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Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost.

ABSTRACT: Daptomycin remains as one of the main treatment options for Methicillin-Resistant Staphylococcus aureus (MRSA). Sporadic resistance cases reported in patients treated with either daptomycin or glycopeptides are a growing concern. In a previous study, we described a clinical case of a patient with a community-acquired MRSA infection resistant to daptomycin and with intermediate resistance to vancomycin who developed a recurrent infection with a susceptible isogenic strain. In the present work, we further investigated the sequential events to determine whether the switch from a daptomycin resistance to a susceptible phenotype was due to a phenomenon of resistance reversion or recurrent infection with a susceptible strain. Pairwise competition experiments showed that the susceptible clinical recurrent SA6850 strain had increased fitness when compared to the resistant counterpart SA6820 strain. In fact, although we have demonstrated that reversion of daptomycin resistance to daptomycin susceptible can occur in vitro after serial passages in drug-free media, phylogenetic analysis suggested that the in vivo process was the result of a recurrent infection with a previous susceptible isolate carried by the patient rather than a resistance reversion of the strain. Whole genome sequence of evolved strains showed that daptomycin resistance in MRSA is associated with a high fitness cost mediated by mutations in mprF gene, revealed as a key element of the biological cost. Moreover, we determined that daptomycin resistance-associated fitness cost was independent of vancomycin intermediate resistance phenotype, as demonstrated in additional clinical MRSA vancomycin susceptible strains. This study highlights important observations as, despite daptomycin offers a useful treatment option for the patients with persistent infections, it has to be carefully monitored. The high fitness cost associated to daptomycin resistance may explain the reduced dissemination of daptomycin resistance and the absence of daptomycin reported outbreaks.

SUBMITTER: Roch M

PROVIDER: S-EPMC5723333 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost.

Roch Melanie M Gagetti Paula P Davis James J Ceriana Paola P Errecalde Laura L Corso Alejandra A Rosato Adriana E AE

Frontiers in microbiology 20171205

Daptomycin remains as one of the main treatment options for Methicillin-Resistant Staphylococcus aureus (MRSA). Sporadic resistance cases reported in patients treated with either daptomycin or glycopeptides are a growing concern. In a previous study, we described a clinical case of a patient with a community-acquired MRSA infection resistant to daptomycin and with intermediate resistance to vancomycin who developed a recurrent infection with a susceptible isogenic strain. In the present work, we ...[more]

PMID: 29259579

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Project description:The reversibility of antibiotic resistance is theoretically attractive due to the prospect of restoring the clinical potency of antibiotics. It is important to find out the factors that affect the reversibility of antibiotic resistance. Here, an mcr-1-positive multidrug-resistant (MDR) environmental Escherichia coli isolate was successively passaged under four antibiotic-free culture conditions. The relative abundances of multiple antibiotic resistance genes (ARGs) kept decreasing during the successive passages. The linear correlations between abundances of ARGs on the same MDR plasmid reflected that the decay of antibiotic resistance during the passage was mainly due to the elimination of the MDR plasmid (pMCR_W5-6). Colistin-susceptible strains were isolated at the end of the passage. The whole-genome sequencing of two susceptible isolates detected the elimination of the MDR plasmid and deletion of the mcr-1 gene. Deletions of DNA fragments from chromosome and plasmid were closely related to a variety of insertion sequences (ISs). The results of coculture of resistant and susceptible strains at different antibiotic concentrations indicated that the high fitness cost led to the poor stability of mobile ARGs. Strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. IMPORTANCE The dissemination of bacterial antibiotic resistance is a serious threat to human health. The development of new antibiotics faces both economic and technological challenges. The reversibility of antibiotic resistance has become an important issue causing wide concern due to the prospect of restoring the clinical potency of antibiotics. Our study suggests that the high mobility of ARGs of high fitness cost may just reflect their poor stability. Therefore, strict control of the use of antibiotics can at least reverse the severe antibiotic resistance caused by mobile ARGs of high fitness cost. This study brings hope for the possibility of curbing the dissemination of antibiotic resistance.

Project description:The cariogenic bacterium Streptococcus mutans can develop stable resistance to fluoride through chromosomal mutations in vitro. Fluoride-resistant S. mutans has seldom been isolated in clinical settings, despite the wide application of fluoride in oral-care products. One explanation is that the fluoride-resistant S. mutans strains have decreased fitness. However, so far, there has been no conclusive evidence to support this idea. The aim of this study was to investigate the fitness cost of 48-h biofilms of two fluoride-resistant S. mutans strains, UF35 and UA159-FR (UAFR), using the wild-type fluoride-sensitive strain UA159 as a reference. The engineered UF35 strain contains one point mutation, whereas UAFR, selected from NaF-containing agar plates, has multiple chromosomal mutations. All biofilms were formed for 48 h under a constantly neutral pH or a pH-cycling (8 h of neutral pH and 16 h of pH 5.5) condition in the absence of fluoride. The biomass of the biofilms was quantified with a crystal violet assay. The biofilms were also treated with chlorhexidine or solutions at pH 3.0, after which their lactic acid production was quantified. Compared to the UF35 and UA159 biofilms, the biomass of UAFR biofilms was two-four fold higher, and the UAFR biofilms were more resistant to chlorhexidine and low pH in terms of lactic acid production. No difference in biomass and lactic acid production was detected between UF35 and UA159 biofilms. The fluoride resistance of UAFR and UF35 strains in biofilms was further confirmed by treating the biofilms with NaF solutions. The level of NaF resistance of the three biofilms is generally ranked as follows: UAFR > UF35 > UA159. In conclusion, there is indeed a fitness consequence in UAFR, but surprisingly, this fluoride-resistant strain performs better than UF35 and UA159 under the described conditions. In addition, UF35 did not display a reduced fitness; it performed as well as the wild-type fluoride-sensitive strain.

Project description:IntroductionVancomycin (VAN) failures associated with the treatment of complicated methicillin-resistant Staphylococcus aureus (MRSA) infections have been well described. The reported "seesaw effect" demonstrates improved β-lactam activity when VAN and/or daptomycin (DAP) susceptibility decreases. However, there are minimal data comparing ceftaroline (CPT) susceptibility with these agents or teicoplanin (TEI). Therefore, to further explore the seesaw effect, we evaluated the relationship between CPT and VAN, TEI, and DAP susceptibilities.MethodsOne hundred and fifty clinical MRSA isolates from the Anti-Infective Research Laboratory (Detroit, MI, USA) from 2008 to 2012 were analyzed. VAN, TEI, DAP and CPT minimum inhibitory concentrations (MIC) were determined via Etest methodology. MIC50 and MIC90 were calculated for each antibiotic. Additionally, four isogenic strain pairs were randomly selected for evaluation by time-kill methodology for the potential of enhanced killing by CPT as MICs increased to VAN, TEI, and DAP.ResultsCPT MICs were inversely correlated with VAN, DAP, and TEI MICs with correlation coefficients of -0.535, -0.483, and -0.386, respectively (P ≤ 0.05). Comparison of the MIC relationship for glycopeptides and lipopeptides resulted in a positive correlation for all agent combinations. In time-kill evaluations, CPT demonstrated greater reductions in log10 colony-forming unit (CFU)/mL against mutant strains (3.73 ± 0.67) versus parents (2.79 ± 0.75) despite no change in CPT MIC (P = 0.112).ConclusionThis study demonstrated a marked "seesaw effect" whereby CPT displayed increased susceptibility as the VAN, DAP, and TEI MICs increased. Additionally, we observed a positive linear correlation between VAN, DAP, and TEI MICs for all agent combinations. Enhanced activity was noted with CPT in mutant strains versus the parent strains despite no change in MIC. Based upon the enhanced CPT activity observed against strains with decreased susceptibility to VAN, DAP and TEI, CPT may provide an option for infections with reduced susceptibility to glycopeptides or lipopeptides. Further evaluation is warranted to investigate the clinical implications of the seesaw effect.

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Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost.

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Daptomycin Resistance in Clinical MRSA Strains Is Associated with a High Biological Fitness Cost.

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