Overcoming the drug resistance barrier: progress in fosfomycin combination therapy against multidrug-resistant...

Area of Science:

• Infectious Diseases
• Microbiology
• Pharmacology

Background:

• Antimicrobial resistance (AMR) is a growing global health crisis.
• Fosfomycin, an older antibiotic, shows activity against multidrug-resistant (MDR) pathogens.
• Monotherapy with fosfomycin leads to rapid resistance development, limiting its clinical use.

Purpose of the Study:

• To review the mechanisms of fosfomycin resistance, including plasmid-mediated genes.
• To evaluate preclinical and clinical evidence for fosfomycin combination therapies.
• To identify barriers and propose future research directions for fosfomycin combinations.

Main Methods:

• Systematic analysis of antibacterial and molecular resistance mechanisms.
• Comprehensive evaluation of preclinical and clinical data for various combination regimens.
• Critical examination of the translational gap between preclinical models and clinical outcomes.

Main Results:

• Fosfomycin exhibits unique mechanisms of action but is prone to resistance.
• Combination therapies (e.g., with β-lactams, aminoglycosides) show synergistic effects.
• Significant promise exists for fosfomycin combinations, but clinical translation faces challenges.

Conclusions:

• Rational combination therapy is essential to preserve and enhance fosfomycin efficacy against MDR infections.
• Further research is needed to bridge the gap between preclinical findings and clinical application.
• Future strategies include PK/PD-guided dosing, non-antibiotic adjuvants, and improved preclinical models.