Fosfomycin Resistance in Escherichia coli: Mechanisms, Trends, and Clinical Challenges

Fosfomycin has reemerged as an important therapeutic option against multidrug-resistant (MDR) Escherichia coli, particularly extended-spectrum β-lactamase (ESBL)-producing strains causing UTIs. The rising incidence of carbapenem-resistant and ESBL-producing E. coli has reduced the number of therapeutic alternatives available and rekindled interest in fosfomycin as a successful therapy alternative, particularly for UTIs. Fosfomycin is a significant therapeutic drug in contemporary clinical practice due to its distinct mode of action, advantageous pharmacokinetic characteristics, oral availability, and high urine concentrations. However, isolates of E. coli have become resistant globally due to the widespread usage of fosfomycin. Resistance mechanisms include reduced drug absorption due to transport system mutations, changes to the MurA target enzyme, enzymatic inactivation due to fos genes, biofilm formation, and plasmid-mediated horizontal gene transfer. A significant obstacle to infection control and antimicrobial stewardship is the spread of resistance factors like fosA3 among MDR strains. The current knowledge on fosfomycin resistance in E. coli, including mechanisms of resistance, molecular genetics, epidemiological trends, laboratory detection techniques, therapeutic uses, and related clinical difficulties, is summarized in this study. In order to maintain the clinical usefulness of fosfomycin against resistant bacterial infections, the review also emphasizes the significance of antimicrobial stewardship, surveillance initiatives, and future research approaches. This narrative review summarizes literature published between 2010 and 2025 on resistance mechanisms, epidemiology, laboratory detection, therapeutic applications, and clinical challenges associated with fosfomycin-resistant E. coli.