Abstract
There are limited intravenous fosfomycin disodium (IVFOS) dosing regimens to treat carbapenem-resistant Enterobacterales (CRE) infections. This study aimed to use Monte Carlo simulation (MCS) for evaluation of IVFOS dosing regimens in critically ill patients with CRE infections. The dosing regimens in critically ill patients with various creatinine clearance were evaluated with MCS using minimum inhibitory concentration (MIC) distributions of fosfomycin against CRE clinical isolates in Thailand and the 24 h area under the plasma drug concentration–time curve over the minimum inhibitory concentration (AUC0-24/MIC) of ≥21.5 to be a target for IVFOS. The achieved goal of the probability of target attainment (PTA) and a cumulative fraction of response (CFR) were ≥90%. A total of 129 non-duplicated CRE clinical isolates had MIC distributions from 0.38 to >1024 mg/L. IVFOS 8 g every 8 h, 1 h, or 4 h infusion, could achieve approximately 90% PTA of AUC0-24/MIC target to treat CRE infections with MICs ≤ 128 mg/L. According to PTA target, an IVFOS daily dose to treat carbapenem-resistant Escherichia coli based on Clinical Laboratory Standards Institute (CLSI) breakpoints for urinary tract infections and one to treatment for CRE infections based on the European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were 16 g/day and 8 g/day, respectively. All dosing regimens of IVFOS against CRE achieved CFR ≤ 70%. This study proposes the IVFOS dosing regimens based on CLSI and EUCAST breakpoints for the treatment of CRE infections. However, further clinical studies are needed to confirm the results of these findings.
Highlights
Carbapenem-resistant Enterobacterales (CRE) infections cause public health problems worldwide with limited antibiotic treatments
Our study showed that the fosfomycin minimum inhibitory concentration (MIC) of carbapenem-resistant Escherichia coli (CR-EC) clinical isolates were lower than that of Carbapenem-resistant Klebsiella pneumoniae (CR-KP) clinical isolates
Our study suggested new dosing regimens are needed for Intravenous fosfomycin disodium (IVFOS) in patients with various degrees of renal function, according to the Clinical Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) for fosfomycin susceptibility breakpoints (Table 2)
Summary
Carbapenem-resistant Enterobacterales (CRE) infections cause public health problems worldwide with limited antibiotic treatments. Intravenous fosfomycin disodium (IVFOS) has been used in combination with other agents to treat multidrug-resistant bacterial infections [3,4]. This formulation is available in many countries outside the United States. The dosage recommendations of IVFOS are 12 to 24 g/day, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines and manufacturer’s recommendations [5,6]. This information is insufficient for guiding treatments for CRE infections
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