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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

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

TargetActionsOrganism
AUDP-N-acetylglucosamine 1-carboxyvinyltransferase
inhibitor
Escherichia 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
Adverseeffects
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Toxicity

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.
DrugInteraction
AbacavirFosfomycin may decrease the excretion rate of Abacavir which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Fosfomycin which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Fosfomycin which could result in a higher serum level.
AcenocoumarolThe risk or severity of bleeding can be increased when Fosfomycin is combined with Acenocoumarol.
AcetaminophenAcetaminophen may decrease the excretion rate of Fosfomycin which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Fosfomycin which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Fosfomycin which could result in a higher serum level.
AclidiniumFosfomycin may decrease the excretion rate of Aclidinium which could result in a higher serum level.
AcrivastineFosfomycin may decrease the excretion rate of Acrivastine which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Fosfomycin which could result in a higher serum level.
Interactions
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Food Interactions
  • Take with or without food. The absorption is unaffected by food.

Products

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Product Ingredients
IngredientUNIICASInChI Key
Fosfomycin calcium monohydrateT330QG2NYS26469-67-0MSHCINMVQZDXTG-JSTPYPERSA-N
Fosfomycin sodium97MMO19FNO26016-99-9QZIQJIKUVJMTDG-JSTPYPERSA-L
Fosfomycin tromethamine7FXW6U30GY78964-85-9QZJIMDIBFFHQDW-LMLSDSMGSA-N
International/Other Brands
Veramina (Roux-Ocefa)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Fosfomycin Powder for Oral SolutionPowder, for solution3 g / sachetOralEndo Ventures LtdNot applicableNot applicableCanada flag
IvozfoPowder, for solution2 g / vialIntravenousVerity Pharmaceuticals Inc.Not applicableNot applicableCanada flag
IvozfoPowder, for solution8 g / vialIntravenousVerity Pharmaceuticals Inc.Not applicableNot applicableCanada flag
IvozfoPowder, for solution4 g / vialIntravenousVerity Pharmaceuticals Inc.2020-02-12Not applicableCanada flag
MonurolPowder, for solution3 g / sachetOralPaladin Labs Inc1999-09-15Not applicableCanada flag
MonurolPowder3 g/1OralAllergan, Inc.1996-12-19Not applicableUS flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Fosfomycin TromethaminePowder3 g/1OralZambon USA, Ltd2021-08-25Not applicableUS flag
Fosfomycin TromethaminePowder3 g/1OralA-S Medication Solutions2020-10-06Not applicableUS flag
Fosfomycin TromethaminePowder3 g/1OralXiromed Llc2020-10-06Not applicableUS flag
Fosfomycin TromethamineGranule, for solution3 g/1OralAscend Laboratories, LLC2021-10-22Not applicableUS flag
Jamp-fosfomycinPowder, for solution3 g / sachetOralJamp Pharma Corporation2018-08-02Not applicableCanada flag

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
  1. 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]
  2. Rodriguez-Gascon A, Canut-Blasco A: Deciphering pharmacokinetics and pharmacodynamics of fosfomycin. Rev Esp Quimioter. 2019 May;32 Suppl 1:19-24. [Article]
  3. 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]
  4. Segal AW: How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197-223. doi: 10.1146/annurev.immunol.23.021704.115653. [Article]
  5. Diez-Aguilar M, Canton R: New microbiological aspects of fosfomycin. Rev Esp Quimioter. 2019 May;32 Suppl 1:8-18. [Article]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. FDA Approved Drug Products: Monurol (fosfomycin tromethamine) [Link]
Human Metabolome Database
HMDB0014966
KEGG Drug
D04253
KEGG Compound
C06454
PubChem Compound
446987
PubChem Substance
46506665
ChemSpider
394204
BindingDB
50024894
RxNav
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
PhaseStatusPurposeConditionsCount
4Active Not RecruitingPreventionComplications / Infection / Prostate Cancer1
4CompletedPreventionAllograft Rejection / Asymptomatic Bacteriuria / Hospitalizations / Microbiologic Resistance / Urinary Tract Infection1
4CompletedPreventionAsymptomatic Bacteriuria / Urinary Tract Infection1
4CompletedPreventionUrinary Tract Infection1
4CompletedTreatmentInfective Endocarditis (IE)1
4CompletedTreatmentUrinary Tract Infection2
4Not Yet RecruitingTreatmentUrinary Tract Infection1
4RecruitingTreatmentProsthetic Joint Infections1
4TerminatedTreatmentUrinary Tract Infection1
4Unknown StatusTreatmentCystitis / Urinary Tract Infection1

Pharmacoeconomics

Manufacturers
  • Zambon spa italy
Packagers
  • Forest Pharmaceuticals
  • Zambon Ltd.
Dosage Forms
FormRouteStrength
Powder, for solutionOral
Injection, powder, for solutionIntravenous4 g
Injection, powder, for solutionParenteral40 mg/ml
Tablet, effervescent
Capsule
Tablet
Injection, powder, for solutionIntravenous8 g
Injection, powder, for solutionParenteral4 g
Injection, powder, for solutionParenteral8 g
Granule, for solutionOral
Injection, powder, for solution
Granule, for solutionOral3 g/1
Injection, powder, lyophilized, for solutionIntravenous
PowderOral1 g
Powder, for suspensionOral3 g
Powder, for solutionParenteral40 MG/ML
Powder, for solutionIntravenous2 g / vial
Powder, for solutionIntravenous4 g / vial
Powder, for solutionIntravenous8 g / vial
Granule, for solutionOral2 G
Granule, for solutionOral3 G
GranuleOral
PowderOral3 g/1
Powder, for solutionOral3 g / sachet
Granule, for suspensionOral3 g
Capsule, coatedOral500 mg
Powder, for solutionOral3 g
PowderOral
Injection, powder, for solutionIntravenous1 g
PowderOral2 g
GranuleOral3 g
Prices
Unit descriptionCostUnit
Monurol 3 gm Packets50.87USD packet
Monurol 3 gm sachet47.07USD each
Viramune 200 mg tablet9.48USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)94 °CPhysProp
water solubility50 mg/mL (Sodium salt)Not Available
logP-1.6Not Available
Predicted Properties
PropertyValueSource
Water Solubility46.9 mg/mLALOGPS
logP-0.86ALOGPS
logP-0.74ChemAxon
logS-0.47ALOGPS
pKa (Strongest Acidic)1.25ChemAxon
pKa (Strongest Basic)-4.3ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area70.06 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity25.87 m3·mol-1ChemAxon
Polarizability10.8 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.5
Blood Brain Barrier+0.9382
Caco-2 permeable-0.6652
P-glycoprotein substrateNon-substrate0.7234
P-glycoprotein inhibitor INon-inhibitor0.8938
P-glycoprotein inhibitor IINon-inhibitor0.9878
Renal organic cation transporterNon-inhibitor0.9505
CYP450 2C9 substrateNon-substrate0.7514
CYP450 2D6 substrateNon-substrate0.8332
CYP450 3A4 substrateNon-substrate0.6513
CYP450 1A2 substrateNon-inhibitor0.8492
CYP450 2C9 inhibitorNon-inhibitor0.8551
CYP450 2D6 inhibitorNon-inhibitor0.9202
CYP450 2C19 inhibitorNon-inhibitor0.8016
CYP450 3A4 inhibitorNon-inhibitor0.9624
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.944
Ames testNon AMES toxic0.6575
CarcinogenicityNon-carcinogens0.6059
BiodegradationNot ready biodegradable0.894
Rat acute toxicity2.5802 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9456
hERG inhibition (predictor II)Non-inhibitor0.9491
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
GC-MS Spectrum - GC-MS (2 TMS)GC-MSsplash10-03di-2980000000-005d5b96a1e9219362d0
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - GC-MSGC-MSsplash10-03di-2980000000-005d5b96a1e9219362d0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Targets

Drugtargets2
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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
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [Article]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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 at June 13, 2005 13:24 / Updated at November 28, 2021 11:56