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 Gramnegative 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 (MIC 90 Յ 16 g/ml) but not against Klebsiella spp. (MIC 90 Ͼ 512 g/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 Յ64 mg/liter was able to achieve a PTA of Ն90% 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, fosfomycin, Monte Carlo simulation, acidic pH, pharmacodynamics, urinary tract infection U rinary tract infections (UTIs) are the most common infections worldwide, and members of the family Enterobacteriaceae are the main pathogens responsible for UTIs (1). The rise in the rate of antibiotic resistance over the last several years has resulted in limited treatment options currently available for the treatment of infections caused by multidrug-resistant (MDR) bacteria. Fosfomycin is an old antibiotic agent frequently used to treat uncomplicated UTIs and has been reevaluated as a potential option for the treatment of infections caused by MDR Gram-negative bacteria (2). The dosage currently approved for the treatment of an uncomplicated UTI is a single

Urinary Tract Conditions Affect Fosfomycin Activity against Escherichia coli Strains Harboring Chromosomal Mutations Involved in Fosfomycin Uptake

“…Our results confirm that low pH values increase FOS activity (41,43). In an acidic urine (pH values of 5 to 6), FOS is partially protonated and in a more lipophilic state, allowing FOS to enter bacteria and resulting in higher antimicrobial activity (43). As we previously demonstrated, the urine pH for patients with UTI caused by E. coli is mainly acidic (85.38% of patients have a urine pH of Յ6.5) (35).…”

“…Our results confirm that low pH values increase FOS activity (41,43). In an acidic urine (pH values of 5 to 6), FOS is partially protonated and in a more lipophilic state, allowing FOS to enter bacteria and resulting in higher antimicrobial activity (43).…”

Unexpected activity of oral fosfomycin against resistant strains ofEscherichia coliin murine pyelonephritis

“…Fosfomycin activity observed in infected kidneys may result from the combination of local specific physiological conditions in urine and of fosfomycin concentrations in the kidneys. Indeed, several authors have already shown that low pH values increased fosfomycin in vitro activity (12, 19, 20). In an acidic environment such as urine, fosfomycin is partially protonated, being in a more lipophilic state, allowing fosfomycin entry into bacteria, and resulting in higher antimicrobial activity (20).…”

“…Indeed, several authors have already shown that low pH values increased fosfomycin in vitro activity (12, 19, 20). In an acidic environment such as urine, fosfomycin is partially protonated, being in a more lipophilic state, allowing fosfomycin entry into bacteria, and resulting in higher antimicrobial activity (20). Our results support these findings, as low pH values were associated with a significant decrease in fosfomycin MIC values for resistant strains into the susceptible range (Table 1).…”

Unexpected Activity of Oral Fosfomycin against Resistant Strains of Escherichia coli in Murine Pyelonephritis

“…Indeed, several authors have already shown that low pH values increased the fosfomycin in vitro activity (12,18,19). In an acidic environment, such as urine, fosfomycin is partially protonated, thus being in a more lipophilic state, allowing fosfomycin entry into bacteria and resulting in higher antimicrobial activity (19).…”