Comprehensive pharmacokinetic/pharmacodynamic analysis of commercially available premixed daptomycin preparations against Staphylococcus aureus and Enterococcus spp. bloodstream infections using Monte Carlo simulation in adult patients

Abstract Objectives The current approach to dosing daptomycin is primarily weight-based, requiring time-consuming sterile product preparation. Commercially available, premixed formulations have the potential to streamline workflow. Materials and methods We conducted Monte Carlo simulations using pharmacokinetic (PK) models of daptomycin. PTA for the treatment of staphylococcal and enterococcal bloodstream infections for adjusted body weight (ABW) categories of 40–100 kg, creatinine clearances (CrCl) of 10–120 mL/min and for renal replacement therapy (RRT) were investigated. A 24-h area under the curve to minimum inhibitory concentration ratio (AUC24h/MIC) of  ≥ 666 and a free (f) AUC24h/MIC of  > 27.43 were used as the threshold for efficacy for staphylococcal and enterococcal infections, respectively. A PTA of  > 51.6% for achieving a trough level ≥ 24.3 mg/L in a 90 kg patient with a CrCl of 40 mL/min was used as the cut-off for toxicity. Resulting PD indices of the premixed formulations were compared with those achieved by the 6, 8 and 10 mg/kg dosing regimens. Results The doses provided by the premixed bags demonstrated increased likelihood of target attainment over the weight-based approaches. Analysis for the toxicity index also showed comparable risk of exposure, although PTAs of patients with ABW of 80 kg or more and with the CrCl of 10 and 40 mL/min are likely to surpass the toxicity threshold when the 1000 mg bag is administered. Conclusions Based on the results, the commercially available fixed-dose premixed formulations of daptomycin can be integrated into day-to-day clinical practice with the expected benefit of improved efficacy target attainment.