Fidaxomicin is a macrolide antibiotic that treats diarrhea caused by Clostridium difficile infection. Learn how to take fidaxomicin, what precautions to follow, and what interactions to avoid.

Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection

Fidaxomicin is the first macrocyclic lactone antibiotic with activity versus C difficile. It inhibits RNA polymerase, therefore, preventing transcription. Fidaxomicin (and its active metabolite OP-1118) is bactericidal against C difficile and exhibits a prolonged postantibiotic effect (approximately 10 h). Other than for C difficile, it demonstrated only moderate inhibitory activity against Gram-positive bacteria and was a poor inhibitor of normal colonic flora, including anaerobes and enteric Gram-negative bacilli. After oral administration (200 mg two times per day for 10 days), fidaxomicin achieved low serum concentration levels but high fecal concentration levels (mean approximately 1400 μg/g stool). Phase 3 clinical trials involving adults with CDI demonstrated that 200 mg fidaxomicin twice daily for 10 days was noninferior to 125 mg oral vancomycin four times daily for 10 days in regard to clinical response at the end of therapy. Fidaxomicin was, however, reported to be superior to oral vancomycin in reducing recurrent CDI and achieving a sustained clinical response (assessed at day 28) for patients infected with non-BI/NAP1/027 strains. It was noninferior to oral vancomycin with regard to clinical response at the end of CDI therapy. Fidaxomicin has been demonstated to be as safe as oral vancomycin, but superior to vancomycin in achieving a sustained clinical response for CDI in patients infected with non-BI/NAP1/027 strains. Caution should be exercised in using fidaxomicin monotherapy for treatment of severe complicated CDI because limited data are available. Whether fidaxomicin is cost effective (due to its significantly higher acquisition cost versus oral vancomycin) depends on the acceptable willingness to pay threshold per quality-adjusted life year as a measure of assessing cost effectiveness.[1]

Two large, randomized, multicentre, double-blind phase 3 clinical trials examined the efficacy and safety of oral fidaxomicin versus oral vancomycin in adult patients with CDI. Study OPT-80-003 comprised 596 patients from the US and Canada, and study OPT-80-004 comprised 509 patients from the US, Europe and Canada. Patients with confirmed CDI who were ≥16 years of age and had no history or only one previous CDI episode in the past 90 days were eligible for inclusion. The presence of CDI was defined as diarrhea with >3 unformed stools 24 h before randomization and a positive toxin test for toxin A, B or both. Patients who were pregnant or breastfeeding, had previous fidaxomicin exposure, life-threatening or fulminant CDI, toxic megacolon, a history of ulcerative colitis or Crohn disease, or >1 CDI episode in the preceding three months were excluded. Patients were also excluded if they were presently taking other antibiotics for CDI, although they could have received up to four doses of oral vanco-mycin or oral metronidazole in the 24 h before randomization. The treatment outcomes for study OPT-80-003 and OPT-80-004 are summarized.In both clinical trials, oral fidaxomicin was noninferior to oral vancomycin for clinical response, with cure rates of approximately 87% in both treatment groups. Fidaxomicin demonstrated superiority to vancomycin for recurrence. The relative reduction in recurrence with fidaxomicin treatment was 39.1% and 52.8% in study OPT-80-003 and OPT-80-004, respectively. Fidaxomicin was also superior for sustained clinical response, demonstrating higher global cure rates compared with vancomycin in the two trials. In study OPT-80-003 (North America only), 38.1% of patients were infected with the BI/NAP1/027 strain. The lower CDI recurrence rate among patients treated with fidaxomicin relative to vancomycin was only observed for those infected with non-BI/NAP1/027 strains. Infection rates with the BI/NAP1/027 strain differed according to region in study OPT-80-004, with rates of 45.9% in the US and Canada, and 10.4% in Europe. In the OPT-80-004 study, CDI recurrence rates were numerically lower among fidaxomicin-treated patients infected with the BI/NAP1/027 and non-BI/NAP1/027 strains relative to those receiving vancomycin; however, the difference was statistically significant only for the non-BI/NAP1/027 subgroup.

Fidaxomicin in Clostridium difficile infection

The incidence of Clostridium difficile infection (CDI) has risen 400% in the last decade. It currently ranks as the third most common nosocomial infection. CDI has now crossed over as a community-acquired infection. The major failing of current therapeutic options for the management of CDI is recurrence of disease after the completion of treatment. Fidaxomicin has been proven to be superior to vancomycin in successful sustained clinical response to therapy. Improved outcomes may be due to reduced collateral damage to the gut microflora by fidaxomicin, bactericidal activity, inhibition of Clostridial toxin formation and inhibition of new sporulation. This superiority is maintained in groups previously reported as being at high risk for CDI recurrence including those: with relapsed infection after a single treatment course; on concomitant antibiotic therapy; aged >65 years; with cancer; and with chronic renal insufficiency. Because the acquisition cost of fidaxomicin far exceeds that of metronidazole or vancomycin, in order to rationally utilize this agent, it should be targeted to those populations who are at high risk for relapse and in whom the drug has demonstrated superiority. In this manuscript is reviewed the changing epidemiology of CDI, current treatment options for this infection, proposed benefits of fidaxomicin over currently available antimicrobial options, available analysis of cost effectiveness of the drug, and is given recommendations for judicious use of the drug based upon the available published literature.[2]

In May 2011, the United States Food and Drug Administration (FDA) approved fidaxomicin making it only the second agent, after vancomycin, to be approved by this agency for the treatment of CDI. Soon afterwards, in December 2011, the European Medicines Agency (EMA) granted marketing authorization throughout the European Union followed by Japan, Australia, and Canada. Fidaxomicin is a first-in-class 18-membered macrocyclic antibiotic previously known as OPT-80, PAR-101, and difimicin. In the United States and in Japan, fidaxomicin is classified as a macrolide antibiotic. A post hoc exploratory intention-to-treat (ITT) time-to-event meta-analysis of the combined data from these two trials was performed, to allow increased power with a total of 1164 subjects, using fixed-effects meta-analysis and Cox regression models. There was no evidence found of heterogeneity in the primary and secondary outcomes in either the mITT or per-protocol populations (p > 0.3). Overall, the results of this analysis demonstrated noninferiority of fidaxomicin when compared with vancomycin for clinical cure and superiority of fidaxomicin over vancomycin in the reduction of recurrence and global cure (p < 0.0001). When compared with vancomycin, treatment with fidaxomicin was associated with an overall 40% reduction in persistent diarrhea, recurrence, or death through the 40-day study period (p < 0.001). When comparing the fidaxomicin-treated with the vancomycin-treated subjects there was no evidence to show that the significant differences in relapse and global cure were altered according to disease severity, prior history of CDI, previous antibiotic therapy for CDI, inpatient/outpatient status, age, baseline albumin, or creatinine levels. In the combined dataset, the number of NAP1/BI/027 CDI cases remained underpowered to definitively conclude whether or not fidaxomicin had a beneficial effect over vancomycin for treating CDI due to NAP1/BII/027 strains.

Fidaxomicin represents an important development in the treatment of CDI with significant advantages over the other currently available antimicrobial agents. These advantages include lower rates of CDI recurrence, twice-daily dosing, and minimal side effects. Fidaxomicin should be considered as first-line therapy for the management of CDI in patients with multiple factors cited in the literature that would place them at high risk for relapse and recurrent CDI especially in those populations that have been identified as having improved outcomes with fidaxomicin use: those receiving concomitant antibiotics, those with renal dysfunction, older individuals, and in those with malignancies.

References

[1]Zhanel GG, Walkty AJ, Karlowsky JA. Fidaxomicin: A novel agent for the treatment of Clostridium difficile infection. Can J Infect Dis Med Microbiol. 2015 Nov-Dec;26(6):305-12. doi: 10.1155/2015/934594. PMID: 26744587; PMCID: PMC4692299.

[2]Mullane K. Fidaxomicin in Clostridium difficile infection: latest evidence and clinical guidance. Ther Adv Chronic Dis. 2014 Mar;5(2):69-84. doi: 10.1177/2040622313511285. PMID: 24587892; PMCID: PMC3926343.