Fidaxomicin
Identification
- Summary
Fidaxomicin is a macrolide antibiotic used to treat diarrhea associated with Clostridium difficile infection.
- Brand Names
- Dificid
- Generic Name
- Fidaxomicin
- DrugBank Accession Number
- DB08874
- Background
Fidaxomicin is a novel macrolide antibiotic used in the treatment of diarrhea caused by Clostridioides (formerly Clostridium) difficile in adult and pediatric patients over the age of 6 months.10 Fidaxomicin is a naturally-occurring 18-member macrocycle derived from fermentation.8 Because fidaxomicin contains an 18-membered lactone ring in its structure, it is referred to as a macrocyclic lactone antibiotic drug.6 The antibacterial activity of fidaxomicin is distinct from macrolides and rifamycins, as the bactericidal activity is time-dependent, and not concentration-dependent.6 Fidaxomicin was the first macrocyclic lactone antibiotic with activity against C. difficile,4 and it displays a narrow spectrum of activity against gram-positive anaerobes.2 It mediates its potent bactericidal action on the bacteria by inhibiting the bacterial RNA synthase, thereby disrupting bacterial transcription.4 The minimum inhibitory concentration (MIC90) for fidaxomicin is four times less than that of vancomycin, which was the primary drug of choice for C. difficile infection before the approval of fidaxomicin.6 Unlike vancomycin, however, fidaxomicin has a negligible effect on normal colonic microflora.7
The FDA initially approved fidaxomicin in May 2011 for the treatment of C. difficile-associated diarrhea in adult patients over the age of 18.6 Later that year in December, the drug was also approved by the European Medicine Agency.6 In June 2012, fidaxomicin was also granted approval by Health Canada.4 The approved indication of fidaxomicin was expanded by the FDA in January 2020 to include pediatric patients over the age of 6 months in the treatment population.10
- Type
- Small Molecule
- Groups
- Approved
- Structure
- Weight
- Average: 1058.05
Monoisotopic: 1056.4252209 - Chemical Formula
- C52H74Cl2O18
- Synonyms
- Difimicin
- Fidaxomicin
- Fidaxomicina
- Lipiarmicin
- Lipiarmycin
- Lipiarrmycin
- Tiacumicin B
- External IDs
- OPT 80
- OPT-80
- PAR 01
- PAR 101
- PAR-101
Pharmacology
- Indication
Fidaxomicin is indicated for the treatment of Clostridioides (formerly Clostridium) difficile-associated diarrhea in adult and pediatric patients 6 months of age and older.10
Fidaxomicin should only be used in patients with proven or strongly suspected C. difficile infection to reduce the risk of development of drug-resistant bacteria and maximize the therapeutic effectiveness of fidaxomicin and other antimicrobial agents.10
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Clostridium difficile-associated diarrhea (cdad) •••••••••••• •••• •••••• •• •• ••••• •••• •• •••••••• ••••••• •••••• Treatment of Clostridium difficile-associated diarrhea (cdad) •••••••••••• •••••• ••••••••• •••••• - Contraindications & Blackbox Warnings
- Prevent Adverse Drug Events TodayTap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.Avoid life-threatening adverse drug events with our Clinical API
- Pharmacodynamics
Fidaxomicin has a narrow-spectrum antibacterial profile, with potent bactericidal activity specifically against C. difficile.5 The minimum inhibitory concentration for 90% of organisms for fidaxomicin against C. difficile ranged from 0.0078 to 2 μg/mL in vitro.2 The bactericidal activity of fidaxomicin is time-dependent.6 Other than C. difficile, fidaxomicin has moderate inhibitory activity against Gram-positive bacteria (S. aureus and Enterococcus spp.) 5 and poor activity against normal colonic flora, including anaerobes and enteric Gram-negative bacilli.4 Isolates of C. difficile that are resistant to rifamycins or other antimicrobial classes (such as cephalosporins, fluoroquinolones, clindamycin) were not shown to be cross-resistant to fidaxomicin.4
- Mechanism of action
Clostridium difficile is a Gram-positive bacterium that causes various gastrointestinal complications, such as antibiotic-associated diarrhea. C. difficile infection can be caused by antibiotic therapy, resulting in the disruption of the human gut flora leads to an overgrowth of C. difficile. The consequences of C. difficile infection can be mild to severe and sometimes fatal.6
Fidaxomicin gets hydrolyzed to its active metabolite, OP-1118, upon oral administration. Both compounds mediate a bactericidal activity against C. difficile by inhibiting bacterial RNA polymerase at the initiation phase of the transcription cycle.4 The RNA polymerase is an essential bacterial enzyme that regulates gene expression, catalyzes nucleic acid interactions, and promotes several bacterial enzymatic reactions critical for bacterial survival.4 The core RNA polymerase is composed of a complex of different subunits and contains the active site.9 To initiate bacterial transcription, the active site of the core RNA polymerase binds to a promoter-specificity σ initiation factor, which locates and binds to a promoter region of the DNA. The DNA-RNA polymerase interaction promotes subsequent steps of transcription, which involves the separation of DNA strands.1 Fidaxomicin binds to the DNA template-RNA polymerase complex, thereby preventing the initial separation of DNA strands during transcription and inhibiting messenger RNA synthesis.4 The narrow spectrum of antimicrobial activity of fidaxomicin may be explained by the unique target site of fidaxomicin and differing σ subunits of the core structure of RNA polymerase among bacterial species.4
Target Actions Organism ARNA polymerase sigma factor inhibitorClostridium difficile (strain 630) - Absorption
Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the Cmax of fidaxomicin and its main metabolite OP-1118 were 5.20 ± 2.81 ng/mL and 12.0 ± 6.06, respectively. The median Tmax of fidaxomicin was 2 hours. The systemic absorption of fidaxomicin following oral administration is minimal.10
In a food-effect study involving healthy adults in either with a high-fat meal versus under fasting conditions, the Cmax of fidaxomicin and OP-1118 were decreased by 21.5% and 33.4%, respectively; however, this effect is deemed to be clinically insignificant as the therapeutic action of fidaxomicin does not depend on drug concentrations in the systemic circulation.10
- Volume of distribution
Fidaxomicin is mainly confined to the gastrointestinal tract when orally administered.10 There is limited information on the volume of distribution of fidaxomicin.
- Protein binding
Since fidaxomicin has minimal systemic absorption following oral administration, there is limited information on the plasma protein binding profile of fidoxamicin.
- Metabolism
Following oral administration, fidaxomicin is transformed to its main and pharmacologically active metabolite, OP-1118, via hydrolysis at the isobutyryl ester. As cytochrome enzymes are not involved in the metabolism of fidaxomicin, it is speculated that this biotransformation is mediated by gastric acid or enzymatic activity of intestinal microsomes.6,10
Hover over products below to view reaction partners
- Route of elimination
Following oral administration, fidaxomicin is mainly excreted in feces. More than 92% of the dose was recovered in the faces as either the unchanged parent drug or metabolites in one study consisting of healthy adults receiving single doses of 200 mg and 300 mg of fidaxomicin. In another study of healthy adults, approximately 0.59% fo the oral dose (200 mg) administered was recovered in the urine as the main metabolite, OP-1118.10
- Half-life
Following oral administration of a single dose of 200 mg fidaxomicin in healthy adults, the elimination half-life of fidaxomicin was approximately 11.7 ± 4.80 hours.10
- Clearance
There is limited information on the clearance of fidaxomicin.
- Adverse Effects
- Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.
- Toxicity
In rats, the LD50 of fidaxomicin was approximately 200 mg/kg and the no observed adverse effect level (NOAEL) was determined to be 62.5 mg/kg following administration of a single intravenous dose.5
There is limited clinical data on acute overdose in humans.10
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- 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 softwareAcenocoumarol The risk or severity of bleeding can be increased when Fidaxomicin is combined with Acenocoumarol. Ambroxol The risk or severity of methemoglobinemia can be increased when Fidaxomicin is combined with Ambroxol. Articaine The risk or severity of methemoglobinemia can be increased when Fidaxomicin is combined with Articaine. BCG vaccine The therapeutic efficacy of BCG vaccine can be decreased when used in combination with Fidaxomicin. Benzocaine The risk or severity of methemoglobinemia can be increased when Fidaxomicin is combined with Benzocaine. - Food Interactions
- Take with or without food. High-fat meal decreases the Cmax of fidaxomicin and its metabolite in a clinically insignificant way.
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.
- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Dificid Tablet 200 mg Oral Merck Ltd. 2012-06-21 Not applicable Canada Dificid Tablet, film coated 200 mg/1 Oral Merck Sharp & Dohme Llc 2011-05-27 Not applicable US Dificid Tablet, film coated 200 mg/1 Oral Avera McKennan Hospital 2015-04-17 2017-05-24 US Dificid Granule, for suspension 200 mg/5mL Oral Merck Sharp & Dohme Llc 2020-02-18 Not applicable US Dificlir Tablet, film coated 200 mg Oral Tillotts Pharma Gmb H 2016-09-08 Not applicable EU
Categories
- ATC Codes
- A07AA12 — Fidaxomicin
- Drug Categories
- Alimentary Tract and Metabolism
- Anti-Bacterial Agents
- Anti-Infective Agents
- Antidiarrheals, Intestinal Antiinflammatory/antiinfective Agents
- Carbohydrates
- Cytochrome P-450 CYP3A Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors
- Cytochrome P-450 CYP3A4 Inhibitors (strength unknown)
- Cytochrome P-450 Enzyme Inhibitors
- Intestinal Antiinfectives
- Lactones
- Macrolide Antibacterial
- Macrolides
- Other Macrolides
- P-glycoprotein substrates
- Polyketides
- Classification
- Not classified
- Affected organisms
- Gram-positive Bacteria
- Peptoclostridium difficile
Chemical Identifiers
- UNII
- Z5N076G8YQ
- CAS number
- 873857-62-6
- InChI Key
- ZVGNESXIJDCBKN-UUEYKCAUSA-N
- InChI
- InChI=1S/C52H74Cl2O18/c1-13-30-22-26(6)33(56)18-16-15-17-31(23-66-51-45(65-12)42(61)44(29(9)67-51)69-49(64)35-32(14-2)36(53)39(58)37(54)38(35)57)48(63)68-34(28(8)55)20-19-25(5)21-27(7)43(30)70-50-41(60)40(59)46(52(10,11)72-50)71-47(62)24(3)4/h15-17,19,21-22,24,28-30,33-34,40-46,50-51,55-61H,13-14,18,20,23H2,1-12H3/b16-15+,25-19+,26-22+,27-21+,31-17+/t28-,29-,30+,33+,34+,40-,41+,42+,43+,44-,45+,46+,50-,51-/m1/s1
- IUPAC Name
- (2R,3S,4S,5S,6R)-6-{[(3E,5E,8S,9E,11S,12R,13E,15E,18S)-12-{[(2R,3S,4R,5S)-3,4-dihydroxy-6,6-dimethyl-5-[(2-methylpropanoyl)oxy]oxan-2-yl]oxy}-11-ethyl-8-hydroxy-18-[(1R)-1-hydroxyethyl]-9,13,15-trimethyl-2-oxo-1-oxacyclooctadeca-3,5,9,13,15-pentaen-3-yl]methoxy}-4-hydroxy-5-methoxy-2-methyloxan-3-yl 3,5-dichloro-2-ethyl-4,6-dihydroxybenzoate
- SMILES
- [H][C@@]1(O[C@@H]2[C@@H](CC)\C=C(C)\[C@@H](O)C\C=C\C=C(CO[C@@H]3O[C@H](C)[C@@H](OC(=O)C4=C(CC)C(Cl)=C(O)C(Cl)=C4O)[C@H](O)[C@@H]3OC)\C(=O)O[C@@H](C\C=C(/C)\C=C2/C)[C@@H](C)O)OC(C)(C)[C@@H](OC(=O)C(C)C)[C@H](O)[C@@H]1O
References
- Synthesis Reference
Youe-Kong Shue, Chi-Jen Frank Du, Ming-Hsi Chiou, Mei-Chiao Wu, Yuan-Ting Chen, Franklin W. Okumu, Jonathan James Duffield, "Medium for the Production of Tiacumicin B." U.S. Patent US20100028970, issued February 04, 2010.
US20100028970- General References
- Artsimovitch I, Seddon J, Sears P: Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis. Clin Infect Dis. 2012 Aug;55 Suppl 2:S127-31. doi: 10.1093/cid/cis358. [Article]
- Crawford T, Huesgen E, Danziger L: Fidaxomicin: a novel macrocyclic antibiotic for the treatment of Clostridium difficile infection. Am J Health Syst Pharm. 2012 Jun 1;69(11):933-43. doi: 10.2146/ajhp110371. [Article]
- Authors unspecified: Fidaxomicin: Difimicin; Lipiarmycin; OPT 80; OPT-80; PAR 101; PAR-101. Drugs R D. 2010;10(1):37-45. doi: 10.2165/11537730-000000000-00000. [Article]
- Zhanel GG, Walkty AJ, Karlowsky JA: Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. Can J Infect Dis Med Microbiol. 2015 Nov-Dec;26(6):305-12. doi: 10.1155/2015/934594. [Article]
- Weiss K, Allgren RL, Sellers S: Safety analysis of fidaxomicin in comparison with oral vancomycin for Clostridium difficile infections. Clin Infect Dis. 2012 Aug;55 Suppl 2:S110-5. doi: 10.1093/cid/cis390. [Article]
- Vaishnavi C: Fidaxomicin--the new drug for Clostridium difficile infection. Indian J Med Res. 2015 Apr;141(4):398-407. doi: 10.4103/0971-5916.159251. [Article]
- Louie TJ, Cannon K, Byrne B, Emery J, Ward L, Eyben M, Krulicki W: Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012 Aug;55 Suppl 2:S132-42. doi: 10.1093/cid/cis338. [Article]
- Shue YK, Sears PS, Shangle S, Walsh RB, Lee C, Gorbach SL, Okumu F, Preston RA: Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother. 2008 Apr;52(4):1391-5. doi: 10.1128/AAC.01045-07. Epub 2008 Feb 11. [Article]
- Mariani R, Maffioli SI: Bacterial RNA polymerase inhibitors: an organized overview of their structure, derivatives, biological activity and current clinical development status. Curr Med Chem. 2009;16(4):430-54. doi: 10.2174/092986709787315559. [Article]
- FDA Approved Drug Products: DIFICID (fidaxomicin) tablets, for oral use [Link]
- Santa Cruz Biotechnology, Inc.: Fidaxomicin Safety Data Sheet [Link]
- External Links
- KEGG Drug
- D09394
- PubChem Compound
- 70678896
- PubChem Substance
- 175427128
- ChemSpider
- 8209640
- 1111103
- ChEBI
- 68590
- ChEMBL
- CHEMBL1255800
- PDBe Ligand
- FI8
- RxList
- RxList Drug Page
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Fidaxomicin
- PDB Entries
- 6bzo / 6c06 / 6fbv / 7l7b
- FDA label
- Download (207 KB)
- MSDS
- Download (143 KB)
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Phase Status Purpose Conditions Count 4 Completed Treatment Clostridium Difficile 1 4 Completed Treatment Clostridium Difficile (C. Difficile) / Diarrhea / Enterocolitis 1 4 Completed Treatment Clostridium Difficile Infection (CDI) 2 4 Completed Treatment Clostridium Difficile Infection (CDI) / Inflammatory Bowel Diseases (IBD) 1 4 Recruiting Treatment Clostridium / Clostridium Difficile (C. Difficile) / Coronavirus Disease 2019 (COVID‑19) / Fidaxomicin / Vancomycin 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Granule, for suspension Oral 200 mg/5mL Tablet Oral 200 mg Tablet Oral 200.000 mg Tablet, film coated Oral 200 mg/1 Granule Oral 40 MG/ML Tablet, film coated Oral 200 MG - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US8859510 Yes 2014-10-14 2028-01-31 US US7906489 Yes 2011-03-15 2027-09-04 US US7378508 Yes 2008-05-27 2028-01-31 US US7863249 Yes 2011-01-04 2028-01-31 US US8586551 Yes 2013-11-19 2024-01-15 US US9808530 Yes 2017-11-07 2034-11-28 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 1046.4 MSDS (Santa Cruz Biotechnology) - Predicted Properties
Property Value Source Water Solubility 0.0125 mg/mL ALOGPS logP 5.59 ALOGPS logP 8.56 Chemaxon logS -4.9 ALOGPS pKa (Strongest Acidic) 5.87 Chemaxon pKa (Strongest Basic) -1.4 Chemaxon Physiological Charge -1 Chemaxon Hydrogen Acceptor Count 15 Chemaxon Hydrogen Donor Count 7 Chemaxon Polar Surface Area 266.66 Å2 Chemaxon Rotatable Bond Count 15 Chemaxon Refractivity 269.66 m3·mol-1 Chemaxon Polarizability 109.15 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption - 0.6628 Blood Brain Barrier - 0.8559 Caco-2 permeable - 0.6641 P-glycoprotein substrate Substrate 0.8975 P-glycoprotein inhibitor I Non-inhibitor 0.5357 P-glycoprotein inhibitor II Non-inhibitor 0.902 Renal organic cation transporter Non-inhibitor 0.9112 CYP450 2C9 substrate Non-substrate 0.8485 CYP450 2D6 substrate Non-substrate 0.8756 CYP450 3A4 substrate Substrate 0.6796 CYP450 1A2 substrate Non-inhibitor 0.7059 CYP450 2C9 inhibitor Non-inhibitor 0.6775 CYP450 2D6 inhibitor Non-inhibitor 0.8859 CYP450 2C19 inhibitor Non-inhibitor 0.6826 CYP450 3A4 inhibitor Non-inhibitor 0.899 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7301 Ames test Non AMES toxic 0.7118 Carcinogenicity Non-carcinogens 0.928 Biodegradation Not ready biodegradable 0.9721 Rat acute toxicity 2.6789 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9875 hERG inhibition (predictor II) Non-inhibitor 0.7335
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
Targets
![](https://go.drugbank.com/assets/locked/DrugTargets2-682eb846d210ae4bf33ca03febccfb57bb1c61318e699b729e5df4dfab2c5b67.png)
- Kind
- Protein
- Organism
- Clostridium difficile (strain 630)
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General Function
- Transcription factor activity, sequence-specific dna binding
- Specific Function
- Sigma factors are initiation factors that promote the attachment of RNA polymerase to specific initiation sites and are then released.Sigma factors are initiation factors that promote the attachmen...
- Gene Name
- sigA1
- Uniprot ID
- Q18BX5
- Uniprot Name
- RNA polymerase sigma factor SigA
- Molecular Weight
- 44426.185 Da
References
- Venugopal AA, Johnson S: Fidaxomicin: a novel macrocyclic antibiotic approved for treatment of Clostridium difficile infection. Clin Infect Dis. 2012 Feb 15;54(4):568-74. doi: 10.1093/cid/cir830. Epub 2011 Dec 7. [Article]
- Zhanel GG, Walkty AJ, Karlowsky JA: Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. Can J Infect Dis Med Microbiol. 2015 Nov-Dec;26(6):305-12. doi: 10.1155/2015/934594. [Article]
- Artsimovitch I, Seddon J, Sears P: Fidaxomicin is an inhibitor of the initiation of bacterial RNA synthesis. Clin Infect Dis. 2012 Aug;55 Suppl 2:S127-31. doi: 10.1093/cid/cis358. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Spina E, Pisani F, Perucca E: Clinically significant pharmacokinetic drug interactions with carbamazepine. An update. Clin Pharmacokinet. 1996 Sep;31(3):198-214. doi: 10.2165/00003088-199631030-00004. [Article]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- Curator comments
- FDA label describes that fidaxomicin and its main metabolite, OP-1118, are substrates of the efflux transporter, P-glycoprotein (P-gp), which is expressed in the gastrointestinal tract.
- General Function
- Xenobiotic-transporting atpase activity
- Specific Function
- Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- Multidrug resistance protein 1
- Molecular Weight
- 141477.255 Da
References
Drug created at May 12, 2013 22:32 / Updated at February 20, 2024 23:54