In vitro enrichment of resistant Staphylococcus aureus at daptomycin subtherapeutic concentrations within the mutant selection window: effect of treatment duration

Abstract number: P1053

Vostrov S., Lubenko I., Zinner S., Firsov A.

Objective: To study time-dependent enrichment of resistant sub-populations and concomitant loss in susceptibility of S. aureus, ten-day treatments with daptomycin (DAP) were simulated in vitro.

Methods:S. aureus ATCC 43300 (MICDAP 0.2 mg/L) was exposed to once-daily dosing of DAP at subtherapeutic ratios of area under the curve (AUC) to the MIC of 32 and 64 h, which have been reported recently to result in maximal selection of resistant mutants. Susceptibility (culture MIC) and bacterial growth on agar plates containing 2× and 4×MIC were tested daily. To provide an integral presentation of the time course of mutants grown on DAP-containing plates, areas under the bacterial mutant kinetic curves (AUBMCs) were calculated from the start of treatment to the 3rd (AUBMC3), 5th (AUBMC5) and 10th day (AUBMC10) of treatment.

Results: With both dosing regimens, DAP-resistant S. aureus were enriched on the third day. Further enrichment occurred gradually, without abrupt increases in mutant numbers. By the end of each treatment, numbers of mutants resistant to 2× and 4×MIC of DAP were comparable to those of susceptible organisms, but they were not completely replaced by DAP-resistant mutants. Similar patterns were inherent in the time course of susceptibility of DAP-exposed cultures, with 16- and 8-fold increases in the MIC by the end of treatment at AUC/MIC of 32 and 64 h, respectively. This gradual enrichment of resistant mutants and concomitant loss in susceptibility were confirmed by the AUBMC analysis. At AUC/MIC of 32 h, production of mutants resistant to 4×MIC was reflected by a 2.9 times greater AUBMC10 than AUBMC5 and by a 2.2 times greater AUBMC5 than AUBMC3. At AUC/MIC of 64 h, AUBMC10 was 3 times greater than AUBMC5 and AUBMC5 was 2.1 times greater than AUBMC3.

Conclusions: The time-resistance relationships established in this study: (1) allow prediction of subsequent enrichment of DAP-resistant mutants and concomitant loss in susceptibility after long-term treatments based on data obtained in shorter treatments, and (2) show that relatively minimal early expressions of resistance seen in short treatments are precursors of more resistance that occurs with longer DAP treatments.

Session Details

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