Pharmacodynamic evaluation of fosfomycin against E. coli and Klebsiella spp. from urinary tract infections and the influence of pH on fosfomycin activities [PublishAheadOfPrint]

Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI) and recently have been recommended for treating multidrug-resistant (MDR) gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimen has not been analyzed. Minimal inhibitory concentration (MIC) was determined using agar dilution in pH 6.0 and 7.0 for 245 Gram negative bacterial isolates, consisting of 158 E. coli and 87 Klebsiella spp. which were collected from patients with UTI. Monte Carlo simulation of urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3000 mg fosfomycin and MIC distribution were used to determine the probability of target attainment (PTA). Fosfomycin was effective against E. coli (MIC₉₀ ≤ 16 μg/mL) but not against Klebsiella spp. (MIC₉₀ > 512 μg/mL). Acidification of pH environment increased bacterial susceptibility in 71% of the isolates and resulted in a statistically significant decrease in bacterial survival. Fosfomycin oral single dose regimen against E. coli isolate with MIC ≤64 mg/L was able to achieve ≥90% PTA for a target pharmacodynamic index of 23 AUC/MIC in the urine; PTA was not achieve when MIC is higher than 64 mg/L. Cumulative fractions of responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in an acidic urine pH of 6.0. Decreased pH from 7.0 to 6.0 improves PTA and CFR of the target PD index in both E. coli and Klebsiella isolates.

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