Fidaxomicin, sold under the brand nameDificid among others, is the first member of a class of narrow spectrum macrocyclicantibiotic drugs called tiacumicins. It is a fermentation product obtained from the actinomycete Dactylosporangium aurantiacum subspecies hamdenesis. Fidaxomicin is minimally absorbed into the bloodstream when taken orally, is bactericidal, and selectively eradicates pathogenicClostridium 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. 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.
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. It has minimal systemic absorption and a narrow spectrum of activity; it is active against Gram positive bacteria, especially clostridia. The minimal inhibitory concentration range for C. difficile is 0.03–0.25 μg/mL.
Clinical trials
Good results were reported by the company in 2009, from a North AmericanPhase III clinical trial comparing it with oral vancomycin for the treatment of Clostridium difficile infection. The study met its primary endpoint of clinical cure, showing that fidaxomicin was non-inferior to oral vancomycin. 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. 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. Fidaxomicin was shown to be as good as the standard-of-care, vancomycin, for treating Clostridium difficile infection in a Phase IIIclinical trial published in February 2011. 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. 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.
Approvals and indications
On April 5, 2011, the drug won an FDA advisory panel's unanimous approval for the treatment of Clostridium difficile infection, and gained full FDA approval on May 27, 2011. As of January 2020, fidaxomicin is FDA-approved for use in children aged 6 months and older for C. difficile associated diarrhea.
