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
Thumb
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

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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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

TargetActionsOrganism
ARNA polymerase sigma factor
inhibitor
Clostridium 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
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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
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
AcenocoumarolThe risk or severity of bleeding can be increased when Fidaxomicin is combined with Acenocoumarol.
BCG vaccineThe therapeutic efficacy of BCG vaccine can be decreased when used in combination with Fidaxomicin.
DicoumarolThe risk or severity of bleeding can be increased when Fidaxomicin is combined with Dicoumarol.
EstetrolThe therapeutic efficacy of Estetrol can be decreased when used in combination with Fidaxomicin.
FluindioneThe risk or severity of bleeding can be increased when Fidaxomicin is combined with Fluindione.
LactuloseThe therapeutic efficacy of Lactulose can be decreased when used in combination with Fidaxomicin.
PhenindioneThe risk or severity of bleeding can be increased when Fidaxomicin is combined with Phenindione.
PhenprocoumonThe risk or severity of bleeding can be increased when Fidaxomicin is combined with Phenprocoumon.
Picosulfuric acidThe therapeutic efficacy of Picosulfuric acid can be decreased when used in combination with Fidaxomicin.
Typhoid vaccineThe therapeutic efficacy of Typhoid vaccine can be decreased when used in combination with Fidaxomicin.
Interactions
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Food Interactions
  • Take with or without food. High-fat meal decreases the Cmax of fidaxomicin and its metabolite in a clinically insignificant way.

Products

Products
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
DificidTablet, film coated200 mg/1OralAvera McKennan Hospital2015-04-172017-05-24US flag
DificidGranule, for suspension200 mg/5mLOralMerck Sharp & Dohme Corp.2020-02-18Not applicableUS flag
DificidTablet200 mgOralMerck Ltd.2012-06-21Not applicableCanada flag
DificidTablet, film coated200 mg/1OralMerck Sharp & Dohme Corp.2011-05-27Not applicableUS flag
DificlirTablet, film coated200 mgOralTillotts Pharma Gmb H2016-09-08Not applicableEU flag
DificlirGranule40 mg/mlOralTillotts Pharma Gmb H2020-12-16Not applicableEU flag
DificlirTablet, film coated200 mgOralTillotts Pharma Gmb H2016-09-08Not applicableEU flag
DificlirTablet, film coated200 mgOralTillotts Pharma Gmb H2016-09-08Not applicableEU flag
DificlirTablet, film coated200 mgOralTillotts Pharma Gmb H2016-09-08Not applicableEU flag

Categories

ATC Codes
A07AA12 — Fidaxomicin
Drug Categories
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
  1. 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]
  2. 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]
  3. 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]
  4. 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]
  5. 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]
  6. 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]
  7. 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]
  8. 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]
  9. 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]
  10. FDA Approved Drug Products: DIFICID (fidaxomicin) tablets, for oral use [Link]
  11. Santa Cruz Biotechnology, Inc.: Fidaxomicin Safety Data Sheet [Link]
KEGG Drug
D09394
PubChem Compound
70678896
PubChem Substance
175427128
ChemSpider
8209640
RxNav
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
FDA label
Download (207 KB)
MSDS
Download (143 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentClostridium Difficile1
4CompletedTreatmentClostridium Difficile (C. Difficile) / Diarrhoea / Enterocolitis1
4CompletedTreatmentClostridium Difficile Infection (CDI)2
4CompletedTreatmentClostridium Difficile Infection (CDI) / Inflammatory Bowel Diseases (IBD)1
4RecruitingTreatmentClostridium / Clostridium Difficile (C. Difficile) / Coronavirus Disease 2019 (COVID‑19) / Fidaxomicin / Vancomycin1
4TerminatedTreatmentClostridium Difficile1
4TerminatedTreatmentClostridium Difficile / Spinal Cord Injuries (SCI)1
4WithdrawnPreventionClostridium Difficile Infection (CDI)1
4WithdrawnTreatmentClostridium Difficile Infection (CDI) / Solid Organ Transplant1
3CompletedPreventionClostridium Difficile Associated Diarrhea (CDAD)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Granule, for suspensionOral200 mg/5mL
TabletOral200 mg
Tablet, film coatedOral200 mg/1
GranuleOral
GranuleOral40 mg/ml
Tablet, film coatedOral
Tablet, film coatedOral200 mg
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8859510Yes2014-10-142028-01-31US flag
US7906489Yes2011-03-152027-09-04US flag
US7378508Yes2008-05-272028-01-31US flag
US7863249Yes2011-01-042028-01-31US flag
US8586551Yes2013-11-192024-01-15US flag
US9808530Yes2017-11-072034-11-28US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)1046.4MSDS (Santa Cruz Biotechnology)
Predicted Properties
PropertyValueSource
Water Solubility0.0125 mg/mLALOGPS
logP5.59ALOGPS
logP8.56ChemAxon
logS-4.9ALOGPS
pKa (Strongest Acidic)5.87ChemAxon
pKa (Strongest Basic)-1.4ChemAxon
Physiological Charge-1ChemAxon
Hydrogen Acceptor Count15ChemAxon
Hydrogen Donor Count7ChemAxon
Polar Surface Area266.66 Å2ChemAxon
Rotatable Bond Count15ChemAxon
Refractivity269.66 m3·mol-1ChemAxon
Polarizability109.15 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.6628
Blood Brain Barrier-0.8559
Caco-2 permeable-0.6641
P-glycoprotein substrateSubstrate0.8975
P-glycoprotein inhibitor INon-inhibitor0.5357
P-glycoprotein inhibitor IINon-inhibitor0.902
Renal organic cation transporterNon-inhibitor0.9112
CYP450 2C9 substrateNon-substrate0.8485
CYP450 2D6 substrateNon-substrate0.8756
CYP450 3A4 substrateSubstrate0.6796
CYP450 1A2 substrateNon-inhibitor0.7059
CYP450 2C9 inhibitorNon-inhibitor0.6775
CYP450 2D6 inhibitorNon-inhibitor0.8859
CYP450 2C19 inhibitorNon-inhibitor0.6826
CYP450 3A4 inhibitorNon-inhibitor0.899
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7301
Ames testNon AMES toxic0.7118
CarcinogenicityNon-carcinogens0.928
BiodegradationNot ready biodegradable0.9721
Rat acute toxicity2.6789 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9875
hERG inhibition (predictor II)Non-inhibitor0.7335
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets
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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
  1. 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]
  2. 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]
  3. 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
  1. 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
  1. 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]
  2. FDA Approved Drug Products: DIFICID (fidaxomicin) tablets, for oral use [Link]

Drug created on May 12, 2013 22:32 / Updated on July 29, 2021 06:27