Fidaxomicin

Fidaxomicin (trade names Dificid, Dificlir, and previously OPT-80 and PAR-101) is the first member of a 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 minimally absorbed into the bloodstream when taken orally, 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 flora. The maintenance of normal physiological conditions in the colon may reduce the probability of recurrence of Clostridium difficile infection.[5][6]

Fidaxomicin
Clinical data
Trade namesDificid, Dificlir
Other namesClostomicin B1, lipiarmicin, lipiarmycin, lipiarmycin A3, OPT 80, PAR 01, PAR 101, tiacumicin B
License data
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    BioavailabilityMinimal systemic absorption[1]
    Elimination half-life11.7 ± 4.80 hours[1]
    ExcretionUrine (<1%), faeces (92%)[1]
    Identifiers
    CAS Number
    PubChem CID
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.220.590
    Chemical and physical data
    FormulaC52H74Cl2O18
    Molar mass1058.04 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    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, and can develop into Clostridium difficile colitis and pseudomembranous colitis.

    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 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.[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.[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 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.[12]

    Fidaxomicin was shown to be as good as the standard-of-care, vancomycin, for treating Clostridium difficile infection 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.

    Based on a multicenter clinical trial studi, fidaxomicin was reported well tolerated in children with Clostridium difficile–associated diarrhea and has a pharmacokinetic profile in children similar to that in adults.[14]

    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.[15]

    Approvals and indications

    On April 5, 2011, the drug won an FDA advisory panel's unanimous approval for the treatment of Clostridium difficile infection,[16] and gained full FDA approval on May 27, 2011.[17]

    References
    1. "Dificid" (PDF). TGA eBusiness Services. Specialised Therapeutics Australia Pty Ltd. 23 April 2013. Retrieved 31 March 2014.
    2. Revill, P.; Serradell, N.; Bolós, J. (2006). "Tiacumicin B". Drugs of the Future. 31 (6): 494. doi:10.1358/dof.2006.031.06.1000709.
    3. "Dificid, Full Prescribing Information" (PDF). Optimer Pharmaceuticals. 2013. Archived from the original (PDF) on 2011-06-26.
    4. "Fidaxomicin". Drugs in R&D. 10 (1): 37–45. 2012. doi:10.2165/11537730-000000000-00000. PMC 3585687. PMID 20509714.
    5. 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.
    6. 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.
    7. "Digital Medicines Information Suite". MedicinesComplete.
    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. "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.
    10. "Optimer Pharmaceuticals Presents Results From Fidaxomicin Phase 3 Study for the Treatment" (Press release). Optimer Pharmaceuticals. May 17, 2009. Retrieved May 7, 2013.
    11. 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.
    12. 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.
    13. 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.
    14. 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.
    15. 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.
    16. Peterson, Molly (Apr 5, 2011). "Optimer wins FDA panel's backing for antibiotic fidaxomicin". Bloomberg.
    17. Nordqvist, Christian (27 May 2011). "Dificid (fidaxomicin) approved for Clostridium difficile-associated diarrhea". Medical News Today.
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