Population pharmacokinetics of daptomycin in patients with haematological malignancies and vancomycin-resistant Enterococcus bloodstream infections.

INTRODUCTION: Treatment of vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) in patients with haematological malignancies remains challenging, with the optimal dosing regimen of the highly protein bound daptomycin uncertain. METHODS: Patients with haematological malignancies receiving contemporary daptomycin doses for confirmed VREfm BSIs had total daptomycin steady-state concentrations measured. Population pharmacokinetic (popPK) modelling and Monte Carlo simulations were performed to predict probabilities of target attainment (PTA). Targets utilised were fAUC24h,ss/MIC >27.43 or >81.87 (efficacy) and trough (Cmin) levels ≥24.3 mg/L or ≥60 mg/L (toxicity). fAUC was estimated using unbound fractions of 0.07, 0.10 and 0.14. RESULTS: Ten patients contributed 30 daptomycin concentrations. A two-compartment model, with creatinine clearance and lean body weight as covariates best described the data. Simulations showed that PTA increased as protein binding (PB) estimates decreased. 1200 mg was the only dose able to achieve PTA>90% for MICs of 4 mg/L when targeting fAUC24h,ss/MIC >27.43, PB 86%. PTA >90% was achievable for MICs ≤1 mg/L with doses ≥10 mg/kg or doses ≥850 mg daily (fAUC24h,ss/MIC>81.87, PB 86%). No doses achieved PTA >90% for MICs >4 mg/L for either efficacy target. Cmin increased with fixed and mg/kg dosing. CONCLUSION: In patients with VREfm BSIs with underlying haematological malignancies, PTA for daptomycin efficacy increases inversely to PB. Fixed 1200 mg doses may achieve desired PTA for higher MIC isolates (4 mg/L) in patients with lower albumin, however Cmin increases with daptomycin dose. Dosing strategies supported by therapeutic drug monitoring are recommended to optimise efficacy and minimise toxicity.