Fosfomycin

Not to be confused with Fosmidomycin.

Fosfomycin
Structural formula of fosfomycin
Ball-and-stick model of the fosfomycin molecule
Clinical data
Trade namesMonuril, Monurol, Ivozfo, others
Other namesPhosphomycin, phosphonomycin, fosfomycin tromethamine
AHFS/Drugs.comMonograph
MedlinePlusa697008
License data
Routes of
administration		Intravenous, By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability30–37% (by mouth, fosfomycin tromethamine); varies with food intake
Protein bindingNil
MetabolismNil
Elimination half-life5.7 hours (mean)
ExcretionKidney, unchanged
Identifiers
  • [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.041.315 Edit this at Wikidata
Chemical and physical data
FormulaC3H7O4P
Molar mass138.059 g·mol−1
3D model (JSmol)
Melting point94 °C (201 °F)
  • C[C@H]1[C@H](O1)P(=O)(O)O
  • InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1 checkY
  • Key:YMDXZJFXQJVXBF-STHAYSLISA-N checkY
  (verify)

Fosfomycin, sold under the brand name Monurol among others, is an antibiotic primarily used to treat lower urinary tract infections.[8] It is not indicated for kidney infections.[8] Occasionally it is used for prostate infections.[8] It is generally taken by mouth.[8]

Common side effects include diarrhea, nausea, headache, and vaginal yeast infections.[8] Severe side effects may include anaphylaxis and Clostridioides difficile-associated diarrhea.[8] While use during pregnancy has not been found to be harmful, such use is not recommended.[9] A single dose when breastfeeding appears safe.[9] Fosfomycin works by interfering with the production of the bacterial cell wall.[8]

Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996 [globalize][8][10] It is on the World Health Organization's List of Essential Medicines.[11] The World Health Organization classifies fosfomycin as critically important for human medicine.[12] It is available as a generic medication.[13] It was originally produced by certain types of Streptomyces, although it is now made chemically.[10]

Medical uses

Fosfomycin is used to treat bladder infections as well as urinary tract infections (UTIs), where it is usually given as a single dose by mouth.[14]

Oral fosfomycin is not recommended for children under 12 years old.[15]

Additional uses have been proposed.[16] The global problem of advancing antimicrobial resistance has led to a renewed interest in its use more recently.[17]

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.[18]

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.[19] 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.[20]

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.[21][22][23] Still, fosfomycin can be used to treat MRSA bacteremia.[24]

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.[19][25]

Enzymes conferring resistance to fosfomycin have also been identified and are encoded both chromosomally and on plasmids.[26]

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,[27][28] and water for FosX.[26]

In general, FosA and FosX enzymes are produced by Gram-negative bacteria, whereas FosB is produced by Gram-positive bacteria.[26]

FosC uses ATP and adds a phosphate group to fosfomycin, thus altering its properties and making the drug ineffective.[29]

Side effects

The drug is well tolerated and has a low incidence of harmful side effects.[14]

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.[30] 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).[31][32]

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[33]

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.[34] CEPA began producing fosfomycin on an industrial scale in 1971 at its Aranjuez facility.[35]

Biosynthesis

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.[36]

Synthetic manufacture

Large scale production of fosfomycin is achieved by making an epoxide of cis-propenylphosphonic acid to yield racemic mixture fosfomycin.[37]

References

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List of Ottawa municipal elections

This is a list of elections held in Ottawa, Ontario. Direct elections for mayor have been held continuously since 1873.[1] City of Ottawa mayoral election results since 1887 1887 McLeod Stewart, 2,169[2] W. E. Brown, 1,790 1888 McLeod Stewart, 1,957[3] W. E. Brown, 1,643 W. H. Lewis, 360 1889 Jacob Erratt, 2,823[4] Dr. Valade, 2,345 1890 Jacob Erratt, 2,620[5] W. H. Lewis, 1,419 1891 Thomas Birkett, 2,396[6] Dr. St. Jean, 1,459 John Heney, 1,09...