# 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

## TL;DR

This study evaluates how well premixed daptomycin doses work against bloodstream infections caused by Staphylococcus aureus and Enterococcus species in adult patients.

## Contribution

The study introduces a pharmacokinetic/pharmacodynamic analysis of premixed daptomycin formulations using Monte Carlo simulation for bloodstream infections.

## Key findings

- Premixed daptomycin formulations showed increased likelihood of target attainment compared to weight-based dosing.
- Patients with higher adjusted body weight and lower creatinine clearance may exceed toxicity thresholds with 1000 mg doses.
- Premixed formulations can be integrated into clinical practice for improved efficacy.

## Abstract

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.

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.

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.

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.