Fosfomycin Use in Treating Severe Difficult-to-Treat Gram-Negative Infections—A Comprehensive Review

Background/Objectives: Fosfomycin is an old antimicrobial agent historically used in its oral formulation for uncomplicated urinary tract infections. In the current context of rising antimicrobial resistance and limited antimicrobial options, fosfomycin has attracted renewed interest. Methods: A comprehensive review on the IV fosfomycin use focusing on critically ill patients and/or severe infections due to difficult-to-treat (DTR) Gram-negative bacilli (GNB). Results: Fosfomycin’s IV formulation is now being used more widely, particularly in critically ill patients with multidrug-resistant (MDR) or DTR-GNB infections. It offers several attractive features: a unique mechanism of action that minimizes cross-resistance; a broad spectrum of activity, covering both Gram-negative and Gram-positive pathogens; and consistent synergy with multiple pivotal antimicrobials. Its pharmacokinetic/pharmacodynamic (PK/PD) profile is favorable, with extensive tissue penetration, including the central nervous system. The ratio of area under the concentration–time curve to the minimum inhibitory concentration of the pathogen (AUC/MIC) is considered the optimal PK/PD target for fosfomycin. The adverse events are mainly non-serious (most frequently, hypernatremia and hypokalemia), although safety data for higher dosing regimens remain limited. Growing clinical evidence supports IV fosfomycin as an effective and well-tolerated component of combination therapy for severe infections in critically ill patients, including those infections caused by extended-spectrum beta-lactamases-, carbapenemase-producing Enterobacterales, and DTR non-fermentative GNB. Nevertheless, as with many rediscovered antimicrobials, its expanded role requires confirmation through rigorously designed clinical trials to better define its efficacy, optimal use, and safety profile in the treatment of severe DTR-GNB infections.