Indications
Fosfomycin is primarily indicated for the treatment of uncomplicated cystitis caused by susceptible strains of Escherichia coli and Enterococcus faecalis. While it is not officially approved for the treatment of pyelonephritis or perinephric abscess, there are documented cases of off-label use for these conditions.
Pharmacodynamics
Fosfomycin is predominantly utilized for urinary tract infections and exhibits synergistic effects when combined with other antibiotics against clinically significant bacteria. Interest is increasing in its application for more complex infections due to its effectiveness against many difficult-to-treat bacterial strains, such as methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Enterobacteriaceae. Its unique mechanism of action minimizes the risk of cross-resistance with other antibiotics. Additionally, fosfomycin has immunomodulating properties, affecting elements of the acute inflammatory cytokine response and enhancing the phagocytic function of neutrophils. It effectively penetrates biofilms, not only reducing or eliminating microorganisms within biofilms but also altering their structure.
Absorption
Fosfomycin is a low-molecular-weight, hydrophilic drug that is rapidly absorbed in the small intestine and widely distributed throughout the body when administered orally. Its oral bioavailability ranges from 34% to 58%. The presence of food can reduce its gastrointestinal absorption to about 30%. The reported area under the curve (AUC) is between 145 and 228 mg·h/L, while the maximum concentration (Cmax) is 26.1 (±9.1) mcg/mL.
Metabolism
Fosfomycin undergoes no metabolic transformation and is primarily excreted unchanged in the urine.
Mechanism of Action
Fosfomycin exerts its bactericidal action by covalently binding to a cysteine residue in the active site of the enzyme UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), thereby inactivating it. This inhibition prevents MurA from catalyzing the crucial condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine, effectively halting the production of the peptidoglycan precursor UDP N-acetylmuramic acid. As a result, the initial stage of bacterial cell wall synthesis is disrupted. In Escherichia coli, fosfomycin enters the bacterial cells through two pathways: the L-alpha-glycerophosphate transporter system and the hexose-6-phosphate transporter system. Additionally, fosfomycin significantly impacts cell adhesion, reducing the adherence of bacterial cells to urinary epithelial cells, as well as the adhesion of Streptococcus pneumoniae and Haemophilus influenzae to respiratory epithelial cells.
