Can Fidaxomicin Provide Effective C difficile-Associated Diarrhea Prophylaxis for HSCT Recipients?
Clostridium difficile rates in stem cell transplant patients are approximately 9 times greater than in hospitalized patients, with rates about twice as high in allogeneic vs autologous transplants.
Clostridium difficile rates in stem cell transplant patients are approximately 9 times greater than in hospitalized patients, with rates about twice as high in allogeneic vs autologous transplants.1-7 Contributing risk factors include cytotoxic chemotherapy, broad spectrum antibiotics and, possibly graft-versus-host disease (GVHD). C difficile-associated diarrhea (CDAD) after allogeneic hematopoietic stem cell transplantation (HSCT) affects about 1 in 10 patients and has been associated with higher rates of new-onset GVHD, blood stream infections, and mortality.7-10 Despite this increased risk, there are no recommended preventative agents.11-18 Compared to vancomycin, fidaxomicin has shown to have both, higher CDAD cure rates (in patients receiving concomitant antibiotics) and lower recurrences (regardless of concomitant antibiotics use), with significant benefit in cancer patients.19-20 Two studies have evaluated oral vancomycin 125mg twice daily vs. placebo as HSCT-CDAD prophylaxis in allo-HSCT patients. The first study reported a 0% CDAD occurrence (for the time period of inpatient admission to discharge) with vancomycin vs 20% placebo (p <.001).21 However the second study found no evidence of protection in with no difference between patients receiving vancomycin prophylaxis (16.6%) and those who did not (14.3%).21-22
DEFLECT-1 is the first trial to examine fidaxomicin for HSCT-CDAD prophylaxis in adults (with or without prior CDAD) receiving fluoroquinolones during periods of neutropenia.23 Fidaxomicin is much more selective for C difficile compared to vancomycin, with the potential for less impact on gut microbiome and/or selection for vancomycin-resistant enterococci. This was a randomized, double blind, placebo controlled, multi-center trial.23 Fidaxomicin at 200 mg once daily24-25 was initiated within 2 days of the conditioning regimen or fluoroquinolone start, and continued until 7 days after neutrophil engraftment, completion of fluoroquinolone/clinically indicated antibiotics or confirmation of CDAD.
The primary endpoint of CDAD incidence through 30 days of study drug was analyzed as a composite of failures: confirmed CDAD, initiation of anti-CDAD therapy, or any missing assessments (including death). A sensitivity analysis of patients with confirmed CDAD was also performed. Secondary endpoints assessed included CDAD incidence beyond 30 days, baseline C difficile colonization, and adverse events. A Wald unpooled estimate of variance was applied to test the superiority of fidaxomicin with 1-sided α = .025.
Of the 600 subjects in the mITT group, 227 (75.4%) fidaxomicin and 218 (72.9%) placebo recipients completed the study. Overall, only 64% completed the study treatment and follow-up with a mean treatment duration of 22 (+8.61) days in fidaxomicin and 22.7 (+ 8.99) days in placebo groups. In addition to prophylactic fluoroquinolones, 75% also received other antibiotics: cephalosporins (56.2%), IV vancomycin (52.2%) and carbapenems (18.8%). The majority of patients received auto-HSCT (59%) and most received myeloablative conditioning.
No difference in the primary composite outcome was found; fidaxomicin 86/301 (28.6%) vs placebo 92/299 (30.8%), p = .28). However, most failures were due to non—CDAD events. Rates of confirmed CDAD were consistently lower in fidaxomicin through 30 days (6.4% difference, p = 0.0014), 60 days (5.1% difference, p = 0.0177), auto-HSCT through 30 days (5.1%. difference, p = 0.0163), allo-HSCT through 30 days (8.2% difference, p = 0.0166), 70 days from treatment start (6.1% difference, p = 0.0026) and in those colonized at baseline (37.6% difference, p<0.0001). HSCT CDAD beyond 30 days, adverse events, and CDAD in those without baseline colonization were similar in both groups.
Since either NAAT or direct toxin (e.g. ELISA) testing was allowed for CDAD confirmation, inter site variation in potential over-diagnosis with NAAT assays and under-diagnosis with ELISA methods may have existed. Of note, 29/46 (63%) of cases were confirmed using direct toxin detection.
Although the investigators mention two previous studies evaluating oral vancomycin for HSCT-CDAD prophylaxis with variable outcomes,21-22 they conducted a placebo controlled trial. At this time, it is unknown how fidaxomicin compares to oral vancomycin, with superiority/noninferiority and vancomycin resistance enterococcus emergence yet to be demonstrated.
Despite the low completion rates and lack of accounting for Infection Prevention and Antimicrobial Stewardship Practice variances, history/concomitant antimicrobials, and gastric acid suppressants, the results are promising (see Table). Further investigation of optimal and cost effective prophylaxis strategies including CDAD screening, agent and dosing (e.g. fidaxomicin vs oral vancomycin) or novel agents capable of inhibition of C difficile spore germination or vaccination modalities are warranted. Considering the potentially large impact on disease prevention and safety profile, it may be prudent to administer low doses of fidaxomicin in high risk HSCT patients with history of CDAD while on systemic antibiotics. However, it is important to note that this study did not evaluate the development of C difficile resistance against fidaxomicin.
Dr.Vaezi is the Antimicrobial Stewardship Program co-director, Pharmacy and Therapeutics coordinator, and Critical Care and Infectious Disease Pharmacist at Virginia Mason Medical Center in Seattle, Washington. She is also a clinical associate professor at the University of Washington.
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