Daptomycin Exposure as a Risk Factor for Daptomycin-Induced Eosinophilic Pneumonia and Muscular Toxicity

Area of Science:

• Pharmacology
• Infectious Diseases
• Clinical Toxicology

Background:

• High-dose daptomycin use for bone and joint infections (BJI) is rising.
• This increases concerns regarding adverse events (AEs), specifically daptomycin-induced eosinophilic pneumonia (DIEP) and myotoxicity.
• Identifying determinants of these AEs is crucial for patient safety.

Purpose of the Study:

• To investigate pharmacokinetic and other factors influencing DIEP and myotoxicity in BJI patients on daptomycin.
• To analyze risk factors associated with daptomycin-related AEs in this population.

Main Methods:

• Prospective cohort study of BJI patients receiving daptomycin.
• Case-control analysis matching DIEP/myotoxicity cases (9/26) with controls (106) at a 1:3 ratio.
• Bayesian estimation of daptomycin AUC24h using therapeutic drug monitoring (TDM) data and Cox proportional hazards modeling for risk factor analysis.

Main Results:

• Daptomycin AUC24h, C-reactive protein, and serum protein levels were linked to AE risk.
• Higher daptomycin AUC24h (>939 mg/h/L) increased AE risk (HR 3.1).
• Elevated C-reactive protein (>21.6 mg/L) and low serum protein (<72 g/L) were also significant risk factors.

Conclusions:

• Common determinants for DIEP and myotoxicity in BJI patients were identified.
• Daptomycin TDM and model-informed precision dosing can enhance treatment efficacy and safety.
• A target AUC24h range of 666-939 mg/h/L is proposed for daptomycin therapy in BJI.