Fosfomycin

Fosfomycin, a phosphonic acid that contains a carbon-phosphorus bond, is a natural antibiotic produced by Streptomyces fradiae. It is a phosphoenolpyruvate analogue that irreversibly inhibits phosphoenolpyruvate transferase, an enzyme that catalyzes the first step of peptidoglycan synthesis of microbial cell walls. Its in vitro spectrum is broad, with potential efficacy toward isolates expressing multidrug resistance, including Escherichia coli and methicillin-resistant staphylococci. As a cell wall inhibitor, fosfomycin is bactericidal when present at the site of infection at therapeutic concentrations. Cell wall inhibition is time dependent, but fosfomycin also exhibits a concentration-dependent effect. Resistance to fosfomycin is uncommon and reflects the FosX or FosA enzyme, which hydrolyzes the drug. The gene for this protein is chromosomally mediated. When resistance occurs, it generally is not associated with multidrug resistance. Studies in people have demonstrated that fosfomycin distributes well to soft tissues, reaching therapeutic breakpoints. Adverse effects of fosfomycin appear to be limited to diarrhea. Approved for human use in the USA as the tromethamine salt, its indication is as a one time (or up to 3 days) treatment of uncomplicated urinary tract infections in people. Fosfomycin has been added to the World Health Organization's list of critically important drugs. Accordingly, its use should be reserved, along with other critically important drugs, to situations in which lower-tier drugs are no longer appropriate.