Pharmacodynamic Evaluation of Fosfomycin against Escherichia coli and Klebsiella spp. from Urinary Tract Infections and the Influence of pH on Fosfomycin Activities

Abstract

Fosfomycin is widely used for the treatment of uncomplicated urinary tract infection (UTI), and it has recently been recommended that fosfomycin be used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacilli. Whether urine acidification can improve bacterial susceptibility to fosfomycin oral dosing regimens has not been analyzed. The MIC of fosfomycin for 245 Gram-negative bacterial isolates, consisting of 158 Escherichia coli isolates and 87 Klebsiella isolates which were collected from patients with urinary tract infections, were determined at pH 6.0 and 7.0 using the agar dilution method. Monte Carlo simulation of the urinary fosfomycin area under the concentration-time curve (AUC) after a single oral dose of 3,000 mg fosfomycin and the 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 the environment increased the susceptibility of 71% of the bacterial isolates and resulted in a statistically significant decrease in bacterial survival. The use of a regimen consisting of a single oral dose of fosfomycin against an E. coli isolate with an MIC of ≤64 mg/liter was able to achieve a PTA of ≥90% for a target pharmacodynamic index (AUC/MIC) of 23 in urine; PTA was not achieved when the MIC was higher than 64 mg/liter. The cumulative fractions of the bacterial responses (CFR) were 99% and 55% against E. coli and Klebsiella spp., respectively, based on simulated drug exposure in urine with an acidic pH of 6.0. A decrease of the pH from 7.0 to 6.0 improved the PTA and CFR of the target pharmacodynamic index in both E. coli and Klebsiella isolates.

Keywords: Enterobacteriaceae; Monte Carlo simulation; acidic pH; fosfomycin; pharmacodynamics; urinary tract infection.

FIG 1

Survival-type antimicrobial susceptibility curves for Escherichia coli isolates (n = 158) and Klebsiella isolates (n = 87) from patients with urinary tract infections stratified on the basis of pHs of 6.0 (solid line) and 7.0 (dotted line).

FIG 2

Fosfomycin MIC frequency in 158 Escherichia coli and 87 Klebsiella clinical isolates at pH 6.0 and 7.0 and probability of target attainment of an AUC/MIC of 23 against E. coli (right) and Klebsiella spp. (left) in serum (top) and urine (bottom) matrices for a fosfomycin dosing regimen consisting of a single dose of 3,000 mg in 10,000 virtual patients. PTA, probability of target attainment; AUC, area under the concentration-time curve.

FIG 3

Molecular structure of fosfomycin and pK_a values derived from the Chemicalize database (https://chemicalize.com/#/calculation).

FIG 4

Relationship between the microspecies distribution percentage for fosfomycin and pH adapted from the Chemicalize database (https://chemicalize.com/#/calculation).