|Trade names||Monuril, Monurol, others|
|Other names||Phosphomycin, phosphonomycin, fosfomycin tromethamine|
|Bioavailability||30–37% (by mouth, fosfomycin tromethamine); varies with food intake|
|Elimination half-life||5.7 hours (mean)|
|Excretion||Kidney and fecal, unchanged|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||138.059 g/mol g·mol−1|
|3D model (JSmol)|
|Melting point||94 °C (201 °F)|
Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat bladder infections. It is not recommended for kidney infections. Occasionally it is used for prostate infections. It is generally taken by mouth.
Common side effects include diarrhea, nausea, headache, and vaginal yeast infections. Severe side effects may include anaphylaxis and Clostridium difficile-associated diarrhea. Well use during pregnancy has not been found to be harmful, such use is not recommended. A single dose when breastfeeding appears safe. Fosfomycin works by interfering with the production of the bacterial cell wall.
Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996. It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system. It is avaliable as a generic medication. In the United Kingdom it costs the NHS about £4.86 for a course of treatment. This amount in the United States has a costs of about US$95 as of 2019. It was originally produced by certain types of Streptomyces, although it is now made chemically.
It is not recommended for children and those over 75 years old.
Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives such as Citrobacter and Proteus. Given a greater activity in a low-pH milieu, and predominant excretion in active form into the urine, fosfomycin has found use for the prophylaxis and treatment of UTIs caused by these uropathogens. Of note, activity against S. saprophyticus, Klebsiella, and Enterobacter is variable and should be confirmed by minimum inhibitory concentration testing. Activity against extended-spectrum β-lactamase-producing pathogens, notably ESBL-producing E. coli, is good to excellent, because the drug is not affected by cross-resistance issues. Existing clinical data support use in uncomplicated UTIs, caused by susceptible organisms. However, susceptibility break-points of 64 mg/l should not be applied for systemic infections.
Development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections. Mutations that inactivate the nonessential glycerophosphate transporter render bacteria resistant to fosfomycin.
Three related fosfomycin resistance enzymes (named FosA, FosB, and FosX) are members of the glyoxalase superfamily. These enzymes function by nucleophilic attack on carbon 1 of fosfomycin, which opens the epoxide ring and renders the drug ineffective.
In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.
The drug is well tolerated and has a low incidence of harmful side effects.
Mechanism of action
Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA. This enzyme catalyzes the committed step in peptidoglycan biosynthesis, namely the ligation of phosphoenolpyruvate (PEP) to the 3'-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan. Fosfomycin is a PEP analog that inhibits MurA by alkylating an active site cysteine residue (Cys 115 in the Escherichia coli enzyme).
Fosfomycin enters the bacterial cell through the glycerophosphate transporter.
Fosfomycin (originally known as phosphonomycin) was discovered in a joint effort of Merck and Co. and Spain's Compañía Española de Penicilina y Antibióticos (CEPA). It was first isolated by screening broth cultures of Streptomyces fradiae isolated from soil samples for the ability to cause formation of spheroplasts by growing bacteria. The discovery was described in a series of papers published in 1969. CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.
The complete fosfomycin biosynthetic gene cluster from Streptomyces fradiae has been cloned and sequenced and the heterologous production of fosfomycin in S. lividans has been achieved by Ryan Woodyer of the Huimin Zhao and Wilfred van der Donk research groups.
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