A Pharmacokinetic-Pharmacodynamic Analysis to Dose Optimize Daptomycin in Vancomycin-Resistant Enterococcus faecium : Is the Answer Fixed Dosing or Lowering Breakpoints?

Abstract

Background:

The optimal daptomycin dose for vancomycin-resistant Enterococcus faecium remains unclear. Dosing of 8 to 12 mg/kg/d has been recommended to improve outcomes, but literature suggests fixed dosing may improve methicillin-resistant Staphylococcus aureus bacteremia pharmacodynamic (PD) targets.

Objective:

This study sought to evaluate weight-based versus fixed dosing of daptomycin based on pharmacokinetic and PD (PK-PD) targets in vancomycin-resistant E faecium bacteremia.

Methods:

PK-PD analyses were conducted using previously published PK models for daptomycin. Probability of target attainment (PTA) was assessed for 8 to 12 mg/kg/d and various fixed doses. The percentage of simulated participants who achieved a free area under the concentration-time curve from 0 to 24 hours to minimum inhibitory concentration ratio (fAUC_0-24/MIC) >27.43 for susceptible dose-dependent (SDD) MICs and the probability of a minimum concentration (C_min) > 24.3 mg/L were calculated.

Results:

At MICs ≤2 mg/L, fixed doses had the best overall PTA. At the SDD breakpoint of 4 mg/L, all weight-based doses had <60% PTA. A fixed dose of 1500 mg/d was necessary for >/= 90% PTA at higher MICs considered SDD; however, this dose had elevated risks of C_min ≥24.3 mg/L.

Conclusion and Relevance:

Fixed doses were more likely to achieve a fAUC/MIC of 27.43 than weight-based doses up to 12 mg/kg/d. However, fixed doses necessary for 90% PTA against SDD isolates with higher MICs were associated with elevated risks of toxicity. A reevaluation of Clinical Laboratory Standards Institute breakpoints may need to be considered, with an emphasis on lowering the SDD breakpoint to 1 mg/L.