Treatment of vancomycin-resistant Enterococcus faecium with RP 59500 (quinupristin-dalfopristin) administered by intermittent or continuous infusion, alone or in combination with doxycycline, in an in vitro pharmacodynamic infection model with simulated endocardial vegetations.
Quinupristin-dalfopristin is a streptogramin antibiotic combination with activity against vancomycin-resistant Enterococcus faecium (VREF), but emergence of resistance has been recently reported. We studied the activity of quinupristin-dalfopristin against two clinical strains of VREF (12311 and 12366) in an in vitro pharmacodynamic model with simulated endocardial vegetations (SEVs) to determine the potential for resistance selection and possible strategies for prevention. Baseline MICs/minimal bactericidal concentrations (microg/ml) for quinupristin-dalfopristin, quinupristin, dalfopristin, and doxycycline were 0.25/2, 64/>512, 4/512, and 0.125/8 for VREF 12311 and 0.25/32, 128/>512, 2/128, and 0.25/16 for VREF 12366, respectively. Quinupristin-dalfopristin regimens had significantly less activity against VREF 12366 than VREF 12311. An 8-microg/ml simulated continuous infusion was the only bactericidal regimen with time to 99.9% killing = 90 hours. The combination of quinupristin-dalfopristin every 8 h with doxycycline resulted in more killing compared to either drug alone. Quinupristin-dalfopristin-resistant mutants (MICs, 4 microg/ml; resistance proportion, approximately 4 x 10(-4)) emerged during the quinupristin-dalfopristin monotherapies for both VREF strains. Resistance was unstable in VREF 12311 and stable in VREF 12366. The 8-microg/ml continuous infusion or addition of doxycycline to quinupristin-dalfopristin prevented the emergence of resistance for both strains over the 96-h test period. These findings replicated the development of resistance reported in humans and emphasized bacterial factors (drug susceptibility, high inoculum, organism growth phase) and infectious conditions (penetration barriers) which could increase chances for clinical resistance. The combination of quinupristin-dalfopristin with doxycycline and the administration of quinupristin-dalfopristin as a high-dose continuous infusion warrant further study to determine their potential clinical utility.
The Anti-Infective Research Laboratory, Department of Pharmacy Services, Detroit Receiving Hospital and University Health Center, Wayne State University, Detroit, Michigan 48201, USA.
J R
JR
Aeschlimann
M J
MJ
Zervos
M J
MJ
Rybak
D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004318:Doxycycline / Q000008:administration & dosage*; D004352:Drug Resistance, Microbial; D004359:Drug Therapy, Combination / Q000008:administration & dosage*; D016984:Enterococcus faecium / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000494:pharmacology*; D014769:Virginiamycin / Q000008:administration & dosage* / Q000493:pharmacokinetics
D000900:Anti-Bacterial Agents; D014769:Virginiamycin; C062940:quinupristin-dalfopristin; D014640:Vancomycin; D004318:Doxycycline