Fidaxomicin

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Fidaxomicin
File:Fidaxomicin.svg
Systematic (IUPAC) name
3-(((6-Deoxy-4-O-(3,5-dichloro-2-ethyl-4,6-dihydroxybenzoyl)-2-O-methyl-β-D-mannopyranosyl)oxy)-methyl)-12(R)-[(6-deoxy-5-C-methyl-4-O-(2-methyl-1-oxopropyl)-β-D-lyxo-hexopyranosyl)oxy]-11(S)-ethyl-8(S)-hydroxy-18(S)-(1(R)-hydroxyethyl)-9,13,15-trimethyloxacyclooctadeca-3,5,9,13,15-pentaene-2-one
Clinical data
Trade names Dificid, Dificlir
Licence data US FDA:link
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability Minimal systemic absorption[1]
Biological half-life 11.7 ± 4.80 hours[1]
Excretion Urine (<1%), faeces (92%)[1]
Identifiers
CAS Number 873857-62-6 YesY
ATC code A07AA12 (WHO)
PubChem CID: 11528171
ChemSpider 8209640 N
UNII Z5N076G8YQ N
KEGG D09394 YesY
ChEBI CHEBI:68590 N
ChEMBL CHEMBL1255800 N
Synonyms Clostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
Chemical data
Formula C52H74Cl2O18
Molecular mass 1058.04 g/mol
  • CC[C@H]1/C=C(/[C@H](C/C=C/C=C(/C(=O)O[C@@H](C/C=C(/C=C(/[C@@H]1O[C@H]2[C@H]([C@H]([C@@H](C(O2)(C)C)OC(=O)C(C)C)O)O)\C)\C)[C@@H](C)O)\CO[C@H]3[C@H]([C@H]([C@@H]([C@H](O3)C)OC(=O)C4=C(C(=C(C(=C4O)Cl)O)Cl)CC)O)OC)O)\C
  • 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 N
  • Key:ZVGNESXIJDCBKN-UUEYKCAUSA-N N
 NYesY (what is this?)  (verify)

Fidaxomicin(trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first in a new class of narrow spectrum macrocyclic antibiotic drugs.[2] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.[3][4] Fidaxomicin is non-systemic, meaning it is minimally absorbed into the bloodstream, it is bactericidal, and it has demonstrated selective eradication of pathogenic Clostridium difficile with minimal disruption to the multiple species of bacteria that make up the normal, healthy intestinal flora. The maintenance of normal physiological conditions in the colon can reduce the probability of Clostridium difficile infection recurrence.[5] [6]

It is marketed by Cubist Pharmaceuticals after acquisition of its originating company Optimer Pharmaceuticals. The target use is for treatment of Clostridium difficile infection.

Fidaxomicin is available in a 200 mg tablet that is administered every 12 hours for a recommended duration of 10 days. Total duration of therapy should be determined by the patient's clinical status. It is currently one of the most expensive antibiotics approved for use. A standard course costs upwards of £1350.[7]

Mechanism

Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNAP polymerase. Switch motion is important for opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but especially during opening of double standed DNA during transcription initiation.[8] It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria especially clostridia. The minimal inhibitory concentration (MIC) range for C. difficile (ATCC 700057) is 0.03–0.25 μg/mL.[3]

Clinical trials

Good results were reported by the company in 2009 from a North American phase III trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection (CDI)[9][10] The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin (92.1% vs. 89.8%). In addition, the study met its secondary endpoint of recurrence: 13.3% of the subjects had a recurrence with fidaxomicin vs. 24.0% with oral vancomycin. The study also met its exploratory endpoint of global cure (77.7% for fidaxomicin vs. 67.1% for vancomycin).[11] Clinical cure was defined as patients requiring no further CDI therapy two days after completion of study medication. Global cure was defined as patients who were cured at the end of therapy and did not have a recurrence in the next four weeks.[12]

Fidaxomicin was shown to be as good as the current standard-of-care, vancomycin, for treating CDI in a Phase III trial published in February 2011.[13] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Approvals and indications

For the treatment of Clostridium difficile-associated diarrhea (CDAD), the drug won an FDA advisory panel's unanimous approval on April 5, 2011[14] and full FDA approval on May 27, 2011.[15]

References

  1. ↑ 1.0 1.1 1.2 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  7. ↑ http://www.medicinescomplete.com/mc/bnf/current/PHP18388-dificlir.htm#PHP18388-dificlir
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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