Weight-based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety.

Simulations of meropenem, cefepime, and aztreonam by i.v. push over 5 minutes indicated that there would be minimal or no effect on pharmacodynamic exposures compared with the effect when administered by 30-minute infusions.

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.