Could a Reduced Dose of 8 g of Continuous Infusion Fosfomycin Be Considered as Effective as and Safer than a Standard 16 g Dose When Combined with High-Dose Daptomycin in the Treatment of Staphylococcal osteoarticular Infections?

Background: Daptomycin plus fosfomycin combination therapy is a valuable strategy for treating staphylococcal osteoarticular infections (OIs), but hypernatremia and hypokalemia due to sodium overload are important issues. The aim of this study was to assess the likelihood of attaining a pharmacokinetic/pharmacodynamic (PK/PD) target of AUC/MIC > 66.6 and/or of 70%t > MIC with continuous infusion (CI) fosfomycin at the recommended vs. reduced dose in patients with OIs receiving combination therapy with high-dose daptomycin. Adverse events were also evaluated. Methods: Patients with OIs treated with 8-10 mg/kg daily daptomycin plus CI fosfomycin, and who had a ≥1 TDM assessment of CI fosfomycin, were retrospectively included in the high-dose (16 g daily) or reduced-dose (<16 g daily) groups. The attainment of the PK/PD targets of 70%t > MIC and AUC/MIC > 66.6 up to an MIC of 32 mg/L was calculated. A CART analysis was used to identify a cut-off of fosfomycin AUC that indicated occurrence of hypernatremia and/or hypokalemia. Results: A total of 44 and 39 patients were included in the high- and reduced-dose groups, respectively. The two groups did not differ in terms of demographic characteristics, underlying infectious diseases and microbiological isolates. No differences between groups in attaining both PK/PD targets up to an MIC of 32 mg/L and in C-reactive protein reduction at the end of treatment were observed. Fosfomycin AUC > 8245 mg × h/L and >8326 mg × h/L were associated with hypernatremia and hypokalemia, respectively. Conclusions: CI fosfomycin at 8 g daily may reach optimal PK/PD target attainment with better safety than the recommended 16 g daily dose in patients with preserved renal function. Targeting fosfomycin AUC at 2131-8326 mg × h/L or steady-state concentration at 88.8-347 mg/L may be adequate for optimizing drug pharmacodynamics up to an MIC of 32 mg/L and minimizing the risk of hypernatremia and hypokalemia.