AN INNOVATIVE APPROACH TO OPTIMIZE THE EFFICACY AND SAFETY PROFILE OF DAPTOMYCIN IN PERIPROSTHETIC JOINT INFECTIONS BY EXPLOITING ITS PHARMACOKINETIC AND PHARMACODYNAMIC PROPERTIES

Aim Daptomycin has become a widely used treatment for periprosthetic joint infections (PJI) over the past decade, due to its efficacy against gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). Despite its effectiveness, daptomycin is associated with potential toxicity, such as myopathy, rhabdomyolysis, eosinophilic pneumonia, and hypersensitivity reactions. This study aimed to retrospectively evaluate plasma concentrations of daptomycin and the incidence of adverse events (AEs) in a cohort of patients treated for PJI. Methods We retrospectively included patients treated with daptomycin in combination with other antibiotics within two weeks after revision surgery (either first- and second-stage procedures) for PJIs from 2014 to 2024. Toxicity incidence was assessed alongside key pharmacokinetic (PK) and pharmacodynamic (PD) parameters, measured through Therapeutic Drug Monitoring (TDM), specifically trough plasma concentrations (C min ) and estimated 24-hour area under the curve (eAUC 0–24h ). Overexposure was defined as C min > 24.3 mg/L and/or eAUC 0–24h > 1174 mg·h/L, according to existing literature. Continuous variables were reported as median and interquartile range (IQR), while categorical data were reported as counts and percentages. Appropriate statistical tests (Kruskal–Wallis, t-test, Mann–Whitney, chi-square) were applied according to data distribution. Statistical significance was set at p ≤ 0.05. Results A total of 340 patients were included (183 hips, 154 knees, 1 ankle, 2 shoulders), with a median age of 72.9 years (IQR 64.8–78.7) and median BMI of 27.3 kg/m² (IQR 24.4–30.8). The median daily dose of daptomycin was 700 mg (IQR 600–800). Eosinophilic pneumonia occurred in 11 of 271 patients (4.1%). Patients who experienced toxicity showed a higher median eAUC 0–24h compared to those without toxicity (1277 vs 948 mg·h/L, p = 0.067), although the difference did not reach statistical significance, likely due to the low number of events. C min levels were comparable between groups (20.24 vs 17.05 mg/L, p = 0.431). Conclusions AEs are an uncommon but potentially severe incidents during daptomycin therapy. Elevated eAUC 0–24h appears more closely associated with toxicity than C min alone. Standard dosing of daptomycin may lead to overexposure in some patients, increasing the risk of AEs. As increasing literature suggests, TDM plays a critical role in identifying at-risk individuals and guiding personalized dosing strategies to optimize daptomycin efficacy while minimizing toxicity and antimicrobial resistance.