Abstract
Background: Clostridium difficile infection causes severe complications and frequently recurs. An extended-pulsed fidaxomicin regimen might facilitate sustained clinical cure by prolonging C difficile suppression and supporting gut microbiota recovery. We aimed to compare clinical outcomes of extended-pulsed fidaxomicin with standard vancomycin. Methods: In this randomised, controlled, open-label, superiority study, we recruited hospitalised adults aged 60 years and older with confirmed C difficile infection at 86 European hospitals. Patients were randomly assigned (1:1) using an interactive web response system to receive extended-pulsed fidaxomicin (200 mg oral tablets, twice daily on days 1–5, then once daily on alternate days on days 7–25) or vancomycin (125 mg oral capsules, four times daily on days 1–10), stratified by baseline C difficile infection severity, cancer presence, age (≥75 years vs <75 years), and number of previous C difficile infection occurrences. The primary endpoint was sustained clinical cure 30 days after end of treatment (day 55 for extended-pulsed fidaxomicin and day 40 for vancomycin), assessed in all randomised patients who met the inclusion criteria and received at least one dose of study medication (modified full analysis set). Adverse events were assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov, number NCT02254967. Findings: Between Nov 6, 2014, and May 5, 2016, 364 patients were enrolled and randomly assigned to receive extended-pulsed fidaxomicin or vancomycin. 362 patients received at least one dose of study medication (181 in each group). 124 (70%) of 177 patients in the modified full analysis set receiving extended-pulsed fidaxomicin achieved sustained clinical cure 30 days after end of treatment, compared with 106 (59%) of 179 patients receiving vancomycin (difference 11% [95% CI 1·0–20·7], p=0·030; odds ratio 1·62 [95% CI 1·04–2·54]). Incidence of treatment-emergent adverse events did not differ between extended-pulsed fidaxomicin (121 [67%] of 181) and vancomycin (128 [71%] of 181) treatment arms. One death in the vancomycin arm was considered by the investigator to be related to study drug. Interpretation: Extended-pulsed fidaxomicin was superior to standard-dose vancomycin for sustained cure of C difficile infection, and, to our knowledge, extended-pulsed fidaxomicin recurrence rates in this study are the lowest observed in a randomised clinical trial of antibiotic treatment for C difficile infection. Funding: Astellas Pharma, Inc.
| Original language | English |
|---|---|
| Journal | The Lancet Infectious Diseases |
| Volume | 18 |
| Issue number | 3 |
| Pages (from-to) | 296-307 |
| Number of pages | 12 |
| ISSN | 1473-3099 |
| DOIs | |
| Publication status | Published - 01.03.2018 |
| Externally published | Yes |
Funding
In this multicentre, randomised C difficile infection study testing the concept of pulsed dosing as a microbiota-sparing strategy, extended-pulsed fidaxomicin was superior to standard-dose vancomycin for the primary endpoint of sustained clinical cure of C difficile infection in patients aged 60 years and older. Crucial to the achievement of sustained clinical cure, the recurrence rate observed in the present study was lower in the extended-pulsed fidaxomicin arm than in the vancomycin arm at every visit up to day 90. The recurrence rate at day 90 in the extended-pulsed fidaxomicin arm (6%) was lower than was reported in previous randomised, controlled studies of standard regimens of fidaxomicin, vancomycin, and metronidazole. 3,12,13 A recurrence rate of 8–26%, depending on previous recurrence, was observed in a real-world study of fidaxomicin. 16 Follow-up to day 90, as in our study, is unusual and gives added insight and, to our knowledge, such a long follow-up has only been reported in the registration study of the monoclonal antibody bezlotoxumab. 17 Although the sustained clinical cure of C difficile infection achieved at 30 days after the end of extended-pulsed fidaxomicin treatment in our study (70%) was similar to that achieved in phase 3 studies with a standard twice-daily, 10-day course of fidaxomicin (214 [75%] of 287 patients; 13 221 [88%] of 252 patients 12 ), the results of these previous studies are not directly comparable to ours because of differences in study design and outcome criteria. Patients in EXTEND were older than were those in previous studies (mean 75·1 years [SD 8·7] compared with 61·6 years [16·9] 13 and 63·4 years [18·1] 12 ) to stress test the regimen, and the recurrence rate was substantially lower at 90 days with extended-pulsed fidaxomicin in EXTEND (6%) than it was at 40 days with standard fidaxomicin in previous phase 3 studies (39 [15%] of 253 patients; 13 28 [13%] of 221 patients 12 ). Patients older than 65 years have a greater relative risk of C difficile infection recurrence than do younger patients, and patients aged at least 75 years have a higher odds ratio for mortality before 30 days. 18 The reduction in recurrence rates observed with extended-pulsed fidaxomicin compared with previous studies suggests potential health-care benefits beyond the studied clinical endpoints. In the extended-pulsed fidaxomicin regimen, the same number of fidaxomicin tablets is administered as in the standard licensed regimen, but enhanced outcomes are seen compared with vancomycin, potentially resulting in a cost-effectiveness benefit. Additionally, as C difficile infection recurrence has high cost implications, avoidance of recurrence is considered economically important, particularly in high-risk patients. 19 For every seven patients treated with fidaxomicin, an estimated one hospital readmission for C difficile infection is prevented compared with patients treated with vancomycin. 20 In our study of an older patient population, the number needed to treat with extended-pulsed fidaxomicin is estimated at 6·6, derived from the absolute difference in recurrence rate with vancomycin at a similar timepoint of 40 days. Recurrence rates observed in the vancomycin arm were lower than those previously reported in the vancomycin arm of fidaxomicin phase 3 registration trials. 12,13 Epidemiological changes, differences in antimicrobial stewardship and infection control, and differences in the characteristics or treatment of the patient population might have contributed to this reduction in recurrence with vancomycin. However, reported recurrence rates with vancomycin in this study align with reported recurrence rates in a retrospective cohort study. 21 In phase 3 studies, no significant difference in efficacy was observed between fidaxomicin and vancomycin in patients with PCR ribotype 027 infections. 13 In our study, extended-pulsed fidaxomicin was associated with an increased rate of sustained clinical cure compared with vancomycin at 30 days after end of treatment in this patient subgroup. However, as with previous studies, EXTEND was not sufficiently powered to permit strong conclusions on differences in efficacy in patients with PCR ribotype 027 infections. Vancomycin therapy is detrimental to the gut microbiota, with depletion of many bacterial types (operational taxonomic units), particularly from the Bacteroidetes phylum, and the proportion of several organisms associated with human infection, such as Klebsiella spp, Escherichia spp, vancomycin-resistant enterococci, and Candida spp, is increased after treatment. 11,22 Analysis of the Shannon index of α diversity indicated that extended-pulsed fidaxomicin enhanced microbiota recovery over our study period to a significantly higher degree than did vancomycin, providing support for extended-pulsed fidaxomicin as a microbiota-sparing treatment strategy. This increased microbial diversity in patients treated with extended-pulsed fidaxomicin will be of interest for future studies, and suggests a possible mechanistic basis for the reduced recurrence rates observed in this study. More deaths occurred in the vancomycin arm of our study, but of greater interest is the higher number of deaths among vancomycin recipients after day 27. Recurrence has been found to be associated with increased mortality by day 90 after hospital discharge. 23 A limitation of our study is the absence of standard fidaxomicin or extended-pulsed vancomycin arms. Although additional treatment arms offer improved certainty and depth of information, they also represent a major cost driver in clinical trials, which can limit their feasibility. Furthermore, vancomycin is considered the standard of care for C difficile infection and was therefore the most appropriate comparator arm. 3 In the present setting, data from previous studies provide sufficient insight to justify omission of additional treatment arms. In-vitro data from a gut model of C difficile infection primed with faeces from an older population (aged >60 years) do not suggest that incorporating standard and extended-pulsed regimens of fidaxomicin would differ in terms of efficacy in resolving C difficile infection, 14 and our observed similarity in clinical response rates at day 12 between extended-pulsed fidaxomicin and vancomycin supports this hypothesis. This observation, combined with data from randomised clinical studies showing a recurrence rate of 15·4% or lower for the standard fidaxomicin regimen, 12,13 suggests outcomes that are at least as good for extended-pulsed fidaxomicin compared with standard fidaxomicin; however, a future indirect treatment comparison of these regimens could be of interest to further understand their relative effectiveness. Retrospective observational data suggest potential efficacy of extended-pulsed vancomycin for recurrent C difficile infection. 24 However, laboratory studies have shown the disruptive effect of vancomycin on gut microbiota, 25 and such an extended regimen could further exacerbate post-treatment gut microbiota dysbiosis. This study's definition of C difficile infection recurrence—based on worsening symptoms—reflected clinical practice, but could be perceived as yielding a low threshold for examining recurrence. Nevertheless, diagnosis required the investigator to treat for recurrence based on their clinical judgment. The absence of blinding and insufficient racial diversity in the study population might also be considered limitations of this study. Furthermore, the study does not provide information on the use of extended-pulsed fidaxomicin in patients younger than 60 years, or in those with at least three C difficile infection recurrences. Our study has many strengths, including, to our knowledge, the first demonstration in a randomised clinical trial setting of a C difficile infection recurrence rate less than 7% by optimising the delivery of an already available antibiotic. This hypothesis-driven study uses our understanding of C difficile infection pathogenesis and the method of action of fidaxomicin to enhance the dosing regimen and improve outcomes in a high-risk patient population. 90-day follow-up provided an extensive period over which reinfection or recurrence could be studied and gave important new data on C difficile infection recurrence. Incorporation of a microbiota substudy analysis also provided evidence to explain and validate observed clinical outcomes. EXTEND is an uncommon positive superiority antibiotic trial, showing an improvement in sustained clinical cure of C difficile infection with extended-pulsed fidaxomicin and a significant reduction in recurrence rates compared with vancomycin treatment, even up to day 90, with simultaneous enhanced microbiota recovery. Since the extended-pulsed regimen of fidaxomicin administers the same number of tablets as the standard regimen, the observed benefits are derived with no increase in treatment costs and with a similar positive safety profile to that of standard-regimen vancomycin and fidaxomicin. Furthermore, the C difficile recurrence rate of 4% at 30 days after end of treatment is, to date, the lowest observed in a randomised clinical trial. Contributors AK and CL developed the extended-pulsed fidaxomicin regimen and, together with NA, conceived the study. BG, FM, V-JA, NA, AK, GK, JMA, KB, AG, SDG, CL, JAP-F, OAC, and MJGTV contributed to study design and execution. All authors contributed to the collection, interpretation and analysis of data, and preparation of the manuscript. The manuscript was reviewed, edited, and approved by all authors, who vouch for the accuracy and completeness of the data obtained and for adherence with the trial's protocol. Declaration of interests BG has received honoraria for speaking or participating in advisory boards, and research grants from Pfizer and Astellas. V-JA has received lecture fees from Astellas, MSD, Roche, and Pfizer, and funding to attend congresses from Astellas and Pfizer. SDG has received grants and personal fees from Astellas. JMA has received honoraria for speaking or participating in advisory boards and research grants from Gilead Sciences, Pfizer, Roche, Merck, and Novartis. AK, NA, AG, and JAP-F are full-time employees of Astellas Pharma. CL was a full-time employee of Astellas Pharma, Inc, during the study conduct and is now an employee of Basilea Pharmaceuticals. AK and CL have a patent WO2015169451 A1, and AK and JAP-F have a patent EP17167541.6, both pending to Astellas Pharma Europe Ltd. GK is a consultant statistician working on behalf of Astellas Pharma, Inc. OAC has received grants from Actelion, Aranis, Astellas, AstraZeneca, Basilea, Bayer, Cidara, Duke University, F2G, Gilead, GSK, Leeds University, MedPace, Melinta Therapeutics, Merck/MSD, Miltenyi, Pfizer, Rempex, Roche, Sanofi Pasteur, Scynexis, Seres Therapeutics, and The Medicines Company; and personal fees for consulting or advisory boards from Actelion, Amplyx, Anacor, Astellas, Basilea, Cidara, Da Volterra, F2G, Gilead, Janssen Pharmaceuticals, Matinas, Menarini Richerche, Merck/MSD, Paratek Pharmaceuticals, Scynexis, Seres Therapeutics, Summit, Vical, and Vifor. MJGTV has been a consultant to Berlin Chemie, MSD/Merck, and Astellas Pharma; served at the speakers' bureaus of Pfizer, Merck/MSD, Gilead Sciences, Organobalance, and Astellas Pharma; and received research funding from 3M, Astellas Pharma, Merck/MSD, Organobalance, Da Volterra, Seres Therapeutics, and Gilead Sciences. KB has received personal fees for consulting from Astellas Pharma. FM declares no competing interests. Acknowledgments We acknowledge the important contributions of the EXTEND Clinical Study Group and study site personnel. We thank Achyut Guleri (Blackpool, UK), Jolanta Kłobukowska (Gdynia, Poland), Catalina M Luca and Mihaela Lupse (Lasi, Romania), and Adrian Streinu-Cercel (Bucharest, Romania) for their substatntial role in patient recruitment. The study was initiated and funded by Astellas Pharma. Medical writing support was provided by Rhian Harper Owen for Cello Health MedErgy (Europe), funded by Astellas Pharma.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
