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Fosfomycin

From Wikipedia, the free encyclopedia
Not to be confused withFosmidomycin.

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/DrugsMonograph
MedlinePlusa697008
License data
Routes of
administration		Intravenous,By mouth
ATC code
Legal status
Legal status
Pharmacokineticdata
Bioavailability30–37% (by mouth, fosfomycintromethamine); varies with food intake
Protein bindingNil
MetabolismNil
Eliminationhalf-life5.7 hours (mean)
ExcretionKidney,unchanged
Identifiers
  • [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
CAS Number
PubChemCID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.041.315Edit this at Wikidata
Chemical and physical data
FormulaC3H7O4P
Molar mass138.059g·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/s1checkY
  • Key:YMDXZJFXQJVXBF-STHAYSLISA-NcheckY
(verify)

Fosfomycin,sold under the brand nameMonurolamong others, is anantibioticprimarily used to treat lowerurinary tract infections.[7]It is not indicated forkidney infections.[7]Occasionally it is used forprostate infections.[7]It is generally taken by mouth.[7]

Common side effects include diarrhea, nausea, headache, andvaginal yeast infections.[7]Severe side effects may includeanaphylaxisandClostridioides difficile-associated diarrhea.[7]While use duringpregnancyhas not been found to be harmful, such use is not recommended.[8]A single dose when breastfeeding appears safe.[8]Fosfomycin works by interfering with the production of thebacterial cell wall.[7]

Fosfomycin was discovered in 1969 and approved for medical use in the United States in 1996[globalize].[7][9]It is on theWorld Health Organization's List of Essential Medicines.[10]The World Health Organization classifies fosfomycin as critically important for human medicine.[11]It is available as ageneric medication.[12]It was originally produced by certain types ofStreptomyces,although it is now made chemically.[9]

Medical uses

[edit]

Fosfomycin is used to treatbladder 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 advancingantimicrobial resistancehas 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 bymultidrug-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, aloading doseof 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

[edit]

The fosfomycin molecule has anepoxideor oxirane ring, which is highlystrainedand thus very reactive.[citation needed]

Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity againstE. faecalis,E. coli,and various Gram-negatives such asCitrobacterandProteus.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 againstS. saprophyticus,Klebsiella,andEnterobacteris variable and should be confirmed byminimum inhibitory concentrationtesting. Activity againstextended-spectrum β-lactamase-producing pathogens, notably ESBL-producingE. 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

[edit]

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]

Enzymesconferring resistance to fosfomycin have also been identified and are encoded bothchromosomallyand onplasmids.[25]

Three related fosfomycin resistance enzymes (named FosA, FosB, and FosX) are members of theglyoxalasesuperfamily. 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:glutathionefor FosA,bacillithiolfor 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 usesATPand adds aphosphategroup to fosfomycin, thus altering its properties and making the drug ineffective.[28]

Side effects

[edit]

The drug is well tolerated and has a low incidence of harmful side effects.[13]

Mechanism of action

[edit]

Despite its name (ending in -omycin) Fosfomycin is not amacrolide,but a member of a novel class of phosphonic antibiotics. Fosfomycin is bactericidal and inhibits bacterial cell wall biogenesis by inactivating the enzymeUDP-N-acetylglucosamine-3-enolpyruvyltransferase,also known as MurA.[29]This enzyme catalyzes thecommitted stepinpeptidoglycanbiosynthesis, namely the ligation ofphosphoenolpyruvate(PEP) to the 3'-hydroxyl group ofUDP-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 byalkylatingan active sitecysteineresidue (Cys 115 in theEscherichia colienzyme).[30][31]

Fosfomycin enters the bacterial cell through the glycerophosphate transporter.[32]

History

[edit]

Fosfomycin (originally known as phosphonomycin) was discovered in a joint effort ofMerck and Co.and Spain's Compañía Española de Penicilina y Antibióticos (CEPA). It was first isolated by screening broth cultures ofStreptomyces fradiaeisolated from soil samples for the ability to cause formation ofspheroplastsby 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 itsAranjuezfacility.[34]

Biosynthesis

[edit]

The complete fosfomycin biosyntheticgene clusterfromStreptomyces fradiaehas been cloned and sequenced and the heterologous production of fosfomycin inS. lividanshas been achieved by Ryan Woodyer of theHuimin ZhaoandWilfred van der Donkresearch groups.[35]

Synthetic manufacture

[edit]

Large scale production of fosfomycin is achieved by making anepoxideof cis-propenylphosphonic acid to yieldracemic mixturefosfomycin.[36]

References

[edit]
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  35. ^Woodyer RD, Shao Z, Thomas PM, Kelleher NL, Blodgett JA, Metcalf WW, et al. (November 2006)."Heterologous production of fosfomycin and identification of the minimal biosynthetic gene cluster".Chemistry & Biology.13(11): 1171–1182.doi:10.1016/j.chembiol.2006.09.007.PMID17113999.
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