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Evaluation of daptomycin activity against Staphylococcus aureus following vancomycin exposure in an in vitro pharmacodynamic model with simulated endocardial vegetations

Abstract number: 1733_1560

Rose W., Rybak M., Leonard S., Sakoulas G., Kaatz G., Zervos M., Sheth A., Carpenter C.

Objective:Staphylococcus aureus (SA) remains clinically problematic due to multidrug resistance. Vancomycin (V) has been the primary therapy though its efficacy has recently come into question. Daptomycin (D) is bactericidal against SA and often used following V failure. The objective of this study was to use an in vitro pharmacodynamic model with simulated endocardial vegetations (IVPD-SEV) model to evaluate if V exposure affects D activity.

Methods: 5 clinical isolates were evaluated. 4 isolates (3 MRSA, 1 MSSA) were reported to demonstrate D non-susceptibility following V exposure and 1 MRSA that was not exposed to V but became D non-susceptible after suboptimal dosing of D. All pre-V isolates were susceptible to D with MICs of 0.125–0.5 mg/L. Two simulations were evaluated: (1) 4 d of V 1 g q 12 h (Cmax 30 mg/L, Cmin 10 mg/L) followed by 4 d of D 6 mg/kg q 24 h, and (2) 8 d of D6 q 24 h. Time to 99% kill (T99) was calculated for each regimen. Changes in MIC over 8 d were evaluated using D 1.5, 2 and 3×MIC screening plates. D Etest MICs were performed for all model samples including any growth on screening plates to confirm changes in MIC. If changes in MIC were demonstrated, model experiments of no V treatment × 4 d (growth control) were followed by D6 q 24 h × 4 d to confirm a possible relationship to V. Additional regimens of V × 4 d followed by D 10 mg/kg q 24 h × 4 d and D10 × 8 d were also analysed.

Results: Pre-exposure MICs for V/D were 2/0.25 for MRSA isolates and 1/0.125 for the MSSA. The MSSA demonstrated D heteroresistance at baseline; the MRSA isolates did not. No change in MIC was detected for any MRSA isolate treated with D following V for any regimen tested. T99 was 1.39–11.36 h for D6 regimens without V exposure and 3.43–9.41 h following V. MIC elevations to D > 1 mg/L for the MSSA isolate were noted after 96 h of D6 following V but not when D6 was used alone during the 8 d simulation. Increases in MIC remained stable to serial passage for 5 d. D maintained bactericidal activity against the MSSA isolate even during the post V period with T99 achieved at 9.46–9.91 h. No resistance was detected when D6 followed 4 d of growth control, D10 post V, or D10 alone × 8 d.

Conclusion: Exposure to V prior to D therapy resulted in no change in MIC for all MRSA strains. The MSSA isolate demonstrated MIC changes post V; however, effective D kill was maintained. The pre-existing heteroresistance to D with the MSSA isolate suggests that the exposure to V may not have induced this phenomenon. Further investigation is warranted to confirm these results.

Session Details

Date: 31/03/2007
Time: 00:00-00:00
Session name: European Society of Clinical Microbiology and Infectious Diseases
Subject:
Location: ICC, Munich, Germany
Presentation type:
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