Fidaxomicin

Fidaxomicin is an antibiotic that belongs to the class of the macrocyclics and is indicated for the treatment of CDI. In clinical trials, fidaxomicin, when compared to vancomycin, was non-inferior for the clinical cure of patients with CDI and superior for the reduction of recurrence rates, with a greater sustained response after 30 days. Of the patients included in the clinical trials, additional subgroup analyses were performed in patient subgroups with a higher risk of recurrence than the overall CDI population. These subgroups were patients with cancer [odds ratio (OR)=0.37; p=0.018], patients treated with concomitant antibiotic treatment (OR=0.492; p=0.0499) and patients with renal impairment (OR=0.487; p<0.001). Moreover, in these patients, CDI had a greater impact on morbidity and mortality and increased hospital costs compared to the overall CDI patient group.

Newer treatment modalities include fidaxomicin (a nonabsorbable antibiotic with narrow spectrum of action that has shown to be noninferior to vancomycin) and fecal transplantation, a modality that attempts to restore the intestinal flora and has shown to be superior to oral vancomycin in a randomized controlled trial. The 2013 European guidelines state there is not enough evidence to make a recommendation regarding the use of fidaxomicin. A retrospective single-center study of the use of fidaxomicin in transplant (mainly solid organ) recipients did not find significant differences in outcome among the fifteen patients (including one HSCT recipient) who received fidaxomicin and the 44 who received conventional treatment. The authors emphasize no VRE colonization was observed in the fidaxomicin recipients, although this was not statistically significant. A subgroup analysis of the fidaxomicin trials focusing in cancer patients suggests it may be superior to vancomycin in this population, but by its nature it cannot be considered other than hypothesis-generating (no HSCT recipients seem to have been included). The first report of successful use of fecal transplantation in an HSCT recipient with severe CDI refractory to medical therapy CDI was published in 2012. The patient developed CDI almost a year after HSCT, following chemotherapy for a relapse of the acute lymphoblastic leukemia that had been the indication for transplant, and over the course of three weeks failed treatment with metronidazole, vancomycin, intravenous immunoglobulin, fidaxomicin, rifaximin and tigecycline. She responded promptly to a fecal transplant from her husband, instilled in the upper jejunum by a naso-jejunal tube.

In May 2011, fidaxomicin became the second drug to be approved by the FDA for treatment of CDI in adults, with a recommended dose of 200 mg twice daily. Fidaxomicin has several potential advantages in that it is associated with minimal systemic absorption, it has a narrow spectrum of activity with less effect on the normal colonic flora compared to other agents with an associated lower risk of selecting for resistant pathogens, and it is a bactericidal antibiotic unrelated to antibiotics used for systemic infections. The FDA’s approval of fidaxomicin was based on a the results of a multicenter, double-blind, randomized, parallel-group trial in which 629 patients with CDI were randomized to receive either fidaxomicin (200 mg by mouth every 12 hours) or oral vancomycin (125 mg every 6 hours) for 10 days. Patients were evaluated for clinical cure and for recurrence within 4 weeks of completing treatment. The rates of clinical cure with fidaxomicin were not inferior to those with vancomycin in both the modified intention-to-treat analysis (88.2 % for fidaxomicin, 85 % with vancomycin) and the per-protocol analysis (92.1 % with fidaxomicin, 89.8 % with vancomycin). Significantly fewer patients in the fidaxomicin group experienced a recurrence of CDI relative to the vancomycin group in both analyses (15.4 % vs. 25.3 %, P00.005, in the modified intention-to-treat analysis). Lower rates of recurrence were not seen in patients infected with the NAP-1 strain, however, and there was a similar loss of efficacy for both drugs in these patients. In a subgroup analysis of 128 patients in the per-protocol population that had had a recent episode of CDI prior to the diagnosis of CDI at study enrollment, initial response to therapy was similar with both drugs (>90 % cure). However, a second recurrence occurred within 4 weeks in 35.5 % of patients treated with vancomycin and in 19.7 % of patients treated with fidaxomicin (P0 0.045). This is the only study to date evaluating the efficacy of fidaxomicin for the treatment of recurrent disease. Fidaxomicin is expensive, and its place in treatment algorithms for CDI, both initial and recurrent, remains to be fully determined. Additional studies of the efficacy of fidaxomicin in treating patients with multiple recurrences are needed and currently there are no published trials to support its use in this context.

CDI can be difficult to treat with antibiotics, since recurrent infection is common. C. difficile forms dormant, persistent spores that are difficult to eradicate from hospitals and contribute to transmission, reinfection, and disease relapse. Metronidazole and vancomycin do not prevent spore formation or spore viability whereas fidaxomicin partially inhibits spore formation, which may contribute to reduced relapse rates in patients treated with the latter antibiotic. Antibiotic treatment also causes further damage to the gut microbiome, increasing patient susceptibility to recurrent disease. Vancomycin and metronidazole are broad spectrum antibiotics that can kill beneficial intestinal microbiota, while fidaxomicin has a narrower range, which probably allows the natural microbiota to be somewhat restored and therefore reduces CDI recurrence. Recurrent infection is increasingly being treated with microbiota restorative approaches, with fecal transplant as the most common approach. Emerging antimicrobial treatment options are focused on reducing recurrence by the development of C. difficile selective antimicrobials that are sporicidal and/or effective at inhibiting spore formation or outgrowth. Antimicrobial agents that are orally delivered but not absorbed well in the gastrointestinal tract are also preferred as this results in high concentrations in the colon and limits systemic side effects.