Fosfomycin: Mechanism and Resistance

Area of Science:

• Pharmacology and Microbiology
• Infectious Diseases

Background:

• Fosfomycin, a broad-spectrum antibiotic, has been clinically used for over two decades for various infections, including urinary tract infections (UTIs).
• It functions as a time-dependent inhibitor of MurA, a key enzyme in bacterial peptidoglycan synthesis, and exhibits low toxicity.
• While rapid in vitro resistance can emerge via transport mechanism loss, clinical resistance during UTIs is infrequent due to reduced pathogen fitness.

Purpose of the Study:

• To review the established use of fosfomycin in uncomplicated UTIs.
• To explore the growing interest in fosfomycin for treating multidrug-resistant (MDR) pathogens.
• To discuss the development of a parenteral formulation for complicated UTIs and potential resistance implications.

Main Methods:

• Literature review of fosfomycin's clinical use, mechanism of action, and resistance patterns.
• Analysis of in vitro versus in vivo resistance development.
• Examination of recent developments in parenteral fosfomycin formulations.

Main Results:

• Fosfomycin is effective and rarely encounters resistance in uncomplicated UTIs.
• In vitro resistance develops quickly, but resistant strains show lower fitness, limiting in vivo emergence.
• A parenteral formulation is under development for complicated UTIs and other indications involving MDR pathogens.

Conclusions:

• Fosfomycin remains a valuable therapeutic option for uncomplicated UTIs with a favorable resistance profile.
• The expansion of fosfomycin use to MDR pathogens and complicated infections requires careful monitoring of resistance.
• Further research is needed to assess the long-term resistance trends with new fosfomycin applications.