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 ( fAUC0-24/MIC) >27.43 for susceptible dose-dependent (SDD) MICs and the probability of a minimum concentration ( Cmin) > 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 Cmin ≥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.

Daptomycin versus Glycopeptides for the Treatment of Enterococcus faecium Bacteraemia: A Cohort Study

“…Higher rates of microbiological failure and mortality have been reported in BSIs caused by E. faecium strains with daptomycin MIC 3-4 mg/L when treated with daptomycin [20,21]. In fact, two recent studies found that no dose presented an acceptable PTA against a MIC of 4 mg/L in the Monte Carlo simulation [22,23]. When MICs of 2-4 mg/L were analysed, a fixed dose of 1500 mg daily was needed for ≥ 90% PTA, but this dosage carried an undue risk of toxicity as was associated with an increased 24.5-80.5% risk of achieving a Cmin ≥ 24.3 mg/L [24].…”

Treatment decisions in VRE bacteraemia: a survey of infectious diseases pharmacists

“… 32 Although daptomycin is weight-based, its pharmacokinetics do not scale linearly with weight, and fixed-dose regimens for VRE BSI have been suggested. 33 The evidence for daptomycin use in VRE BSI was established in patients with a median BMIs of 26 kg/m 2 or weights of 50–60 kg, and are not representative of the increased obesity seen in clinical practice. 11 , 13 , 26 Although retrospective data for combined Gram-positive infections have shown no changes in outcomes for using adjusted body weight for daptomycin dosing, 34 specific studies are lacking for VRE BSI.…”