Fidaxomicin after Vancomycin for Patients with Multiple C. difficile Recurrences
By Richard R. Watkins, MD, MS, FACP, Division of Infectious Diseases, Akron General Medical Center, Akron, OH; Associate Professor of Internal Medicine, Northeast Ohio Medical University, Rootstown, OH, is Associate Editor for Infectious Disease Alert.
Dr. Watkins reports no financial relationships in this field of study.
Synopsis: Three patients with multiple recurrences of C. difficile infection who were on prolonged maintenance therapy with low-dose vancomycin were treated with a standard course of fidaxomicin. Two had no further recurrences, and one recurred three months later following a course of levofloxacin.
Source: Johnson S, Gerding DN. Fidaxomicin 'Chaser' Regimen following Vancomycin for Patients with Multiple C. difficile Recurrences. Clin Infect Dis 2012; Sep 28. [Epub ahead of print]
Recurrent C. difficile infection (CDI) is a challenging condition to manage. Current guidelines estimate that 25% of patients treated for CDI experience at least 1 additional episode, with those aged 65 years or greater at highest risk.1 Recurrences are thought to occur either from relapse by the original strain through germination of residual spores, or re-infection in patients who remained susceptible and are exposed to new strains. Possible treatment options for recurrent CDI include oral vancomycin given in tapering doses (usually over six weeks), rifaximin, nitazoxanide, intravenous immunoglobulin, and fecal transplantation. Fortunately, most patients are eventually cured. However, some experience multiple recurrences, for which treatment data are limited.
Fidaxomicin, a macrolide antibacterial, was approved in May 2011 for treatment of CDI. Drs. Johnson and Gerding have reported their experience using fidaxomicin to treat three patients with multiple recurrences of CDI, a male aged 67 years, a female aged 80 years, and a female aged 32 years. All three had received tapering courses of vancomycin, followed by maintenance with low-dose vancomycin for five to six months. One of them had been given two rifaximin 'chasers' after vancomycin tapers and initially did well, but eventually developed mucous stools and abdominal cramps necessitating another course of oral vancomycin. One patient also received intravenous immunoglobulin. After a 10-day course of fidaxomicin, two of the patients have had no CDI recurrences to date. The third did well until receiving a 3-day course of levofloxacin for a urinary tract infection. One week later a symptomatic recurrence developed. The authors did not describe how this was managed.
Commentary
While this was a very small (n = 3), nonrandomized interventional study, fidaxomicin looks promising for multiple recurrences of CDI. While the exact mechanism for reducing recurrences is not known, one possible explanation is that the drug produces an inhibitory effect on sporulation. This was shown in a study sponsored by the drug manufacturer wherein fidaxomicin inhibited the specific sporulation genes spoIIID and spoIIR.2 Results from two phase three trials, OPT-80-003 and OPT-80-004, showed fidaxomicin was noninferior to vancomycin for curing CDI and superior for reducing CDI recurrences.3Fidaxomicin reduced persistent diarrhea, recurrence, or death by 40% (95% confidence interval, 26%-51%; P < .0001) compared with vancomycin through day 40. The novel hypothesis that fidaxomicin might be effective for multiple recurrences needs to be tested by a large, randomized clinical trial. Moreover, the efficacy of combination therapy with fidaxomicin and a second agent (e.g. rifaximin) is not known. The combination of tigecycline and rifaximin was recently reported to successfully cure a patient with recurrent refractory CDI.4
Johnson and Gerding did not determine the strain of C. difficile causing their patient's infections. In the clinical trials that led to the drugs approval, sustained response was not seen in the sub-group of patients infected with the C. difficile NAP1/B1/027 strain. While this could potentially be the "Achilles heel" of fidaxomicin, the cure rates for the NAP1/B1/027 strain have been similar to those from vancomycin. Furthermore, it would have been interesting to know whether the patients in this study had co-morbid illnesses, particularly those that lead to immune compromise. For instance, a defect in immune response to toxin A has been associated with recurrences.1 Finally, fidaxomicin is expensive (like oral vancomycin) and its cost-effectiveness remains to be elucidated.
References
- 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.
- Babakhani F, et al. Fidaxomicin inhibits spore production in Clostridium difficile. Clin Infect Dis 2012;55 Suppl 2:S162-169.
- Crook DW, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis 2012;55 Suppl 2:S93-103.
- El-Herte RI, et al. Recurrent refractory Clostridium difficile colitis treated successfully with rifaximin and tigecycline: a case report and review of the literature. Scand J Infect Dis 2012;44:228-230.
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