Fidaxomicin: A Novel Macrocyclic Antibiotic for the Treatment of Clostridium difficile Infection

Tonya Crawford, Pharm.D; Emily Huesgen, Pharm.D; Larry Danziger, Pharm.D

Disclosures

Am J Health Syst Pharm. 2012;69(11):933-943. 

In This Article

Discussion

Oral vancomycin and metronidazole are the primary agents currently recommended for the treatment of C. difficile by SHEA and IDSA.[18] Of growing concern is the increased number of failures reported with metronidazole therapy.[51,52] A randomized, double-blind, placebo-controlled trial found that vancomycin and metronidazole were equally efficacious in the treatment of mild-to-moderate CDI, but vancomycin was more effective in treating severe infection (97% versus 76%, p = 0.02).[21]

Subsequently, only oral vancomycin 125 mg four times daily for 10–14 days is recommended for the treatment of severe CDI.[18] For the treatment of severe complicated CDI episodes (defined as involving hypotension, shock, megacolon, or ileus), vancomycin is recommended at an increased dosage of 500 mg four times daily either orally or via nasogastric tube in combination with i.v. metronidazole 500 mg every eight hours.[18] If complete ileus is involved, the addition of a rectal instillation of vancomycin to the above therapy should be considered.

Although vancomycin and metronidazole are equally efficacious for the treatment of mild-to-moderate CDI, metronidazole 500 mg orally three times daily for 10–14 days is recommended for the treatment of mild-to-moderate episodes, due to possible acquisition of VRE with frequent vancomycin exposure.[18] Other considerations for reserving vancomycin for severe CDI include cost and patient compliance with frequency of dose administration. For a 10-day course of CDI treatment, the average wholesale price (AWP) of Vancocin capsules (ViroPharma) is $2327.68, and that of compounded oral vancomycin solution from vancomycin injection is $31.80; these compare with metronidazole, whose AWP is $5.93–85.11, depending on the manufacturer.[53]

Fidaxomicin's narrow spectrum of activity and bactericidal properties make it an appealing alternative for the treatment of CDI. When compared with vancomycin, fidaxomicin was found to be noninferior in the treatment of mild-to-moderately severe CDI.[48] Fidaxomicin has been documented to have minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile.[36] Fidaxomicin has demonstrated lower CDI recurrence rates compared with vancomycin in patients diagnosed with the non-NAP/BI/027 C. difficile strain, but data from subset analyses indicated that recurrence rates with the NAP1/BI/027 strain were not statistically significant between patients who received vancomycin or fidaxomicin.[48] Additional subgroup analyses did not find a significant difference in patients with a prior CDI episode or who did not respond to metronidazole therapy before study enrollment.[49]

One of the challenges in identifying fidaxomicin's place in CDI therapy is a lack of uniform criteria for categorizing CDI severity and the varying definitions of recurrence used in studies. Table 5 compares the criteria used in the fidaxomicin Phase III clinical trial,[48] the study by Zar et al.,[21] and the SHEA–IDSA guidelines.[18] Both the SHEA–IDSA guidelines and Zar et al. used laboratory test markers to categorize CDI severity, whereas definitions of severity in the fidaxomicin Phase III clinical trial included subjective clinical symptoms.

Overall, fidaxomicin appears to be as efficacious as vancomycin in the treatment of mild-to-moderately severe CDI and is associated with fewer recurrences in CDI associated with non-NAP1/BI/027 strains.[47,48] Some key issues to consider when determining fidaximicin's place in therapy will include cost and the capability of an institution to perform C. difficile strain typing. The wholesale acquisition cost for a 10-day course of fidaxomicin is $2,800.[54] The assay for typing C. difficile strains costs $420 for 10 cartridges, with 1 cartridge being used to type a single strain (Customer Service, Cepheid, personal communication, 2011 Jun 15). The minimum cost to purchase Cepheid's GeneXpert instrumentation to conduct strain typing is $78,200 (Customer Service, Cepheid, personal communication, 2011 Jun 15). Considering these costs and the clinical data currently available, fidaxomicin will likely be considered an alternative agent to vancomycin for the treatment of CDI recurrence for the near future.

Based on current clinical trials reporting fewer recurrences among patients treated with fidaxomicin in which the non-NAP1/BI/027 strains were isolated, fidaxomicin should be considered for patients diagnosed with recurrent CDI who were previously treated with metronidazole or vancomycin for CDI in which a non-NAP1/BI/027 strain is isolated (Figure 1). At institutions in which strain typing is not available, recurrent CDI should be treated with the same agents used for the first episode of CDI.[18] Fidaxomicin may also be considered in patients with recurrent CDI who have not responded to treatment with the regimen used for the first episode of CDI.

Figure 1.

Proposed place in therapy of fidaxomicin in treatment of recurrent Clostridium difficile infection (CDI).

Further research regarding the use of fidaxomicin for the treatment of CDI remains a high priority due to increases in frequency and severity of the disease. Clinical trials demonstrated fidaxomicin's noninferiority to vancomycin in the treatment of mild-to-moderately severe CDI. Clinical trials comparing fidaxomicin to metronidazole for the treatment of mild-to-moderately severe CDI have yet to be conducted. However, a comparison of the clinical outcomes of patients randomized to receive fidaxomicin or metronidazole for the treatment of mild-to-moderately severe CDI would be beneficial. Further investigation of the efficacy and safety of fidaxomicin versus vancomycin in patients with multiple recurrences and severe CDI is warranted. Another area of research that warrants further investigation is the efficacy of fidaxomicin for salvage therapy for refractory or recurrent CDI. In addition, a pharmacoeconomic analysis investigating the cost of preventing hospitalization and complications due to recurrent CDI would be of interest to clinicians.

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