Molecular characterisation of linezolid resistance in two vancomycin-resistant (VanB) Enterococcus faecium isolates using Pyrosequencing™

Saager, B.; Rohde, Holger; Timmerbeil, B. S.; Franke, Gefion; Pothmann, W.; Dahlke, Joachim; Scherpe, Stefanie; Sobottka, Ingo; Heisig, Peter; Horstkotte, Matthias A.

doi:10.1007/s10096-008-0514-6

Cited by 21 publications

(9 citation statements)

References 13 publications

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“…The times to reversion which we observed in our model are compatible with the time frames reported in clinical studies (29,33,57,70) (see Fig. S1 in the supplemental material).…”

Section: Discussionsupporting

confidence: 89%

“…While these theoretical findings are in agreement with many epidemiological and experimental studies, genetic reversion to susceptibility has been described repeatedly, and several experimental studies describe reversion of clinical isolates after serial passages without antibiotic in vitro (16,56,81). Reversion may be more likely in vivo than in vitro (12) and was also found within single patients (29,33,48,57,70).…”

supporting

confidence: 83%

“…Bacteria that are part of the microflora and may cause endogenous infections might face bottlenecks only infrequently, such that the model presented here may be more applicable. Although both persistence and disappearance of resistant and resistant compensated bacteria in the gut microflora have been reported (e.g., see references 21, 47, and 75), the pathogens in the majority of clinical studies that reported reversion were part of the normal human microflora (16,29,33,56,57,70). Although this remains to be investigated fully, the diverging theoretical predictions from the model presented here and the one by Levin et al (43) are likely due to the absence of serial bottlenecks in our models.…”

Section: Discussionmentioning

confidence: 99%

“…Reversion was extremely slow with high RC fitness and/or a low kill rate (in the range of years for our parameterization), so it is not surprising that reversion was rarely observed under laboratory conditions. Saager et al (70) and Meka et al (57) studied clonally related strains within single patients and found reversion of linezolid resistance after 4 months in vancomycinresistant enterococci and after 7 months in methicillin-resistant Staphylococcus aureus (MRSA). Loss of resistance to several antibiotics within a few weeks to months was described in a detailed case report of an elderly patient with recurrent MRSA infections (33) (see Fig.…”

Section: Discussionmentioning

confidence: 99%

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Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Wiesch

Engelstädter

Bonhoeffer

2010

Antimicrob Agents Chemother

146

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Strains of bacterial pathogens that have acquired mutations conferring antibiotic resistance often have a lower growth rate and are less invasive or transmissible initially than their susceptible counterparts. However, fitness costs of resistance mutations can be ameliorated by secondary site mutations. These so-called compensatory mutations may restore fitness in the absence and/or presence of antimicrobials. We review literature data and show that the fitness gains in the absence and presence of antibiotic treatment need not be correlated. The aim of this study is to gain a better conceptual grasp of how compensatory mutations with different fitness gains affect evolutionary trajectories, in particular reversibility. To this end, we developed a theoretical model with which we consider both a resistance and a compensation locus. We propose an intuitively understandable parameterization for the fitness values of the four resulting genotypes (wild type, resistance mutation only, compensatory mutation only, and both mutations) in the absence and presence of treatment. The differential fitness gains, together with the turnover rate and the mutation rate, strongly affected the success of antibacterial treatment, reversibility, and long-term abundance of resistant strains. We therefore propose that experimental studies of compensatory mutations should include fitness measurements of all possible genotypes in both the absence and presence of an antibiotic.The global rise of antimicrobial resistance in bacteria, combined with the decreasing number of innovative antibacterial agents, has led to warnings that we may soon lose our ability to treat bacterial infections (82). This spread of strains that are genetically resistant is occurring despite the fact that resistance is often costly. When resistance is due to an altered target, this target might not work as well as its progenitor. Efflux pumps or bacterial enzymes that modify the antibiotic often lead to metabolic costs (1). This fitness loss may be reflected in a reduced growth rate in vivo (e.g., see reference 51) or in vitro (reviewed in references 3 and 85), a reduced transmission rate (66), a higher clearance rate (29), or decreased invasiveness (22) in the absence of antibiotics. The costs of resistance are among the most important factors determining both the rate and extent of resistance emergence (2,3,15,32,44,50). In order to devise strategies to contain antibacterial resistance, we therefore need to predict the fitness trajectories (i.e., how the fitness of a strain will change over time) of resistant strains and to investigate whether and how resistance may be reversible once it has emerged. Antimicrobial-induced killing or growth suppression does not necessarily increase monotonically with drug concentration. Therefore, it is not always clear how the MIC and the growth rate at a defined concentration are correlated. Rather than making assumptions about the fitness landscape, in the following material we take the growth rate at therapeutic concentrations ...

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“…The times to reversion which we observed in our model are compatible with the time frames reported in clinical studies (29,33,57,70) (see Fig. S1 in the supplemental material).…”

Section: Discussionsupporting

confidence: 89%

supporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Wiesch

Engelstädter

Bonhoeffer

2010

Antimicrob Agents Chemother

146

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“…Oxazolidinones have a common 2-oxazolidone ring and inhibit initiation of protein synthesis by preventing formation of ribosome and N-formylmethionyl-tRNA complex [5]. Resistance to oxazolidinones generally results from mutation in 23S rRNA [6, 7] which supports its mechanism of action, or due to activity of efflux pumps [8]. Toxicities associated with long term use of linezolid has spawn interest in newer oxazolidinones that improve on safety profile without compromising potency [9–11].…”

mentioning

confidence: 99%

An evolved oxazolidinone with selective potency against Mycobacterium tuberculosis and gram positive bacteria

Kaushik

Heuer

Bell

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Innovation of new antibacterials that are effective against strains that have developed resistance to existing drugs would strengthen our ability to treat and subsequently control spread of pathogenic bacteria. Increasing incidence of infections with drug resistant bacteria has become a common occurrence in recent times. We have developed an evolved oxazolidinone, T145, which inhibits growth of Enterococcus faecalis, Staphylococcus aureus and Mycobacterium tuberculosis (Mtb) with sub μg/ml potencies that are potentially therapeutically valuable. The oxazolidinone is bactericidal against Mtb but bacteriostatic against E. faecalis and S. aureus. In addition to therapeutically valuable potency and bactericidal activity against Mtb, T145 minimizes selection of spontaneous resistant mutants, a trait that prolongs longevity of a drug in clinical use.

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Antimicrobials

2014

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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein.

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Molecular characterisation of linezolid resistance in two vancomycin-resistant (VanB) Enterococcus faecium isolates using Pyrosequencing™

Cited by 21 publications

References 13 publications

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

An evolved oxazolidinone with selective potency against Mycobacterium tuberculosis and gram positive bacteria

Antimicrobials

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