Abstract & Commentary

Fidaxomicin for CDI in Patients Who Continue Concomitant Antibiotics: Arrival of a Superior Treatment Option?

By Brian G. Blackburn, MD, Clinical Assistant Professor of Medicine, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, is Associate Editor for Infectious Disease Alert.

Dr. Blackburn reports no financial relationship to this field of study.

Synopsis: Among patients with C. difficile infection (CDI) who continued to take concomitant antibiotics (CA), patients treated with fidaxomicin were cured more often and had fewer relapses than patients treated with oral vancomycin.

Source: Subbarayan Mullane KM, et al. Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections. Clin Infect Dis 2011;53:440-447.

CDI can be a difficult-to-manage complication of antibiotic therapy. Although it is preferable to discontinue the inciting antibiotic when CDI occurs, this is not always possible given that many patients have serious infections, which require ongoing antibiotic therapy.

While oral vancomycin is recommended as first-line therapy for severe or complicated CDI (and metronidazole for mild-to-moderate CDI), relapse rates are high even with appropriate therapy.1 Unfortunately, the number of alternative treatments available for CDI is small.1 A new treatment option is fidaxomicin, a macrocyclic antibiotic that is more active in vitro against C. difficile than vancomycin. This drug also is found in high fecal concentrations after oral dosing, is absorbed minimally, and has limited activity against the normal intestinal flora. Recently, fidaxomicin was shown in a prospective, double-blind, randomized trial to be non-inferior to oral vancomycin for the cure of uncomplicated CDI, and was associated with lower relapse rates.2

Few studies have addressed the outcomes of treatment for CDI in patients who continue CA. The authors therefore performed post-hoc analysis of the above trial and pooled these data with a second, similar study to examine the outcome of CDI treatment in patients who continued to receive CA (i.e., in addition to treatment for CDI).

Adult patients were enrolled into the studies if they had diarrhea and a positive stool test for C. difficile toxin A or B. They were randomized 1:1 to receive either a 10-day course of fidaxomicin 200 mg orally twice daily or vancomycin 125 mg orally four times daily. The study was sponsored by Optimer Pharmaceuticals, the company that manufactures fidaxomicin. Patients with life-threatening or fulminant C. difficile infection, or toxic megacolon, were excluded.

Overall, 28% of the 999 patients evaluable for cure took at least one CA during the CDI treatment period, and 23% of the 794 patients evaluable for relapse took at least one CA during CDI treatment or the 40-day follow-up period. Ninety-three percent of patients who did not take CA were clinically cured, compared to 84% of those who did take CA (P < 0.001). The median time to cure was 54 hours among those who did not take CA, and 97 hours for those who did (P < 0.001). Recurrence was seen in 18% of those who did not take CA and in 23% of those who did (P = 0.08).

Among those who took CA, 90% of fidaxomicin-treated patients were clinically cured, compared to 79% of vancomycin-treated patients (P < 0.05); recurrence rates were 17% and 29%, respectively (P < 0.05). Among those who did not take CA, fidaxomicin-treated patients were clinically cured 92% of the time compared to 93% of vancomycin-treated patients (P = 0.80); recurrence rates were 12% and 23%, respectively (P < 0.001).

Commentary

Although it is preferable that CA be discontinued once CDI is diagnosed, this is not always possible; in this study, more than a quarter of patients continued CA during CDI therapy. This study demonstrates (perhaps better than any other to date) that continued CA during therapy for CDI significantly decreases the chances of cure, delays the time to cure in those who are successfully treated, and tends to increase the risk of relapse.

Compared to vancomycin, fidaxomicin has previously been shown to be non-inferior for the treatment of CDI and to be associated with significantly fewer relapses.2 In the current paper, fidaxomicin was again non-inferior to vancomycin for cure of CDI among patients overall; it also was significantly better among those who took CA for both cure and relapse. Even among those who did not take CA, fidaxomicin-treated patients experienced fewer relapses than vancomycin-treated patients, although the cure rates were the same for both drugs in this cohort.

The mechanism that renders fidaxomicin superior to vancomycin in patients receiving CA is unknown. Fidaxomicin does achieve high levels in the GI tract, and spares the commensal flora, perhaps reducing the risk that residual C. difficile could propagate and cause recurrence. The drug also is more active against C. difficile than vancomycin in vitro.

Fidaxomicin is a promising new option for the treatment of CDI. Based on these preliminary data in a drug company-sponsored trial, it appears superior to vancomycin (at least in certain circumstances), and has few adverse effects. Fidaxomicin is expensive, and cost could be a factor limiting widespread use of this agent. Another limitation is that fidaxomicin has not yet been tested in patients with severe CDI, nor has it been compared to other treatment regimens aside from vancomycin monotherapy. Still, fidaxomicin seems to be a welcome addition to the armamentarium for the treatment of CDI.

References

  1. Cohen SH, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-455.
  2. Louie TJ, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431.