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

Abstract

The steps by which Escherichia coli strains harboring mutations related to fosfomycin (FOS) resistance arise and spread during urinary tract infections (UTIs) are far from being understood. The aim of this study was to evaluate the effects of urine, pH, and anaerobiosis on FOS activity against a set of isogenic strains carrying the most prevalent chromosomal mutations conferring FOS resistance (ΔuhpT, ΔglpT, ΔcyaA, and ΔptsI), either singly or in combination. We also studied fosfomycin-resistant E. coli clinical isolates from patients with UTI. Our results demonstrate that urinary tract physiological conditions might have a profound impact on FOS activity against strains with chromosomal FOS resistance mutations. Specifically, acidic pH values and anaerobiosis convert most of the strains categorized as resistant to fosfomycin according to the international guidelines to a susceptible status. Therefore, urinary pH values may have practical interest in the management of UTIs. Finally, our results, together with the high fitness cost associated with FOS resistance mutations, might explain the low prevalence of fosfomycin-resistant E. coli variants in UTIs.

Keywords: Escherichia coli; UTI; chromosomal mutations; fosfomycin activity; fosfomycin resistance; urinary tract infection.

FIG 1

In vitro maximal growth rates (ΔOD per hour) for strain BW25113 and 10 isogenic LLFR and FOS-resistant strains in MH broth and urine at different pH values. Error bars represent interquartile ranges. Asterisks denote statistically significant differences (P < 0.05 [Mann-Whitney U test]) between the indicated strains and wild-type strain BW25113 under the same conditions.