By David Ha, PharmD
Infectious Diseases and Antimicrobial Stewardship Pharmacist; Manager, Stanford Antimicrobial Safety and Sustainability Program, Stanford Health Care; Lecturer, Stanford University School of Medicine, Division of Infectious Diseases and Geographic Medicine; Program Coordinator, PGY2 Infectious Diseases Pharmacy Residency Program, Stanford Healthcare
SYNOPSIS: This open-label, randomized trial of patients with Clostridioides difficile infection receiving concomitant antibiotics found no difference in clinical cure between fidaxomicin and oral vancomycin.
SOURCE: Rao K, Zhao Q, Bell J, et al. An open-label, randomized trial comparing fidaxomicin to oral vancomycin for the treatment of Clostridioides difficile infection in hospitalized patients receiving concomitant antibiotics for concurrent infections. Clin Infect Dis 2023;Oct 5:ciad606. doi: 10.1093/cid/ciad606. [Online ahead of print].
In this open-label, randomized trial at two Michigan centers, Rao and colleagues sought to compare fidaxomicin with oral vancomycin in hospitalized patients with Clostridioides difficile infection (CDI) who also were receiving concomitant antibiotics (CA) for concurrent infections.
They enrolled adult inpatients with diarrhea and a positive C. difficile stool test planned to receive at least five days of concomitant medium to high CDI-risk antibiotics to either fidaxomicin 200 mg orally twice daily or vancomycin 125 mg orally four times daily. Anti-CDI therapy was continued for 10 days or until the end of the duration of CA, whichever was longer up to a maximum of 12 weeks of treatment. Patients were excluded if they had severe complicated CDI, had or planned to have an ileostomy or colostomy, received metronidazole as part of CA, received greater than 24 hours of prior CDI therapy or any duration of adjunctive CDI therapy, or planned to receive more than 12 weeks of CA (e.g., antibiotic prophylaxis). The primary outcome measure was clinical cure proportion with secondary outcome measures including recurrence and 30-day mortality.
After a four-year enrollment period (May 2017 to May 2021), 118 patients met eligibility criteria, with 64 in the fidaxomicin arm and 54 in the vancomycin arm. Demographics were similar between groups with some notable exceptions. The vancomycin arm was slightly older, with 42.9% of patients 65 years and older, vs. 31.1% in the fidaxomicin arm. History of CDI was more common in the fidaxomicin arm (21.6% vs. 11.4%), and history of stem cell transplant was more common in the vancomycin arm (14.3% vs. 5.4%). Additionally, duration of CAs was longer in the vancomycin arm (mean, 20.6; standard deviation [SD], 19.7] days vs. 16.5 [SD 13.1] days) as was duration of CDI therapy (mean, 17.2 [SD 17] days vs. 15 [SD 12.2] days). The vast majority of CA administered were broad-spectrum beta-lactams, including piperacillin/tazobactam, cefepime, ceftriaxone, and ampicillin/sulbactam.
In terms of concomitant infections, more patients in the fidaxomicin arm had urinary tract infection (UTI) (28% vs. 11%), abdominal infections (28% vs. 16%), and extraventricular drain prophylaxis (15% vs. 0%), while more patients in the vancomycin arm had bloodstream infections (20% vs. 8%), skin infections (13% vs. 4%), and neutropenic fever (13% vs. 8%). Both arms had similar incidence of pneumonia (14% and 16% for the fidaxomicin and vancomycin arms, respectively).
The authors found no difference in clinical cure between the fidaxomicin and vancomycin arms in either the intent-to-treat (73.0% vs. 62.9%; P = 0.195) or per protocol (84.4% vs. 81.5%; P = 0.864). There also was no difference in recurrence (3.3% vs. 4.0%; P > 0.99) or mortality (6.3% vs. 7.4%; P > 0.99).
The authors concluded that their study failed to demonstrate a significant difference between fidaxomicin and vancomycin for clinical cure of CDI in patients receiving CAs for another indication.
COMMENTARY
In more recent guidance from the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), fidaxomicin has been favored compared with oral vancomycin for the treatment of CDI for various reasons, including reduced recurrence possibly due to its narrower antimicrobial spectrum minimizing off-target killing of non-C. difficile gastrointestinal flora.1 It is not uncommon for patients being treated for CDI to also be receiving broad-spectrum antibiotics for other indications, but data are limited on the comparative efficacy of fidaxomicin and vancomycin in such cases, and no formal guidance exists in these scenarios. Thus, Rao and colleagues’ study is a welcome addition to the literature to possibly shed light on this challenging subpopulation of CDI patients.
Cornely and colleagues, in a randomized controlled trial comparing fidaxomicin and oral vancomycin for CDI found, in subgroup analysis of 96 patients, that patients receiving concomitant antibiotics for other infections had a higher cure rate with fidaxomicin (90.2% vs. 73.3%; P = 0.031). However, Louie and colleagues in a randomized trial of fidaxomicin vs. oral vancomycin in 629 patients with CDI, found no difference in rates of clinical cure in either the modified intent-to-treat (80.7% vs. 76.6%) or per-protocol (88.7% vs. 83.8%) cohorts.2 Mullane and colleagues, using pooled data from both trials, found that CAs were associated with a lower overall cure rate (84.4% vs. 92.6%; P < 0.001) and an extended time to resolution of diarrhea (97 vs. 54 hours; P < 0.001).3 They also found improved cure with fidaxomicin compared with oral vancomycin (90% vs. 79.4%; P = 0.04). However, as Rao and colleagues noted in their paper, the definition of CA that was employed in the study by Mullane and colleagues included patients who received one or more doses of any antibiotic but excluded those who were expected to receive more than seven days of therapy. This definition is less practical for general clinical application, however, given that low CDI risk drugs and brief antibiotic courses could have been included and extended courses beyond seven days, which are relatively common in practice, were not.
Ultimately, Rao and colleagues did not demonstrate superiority of fidaxomicin over vancomycin. Unfortunately, their study was underpowered because of lower-than-expected enrollment since it was conducted in the midst of both the COVID-19 pandemic as well as new IDSA/SHEA guidelines favoring fidaxomicin. They used a more stringent, clinically applicable definition of CA, but this may have led to an overestimate of effect size compared with the aforementioned trials, further decreasing statistical power to discriminate a difference in outcomes. They expected a 90% cure with fidaxomicin and 75% cure with vancomycin, but instead observed lower cure rates of 73% and 62.9%, respectively.
Notably, they found very low recurrence rates: 3.3% and 4% in the fidaxomicin and vancomycin arms, respectively. This is markedly lower than the recurrence rates shown in prior trials, irrespective of receipt of CAs. For example, 14.5% vs. 24% in the fidaxomicin and vancomycin cohorts, respectively, not receiving CAs and 17.3% vs. 27.8% in those receiving CAs in the large, randomized trial published by Louie and colleagues. It is unclear why this would be the case, especially in the vancomycin arm. In a more recent study of fidaxomicin as an extended pulsed dose regimen, recurrence rates were similarly low at 2% at day 40, but higher (17%) in the vancomycin comparator cohort.4
So, what is the clinician left to do given these conflicting data? Unfortunately, there is no clear answer. One could rationalize that fidaxomicin should be preferred in patients with CAs given its advantage in prior studies from Mullane and colleagues and others and that the study by Rao and colleagues was simply underpowered and/or effect size was overestimated. Similarly, one could argue that neither is preferred since Rao and colleagues’ negative findings using clinically relevant inclusion criteria supersede prior studies’ findings due to their overly liberal definition of CAs inappropriately including patients who received very brief CA courses or low CDI risk CAs. As Rao and colleagues’ mentioned in their concluding statements, “future studies are warranted.”
References
- 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:e1029-e1044.
- Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med 2011;364:422-431.
- 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;53:440-447.
- Guery B, Menichetti F, Anttila VJ, et al. 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;18:296-307.
