Vancomycin tolerance in methicillin-resistant Staphylococcus aureus: influence of vancomycin, daptomycin, and telavancin on differential resistance gene expression.
Methicillin-resistant Staphylococcus aureus (MRSA) isolates that are susceptible to vancomycin but are tolerant to its killing effect may present a potential challenge for effective treatment. This study compared the microbiologic characteristics of clinical vancomycin-tolerant (VT-MRSA) and vancomycin-susceptible (VS-MRSA) strains using phenotypic and gene regulation studies. MRSA isolates collected from vancomycin-treated patients with bacteremia over a 5-year period were analyzed for vancomycin, daptomycin, and telavancin susceptibility, as well as accessory gene regulator (agr) group and function. Vancomycin tolerance was defined by a minimum bactericidal concentration (MBC)/minimum inhibitor concentration (MIC) ratio of ≥32 mg/liter. VT-MRSA isolates were compared to VS-MRSA isolates for differences in antimicrobial susceptibility, time-kill activity, and gene expression of key cell envelope response genes vraSR, dltA, and mprF. All 115 isolates evaluated were susceptible to vancomycin, daptomycin, and telavancin. Seven isolates (6%) were VT-MRSA. agr group II was more prevalent in isolates with vancomycin MBC/MIC ratios of ≥8. In time-kill analyses, VT-MRSA had reduced vancomycin killing, but daptomycin and telavancin activities were maintained. Significantly greater gene expression was observed in VT-MRSA after 72 h of subinhibitory antibiotic exposures. Vancomycin most notably increased vraSR expression (P = 0.002 versus VS-MRSA strains). Daptomycin and telavancin increased expression of all genes studied, most significantly mprF expression (P < 0.001). Longer durations of antibiotic exposure (72 h versus 24 h) resulted in substantial increases in gene expression in VT-MRSA. Although the clinical impact of VT-MRSA is not fully recognized, these data suggest that VT-MRSA strains, while still susceptible, have altered gene regulation to adapt to the antimicrobial effects of glyco- and lipopeptides that may emerge during prolonged durations of exposure.
Pharmacy Practice Division, University of Wisconsin-Madison School of Pharmacy, Madison, Wisconsin, USA. werose@pharmacy.wisc.edu
Warren E
WE
Rose
Michael
M
Fallon
John J M
JJ
Moran
Joshua P
JP
Vanderloo
D019881:Aminoacyltransferases / Q000235:genetics; D000617:Aminoglycosides / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D017576:Daptomycin / Q000494:pharmacology*; D004361:Drug Tolerance; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D000077427:Lipoglycopeptides; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000494:pharmacology*; D020713:Vancomycin Resistance / Q000235:genetics*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D000077427:Lipoglycopeptides; C478170:VraR protein, Staphylococcus aureus; C478169:VraS protein, Staphylococcus aureus; D014640:Vancomycin; D019881:Aminoacyltransferases; C429146:mprF protein, Staphylococcus aureus; D017576:Daptomycin; C487637:telavancin