Fidaxomicin

Fidaxomicin
Names
Trade namesDificid, Dificlir
Other namesClostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT-80, PAR 01, PAR-101, tiacumicin B
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
Drug classMacrocyclic[1]
Main usesClostridioides difficile diarrhea[1]
Side effectsNausea, constipation[2]
Pregnancy
category
  • AU: B1
    Routes of
    use    		By mouth
    Typical dose200 mg BID[1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    Pharmacokinetics
    BioavailabilityMinimal systemic absorption[4]
    Elimination half-life11.7 ± 4.80 hours[4]
    ExcretionUrine (<1%), faeces (92%)[4]
    Chemical and physical data
    FormulaC52H74Cl2O18
    Molar mass1058.05 g·mol−1
    3D model (JSmol)
    SMILES
    • 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
    • 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

    Fidaxomicin, sold under the brand name Dificid among others, is an antibiotic used to treat Clostridioides difficile diarrhea.[1] Evidence for use in severe disease is limited and in such cases vancomycin is preferred.[1][5] It is taken by mouth.[1]

    Common side effects include nausea and constipation.[2] Other side effects may include gastrointestinal bleeding, abdominal pain, allergic reaction, and liver problems.[6] Safety in pregnancy and breastfeeding is unclear.[1] It is a macrocyclic which works by blocking bacterial RNA polymerase.[1][2]

    Fidaxomicin was approved for medical use in the United States and Europe in 2011.[5][2] In the United Kingdom a course of treatment costs the NHS about £1350 as of 2021.[1] In the United States this amount costs about 4,150 USD.[7] It is made from the actinomycete Dactylosporangium aurantiacum.[6]

    Medical uses

    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.

    It can be used for mild to moderate disease, though vancomycin may also be used and is preferred for severe disease.[5]

    Dosage

    Fidaxomicin is available in a 200 mg tablet that are taken every 12 hours for 10 days.[1] Though total duration of therapy may be determined by the persons symptoms.

    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.[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.[6]

    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.[9][10]

    Society and culture

    It is marketed by Merck, which acquired Cubist Pharmaceuticals in 2015, and had in turn bought the originating company, Optimer Pharmaceuticals.

    Approvals

    On April 5, 2011, the drug won an FDA advisory panel's unanimous approval for the treatment of Clostridium difficile infection,[11] and gained full FDA approval on May 27, 2011.[12] As of January 2020, fidaxomicin is FDA-approved for use in children aged 6 months and older for C. difficile associated diarrhea (CDAD).

    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.[13][14] 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).[15] 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.[16]

    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.[17] 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.[18]

    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.[19]

    References

    1. 1 2 3 4 5 6 7 8 9 10 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 607. ISBN 978-0857114105.
    2. 1 2 3 4 "Dificlir". Archived from the original on 28 January 2021. Retrieved 10 December 2021.
    3. ↑ "Dificlir EPAR". European Medicines Agency (EMA). Archived from the original on 28 January 2021. Retrieved 18 January 2021.
    4. 1 2 3 "Dificid" (PDF). TGA eBusiness Services. Specialised Therapeutics Australia Pty Ltd. 23 April 2013. Archived from the original on 19 January 2021. Retrieved 31 March 2014.
    5. 1 2 3 "Fidaxomicin Monograph for Professionals". Drugs.com. Archived from the original on 28 February 2020. Retrieved 10 December 2021.
    6. 1 2 3 "Dificid- fidaxomicin tablet, film coated Dificid- fidaxomicin granule, for suspension". DailyMed. 18 February 2020. Archived from the original on 7 August 2020. Retrieved 26 March 2020.
    7. ↑ "Fidaxomicin Prices, Coupons & Savings Tips - GoodRx". GoodRx. Archived from the original on 29 October 2016. Retrieved 10 December 2021.
    8. ↑ 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.
    9. ↑ 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.
    10. ↑ 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.
    11. ↑ Peterson, Molly (Apr 5, 2011). "Optimer wins FDA panel's backing for antibiotic fidaxomicin". Bloomberg. Archived from the original on 2014-07-28. Retrieved 2021-07-05.
    12. ↑ Nordqvist, Christian (27 May 2011). "Dificid (fidaxomicin) approved for Clostridium difficile-associated diarrhea". Medical News Today. Archived from the original on 13 November 2018. Retrieved 5 July 2021.
    13. ↑ "Optimer's North American phase 3 Fidaxomicin study results presented at the 49th ICAAC" (Press release). Optimer Pharmaceuticals. September 16, 2009. Archived from the original on September 27, 2012. Retrieved May 7, 2013.
    14. ↑ "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.
    15. ↑ 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.
    16. ↑ 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.
    17. ↑ 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.
    18. ↑ 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.
    19. ↑ 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.
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