Fidaxomicin

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Fidaxomicin
Fidaxomicin.svg
Names
Trade namesDificid, Dificlir
Other namesClostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT-80, PAR 01, PAR-101, tiacumicin B
  • 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
Pregnancy
category
  • AU: B1
Routes of
use
By mouth
External links
AHFS/Drugs.comMonograph
US NLMFidaxomicin
Legal
License data
Legal status
Pharmacokinetics
BioavailabilityMinimal systemic absorption[2]
Elimination half-life11.7 ± 4.80 hours[2]
ExcretionUrine (<1%), faeces (92%)[2]
Chemical and physical data
FormulaC52H74Cl2O18
Molar mass1058.05 g·mol−1
3D model (JSmol)
  • 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
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Fidaxomicin, sold under the brand name Dificid among others, is an antibiotic.

It is a macrocyclic and tiacumicin.[3] It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis.[4][5]

A standard course costs upwards of £1350.[6]

Medical uses

Fidaxomicin is minimally absorbed into the bloodstream when taken by mouth, is bactericidal, and selectively eradicates pathogenic Clostridium difficile with relatively little disruption to the multiple species of bacteria that make up the normal, healthy intestinal microbiota. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridium difficile infection.[7][8]

It is marketed by Merck, which acquired Cubist Pharmaceuticals in 2015, and had in turn bought the originating company, Optimer Pharmaceuticals. It is used for the treatment of Clostridium difficile infection, which is also known as Clostridium difficile-associated diarrhea or Clostridium difficile-associated illness (CDI), and can develop into Clostridium difficile colitis and pseudomembranous colitis.

Dosage

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.

Mechanism

Fidaxomicin binds to and prevents movement of the "switch regions" of bacterial RNA polymerase. Switch motion occurs during the opening and closing of the DNA:RNA clamp, a process that occurs throughout RNA transcription but is especially important in the opening of double-stranded DNA during the initiation of transcription.[9] 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.[4]

Society and culture

Approvals

On April 5, 2011, the drug won an FDA advisory panel's unanimous approval for the treatment of Clostridium difficile infection,[10] and gained full FDA approval on May 27, 2011.[11] As of January 2020, fidaxomicin is FDA-approved for use in children aged 6 months and older for C. difficile associated diarrhea (CDAD).[citation needed]

Research

Good results were reported by the company in 2009, from a North American Phase III clinical trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection.[12][13] 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).[14] Clinical cure was defined as patients requiring no further therapy for the treatment of 'Clostridium difficile infection 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.[15]

Fidaxomicin was shown to be as good as the standard-of-care, vancomycin, for treating Clostridium difficile infection in a Phase III clinical trial published in February 2011.[16] The authors also reported significantly fewer recurrences of infection, a frequent problem with C. difficile, and similar drug side effects.

Based on a multicenter clinical trial, fidaxomicin was reported well tolerated in children with Clostridium difficile–associated diarrhea and has a pharmacokinetic profile in children similar to that in adults.[17]

Regarding the high budget to spend for fidaxomicin, a systematic literature review published in 2017, showed that fidaxomicin was demonstrated to be cost-effective versus metronidazole and vancomycin in patients with Clostridium difficile infection.[18]

References

  1. "Dificlir EPAR". European Medicines Agency (EMA). Retrieved 18 January 2021.
  2. 2.0 2.1 2.2 "Dificid" (PDF). TGA eBusiness Services. Specialised Therapeutics Australia Pty Ltd. 23 April 2013. Retrieved 31 March 2014.
  3. Revill, P.; Serradell, N.; Bolós, J. (2006). "Tiacumicin B". Drugs of the Future. 31 (6): 494. doi:10.1358/dof.2006.031.06.1000709.
  4. 4.0 4.1 "Dificid- fidaxomicin tablet, film coated Dificid- fidaxomicin granule, for suspension". DailyMed. 18 February 2020. Retrieved 26 March 2020.
  5. "Fidaxomicin". Drugs in R&D. 10 (1): 37–45. 2012. doi:10.2165/11537730-000000000-00000. PMC 3585687. PMID 20509714.
  6. "Digital Medicines Information Suite". MedicinesComplete.
  7. Louie, T. J.; Emery, J.; Krulicki, W.; Byrne, B.; Mah, M. (2008). "OPT-80 Eliminates Clostridium difficile and is Sparing of Bacteroides Species during Treatment of C. Difficile Infection". Antimicrobial Agents and Chemotherapy. 53 (1): 261–3. doi:10.1128/AAC.01443-07. PMC 2612159. PMID 18955523.
  8. Johnson, Stuart (2009). "Recurrent Clostridium difficile infection: A review of risk factors, treatments, and outcomes". Journal of Infection. 58 (6): 403–10. doi:10.1016/j.jinf.2009.03.010. PMID 19394704.
  9. Srivastava, Aashish; Talaue, Meliza; Liu, Shuang; Degen, David; Ebright, Richard Y; Sineva, Elena; Chakraborty, Anirban; Druzhinin, Sergey Y; Chatterjee, Sujoy; Mukhopadhyay, Jayanta; Ebright, Yon W; Zozula, Alex; Shen, Juan; Sengupta, Sonali; Niedfeldt, Rui Rong; Xin, Cai; Kaneko, Takushi; Irschik, Herbert; Jansen, Rolf; Donadio, Stefano; Connell, Nancy; Ebright, Richard H (2011). "New target for inhibition of bacterial RNA polymerase: 'switch region'". Current Opinion in Microbiology. 14 (5): 532–43. doi:10.1016/j.mib.2011.07.030. PMC 3196380. PMID 21862392.
  10. Peterson, Molly (Apr 5, 2011). "Optimer wins FDA panel's backing for antibiotic fidaxomicin". Bloomberg.
  11. Nordqvist, Christian (27 May 2011). "Dificid (fidaxomicin) approved for Clostridium difficile-associated diarrhea". Medical News Today.
  12. "Optimer's North American phase 3 Fidaxomicin study results presented at the 49th ICAAC" (Press release). Optimer Pharmaceuticals. September 16, 2009. Retrieved May 7, 2013.
  13. "Optimer Pharmaceuticals Presents Results From Fidaxomicin Phase 3 Study for the Treatment" (Press release). Optimer Pharmaceuticals. May 17, 2009. Archived from the original on November 14, 2012. Retrieved May 7, 2013.
  14. Golan Y, Mullane KM, Miller MA (September 12–15, 2009). Low recurrence rate among patients with C. difficile infection treated with fidaxomicin. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  15. Gorbach S, Weiss K, Sears P, et al. (September 12–15, 2009). Safety of fidaxomicin versus vancomycin in treatment of Clostridium difficile infection. 49th interscience conference on antimicrobial agents and chemotherapy. San Francisco.
  16. Louie, Thomas J.; Miller, Mark A.; Mullane, Kathleen M.; Weiss, Karl; Lentnek, Arnold; Golan, Yoav; Gorbach, Sherwood; Sears, Pamela; Shue, Youe-Kong; Opt-80-003 Clinical Study, Group (2011). "Fidaxomicin versus vancomycin for Clostridium difficile infection". New England Journal of Medicine. 364 (5): 422–31. doi:10.1056/NEJMoa0910812. PMID 21288078.
  17. O'Gorman, MA; Michaels, MG; Kaplan, SL; Otley, A; Kociolek, LK; Hoffenberg, EJ; Kim, KS; Nachman, S; Pfefferkorn, MD; Sentongo, T; Sullivan, JE; Sears, P (Aug 17, 2018). "Safety and Pharmacokinetic Study of Fidaxomicin in Children With Clostridium difficile-Associated Diarrhea: A Phase 2a Multicenter Clinical Trial". J Pediatric Infect Dis Soc. 7 (3): 210–218. doi:10.1093/jpids/pix037. PMID 28575523.
  18. Burton, HE; Mitchell, SA; Watt, M (Nov 2017). "A Systematic Literature Review of Economic Evaluations of Antibiotic Treatments for Clostridium difficile Infection". Pharmacoeconomics. 35 (11): 1123–1140. doi:10.1007/s40273-017-0540-2. PMC 5656734. PMID 28875314.

External links

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