Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections
Issued Date
2024-06-01
Resource Type
ISSN
03057453
eISSN
14602091
Scopus ID
2-s2.0-85195066735
Pubmed ID
38597137
Journal Title
Journal of Antimicrobial Chemotherapy
Volume
79
Issue
6
Start Page
1372
End Page
1379
Rights Holder(s)
SCOPUS
Bibliographic Citation
Journal of Antimicrobial Chemotherapy Vol.79 No.6 (2024) , 1372-1379
Suggested Citation
Wangchinda W., Pogue J.M., Thamlikitkul V., Leelawattanachai P., Koomanachai P., Pai M.P. Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections. Journal of Antimicrobial Chemotherapy Vol.79 No.6 (2024) , 1372-1379. 1379. doi:10.1093/jac/dkae111 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/98683
Title
Population pharmacokinetic/pharmacodynamic target attainment analysis of IV fosfomycin for the treatment of MDR Gram-negative bacterial infections
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Corresponding Author(s)
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Abstract
Background: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function. Objectives: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function. Methods: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions. Results: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa. Conclusions: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited.