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What Is a Better Treatment Approach for Immunocompromised Hosts With Clostridioides difficile Infection?


Clostridioides difficile infection (CDI) is a significant cause of health care– associated diarrhea that affects immunocompromised patients more than immunocompetent patients.1,2 The Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) CDI guidelines, updated in 2021, recommend fidaxomicin over oral vancomycin for initial and recurrent episodes of CDI.

The majority of clinical trial data involve the use of vancomycin.3 Additionally, randomized controlled trials (RCT) data forming this recommendation were collected primarily from immunocompetent patients who did not receive transplantation or immunosuppression.4-7 Data assessing fidaxomicin efficacy in patients with immunocompromise also are lacking.8,9 This gap in data presents a clinical dilemma. In immunocompromised patients with CDI, which leads to better outcomes: fidaxomicin or oral vancomycin?

To address this gap, Alsoubani et al performed a retrospective, single-center, observational study to better determine the difference in CDI outcomes among patients with immunosuppressing conditions treated with fidaxomicin or oral vancomycin.10 From March 2011 to December 2021, patients 18 years and older were included if they had received a solid organ transplant or hematologic stem cell transplant or were receiving chemotherapy or immunomodulatory agents for leukemia, lymphoma, or solid tumors prior to CDI diagnosis. Patients were excluded if they did not receive treatment for CDI, underwent fecal microbiota transplant, or received metronidazole monotherapy or bezlotoxumab. CDI diagnosis was confirmed by positive glutamate dehydrogenase antigen and toxin assays or nucleic acid amplification test (NAAT) in patients with CDI symptoms (eg, diarrhea, abdominal pain, ileus, etc). The composite primary outcome consisted of clinical failure, relapse within 30 days following completion of initial CDI treatment, or death related to CDI. Secondary outcomes included relapse at 90 days and total relapse following completion of initial CDI treatment. Overall, 238 patients met inclusion criteria, of which 38 (16%) received fidaxomicin and 200 (84%) received vancomycin. Baseline characteristics were similar between groups with the following key exceptions between fidaxomicin and oral vancomycin, respectively: concurrent antibiotics (3 [16.7%] vs 42 [40%]), receipt of gastric acid suppression (30 [78.9%] vs 111 [55.4%]; P < .01), and community acquired infection (4 [9.5%] vs 62 [31.1%]; P = .03).

Additionally, 29 (12.2%) patients had a prior episode of CDI (7 [18.4%] vs 22 [11%]; P = .23). Overall, 42 (17.6%) patients developed the composite primary outcome, 4 (10.5%) in the fidaxomicin group and 38 (19.0%) patients in the vancomycin group. Of those patients, 6 (14.3%) met criteria for clinical failure (2 [33.3%] vs 4 [66.7%]), and 26 (61.9%) relapsed within 30 days of completing treatment (1 [3.8%] vs 25 [96.1%]). Sixteen patients relapsed between day 30 and day 90 (2 [12.5%] vs 14 (87.5%]). Additionally, there were 10 deaths related to CDI during the follow-up period (1 [10.0%] vs 9 [90.0%]). Patients who developed the composite primary outcome were more likely to have been diagnosed using a toxin test and received antibiotics compared with those who did not develop the composite primary outcome.

Altogether, fidaxomicin was associated with a 72% reduction in treatment failure compared to vancomycin (HR, 0.28; 95% CI, 0.08-0.93). Relapse risk was the only secondary outcome with a significant difference between treatment groups (HR, 0.27; 95% CI, 0.08-0.91). Key study limitations include the retrospective, single-center nature of the study along with the small cohort of patients. There was also a considerable difference between group sample sizes with 38 patients in the fidaxomicin group and 200 in the vancomycin group.

Significant differences in baseline characteristics including rates of concurrent antibiotics, community-acquired infection, and concurrent gastric acid suppression may have contributed to differences in treatment success between groups. Investigators also included patients with positive NAATs in the event of inconclusive antigen and toxin assays. Consequently, NAAT test positivity is not specific for active CDI and may have led to inclusion of patients with C difficile colonization rather than active infection. Acknowledging these limitations, the study findings suggest fidaxomicin may provide superior protection from treatment failure and relapse compared with oral vancomycin in immunocompromised patients with an initial or recurrent episode of CDI. These results coincide with IDSA/SHEA recommendations favoring fidaxomicin over vancomycin despite the low number of immunocompromised patients included among the evaluated RCTs. There may be cost savings benefits based on a 2013 analysis by Stranges et al comparing cost-effectiveness of fidaxomicin and oral vancomycin in the United States.11 The analysis found a cost-effectiveness ratio of fidaxomicin compared with oral vancomycin of $67,576 per quality-adjusted life-year (QALY). Additionally, Monte Carlo sensitivity analyses showed fidaxomicin had an 80.2% likelihood of being cost-effective at a willingness-to-pay threshold of $100,000/QALY.

From this analysis, fidaxomicin appears to be cost-effective in most situations including when patients were initially treated as outpatients, received concomitant antimicrobials, and especially if brand-name oral vancomycin was used instead of compounding from the intravenous product. With these results, infectious diseases specialists and antimicrobial stewards may feel more confident with using fidaxomicin for these patients given the significant cost difference with oral vancomycin. Clinicians should also consider the intrinsic benefits fidaxomicin has over oral vancomycin given its twice-daily oral tablet dosing, which can be easier for patients to take compared with oral capsules or liquid dosed 4 times daily. Additional prospective randomized data are still needed to confirm the observed benefits of fidaxomicin in this study given the limitations.

Highlighted Study
Comparative effectiveness of fidaxomicin vs vancomycin in populations with immunocompromising conditions for the treatment of Clostridioides difficile Infection: A single-center study. OFID https://academic.oup.com/ofid/ article/11/1/ofad622/7462571

References

  1. Revolinski SL, Munoz-Price LS. Clostridium difficile in immunocompromised hosts: a review of epidemiology, risk factors, treatment, and prevention. Clin Infect Dis. 2019;68(12):2144-2153. doi:10.1093/cid/ciy845
  2. Avni T, Babitch T, Ben-Zvi H, et al. Clostridioides difficile infection in immunocompromised hospitalized patients is associated with a high recurrence rate. Int J Infect Dis. 2020;90:237-242. doi:10.1016/j.ijid.2019.10.028
  3. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549
  4. Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431. doi:10.1056/NEJMoa0910812
  5. Mikamo H, Tateda K, Yanagihara K, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative phase III study in Japan. J Infect Chemother. 2018;24(9):744-752. doi:10.1016/j.jiac.2018.05.010
  6. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289. doi:10.1016/S1473-3099(11)70374-7
  7. Guery B, Menichetti F, Anttila VJ, et al; EXTEND Clinical Study Group. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307. doi:10.1016/S1473-3099(17)30751-X
  8. 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;31(19):2493-2499. doi:10.1200/JCO.2012.45.5899
  9. Prohaska L, Mahmoudjafari Z, Shune L, et al. Retrospective evaluation of fidaxomicin versus oral vancomycin for treatment of Clostridium difficile infections in allogeneic stem cell transplant. Hematol Oncol Stem Cell Ther. 2018;11(4):233-240. doi:10.1016/j.hemonc.2018.05.001
  10. Alsoubani M, Chow JK, Rodday AM, Kent D, Snydman DR. Comparative effectiveness of fidaxomicin vs vancomycin in populations with immunocompromising conditions for the treatment of Clostridioides difficile infection: a single-center study. Open Forum Infect Dis. 2023;11(1):ofad622. doi:10.1093/ofid/ofad622
  11. Stranges PM, Hutton DW, Collins CD. Cost-effectiveness analysis evaluating fidaxomicin versus oral vancomycin for the treatment of Clostridium difficile infection in the United States. Value Health. 2013;16(2):297-304. doi:10.1016/j.jval.2012.11.004



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