Fosfomycin is used to treat
bladder infections, where it is usually given as a single dose by mouth.[13]
Oral fosfomycin is not recommended for children under 12 years old.[14]
Additional uses have been proposed.[15] The global problem of advancing
antimicrobial resistance has led to a renewed interest in its use more recently.[16]
Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis. The standard regimen for complicated UTIs is an oral 3 g dose administered once every 48 or 72 hours for a total of 3 doses or a 6 g dose every 8 hours for 7–14 days when fosfomycin is given in IV form.[17]
Intravenous fosfomycin is being increasingly used for treating infections caused by
multidrug-resistant bacteria, mostly as a partner drug in order to avoid the occurrence of resistances and to take advantage of its synergistic activity with several other antimicrobials. Daily adult dose usually ranges from 12 to 24 grams.[18] When administered in continuous infusion, a
loading dose of fosfomycin 8 g followed by a daily dose of 16 g or 24 g. Continuous infusion is suggested in patients with normal renal function.[19]
Bacterial sensitivity
The fosfomycin molecule has an
epoxide or oxirane ring, which is highly
strained and thus very reactive.[citation needed]
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.[citation needed]
Resistance
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.[20][21][22] Still, fosfomycin can be used to treat MRSA bacteremia.[23]
Prescribing fosfomycin together with at least another active drug reduces the risk of developing bacterial resistance. Fosfomycin acts synergistically with many other antibiotics, including aminoglycosides, carbapenems, cephalosporins, daptomycin and oritavancin.[18][24]
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.[citation needed]
The enzymes differ by the identity of the nucleophile used in the reaction:
glutathione for FosA,
bacillithiol for FosB,[26][27] and water for FosX.[25]
In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[25]
FosC uses
ATP and adds a
phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[28]
Side effects
The drug is well tolerated and has a low incidence of harmful side effects.[13]
Mechanism of action
Despite its name (ending in -omycin) Fosfomycin is not a
macrolide, but a member of a novel class of phosphonic antibiotics. Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzyme
UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA.[29] 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).[30][31]
Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[32]
History
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.[33] CEPA began producing fosfomycin on an industrial scale in 1971 at its
Aranjuez facility.[34]
Manufacture
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.[35]
Large scale production of fosfomycin is achieved by making an
epoxide of cis-propenylphosphonic acid to yield
racemic mixture fosfomycin.[36]
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^Omori K, Kitagawa H, Takada M, Maeda R, Nomura T, Kubo Y, Shigemoto N, Ohge H (April 2024). "Fosfomycin as salvage therapy for persistent methicillin-resistant Staphylococcus aureus bacteremia: A case series and review of the literature". J Infect Chemother. 30 (4): 352–356.
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^Sharma SV, Jothivasan VK, Newton GL, Upton H, Wakabayashi JI, Kane MG, et al. (July 2011). "Chemical and Chemoenzymatic syntheses of bacillithiol: a unique low-molecular-weight thiol amongst low G + C Gram-positive bacteria". Angewandte Chemie. 50 (31): 7101–7104.
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^Krekel F, Samland AK, Macheroux P, Amrhein N, Evans JN (October 2000). "Determination of the pKa value of C115 in MurA (UDP-N-acetylglucosamine enolpyruvyltransferase) from Enterobacter cloacae". Biochemistry. 39 (41): 12671–12677.
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^Santoro A, Cappello AR, Madeo M, Martello E, Iacopetta D, Dolce V (December 2011). "Interaction of fosfomycin with the glycerol 3-phosphate transporter of Escherichia coli". Biochimica et Biophysica Acta (BBA) - General Subjects. 1810 (12): 1323–1329.
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^Silver LL (2011). "Rational Approaches to Antibacterial Discovery: Pre-Genomic Directed and Phenotypic Screening". In Dougherty T, Pucci MJ (eds.). Antibiotic Discovery and Development. Springer. p. 46.
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^Marocco CP, Davis EV, Finnell JE, Nguyen PH, Mateer SC, Ghiviriga I, et al. (2011). "Asymmetric synthesis of (−)-fosfomycin and its trans-(1S,2S)-diastereomer using a biocatalytic reduction as the key step". Tetrahedron: Asymmetry. 22 (18–19). Elsevier BV: 1784–1789.
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