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Selection of daptomycin (DAP)-resistant Staphylococcus aureus mutants with DAP alone and in combination with rifampicin at subtherapeutic concentrations: simulations using an in vitro dynamic model

Abstract number: O148

Smirnova M., Strukova E., Vostrov S., Lubenko I., Zinner S.

Objective: A bell-shaped relationship between the ratio of area under the curve (AUC) to the MIC and the enrichment of daptomycin (DAP)-resistant S. aureus have been reported in our simulations of multiple-dose DAP pharmacokinetics. AUC/MICs near 200 h (that are lower than the therapeutic AUC/MICs) protected against the selection of resistant mutants whereas they were maximally enriched at AUC/MICs of 32–64 h. To determine if such selection could be prevented with DAP in combination with other agents, the pharmacodynamics of DAP alone and combined with rifampicin (RIF) at the subtherapeutic AUC/MICs were studied in an in vitro model.

Methods:S. aureus ATCC 43300 and a clinical isolate S. aureus 866 with MICDAPs of 0.2 and 0.4 mg/L, respectively, and MICRIF of 0.012 mg/L were exposed to five-day dosing of DAP (AUC/MIC 64 h) alone and in combination with RIF (AUC/MIC 100 and 500 h). Bacterial growth on agar plates containing 0x, 2x and 4xMICDAP was examined daily. The cumulative effect of each simulated treatment on susceptible S. aureus sub-populations was expressed by area under the time-kill curve (AUBC) measured from time zero to 120 h.

Results: Both simulated DAP+RIF regimens were more efficient against the two organisms and the DAP-resistant mutants. With S. aureus ATCC 43300, RIF100 and RIF500 lowered the AUBC 1.4- and 1.9-fold relative to DAP alone. With S. aureus 866, 1.6- and 1.8-fold reductions in AUBC were observed, respectively. With both organisms, mutants resistant to 2x and, to a lesser extent, 4xMICDAP were enriched in the mono-treatments with DAP but not in the DAP+RIF500 treatments. RIF500 resulted in a 1.3 (S. aureus ATCC 43300) and 3.4 (S. aureus 866) fold reduction in the area under the bacterial mutant curve (AUBMC) for mutants grown in the presence of 2xMICDAP. The protective abilities of DAP+RIF100 were similar to those of DAP+RIF500 for S. aureus 866 but were weaker for S. aureus ATCC 43300. The DAP+RIF100 combination postponed but did not prevent the production of DAP-resistant mutants.

Conclusions: This study suggests that DAP+RIF combinations can reduce the selection of DAP-resistant S. aureus mutants.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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