ABSTRACT & COMMENTARY
Fidaxomicin More Effective than Vancomycin for Clostridium difficile Infection in Cancer Patients?
Superior cure rates, fewer C. diff recurrences, but limitations warrant larger trial
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.
Dr. Watkins reports no financial relationships in this field of study.
This article originally appeared in the December 2013 issue of Infectious Disease Alert. It was edited by Stan Deresinski, MD, FACP, FIDSA, and peer reviewed by Timothy Jenkins, MD. Dr. Deresinki is Clinical Professor of Medicine, Stanford University, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, and Dr. Jenkins is Assistant Professor of Medicine, University of Colorado, Denver Health Medical Center. Dr. Deresinski does research for the National Institutes of Health, and is an advisory board member and consultant for Merck, and Dr. Jenkins reports no financial relationships relevant to this field of study.
Source: Cornely OA, et al. Resolution of Clostridium difficile-associated diarrhea in patients with cancer treated with fidaxomicin or vancomycin. J Clin Oncol 2013; 31:2493-2499.
The burden of C. difficile infection (CDI) among oncology patients is high, resulting in significant morbidity and mortality. These patients have multiple risk factors that predispose them to CDI including depressed immune function, prolonged hospitalizations, antibiotic treatments, and the adverse effects of chemotherapy on the gut microbiome. Moreover, patients who undergo stem-cell transplantation and develop graft-vs.-host disease are particularly susceptible to developing CDI. In an industry-sponsored study, Cornely et al present favorable data for fidaxomicin compared to vancomycin in the treatment of CDI in adult patients with cancer.
The study was a post-hoc analysis of data from two independent, double-blind, controlled trials that enrolled 1,105 patients with CDI and randomized them to receive either fidaxomicin or oral vancomycin. Of these, 183 had cancer (124 with solid tumors and the rest had either hematologic malignancy alone or hematologic malignancy and a solid tumor). The investigators assessed clinical cure which they defined as fewer than 3 unformed bowel movements in 24 hours for 2 consecutive days maintained until end of therapy and 2 days thereafter, and also examined recurrence of CDI, sustained response at 4 weeks after completing therapy, and all-cause mortality in both treatment arms.
Cure rates were similar with fidaxomicin and vancomycin in patients without cancer (88.5% vs. 88.7%, respectively P = .913). However, in those with cancer, fidaxomicin had a nonsignificantly higher cure rate (85.1%) compared to vancomycin (74%) (OR = 2.0; 95% CI, 0.95 to 4.22; P = .065). Median time to resolution of diarrhea in cancer patients was 74 hours with fidaxomicin and 123 hours with vancomycin (P = .045). The likelihood of recurrence in cancer patients treated with vancomycin was double that of those treated with fidaxomicin. Furthermore, the relative odds of a sustained response at 28 days in patients with cancer were more than 2.5 times for the fidaxomicin group vs. vancomycin. The adverse event rate was not significantly different between the two treatment arms and was relatively high for both groups (85.3% for fidaxomicin and 83.5% for vancomycin), which is likely a consequence of the underlying malignancy. Finally, there was no significant difference in mortality between the two treatment arms.
The main finding from this study, that fidaxomicin is superior to vancomycin for CDI in patients with cancer, is interesting and important especially given the high prevalence of CDI in this population. Indeed, earlier resolution of diarrhea often allows for the resumption of chemotherapy, potentially improving the chances for remission of the underlying malignancy. However, there are several limitations to the study that deserve mention. First, the overall number of patients with cancer who were treated in the two study arms was relatively modest which increases the risk of sampling error. Second, as mentioned in a follow-up letter to the editor, the cohort was heterogeneous in the immune competency of the subjects resulting from their chemotherapy, their intrinsic immunity due to the different underlying malignancies, different anticancer regimens, and different supportive therapies.1 For example, patients with hematologic malignancies are more likely than those with solid tumors to receive antibiotic prophylaxis with a fluoroquinolone and a proton pump inhibitor to lessen the effects of oral steroids, and have prolonged neutropenia. Third, the study was a post-hoc subset analysis and not specifically designed to evaluate the efficacy of treatment in cancer patients. Fourth, a third treatment arm that included oral metronidazole would have been useful since this agent is still frequently used in cancer patients with mild to moderate CDI. Finally, the study was industry sponsored and multiple authors had a direct financial interest in the manufacturer of fidaxomicin.
Cornely et al have provided us with good preliminary evidence for the effectiveness of fidaxomicin in treating cancer patients with CDI. However, I believe the limitations of the study (particularly the small sample size) mandate that additional larger, multicenter, randomized clinical trials be conducted before any major changes to clinical practice are implemented.
- Green MR, et al. Is fidaxomicin the drug of choice for treating Clostridium difficile-associated diarrhea in patients with cancer? J Clin Oncol 2013; Oct 28. [Epub ahead of print]