Fosfomycin
Identification
- Summary
Fosfomycin is a broad spectrum antibiotic used to treat uncomplicated urinary tract infections.
- Brand Names
- Monurol
- Generic Name
- Fosfomycin
- DrugBank Accession Number
- DB00828
- Background
Fosfomycin was discovered in 1969 by scientists at the Spanish Penicillin and Antibiotics Company and is produced by Streptomyces fradiae.1,5 It may also be produced synthetically and is commercially available as the disodium salt for intravenous administration and as the calcium or trometamol salt for oral administration.5 In terms of chemical structure, fosfomycin is a phosphoenolpyruvate analog and contains a phosphonic group and an epoxide ring.5
Due to its ease of administration as a single 3-gram oral dose and desirable safety profile, fosfomycin has largely become a first-line therapeutic option for the treatment of uncomplicated urinary tract infections (UTIs) in females.8 Despite being FDA approved only for urinary tract infections, fosfomycin actually has a broad spectrum of activity and is active against both gram-positive and gram-negative bacteria.5 As such there is great interest in exploring the usefulness of fosfomycin for indications beyond the treatment of UTIs.6,7
- Type
- Small Molecule
- Groups
- Approved
- Structure
Structure for Fosfomycin (DB00828)
- Weight
- Average: 138.059
Monoisotopic: 138.008195224 - Chemical Formula
- C3H7O4P
- Synonyms
- (-)-(1R,2S)-(1,2-Epoxypropyl)phosphonic acid
- (1R,2S)-epoxypropylphosphonic acid
- (2R-cis)-(3-Methyloxiranyl)phosphonic acid
- 1R-cis-(1,2-epoxypropyl)phosphonic acid
- cis-(1R,2S)-epoxypropylphosphonic acid
- FCM
- Fosfocina
- Fosfomicina
- Fosfomycin
- Fosfomycine
- Fosfomycinum
- L-cis-1,2-epoxypropylphosphonic acid
- Phosphomycin
- Phosphonemycin
- Phosphonomycin
- External IDs
- J01XX01
Pharmacology
- Indication
Fosfomycin is indicated for the treatment of uncomplicated cases of cystitis caused by susceptible strains of Escherichia coli and Enterococcus faecalis.10 Fosfomycin is not officially indicated for the treatment of pyelonephritis or perinephric abscess, although there have been reported cases of off-label usage in these situations.10
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- Contraindications & Blackbox Warnings
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Although used primarily to treat urinary tract infections, fosfomycin has been shown to act synergistically with other antibiotics against clinically relevant bacteria.1 There is also growing interest in the potential of fosfomycin to treat more complex infections since it has retained activity against many difficult-to-treat strains of bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant enterobacteria.7 Further, since fosfomycin has a unique and singular mechanism of action, the risk of cross-resistance with other antibiotics is low.6,5
Fosfomycin also demonstrates immunomodulating properties. For example, the antibiotic may influence components of the acute inflammatory cytokine response and enhances neutrophil phagocytic destruction of pathogens.1,4
Fosfomycin penetrates biofilms effectively and is capable of not only reducing or eliminating microorganisms in biofilms but can also alter the biofilm structure.1,7
- Mechanism of action
Fosfomycin exerts its bactericidal effects by binding covalently to a cysteine in the active site of the UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) enzyme, rendering it inactive. By preventing MurA from catalyzing the condensation of phosphoenolpyruvate (PEP) with UDP-N-acetylglucosamine (UNAG), fosfomycin inhibits the production of the peptidoglycan precursor UDP N-acetylmuramic acid (UDP-MurNAc).1,10 Ultimately, the first step of bacterial cell wall synthesis is disrupted.5
In Escherichia coli, fosfomycin gains entry into bacterial cells via two mechanisms: the L-alpha-glycerophosphate system and the hexose-6-phosphate transporter system.1
Fosfomycin also has important effects on cell adhesion. For example, the adhesion of bacterial cells to urinary epithelial cells is reduced in the presence of fosfomycin. The adhesion of Streptococcus pneumoniae and Haemophilus influenzae to respiratory epithelial cells is also reduced1
Target Actions Organism AUDP-N-acetylglucosamine 1-carboxyvinyltransferase inhibitorEscherichia coli (strain K12) - Absorption
Fosfomycin is a low molecular weight and hydrophilic drug. When administered orally, fosfomycin is rapidly absorbed in the small intestine and distributed widely to the tissues.1,2,3,10 The oral bioavailability ranges from 34-58%.1 Co-administration of fosfomycin with food decreases gastrointestinal absorption to approximately 30%.1 The reported AUC = 145-228 mg x h/L, while the reported Cmax = 26.1 (∓9.1) mcg/mL.1,10
- Volume of distribution
In healthy subjects, the volume of distribution (Vd) of fosfomycin is approximately 0.3 L/Kg.2 Due to changes in the vascular endothelium, the Vd can be up to 50% higher in critically ill patients.2
- Protein binding
Fosfomycin does not bind to plasma proteins to any significant extent.2,3
- Metabolism
Fosfomycin is not metabolized and is predominantly excreted unchanged in the urine.2,3
- Route of elimination
Fosfomycin is excreted almost entirely by the kidneys.2 Factors including administration with food, impaired renal function, and older age may reduce the rate of fosfomycin elimination.1
- Half-life
The mean elimination half-life of fosfomycin is 5.7 (∓2.8) hours.10
- Clearance
In one study, the reported CL/F of fosfomycin in healthy volunteers was 17 ∓ 4.7 L/hour.9
- Adverse Effects
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Acute toxicology studies have found that oral fosfomycin doses 50-125 times the human therapeutic dose were well-tolerated in rats and mice, resulted in minor and transient watery stools in rabbits, and caused diarrhea with anorexia in dogs 2-3 days after single-dose administration.10
In humans, symptoms of overdose have included impaired hearing, vestibular loss, general decline in taste perception, and metallic taste. In the event of overdose, the patient should be managed with symptomatic and supportive measures.10
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAbacavir Fosfomycin may decrease the excretion rate of Abacavir which could result in a higher serum level. Aceclofenac Aceclofenac may decrease the excretion rate of Fosfomycin which could result in a higher serum level. Acemetacin Acemetacin may decrease the excretion rate of Fosfomycin which could result in a higher serum level. Acenocoumarol The risk or severity of bleeding can be increased when Fosfomycin is combined with Acenocoumarol. Acetaminophen Acetaminophen may decrease the excretion rate of Fosfomycin which could result in a higher serum level. Acetazolamide Acetazolamide may increase the excretion rate of Fosfomycin which could result in a lower serum level and potentially a reduction in efficacy. Acetylsalicylic acid Acetylsalicylic acid may decrease the excretion rate of Fosfomycin which could result in a higher serum level. Aclidinium Fosfomycin may decrease the excretion rate of Aclidinium which could result in a higher serum level. Acrivastine Fosfomycin may decrease the excretion rate of Acrivastine which could result in a higher serum level. Acyclovir Acyclovir may decrease the excretion rate of Fosfomycin which could result in a higher serum level. 
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- Take with or without food. The absorption is unaffected by food.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Fosfomycin calcium monohydrate T330QG2NYS 26469-67-0 MSHCINMVQZDXTG-JSTPYPERSA-N Fosfomycin disodium 97MMO19FNO 26016-99-9 QZIQJIKUVJMTDG-UHFFFAOYSA-L Fosfomycin tromethamine 7FXW6U30GY 78964-85-9 QZJIMDIBFFHQDW-LMLSDSMGSA-N - International/Other Brands
- Veramina (Roux-Ocefa)
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fosfomycin Powder for Oral Solution Powder, for solution 3 g / sachet Oral Endo Ventures Ltd Not applicable Not applicable Canada 
Ivozfo Powder, for solution 4 g / vial Intravenous Verity Pharmaceuticals Inc. 2020-02-12 Not applicable Canada Ivozfo Powder, for solution 2 g / vial Intravenous Verity Pharmaceuticals Inc. Not applicable Not applicable Canada Ivozfo Powder, for solution 8 g / vial Intravenous Verity Pharmaceuticals Inc. Not applicable Not applicable Canada Monurol Powder 3 g/1 Oral Allergan, Inc. 1996-12-19 Not applicable US 
Monurol Powder, for solution 3 g / sachet Oral Paladin Labs Inc 1999-09-15 Not applicable Canada - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fosfomycin Tromethamine Powder 3 g/1 Oral Xiromed Llc 2020-10-06 Not applicable US Fosfomycin Tromethamine Powder 3 g/1 Oral Zambon USA, Ltd 2021-08-25 Not applicable US Jamp-fosfomycin Powder, for solution 3 g / sachet Oral Jamp Pharma Corporation 2018-08-02 Not applicable Canada
Categories
- ATC Codes
- J01XX01 — Fosfomycin
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as organic phosphonic acids. These are organic compounds containing phosphonic acid.
- Kingdom
- Organic compounds
- Super Class
- Organic acids and derivatives
- Class
- Organic phosphonic acids and derivatives
- Sub Class
- Organic phosphonic acids
- Direct Parent
- Organic phosphonic acids
- Alternative Parents
- Oxacyclic compounds / Epoxides / Organopnictogen compounds / Organophosphorus compounds / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
- Substituents
- Aliphatic heteromonocyclic compound / Hydrocarbon derivative / Organic oxide / Organic oxygen compound / Organoheterocyclic compound / Organooxygen compound / Organophosphonic acid / Organophosphorus compound / Organopnictogen compound / Oxacycle
- Molecular Framework
- Aliphatic heteromonocyclic compounds
- External Descriptors
- epoxide, phosphonic acids (CHEBI:28915) / Aliphatic compounds (C06454)
- Affected organisms
- Enteric bacteria and other eubacteria
Chemical Identifiers
- UNII
- 2N81MY12TE
- CAS number
- 23155-02-4
- InChI Key
- YMDXZJFXQJVXBF-STHAYSLISA-N
- InChI
- InChI=1S/C3H7O4P/c1-2-3(7-2)8(4,5)6/h2-3H,1H3,(H2,4,5,6)/t2-,3+/m0/s1
- IUPAC Name
- [(2R,3S)-3-methyloxiran-2-yl]phosphonic acid
- SMILES
- C[C@@H]1O[C@@H]1P(O)(O)=O
References
- Synthesis Reference
Graziano Castaldi, Claudio Giordano, "Process for the preparation of intermediates for the synthesis of fosfomycin." U.S. Patent US4937367, issued March, 1972.
US4937367- General References
- Falagas ME, Vouloumanou EK, Samonis G, Vardakas KZ: Fosfomycin. Clin Microbiol Rev. 2016 Apr;29(2):321-47. doi: 10.1128/CMR.00068-15. [Article]
- Rodriguez-Gascon A, Canut-Blasco A: Deciphering pharmacokinetics and pharmacodynamics of fosfomycin. Rev Esp Quimioter. 2019 May;32 Suppl 1:19-24. [Article]
- Raz R: Fosfomycin: an old--new antibiotic. Clin Microbiol Infect. 2012 Jan;18(1):4-7. doi: 10.1111/j.1469-0691.2011.03636.x. Epub 2011 Sep 13. [Article]
- Segal AW: How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197-223. doi: 10.1146/annurev.immunol.23.021704.115653. [Article]
- Diez-Aguilar M, Canton R: New microbiological aspects of fosfomycin. Rev Esp Quimioter. 2019 May;32 Suppl 1:8-18. [Article]
- Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI: Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008 Apr 1;46(7):1069-77. doi: 10.1086/527442. [Article]
- Veganzones J, Montero A, Maseda E: New evidence on the use of fosfomycin for bacteremia and infectious endocarditis. Rev Esp Quimioter. 2019 May;32 Suppl 1:25-29. [Article]
- Gardiner BJ, Stewardson AJ, Abbott IJ, Peleg AY: Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems. Aust Prescr. 2019 Feb;42(1):14-19. doi: 10.18773/austprescr.2019.002. Epub 2019 Feb 1. [Article]
- Wenzler E, Ellis-Grosse EJ, Rodvold KA: Pharmacokinetics, Safety, and Tolerability of Single-Dose Intravenous (ZTI-01) and Oral Fosfomycin in Healthy Volunteers. Antimicrob Agents Chemother. 2017 Aug 24;61(9). pii: AAC.00775-17. doi: 10.1128/AAC.00775-17. Print 2017 Sep. [Article]
- FDA Approved Drug Products: Monurol (fosfomycin tromethamine) [Link]
- External Links
- Human Metabolome Database
- HMDB0014966
- KEGG Drug
- D04253
- KEGG Compound
- C06454
- PubChem Compound
- 446987
- PubChem Substance
- 46506665
- ChemSpider
- 394204
- BindingDB
- 50024894
- 4550
- ChEBI
- 28915
- ChEMBL
- CHEMBL1757
- ZINC
- ZINC000001530427
- Therapeutic Targets Database
- DAP000767
- PharmGKB
- PA164748039
- PDBe Ligand
- FCN
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- PDRhealth
- PDRhealth Drug Page
- Wikipedia
- Fosfomycin
- PDB Entries
- 1lqp / 2bnn / 3d41 / 3quo / 4ir0 / 4jd1 / 4jh3 / 4jh4 / 4jh5 / 4jh6 … show 2 more
- FDA label
- Download (267 KB)
- MSDS
- Download (61.1 KB)
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 4 Completed Prevention Allograft Rejection / Asymptomatic Bacteriuria / Hospitalizations / Microbiologic Resistance / Urinary Tract Infection 1 4 Completed Prevention Asymptomatic Bacteriuria / Urinary Tract Infection 1 4 Completed Prevention Urinary Tract Infection 1 4 Completed Treatment Infective Endocarditis (IE) 1 4 Completed Treatment Urinary Tract Infection 2 4 Not Yet Recruiting Treatment Urinary Tract Infection 1 4 Recruiting Prevention Complications / Infection / Prostate Cancer 1 4 Recruiting Treatment Prosthetic Joint Infections 1 4 Terminated Treatment Urinary Tract Infection 1 4 Unknown Status Treatment Cystitis / Urinary Tract Infection 1
Pharmacoeconomics
- Manufacturers
- Zambon spa italy
- Packagers
- Forest Pharmaceuticals
- Zambon Ltd.
- Dosage Forms
Form Route Strength Powder, for solution Oral Injection, powder, for solution Parenteral 40 mg/ml Tablet, effervescent Capsule Tablet Injection, powder, for solution Intravenous 8 g Injection, powder, for solution Intravenous 1 g Injection, powder, for solution Intravenous 4 g Injection, powder, for solution Parenteral 4 g Injection, powder, for solution Parenteral 8 g Granule, for solution Oral Injection, powder, for solution Injection, powder, lyophilized, for solution Intravenous Powder Oral 1 g Powder, for suspension Oral 3 g Powder, for solution Parenteral 40 MG/ML Powder, for solution Intravenous 2 g / vial Powder, for solution Intravenous 4 g / vial Powder, for solution Intravenous 8 g / vial Granule, for solution Oral 2 G Granule, for solution Oral 3 G Granule Oral Powder Oral 3 g/1 Powder, for solution Oral 3 g / sachet Capsule, coated Oral 500 mg Powder, for solution Oral 3 g Powder Oral Powder Oral 2 g Granule Oral 3 g - Prices
Unit description Cost Unit Monurol 3 gm Packets 50.87USD packet Monurol 3 gm sachet 47.07USD each Viramune 200 mg tablet 9.48USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 94 °C PhysProp water solubility 50 mg/mL (Sodium salt) Not Available logP -1.6 Not Available - Predicted Properties
Property Value Source Water Solubility 46.9 mg/mL ALOGPS logP -0.86 ALOGPS logP -0.74 ChemAxon logS -0.47 ALOGPS pKa (Strongest Acidic) 1.25 ChemAxon pKa (Strongest Basic) -4.3 ChemAxon Physiological Charge -1 ChemAxon Hydrogen Acceptor Count 4 ChemAxon Hydrogen Donor Count 2 ChemAxon Polar Surface Area 70.06 Å2 ChemAxon Rotatable Bond Count 1 ChemAxon Refractivity 25.87 m3·mol-1 ChemAxon Polarizability 10.8 Å3 ChemAxon Number of Rings 1 ChemAxon Bioavailability 1 ChemAxon Rule of Five Yes ChemAxon Ghose Filter No ChemAxon Veber's Rule No ChemAxon MDDR-like Rule No ChemAxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.5 Blood Brain Barrier + 0.9382 Caco-2 permeable - 0.6652 P-glycoprotein substrate Non-substrate 0.7234 P-glycoprotein inhibitor I Non-inhibitor 0.8938 P-glycoprotein inhibitor II Non-inhibitor 0.9878 Renal organic cation transporter Non-inhibitor 0.9505 CYP450 2C9 substrate Non-substrate 0.7514 CYP450 2D6 substrate Non-substrate 0.8332 CYP450 3A4 substrate Non-substrate 0.6513 CYP450 1A2 substrate Non-inhibitor 0.8492 CYP450 2C9 inhibitor Non-inhibitor 0.8551 CYP450 2D6 inhibitor Non-inhibitor 0.9202 CYP450 2C19 inhibitor Non-inhibitor 0.8016 CYP450 3A4 inhibitor Non-inhibitor 0.9624 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.944 Ames test Non AMES toxic 0.6575 Carcinogenicity Non-carcinogens 0.6059 Biodegradation Not ready biodegradable 0.894 Rat acute toxicity 2.5802 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9456 hERG inhibition (predictor II) Non-inhibitor 0.9491
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key GC-MS Spectrum - GC-MS (2 TMS) GC-MS splash10-03di-2980000000-005d5b96a1e9219362d0 Predicted GC-MS Spectrum - GC-MS Predicted GC-MS Not Available GC-MS Spectrum - GC-MS GC-MS splash10-03di-2980000000-005d5b96a1e9219362d0 Predicted MS/MS Spectrum - 10V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Positive (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 10V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 20V, Negative (Annotated) Predicted LC-MS/MS Not Available Predicted MS/MS Spectrum - 40V, Negative (Annotated) Predicted LC-MS/MS Not Available
Targets
- Kind
- Protein
- Organism
- Escherichia coli (strain K12)
- Pharmacological action
- Yes
- Actions
- Inhibitor
- Curator comments
- Note: The above was chosen as a representative target protein in a representative bacterium, and does not encompass all proteins/bacteria affected by this agent.
- General Function
- Udp-n-acetylglucosamine 1-carboxyvinyltransferase activity
- Specific Function
- Cell wall formation. Adds enolpyruvyl to UDP-N-acetylglucosamine. Target for the antibiotic fosfomycin.
- Gene Name
- murA
- Uniprot ID
- P0A749
- Uniprot Name
- UDP-N-acetylglucosamine 1-carboxyvinyltransferase
- Molecular Weight
- 44817.24 Da
References
- Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
- Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [Article]
- Kim DH, Lees WJ, Kempsell KE, Lane WS, Duncan K, Walsh CT: Characterization of a Cys115 to Asp substitution in the Escherichia coli cell wall biosynthetic enzyme UDP-GlcNAc enolpyruvyl transferase (MurA) that confers resistance to inactivation by the antibiotic fosfomycin. Biochemistry. 1996 Apr 16;35(15):4923-8. [Article]
- Eschenburg S, Priestman M, Schonbrunn E: Evidence that the fosfomycin target Cys115 in UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is essential for product release. J Biol Chem. 2005 Feb 4;280(5):3757-63. Epub 2004 Nov 5. [Article]
- McCoy AJ, Sandlin RC, Maurelli AT: In vitro and in vivo functional activity of Chlamydia MurA, a UDP-N-acetylglucosamine enolpyruvyl transferase involved in peptidoglycan synthesis and fosfomycin resistance. J Bacteriol. 2003 Feb;185(4):1218-28. [Article]
- Brown ED, Vivas EI, Walsh CT, Kolter R: MurA (MurZ), the enzyme that catalyzes the first committed step in peptidoglycan biosynthesis, is essential in Escherichia coli. J Bacteriol. 1995 Jul;177(14):4194-7. [Article]
- Samland AK, Amrhein N, Macheroux P: Lysine 22 in UDP-N-acetylglucosamine enolpyruvyl transferase from Enterobacter cloacae is crucial for enzymatic activity and the formation of covalent adducts with the substrate phosphoenolpyruvate and the antibiotic fosfomycin. Biochemistry. 1999 Oct 5;38(40):13162-9. [Article]
- Silver LL: Fosfomycin: Mechanism and Resistance. Cold Spring Harb Perspect Med. 2017 Feb 1;7(2). pii: cshperspect.a025262. doi: 10.1101/cshperspect.a025262. [Article]
Drug created on June 13, 2005 13:24 / Updated on September 19, 2021 19:53