomycin and ethambutol was carried out in the provincial laboratories. For purposes of quality assurance, a random sample (11.6%) was re-tested by the national reference laboratory (NRL). Results Of 14,059 patients tested 11,052 (79%) were new TB cases. The weighted mean prevalence of multi-drug resistant tuberculosis (MDR-TB) among all cases was 9.3% (range 2.2%–10.4%); 5.4% (range 2.1% – 10.4%) among new cases and 25.6% (range 11.7%–36.9%) among previously treated cases. Adjusting the drug resistance proportions using the re-testing results did not change the estimated national mean prevalence significantly. However, in some individual provinces the estimated resistance proportions were greatly influenced, especially among re-treatment patients. Conclusion MDR-TB levels varied greatly between provinces in China, but on average were high compared to the global estimated average of 4.8%. This study shows the importance of quality-assured laboratory performance. Programmatic management of drug-resistant TB, including high quality DST for patients at high risk of resistance and treatment with second-line drugs, should become the standard, especially in high MDR-TB settings.

He, Guang Xue; Zhao, Yan Lin; Jiang, Guang Lu; Liu, Yu Hong; Xia, Hui; Wang, Sheng Fen; Wang, Li Xia; Borgdorff, Martien W; van der Werf, Marieke J; van den Hof, Susan

2008-01-01

184

Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis.  

PubMed

Tuberculosis (TB) is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB) and extensive drug-resistant tuberculosis (XDR-TB). Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB and XDR-TB relies on the drugs, which are less potent, more toxic and more costly and have to be administered for the longer duration. No new drug had come in to market for last 40 years, but the emergence of MDR-TB and XDR-TB has spurred interest in the development of novel drugs. For the effective treatment outcome, there is a dire need of new drugs with a different mechanism of action that can tackle both drug sensitive as well as drug-resistant strains. Bedaquiline is one such new drug with unique mechanism of action. Food and Drug Administration has approved bedaquiline for MDR-TB in December 2012. This article reviews the available evidence of efficacy and safety of bedaquiline. PMID:24554919

Goel, Divya

2014-01-01

185

The evolution of drug-resistant malaria: the role of drug elimination half-life.  

PubMed Central

This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance both evolve much faster if the antimalarial drug has a long half-life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of drug half-life. The methodology has been extended to investigate (i) the effects of using drugs in combination, particularly when the components have differing half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate drug pharmacokinetics to avoid potentially large errors in their predictions.

Hastings, Ian M; Watkins, William M; White, Nicholas J

2002-01-01

186

Bacterial Magnetosome: A Novel Biogenetic Magnetic Targeted Drug Carrier with Potential Multifunctions  

PubMed Central

Bacterial magnetosomes (BMs) synthesized by magnetotactic bacteria have recently drawn great interest due to their unique features. BMs are used experimentally as carriers for antibodies, enzymes, ligands, nucleic acids, and chemotherapeutic drugs. In addition to the common attractive properties of magnetic carriers, BMs also show superiority as targeting nanoscale drug carriers, which is hardly matched by artificial magnetic particles. We are presenting the potential applications of BMs as drug carriers by introducing the drug-loading methods and strategies and the recent research progress of BMs which has contributed to the application of BMs as drug carriers.

Sun, Jianbo; Li, Ying; Liang, Xing-Jie; Wang, Paul C.

2012-01-01

187

Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh  

PubMed Central

Background Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Methods Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. Results All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Conclusion Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary.

2011-01-01

188

A functional variomics tool for discovering drug resistance genes and drug targets  

PubMed Central

Comprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible novel target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems such as human cell lines will also be useful.

Huang, Zhiwei; Chen, Kaifu; Zhang, Jianhuai; Li, Yongxiang; Wang, Hui; Cui, Dandan; Tang, Jiangwu; Liu, Yong; Shi, Xiaomin; Li, Wei; Liu, Dan; Chen, Rui; Sucgang, Richard S.; Pan, Xuewen

2013-01-01

189

Diabetes drug points the way to overcoming drug resistance in melanoma  

Cancer.gov

Advanced metastatic melanoma is a disease that has proven difficult to eradicate. Despite the success of melanoma-targeting drugs, tumors inevitably become drug resistant and return, more aggressive than before. In the current issue of the journal Cancer Cell, researchers at The Wistar Institute describe how they increase the effectiveness of anti-melanoma drugs by combining anticancer therapies with diabetes drugs. Their studies, conducted in cell and animal models of melanoma, demonstrate that the combined therapy could destroy a subset of drug-resistant cells within a tumor.

190

Thermal resistance of naturally occurring airborne bacterial spores.  

PubMed Central

Simulation of a heat process used in the terminal dry-heat decontamination of the Viking spacecraft is reported. Naturally occurring airborne bacterial spores were collected on Teflon ribbons in selected spacecraft assembly areas and subsequently subjected to dry heat. Thermal inactivation experiments were conducted at 105, 111.7, 120, 125, 130, and 135 degrees C with a moisture level of 1.2 mg of water per liter. Heat survivors were recovered at temperatures of 135 degrees C when a 30-h heating cycle was employed. Survivors were recovered from all cycles studied and randomly selected for identification. The naturally occurring spore population was reduced an average of 2.2 to 4.4 log cycles from 105 to 135 degrees C. Heating cycles of 5 and 15 h at temperature were compared with the standard 30-h cycle at 111.7, 120, and 125 degrees C. No significant differences in inactivation (alpha = 0.05) were observed between 111.7 and 120 degrees C. The 30-h cycle differs from the 5-and 15-h cycles at 125 degrees C. Thus, the heating cycle can be reduced if a small fraction (about 10-3 to 10-4) of very resistant spores can be tolerated.

Puleo, J R; Bergstrom, S L; Peeler, J T; Oxborrow, G S

1978-01-01

191

Thermal resistance of naturally occurring airborne bacterial spores.  

PubMed

Simulation of a heat process used in the terminal dry-heat decontamination of the Viking spacecraft is reported. Naturally occurring airborne bacterial spores were collected on Teflon ribbons in selected spacecraft assembly areas and subsequently subjected to dry heat. Thermal inactivation experiments were conducted at 105, 111.7, 120, 125, 130, and 135 degrees C with a moisture level of 1.2 mg of water per liter. Heat survivors were recovered at temperatures of 135 degrees C when a 30-h heating cycle was employed. Survivors were recovered from all cycles studied and randomly selected for identification. The naturally occurring spore population was reduced an average of 2.2 to 4.4 log cycles from 105 to 135 degrees C. Heating cycles of 5 and 15 h at temperature were compared with the standard 30-h cycle at 111.7, 120, and 125 degrees C. No significant differences in inactivation (alpha = 0.05) were observed between 111.7 and 120 degrees C. The 30-h cycle differs from the 5-and 15-h cycles at 125 degrees C. Thus, the heating cycle can be reduced if a small fraction (about 10-3 to 10-4) of very resistant spores can be tolerated. PMID:727780

Puleo, J R; Bergstrom, S L; Peeler, J T; Oxborrow, G S

1978-09-01

192

Drug-resistant Mycobacterium tuberculosis in California, 1991 to 1992.  

PubMed Central

To determine the proportion and distribution of drug-resistant Mycobacterium tuberculosis in California, we surveyed all California counties for drug-susceptibility test results for initial isolates from tuberculosis cases counted during the first quarters of 1991 and 1992. Overall, drug-susceptibility test results were not available for 17% of isolates. Among isolates with available test results, the proportion with resistance to isoniazid averaged 8.7%, and the proportion with resistance to at least 2 drugs, multidrug resistance, averaged 5.9% during these two quarters. The proportion of isolates with drug resistance did not change substantially during these time periods. The proportion with combined isoniazid and rifampin resistance remained stable at about 1.1%. Among persons whose isolates were tested for drug resistance, those with a known previous diagnosis of tuberculosis (relative risk [RR] = 2.6; 95% confidence interval [CI], 1.6 to 4.3; P < .01) and persons who were foreign born (RR = 1.7; 95% CI, 1.1 to 2.7; P = .014) were more likely to have isoniazid-resistant organisms. These statewide data suggest that the initial tuberculosis treatment regimen in California should include 4 antituberculosis drugs, as recommended by the American Thoracic Society and the Centers for Disease Control and Prevention for areas with a prevalence of isoniazid resistance of 4% or greater. The lack of test results for 1 in 6 patients with tuberculosis suggests the need for improved physician and laboratorian education to implement the recommendations that drug susceptibility be tested on all initial isolates.

Koo, D; Royce, S; Rutherford, G W

1995-01-01

193

Origin of robustness in generating drug-resistant malaria parasites.  

PubMed

Biological robustness allows mutations to accumulate while maintaining functional phenotypes. Despite its crucial role in evolutionary processes, the mechanistic details of how robustness originates remain elusive. Using an evolutionary trajectory analysis approach, we demonstrate how robustness evolved in malaria parasites under selective pressure from an antimalarial drug inhibiting the folate synthesis pathway. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. Nevertheless, the stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. Here, we report the epistatic interaction between dhfr mutations and amplification of the gene encoding the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and would thus be selected for by pyrimethamine treatment. Interestingly, the gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The compensation of compromised fitness by extra GCH1 is an example of how robustness can evolve in a system and thus expand the accessibility of evolutionary trajectories leading toward highly resistant alleles. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs. PMID:24739308

Kümpornsin, Krittikorn; Modchang, Charin; Heinberg, Adina; Ekland, Eric H; Jirawatcharadech, Piyaporn; Chobson, Pornpimol; Suwanakitti, Nattida; Chaotheing, Sastra; Wilairat, Prapon; Deitsch, Kirk W; Kamchonwongpaisan, Sumalee; Fidock, David A; Kirkman, Laura A; Yuthavong, Yongyuth; Chookajorn, Thanat

2014-07-01

194

Biochemistry of Bacterial Multidrug Efflux Pumps  

PubMed Central

Bacterial pathogens that are multi-drug resistant compromise the effectiveness of treatment when they are the causative agents of infectious disease. These multi-drug resistance mechanisms allow bacteria to survive in the presence of clinically useful antimicrobial agents, thus reducing the efficacy of chemotherapy towards infectious disease. Importantly, active multi-drug efflux is a major mechanism for bacterial pathogen drug resistance. Therefore, because of their overwhelming presence in bacterial pathogens, these active multi-drug efflux mechanisms remain a major area of intense study, so that ultimately measures may be discovered to inhibit these active multi-drug efflux pumps.

Kumar, Sanath; Varela, Manuel F.

2012-01-01

195

[Evolution of bacterial resistance to antibiotics in México, 1973-2013].  

PubMed

Introduction: Bacterial resistance to antibiotics is a worldwide public health concern. Research priorities for the study and control of this emerging problem include country-wide surveillance. Objective: To review and comment on the contributions by Mexican investigators towards a greater understanding of the mechanisms of bacterial antibiotic resistance. Materials and methods: A comprehensive search of the medical literature on Medline/PubMed between 1973 and July 2013 was performed. Results: The contributions of Mexican investigators have included descriptions of resistance in enteric pathogens, such as Salmonella Typhi, publications on the production of extended spectrum beta-lactamases, metallo-beta-lactamases, and carbapenemases, resistance mechanisms of Pseudomonas aeruginosa , and the evolution of resistance in Gram-positive pathogens, including Streptococcus pneumoniae , Staphylococcus aureus , and Enterococcus spp. Conclusion: The Mexican literature on mechanisms of bacterial resistance is relevant for the development of plans to control the antibiotic resistance crisis. PMID:24968050

Rodríguez-Noriega, Eduardo; León-Garnica, Gerardo; Petersen-Morfín, Santiago; Pérez-Gómez, Héctor Raúl; González-Díaz, Esteban; Morfín-Otero, Rayo

2014-04-01

196

Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population  

Microsoft Academic Search

BACKGROUND: The emergence of drug resistance is a major problem in malaria control. For mathematical modelling of the transmission and spread of drug resistance the determinant parameters need to be identified and measured. The underlying hypothesis is that mutations associated with drug resistance incur fitness costs to the parasite in absence of drug pressure. The distribution of drug resistance haplotypes

Sonja Schoepflin; Jutta Marfurt; Mary Goroti; Moses Baisor; Ivo Mueller; Ingrid Felger

2008-01-01

197

Phage-based detection of bacterial pathogens.  

PubMed

Bacterial pathogens cause significant morbidity and mortality annually to both humans and animals. With the rampant spread of drug resistance and the diminishing effectiveness of current antibiotics, there is a pressing need for effective diagnostics for detection of bacterial pathogens and their drug resistances. Bacteriophages offer several unique opportunities for bacterial detection. This review highlights the means by which bacteriophages have been utilized to achieve and facilitate specific bacterial detection. PMID:24658771

van der Merwe, R G; van Helden, P D; Warren, R M; Sampson, S L; Gey van Pittius, N C

2014-05-01

198

Horizontal transfer of drug-resistant aminoacyl-transfer-RNA synthetases of anthrax and Gram-positive pathogens  

Microsoft Academic Search

The screening of new antibiotics against several bacterial strains often reveals unexpected occurrences of natural drug resistance. Two examples of this involve specific inhibitors of Staphylococcus aureus isoleucyl-transfer-RNA synthetase 1 (IleRS1) and, more recently, Streptococcus pneumoniae methionyl-tRNA synthetase 1 (MetRS1). In both cases, resistance is due to the presence of a second gene that encodes another synthetase (IleRS2 or MetRS2).

Daniel Gentry; Julie A. Becker; Karen Ingraham; David J. Holmes; James R. Brown; Michael J. Stanhope

2003-01-01

199

[Identification of Mycobacterium tuberculosis strains and a simultaneous identification of their drug resistance by the hybridization method on oligonucleotide microchips].  

PubMed

A method of multiplex polymerase chain reaction (PCR) with subsequent hyoridization on oligonucleotide microchips was worked out to identify the Mycobacterium tuberculosis complex and to determine simultaneously the bacterial sensitivity to 2 first-line drugs, i.e. rifampin and isoniazid. The method provides for detecting above 95% of rifampin-resistant and around 80% of isoniazid-resistant strains within 1 day. PMID:14664159

Griadunov, D A; Mikha?lovich, V M; Lapa, S A; Rudinski?, N I; Barski?, V E; Chudinov, A V; Zasedatelev, A S; Mirzabekov, A D

2003-01-01

200

Method and Kit for Detecting Resistance to Anitviral Drugs.  

National Technical Information Service (NTIS)

Assays and kits for the detection of phenotypic resistance of a retrovirus to reverse transcriptase inhibitor-drugs in a biological sample. The assays are based on the direct analysis of the susceptibility of retroviral reverse transcriptase to inhibition...

G. G. Lerma S. Yamamoto T. M. Folks W. M. Heneine W. M. Switzer

2005-01-01

201

Drug resistance in an immunological model of HIV-1 infection with impulsive drug effects.  

PubMed

We consider an SIR-type model of immunological behaviour for HIV dynamics, including the effects of reverse transcriptase inhibitors and other drugs which prevent cellular infection. We use impulsive differential equations to model drug behaviour. We classify different regimes according to whether the drug efficacy is negligible, intermediate or high. We consider two strains of the virus: a wild-type strain that can be controlled by both intermediate and high drug concentrations, and a mutant strain that can only be controlled by high drug concentrations. Drug regimes may take trajectories through one, two or all three regimes, depending on the dosage and the dosing schedule. We demonstrate that drug resistance arises at both intermediate and high drug levels. At low drug levels resistance does not emerge, but the total T cell count is proven to be significantly lower than in the disease-free state. At intermediate drug levels, drug resistance is guaranteed to emerge. At high drug levels, either the drug-resistant strain will dominate or, in the absence of longer-lived reservoirs of infected cells, both viral sub-populations will be cleared. In the latter case the immune system is maintained by a population of T cells which have absorbed sufficient quantities of the drug to prevent infection by even the drug-resistant strain. We provide estimates of a range of dosages and dosing schedules which would, if physiologically tolerable, theoretically eliminate free virus in this system. Our results predict that to control viral load, decreasing the interval between doses is more effective than increasing the dose. PMID:15893553

Smith, R J; Wahl, L M

2005-07-01

202

Electrical Stimulation for Drug-Resistant Epilepsy  

PubMed Central

Objective The objective of this analysis was to evaluate the effectiveness of deep brain stimulation (DBS) and vagus nerve stimulation (VNS) for the treatment of drug-resistant epilepsy in adults and children. Data Sources A literature search was performed using MEDLINE, EMBASE, the Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 2007 until December 2012. Review Methods Systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies (in the absence of RCTs) of adults or children were included. DBS studies were included if they specified that the anterior nucleus of thalamus was the area of the brain stimulated. Outcomes of interest were seizure frequency, health resource utilization, and safety. A cost analysis was also performed. Results The search identified 6 studies that assessed changes in seizure frequency after electrical stimulation: 1 RCT on DBS in adults, 4 RCTs on VNS in adults, and 1 RCT on VNS in children. The studies of DBS and VNS in adults found significantly improved rates of seizure frequency, but the study of VNS in children did not find a significant difference in seizure frequency between the high and low stimulation groups. Significant reductions in hospitalizations and emergency department visits were found for adults and children who received VNS. No studies addressed the use of health resources for patients undergoing DBS. Five studies reported on adverse events, which ranged from serious to transient for both procedures in adults and were mostly transient in the 1 study of VNS in children. Limitations We found no evidence on DBS in children or on health care use related to DBS. The measurement of seizure frequency is self-reported and is therefore subject to bias and issues of compliance. Conclusions Based on evidence of low to moderate quality, both DBS and VNS seemed to reduce seizure frequency in adults. In children, VNS did not appear to be as effective at reducing seizure frequency, but children had significantly fewer hospitalizations and ED visits after VNS implantation. Despite the considerable risks associated with these invasive procedures, long-term adverse events appear to be limited. Plain Language Summary Electrical stimulation of specific areas of the brain is a procedure used to control epileptic seizures when more conventional treatments are not working. Most adults and children with epilepsy are able to control their seizures with medication, but for some patients, drugs are not effective and surgery to remove the part of the brain where the seizures start is not an appropriate option. This study looked at the research available on the effectiveness, safety, and cost of two types of electrical stimulation devices currently licensed for treatment of epilepsy for adults and children in Canada: vagus nerve stimulation (VNS) and deep brain stimulation (DBS). Both approaches appear to be effective at reducing the frequency of seizures in adults. However, the evidence on DBS is limited to a single study with adults; we found no studies of DBS with children. Studies on VNS showed that both adults and children had fewer hospitalizations and emergency department visits after the procedure. Both procedures carry serious risks, but several longer-term studies have found that adverse events appear to be limited. The cost of VNS, including the process of assessing whether or not patients are good candidates for the procedure, is estimated to be about $40,000 per person (and higher for DBS because the device is more expensive and the operating time is longer). Of the 70,000 people in Ontario with epilepsy, about 1,400 (300 children and 1,110 adults) may be candidates for VNS to reduce their seizures.

Chambers, A; Bowen, JM

2013-01-01

203

Human Immunodeficiency Virus: Resistance to Antiretroviral Drugs in Developing Countries  

Microsoft Academic Search

\\u000a This chapter reviews issues central to understanding the emergence and transmission of drug-resistant human immunodeficiency\\u000a virus (HIV) and its impact on developing countries. We first give an overview of HIV, HIV treatment using antiretroviral drugs,\\u000a and access to treatment in developing countries. Then we review current understanding of the impact of adherence and treatment\\u000a interruption on the emergence of resistance

Rebecca F. Baggaley; Maya L. Petersen; Marcelo A. Soares; Marie-Claude Boily; Francisco I. Bastos

204

Extensively drug-resistant tuberculosis: epidemiology and management.  

PubMed

The advent of antibiotics for the treatment of tuberculosis (TB) represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR) strains (ie, strains resistant to both isoniazid and rifampicin) has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB). The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR-TB. PMID:24729727

Matteelli, Alberto; Roggi, Alberto; Carvalho, Anna Cc

2014-01-01

205

Extensively drug-resistant tuberculosis: epidemiology and management  

PubMed Central

The advent of antibiotics for the treatment of tuberculosis (TB) represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR) strains (ie, strains resistant to both isoniazid and rifampicin) has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB). The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR-TB.

Matteelli, Alberto; Roggi, Alberto; Carvalho, Anna CC

2014-01-01

206

Treatment of Tuberculosis in a Region with High Drug Resistance: Outcomes, Drug Resistance Amplification and Re-Infection  

PubMed Central

Introduction Emerging antituberculosis drug resistance is a serious threat for tuberculosis (TB) control, especially in Eastern European countries. Methods We combined drug susceptibility results and molecular strain typing data with treatment outcome reports to assess the influence of drug resistance on TB treatment outcomes in a prospective cohort of patients from Abkhazia (Georgia). Patients received individualized treatment regimens based on drug susceptibility testing (DST) results. Definitions for antituberculosis drug resistance and treatment outcomes were in line with current WHO recommendations. First and second line DST, and molecular typing were performed in a supranational laboratory for Mycobacterium tuberculosis (MTB) strains from consecutive sputum smear-positive TB patients at baseline and during treatment. Results At baseline, MTB strains were fully drug-susceptible in 189/326 (58.0%) of patients. Resistance to at least H or R (PDR-TB) and multidrug-resistance (MDR-TB) were found in 69/326 (21.2%) and 68/326 (20.9%) of strains, respectively. Three MDR-TB strains were also extensively resistant (XDR-TB). During treatment, 3/189 (1.6%) fully susceptible patients at baseline were re-infected with a MDR-TB strain and 2/58 (3.4%) PDR-TB patients became MDR-TB due to resistance amplification. 5/47 (10.6%) MDR- patients became XDR-TB during treatment. Treatment success was observed in 161/189 (85.2%), 54/69 (78.3%) and 22/68 (32.3%) of patients with fully drug susceptible, PDR- and MDR-TB, respectively. Development of ofloxacin resistance was significantly associated with a negative treatment outcome. Conclusion In Abkhazia, a region with high prevalence of drug resistant TB, the use of individualized MDR-TB treatment regimens resulted in poor treatment outcomes and XDR-TB amplification. Nosocomial transmission of MDR-TB emphasizes the importance of infection control in hospitals.

Bonnet, Maryline; Pardini, Manuela; Meacci, Francesca; Orru, Germano; Yesilkaya, Hasan; Jarosz, Thierry; Andrew, Peter W.; Barer, Mike; Checchi, Francesco; Rinder, Heinz; Orefici, Graziella; Rusch-Gerdes, Sabine; Fattorini, Lanfranco; Oggioni, Marco Rinaldo; Melzer, Juliet

2011-01-01

207

The medical and surgical treatment of drug-resistant tuberculosis.  

PubMed

Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migration and travel, healthcare workers, researchers, and policy makers in TB endemic and non-endemic countries should familiarise themselves with issues relevant to the management of these patients. Given the lack of novel TB drugs and limited access to existing drugs such as linezolid and bedaquiline in TB endemic countries, significant numbers of therapeutic failures are emerging from the ranks of those with XDR-TB. Given the lack of appropriate facilities in resource-limited settings, such patients are being discharged back into the community where there is likely ongoing disease spread. In the absence of effective drug regimens, in appropriate patients, surgery is a critical part of management. Here we review the diagnosis, medical and surgical management of MDR-TB and XDR-TB. PMID:24624282

Calligaro, Gregory L; Moodley, Loven; Symons, Greg; Dheda, Keertan

2014-03-01

208

Sparse Representation for Prediction of HIV-1 Protease Drug Resistance  

PubMed Central

HIV rapidly evolves drug resistance in response to antiviral drugs used in AIDS therapy. Estimating the specific resistance of a given strain of HIV to individual drugs from sequence data has important benefits for both the therapy of individual patients and the development of novel drugs. We have developed an accurate classification method based on the sparse representation theory, and demonstrate that this method is highly effective with HIV-1 protease. The protease structure is represented using our newly proposed encoding method based on Delaunay triangulation, and combined with the mutated amino acid sequences of known drug-resistant strains to train a machine-learning algorithm both for classification and regression of drug-resistant mutations. An overall cross-validated classification accuracy of 97% is obtained when trained on a publically available data base of approximately 1.5×104 known sequences (Stanford HIV database http://hivdb.stanford.edu/cgi-bin/GenoPhenoDS.cgi). Resistance to four FDA approved drugs is computed and comparisons with other algorithms demonstrate that our method shows significant improvements in classification accuracy.

Yu, Xiaxia; Weber, Irene T.; Harrison, Robert W.

2013-01-01

209

Dynamical Basis for Drug Resistance of HIV-1 Protease  

PubMed Central

Background Protease inhibitors designed to bind to protease have become major anti-AIDS drugs. Unfortunately, the emergence of viral mutations severely limits the long-term efficiency of the inhibitors. The resistance mechanism of these diversely located mutations remains unclear. Results Here I use an elastic network model to probe the connection between the global dynamics of HIV-1 protease and the structural distribution of drug-resistance mutations. The models for study are the crystal structures of unbounded and bound (with the substrate and nine FDA approved inhibitors) forms of HIV-1 protease. Coarse-grained modeling uncovers two groups that couple either with the active site or the flap. These two groups constitute a majority of the drug-resistance residues. In addition, the significance of residues is found to be correlated with their dynamical changes in binding and the results agree well with the complete mutagenesis experiment of HIV-1 protease. Conclusions The dynamic study of HIV-1 protease elucidates the functional importance of common drug-resistance mutations and suggests a unifying mechanism for drug-resistance residues based on their dynamical properties. The results support the robustness of the elastic network model as a potential predictive tool for drug resistance.

2011-01-01

210

Resistance to antituberculosis drugs in treated patients in Lagos, Nigeria.  

PubMed

The extent and pattern of drug resistance among previously treated tuberculosis patients was investigated. Ninety-six patients with a total treatment duration of between 6 and 18 months and still smear and culture positive were examined. Treatment was either continuous or in intermittent blocks. Drug susceptibility tests on strains of tubercle bacilli isolated from the patients were performed against isoniazid, streptomycin, p-aminosalicylic acid, ethambutol and rifampicin by the proportion method using LJ medium without potato starch. A total of 56% of the strains were resistant to one or more of the drugs tested. Resistance to isoniazid (38%) and streptomycin (29%) was most common. A significant finding in the study was the low level of resistance to rifampicin (2%) and ethambutol (3%). A relationship between the incidence of drug resistance and the nature and duration of previous treatment appeared likely since susceptible strains were isolated more often from patients with continuous treatment than from patients on intermittent blocks of long-course regimens. It is therefore suggested that the introduction of better supervision of drug taking and the adoption of continuous short-course regimens on a nationwide level will contribute immensely towards the reduction of the drug resistance problems in Nigeria as well as in other developing countries. PMID:1597874

Idigbe, E O; Duque, J P; John, E K; Annam, O

1992-06-01

211

Evolution of Drug Resistance in Experimental Populations of Candida albicans  

PubMed Central

Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast Candida albicans and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIC; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes, CDR1 and CDR2; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway, ERG11; and the major facilitator gene, MDR1. Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of C. albicans.

Cowen, Leah E.; Sanglard, Dominique; Calabrese, David; Sirjusingh, Caroline; Anderson, James B.; Kohn, Linda M.

2000-01-01

212

Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.  

PubMed

The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak. PMID:23935910

Joice, Regina; Lipsitch, Marc

2013-01-01

213

In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species  

Microsoft Academic Search

The antibacterial activity of XF-73, a dicationic porphyrin drug, was investigated against a range of Gram-positive and Gram-negative bacteria with known antibiotic resistance profiles, including resistance to cell wall synthesis, protein synthesis, and DNA and RNA synthesis inhibitors as well as cell membrane-active antibiotics. Antibiotic-sensitive strains for each of the bacterial species tested were also included for comparison purposes. XF-73

David J. Farrell; Marion Robbins; William Rhys-Williams; William G. Love

2010-01-01

214

Glutathione-associated Enzymes in Anticancer Drug Resistance1  

Microsoft Academic Search

The importance of thiol-mediated detoxification of anticancer drugs that produce toxic electrophiles has been of considerable interest to many investigators. Glutathione and glutathione S-transferases (GST) are the focus of much attention in characterizing drug resistant cells. However, ambiguous and sometimes conflicting data have complicated the field. This article attempts to clarify some of the confusion. The following observations are well

Kenneth D. Tew

1994-01-01

215

Studies on the Chemotherapy of Rodent Malaria and Drug Resistance.  

National Technical Information Service (NTIS)

The development of techniques for the evaluation of the level and mode of action of antimalarial drugs against normal and drug-resistant strains has been initiated. Much reliance is being placed upon variations of the bioassay techniques. Many baseline da...

W. Peters

1969-01-01

216

Impact Evaluation of Drug Abuse Resistance Education (DARE).  

ERIC Educational Resources Information Center

Assessed impact of Drug Abuse Resistance Education (DARE) on approximately 3,000 fifth-grade students in 1 school district. Findings from pretest and posttest self-report survey suggest that DARE did not significantly change amount of drug use, which was minimal at fifth-grade level. In general, children receiving DARE during the study period…

Becker, Harold K.; And Others

1992-01-01

217

World Antimalarial Resistance Network I: clinical efficacy of antimalarial drugs.  

PubMed

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates of antimalarial efficacy can be derived and monitored over time from diverse geographical and endemic regions. The emphasis of this initiative is on five key variables which define the therapeutic response. Ensuring that these data are collected at the individual patient level in a consistent format will facilitate better data management and analytical practices, and ensure that clinical data can be readily collated and made amenable for pooled analyses. Such an approach, if widely adopted will permit accurate and timely recognition of trends in drug efficacy. This will guide not only appropriate interventions to deal with established multidrug resistant strains of malaria, but also facilitate prompt action when new strains of drug resistant plasmodia first emerge. A comprehensive global database incorporating the key determinants of the clinical response with in vitro, molecular and pharmacokinetic parameters will bring together relevant data on host, drug and parasite factors that are fundamental contributors to treatment efficacy. This resource will help guide rational drug policies that optimize antimalarial drug use, in the hope that the emergence and spread of resistance to new drugs can be, if not prevented, at least delayed. PMID:17822532

Price, Ric N; Dorsey, Grant; Ashley, Elizabeth A; Barnes, Karen I; Baird, J Kevin; d'Alessandro, Umberto; Guerin, Philippe J; Laufer, Miriam K; Naidoo, Inbarani; Nosten, François; Olliaro, Piero; Plowe, Christopher V; Ringwald, Pascal; Sibley, Carol H; Stepniewska, Kasia; White, Nicholas J

2007-01-01

218

The culturable intestinal microbiota of triploid and diploid juvenile Atlantic salmon (Salmo salar) - a comparison of composition and drug resistance  

PubMed Central

Background With the increased use of ploidy manipulation in aquaculture and fisheries management this investigation aimed to determine whether triploidy influences culturable intestinal microbiota composition and bacterial drug resistance in Atlantic salmon (Salmo salar). The results could provide answers to some of the physiological differences observed between triploid and diploid fish, especially in terms of fish health. Results No ploidy effect was observed in the bacterial species isolated, however, triploids were found to contain a significant increase in total gut microbiota levels, with increases in Pseudomonas spp., Pectobacterium carotovorum, Psychrobacter spp., Bacillus spp., and Vibrio spp., (12, 42, 9, 10, and 11% more bacteria in triploids than diploids, respectively), whereas a decrease in Carnobacterium spp., within triploids compared to diploids was close to significant (8% more bacteria in diploids). With the exception of gentamicin, where no bacterial resistance was observed, bacterial isolates originating from triploid hosts displayed increased resistance to antibacterials, three of which were significant (tetracycline, trimethoprim, and sulphonamide). Conclusion Results indicate that triploidy influences both the community and drug resistance of culturable intestinal microbiota in juvenile salmon. These results demonstrate differences that are likely to contribute to the health of triploid fish and have important ramifications on the use of antibacterial drugs within aquaculture.

2011-01-01

219

The multiple facets of drug resistance: one history, different approaches.  

PubMed

Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated. PMID:24775603

Niero, Evandro Luís; Rocha-Sales, Bianca; Lauand, Camila; Cortez, Beatriz Araujo; de Souza, Marcelo Medina; Rezende-Teixeira, Paula; Urabayashi, Marcel Shiniti; Martens, Adam Arai; Neves, Jorge Henrique; Machado-Santelli, Gláucia Maria

2014-01-01

220

The multiple facets of drug resistance: one history, different approaches  

PubMed Central

Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated.

2014-01-01

221

Emergence of HIV1 Drug Resistance During Antiretroviral Treatment  

Microsoft Academic Search

Treating HIV-infected patients with a combination of several antiretroviral drugs usually contributes to a substantial decline\\u000a in viral load and an increase in CD4+ T cells. However, continuing viral replication in the presence of drug therapy can lead to the emergence of drug-resistant\\u000a virus variants, which subsequently results in incomplete viral suppression and a greater risk of disease progression. In

Libin Rong; Zhilan Feng; Alan S. Perelson

2007-01-01

222

MicroRNA-mediated drug resistance in breast cancer  

Microsoft Academic Search

Chemoresistance is one of the major hurdles to overcome for the successful treatment of breast cancer. At present, there are\\u000a several mechanisms proposed to explain drug resistance to chemotherapeutic agents, including decreased intracellular drug\\u000a concentrations, mediated by drug transporters and metabolic enzymes; impaired cellular responses that affect cell cycle arrest,\\u000a apoptosis, and DNA repair; the induction of signaling pathways that

Kristy R. Kutanzi; Olga V. Yurchenko; Frederick A. Beland; Vasyl’ F. Checkhun; Igor P. Pogribny

223

Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria.  

PubMed

Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacterium kansasii) and rapid growers (e.g. Mycobacterium abscessus, Mycobacterium fortuitum). In general, drug treatment is long, costly, and often associated with drug-related toxicities; outcome of drug treatment is poor and is likely related to the high levels of natural antibiotic resistance in NTM. The role of drug susceptibility testing (DST) in the choice of agents for antimicrobial treatment of NTM disease, mainly that by slow growers, remains subject of debate. There are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo. In part, these discrepancies derive from laboratory technical issues. There is still no consensus on a standardized method. With the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. This review provides a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods for testing susceptibility in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance. PMID:22525524

van Ingen, Jakko; Boeree, Martin J; van Soolingen, Dick; Mouton, Johan W

2012-06-01

224

Trends in antimicrobial-drug resistance in Japan.  

PubMed Central

Multidrug resistance in gram-positive bacteria has become common worldwide. In Japan until recently, gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Serratia marcescens were controlled by carbapenems, fluoroquinolones, and aminoglycosides. However, several of these microorganisms have recently developed resistance against many antimicrobial drugs.

Arakawa, Y.; Ike, Y.; Nagasawa, M.; Shibata, N.; Doi, Y.; Shibayama, K.; Yagi, T.; Kurata, T.

2000-01-01

225

Antimicrobial Drug Use and Macrolide-Resistant Streptococcus pyogenes, Belgium  

PubMed Central

In Belgium, decreasing macrolide, lincosamide, streptogramins B, and tetracycline use during 1997–2007 correlated significantly with decreasing macrolide-resistant Streptococcus pyogenes during 1999–2009. Maintaining drug use below a critical threshold corresponded with low-level macrolide-resistant S. pyogenes and an increased number of erm(A)-harboring emm77 S. pyogenes with low fitness costs.

Van Heirstraeten, Liesbet; Coenen, Samuel; Lammens, Christine; Hens, Niel; Goossens, Herman

2012-01-01

226

A Research-Inspired Laboratory Sequence Investigating Acquired Drug Resistance  

ERIC Educational Resources Information Center

Here, we present a six-session laboratory exercise designed to introduce students to standard biochemical techniques in the context of investigating a high impact research topic, acquired resistance to the cancer drug Gleevec. Students express a Gleevec-resistant mutant of the Abelson tyrosine kinase domain, the active domain of an oncogenic…

Taylor, Elizabeth Vogel; Fortune, Jennifer A.; Drennan, Catherine L.

2010-01-01

227

Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand  

Microsoft Academic Search

BACKGROUND: The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ) in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. METHODS: In the present study, we have established the in vitro sensitivity to

Dinora Lopes; Kanchana Rungsihirunrat; Fátima Nogueira; Aree Seugorn; José Pedro Gil; Virgilio E do Rosário; Pedro Cravo

2002-01-01

228

Prevalence and antimicrobial resistance pattern of bacterial meningitis in Egypt  

Microsoft Academic Search

Infectious diseases are the leading cause of morbidity and mortality in the developing world. In Egypt bacterial diseases constitute a great burden, with several particular bacteria sustaining the leading role of multiple serious infections. This article addresses profound bacterial agents causing a wide array of infections including but not limited to pneumonia and meningitis. The epidemiology of such infectious diseases

Lamyaa Shaban; Rania Siam

2009-01-01

229

'A'ole Drugs! Cultural Practices and Drug Resistance of Rural Hawaiian Youth  

PubMed Central

This qualitative study examined how Native Hawaiian youth from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from 5 different middle schools participated in gender specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawaiian youth. The findings described culturally specific activities that participants used in drug related problem situations. The findings also suggested that those youth with higher levels of enculturation were able to resist drugs more effectively than those youth who were disconnected from their culture. The implications of these findings for social work practice are discussed.

PO'A-KEKUAWELA, KA'OHINANI; OKAMOTO, SCOTT K.; NEBRE, LA RISA H.; HELM, SUSANA; CHIN, CORALEE I. H.

2009-01-01

230

Molecular epidemiology of drug-resistant Salmonella Typhimurium in Spain  

Microsoft Academic Search

SUMMARY One hundred and forty-seven Salmonella serotype Typhimurium strains isolated in three provinces in the midwest of Spain were studied. Of these, 93.6% were drug resistant. There were two predominant resistance phenotypes: 43 isolates (29.3%) were resistant to amoxicillin, tet- racyclines, chloramphenicol, streptomycin and sulphamethoxazole and 27 isolates (18.4%) to amoxicillin, amoxicillin\\/clavulanic acid, tetracy- clines, chloramphenicol, streptomycin and sulphamethoxazole. Randomly

N. Delgado Ronda; J. L. Muñoz Bellido; M. I. García García; R. Ibáñez Pérez; S. Muñoz Criado; R. Serrano Heranz; M. C. Sáenz González; J. A. García Rodríguez

2006-01-01

231

Ampicillin-chloramphenicol-resistant Haemophilus influenzae: plasmid-mediated resistance in bacterial meningitis.  

PubMed

A 4-month-old infant with congenital heart disease and sepsis and arthritis, and subsequently meningitis, caused by an antibiotic-resistant strain of Haemophilus influenzae type b, failed to respond to sequential therapy with ampicillin and trimethoprim/sulfamethoxazole. Following treatment with ceftizoxime, the infant was well for 42 days, until he returned to the hospital and died. A total of 10 Haemophilus influenzae type b isolates, all outer membrane protein subtype 51, was isolated from the pretreatment blood and synovium, cerebrospinal fluid and subdural fluids, and the petrous pyramids at autopsy. Pretreatment isolates had no detectable plasmid DNA, chloramphenicol acetyltransferase or beta-lactamase; the minimal inhibitory concentration for ampicillin (AM) and chloramphenicol (CM) was 0.2 and 0.8 microgram/ml, respectively. However, all cerebrospinal fluid isolates had a 42-44 mD plasmid and produced chloramphenicol acetyltransferase and beta-lactamase; the minimal inhibitory concentration of these isolates to AM and CM were 12.5 and 25 micrograms/ml, respectively, and were also resistant to tetracycline and sulfonamide. Resistance to AM and CM was cotransferred by filter-mating conjugation at a frequency of one to two transconjugants per 10(5) to an Rd haemophilus recipient. Posttreatment isolates from the petrous pyramids also were resistant to AM and CM and produced chloramphenicol acetyltransferase and beta-lactamase activity, but had no plasmid DNA. These findings and data from genetic studies suggested that plasmid-bearing antibiotic-resistant Haemophilus influenzae type b was selected from a heterogenous population, and that the AM/CM resistance transposons were incorporated into the bacterial chromosome. PMID:3500449

Overturf, G D; Cable, D; Ward, J

1987-10-01

232

Bacterial resistance surveillance in China: a report from Mohnarin 2004–2005  

Microsoft Academic Search

The aim of this study was to establish a nationwide antimicrobial resistant surveillance network and obtain information on\\u000a bacterial resistance in China. A total of 4075 clinical bacterial isolates were collected from 17 hospitals in 15 cities throughout\\u000a China. Antibacterial minimal inhibitory concentrations (MICs) were determined by the standard agar dilution method recommended\\u000a by Clinical and Laboratory Standards Institute. The

Y. H. Xiao; J. Wang; Y. Li

2008-01-01

233

Diversity of Dominant Bacterial Taxa in Activated Sludge Promotes Functional Resistance following Toxic Shock Loading  

Microsoft Academic Search

Examining the relationship between biodiversity and functional stability (resistance and resilience) of activated sludge bacterial\\u000a communities following disturbance is an important first step towards developing strategies for the design of robust biological\\u000a wastewater treatment systems. This study investigates the relationship between functional resistance and biodiversity of dominant\\u000a bacterial taxa by subjecting activated sludge samples, with different levels of biodiversity, to

Pascal E. Saikaly; Daniel B. Oerther

2011-01-01

234

Therapeutic Implications of Hepatitis C virus Resistance to Antiviral Drugs  

PubMed Central

Treatment of chronic hepatitis C is currently based on a combination of pegylated interferon-o! and ribavirin. Neither drug exerts direct selective pressure on viral functions, meaning that interferon-a/ribavirin treatment failure is not due to selection of interferon-a- or ribavirin-resistant viral variants. Several novel antiviral approaches are currently in preclinical or clinical development, and most target viral enzymes and functions, such as hepatitis C virus protease and polymerase. These new drugs all potentially select resistant viral variants both in vitro and in vivo, and resistance is therefore likely to become an important issue in clinical practice.

2009-01-01

235

Molecular Biology of Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Tuberculosis (TB) has become a curable disease thanks to the discovery of antibiotics. However, it has remained one of the most difficult infections to treat. Most current TB regimens consist of six to nine months of daily doses of four drugs that are highly toxic to patients. The purpose of these lengthy treatments is to completely eradicate Mycobacterium tuberculosis, notorious for its ability to resist most antibacterial agents, thereby preventing the formation of drug resistant mutants. On the contrary, the prolonged therapies have led to poor patient adherence. This, together with a severe limit of drug choices, has resulted in the emergence of strains that are increasingly resistant to the few available antibiotics. Here we review our current understanding of molecular mechanisms underlying the profound drug resistance of M. tuberculosis. This knowledge is essential for the development of more effective antibiotics that not only are potent against drug resistant M. tuberculosis strains but also help shorten the current treatment courses required for drug susceptible TB.

Smith, Tasha; Wolff, Kerstin A.; Nguyen, Liem

2014-01-01

236

Indoleamides are active against drug-resistant Mycobacterium tuberculosis  

PubMed Central

Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis.

Lun, Shichun; Guo, Haidan; Onajole, Oluseye K.; Pieroni, Marco; Gunosewoyo, Hendra; Chen, Gang; Tipparaju, Suresh K.; Ammerman, Nicole C.; Kozikowski, Alan P.; Bishai, William R.

2014-01-01

237

Surveillance for antimicrobial drug resistance in under-resourced countries.  

PubMed

Antimicrobial drug resistance is usually not monitored in under-resourced countries because they lack surveillance networks, laboratory capacity, and appropriate diagnostics. This accelerating problem accounts for substantial number of excess deaths, especially among infants. Infections particularly affected by antimicrobial drug resistance include tuberculosis, malaria, severe acute respiratory infections, and sepsis caused by gram-negative bacteria. Nonetheless, mapping antimicrobial drug resistance is feasible in under-resourced countries, and lessons can be learned from previous successful efforts. Specimen shipping conditions, data standardization, absence of contamination, and adequate diagnostics must be ensured. As a first step toward solving this problem, we propose that a road map be created at the international level to strengthen antimicrobial resistance surveillance in under-resourced countries. This effort should include a research agenda; a map of existing networks and recommendations to unite them; and a communication plan for national, regional, and international organizations and funding agencies. PMID:24564906

Vernet, Guy; Mary, Catherine; Altmann, Dany M; Doumbo, Ogobara; Morpeth, Susan; Bhutta, Zulfiqar A; Klugman, Keith P

2014-03-01

238

A Reservoir of Drug-Resistant Pathogenic Bacteria in Asymptomatic Hosts  

PubMed Central

The population genetics of pathogenic bacteria has been intensively studied in order to understand the spread of disease and the evolution of virulence and drug resistance. However, much less attention has been paid to bacterial carriage populations, which inhabit hosts without producing disease. Since new virulent strains that cause disease can be recruited from the carriage population of bacteria, our understanding of infectious disease is seriously incomplete without knowledge on the population structure of pathogenic bacteria living in an asymptomatic host. We report the first extensive survey of the abundance and diversity of a human pathogen in asymptomatic animal hosts. We have found that asymptomatic swine from livestock productions frequently carry populations of Salmonella enterica with a broad range of drug-resistant strains and genetic diversity greatly exceeding that previously described. This study shows how agricultural practice and human intervention may lead and influence the evolution of a hidden reservoir of pathogens, with important implications for human health.

Perron, Gabriel G.; Quessy, Sylvain; Bell, Graham

2008-01-01

239

Effect of electron beam irradiation on bacterial cellulose membranes used as transdermal drug delivery systems  

NASA Astrophysics Data System (ADS)

Ionizing radiation is an effective energetic source for polymer surfaces modification in order to obtain transdermal systems with different controlled release properties. In this work, gamma rays have been applied to induce changes in bacterial cellulose membranes. Permeation of drug (tetracycline) was theoretically and experimentally investigated starting from the effect of ?-irradiation on membranes permeability. Release and permeation of drug from irradiated and non-irradiated membranes have been performed using a diffusion cell.

Stoica-Guzun, Anicuta; Stroescu, Marta; Tache, Florin; Zaharescu, Traian; Grosu, Elena

2007-12-01

240

Dynamics of immune response and drug resistance in malaria infection  

PubMed Central

Background Malaria parasites that concurrently infect a host compete on the basis of their intrinsic growth rates and by stimulating cross-reactive immune responses that inhibit each others' growth. If the phenotypes also show different drug sensitivities ('sensitive' vs. 'resistant' strains), drug treatment can change their joint dynamics and the long-term outcome of the infection: most obviously, persistent drug pressure can permit the more resistant, but otherwise competitively-inferior, strains to dominate. Methods Here a mathematical model is developed to analyse how these and more subtle effects of antimalarial drug use are modulated by immune response, repeated re-inoculation of parasites, drug pharmacokinetic parameters, dose and treatment frequency. Results The model quantifies possible effects of single and multiple (periodic) treatment on the outcome of parasite competition. In the absence of further inoculation, the dosage and/or treatment frequency required for complete clearance can be estimated. With persistent superinfection, time-average parasite densities can be derived in terms of the basic immune-regulating parameters, the drug efficacy and treatment regimen. Conclusion The functional relations in the model are applicable to a wide range of conditions and transmission environments, allowing predictions to be made on both the individual and the community levels, and, in particular, transitions from drug-sensitive to drug-resistant parasite dominance to be projected on both levels.

Gurarie, David; McKenzie, F Ellis

2006-01-01

241

Establishing Drug Resistance in Microorganisms by Mass Spectrometry  

NASA Astrophysics Data System (ADS)

A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and 13C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well.

Demirev, Plamen A.; Hagan, Nathan S.; Antoine, Miquel D.; Lin, Jeffrey S.; Feldman, Andrew B.

2013-08-01

242

Hsp90 Governs Dispersion and Drug Resistance of Fungal Biofilms  

PubMed Central

Fungal biofilms are a major cause of human mortality and are recalcitrant to most treatments due to intrinsic drug resistance. These complex communities of multiple cell types form on indwelling medical devices and their eradication often requires surgical removal of infected devices. Here we implicate the molecular chaperone Hsp90 as a key regulator of biofilm dispersion and drug resistance. We previously established that in the leading human fungal pathogen, Candida albicans, Hsp90 enables the emergence and maintenance of drug resistance in planktonic conditions by stabilizing the protein phosphatase calcineurin and MAPK Mkc1. Hsp90 also regulates temperature-dependent C. albicans morphogenesis through repression of cAMP-PKA signalling. Here we demonstrate that genetic depletion of Hsp90 reduced C. albicans biofilm growth and maturation in vitro and impaired dispersal of biofilm cells. Further, compromising Hsp90 function in vitro abrogated resistance of C. albicans biofilms to the most widely deployed class of antifungal drugs, the azoles. Depletion of Hsp90 led to reduction of calcineurin and Mkc1 in planktonic but not biofilm conditions, suggesting that Hsp90 regulates drug resistance through different mechanisms in these distinct cellular states. Reduction of Hsp90 levels led to a marked decrease in matrix glucan levels, providing a compelling mechanism through which Hsp90 might regulate biofilm azole resistance. Impairment of Hsp90 function genetically or pharmacologically transformed fluconazole from ineffectual to highly effective in eradicating biofilms in a rat venous catheter infection model. Finally, inhibition of Hsp90 reduced resistance of biofilms of the most lethal mould, Aspergillus fumigatus, to the newest class of antifungals to reach the clinic, the echinocandins. Thus, we establish a novel mechanism regulating biofilm drug resistance and dispersion and that targeting Hsp90 provides a much-needed strategy for improving clinical outcome in the treatment of biofilm infections.

Nett, Jeniel; Rajendran, Ranjith; Ramage, Gordon; Lopez-Ribot, Jose L.; Andes, David; Cowen, Leah E.

2011-01-01

243

Cooperative Antibiotic Resistance in a Multi-Drug Environment  

NASA Astrophysics Data System (ADS)

The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share" their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.

Yurtsev, Eugene; Dai, Lei; Gore, Jeff

2013-03-01

244

Modeling the evolution of drug resistance in malaria  

PubMed Central

Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development.

Fogel, Gary B.

2012-01-01

245

Drug Resistance Pattern of MTB Isolates from PTB Patients  

PubMed Central

Background. TB is a global pandemic disease. All TB control programs were not successful due to the emergence of multidrug resistance in M. tuberculosis strains. Objective of the present study was to detect the rate of MDR-MTB in this part of India. Methods. One hundred and thirty clinical MTB strains isolated from patients on treatment and confirmed as MTB by MPT64 antigen detection were tested for drug susceptibility against Streptomycin, INH, Rifampicin, and Ethambutol by MBBact automated system. Result. Thirty-two were MDRs (25.61%). 31.2%, 28%, 17.6%, and 21.6% were resistant to INH, RIF, Ethambutol, and Streptomycin, respectively. Resistance to either INH or Rifampicin was 20.8% and 13.88%, respectively. Combined INH and Rifampicin resistance was seen in 18.05% isolates. Conclusion. Drug resistance rate is high in patients treated previously and who have been irregular on treatment.

Ranganath, Rajani; Kumar, Vijay G. S.; Ranganath, Ravi; Goud, Gangadhar; Javali, Veerabhadra

2013-01-01

246

Research Highlights: Helping Adolescents Resist Drugs.  

National Technical Information Service (NTIS)

Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills. Instead, Project ALERT is based on the theory that ado...

2000-01-01

247

Nanomechanics of drug-target interactions and antibacterial resistance detection.  

PubMed

The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures. We developed a new model(1) which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful agents to combat superbug infections. PMID:24192763

Ndieyira, Joseph W; Watari, Moyu; McKendry, Rachel A

2013-01-01

248

Antiviral drug resistance in herpesviruses other than cytomegalovirus.  

PubMed

The discovery of acyclovir (ACV), a nucleoside analogue, more than 30?years ago, represents a milestone in the management of HSV and VZV infections. The modest activity of ACV against CMV prompted the development of another nucleoside analogue, ganciclovir, for the management of systemic and organ-specific CMV diseases. Second-line agents such as the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir have been approved subsequently. In contrast to ACV and ganciclovir, the latter drugs do not require selective phosphorylation by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug-resistant mutants has been constantly reported particularly in severely immunocompromised patients such as bone marrow and solid organ transplant recipients as well as HIV-infected individuals. In this manuscript, we discuss the characteristics of the antiviral agents currently approved for the management of HSV, VZV and CMV diseases. In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed. The emergence of antiviral drug resistance is also observed with other members of the Herpesviridae family, namely HSV-1, HSV-2, VZV and HHV-6, which are the focus of this review. More specifically, we describe the laboratory methods for assessing drug susceptibilities, the frequency and clinical significance of drug-resistant infections and their management. Copyright © 2014 John Wiley & Sons, Ltd. PMID:24604770

Piret, Jocelyne; Boivin, Guy

2014-05-01

249

Neighborhood Drug Markets: A risk environment for bacterial sexually transmitted infections among urban youth  

PubMed Central

We hypothesized that neighborhoods with drug markets, as compared to those without, have a greater concentration of infected sex partners, i.e. core transmitters, and that in these areas, there is an increased risk environment for STIs. This study determined if neighborhood drug markets were associated with a high-risk sex partnership and, separately, with a current bacterial STI (chlamydia and/or gonorrhea) after controlling for individual demographic and sexual risk factors among a household sample of young people in Baltimore City, MD. Analyses also tested whether links were independent of neighborhood socioeconomic status. Data for this study were collected from a household study, systematic social observations and police arrest, public health STI surveillance and U.S. census data. Nonlinear multilevel models showed that living in neighborhoods with household survey-reported drug markets increased the likelihood of having a high-risk sex partnership after controlling for individual level demographic factors and illicit drug use and neighborhood socioeconomic status. Further, living in neighborhoods with survey-reported drug markets increased the likelihood of having a current bacterial STI after controlling for individual level demographic and sexual risk factors and neighborhood socioeconomic status. The results suggest that local conditions in neighborhoods with drug markets may play an important role in setting-up risk environments for high-risk sex partnerships and bacterial STIs. Patterns observed appeared dependent on the type of drug market indicator used. Future studies should explore how conditions in areas with local drug markets may alter sexual networks structures and whether specific types of drug markets are particularly important in determining STI risk.

Jennings, Jacky M.; Taylor, Ralph B.; Salhi, Rama A.; Furr-Holden, C.Debra M.; Ellen, Jonathan M.

2012-01-01

250

Drug rechallenge and treatment beyond progression--implications for drug resistance.  

PubMed

The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. PMID:23999218

Kuczynski, Elizabeth A; Sargent, Daniel J; Grothey, Axel; Kerbel, Robert S

2013-10-01

251

Drug abuse profile - patient delay, diagnosis delay and drug resistance pattern - among addict patients with tuberculosis.  

PubMed

Socioeconomic problems limit the access of drug users to health-care services. This descriptive cross-sectional study was carried out by making use of the medical records of new case tuberculosis (TB) patients hospitalized at Masih Daneshvari Hospital, the national referral centre in Iran, from 2003 to 2006. Demographic and personal characteristics of the patients and type of disease were collected and categorized. Of the 944 patients with confirmed TB, 143 (15.1%) were drug users, among whom 140 (97.9%) were men with just three women drug users. The mean age of the drug users group was 43.04 +/- 13.81 years. The type of drug used was opium in 100 cases (69.9%), heroin in 29 (20.3%), opium and heroin together in four (2.8%) and all three, opium, heroin and crack, in two (1.4%). For 238 high-risk patients, an HIV test was performed and HIV infection was confirmed in 33 cases. Patient delay was longer in drug users (P = 0.000) against other patients, whereas diagnosis delay was shorter (P = 0.007). Drug susceptibility tests were performed for 515 patients with positive cultures. One hundred and thirty-three (14.1%) were found to have 'any resistance' to anti-TB drugs, and 10 (1.1%) individuals had multidrug-resistant TB. Twenty-six (19.5%) of the individuals who showed resistance to first-line agents were drug users. There was no significant relation between drug resistance and drug use (P = 0.4). In conclusion, it seems that active case finding for TB and HIV in addict cases must be contained in harm reduction packages. Moreover, the manifestations of the disease should be considered seriously regardless of attributing them to drug use. PMID:19386968

Shamaei, M; Marjani, M; Baghaei, P; Chitsaz, E; Rezaei Tabar, E; Abrishami, Z; Tabarsi, P; Mansouri, D; Masjedi, M R

2009-05-01

252

Drug-resistant ventilator associated pneumonia in a tertiary care hospital in Saudi Arabia  

PubMed Central

BACKGROUND: There is a wide geographic and temporal variability of bacterial resistance among microbial causes of ventilator-associated pneumonia (VAP). The contribution of multi-drug resistant (MDR) pathogens to the VAP etiology in Saudi Arabia was never studied. We sought to examine the extent of multiple-drug resistance among common microbial causes of VAP. MATERIALS AND METHODS: We conducted a retrospective susceptibility study in the adult intensive care unit (ICU) of King Abdulaziz Medical City, Riyadh, Saudi Arabia. Susceptibility results of isolates from patients diagnosed with VAP between October 2004 and June 2009 were examined. The US National Healthcare Safety Network definition of MDR was adopted. RESULTS: A total of 248 isolates including 9 different pathogens were included. Acinetobacter spp. was highly (60-89%) resistant to all tested antimicrobials, including carbapenems (three- and four-class MDR prevalence were 86% and 69%, respectively). Pseudomonas aeruginosa was moderately (13-31%) resistant to all tested antimicrobials, including antipseudomonal penicillins (three- and four-class MDR prevalence were 13% and 10%, respectively). With an exception of ampicillin (fully resistant), Klebsiella spp. had low (0-13%) resistance to other tested antimicrobials with no detected MDR. Staphylococcus aureus was fully susceptible to vancomycin with 42% resistance to oxacillin. There were significant increasing trends of MDR Acinetobacter spp. however not P. aeruginosa during the study. Resistant pathogens were associated with worse profile of ICU patients but not patients’ outcomes. CONCLUSION: Acinetobacter in the current study was an increasingly resistant VAP-associated pathogen more than seen in many parts of the world. The current finding may impact local choice of initial empiric antibiotics.

Balkhy, Hanan H.; El-Saed, Aiman; Maghraby, Rana; Al-Dorzi, Hasan M.; Khan, Raymond; Rishu, Asgar H.; Arabi, Yaseen M.

2014-01-01

253

Drug Resistance in Malaria in Developing Countries  

Microsoft Academic Search

\\u000a A combination of complementary strategies is needed to control malaria, the most important parasitic infection causing an\\u000a enormous burden of disease throughout the world. Antimalarial drugs play a crucial role among such strategies, as they may\\u000a be used both for the treatment of cases and for their prevention. In the recent years, the treatment of malaria has been hampered\\u000a by

Quique Bassat; Pedro L. Alonso

254

Bypassing cancer drug resistance by activating multiple death pathways – A proposal from the study of circumventing cancer drug resistance by induction of necroptosis  

Microsoft Academic Search

Cancer drug resistance is a complex, dynamic, and “elusive” system rather than merely a matter of some drug-resistant factors. Current pharmacological approaches aim to restore the efficacy of the standard chemotherapy against drug-resistant cancers via reactivating apoptosis and inhibiting drug transporters, simply because the current available anticancer drugs mostly induce apoptosis and many of them are the substrates\\/inducers of the

Xun Hu; Yanyan Xuan

2008-01-01

255

Expression of Xa1, a Bacterial Blight-Resistance Gene in Rice, is Induced by Bacterial Inoculation  

Microsoft Academic Search

The Xa1 gene in rice confers resistance to Japanese race 1 of Xanthomonas oryzae pv. oryzae, the causal pathogen of bacterial blight (BB). We isolated the Xa1 gene by a map-based cloning strategy. The deduced amino acid sequence of the Xa1 gene product contains nucleotide binding sites (NBS) and a new type of leucine-rich repeats (LRR); thus, Xa1 is a

Satomi Yoshimura; Utako Yamanouchi; Yuichi Katayose; Seiichi Toki; Zi-Xuan Wang; Izumi Kono; Nori Kurata; Masahiro Yano; Nobuo Iwata; Takuji Sasaki

1998-01-01

256

New insights in the bacterial spore resistance to extreme terrestrial and extraterrestrial factors  

Microsoft Academic Search

Based on their unique resistance to various space parameters, Bacillus endospores are one of the model systems used for astrobiological studies. The extremely high resistance of bacterial endospores to environmental stress factors has intrigued researchers since long time and many characteristic spore features, especially those involved in the protection of spore DNA, have already been uncovered. The disclosure of the

Ralf Moeller; Gerda Horneck; Guenther Reitz

2010-01-01

257

Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models  

PubMed Central

Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 ?g/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD50) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria.

Li, Sheng-An

2012-01-01

258

Preventing bacterial infections and antimicrobial resistance in dialysis patients  

Microsoft Academic Search

Antimicrobial use, in concert with patient-to-patient transmission of resistant strains, has caused a rapid increase in the prevalence of antimicrobial resistance in recent years. This increase is a particular threat to dialysis patients, who often have been in the forefront of the epidemic of resistance. In this report, which was written in collaboration between the American Society of Nephrology and

Jeffrey S. Berns; Jerome I. Tokars

2002-01-01

259

Long-term evaluation of drug abuse resistance education.  

PubMed

Project DARE (Drug Abuse Resistance Education) is the most prevalent school-based drug-use prevention program in the United States, but there is little evidence of its effectiveness. Results from a longitudinal evaluation of the program in 36 schools in Illinois provide only limited support for DARE's impact on student's drug use immediately following the intervention, and no support for either continued or emerging impact on drug use 1 or 2 years after receiving DARE instruction. In addition, DARE had only limited positive effects on psychological variables (i.e., self-esteem) and no effect on social variables (e.g., peer resistance skills). Possible substantive and methodological explanations for the relative lack of DARE's effectiveness observed in this study are discussed. PMID:8036959

Ennett, S T; Rosenbaum, D P; Flewelling, R L; Bieler, G S; Ringwalt, C L; Bailey, S L

1994-01-01

260

Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use  

Microsoft Academic Search

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although\\u000a primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases\\u000a the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among\\u000a various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk

Richard H. Drew; Mary L. Townsend

2010-01-01

261

Role of Integrin Alpha4 in Drug Resistance of Leukemia  

PubMed Central

Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell–cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-?B signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia.

Shishido, Stephanie; Bonig, Halvard; Kim, Yong-Mi

2014-01-01

262

Combinatorial discovery of polymers resistant to bacterial attachment  

PubMed Central

Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these ‘hit’ materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions.

Luckett, Jeni; Cockayne, Alan; Atkinson, Steve; Mei, Ying; Bayston, Roger; Irvine, Derek J; Langer, Robert; Anderson, Daniel G; Williams, Paul; Davies, Martyn C; Alexander, Morgan R

2013-01-01

263

A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.  

PubMed

The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into the mechanisms behind and the extent of multi-drug resistance among bacteria living under an extreme antibiotic selection pressure. PMID:24204801

Marathe, Nachiket P; Regina, Viduthalai R; Walujkar, Sandeep A; Charan, Shakti Singh; Moore, Edward R B; Larsson, D G Joakim; Shouche, Yogesh S

2013-01-01

264

HIV-1 genotypic drug resistance interpretation rules - 2009 Spanish guidelines.  

PubMed

Interpreting the results of drug resistance tests for HIV-1 is one of the most difficult tasks for both clinicians and virologists. There are many amino acid changes in viral proteins influencing the susceptibility to specific drugs, causing loss of activity or conversely hypersusceptibility. Moreover, the results of interactions derived from complex mutational patterns are difficult to predict. Different interpretation algorithms have been developed to facilitate the translation of information obtained in the genotypes to clinicians. Controversy exists, however, regarding the impact of genotypic changes over the activity of many antiretroviral drugs. Based on virologic outcomes, scientific literature, and expert opinion, the Drug Resistance Platform of the Spanish AIDS Research Network (RIS, Red de Investigación en SIDA) has developed over the last years its own interpretation system. Herein, we present the 2009 guidelines, in which special efforts have been made to standardize the criteria for interpreting resistance mutations for compounds within the same drug family and to facilitate the clinical interpretation of HIV-1 resistance genotypes. PMID:19290033

de Mendoza, Carmen; Anta, Lourdes; García, Federico; Pérez-Elías, M Jesús; Gutiérrez, Félix; Llibre, Josep M; Menéndez-Arias, Luis; Dalmau, David; Soriano, Vincent

2009-01-01

265

Antimicrobial (Drug) Resistance: Vancomycin-Resistant Enterococci (VRE) Frequently Asked Questions  

MedlinePLUS

... Tools Print this page Get email updates Order publications Volunteer for NIAID-funded clinical studies related to antimicrobial (drug) resistance on ClinicalTrials.gov. Javascript Error Your browser JavaScript is turned off causing certain ...

266

Ecology and Evolution as Targets: the Need for Novel Eco-Evo Drugs and Strategies To Fight Antibiotic Resistance?†  

PubMed Central

In recent years, the explosive spread of antibiotic resistance determinants among pathogenic, commensal, and environmental bacteria has reached a global dimension. Classical measures trying to contain or slow locally the progress of antibiotic resistance in patients on the basis of better antibiotic prescribing policies have clearly become insufficient at the global level. Urgent measures are needed to directly confront the processes influencing antibiotic resistance pollution in the microbiosphere. Recent interdisciplinary research indicates that new eco-evo drugs and strategies, which take ecology and evolution into account, have a promising role in resistance prevention, decontamination, and the eventual restoration of antibiotic susceptibility. This minireview summarizes what is known and what should be further investigated to find drugs and strategies aiming to counteract the “four P's,” penetration, promiscuity, plasticity, and persistence of rapidly spreading bacterial clones, mobile genetic elements, or resistance genes. The term “drug” is used in this eco-evo perspective as a tool to fight resistance that is able to prevent, cure, or decrease potential damage caused by antibiotic resistance, not necessarily only at the individual level (the patient) but also at the ecological and evolutionary levels. This view offers a wealth of research opportunities for science and technology and also represents a large adaptive challenge for regulatory agencies and public health officers. Eco-evo drugs and interventions constitute a new avenue for research that might influence not only antibiotic resistance but the maintenance of a healthy interaction between humans and microbial systems in a rapidly changing biosphere.

Baquero, Fernando; Coque, Teresa M.; de la Cruz, Fernando

2011-01-01

267

The new concepts on overcoming drug resistance in lung cancer  

PubMed Central

Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.

Zhang, Weisan; Lei, Ping; Dong, Xifeng; Xu, Cuiping

2014-01-01

268

Production of bacterial blight resistant lines from somatichybridization between Oryza sativa L. and Oryza meyeriana L.*  

PubMed Central

Novel bacterial blight (BB) resistance gene(s) for rice was (were) introduced into a cultivated japonica rice variety Oryza sativa (cv. 8411), via somatic hybridization using the wild rice Oryza meyeriana as the donor of the resistance gene(s). Twenty-nine progenies of somatically hybridized plants were obtained. Seven somatically hybridized plants and their parents were used for AFLP (amplified fragment length polymorphism) analysis using 8 primer pairs. Results confirmed that these plants were somatic hybrids containing the characteristic bands of both parents. The morphology of the regenerated rice showed characters of both O. sativa and O. meyeriana. Two somatic hybrids showed highest BB resistance and the other 8 plants showed moderate resistance. The new germplasms with highest resistance have been used in the rice breeding program for the improvement of bacterial blight resistance.

Yan, Cheng-qi; Qian, Kai-xian; Xue, Gang-ping; Wu, Zhong-chang; Chen, Yue-lei; Yan, Qiu-sheng; Zhang, Xue-qing; Wu, Ping

2004-01-01

269

Bacterial flora and antimicrobial resistance in raw frozen cultured seafood imported to Denmark.  

PubMed

Intensified aquaculture includes the use of antimicrobials for disease control. In contrast to the situation in livestock, Escherichia coli and enterococci are not part of the normal gastrointestinal flora of fish and shrimp and therefore not suitable indicators of antimicrobial resistance in seafood. In this study, the diversity and phenotypic characteristics of the bacterial flora in raw frozen cultured and wild-caught shrimp and fish were evaluated to identify potential indicators of antimicrobial resistance. The bacterial flora cultured on various agar media at different temperatures yielded total viable counts of 4.0 × 10(4) to 3.0 × 10(5) CFU g(-1). Bacterial diversity was indicated by 16S rRNA sequence analysis of 84 isolates representing different colony types; 24 genera and 51 species were identified. Pseudomonas spp. (23% of isolates), Psychrobacter spp. (17%), Serratia spp. (13%), Exiguobacterium spp. (7%), Staphylococcus spp. (6%), and Micrococcus spp. (6%) dominated. Disk susceptibility testing of 39 bacterial isolates to 11 antimicrobials revealed resistance to ampicillin, amoxicillin-clavulanic acid, erythromycin, and third generation cephalosporins. Resistance to third generation cephalosporins was found in Pseudomonas, a genus naturally resistant to most ?-lactam antibiotics, and in Staphylococcus hominis. Half of the isolates were susceptible to all antimicrobials tested. Results indicate that identification of a single bacterial resistance indicator naturally present in seafood at point of harvest is unlikely. The bacterial flora found likely represents a processing rather than a raw fish flora because of repeated exposure of raw material to water during processing. Methods and appropriate indicators, such as quantitative PCR of resistance genes, are needed to determine how antimicrobials used in aquaculture affect resistance of bacteria in retailed products. PMID:23462087

Noor Uddin, Gazi M; Larsen, Marianne Halberg; Guardabassi, Luca; Dalsgaard, Anders

2013-03-01

270

Multi-drug resistant non-typhi salmonellae in Kenya  

Microsoft Academic Search

Two methods of plasmid characterization, restriction digest patterns and incompatibility grouping, were used to study self-transmissible multi-drug resistance among non-typhi salmonellae (NTS). Resistance to ampicillin and other commonly applied \\/Mactams was evaluated by iso-electric focusing and disc inactivation. Of the NTS isolated from blood, 75% were Salmonella typhimurium but those included several different phage types. Over 47% of isolates were

S. Kariaki; C. Gilks; J. Corkill; J. Kimari; A. Benea; P. Waiyaki; C. A. Hart

1996-01-01

271

Fine mapping of a resistance gene to bacterial leaf pustule in soybean  

Microsoft Academic Search

Soybean bacterial leaf pustule (BLP) is a prevalent disease caused by Xanthomonas axonopodis pv. glycines. Fine mapping of the BLP resistant gene, rxp, is needed to select BLP resistant soybean cultivars by marker-assisted selection (MAS). We used a total of 227 recombinant\\u000a inbred lines (RILs) derived from a cross between ‘Taekwangkong’ (BLP susceptible) and ‘Danbaekkong’ (BLP resistant) for rxp fine

Dong Hyun Kim; Kil Hyun Kim; Kyujung Van; Moon Young Kim; Suk-Ha Lee

2010-01-01

272

Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance  

PubMed Central

Purpose Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. Experimental Design Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. Results After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of ?II-tubulin, which physically interacted with shikonin. Conclusion Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.

Wu, Hao; Xie, Jiansheng; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

2013-01-01

273

Protoplast Dehydration Correlated with Heat Resistance of Bacterial Spores.  

National Technical Information Service (NTIS)

Water content of the protoplast in situ within the fully hydrated dormant bacterial spore was quantified by use of a spore in a which the complex of coat and outer (pericortex) membrane was genetically defective or chemically removed, as evidenced by susc...

S. Nakashio P. Gerhardt

1986-01-01

274

Relationship between ceftolozane-tazobactam exposure and drug resistance amplification in a hollow-fiber infection model.  

PubMed

In an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of blaCTX-M-15. This organism's blaCTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), ?-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative- and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least- and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drug-resistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification. PMID:23774429

Vanscoy, Brian; Mendes, Rodrigo E; Castanheira, Mariana; McCauley, Jennifer; Bhavnani, Sujata M; Forrest, Alan; Jones, Ronald N; Okusanya, Olanrewaju O; Friedrich, Lawrence V; Steenbergen, Judith; Ambrose, Paul G

2013-09-01

275

Antibiotic Resistance Patterns of Bacterial Isolates from Blood in San Francisco County, California, 1996-1999  

PubMed Central

Countywide antibiotic resistance patterns may provide additional information from that obtained from national sampling or individual hospitals. We reviewed susceptibility patterns of selected bacterial strains isolated from blood in San Francisco County from January 1996 to March 1999. We found substantial hospital-to-hospital variability in proportional resistance to antibiotics in multiple organisms. This variability was not correlated with hospital indices such as number of intensive care unit or total beds, annual admissions, or average length of stay. We also found a significant increase in methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, and proportional resistance to multiple antipseudomonal antibiotics. We describe the utility, difficulties, and limitations of countywide surveillance.

Labus, Brian J.; Samuel, Michael C.; Wan, Dairian T.; Reingold, Arthur L.

2002-01-01

276

Drug resistance mediated by AEG-1/MTDH/LYRIC.  

PubMed

AEG-1/MTDH/LYRIC has been shown to promote cancer progression and development. Overexpression of AEG-1/MTDH/LYRIC correlates with angiogenesis, metastasis, and chemoresistance to various chemotherapy agents in cancer cells originating from a variety of tissues. In this chapter, we focus on the role of AEG-1/MTDH/LYRIC in drug resistance. Mechanistic studies have shown that AEG-1/MTDH/LYRIC is involved in classical oncogenic pathways including Ha-Ras, myc, NF?B, and PI3K/Akt. AEG-1/MTDH/LYRIC also promotes protective autophagy by activating AMP kinase and autophagy-related gene 5. Another reported mechanism by which AEG-1/MTDH/LYRIC regulates drug resistance is by increasing loading of multidrug resistance gene (MDR) 1 mRNA to the polysome, thereby facilitating MDR1 protein translation. More recently, a novel function for AEG-1/MTDH/LYRIC as an RNA-binding protein was elucidated, which has the potential to impact expression of drug sensitivity or resistance genes. Finally, AEG-1/MTDH/LYRIC acts in microRNA-directed gene silencing via an interaction with staphylococcal nuclease and tudor domain containing 1, a component of the RNA-induced silencing complex. Altered microRNA expression and activity induced by AEG-1/MTDH/LYRIC represent an additional way that AEG-1/MTDH/LYRIC may cause drug resistance in cancer. The multiple functions of AEG-1/MTDH/LYRIC in drug resistance highlight that it is a viable target as an anticancer agent for a wide variety of cancers. PMID:23889990

Meng, Xiangbing; Thiel, Kristina W; Leslie, Kimberly K

2013-01-01

277

Drug resistant Shigella flexneri in & around Dibrugarh, north-east India  

PubMed Central

Background & objectives: Shigella flexneri is the most common species of Shigella causing diarrhoea and dysentery in Asia including India. Multidrug resistance in Shigella species has been reported worldwide and there is rising concern regarding development of fluoroquinolone resistance. This study was undertaken to find out the resistance pattern of Sh. flexneri, the commonest shigella isolated in Dibrugarh, north east India, including detection of fluoroquinolone resistance and extended spectrum beta lactamases. Methods: Stool samples collected from patients of diarrhoea and dysentery were tested for bacterial enteropathogens. Strains of Shigella species were confirmed by biochemical tests. Speciation was done using commercially available polyvalent antiserum. Antimicrobial susceptibility test was performed by Kirby Bauer disc diffusion method against 18 different antibiotics. Extended spectrum beta lactamase (ESBL) detection was done by disc approximation test as well as combination disc method and minimum inhibitory concentrations (MIC) of different antibiotics were also measured. Results: Multidrug resistance in Sh. flexneri was found to be common (90.2%) and the commonest phenotypic multi-drug resistance profile was ampicillin-tetracycline-co-trimoxazole-nalidixic acid. High resistance to nalidixic acid was detected in 90.3 per cent isolates (MIC >240 ?g/ml) and ciprofloxacin resistance was seen emerging in this region (11.2%, MIC >4 ?g/ml). Present of ESBL was phenotypically confirmed in two cases. Besides the fluoroquinolones, chloramphenicol, piperacillin-tazobactum and the third generation cephalosporins were effective in 87-100 per cent of the isolates. Interpretation & conclusions: Our study showed high resistance (MIC >240 ?g/ml) against nalidixic acid in Sh. flexneri isolates. Ciprofloxacin resistance is also emerging in this region. Shigellosis due to ESBL carrying Shigella can become a serious threat to public health. Guidelines for therapy should be monitored and modified based on regional reports of resistance to antimicrobial agents.

Nath, Reema; Saikia, Lahari; Choudhury, Gargi; Sharma, Daisy

2013-01-01

278

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa  

PubMed Central

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance.

Upcroft, Peter; Upcroft, Jacqueline A.

2001-01-01

279

Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions  

PubMed Central

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane’s biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug, 5-aza-2?-deoxycytidine (decitabine), significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod

2012-01-01

280

Bacterial hypermutation: clinical implications.  

PubMed

Heritable hypermutation in bacteria is mainly due to alterations in the methyl-directed mismatch repair (MMR) system. MMR-deficient strains have been described from several bacterial species, and all of the strains exhibit increased mutation frequency and recombination, which are important mechanisms for acquired drug resistance in bacteria. Antibiotics select for drug-resistant strains and refine resistance determinants on plasmids, thus stimulating DNA recombination via the MMR system. Antibiotics can also act as indirect promoters of antibiotic resistance by inducing the SOS system and certain error-prone DNA polymerases. These alterations have clinical consequences in that efficacious treatment of bacterial infections requires high doses of antibiotics and/or a combination of different classes of antimicrobial agents. There are currently few new drugs with low endogenous resistance potential, and the development of such drugs merits further research. PMID:21349992

Jolivet-Gougeon, Anne; Kovacs, Bela; Le Gall-David, Sandrine; Le Bars, Hervé; Bousarghin, Latifa; Bonnaure-Mallet, Martine; Lobel, Bernard; Guillé, François; Soussy, Claude-James; Tenke, Peter

2011-05-01

281

"Applied" Aspects of the Drug Resistance Strategies Project  

ERIC Educational Resources Information Center

This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1," in order to consider theory-grounded, theory testing and theory developing applied research. We…

Hecht, Michael L.; Miller-Day, Michelle A.

2010-01-01

282

Use of intravenous immunoglobulins in drug-resistant epilepsy  

Microsoft Academic Search

Among the 257 pediatric patients examined, 104 were classified as having drug-resistant epilepsy (DRE). In all of them genetic, metabolic, chromosomal and infectious causes were investigated, and brain imaging with computed tomography scans and nuclear magnetic resonance were obtained. Since treatment with gammaglobulins (GGs) has been reported to be useful in pediatric cases of epilepsy, informed consent for GGs treatment

A. Fois; M. Vascotto

1990-01-01

283

Drug Abuse Resistance Education Program (DARE). Evaluation Report.  

ERIC Educational Resources Information Center

This paper presents an evaluation of the Drug Abuse Resistance Education (DARE) Program, an integral part of the fifth grade curriculum in 84 elementary schools in the Broward County (Florida) Public Schools. During the 1992-93 school year, nearly 12,000 fifth grade students attended DARE classes taught by 43 trained law enforcement officers.…

Blasik, Katherine A.; Belsito, Roseanne

284

Trypanocidal drug resistance in eastern province of Zambia  

Microsoft Academic Search

A survey to investigate resistance to drugs used in the treatment of bovine trypanosomosis was conducted in the eastern province of Zambia between 1996 and 1998. A cross-sectional study was conducted in three districts (Petauke, Katete, Lundazi) at 34 village sampling sites selected at random from villages that had shown greater than 6% prevalence of bovine trypanosomosis during an earlier

L. Sinyangwe; V. Delespaux; J. Brandt; S. Geerts; J. Mubanga; N. Machila; P. H. Holmes; M. C. Eisler

2004-01-01

285

Excess Mortality Associated with Antimicrobial Drug-Resistant Salmonella Typhimurium  

Microsoft Academic Search

In a matched cohort study, we determined the death rates associated with drug resistance in Salmonella Typhimurium. We linked data from the Danish Surveillance Registry for Enteric Pathogens with the Civil Registration System and the Danish National Discharge Registry. By survival analysis, the 2-year death rates were compared with a matched sample of the general Danish population, after the data

Morten Helms; Pernille Vastrup; Peter Gerner-Smidt; Kåre Mølbak

286

Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents  

ERIC Educational Resources Information Center

This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and…

Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.

2011-01-01

287

P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases  

PubMed Central

Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive.

Picchianti-Diamanti, Andrea; Rosado, Maria Manuela; Scarsella, Marco; Lagana, Bruno; D'Amelio, Raffaele

2014-01-01

288

Enterococcus faecalis Constitutes an Unusual Bacterial Model in Lysozyme Resistance  

Microsoft Academic Search

Lysozyme is an important and widespread compound of the host constitutive defense system, and it is assumed that Enterococcus faecalis is one of the few bacteria that are almost completely lysozyme resistant. On the basis of the sequence analysis of the whole genome of E. faecalis V583 strain, we identified two genes that are potentially involved in lysozyme resistance, EF_0783

Laurent Hebert; Pascal Courtin; Riccardo Torelli; Maurizio Sanguinetti; Marie-Pierre Chapot-Chartier; Yanick Auffray; Abdellah Benachour

2007-01-01

289

Resistance of bacterial biofilms to disinfectants: a review  

Microsoft Academic Search

A biofilm can be defined as a community of microorganisms adhering to a surface and surrounded by a complex matrix of extrapolymeric substances. It is now generally accepted that the biofilm growth mode induces microbial resistance to disinfection that can lead to substantial economic and health concerns. Although the precise origin of such resistance remains unclear, different studies have shown

A. Bridier; R. Briandet; V. Thomas; F. Dubois-Brissonnet

2011-01-01

290

Protein expression profiles indicative for drug resistance of non-small cell lung cancer  

Microsoft Academic Search

Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic

M Volm; R Koomägi; J Mattern; T Efferth

2002-01-01

291

Characterization of a novel metabolic strategy used by drug-resistant tumor cells  

Microsoft Academic Search

Acquired or inherent drug resistance is the major problem in achieving successful cancer treat- ment. However, the mechanism(s) of pleiotropic drug resistance remains obscure. We have identified and characterized a cellular metabolic strategy that differ- entiates drug-resistant cells from drug-sensitive cells. This strategy may serve to protect drug-resistant cells from damage caused by chemotherapeutic agents and radiation. We show that

MARY-ELLEN HARPER; ANDREAS ANTONIOU; ELIZABETH VILLALOBOS-MENUEY; ALICIA RUSSO; RICHARD TRAUGER; MINDA VENDEMELIO; AMANDA GEORGE; RICHARD BARTHOLOMEW; DENNIS CARLO; AZHAR SHAIKH; JAMI KUPPERMAN; EVAN W. NEWELL; IVAN A. BESPALOV; SUSAN S. WALLACE; YE LIU; JEFFREY R. ROGERS; GREGORY L. GIBBS; JACK L. LEAHY; ROBERT E. CAMLEY; ROBERT MELAMEDE; M. KAREN NEWELL

2002-01-01

292

Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Efflux pumps are membrane proteins capable of actively transporting a broad range of substrates from the cytoplasm to the exterior of the cell. Increased efflux activity in response to drug treatment may be the first step in the development of bacterial drug resistance. Previous studies showed that the efflux pump Mmr was significantly overexpressed in strains exposed to isoniazid. In the work to be described, we constructed mutants lacking or overexpressing Mmr in order to clarify the role of this efflux pump in the development of resistance to isoniazid and other drugs in M. tuberculosis. The mmr knockout mutant showed an increased susceptibility to ethidium bromide, tetraphenylphosphonium, and cetyltrimethylammonium bromide (CTAB). Overexpression of mmr caused a decreased susceptibility to ethidium bromide, acriflavine, and safranin O that was obliterated in the presence of the efflux inhibitors verapamil and carbonyl cyanide m-chlorophenylhydrazone. Isoniazid susceptibility was not affected by the absence or overexpression of mmr. The fluorometric method allowed the detection of a decreased efflux of ethidium bromide in the knockout mutant, whereas the overexpressed strain showed increased efflux of this dye. This increased efflux activity was inhibited in the presence of efflux inhibitors. Under our experimental conditions, we have found that efflux pump Mmr is mainly involved in the susceptibility to quaternary compounds such as ethidium bromide and disinfectants such as CTAB. The contribution of this efflux pump to isoniazid resistance in Mycobacterium tuberculosis still needs to be further elucidated.

Rodrigues, Liliana; Villellas, Cristina; Bailo, Rebeca; Viveiros, Miguel

2013-01-01

293

Antimicrobial drug resistance of Staphylococcus aureus in dairy products  

PubMed Central

Objective To evaluate the prevalence of multidrug resistant Staphylococcus aureus (S. aureus) in dairy products. Methods Isolation and identification of S. aureus were performed in 3 dairy-based food products. The isolates were tested for their susceptibility to 5 different common antimicrobial drugs. Results Of 50 samples examined, 5 (10%) were contaminated with S. aureus. Subsequently, the 5 isolates were subjected to antimicrobial resistance pattern using five antibiotic discs (methicillin, vancomycin, kanamycin, chloramphenicol and tetracycline). Sample 29 showed resistance to methicillin and vancomycin. Sample 18 showed intermediate response to tetracycline. The other samples were susceptible to all the antibiotics tested. Conclusions The results provide preliminary data on sources of food contamination which may act as vehicles for the transmission of antimicrobial-resistant Staphylococcus. Therefore, it enables us to develop preventive strategies to avoid the emergence of new strains of resistant S. aureus.

Sasidharan, S; Prema, B; Yoga, Latha L

2011-01-01

294

Diagnostic microarray for human and animal bacterial diseases and their virulence and antimicrobial resistance genes.  

PubMed

Rapid diagnosis and treatment of disease is often based on the identification and characterization of causative agents derived from phenotypic characteristics. Current methods can be laborious and time-consuming, often requiring many skilled personnel and a large amount of lab space. The objective of our study was to develop a spotted microarray for rapid identification and characterization of bacterial pathogens and their antimicrobial resistance genes. Our spotted microarray consists of 489 70mer probes that detect 40 bacterial pathogens of medical, veterinary and zoonotic importance (including 15 NIAID Category A, B and C pathogens); associated genes that encode resistance for antimicrobial and metal resistance; and DNA elements that are important for horizontal gene transfer among bacteria. High specificity and reliability of the microarray was achieved for bacterial pathogens of animal and human importance by validating MDR pathogenic bacteria as pure cultures or by following their inoculation in complex and highly organic sample matrices, such as soil and manure. PMID:20035807

Peterson, Greg; Bai, Jianfa; Nagaraja, T G; Narayanan, Sanjeev

2010-03-01

295

Modeling mass drug treatment and resistant filaria disease transmission  

NASA Astrophysics Data System (ADS)

It has been indicated that a long term application of combined mass drug treatment may contribute to the development of drug resistance in lymphatic filariasis. This phenomenon is not well understood due to the complexity of filaria life cycle. In this paper we formulate a mathematical model for the spread of mass drug resistant in a filaria endemic region. The model is represented in a 13-dimensional Host-Vector system. The basic reproductive ratio of the system which is obtained from the next generation matrix, and analysis of stability of both the disease free equilibrium and the coexistence equilibria are shown. Numerical simulation for long term dynamics for possible field conditions is also shown.

Fuady, A. M.; Nuraini, N.; Soewono, E.; Tasman, H.; Supriatna, A. K.

2014-03-01

296

Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen  

PubMed Central

The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control.

Shenoi, Sheela; Friedland, Gerald

2009-01-01

297

Broad-spectrum in vitro antibacterial activities of clay minerals against antibiotic-susceptible and antibiotic-resistant bacterial pathogens  

PubMed Central

SYNOPSIS Objectives The capacity to properly address the worldwide incidence of infectious diseases lies in the ability to detect, prevent, and effectively treat these infections. Therefore, identifying and analyzing inhibitory agents are worthwhile endeavors in an era when few new classes of effective antimicrobials have been developed. The use of geological nanomaterials to heal skin infections has been evident since the earliest recorded history, and specific clay minerals may prove valuable in the treatment of bacterial diseases, including infections for which there are no effective antibiotics, such as Buruli ulcer and multi-drug resistant infections. Methods We have subjected two iron-rich clay minerals, which have previously been used to treat Buruli ulcer patients, to broth culture testing of antibiotic-susceptible and -resistant pathogenic bacteria to assess the feasibility of using clay minerals as therapeutic agents. Results One specific mineral, CsAg02, demonstrated bactericidal activity against pathogenic Escherichia coli, extended-spectrum ?-lactamase (ESBL) E. coli, S. enterica serovar Typhimurium, Pseudomonas aeruginosa, and Mycobacterium marinum and a combined bacteriostatic/bactericidal effect against Staphylococcus aureus, penicillin-resistant S. aureus (PRSA), methicillin-resistant S. aureus (MRSA), and Mycobacterium smegmatis, while another mineral with similar structure and bulk crystal chemistry, CsAr02, had no effect on or enhanced bacterial growth. The <0.2 ?m fraction of CsAg02 and CsAg02 heated to 200°C or 550°C retained bactericidal activity, while cation-exchanged CsAg02 and CsAg02 heated to 900°C no longer killed E. coli. Conclusions Our results indicate that specific mineral products have intrinsic, heat-stable antibacterial properties, which could provide an inexpensive treatment against numerous human bacterial infections.

HAYDEL, SHELLEY E.; REMENIH, CHRISTINE M.; WILLIAMS, LYNDA B.

2008-01-01

298

Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations  

PubMed Central

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p?=?0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Pena, Alejandro; Delgado, Rafael; Cordoba, Juan; Aguilera, Antonio; Vidal, Carmen; Garcia, Federico; CoRIS

2014-01-01

299

The "Connection" Between HIV Drug Resistance and RNase H  

PubMed Central

Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic analysis for drug resistance is limited to the first ?300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance.

Delviks-Frankenberry, Krista A.; Nikolenko, Galina N.; Pathak, Vinay K.

2010-01-01

300

Latency of Plasmodium merozoites and drug-resistance. A review.  

PubMed

The authors summarize the results of recent work evidencing the existence of latent merozoites during the course of the erythrocytic cycle of the rodent Plasmodia. These merozoites, unlike the majority of merozoites released at schizogony, do not penetrate immediately into the erythrocytes and remain latent for a variable length of time. The merozoites of each of the species or subspecies show marked peculiarities which are responsible for the characteristics of their cycle. The presence of latent merozoites free in the blood, the asynchronous development, and the resistance to chloroquine, are three closely related factors. Knowing that the merozoite is so far drug resistant, and that latent merozoites can maintain the infection for any length of time, it appears important to take into account these purely biological data, when studying the drug resistance of the human falciparum malaria. PMID:9140478

Landau, I; Chabaud, A G

1994-06-01

301

Advances in Molecular Diagnosis of HBV Infection and Drug Resistance  

PubMed Central

Serological markers are key elements in diagnosing acute hepatitis B virus (HBV) infection and determining its possible evolution towards chronicity. Once treatment of chronic HBV is initiated with approved anti-hepadnaviral agents, such as lamivudine, interferon-alpha, or adefovir dipivoxil, the measurement of HBV DNA in serum can not only help monitor treatment efficacy but also indicates breakthrough infection should drug resistance emerge. Advances in the molecular diagnosis of drug resistance using highly sensitive methodologies such as DNA hybridization assays can further pinpoint the type of mutation responsible and, more importantly, detect upcoming viral resistance at an early stage when the variant represents only a minor fraction of the total viral population. Such new tools are especially relevant for patients at high risk for disease progression or acute exacerbation. Recent diagnostic developments including HBV genotyping and precore/core promoter assays that could well play important future roles in HBV patient management are also reviewed.

2005-01-01

302

Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance.  

PubMed Central

Tetracycline has been a widely used antibiotic because of its low toxicity and broad spectrum of activity. However, its clinical usefulness has been declining because of the appearance of an increasing number of tetracycline-resistant isolates of clinically important bacteria. Two types of resistance mechanisms predominate: tetracycline efflux and ribosomal protection. A third mechanism of resistance, tetracycline modification, has been identified, but its clinical relevance is still unclear. For some tetracycline resistance genes, expression is regulated. In efflux genes found in gram-negative enteric bacteria, regulation is via a repressor that interacts with tetracycline. Gram-positive efflux genes appear to be regulated by an attenuation mechanism. Recently it was reported that at least one of the ribosome protection genes is regulated by attenuation. Tetracycline resistance genes are often found on transmissible elements. Efflux resistance genes are generally found on plasmids, whereas genes involved in ribosome protection have been found on both plasmids and self-transmissible chromosomal elements (conjugative transposons). One class of conjugative transposon, originally found in streptococci, can transfer itself from streptococci to a variety of recipients, including other gram-positive bacteria, gram-negative bacteria, and mycoplasmas. Another class of conjugative transposons has been found in the Bacteroides group. An unusual feature of the Bacteroides elements is that their transfer is enhanced by preexposure to tetracycline. Thus, tetracycline has the double effect of selecting for recipients that acquire a resistance gene and stimulating transfer of the gene.

Speer, B S; Shoemaker, N B; Salyers, A A

1992-01-01

303

Validating the Vitality Strategy for Fighting Drug Resistance  

PubMed Central

The current challenge in designing effective drugs against HIV-1 is to find novel candidates with high potency, but with a lower susceptibility to mutations associated with drug resistance. Trying to address this challenge we developed in our previous study1 a novel computational strategy for fighting drug resistance by predicting the likely moves of the virus through constraints on binding and catalysis. This has been based on calculating the vitality values (defined as the ratio ((Kikcat/KM)mutant/ (Kikcat/KM)wild-type) and using it as guide for the moves of the virus. The corresponding calculations of the binding affinity, Ki, were based on using the semi-macroscopic version of the protein dipole Langevin dipole (PDLD/S) in its linear response approximation (LRA) in its ? version (PDLD/S-LRA/?). We, also, calculate the proteolytic efficiency, kcat/KM, by evaluating the transition state (TS) binding free energies using the PDLD/S-LRA/? method. Here we provide an extensive validation of our strategy by calculating the vitality of six existing clinical and experimental drug candidates. It is found that the computationally determined vitalities correlate reasonably well with those derived from the corresponding experimental data. This indicates that the calculated vitality may be used to identify mutations that would be most effective for the survival of the virus. Thus, it should be possible to use our approach in screening for mutations that would provide the most effective resistance to any proposed antiviral drug. This ability should be very useful in guiding the design of drug molecules that will lead to the slowest resistance.

Singh, Nidhi; Frushicheva, Maria P.; Warshel, Arieh

2012-01-01

304

Using experimental evolution to explore natural patterns between bacterial motility and resistance to bacteriophages.  

PubMed

Resistance of bacteria to phages may be gained by alteration of surface proteins to which phages bind, a mechanism that is likely to be costly as these molecules typically have critical functions such as movement or nutrient uptake. To address this potential trade-off, we combine a systematic study of natural bacteria and phage populations with an experimental evolution approach. We compare motility, growth rate and susceptibility to local phages for 80 bacteria isolated from horse chestnut leaves and, contrary to expectation, find no negative association between resistance to phages and bacterial motility or growth rate. However, because correlational patterns (and their absence) are open to numerous interpretations, we test for any causal association between resistance to phages and bacterial motility using experimental evolution of a subset of bacteria in both the presence and absence of naturally associated phages. Again, we find no clear link between the acquisition of resistance and bacterial motility, suggesting that for these natural bacterial populations, phage-mediated selection is unlikely to shape bacterial motility, a key fitness trait for many bacteria in the phyllosphere. The agreement between the observed natural pattern and the experimental evolution results presented here demonstrates the power of this combined approach for testing evolutionary trade-offs. PMID:21509046

Koskella, Britt; Taylor, Tiffany B; Bates, Jennifer; Buckling, Angus

2011-11-01

305

Using experimental evolution to explore natural patterns between bacterial motility and resistance to bacteriophages  

PubMed Central

Resistance of bacteria to phages may be gained by alteration of surface proteins to which phages bind, a mechanism that is likely to be costly as these molecules typically have critical functions such as movement or nutrient uptake. To address this potential trade-off, we combine a systematic study of natural bacteria and phage populations with an experimental evolution approach. We compare motility, growth rate and susceptibility to local phages for 80 bacteria isolated from horse chestnut leaves and, contrary to expectation, find no negative association between resistance to phages and bacterial motility or growth rate. However, because correlational patterns (and their absence) are open to numerous interpretations, we test for any causal association between resistance to phages and bacterial motility using experimental evolution of a subset of bacteria in both the presence and absence of naturally associated phages. Again, we find no clear link between the acquisition of resistance and bacterial motility, suggesting that for these natural bacterial populations, phage-mediated selection is unlikely to shape bacterial motility, a key fitness trait for many bacteria in the phyllosphere. The agreement between the observed natural pattern and the experimental evolution results presented here demonstrates the power of this combined approach for testing evolutionary trade-offs.

Koskella, Britt; Taylor, Tiffany B; Bates, Jennifer; Buckling, Angus

2011-01-01

306

How Fitness Reduced, Antimicrobial Resistant Bacteria Survive and Spread: A Multiple Pig - Multiple Bacterial Strain Model  

PubMed Central

More than 30% of E. coli strains sampled from pig farms in Denmark over the last five years were resistant to the commonly used antimicrobial tetracycline. This raises a number of questions: How is this high level sustained if resistant bacteria have reduced growth rates? Given that there are multiple susceptible and resistant bacterial strains in the pig intestines, how can we describe their coexistence? To what extent does the composition of these multiple strains in individual pigs influence the total bacterial population of the pig pen? What happens to a complex population when antimicrobials are used? To investigate these questions, we created a model where multiple strains of bacteria coexist in the intestines of pigs sharing a pen, and explored the parameter limits of a stable system; both with and without an antimicrobial treatment. The approach taken is a deterministic bacterial population model with stochastic elements of bacterial distributions and transmission. The rates that govern the model are process-oriented to represent growth, excretion, and uptake from environment, independent of herd and meta-population structures. Furthermore, an entry barrier and elimination process for the individual strains in each pig were implemented. We demonstrate how competitive growth between multiple bacterial strains in individual pigs, and the transmission between pigs in a pen allow for strains of antimicrobial resistant bacteria to persist in a pig population to different extents, and how quickly they can become dominant if antimicrobial treatment is initiated. The level of spread depends in a non-linear way of the parameters that govern excretion and uptake. Furthermore, the sampling of initial distributions of strains and stochastic transmission events give rise to large variation in how homogenous and how resistant the bacterial population becomes. Most important: resistant bacteria are demonstrated to survive with a disadvantage in growth rate of well over 10%.

Graesb?ll, Kaare; Nielsen, S?ren Saxmose; Toft, Nils; Christiansen, Lasse Engbo

2014-01-01

307

Management of anthelmintic resistance: inheritance of resistance and selection with persistent drugs.  

PubMed

Resistance to the benzimidazole (BZ) anthelmintics is inherited as an incomplete dominant/ incomplete recessive trait and is now widespread in populations of gastrointestinal nematode parasites of sheep. Unlike benzimidazole resistance, which is common in Haemonchus contortus, Trichostrongylus colubriformis and Ostertagia circumcincta, resistance to levamisole is relatively rare in H. contortus, although common in the other 2 species. One explanation for the slow spread of resistance to levamisole in H. contortus is that it is inherited as an autosomal recessive trait, while in T. colubriformis levamisole resistance is inherited as a recessive sex-linked trait. With the introduction of the avermectin/milbemycin class resistance has developed to the relatively short-acting ivermectin, but this time it is inherited as a completely dominant trait. The potentially more serious situation of a persistent anthelmintic selecting a dominant resistance gene was investigated using a simulation model. Efficacy against incoming infective larvae (L3) was assumed to decline or remain high over the period of drug persistence (3 days to 4 weeks), thus allowing the estimation of the relative importance of selecting resistant L3s on the development of resistance in the worm population. These factors were also examined against a background of initial efficacy levels, against adults, and mode of inheritance. Persistence and initial efficacy were found to be far more important in determining the rate of selection for resistance than was selection of resistant L3 as drug efficacy declined. PMID:8923146

Dobson, R J; LeJambre, L; Gill, J H

1996-01-01

308

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.  

PubMed

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens. PMID:23100499

Falzon, Dennis; Gandhi, Neel; Migliori, Giovanni B; Sotgiu, Giovanni; Cox, Helen S; Holtz, Timothy H; Hollm-Delgado, Maria-Graciela; Keshavjee, Salmaan; DeRiemer, Kathryn; Centis, Rosella; D'Ambrosio, Lia; Lange, Christoph G; Bauer, Melissa; Menzies, Dick

2013-07-01

309

Nanomechanical detection of antibiotic-mucopeptide binding in a model for superbug drug resistance.  

PubMed

The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements have quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions activated by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also have an impact on our understanding of antibiotic drug action in bacteria. PMID:18989336

Ndieyira, Joseph Wafula; Watari, Moyu; Barrera, Alejandra Donoso; Zhou, Dejian; Vögtli, Manuel; Batchelor, Matthew; Cooper, Matthew A; Strunz, Torsten; Horton, Mike A; Abell, Chris; Rayment, Trevor; Aeppli, Gabriel; McKendry, Rachel A

2008-11-01

310

Analysis of some common pathogens and their drug resistance to antibiotics  

PubMed Central

Objective: To investigate the common bacterial resistance of clinical isolates in our hospital in the second half of 2011. Methodology: Pathogens isolated from clinical samples in the second half of 2011 were analyzed and categorized to perform susceptibility tests. Results: In the gram-negative bacteria, Enterobacteriaceae and non-fermenting gram-negative bacilli accounted for 55.89% and 34.51%. In the gram-positive bacteria, Staphylococcus aureus, Coagulase-negative staphylococci, Enterococcus, Strptococcus pneumonia accounted for 32.85%, 40.39%, 12.41% and 10.22%, respectively. Other species accounted for 4.14%. Klebsiella pneumonia and Pseudomonas aeruginosa were sensitive to cepoperazon, cefepime and imipenem. However,Acinetobacter baumannii was more sensitive to carbapenems antibiotics, which was followed by fourth generation cephalosporins. Klebsiella pneumoniae was extremely sensitive to amikacin, cefepime and imipenem, but was resistant to ampicillin. The detection rates of the broad-spectrum Escherichia coli, Pseudomonasaeruginosa and Klebsiella pneumoniae were 54.51%, 52.08% and 38.65%. The gram negative bacilli were the prevalent clinical pathogens in our hospital in the second half of 2011. Conclusion: The drug resistance of pathogenic bacteria has increased significantly recently, thus the surveillance of antibacterial agents is necessary, and rational use of antibiotic will be urgently needed to reduce the production and dissemination of drug resistant strains.

Bao, Lidao; Peng, Rui; Ren, Xianhua; Ma, Ruilian; Li, Junping; Wang, Yi

2013-01-01

311

Differential protein expressions in breast cancer between drug sensitive tissues and drug resistant tissues  

PubMed Central

Objective To investigate the differential expression of the sensitive and resistant relative proteins in human breast cancer tissue. Methods A drug sensitive group and a drug resistant group for chemotherapy in patients with breast cancer were selected through neoadjuvant therapy. The differential protein expression in 2 groups was detected by proteomic techniques, and parts of differential proteins were identified by Western blotting. Results There were 13 differential proteins in the 2 groups, in which the expression of 3 proteins was up-regulated and 10 down-regulated. Seven proteins were identified by Western blotting. The expressions of keratin type I cytoskeletal 19 (KIC19) and thymidine phosphorylase (TYPH) were up-regulated, and the expressions of heat shock protein 27 (HSP27), keratin type I cytoskeletal 9 (KIC9), collagen alpha-2(VI) (CO6A2), vimentin (VIME), and actin cytoplasmic 1 (ACTB) were down-regulated in the drug resistant group. There were significant differences between these 2 groups (P<0.01). Conclusions The expressions of KIC19 and TYPH may be correlated with drug resistance in patients with breast cancer, and HSP27, KIC9, CO6A2, VIME, and ACTB may be correlated with drug sensitivity.

Peng, Jing; Zhang, Yajie; Fu, Fenfen; Zou, Qiongyan; Tang, Yuanyuan

2013-01-01

312

Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?  

PubMed Central

SUMMARY Hosts and bacteria have coevolved over millions of years, during which pathogenic bacteria have modified their virulence mechanisms to adapt to host defense systems. Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. However, although antimicrobial resistance and bacterial virulence have developed on different timescales, they share some common characteristics. This review considers how bacterial virulence and fitness are affected by antibiotic resistance and also how the relationship between virulence and resistance is affected by different genetic mechanisms (e.g., coselection and compensatory mutations) and by the most prevalent global responses. The interplay between these factors and the associated biological costs depend on four main factors: the bacterial species involved, virulence and resistance mechanisms, the ecological niche, and the host. The development of new strategies involving new antimicrobials or nonantimicrobial compounds and of novel diagnostic methods that focus on high-risk clones and rapid tests to detect virulence markers may help to resolve the increasing problem of the association between virulence and resistance, which is becoming more beneficial for pathogenic bacteria.

Beceiro, Alejandro; Tomas, Maria

2013-01-01

313

Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis  

Microsoft Academic Search

Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been

Feng Wang; Catherine Vilchèze; Gulcin Gulten; Robert Langley; Jacobs Jr. William R

2009-01-01

314

Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure.  

PubMed

Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L.?donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb(III) drug pressure. PMID:24020363

Berg, Maya; Vanaerschot, Manu; Jankevics, Andris; Cuypers, Bart; Maes, Ilse; Mukherjee, Sandip; Khanal, Basudha; Rijal, Suman; Roy, Syamal; Opperdoes, Fred; Breitling, Rainer; Dujardin, Jean-Claude

2013-10-01

315

Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors  

NASA Astrophysics Data System (ADS)

The widespread misuse of drugs has increased the number of multiresistant bacteria, and this means that tools that can rapidly detect and characterize bacterial response to antibiotics are much needed in the management of infections. Various techniques, such as the resazurin-reduction assays, the mycobacterial growth indicator tube or polymerase chain reaction-based methods, have been used to investigate bacterial metabolism and its response to drugs. However, many are relatively expensive or unable to distinguish between living and dead bacteria. Here we show that the fluctuations of highly sensitive atomic force microscope cantilevers can be used to detect low concentrations of bacteria, characterize their metabolism and quantitatively screen (within minutes) their response to antibiotics. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing that live bacteria produced larger cantilever fluctuations than bacteria exposed to antibiotics. Our preliminary experiments suggest that the fluctuation is associated with bacterial metabolism.

Longo, G.; Alonso-Sarduy, L.; Rio, L. Marques; Bizzini, A.; Trampuz, A.; Notz, J.; Dietler, G.; Kasas, S.

2013-07-01

316

Prevalence of Extensively Drug Resistant Tuberculosis among Archived Multidrug Resistant Tuberculosis Isolates in Zimbabwe  

PubMed Central

We conducted a cross-sectional study of second line drug resistance patterns and genetic diversity of MDR-TB isolates archived at the BRTI-TB Laboratory, Harare, between January 2007 and December 2011. DSTs were performed for second line antituberculosis drugs. XDR-TB strains were defined as MDR-TB strains with resistance to either kanamycin and ofloxacin or capreomycin and ofloxacin. Strain types were identified by spoligotyping. No resistance to any second line drugs was shown in 73% of the isolates, with 23% resistant to one or two drugs but not meeting the definition of XDR-TB. A total of 26 shared types were identified, and 18 (69%) matched preexisting shared types in the current published spoligotype databases. Of the 11 out of 18 clustered SITs, 4 predominant (>6 isolates per shared type) were identified. The most and least abundant types were SIT 1468 (LAM 11-ZWE) with 12 (18%) isolates and SIT 53 (T1) with 6 (9%) isolates, respectively. XDR-TB strains are rare in Zimbabwe, but the high proportion of “pre-XDR-TB” strains and treatment failure cases is of concern. The genetic diversity of the MDR-TB strains showed no significant association between SITs and drug resistance.

Sagonda, Tichaona; Mupfumi, Lucy; Manzou, Rumbidzai; Makamure, Beauty; Tshabalala, Mqondisi; Gwanzura, Lovemore; Mason, Peter; Mutetwa, Reggie

2014-01-01

317

Polyether ionophores: broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites.  

PubMed

Background: As multidrug-resistant (MDR) pathogens continue to emerge, there is a substantial amount of pressure to identify new drug candidates. Carboxyl polyethers, also referred to as polyether antibiotics, are a unique class of compounds with outstanding potency against a variety of critical infectious disease targets including protozoa, bacteria and viruses. The characteristics of these molecules that are of key interest are their selectivity and high potency against several MDR etiological agents. Objective: Although many studies have been published about carboxyl polyether antibiotics, there are no recent reviews of this class of drugs. The purpose of this review is to provide the reader with an overview of the spectrum of activity of polyether antibiotics, their mechanism of action, toxicity and potential as drug candidates to combat drug-resistant infectious diseases. Conclusion: Polyether ionophores show a high degree of promise for the potential control of drug-resistant bacterial and parasitic infections. Despite the long history of use of this class of drugs, very limited medicinal chemistry and drug optimization studies have been reported, thus leaving the door open to these opportunities in the future. Scifinder and PubMed were the main search engines used to locate articles relevant to the topic presented in the present review. Keywords used in our search were specific names of each of the 88 compounds presented in the review as well as more general terms such as polyethers, ionophores, carboxylic polyethers and polyether antibiotics. PMID:23480512

Kevin Ii, Dion A; Meujo, Damaris Af; Hamann, Mark T

2009-02-01

318

Quantification of antibiotic drug potency by a two-compartment radioassay of bacterial growth  

SciTech Connect

The two-compartment radioassay for microbial kinetics based on continuous measurement of the {sup 14}CO{sub 2} released by bacterial metabolism of 14C-labeled substrate offers a valuable approach to testing the potency of antimicrobial drugs. By using a previously validated radioassay with gram-positive and gram-negative bacteria, a group of protein synthesis inhibitors was evaluated for their effect on microbial growth kinetics. All tested drugs induced changes in both the slopes and intercepts of the growth curves. An exponential growth model was applied to quantify the drug effect on the processes of bacterial {sup 14}CO{sub 2} liberation and cell generation. The response was measured in terms of a generation rate constant. A linear dependence of the generation rate constant on the dose of spectinomycin was observed with Escherichia coli. Sigmoidal-shaped curves were found in the assays of chloramphenicol and tetracycline. The implications of dose-response curves are discussed on the basis of the receptor site concept for drug action. The assay sensitivities for chloramphenicol and tetracycline were similar to those obtained by the cell counting method, but the sensitivity of the radioassay was at least 10 times greater for spectinomycin.

Boonkitticharoen, V.; Ehrhardt, J.C.; Kirchner, P.T. (Univ. of Iowa, Iowa City (USA))

1990-06-01

319

Bacterial resistance ATPases: primary pumps for exporting toxic cations and anions.  

PubMed

Bacterial plasmid resistance systems that maintain low intracellular levels of toxic heavy metals by pumping the substrates out as rapidly as they accumulate sometimes work at the biochemical level as efflux ATPases. The two systems responsible for arsenic and cadmium resistance have recently been sequenced. Comparison of the deduced amino acid sequences with those of better characterized ATPases has revealed certain structural and sequence similarities. PMID:2523097

Silver, S; Nucifora, G; Chu, L; Misra, T K

1989-02-01

320

21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.  

Code of Federal Regulations, 2010 CFR

. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid reagent primers and probes together with software for predicting drug resistance/susceptibility based on results obtained with these primers and...

2009-04-01

321

Chemosensitisation of drug-resistant and drug-sensitive yeast cells to antifungals.  

PubMed

Multidrug resistance in yeast results from overexpression of genes encoding drug efflux transporters owing to gain-of-function mutations in transcription factors regulating their expression. We have screened a library of synthetic compounds for modulators of drug resistance using the multidrug-resistant Saccharomyces cerevisiae pdr3-9 mutant strain. One of the compounds, 7-chlorotetrazolo[5,1-c]benzo[1,2,4]triazine (CTBT), displayed weak antifungal activity and strongly inhibited the growth of yeast cells in combination with subinhibitory concentrations of other antifungals with a different mode of action. Biological activity of CTBT was demonstrated in Saccharomyces, Kluyveromyces and Candida yeast species grown on solid and in liquid media. The chemosensitising effect of CTBT, manifested as increased antifungal activity of fluconazole, was demonstrated in yeast mutant strains with deleted genes encoding the major multidrug resistance transcription factors Yap1p, Pdr1p and Pdr3p as well as the drug efflux pumps Pdr5p and Snq2p in S. cerevisiae or their counterparts in Candida albicans and Candida glabrata, named Cdr1p and Mdr1p, respectively. Importantly, CTBT also increased the sensitivity to fluconazole in multidrug-resistant cells overexpressing the efflux pumps. Yeast cells grown in the presence of subinhibitory concentrations of CTBT exhibited an altered sterol composition and a slightly enhanced accumulation of Rhodamine 6G, which suggests that the plasma membrane plays a role in sensitisation. This novel chemosensitisation by CTBT that can overcome multidrug resistance in yeast may prove useful in combined treatment of infections caused by drug-resistant fungal pathogens. PMID:17204400

Cernicka, Jana; Kozovska, Zuzana; Hnatova, Martina; Valachovic, Martin; Hapala, Ivan; Riedl, Zsuzsanna; Hajós, György; Subik, Julius

2007-02-01

322

Method for Measuring Bacterial Resistance to Metals Employing Epifluorescent Microscopy.  

National Technical Information Service (NTIS)

A direct viable counting method has been developed which can be used to measure resistance of bacteria to metal (DVCMR bio-assay). Results obtained using DVCMR was compared with classical culture methods and proven superior. Evaluation of test strains res...

J. L. Zelibor M. Tamplin R. R. Colwell

1987-01-01

323

International dissemination of antibiotic resistant strains of bacterial pathogens.  

PubMed

The increasing incidence of methicillin and multiple resistant Staphylococcus aureus (MRSA) in nosocomial infections is mainly associated with a wide, international dissemination of well defined clonal lineages (epidemic MRSA) which are clearly different from community acquired MRSA by molecular typing patterns and structure of the staphylococcal cassette chromosome containing the mecA gene. Although belonging to a definite subpopulation within the species Enterococcus faecium, hospital associated vancomycin resistant isolates also containing the esp gene have very likely evolved by acquisition of glycopeptide resistance gene clusters at different occasions and at different times by a susceptible already disseminated clonal lineage. There is obviously a continuous selection of new types of extended spectrum beta-lactamases in enterobacteriaceae and also horizontal spread of bla-genes. Intrahospital dissemination of particular strains has often been observed, however, an international dissemination until now has been described only for Salmonella enterica serovar Typhimurium producing the CTX-M-3 enzyme. Multiresistant isolates of Salmonella enterica serovar Typhimurium phage type DT104 harbour a multiresistant gene cluster with resistance genes from taxonomically more unrelated species (tetG, floR, bla(PSE1)). Although in vitro transduction has been demonstrated, this gene cluster has only rarely been reported from isolates exhibiting other phage patterns of the same serovar or from other serovars of S. enterica. PMID:15450197

Witte, Wolfgang

2004-09-01

324

Beta-Androstenes and Resistance to Viral and Bacterial Infections  

Microsoft Academic Search

This report illustrates that the ?-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels

Roger M. Loria

2009-01-01

325

Life in cellulose houses: Symbiotic bacterial biosynthesis of ascidian drugs and drug leads  

PubMed Central

Ascidians (tunicates; sea squirts) are sources of diverse, bioactive natural products, one of which is an approved drug and many of which are potent drug leads. It has been shown that symbiotic bacteria living with ascidians produce some of the bioactive compounds isolated from whole animals, and indirect evidence strongly implicates symbiotic bacteria in the synthesis of many others. However, for the majority the producing organism has not been identified. In cases where a symbiotic origin has been definitively assigned, the resulting data lead to improved paths to drug discovery and development from marine animals. This review traces evidence for symbiotic production where such evidence exists and describes the strengths and limitations of that evidence.

Schmidt, Eric W.; Donia, Mohamed S.

2010-01-01

326

Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents  

PubMed Central

This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and substance offer-response episodes. Rural youths’ resistance strategies were similar to previous findings with urban adolescents – refuse, explain, avoid, and leave (the REAL typology) – while unique features of these strategies were identified including the importance of personal narratives, the articulation of a non-user identity, and being “accountable” to self and others.

Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.

2011-01-01

327

Coherent feedforward transcriptional regulatory motifs enhance drug resistance  

NASA Astrophysics Data System (ADS)

Fluctuations in gene expression give identical cells access to a spectrum of phenotypes that can serve as a transient, nongenetic basis for natural selection by temporarily increasing drug resistance. In this study, we demonstrate using mathematical modeling and simulation that certain gene regulatory network motifs, specifically coherent feedforward loop motifs, can facilitate the development of nongenetic resistance by increasing cell-to-cell variability and the time scale at which beneficial phenotypic states can be maintained. Our results highlight how regulatory network motifs enabling transient, nongenetic inheritance play an important role in defining reproductive fitness in adverse environments and provide a selective advantage subject to evolutionary pressure.

Charlebois, Daniel A.; Balázsi, Gábor; Kærn, Mads

2014-05-01

328

Recent highlights in antimalarial drug resistance and chemotherapy research  

PubMed Central

This review summarizes recent investigations into antimalarial drug resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of antimalarial chemotherapy and priorities moving forward.

Fidock, David A.; Eastman, Richard T.; Ward, Stephen A.; Meshnick, Steven R.

2009-01-01

329

Structural basis for the inhibition of Mycobacterium tuberculosis l,d-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains  

PubMed Central

Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate l,d-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional l,d-transpeptidases in Mtb, is predominantly expressed over LdtMt1 (Rv0116c). Here, the crystal structure of N-terminally truncated LdtMt2 (residues Leu131–Ala408) is reported in both ligand-free and meropenem-bound forms. The structure of meropenem-inhibited LdtMt2 provides a detailed structural view of the interactions between a carbapenem drug and Mtb l,d-transpeptidase. The structures revealed that the catalytic l,d-­transpeptidase domain of LdtMt2 is preceded by a bacterial immunogloblin-like Big_5 domain and is followed by an extended C-terminal tail that interacts with both domains. Furthermore, it is shown using mass analyses that meropenem acts as a suicide inhibitor of LdtMt2. Upon acylation of the catalytic Cys354 by meropenem, the ‘active-site lid’ undergoes a large conformational change to partially cover the active site so that the bound meropenem is accessible to the bulk solvent via three narrow paths. This work will facilitate structure-guided discovery of l,d-transpeptidase inhibitors as novel antituberculosis drugs against drug-resistant Mtb.

Kim, Hyoun Sook; Kim, Jieun; Im, Ha Na; Yoon, Ji Young; An, Doo Ri; Yoon, Hye Jin; Kim, Jin Young; Min, Hye Kyeoung; Kim, Soon-Jong; Lee, Jae Young; Han, Byung Woo; Suh, Se Won

2013-01-01

330

Exploring N-acylhydrazone derivatives against clinical resistant bacterial strains.  

PubMed

Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO2, N-Br-FUR-NO2, N-F-FUR-NO2, N-Cl-FUR-NO2) showed promising MIC and MBC values (MIC = MBC = 1-16 ?g/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials (e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds. PMID:24807624

Lannes, Andressa C; Leal, Bruno; Novais, Juliana S; Lione, Viviane; Monteiro, Georgia C T S; Lourenço, André L; Sathler, Plínio C; Jordão, Alessandro K; Rodrigues, Carlos R; Cabral, Lúcio M; Cunha, Anna Claudia; Campos, Vinicius; Ferreira, Vítor F; de Souza, Maria Cecília B V; Santos, Dilvani O; Castro, Helena C

2014-09-01

331

Drug resistance in fecal enterococci in Hong Kong.  

PubMed

Our purpose was to estimate the rate of carriage of vancomycin-resistant enterococci (VRE) in hospitalized patients in a district hospital and in healthy subjects in the community in Hong Kong. Rectal swabs were collected from all patients admitted to the intensive care unit, and stool specimens were collected from all patients presenting with suspected antibiotic-associated diarrhea over a 2-month period. Stool specimens were also collected from healthy subjects in the community. Specimens were enriched and cultured on selective media for the isolation of enterococci. All isolates were identified, and their minimum inhibitory concentration for vancomycin was determined. Susceptibility to other antibiotics was investigated. Samples yielded 125 isolates of enterococci, the majority of isolates being Enterococcus faecalis (75) and E. faecium (35). Nine of 11 strains of E. gallinarum and 2 of 2 strains of E. casseliflavus isolated from hospitalized patients were intermediately resistant to vancomycin, but no strains highly resistant to vancomycin were isolated. Resistance to other drugs, including the fluoroquinolones, was present, and a high-level resistance to gentamicin and streptomycin was found in 37% and 46% of strains, respectively. Colonization with VRE remains low in Hong Kong. This result is supported by the low level of isolation of VRE from infections in the region and may be attributable to low levels of vancomycin use. High-level aminoglycoside resistance and fluoroquinolone resistance are common, and continued monitoring for VRE is suggested. PMID:15614455

Boost, Maureen; Lai, Lydia; O'Donoghue, Margaret

2004-12-01

332

Bacterial DNA translocation holds increased insulin resistance and systemic inflammatory levels in morbid obese patients.  

PubMed

Background: Morbidly obese patients show several common comorbidities associated with immunological alterations such as a sustained low-level proinflammatory profile. Bacterial product translocation is frequent in inflammation-related diseases and may aggravate patients' clinical outcome. Design: Consecutively admitted morbidly obese patients who presented indications for bariatric surgery were studied. Before surgery, patients were subjected to a modified fasting diet. Patients underwent surgery by sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass. Clinical and analytical parameters were recorded. Blood samples were collected at baseline, at the end of a 3-month modified fasting period, and 3, 6, and 12 months after surgery. Serum cytokine and endotoxin levels were evaluated by flow cytometry and ELISA, respectively. Bacterial DNA was identified in blood by broad-range PCR of prokaryote 16SrRNA gene and partial sequencing analysis. Results: Fifty-eight patients were included in the study. All patients showed a significantly reduced weight and body mass index at each time-point. Postoperative mortality was null. Bacterial DNA translocation rate was 32.8% (19 of 58) at baseline; 13.8% (8 of 58) after the modified fasting period; and 13.8% (8 of 58), 1.8% (1 of 58), and 5.2% (3 of 58) at 3, 6, and 12 months after surgery. Proinflammatory cytokines, serum endotoxin levels, and insulin resistance remained increased in patients with bacterial DNA despite weight loss and were individually affected by the appearance/clearance of bacterial DNA in blood. Multivariate analyses revealed bacterial DNA as an independent significant factor, explaining the systemic cytokine response and the insulin resistance levels in the studied population. Conclusion: Bacterial DNA translocation holds increased insulin resistance and systemic inflammatory levels in morbidly obese patients despite significant weight loss. PMID:24735424

Ortiz, Sergio; Zapater, Pedro; Estrada, José Luis; Enriquez, Pablo; Rey, Monica; Abad, Angel; Such, José; Lluis, Félix; Francés, Rubén

2014-07-01

333

On the relationship between drug’s size, cell membrane mechanical properties and high levels of multi drug resistance: a comparison to published data  

Microsoft Academic Search

Multi drug resistance (MDR) or cross resistance to drugs was initially explained on the basis that MDR cells express drug\\u000a transporters that expel membrane-embedded drugs. However, it is now clear that transporters are a single piece from a complex\\u000a puzzle. An issue that has been solved recently is, given that these transporters have to handle drugs, why should a membrane-embedded

Cyril Rauch

2009-01-01

334

Multiple Antimicrobial Resistance in a Chronic Bacterial Infection of Koi Carp  

Microsoft Academic Search

Thirty bacterial isolates were obtained from 20 common carp Cyprinus carpio of the strain known as koi during a 2-month disease outbreak. Thirteen were identified as Aeromonas hydrophila, 11 as A. sobria, 2 as A. caviae, 2 as Shewanella putrifaciens, and 1 each as Citrobacter freundii and Pseudomonas spp. Each isolate was tested for resistance to 13 antimicrobial compounds using

P. W. Taylor

2003-01-01

335

Enhanced tomato resistance to bacterial canker by application of turtle oil  

Microsoft Academic Search

Pretreatment with oil of sea turtle Caretta caretta protected tomato plants against bacterial canker caused by Clavibacter michiganensis subsp. michiganensis (Cmm). The turtle oil was ineffective in inhibiting Cmm in an agar diffusion test, suggesting a mechanism of induced resistance. Under controlled conditions in the greenhouse, turtle oil lowered the disease index and had reduced the growth of bacteria up

Ömür Baysal; Y. Ziya Gürsoy; Hakan Örnek; Ahmet Duru

2005-01-01

336

MULTIPLE DISEASE RESISTANCE TO POWDERY MILDEW, BACTERIAL BLIGHT, AND ALTERNARIA BLIGHT IN LILACS (SYRINGA SPP.)  

Microsoft Academic Search

Fifty-six lilac accessions were evaluated in a 4-year study for resistance to powdery mildew caused by Microsphaera syringae, bacterial blight caused by Pseudomonas syringae pv. syringae, and Alternaria blight caused by Alternaria alternata. Accessions included 39 cultivars of Syringa vulgaris, four of S. prestoniae, three of S. hyacinthiflora, two of S. josiflexa, two of S. meyeri, two of S. reticulata,

Margaret T. Mmbaga; Roger J. Sauvé; Emmanuel Nnodu; Suping Zhou

2005-01-01

337

Inducible Resistance of Fish Bacterial Pathogens to the Antimicrobial Peptide Cecropin B  

Microsoft Academic Search

Cecropin B is a cationic antimicrobial peptide originally isolated from the diapausing pupae of the giant silk moth, Hylphora cecropia. Cecropin B elicits its antimicrobial effects through disruption of the anionic cell membranes of gram-negative bacteria. Previous work by our laboratory demonstrated that a constitutively expressed cecropin B transgene conferred enhanced resistance to bacterial infection in medaka. The develop- ment

Ulysses W. Sallum; Thomas T. Chen

2008-01-01

338

Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis  

PubMed Central

Introduction Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. Methods We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. Results We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ? 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. Limitations In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. Discussion Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

Arentz, Matthew; Sorensen, Bess; Horne, David J.; Walson, Judd L.

2013-01-01

339

Research Priorities, Profits, and Public Goods: The Case of Drug Resistant Disease  

Microsoft Academic Search

In this paper I argue that drug resistance is an important ethical issue in virtue of (1) the severe — and potentially catastrophic\\u000a — consequences of drug resistance, (2) the fact that drug resistance largely results from the way that medicines (and research\\u000a resources) are distributed, and (3) the fact that drug resistance is a clear example of a public

Michael J. Selgelid

340

Encircling endocardial resection for sustained drug-resistant ventricular tachycardia.  

PubMed

Localized endocardial resection guided by intraoperative mapping has been used recently to manage patients with drug-resistant ventricular tachycardia. Although not uniformly successful, this procedure is superior to simple aneurysmectomy. This report describes the authors' early experience with encircling endocardial resection with complete removal of endocardial scar in seven patients with drug-resistant, sustained, ventricular tachycardia, as identified by electrophysiologic studies. Intraoperative mapping was not used. Although no spontaneous clinical arrhythmia occurred after operation, ventricular tachycardia could be induced in one patient, but not after loading with procainamide. This was the only patient who required long-term antiarrhythmic therapy. There were no operative deaths, but one patient died 21/2 months after endocardial resection with recurrent ventricular septal defects and another died after 4 months. Our early experience indicates that encircling endocardial resection effectively eliminates re-entrant ventricular tachycardia and identifies ventricular septal defect as a potential postoperative complication following extensive septal endocardial resection. PMID:6467097

Landymore, R W; Kinley, C E; Gardner, M

1984-01-01

341

A Real-Time PCR Antibiogram for Drug-Resistant Sepsis  

PubMed Central

Current molecular diagnostic techniques for susceptibility testing of septicemia rely on genotyping for the presence of known resistance cassettes. This technique is intrinsically vulnerable due to the inability to detect newly emergent resistance genes. Traditional phenotypic susceptibility testing has always been a superior method to assay for resistance; however, relying on the multi-day growth period to determine which antimicrobial to administer jeopardizes patient survival. These factors have resulted in the widespread and deleterious use of broad-spectrum antimicrobials. The real-time PCR antibiogram, described herein, combines universal phenotypic susceptibility testing with the rapid diagnostic capabilities of PCR. We have developed a procedure that determines susceptibility by monitoring pathogenic load with the highly conserved 16S rRNA gene in blood samples exposed to different antimicrobial drugs. The optimized protocol removes heme and human background DNA from blood, which allows standard real-time PCR detection systems to be employed with high sensitivity (<100 CFU/mL). Three strains of E. coli, two of which were antimicrobial resistant, were spiked into whole blood and exposed to three different antibiotics. After real-time PCR-based determination of pathogenic load, a ?Ct<3.0 between untreated and treated samples was found to indicate antimicrobial resistance (P<0.01). Minimum inhibitory concentration was determined for susceptible bacteria and pan-bacterial detection was demonstrated with 3 Gram-negative and 2 Gram-positive bacteria. Species identification was performed via analysis of the hypervariable amplicons. In summary, we have developed a universal diagnostic phenotyping technique that assays for the susceptibility of drug-resistant septicemia with the speed of PCR. The real-time PCR antibiogram achieves detection, susceptibility testing, minimum inhibitory concentration determination, and identification in less than 24 hours.

Mitra, Debkishore; Lee, Luke P.

2011-01-01

342

Bacterial metal resistance genes and metal bioavailability in contaminated sediments.  

PubMed

In bacteria a metal may be defined as bioavailable if it crosses the cytoplasmic membrane to reach the cytoplasm. Once inside the cell, specific metal resistance systems may be triggered. In this research, specific metal resistance genes were used to estimate metal bioavailability in sediment microbial communities. Gene levels were measured by quantitative PCR and correlated to metals in sediments using five different protocols to estimate dissolved, particle-adsorbed and occluded metals. The best correlations were obtained with czcA (a Cd/Zn/Co efflux pump) and Cd/Zn adsorbed or occluded in particles. Only adsorbed Co was correlated to czcA levels. We concluded that the measurement of czcA gene levels by quantitative PCR is a promising tool which may complement the classical approaches used to estimate Cd/Zn/Co bioavailability in sediment compartments. PMID:24662000

Roosa, Stéphanie; Wattiez, Ruddy; Prygiel, Emilie; Lesven, Ludovic; Billon, Gabriel; Gillan, David C

2014-06-01

343

Fluoroquinolone-metal complexes: A route to counteract bacterial resistance?  

PubMed

Microbial resistance to antibiotics is one of the biggest public health threats of the modern world. Antibiotic resistance is an area of much clinical relevance and therefore research that has the potential to identify agents that may circumvent it or treat resistant infections is paramount. Solution behavior of various fluoroquinolone (FQ) complexes with copper(II) in the presence and absence of 1,10-phenanthroline (phen) was studied in aqueous solution, by potentiometry and/or spectrophotometry, and are herein described. The results obtained showed that under physiological conditions (micromolar concentration range and pH7.4) only copper(II):FQ:phen ternary complexes are stable. Hence, these complexes were synthesised and characterised by means of UV-visible and IR spectroscopy, elemental analysis and single-crystal X-ray diffraction. In these complexes, the FQ acts as a bidentate ligand that coordinates the metal cation through the carbonyl and carboxyl oxygen atoms and phen coordinates through two N-atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth position of the penta-coordinated Cu(II) centre is generally occupied axially by an oxygen atom from a water molecule or from a nitrate ion. Minimum inhibitory concentration (MIC) determinations of the complexes and comparison with free FQ in various E. coli strains indicate that the Cu-complexes are as efficient antimicrobials as the free antibiotic. Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complexes' suitability as candidates for further biological testing in FQ-resistant microorganisms. PMID:24952152

Feio, Maria J; Sousa, Isabel; Ferreira, Mariana; Cunha-Silva, Luís; Saraiva, Raúl G; Queirós, Carla; Alexandre, José G; Claro, Vasco; Mendes, Adélia; Ortiz, Rosa; Lopes, Sandra; Amaral, Ana Luísa; Lino, João; Fernandes, Patrícia; Silva, Ana João; Moutinho, Lisete; de Castro, Baltazar; Pereira, Eulália; Perelló, Lourdes; Gameiro, Paula

2014-09-01

344

Comparative Genomic Analysis of Rapid Evolution of an Extreme-Drug-Resistant Acinetobacter baumannii Clone  

PubMed Central

The emergence of extreme-drug-resistant (EDR) bacterial strains in hospital and nonhospital clinical settings is a big and growing public health threat. Understanding the antibiotic resistance mechanisms at the genomic levels can facilitate the development of next-generation agents. Here, comparative genomics has been employed to analyze the rapid evolution of an EDR Acinetobacter baumannii clone from the intensive care unit (ICU) of Rigshospitalet at Copenhagen. Two resistant A. baumannii strains, 48055 and 53264, were sequentially isolated from two individuals who had been admitted to ICU within a 1-month interval. Multilocus sequence typing indicates that these two isolates belonged to ST208. The A. baumannii 53264 strain gained colistin resistance compared with the 48055 strain and became an EDR strain. Genome sequencing indicates that A. baumannii 53264 and 48055 have almost identical genomes—61 single-nucleotide polymorphisms (SNPs) were found between them. The A. baumannii 53264 strain was assembled into 130 contigs, with a total length of 3,976,592 bp with 38.93% GC content. The A. baumannii 48055 strain was assembled into 135 contigs, with a total length of 4,049,562 bp with 39.00% GC content. Genome comparisons showed that this A. baumannii clone is classified as an International clone II strain and has 94% synteny with the A. baumannii ACICU strain. The ResFinder server identified a total of 14 antibiotic resistance genes in the A. baumannii clone. Proteomic analyses revealed that a putative porin protein was down-regulated when A. baumannii 53264 was exposed to antimicrobials, which may reduce the entry of antibiotics into the bacterial cell.

Tan, Sean Yang-Yi; Chua, Song Lin; Liu, Yang; H?iby, Niels; Andersen, Leif Percival; Givskov, Michael; Song, Zhijun; Yang, Liang

2013-01-01

345

Meropenem/clavulanate and linezolid treatment for extensively drug-resistant tuberculosis.  

PubMed

The combination of meropenem with clavulanate has high antimycobacterial activity in vitro against extensively drug-resistant Mycobacterium tuberculosis strains. We report the successful use of this combination in association with linezolid in the management of an advanced extensively drug-resistant tuberculosis disease with complex second-line drug resistance in a 14-year-old teenager. PMID:21378593

Dauby, Nicolas; Muylle, Inge; Mouchet, Françoise; Sergysels, Roger; Payen, Marie-Christine

2011-09-01

346

Vancomycin-resistant Gram-positive bacterial endophthalmitis: epidemiology, treatment options, and outcomes  

PubMed Central

Background The purpose of this study is to evaluate the microbiological profile and treatment outcomes of vancomycin-resistant Gram-positive bacterial endophthalmitis. Medical records of all patients with Gram-positive bacterial endophthalmitis resistant to vancomycin presenting between 1 January 2005 and 31 December 2010 were reviewed in this noncomparative, consecutive, retrospective case series. Favorable outcome was defined as a best-corrected visual acuity of ?20/200. Results Out of 682 culture-positive endophthalmitis isolates, 448/682 (65.6%) were associated with Gram-positive bacteria. In vitro resistance to vancomycin was noted in 7/448 (1.56%). Three cases were posttraumatic, three were postoperative, and one was endogenous in origin. Four Bacillus isolates, two Staphylococcus isolates, and an Enterococcus isolate were resistant. Isolates resistant to vancomycin were sensitive in vitro to ciprofloxacin in 6/7 (86%) patients. Presenting visual acuity was light perception in all seven cases. Favorable outcome was achieved in only 1/7 (14.3%) cases. Conclusions Vancomycin-resistant endophthalmitis is uncommon and usually associated with poor visual outcome. Bacillus sp. is the most frequent Gram-positive bacteria resistant to vancomycin. Fluoroquinolones like ciprofloxacin may be considered as a useful alternative in vancomycin-resistant endophthalmitis.

2013-01-01

347

Impact evaluation of Drug Abuse Resistance Education (DARE).  

PubMed

The purpose of this study was to assess the impact of Drug Abuse Resistance Education (DARE) on fifth-grade students in the Long Beach Unified School District in Long Beach, California. The research suggests that DARE does not significantly change the amount of drug use, which is minimal at the fifth grade level. In general, children receiving DARE during the study period maintained existing levels of drug abuse. Approximately 3,000 students participated in the study. A pretest and posttest self-report survey was utilized during the Fall 1989 semester for experimental and control groups. As DARE programs gain popularity in other school districts, school administrators need more information on the program to decide if DARE should be presented in their schools. Administrative decision-making must consider program effectiveness and curriculum time constraints. PMID:1484326

Becker, H K; Agopian, M W; Yeh, S

1992-01-01

348

Recessive bacterial leaf blight resistance in rice: complexity, challenges and strategy.  

PubMed

Physical mapping and map-based cloning strategies are routinely used for identification of candidate genes for major qualitative traits in rice. Such strategies have enabled mapping and characterization of dominant bacterial leaf blight (blb) resistance genes, but little progress has been made in case of the recessive resistance genes. Two recent studies on map-based cloning of xa5 and xa13 recessive blb resistance genes identified the general transcription factor IIA gamma subunit (TFIIAgamma) and the nodulin MtN21 as candidates, respectively. Subsequently, two other reports have raised discussion on whether the identified candidates are indeed recessive resistance genes, and are sufficient to confer blb resistance in rice. Based on published evidence, and our extensive in silico analyses of the genomic environment around xa5 and xa13 regions, we propose that the recessive gene mediated resistance mechanism is more complex and might not be governed by a single gene. PMID:17307154

Kottapalli, Kameswara R; Kottapalli, Pratibha; Agrawal, Ganesh K; Kikuchi, Shoshi; Rakwal, Randeep

2007-04-01

349

Ethanol-resistant polymeric film coatings for controlled drug delivery.  

PubMed

The sensitivity of controlled release dosage forms to the presence of ethanol in the gastro intestinal tract is critical, if the incorporated drug is potent and exhibits severe side effects. This is for instance the case for most opioid drugs. The co-ingestion of alcoholic beverages can lead to dose dumping and potentially fatal consequences. For these reasons the marketing of hydromorphone HCl extended release capsules (Palladone) was suspended. The aim of this study was to develop a novel type of controlled release film coatings, which are ethanol-resistant: even the presence of high ethanol concentrations in the surrounding bulk fluid (e.g., up to 40%) should not affect the resulting drug release kinetics. Interestingly, blends of ethylcellulose and medium or high viscosity guar gums provide such ethanol resistance. Theophylline release from pellets coated with the aqueous ethylcellulose dispersion Aquacoat® ECD 30 containing 10 or 15% medium and high viscosity guar gum was virtually unaffected by the addition of 40% ethanol to the release medium. Furthermore, drug release was shown to be long term stable from this type of dosage forms under ambient and stress conditions (without packaging material), upon appropriate curing. PMID:23570984

Rosiaux, Y; Muschert, S; Chokshi, R; Leclercq, B; Siepmann, F; Siepmann, J

2013-07-10

350

Reversal of Multidrug Resistance by Guggulsterone in Drug-Resistant MCF7 Cell Lines  

Microsoft Academic Search

Background: Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that the MDR of K562\\/DOX cells could be reversed by guggulsterone through inhibiting the function and expression of P-glycoprotein. The purpose of this study was to investigate the reversal effect of guggulsterone on MDR in drug-resistant MCF-7 cells and the parental MCF-7 cells. Methods:

Hong-Bin Xu; Ling Li; Guo-Qing Liu

2011-01-01

351

Functional studies of cochleate assemblies of an oligo-acyl-lysyl with lipid mixtures for combating bacterial multidrug resistance.  

PubMed

The cationic antimicrobial oligo-acyl-lysyls (OAKs) interact with lipid mixtures mimicking the composition of bacterial cytoplasmic membranes. We have reported the ability of one such OAK, C(12)K-7?(8), to cluster anionic lipids and to promote a structural change with lipid bilayers to form rolled cylindrical structures or cochleates, without requiring divalent cations for their assembly. These assemblies can be exploited for drug delivery, permitting their synergistic use with antibiotics in systemic therapy to increase efficacy and reduce toxicity. Our previous studies of the biophysical properties of these systems led us to select mixtures with the goal of optimizing their potential for enhancing effectiveness in combating bacterial multidrug resistance. Here, we further investigate the properties of such mixtures that result in enhanced in vivo activity. The role of erythromycin in the assembly of cochleates with OAK in the gel and the liquid crystalline states were assessed, as well as the encapsulation efficiency of the systems chosen. In addition, we found that erythromycin did not undermine the ability of OAKs to induce fusion of vesicles, fusion being an essential component of cochleate formation. The in vivo activity of the new assemblies tested resulted in higher survival rates of animals infected with multidrug resistant bacteria. PMID:21676947

Sarig, Hadar; Ohana, Dafna; Epand, Raquel F; Mor, Amram; Epand, Richard M

2011-10-01

352

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease  

PubMed Central

Summary: Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

Shapiro, Rebecca S.; Robbins, Nicole; Cowen, Leah E.

2011-01-01

353

High-content kinetic calcium imaging in drug-sensitive and drug-resistant human breast cancer cells.  

PubMed

Intracellular calcium (Ca2+) is involved in the regulation of a variety of biological functions in cancer cells, including growth inhibition, tumor invasiveness, and drug resistance. To gain insight into the possible role played by Ca2+ in the development of drug resistance in breast cancer, we performed a comparative high-content analysis of the intracellular Ca2+ dynamics in drug-sensitive human breast cancer MCF-7 cells and five drug-resistant, MCF-7-derived clonal cell lines. Fura-2 single cell ratiometric fluorescence microscopy was used to monitor real-time quantitative changes in cytosolic-free Ca2+ concentration ( [Ca2+]i ) upon addition of phosphoinositol-coupled receptor agonists. While the magnitude and the onset kinetics of the [Ca2+]i rise were similar in drug-sensitive and drug-resistant cell lines, the decay kinetics of the [Ca2+]i increase was found to be consistently slower in drug-resistant than drug-sensitive cells. Such a delay in reestablishing homeostatic [Ca2+]i persisted in the absence of extracellular Ca2+ and was independent of the expression or function of specific drug efflux pumps associated with drug resistance. Moreover, intracellular Ca2+ pools releasable by phosphoinositol-coupled receptor agonists or thapsigargin appeared to be differentially shared in drug-sensitive and drug-resistant cells. In light of the clinical relevance that drug resistance has in the treatment of cancer, the molecular and biochemical relationship between alterations in Ca2+ dynamics and drug resistance demands to be further investigated and tested in a wider array of cell types. Automated microscopy will help greatly in this pursuit by facilitating both sample imaging and data analysis, thus allowing high-content as well as high-throughput screening of large sample sets. A protocol for studying [Ca2+]i kinetics with a commercially available automated imaging platform is described. PMID:17110200

DeBernardi, Maria A; Brooker, Gary

2006-01-01

354

Primary trastuzumab resistance: new tricks for an old drug  

PubMed Central

Trastuzumab (Herceptin®) is the first FDA-approved therapeutic targeting a HER-family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2-positive breast cancer, a substantial proportion of patients will not respond to trastuzumab-based regimens (primary resistance), and those who do respond will often lose clinical benefit (i.e., secondary resistance). While multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which, together, demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of “resistance” as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.

Wilken, Jason A.; Maihle, Nita J.

2011-01-01

355

Influence of the Diversity of Bacterial Isolates from Drinking Water on Resistance of Biofilms to Disinfection ?  

PubMed Central

Single- and multispecies biofilms formed by six drinking water-isolated bacterial species were used to assess their susceptibilities to sodium hypochlorite (SHC). In general, multispecies biofilms were more resistant to inactivation and removal than single biofilms. Total biofilm inactivation was achieved only for Acinetobacter calcoaceticus single-species biofilms and for those multispecies biofilms without A. calcoaceticus. Biofilms with all bacteria had the highest resistance to SHC, while those without A. calcoaceticus were the most susceptible. A. calcoaceticus formed single biofilms susceptible to SHC; however, its presence in multispecies biofilms increased their resistance to disinfection.

Simoes, Lucia Chaves; Simoes, Manuel; Vieira, Maria Joao

2010-01-01

356

Excess mortality associated with antimicrobial drug-resistant Salmonella typhimurium.  

PubMed

In a matched cohort study, we determined the death rates associated with drug resistance in Salmonella Typhimurium. We linked data from the Danish Surveillance Registry for Enteric Pathogens with the Civil Registration System and the Danish National Discharge Registry. By survival analysis, the 2-year death rates were compared with a matched sample of the general Danish population, after the data were adjusted for differences in comorbidity. In 2,047 patients with S. Typhimurium, 59 deaths were identified. Patients with pansusceptible strains of S. Typhimurium were 2.3 times more likely to die 2 years after infection than persons in the general Danish population. Patients infected with strains resistant to ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline were 4.8 times (95% CI 2.2 to 10.2) more likely to die, whereas quinolone resistance was associated with a mortality rate 10.3 times higher than the general population. PMID:11996684

Helms, Morten; Vastrup, Pernille; Gerner-Smidt, Peter; Mølbak, Kåre

2002-05-01

357

[Drug resistance of 100 clinical strains of Enterococcus spp].  

PubMed

The aim of this study was to evaluate the drug susceptibility of 100 Enterococcus spp. strains isolated from patients hospitalized in State Clinical Hospital No 1 in Warsaw. All strains were identified (API 20 STREP) and their susceptibility to antibiotics was tested (ATB STREP) in automatic ATB system. Additionally, PYRase activity, beta-lactamase production (in nitrocefin test), MICs for vancomycin and teicoplanin (E test), HLAR--high level aminoglycoside resistance and susceptibility to vancomycin, teicoplanin, piperacillin and piperacillin/tazobactam (disc diffusion method) were determined. E. faecalis ATCC 29212 was used as the control strain. Fifty E. faecalis, 45 E. faecium, 2 E. casseliflavus, 2 E. durans and 1 E. avium strain were cultured. All strains were PYRase-positive and beta-lactamase-negative. Ten isolates demonstrated intermediate susceptibility to vancomycin (6--E. faecalis and 4--E. faecium). One E. faecalis strain was intermediately susceptible to both glycopeptides. One E. casseliflavus strain showed low-level resistance to vancomycin, but this strain was susceptible to teicoplanin--phenotype Van C. HLAR strains were found among 31 E. faecalis and 40 E. faecium strains. 48 E. faecalis strains were susceptible to piperacillin and 49 to piperacillin/tazobactam. Whereas, 41 E. faecium were resistant to both these drugs. Thirty six per cent of isolates were resistant to penicillin and ampicillin, 73% to erythromycin, 87% to tetracycline, 89% to lincomycin and 56% to nitrofurantoin. Some discrepancies were noticed between the results of different methods applied for susceptibility testing--ATB system, E test and disc diffusion. These discrepancies concerned HLAR detection and susceptibility to glycopeptides determination. The best methods were: disc-diffusion for HLAR detection and E test for determination of resistance to vancomycin and teicoplanin. Increasing resistance to antimicrobial agents is observed in clinical Enterococcus spp. isolates cultured in our laboratory, especially in E. faecium strains. It is necessary to control the dissemination of multiresistant Enterococcus spp. strains in hospital wards. PMID:10803253

Sawicka-Grzelak, A; Rokosz, A; Luczak, M

1999-01-01

358

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines  

Microsoft Academic Search

The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression

T Igarashi; H Izumi; T Uchiumi; K Nishio; T Arao; M Tanabe; H Uramoto; K Sugio; K Yasumoto; Y Sasaguri; K Y Wang; Y Otsuji; K Kohno

2007-01-01

359

Multiple Mechanisms Confer Drug Resistance to Mitoxantrone in the Human 8226 Myeloma Cell Line1  

Microsoft Academic Search

Selection for in vitro drug resistance can result in a complex phenotype with more than one mechanism of resistance emerging concurrently or sequentially. We examined emerging mechanisms of drug resistance dur- ing selection with mitoxantrone in the human myeloma cell line 8226. A novel transport mechanism appeared early in the selection process that was associated with a 10-fold resistance to

Lori A. Hazlehurst; Nils E. Foley; Mary C. Gleason-Guzman; Miles P. Hacker; Anne E. Cress; Lee W. Greenberger; Mariska C. De Jong; William S. Dalton

360

Daptomycin resistance and treatment failure following vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) mitral valve acute bacterial endocarditis (ABE)  

Microsoft Academic Search

Acute bacterial endocarditis (ABE) is most commonly due to virulent pathogens, i.e., Staphylococcus aureus. S. aureus ABE may be due to methicillin-sensitive (MSSA) or methicillin-resistant (MRSA) strains and, optimally, ABE should be treated\\u000a with bactericidal antibiotics. Traditionally, vancomycin has long been used to treat MRSA ABE, but it has been shown that\\u000a vancomycin may increase the staphylococcal the thickness, resulting

B. A. Cunha; F. M. Pherez

2009-01-01

361

Characterization of multiple and extensively drug resistant Mycobacterium tuberculosis isolates with different ofloxacin-resistance levels.  

PubMed

The goal of the study was to determine different mutation types in gyrA and gyrB genes in Mycobacterium tuberculosis strains with low-level (2 ?g/ml) and high-level (10 ?g/ml) ofloxacin (OFL) resistance and to compare genetic diversity of ofloxacin-resistant and susceptible M. tuberculosis isolates. M. tuberculosis isolates were collected in Leningrad Region in 2011. DNA sequencing showed that 54.3% of isolates with low-level and 76.9% of isolates with high-level OFL-resistance had mutations in gyrA gene. Few isolates carried mutations in gyrB gene - five among isolates with low-level resistance and two among high-level resistant isolates. Altogether, detection of point mutations in both DNA gyrase genes allows to identify 66.9% of mycobacterial isolates with low-level and 84.5% of isolates with high-level of OFL-resistance. Novel mutations S91L in gyrA gene and S512L in gyrB gene described in this study were detected in OFL-resistant isolates and may play role in M. tuberculosis fluoroquinolone resistance. M. tuberculosis Beijing family spoligotypes were identified among 70.8% of isolates with low-level resistance, 84.6% of isolates with high-level resistance and 50% of strains susceptible to all tuberculosis drugs. Fisher's exact test revealed significant difference between Beijing prevalence in groups of drug-susceptible or high-level OFL-resistant M. tuberculosis strains (p-value = 0.032). PMID:23491718

Chernyaeva, Ekaterina; Fedorova, Ekaterina; Zhemkova, Galina; Korneev, Yuriy; Kozlov, Andrei

2013-05-01

362

Changes in drug sensitivity and anti-malarial drug resistance mutations over time among Plasmodium falciparum parasites in Senegal  

PubMed Central

Background Malaria treatment efforts are hindered by the rapid emergence and spread of drug resistant parasites. Simple assays to monitor parasite drug response in direct patient samples (ex vivo) can detect drug resistance before it becomes clinically apparent, and can inform changes in treatment policy to prevent the spread of resistance. Methods Parasite drug responses to amodiaquine, artemisinin, chloroquine and mefloquine were tested in approximately 400 Plasmodium falciparum malaria infections in Thiès, Senegal between 2008 and 2011 using a DAPI-based ex vivo drug resistance assay. Drug resistance-associated mutations were also genotyped in pfcrt and pfmdr1. Results Parasite drug responses changed between 2008 and 2011, as parasites became less sensitive to amodiaquine, artemisinin and chloroquine over time. The prevalence of known resistance-associated mutations also changed over time. Decreased amodiaquine sensitivity was associated with sustained, highly prevalent mutations in pfcrt, and one mutation in pfmdr1 – Y184F – was associated with decreased parasite sensitivity to artemisinin. Conclusions Directly measuring ex vivo parasite drug response and resistance mutation genotyping over time are useful tools for monitoring parasite drug responses in field samples. Furthermore, these data suggest that the use of amodiaquine and artemisinin derivatives in combination therapies is selecting for increased drug tolerance within this population.

2013-01-01

363

Cultivable Bacterial Microbiota of Northern Bobwhite (Colinus virginianus): A New Reservoir of Antimicrobial Resistance?  

PubMed

The northern bobwhite (Colinus virginianus) is an ecologically and economically important avian species. At the present time, little is known about the microbial communities associated with these birds. As the first step to create a quail microbiology knowledge base, the current study conducted an inventory of cultivable quail tracheal, crop, cecal, and cloacal microbiota and associated antimicrobial resistance using a combined bacteriology and DNA sequencing approach. A total of 414 morphologically unique bacterial colonies were selected from nonselective aerobic and anaerobic cultures, as well as selective and enrichment cultures. Analysis of the first 500-bp 16S rRNA gene sequences in conjunction with biochemical identifications revealed 190 non-redundant species-level taxonomic units, representing 160 known bacterial species and 30 novel species. The bacterial species were classified into 4 phyla, 14 orders, 37 families, and 59 or more genera. Firmicutes was the most commonly encountered phylum (57%) followed by Actinobacteria (24%), Proteobacteria (17%) and Bacteroidetes (0.02%). Extensive diversity in the species composition of quail microbiota was observed among individual birds and anatomical locations. Quail microbiota harbored several opportunistic pathogens, such as E. coli and Ps. aeruginosa, as well as human commensal organisms, including Neisseria species. Phenotypic characterization of selected bacterial species demonstrated a high prevalence of resistance to the following classes of antimicrobials: phenicol, macrolide, lincosamide, quinolone, and sulphate. Data from the current investigation warrant further investigation on the source, transmission, pathology, and control of antimicrobial resistance in wild quail populations. PMID:24937705

Su, Hongwen; McKelvey, Jessica; Rollins, Dale; Zhang, Michael; Brightsmith, Donald J; Derr, James; Zhang, Shuping

2014-01-01

364

Cultivable Bacterial Microbiota of Northern Bobwhite (Colinus virginianus): A New Reservoir of Antimicrobial Resistance?  

PubMed Central

The northern bobwhite (Colinus virginianus) is an ecologically and economically important avian species. At the present time, little is known about the microbial communities associated with these birds. As the first step to create a quail microbiology knowledge base, the current study conducted an inventory of cultivable quail tracheal, crop, cecal, and cloacal microbiota and associated antimicrobial resistance using a combined bacteriology and DNA sequencing approach. A total of 414 morphologically unique bacterial colonies were selected from nonselective aerobic and anaerobic cultures, as well as selective and enrichment cultures. Analysis of the first 500-bp 16S rRNA gene sequences in conjunction with biochemical identifications revealed 190 non-redundant species-level taxonomic units, representing 160 known bacterial species and 30 novel species. The bacterial species were classified into 4 phyla, 14 orders, 37 families, and 59 or more genera. Firmicutes was the most commonly encountered phylum (57%) followed by Actinobacteria (24%), Proteobacteria (17%) and Bacteroidetes (0.02%). Extensive diversity in the species composition of quail microbiota was observed among individual birds and anatomical locations. Quail microbiota harbored several opportunistic pathogens, such as E. coli and Ps. aeruginosa, as well as human commensal organisms, including Neisseria species. Phenotypic characterization of selected bacterial species demonstrated a high prevalence of resistance to the following classes of antimicrobials: phenicol, macrolide, lincosamide, quinolone, and sulphate. Data from the current investigation warrant further investigation on the source, transmission, pathology, and control of antimicrobial resistance in wild quail populations.

Su, Hongwen; McKelvey, Jessica; Rollins, Dale; Zhang, Michael; Brightsmith, Donald J.; Derr, James; Zhang, Shuping

2014-01-01

365

[Pore-forming toxins in bacterial infections: targets for novel drugs].  

PubMed

Pore-forming toxins (PFTs) form a large group of bacterial virulence factors that play an important role in various infectious diseases. These include infections with problematic pathogens such as Streptococcus pneumoniae, Staphylococcus aureus, group A and B streptococci, Escherichia coli and Mycobacterium tuberculosis. PFTs perforate host cell membranes, which contributes to the establishment or exacerbation of an infection mainly in two ways: first, by disrupting the host immune response, and second, by helping bacteria to cross epithelial and endothelial barriers, thus allowing them to spread to other parts of the host. Although perforation of the plasma membrane can lead to host cell death, cells possess molecular defence mechanisms and under certain conditions can successfully defend themselves against PFTs. PFTs, as well as the immune response against PFTs, form a potential target for novel prophylactics and therapeutics against bacterial infectious disease, including against antibiotic-resistant strains. PMID:24713334

Los, Ferdinand C O; Ratner, Adam J

2014-01-01

366

Inhibition of drug-resistant HIV-1 by RNA interference.  

PubMed

RNA interference is a powerful tool used to inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro. Almost all HIV-1 genes have been targets for small interfering RNA (siRNA) molecules, and HIV-1 replication can be specifically and successfully inhibited by this technique. RNA interference has been proposed as an alternative strategy to inhibit replication of drug-resistant viruses that emerge during suboptimal antiretroviral therapy for HIV-1. To investigate specific inhibition of drug-resistant HIV-1 by RNA interference, we designed siRNA molecules that recognize codons 181-188 of the reverse transcriptase (RT) gene of wild-type HIV-1 and HIV-1 carrying the M184V mutation, which confers high-level resistance to the RT inhibitor lamivudine. Using viral variants with single point mutations at codon 184, we measured the impact of these mutations on virus replication. We have demonstrated that siRNA targeting either wild-type HIV-1 or M184V variants inhibits replication of the corresponding virus, but does not influence replication of virus with a mismatch in the targeted region. Combining two effective siRNAs did not show synergistic inhibitory effect on HIV-1 replication. However, a combination of lamivudine and siRNA-M184V was very effective in inhibiting replication of both wild-type and variant M184V viruses in mixed infection experiments. Taken together, these results demonstrate that RNA interference might be useful in the treatment of drug-resistant HIV-1 infection. PMID:16290277

Huelsmann, Peter M; Rauch, Pia; Allers, Kristina; John, Matthias J; Metzner, Karin J

2006-01-01

367

A Decade of Spore-Forming Bacterial Infections Among European Injecting Drug Users: Pronounced Regional Variation  

PubMed Central

The recent anthrax outbreak among injecting drug users (IDUs) in Europe has highlighted an ongoing problem with severe illness resulting from spore-forming bacteria in IDUs. We collated the numbers of cases of 4 bacterial illnesses (botulism, tetanus, Clostridium novyi, and anthrax) in European IDUs for 2000 to 2009 and calculated population rates. Six countries reported 367 cases; rates varied from 0.03 to 7.54 per million people. Most cases (92%) were reported from 3 neighboring countries: Ireland, Norway, and the United Kingdom. This geographic variation needs investigation.

Palmateer, Norah; Wiessing, Lucas; Marongiu, Andrea; White, Joanne; Ncube, Fortune; Goldberg, David

2012-01-01

368

A decade of spore-forming bacterial infections among European injecting drug users: pronounced regional variation.  

PubMed

The recent anthrax outbreak among injecting drug users (IDUs) in Europe has highlighted an ongoing problem with severe illness resulting from spore-forming bacteria in IDUs. We collated the numbers of cases of 4 bacterial illnesses (botulism, tetanus, Clostridium novyi, and anthrax) in European IDUs for 2000 to 2009 and calculated population rates. Six countries reported 367 cases; rates varied from 0.03 to 7.54 per million people. Most cases (92%) were reported from 3 neighboring countries: Ireland, Norway, and the United Kingdom. This geographic variation needs investigation. PMID:22095355

Hope, Vivian D; Palmateer, Norah; Wiessing, Lucas; Marongiu, Andrea; White, Joanne; Ncube, Fortune; Goldberg, David

2012-01-01

369

Treatment of multidrug-resistant and extensively drug-resistant tuberculosis in adolescent patients.  

PubMed

The authors describe 2 pediatric patients with drug-resistant tuberculosis in whom new diagnostic and therapeutic approaches were crucial to good clinical evolution. Although there was good clinical outcome, important side effects with linezolid and amikacin occurred, namely medullary hypoplasia and neurosensorial hypoacusia, respectively. A multidisciplinary approach with close follow up was of major importance in managing these patients. PMID:24642519

Rodrigues, Magda; Brito, Maria; Villar, Miguel; Correia, Paula

2014-06-01

370

Numerical modeling of the transmission dynamics of drug-sensitive and drug-resistant HSV-2  

NASA Astrophysics Data System (ADS)

A competitive finite-difference method will be constructed and used to solve a modified deterministic model for the spread of herpes simplex virus type-2 (HSV-2) within a given population. The model monitors the transmission dynamics and control of drug-sensitive and drug-resistant HSV-2. Unlike the fourth-order Runge-Kutta method (RK4), which fails when the discretization parameters exceed certain values, the novel numerical method to be developed in this paper gives convergent results for all parameter values.

Gumel, A. B.

2001-03-01

371

Structure of Supported Bilayers Composed of Lipopolysaccharides and Bacterial Phospholipids: Raft Formation and Implications for Bacterial Resistance  

PubMed Central

Lipopolysaccharide (LPS), the major lipid on the surface of Gram-negative bacteria, plays a key role in bacterial resistance to hydrophobic antibiotics and antimicrobial peptides. Using atomic force microscopy (AFM) we characterized supported bilayers composed of LPSs from two bacterial chemotypes with different sensitivities to such antibiotics and peptides. Rd LPS, from more sensitive “deep rough” mutants, contains only an inner saccharide core, whereas Ra LPS, from “rough” mutants, contains a longer polysaccharide region. A vesicle fusion technique was used to deposit LPS onto either freshly cleaved mica or polyethylenimine-coated mica substrates. The thickness of the supported bilayers measured with contact-mode AFM was 7 nm for Rd LPS and 9 nm for Ra LPS, consistent with previous x-ray diffraction measurements. In water the Ra LPS bilayer surface was more disordered than Rd LPS bilayers, likely due to the greater volume occupied by the longer Ra LPS polysaccharide region. Since deep rough mutants contain bacterial phospholipid (BPL) as well as LPS on their surfaces, we also investigated the organization of Rd LPS/BPL bilayers. Differential scanning calorimetry and x-ray diffraction indicated that incorporation of BPL reduced the phase transition temperature, enthalpy, and average bilayer thickness of Rd LPS. For Rd LPS/BPL mixtures, AFM showed irregularly shaped regions thinner than Rd LPS bilayers by 2 nm (the difference in thickness between Rd LPS and BPL bilayers), whose area increased with increasing BPL concentration. We argue that the increased permeability of deep rough mutants is due to structural modifications caused by BPL to the LPS membrane, in LPS hydrocarbon chain packing and in the formation of BPL-enriched microdomains.

Tong, Jihong; McIntosh, Thomas J.

2004-01-01

372

Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance  

PubMed Central

Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Furthermore, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/?-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells, but also provide novel therapeutic approaches for targeting refractory tumors.

Liu, Yong-Yu; Li, Yu-Teh

2014-01-01

373

OsEDR1 negatively regulates rice bacterial resistance via activation of ethylene biosynthesis.  

PubMed

Rice OsEDR1 is a sequence ortholog of Arabidopsis EDR1. However, its molecular function is unknown. We show here that OsEDR1-suppressing/knockout (KO) plants, which developed spontaneous lesions on the leaves, have enhanced resistance to Xanthomonas oryzae pv. oryzae (Xoo) causing bacterial blight disease. This resistance was associated with increased accumulation of salicylic acid (SA) and jasmonic acid (JA), induced expression of SA- and JA-related genes and suppressed accumulation of 1-aminocyclopropane-1-carboxylic acid (ACC), the direct precursor of ethylene, and expression of ethylene-related genes. OsEDR1-KO plants also showed suppressed production of ethylene. Knockout of OsEDR1 suppressed the ACC synthase (ACS) gene family, which encodes the rate-limiting enzymes of ethylene biosynthesis by catalysing the formation of ACC. The lesion phenotype and enhanced bacterial resistance of the OsEDR1-KO plants was partly complemented by the treatment with ACC. ACC treatment was associated with decreased SA and JA biosynthesis in OsEDR1-KO plants. In contrast, aminoethoxyvinylglycine, the inhibitor of ethylene biosynthesis, promoted expression of SA and JA synthesis-related genes in OsEDR1-KO plants. These results suggest that ethylene is a negative signalling molecule in rice bacterial resistance. In the rice-Xoo interaction, OsEDR1 transcriptionally promotes the synthesis of ethylene that, in turn, suppresses SA- and JA-associated defence signalling. PMID:20807375

Shen, Xiangling; Liu, Hongbo; Yuan, Bin; Li, Xianghua; Xu, Caiguo; Wang, Shiping

2011-02-01

374

Oscyp71Z2 involves diterpenoid phytoalexin biosynthesis that contributes to bacterial blight resistance in rice.  

PubMed

Bacterial blight is one of the most destructive rice diseases, which caused by Xoo, and results in yield losses, endangering worldwide food security. Diterpenoid phytoalexins, a type of antimicrobials produced in rice, are critical for resistance to fungal and bacterial pathogens. This article reports the characterization of the cytochrome P450 gene Oscyp71Z2, which belongs to the CYP71Z subfamily. Overexpression of Oscyp71Z2 in rice enhanced resistance to Xoo at the booting stage. The accumulation of phytoalexins was rapidly and strongly induced in Oscyp71Z2-overexpressing plants, and the transcript levels of genes related to the phytoalexin biosynthesis pathway were elevated. The H?O? concentration in Oscyp71Z2-overexpressing plants was reduced in accordance with the increase in ROS-scavenging ability due to the induction of SOD as well as POD and CAT activation. We also showed that suppression of Oscyp71Z2 had no significantly effect on disease resistance to Xoo in rice. These results demonstrated that Oscyp71Z2 plays an important role in bacterial blight resistance by regulating the diterpenoid phytoalexin biosynthesis and H?O? generation. PMID:23602104

Li, Wenqi; Shao, Min; Yang, Jie; Zhong, Weigong; Okada, Kazunori; Yamane, Hisakazu; Qian, Guoliang; Liu, Fengquan

2013-06-01

375

MULTI-FUNCTIONAL NANOCARRIERS TO OVERCOME TUMOR DRUG RESISTANCE  

PubMed Central

The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Tumor cells are able to generate a multi-drug resistance (MDR) phenotype due to microenvironmental selection pressures. This review addresses the use of nanotechnology-based delivery systems to overcome MDR in solid tumors. Our own work along with evidence from the literature illustrates the development of various types of engineered nanocarriers specifically designed to enhance tumor-targeted delivery through passive and active targeting strategies. Additionally, multi-functional nanocarriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g., with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors. In preclinical studies, the use of multi-functional nanocarriers has shown significant promise in enhancing cancer therapy, especially against MDR tumors.

Jabr-Milane, Lara S.; van Vlerken, Lilian E.; Yadav, Sunita; Amiji, Mansoor M.

2008-01-01

376

Facultative bacterial symbionts in aphids confer resistance to parasitic wasps.  

PubMed

Symbiotic relationships between animals and microorganisms are common in nature, yet the factors controlling the abundance and distributions of symbionts are mostly unknown. Aphids have an obligate association with the bacterium Buchnera aphidicola (the primary symbiont) that has been shown to contribute directly to aphid fitness. In addition, aphids sometimes harbor other vertically transmitted bacteria (secondary symbionts), for which few benefits of infection have been previously documented. We carried out experiments to determine the consequences of these facultative symbioses in Acyrthosiphon pisum (the pea aphid) for vulnerability of the aphid host to a hymenopteran parasitoid, Aphidius ervi, a major natural enemy in field populations. Our results show that, in a controlled genetic background, infection confers resistance to parasitoid attack by causing high mortality of developing parasitoid larvae. Compared with uninfected controls, experimentally infected aphids were as likely to be attacked by ovipositing parasitoids but less likely to support parasitoid development. This strong interaction between a symbiotic bacterium and a host natural enemy provides a mechanism for the persistence and spread of symbiotic bacteria. PMID:12563031

Oliver, Kerry M; Russell, Jacob A; Moran, Nancy A; Hunter, Martha S

2003-02-18

377

[Drug resistance testing of Mycobacterium tuberculosis isolates from sputum in Chad].  

PubMed

Culture and resistance testing of Mycobacterium tuberculosis are not regularly performed in Chad. Sputa were obtained from three different categories of hospitals (district, regional and national) in Chad. All examined sputa were smear-positive and were investigated by culture and drug resistance testing for first-line antituberculosis drugs. From 232 sputa positive for acid-fast bacilli, 135 isolates of M. tuberculosis from different patients (46 women, 89 men, mean age 34 years) were analyzed. All the patients except one corresponded to new cases of tuberculosis. In total, 27 out of 135 isolates (20%) were resistant to at least one major antituberculosis drug. Resistance to isoniazid was the most frequent resistance observed, with 18 isolates (13%) presenting at least this resistance. Three isolates (2.2%) were resistant to isoniazid and rifampicin (multidrug resistance MDR) including one isolate being concomitantly resistant to streptomycin and ethambutol. The resistance rate differed in relation to the category of the hospital; the most important resistance rate was observed in regional hospitals (33%), while it was 16% and 14% in the national and district hospitals, respectively. HIV serology was performed in 81 patients, among whom 20 (25%) were positive. This is the first study that shows that drug resistance of M. tuberculosis is present in Chad. Besides single drug-resistant isolates, multidrug-resistant strains of M. tuberculosis could also be identified. This result highlights the urgency of initiating actions to detect drug resistance and limit the spread of drug-resistant strains. PMID:21960358

Abdelhadi, O; Ndokaïn, J; Ali, M Moussa; Friocourt, V; Mortier, E; Heym, B

2012-02-01

378

Rifampin drug resistance tests for tuberculosis: challenging the gold standard.  

PubMed

The rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented "disputed" rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified. PMID:23761144

Van Deun, Armand; Aung, Kya J M; Bola, Valentin; Lebeke, Rossin; Hossain, Mohamed Anwar; de Rijk, Willem Bram; Rigouts, Leen; Gumusboga, Aysel; Torrea, Gabriela; de Jong, Bouke C

2013-08-01

379

Rifampin Drug Resistance Tests for Tuberculosis: Challenging the Gold Standard  

PubMed Central

The rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented “disputed” rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified.

Aung, Kya J. M.; Bola, Valentin; Lebeke, Rossin; Hossain, Mohamed Anwar; de Rijk, Willem Bram; Rigouts, Leen; Gumusboga, Aysel; Torrea, Gabriela; de Jong, Bouke C.

2013-01-01

380

Evaluation of radiation resistance of the bacterial contaminants from femoral heads processed for allogeneic transplantation  

NASA Astrophysics Data System (ADS)

Femoral heads excised during surgery were obtained from patients who had a fractured neck of the femur and were processed as bone allograft. The bacterial contaminants were isolated from femoral heads at different stages of processing and identified based on morphological characteristics and biochemical tests. Bacterial contaminants on bone were mainly Gram-positive bacilli and cocci (58.3%). Twenty-four isolates from bone samples were screened for resistance to radiation. The D10 values for Gram-negative bacteria isolated from femoral heads ranged from 0.17 to 0.65 kGy. Higher D10 values 0.56-1.04 kGy were observed for Gram-positive bacterial isolates.

Singh, Rita; Singh, Durgeshwer

2009-09-01

381

Clinical and operational value of the extensively drug-resistant tuberculosis definition  

Microsoft Academic Search

Currently, no information is available on the effect of resistance\\/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB

G. B. Migliori; G. Besozzi; E. Girardi; K. Kliiman; C. Lange; O. S. Toungoussova; G. Ferrara; D. M. Cirillo; A. Gori; A. Matteelli; A. Spanevello; L. R. Codecasa; M. C. Raviglione

2007-01-01

382

Bacteriophages: biosensing tools for multi-drug resistant pathogens.  

PubMed

Pathogen detection is of utmost importance in many sectors, such as in the food industry, environmental quality control, clinical diagnostics, bio-defence and counter-terrorism. Failure to appropriately, and specifically, detect pathogenic bacteria can lead to serious consequences, and may ultimately be lethal. Public safety, new legislation, recent outbreaks in food contamination, and the ever-increasing prevalence of multidrug-resistant infections have fostered a worldwide research effort targeting novel biosensing strategies. This review concerns phage-based analytical and biosensing methods targeted towards theranostic applications. We discuss and review phage-based assays, notably phage amplification, reporter phage, phage lysis, and bioluminescence assays for the detection of bacterial species, as well as phage-based biosensors, including optical (comprising SPR sensors and fiber optic assays), electrochemical (comprising amperometric, potentiometric, and impedimetric sensors), acoustic wave and magnetoelastic sensors. PMID:24434867

Tawil, N; Sacher, E; Mandeville, R; Meunier, M

2014-03-21

383

Capillary Electrophoresis - Single Strand Conformation Polymorphism for the Detection of Multiple Mutations Leading to Tuberculosis Drug Resistance  

PubMed Central

Drug resistant tuberculosis (TB) is a major health problem in both developed and developing countries. Mutations in the Mycobacterium (M.) tuberculosis bacterial genome, such as those to the rpoB gene and mabA-inhA promoter region, have been linked to TB drug resistance in against rifampicin and isoniazid, respectively. The rapid, accurate, and inexpensive identification of these and other mutations leading to TB drug resistance is an essential tool for improving human health. Capillary electrophoresis (CE) single strand conformation polymorphism (SSCP) can be a highly sensitive technique for the detection of genetic mutation that has not been previously explored for drug resistance mutations in M. tuberculosis. This work explores the potential of CE-SSCP through the optimization of variables such as polymer separation matrix concentration, capillary wall coating, electric field strength, and temperature on resolution of mutation detection. The successful detection of an rpoB gene mutation and two mabA-inhA promoter region mutations while simultaneously differentiating a TB-causing mycobacteria from a non-TB bacteria was accomplished using the optimum conditions of 4.5% (w/v) PDMA in a PDMA coated capillary at 20°C using a separation voltage of 278 V/cm. This multiplexed analysis that can be completed in a few hours demonstrates the potential of CE-SSCP to be an inexpensive and rapid analysis method.

Krothapalli, Sowmya; May, Michael K.; Hestekin, Christa N.

2013-01-01

384

Adhesion-induced drug resistance in leukemia stem cells.  

PubMed

The co-culture of TF-1 leukemia cells and MS-5 stromal cells produces a cobblestone area which partially mimics the leukemia stem cell niche. The adhering leukemia cells are shown to become less sensitive to cytarabine, etoposide and daunorubicin. These changes are associated with an increased proportion of the G0/G1 phase, increased upregulation of cyclin-dependent kinase inhibitors, and increased levels of Bcl-2, but not with any change in the expression of BAX or drug transporters such as ABCG2 and MDR1, compared to monocultured leukemic cells. In addition, we demonstrate using a bioimaging technique that daunorubicin accumulates in the lysosomes of the adherent leukemic cells and that V-ATPase is activated. These findings suggest that adhesion alone can lead to drug resistance in leukemic stem cells by various mechanisms. PMID:20689339

Funayama, Keiji; Murai, Fumihiko; Shimane, Miyuki; Nomura, Hitoshi; Asano, Shigetaka

2010-01-01

385

Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis  

PubMed Central

BACKGROUND Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS We enrolled 41 patients who had sputum-culture–positive extensively drug-resistant (XDR) tuberculosis and who did not have a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.)

Lee, Myungsun; Lee, Jongseok; Carroll, Matthew W.; Choi, Hongjo; Min, Seonyeong; Song, Taeksun; Via, Laura E.; Goldfeder, Lisa C.; Kang, Eunhwa; Jin, Boyoung; Park, Hyeeun; Kwak, Hyunkyung; Kim, Hyunchul; Jeon, Han-Seung; Jeong, Ina; Joh, Joon Sung; Chen, Ray Y.; Olivier, Kenneth N.; Shaw, Pamela A.; Follmann, Dean; Song, Sun Dae; Lee, Jong-Koo; Lee, Dukhyoung; Kim, Cheon Tae; Dartois, Veronique; Park, Seung-Kyu; Cho, Sang-Nae; Barry, Clifton E.

2013-01-01

386

Gallium phosphinoarylbisthiolato complexes counteract drug resistance of cancer cells.  

PubMed

In cancer therapy the platinum-based drugs are used frequently with a good clinical outcome, but besides unwanted side effects which occur, the tumour cells subjected to treatment are prone to develop tolerance or even multidrug resistance (MDR). Metal compounds with a central atom other than platinum are efficient in targeting the chemoresistant cells, therefore the biological outcome of two recently synthesized gallium phosphinoarylbisthiolato complexes was studied, having the formula [X][Ga{PPh(2-SC6H4)2-?(3)S,S',P}{PPh(2-SC6H4)2-?(2)S,S'}] where [X] is either the NEt3H (1) or PPh4 (2) cation. Compounds 1 and 2 display in vitro cytotoxicity against both platinum-sensitive and platinum-resistant cell lines (A2780 and A2780cis). Morphological and ultrastructural evidence points toward their capacity to impair tumour cells survival. This behaviour is based on malignant cells capacity to selectively intake gallium, and to bind to the cellular DNA. They are able to cause massive DNA damage in treated cancer cells, focusing on 7-methylguanine and 8-oxoguanine sites and oxidizing the pyrimidine bases; this leads to early apoptosis of a significant percent of treated cells. The intrinsic and extrinsic apoptotic pathways are influenced through the modulation of gene expression following the treatment with complexes 1 and 2, which accompanies the negative regulation of P-glycoprotein 1 (Pgp-1), an important cellular ABC-type transporter from the multidrug resistance (MDR) family. The studied Ga(III) compounds demonstrated the capacity to counteract the chemoresistance mechanisms in the tumours defiant to standard drug action. Compound 2 shows a good anticancer potential and it could represent an alternative to platinum-based drugs especially in the situation of standard treatment failure. PMID:24413432

Fischer-Fodor, Eva; V?lean, Ana-Maria; Virag, Piroska; Ilea, Petru; Tatomir, Corina; Imre-Lucaci, Florica; Schrepler, Maria Perde; Krausz, Ludovic Tibor; Tudoran, Lucian Barbu; Precup, Calin George; Lupan, Iulia; Hey-Hawkins, Evamarie; Silaghi-Dumitrescu, Luminita

2014-04-01

387

An exhaustive yet simple virtual screening campaign against Sortase A from multiple drug resistant Staphylococcus aureus.  

PubMed

Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen due to its acquired resistance to the ? lactam antibiotics. The Sortase A is an enzyme of Gram-positive bacteria including S. aureus to anchor surface proteins to the cell wall. Sortase A is well studied enzyme and considered as the drug target against MRSA. Sortase A plays active role in anchoring the virulence proteins on the cell wall of the Gram-positive bacteria. The inhibition of Sortase A activity results in the separation of S. aureus from the host cells and ultimately alleviation of the infection. Here, we adapted a structure-based virtual screening protocol which helped in identification of novel potential inhibitors of Sortase A. The protocol involved the docking of a chemical library of druglike compounds with the Sortase A binding site represented by multiple crystal structures. The compounds were ranked by multiple scoring functions and shortlisted for future experimental screening. The method resulted in shortlisting of three compounds as potential novel inhibitors of Sortase A out of a large chemical library. The high rankings of shortlisted compounds estimated by multiple scoring functions showed their binding potential with Sortase A. The results are proved to be a simple yet efficient choice of structure-based virtual screening. The identified compounds are druglike and show high rankings among all set protocols of the virtual screening. We hope that the study would eventually help to expedite the discovery of novel drug candidates against MRSA. PMID:24797540

Uddin, Reaz; Saeed, Kiran

2014-08-01

388

Drug efflux by a small multidrug resistance protein is inhibited by a transmembrane peptide.  

PubMed

Drug-resistant bacteria use several families of membrane-embedded transporters to remove antibiotics from the cell. One such family is the small multidrug resistance proteins (SMRs) that, because of their relatively small size (ca. 110 residues with four transmembrane [TM] helices), must form (at least) dimers to efflux drugs. Here, we use a Lys-tagged synthetic peptide with exactly the same sequence as TM4 of the full-length SMR Hsmr from Halobacterium salinarum [TM4 sequence: AcA(Sar)(3)-VAGVVGLALIVAGVVVLNVAS-KKK (Sar = N-methylglycine)] to compete with and disrupt the native TM4-TM4 interactions believed to constitute the locus of Hsmr dimerization. Using a cellular efflux assay of the fluorescent SMR substrate ethidium bromide, we determined that bacterial cells containing Hsmr are able to remove cellular ethidium via first-order exponential decay with a rate constant (k) of 10.1 × 10(-3) ± 0.7 × 10(-3) s(-1). Upon treatment of the cells with the TM4 peptide, we observed a saturable ~60% decrease in the efflux rate constant to 3.7 × 10(-3) ± 0.2 × 10(-3) s(-1). In corresponding experiments with control peptides, including scrambled sequences and a sequence with d-chirality, a decrease in ethidium efflux either was not observed or was marginal, likely from nonspecific effects. The designed peptides did not evoke bacterial lysis, indicating that they act via the ?-helicity and membrane insertion propensities of the native TM4 helix. Our overall results suggest that this approach could conceivably be used to design hydrophobic peptides for disruption of key TM-TM interactions of membrane proteins and represent a valuable route to the discovery of new therapeutics. PMID:22526304

Poulsen, Bradley E; Deber, Charles M

2012-07-01