Background: Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to MDR pathogens.Objective: The aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16g/daily by intermittent (II) or continuous infusion (CI), and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections.Methods: Patients underwent blood sampling on day 5 of therapy (2-3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC, and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20g/day administered by II, extended-infusion (EI) or CI.Results: Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CLCR) was included as covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) may be achieved in three different classes of renal function by administering a daily dosage of: 2g q6h by II against S. aureus, E. coli, ESBL-producing E. Coli and MRSA; 8g by CI against CoNS, K. pneumoniae and ESBL-producing K. pneumoniae; 12g by CI against P. aeruginosa, and 16g by CI against KPC-producing K. pneumoniaeConclusion: Our study provides a strong rationale for considering fosfomycin dosages of  8-16 g daily by CI in several clinical scenarios for OI patients. Feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.

Rinaldi, M., Cojutti, P.G., Zamparini, E., Tedeschi, S., Rossi, N., Conti, M., et al. (2021). Population pharmacokinetics and Monte Carlo simulation for dosage optimization of fosfomycin in the treatment of osteoarticular infections in patients without renal dysfunction. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 65(5), 1-33 [10.1128/AAC.02038-20].

Population pharmacokinetics and Monte Carlo simulation for dosage optimization of fosfomycin in the treatment of osteoarticular infections in patients without renal dysfunction

Rinaldi, Matteo;Cojutti, Pier Giorgio;Tedeschi, Sara;Rossi, Nicolò;Giannella, Maddalena;Pea, Federico;Viale, Pierluigi
2021

Abstract

Background: Fosfomycin is gaining interest in the treatment of complex osteoarticular infections (OI) due to MDR pathogens.Objective: The aims were to conduct population pharmacokinetics of fosfomycin in a cohort of OI patients receiving 16g/daily by intermittent (II) or continuous infusion (CI), and to carry out Monte Carlo simulations for dosage optimization in the treatment of these infections.Methods: Patients underwent blood sampling on day 5 of therapy (2-3 serial samples). Population pharmacokinetics and Monte Carlo simulations were performed to define the probability of target attainment (PTA) of 70% T>MIC, and the cumulative fraction of response (CFR) against common OI pathogens with dosages of 8, 12, 16, and 20g/day administered by II, extended-infusion (EI) or CI.Results: Forty-eight patients were recruited. A two-compartment open model with infusion input and first-order elimination was developed. Estimated creatinine clearance (CLCR) was included as covariate in the final model. Monte Carlo simulations showed that optimal PTAs and CFRs (≥90%) may be achieved in three different classes of renal function by administering a daily dosage of: 2g q6h by II against S. aureus, E. coli, ESBL-producing E. Coli and MRSA; 8g by CI against CoNS, K. pneumoniae and ESBL-producing K. pneumoniae; 12g by CI against P. aeruginosa, and 16g by CI against KPC-producing K. pneumoniaeConclusion: Our study provides a strong rationale for considering fosfomycin dosages of  8-16 g daily by CI in several clinical scenarios for OI patients. Feasibility of administration by CI in an elastomeric pump makes fosfomycin a candidate for OPAT programs.
2021
Rinaldi, M., Cojutti, P.G., Zamparini, E., Tedeschi, S., Rossi, N., Conti, M., et al. (2021). Population pharmacokinetics and Monte Carlo simulation for dosage optimization of fosfomycin in the treatment of osteoarticular infections in patients without renal dysfunction. ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 65(5), 1-33 [10.1128/AAC.02038-20].
Rinaldi, Matteo; Cojutti, Pier Giorgio; Zamparini, Eleonora; Tedeschi, Sara; Rossi, Nicolò; Conti, Matteo; Giannella, Maddalena; Pea, Federico; Viale, Pierluigi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/805186
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