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.

References:

1. Guddati AK, Kumar G, Ahmed S, et al. Incidence and outcomes of Clostridium difficile-associated disease in hematopoietic cell transplant recipients. Int J Hematol. 2014 Jun;99(6):758-765. doi: 10.1007/s12185-014-1577-z.

2. Chopra T, Chandrasekar P, Salimnia H, Heilbrun LK, Smith D, Alangaden GJ. Recent epidemiology of Clostridium difficile infection during hematopoietic stem cell transplantation. Clin Transplant. 2011 Jan-Feb;25(1):E82-E87. doi: 10.1111/j.1399-0012.2010.01331.x.

3. Zacharioudakis IM, Ziakas PD, Mylonakis E. Clostridium difficile infection in the hematopoietic unit: a meta-analysis of published studies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1650-1654. doi: 10.1016/j.bbmt.2014.06.001.

4. Dubberke ER, Reske KA, Olsen MA, et al. Risk for Clostridium difficile infection after allogeneic hematopoietic cell transplant remains elevated in the postengraftment period. Transplant Direct. 2017 Mar 17;3(4):e145. doi: 10.1097/TXD.0000000000000662.

5. Alonso CD, Marr KA. Clostridium difficile infection among hematopoietic stem cell transplant recipients: beyond colitis. Curr Opin Infect Dis. 2013 Aug;26(4):326-331. doi: 10.1097/QCO.0b013e3283630c4c.

6. Kamboj M, Son C, Cantu S, et al. Hospital-onset Clostridium difficile infection rates in persons with cancer or hematopoietic stem cell transplant: a C3IC network report. Infect Control Hosp Epidemiol. 2012 Nov;33(11):1162-1165. doi: 10.1086/668023..

7 . Zacharioudakis IM, Ziakas PD, Mylonakis E. Clostridium difficile infection in the hematopoietic unit: a meta-analysis of published studies. Biol Blood Marrow Transplant. 2014 Oct;20(10):1650-1654. doi: 10.1016/j.bbmt.2014.06.001.

8. Alonso CD, Treadway SB, Hanna DB, et al. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2012 Apr;54(8):1053-1063. doi: 10.1093/cid/cir1035.

9. Trifilio SM, Pi J, Mehta J. Changing epidemiology of Clostridium difficile—associated disease during stem cell transplantation. Biol Blood Marrow Transplant. 2013 Mar;19(3):405-409. doi: 10.1016/j.bbmt.2012.10.030

10. Dubberke ER, Reske KA, Srivastava A, et al. Clostridium difficile—associated disease in allogeneic hematopoietic stem-cell transplant recipients: risk associations, protective associations, and outcomes. Clin Transplant. 2010 Mar-Apr;24(2):192-198. doi: 10.1111/j.1399-0012.2009.01035.x.

11. Vehreschild MJ, Weitershagen D, Biehl LM, et al. Clostridium difficile infection in patients with acute myelogenous leukemia and in patients undergoing allogeneic stem cell transplantation: epidemiology and risk factor analysis. Biol Blood Marrow Transplant. 2014 Jun;20(6):823-828. doi: 10.1016/j.bbmt.2014.02.022.

12.Alonso CD, Marr AK. Clostridium difficile infection among hematopoietic stem cell transplant recipients: beyond colitis. Curr Opin Infect Dis. 2013 Aug;26(4):326-331. doi: 10.1097/QCO.0b013e3283630c4c.

13.Aldrete SD, Kraft CS, Magee MJ, et al. Risk factors and epidemiology of Clostridium difficile infection in hematopoietic stem cell transplant recipients during the peritransplant period. Transpl Infect Dis. 2017 Feb;19(1). doi: 10.1111/tid.12649.

14. Diorio C, Robinson PD, Ammann RA, et al. Guideline for the management of Clostridium difficile, infection in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation recipients. J Clin Oncol. 2018 Sep 14:JCO1800407. doi: 10.1200/JCO.18.00407.

15. Khan A, Raza S, Batul SA, et al. The evolution of Clostridium difficile infection in cancer patients: Epidemiology, pathophysiology, and guidelines for prevention and management. Recent Pat Antiinfect Drug Discov. 2012 Aug;7(2):157-170.

16. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018 Mar 19;66(7):987-994. doi: 10.1093/cid/ciy149.

17. Trubiano JA, Cheng AC, Korman TM, et al. Australasian Society of Infectious Diseases updated guidelines for the management of Clostridium difficile infection in adults and children in Australia and New Zealand. Intern Med J. 2016 Apr;46(4):479-493. doi: 10.1111/imj.13027.

18 Robin C, Héquette-Ruz R, Guery B, Boyle E, Herbaux C, Galperine T. Treating Clostridium difficile infection in patients presenting with hematological malignancies: Are current guidelines applicable? Med Mal Infect. 2017 Dec;47(8):532-539. doi: 10.1016/j.medmal.2017.07.002.

19. Mullane KM, Miller MA, Weiss K, 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 Sep;53(5):440-447. doi: 10.1093/cid/cir404.

20. Cornely OA, Miller MA, Fantin B, Mullane K, Kean Y, Gorbach S. Resolution

of Clostridium difficile—associated diarrhea in patients with cancer treated with fidaxomicin or vancomycin. J Clin Oncol. 2013 Jul 1;31(19):2493-2499. doi: 10.1200/JCO.2012.45.5899.

21. Ganetsky A, Han JH, Hughes ME, et al. Oral vancomycin prophylaxis is highly effective in

preventing Clostridium difficile infection in allogeneic hematopoietic stem cell transplant recipients. Clin Infect Dis. 2018 Sep 26. doi: 10.1093/cid/ciy822.

22. Pereiras MA, Urnoski E, Wynd M, et al. Does oral vancomycin

prophylaxis for Clostridium difficile infection improve allogeneic hematopoietic stem cell transplant outcomes? Biol Blood Marrow Transplant. 2017 March;23(3):S389. doi: 10.1016/j.bbmt.2016.12.615.

23. Mullane KM, Winston DJ, Nooka A, et al. A randomized, placebo-controlled trial of fidaxomicin for prophylaxis of Clostridium difficile—associated diarrhea in adults undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2019 Jan 7;68(2):196-203. doi: 10.1093/cid/ciy484.

24. Shue YK, Sears PS, Shangle S, et al. Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses. Antimicrob Agents Chemother. 2008 Apr;52(4):1391-1395. doi: 10.1128/AAC.01045-07.

25. Louie T, Miller M, Donskey C, Mullane K, Goldstein EJ. Clinical outcomes, safety,

and pharmacokinetics of OPT-80 in a phase 2 trial with patients with Clostridium difficile infection. Antimicrob Agents Chemother. 2009 Jan;53(1):223-228. doi: 10.1128/AAC.01442-07.