Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on the skin of human volunteers

Gustafsson, Ingegerd; Cars, Otto; Andersson, Dan I.

doi:10.1093/jac/dkg331

Cited by 46 publications

(28 citation statements)

References 28 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

“…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).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Wiesch

Engelstädter

Bonhoeffer

2010

Antimicrob Agents Chemother

145

View full text Add to dashboard Cite

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 ...

show abstract

supporting

confidence: 83%

mentioning

confidence: 99%

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Wiesch

Engelstädter

Bonhoeffer

2010

Antimicrob Agents Chemother

145

View full text Add to dashboard Cite

show abstract

“…Symbols for LIVE/DEAD counts: F, total counts; , live-cell counts; E, dead-cell counts. communities, where competition and other community phenomena might dictate against susceptibility changes with associated fitness costs (19,26). In this study, we have investigated the effects of QACs on domestic sink drain bacteria with microcosms and pure cultures derived from them.…”

Section: Resultsmentioning

confidence: 99%

Effects of Quaternary-Ammonium-Based Formulations on Bacterial Community Dynamics and Antimicrobial Susceptibility

McBain

Ledder

Moore

et al. 2004

Appl Environ Microbiol

166

130

View full text Add to dashboard Cite

Quaternary ammonium compounds (QACs) are widely used as adjuncts to hygiene in domestic cleaning products. Current concern that the increased use of such biocides in consumer products might contribute to the emergence of antibiotic resistance has led us to examine the effects of a QAC-containing domestic cleaning fluid on the population dynamics and antimicrobial susceptibility of domestic sink drain biofilm communities. QAC susceptibilities of numerically dominant, culturable drain bacteria (15 genera, 17 species) were determined in vitro before and after repeated QAC exposure (14 passages). A fully characterized drain microcosm was then exposed to short-term (12 days) and long-term (3 months) dosing with a QAC-containing domestic detergent (QD). QAC exposure of isolated cultures caused both increases (three species) and circa twofold decreases (six species) in QAC susceptibility. The susceptibility of Ralstonia sp. was considerably decreased following 14 consecutive QAC passages. Control drain microcosm biofilms maintained dynamic stability, as evidenced by culture and denaturing gradient gel electrophoresis (DGGE) analysis. Bacterial population densities were largely unaffected during short-term exposure to use levels of QD, although 50% QD caused circa 10-fold viability reductions. DGGE analysis supported these observations; identified the major microcosm genera as Pseudomonas, Pseudoalteromonas, Erwinia, and Enterobacter, and showed that aeromonads increased in abundance under 10 to 50% QD. Long-term exposure of the microcosms to QD did not significantly alter the pattern of antimicrobial susceptibility. These data demonstrate the recalcitrance of domestic drain biofilms toward QAC and that although repeated QAC exposure of drain isolates in pure culture results in susceptibility change in some test bacteria, such changes do not necessarily occur within complex communities.

show abstract

“…For example, in vitro and in vivo fitness studies have been performed on the forearms of human volunteers with a fusidic acid-resistant clinical isolate of Staphylo- coccus epidermidis. The resistance to fusidic acid, due to fusA mutations, resulted in a decreased growth rate in vitro and a considerable loss of fitness in competition assays in vivo (55). A set of in vitro stepwise-selected teicoplanin-resistant mutants which were derived from susceptible Staphylococcus aureus SA113 showed slower growth in vitro, thus likely correlating with in vivo fitness costs (56).…”

Section: Discussionmentioning

confidence: 99%

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Lohberger¹,

Coste²,

Sanglard³

2014

Eukaryot Cell

View full text Add to dashboard Cite

Azoles are widely used in antifungal therapy in medicine. Resistance to azoles can occur in Candida albicans principally by overexpression of multidrug transporter gene CDR1, CDR2, or MDR1 or by overexpression of ERG11, which encodes the azole target. The expression of these genes is controlled by the transcription factors (TFs) TAC1 (involved in the control of CDR1 and CDR2), MRR1 (involved in the control of MDR1), and UPC2 (involved in the control of ERG11). Several gain-of-function (GOF) mutations are present in hyperactive alleles of these TFs, resulting in the overexpression of target genes. While these mutations are beneficial to C. albicans survival in the presence of the antifungal drugs, their effects could potentially alter the fitness and virulence of C. albicans in the absence of the selective drug pressure. In this work, the effect of GOF mutations on C. albicans virulence was addressed in a systemic model of intravenous infection by mouse survival and kidney fungal burden assays. We engineered a set of strains with identical genetic backgrounds in which hyperactive alleles were reintroduced in one or two copies at their genomic loci. The results obtained showed that neither TAC1 nor MRR1 GOF mutations had a significant effect on C. albicans virulence. In contrast, the presence of two hyperactive UPC2 alleles in C. albicans resulted in a significant decrease in virulence, correlating with diminished kidney colonization compared to that by the wild type. In agreement with the effect on virulence, the decreased fitness of an isolate with UPC2 hyperactive alleles was observed in competition experiments with the wild type in vivo but not in vitro. Interestingly, UPC2 hyperactivity delayed filamentation of C. albicans after phagocytosis by murine macrophages, which may at least partially explain the virulence defects. Combining the UPC2 GOF mutation with another hyperactive TF did not compensate for the negative effect of UPC2 on virulence. In conclusion, among the major TFs involved in azole resistance, only UPC2 had a negative impact on virulence and fitness, which may therefore have consequences for the epidemiology of antifungal resistance.

show abstract

Fitness of antibiotic resistant Staphylococcus epidermidis assessed by competition on the skin of human volunteers

Abstract: These data show that human volunteers can be used as a simple and relevant model to study the biological cost of resistance.

Cited by 46 publications

References 28 publications

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Compensation of Fitness Costs and Reversibility of Antibiotic Resistance Mutations

Effects of Quaternary-Ammonium-Based Formulations on Bacterial Community Dynamics and Antimicrobial Susceptibility

Distinct Roles of Candida albicans Drug Resistance Transcription Factors TAC1 , MRR1 , and UPC2 in Virulence

Contact Info

Product

Resources

About