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Original Article

Fidaxomicin versus Vancomycin for Clostridium difficile Infection

List of authors.
  • Thomas J. Louie, M.D.,
  • Mark A. Miller, M.D.,
  • Kathleen M. Mullane, D.O.,
  • Karl Weiss, M.D.,
  • Arnold Lentnek, M.D.,
  • Yoav Golan, M.D.,
  • Sherwood Gorbach, M.D.,
  • Pamela Sears, Ph.D.,
  • and Youe-Kong Shue, Ph.D.
  • for the OPT-80-003 Clinical Study Group*

Abstract

Background

Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection.

Methods

Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence).

Results

A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non–North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies.

Conclusions

The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non–North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

Introduction

Clostridium difficile infection generally occurs after exposure to broad-spectrum antibiotics. The incidence and severity of C. difficile infection are increasing. The increases have been ascribed to the emergence of a hypervirulent C. difficile strain, known variously as North American Pulsed Field type 1 (NAP1), restriction-endonuclease analysis (REA) type BI, or polymerase-chain-reaction ribotype 027 (referred to collectively as the NAP1/BI/027 strain). 1-4 Furthermore, the rates of death associated with C. difficile infection are rising,5-7 and the infection is occurring in populations that were previously considered to be at low risk, such as young, healthy persons living in the community and peripartum women.8,9 As compared with observations in the mid-1990s,10 the reduced rates of clinical response and increased recurrence rates seen in more recent studies are cause for concern.11-14

Fidaxomicin (previously referred to as OPT-80), a macrocyclic antibiotic, is more active in vitro than vancomycin, by a factor of approximately 8, against clinical isolates of C. difficile, including NAP1/BI/027 strains. 15-19 This activity, in combination with minimal systemic absorption,20 high fecal concentrations, and limited activity in vitro15-19 and in vivo21 against components of the normal gut flora, makes fidaxomicin a promising candidate that may provide highly active but more selective therapy for C. difficile infection. In a dose-finding, randomized, open-label, phase 2 trial, treatment with fidaxomicin was associated with a good clinical response and a low rate of recurrence.22 The results of a phase 3 noninferiority study comparing fidaxomicin with vancomycin in 629 patients with C. difficile infection are reported here.

Methods

Study Design

This prospective, multicenter, double-blind, randomized, parallel-group trial was conducted between May 9, 2006, and August 21, 2008, in accordance with the ethical principles of the Declaration of Helsinki and the principles of current Good Clinical Practices. The study protocol and amendments were approved by local or central institutional review boards. All patients provided written informed consent. Optimer Pharmaceuticals sponsored the study. The data were monitored and retrieved by INC Research (a contract research organization). The analysis of the data was performed by all the authors, along with an additional investigator at Optimer Pharmaceuticals. The first draft of the manuscript was written by one of the authors who is a part-time employee of Optimer Pharmaceuticals; that author along with the first two authors wrote subsequent drafts of the manuscript. All the authors, on behalf of the OPT-80-003 clinical trial study group, made the decision to submit the manuscript for publication. The protocol, including the statistical analysis plan, is available with the full text of this article at NEJM.org. All the authors vouch for the accuracy and completeness of the data presented and the fidelity of the reported study to the trial protocol.

Study Population

Patients were enrolled at 52 sites in the United States and 15 sites in Canada. Eligible patients were 16 years of age or older with a diagnosis of C. difficile infection, defined by the presence of diarrhea (a change in bowel habits, with more than three unformed bowel movements in the 24-hour period before randomization) and C. difficile toxin A, B, or both in a stool specimen obtained within 48 hours before randomization. Patients could have received up to four doses of metronidazole or vancomycin in the 24 hour-period before randomization and no other potentially effective concurrent treatments for C. difficile infection (e.g., oral bacitracin, fusidic acid, or rifaximin). Patients with life-threatening or fulminant C. difficile infection, toxic megacolon, previous exposure to fidaxomicin, a history of ulcerative colitis or Crohn's disease, or more than one occurrence of C. difficile infection within 3 months before the start of the study were excluded.

Randomization and Treatment

After providing informed consent, patients were stratified according to whether the current C. difficile infection was the first episode (primary occurrence) or second episode (first recurrence) within the 3 months before the start of the study. An interactive voice-response system and computer-generated randomization schedule were used to provide a randomization number and medication-kit number for each patient. Patients received the study medication orally each day for 10 days, according to an every-6-hour regimen: 200 mg of fidaxomicin every 12 hours with intervening matching doses of placebo or 125 mg of vancomycin every 6 hours. The two study medications and placebo were overencapsulated to look the same. Patients were assessed daily for clinical cure or failure during the 10-day course of therapy. If the criteria for clinical cure were met, the patient was followed for recurrence, by means of a weekly assessment, for 28 days after the last dose of study medication had been administered, with immediate patient-initiated reassessment by the study team if diarrhea recurred.

Definitions

Clinical cure was defined by the resolution of diarrhea (i.e., three or fewer unformed stools for 2 consecutive days), with maintenance of resolution for the duration of therapy and no further requirement (in the investigator's opinion) for therapy for C. difficile infection as of the second day after the end of the course of therapy. Patients who had a marked reduction in the number of unformed stools at the end of treatment but who had residual mild abdominal discomfort were considered by the investigator to have met the criteria for clinical cure, providing that no new anti-infective therapy for C. difficile infection was required. Clinical failure was defined by the persistence of diarrhea, the need for additional therapy for C. difficile infection, or both, in the opinion of the investigator. Global cure was defined as the resolution of diarrhea without recurrence.

Patients who remained in the study and had a follow-up assessment between days 36 and 40 after randomization were evaluated for recurrence. Clinical recurrence was defined by the reappearance of more than three diarrheal stools per 24-hour period within 4 weeks after the cessation of therapy; C. difficile toxin A or B, or both, in stool; and a need for retreatment for C. difficile infection.

Outcomes

Efficacy Evaluation

The primary efficacy end point was the rate of clinical cure in the modified intention-to-treat and per-protocol populations at the end of therapy or at the time of early withdrawal from the study. The modified intention-to-treat population comprised patients with documented C. difficile infection who underwent randomization and received at least one dose of study medication. The per-protocol population comprised patients in the modified intention-to-treat group who received treatment for at least 3 days (in the case of patients with treatment failure) or at least 8 days (in the case of patients with clinical cure), had documented adherence to the protocol, and underwent an end-of-therapy evaluation. The secondary efficacy end point was recurrence of C. difficile infection during the 4-week period after the end of the course of therapy and global cure in the modified intention-to-treat and per-protocol populations.

Microbiologic Evaluation

Fecal samples for toxin assays to verify C. difficile infection and microbiologic testing were obtained at the time of screening or enrollment, at the time of early termination or the end-of-therapy visit in the case of patients with clinical failure, and at visits for the diagnosis and treatment of recurrent infection in the case of patients in whom the disease recurred. Toxin tests were performed at individual study sites. Assays for C. difficile isolation and susceptibility were performed by R.M. Alden Research Laboratory with the use of the Clinical and Laboratory Standards Institute agar dilution method (CLSI M11-A7). Restriction-endonuclease typing23,24 was performed at the Edward Hines, Jr., Veterans Affairs Hospital.

Pharmacokinetic Evaluation

Blood samples for pharmacokinetic evaluation were obtained before and 3 to 5 hours after the first dose of the study medication on day 1 and at the end-of-therapy or early-termination visit. Fecal samples were obtained at the end-of-therapy or early-termination visit. Plasma concentrations (Tandem Labs) and fecal concentrations (MicroConstants) of fidaxomicin were determined with the use of reverse-phase, high-performance liquid chromatography with tandem mass spectrometry.

Safety

Safety was assessed from the day informed consent was provided through the day the last dose of the study drug was administered or the last study visit occurred, whichever came later. The assessment included a physical examination, electrocardiography (ERT), and clinical laboratory testing, including hematologic and biochemical tests and urinalysis (Covance). The safety population comprised patients who received at least one dose of the study medication and underwent at least one safety assessment after the first dose of the study medication. Adverse events were classified according to the terms used in the Medical Dictionary for Regulatory Activities. An adverse event could be reported more than once for a patient, but each patient was counted only once in the incidence count for a particular adverse event.

Statistical Analysis

The trial was designed as a noninferiority study. A one-sided lower 97.5% confidence interval was used in the analysis of the primary end point, the rate of clinical cure, with a noninferiority margin of −10 percentage points. If the lower boundary of the confidence limit was within the 10-percentage-point margin, clinical noninferiority was demonstrated. The secondary end points of recurrence and overall cure, which were prospectively defined as descriptive end points, were analyzed by means of post hoc hypothesis tests with the use of two-sided tests of population proportions that were based on the normal approximation to the binomial distribution, at a significance level of 0.05. Treatment differences according to age, inpatient versus outpatient status, prior occurrence of C. difficile infection versus no prior occurrence, disease severity (mild disease, defined by the presence of 4 to 5 unformed bowel movements per day or a white-cell count of ≤12,000 per cubic millimeter; moderate disease, defined by the presence of 6 to 9 unformed bowel movements per day or a white-cell count of 12,001 to 15,000 per cubic millimeter; or severe disease, defined by the presence of ≥10 unformed bowel movements per day or a white-cell count of ≥15,001 per cubic millimeter), and strain type were also assessed by means of post hoc analyses. The time to resolution of diarrhea, defined as the interval, in hours, from the start of treatment until the time the last unformed bowel movement occurred on the day before resolution of diarrhea, was analyzed with the use of the Kaplan–Meier method, with a Gehan–Wilcoxon test for comparison of resolution time curves. All summary statistics are presented as means ±SD for continuous variables and as numbers and percentages for categorical variables.

Results

Patients

Figure 1. Figure 1. Randomization and Follow-up. Table 1. Table 1. Demographic and Baseline Clinical Characteristics of the Patients in the Modified Intention-to-Treat and Per-Protocol Populations.

A total of 629 patients were enrolled and underwent randomization: 302 received fidaxomicin, and 327 received vancomycin. Figure 1 shows the randomization and follow-up of patients in the study. A total of 596 patients were included in the modified intention-to-treat analysis (287 in the fidaxomicin group and 309 in the vancomycin group) and 548 were included in the per-protocol analysis (265 in the fidaxomicin group and 283 in the vancomycin group). Adherence to the study medication was similar in the two treatment groups; in the modified intention-to-treat population, 91.7% in the fidaxomicin group and 91.4% in the vancomycin group took the assigned doses, and in the per-protocol population, 95.8% and 96.1% in the two groups, respectively, took the assigned doses. The safety population comprised 623 patients — 300 in the fidaxomicin group and 323 in the vancomycin group. The two treatment groups did not differ significantly with respect to baseline characteristics (Table 1).

Clinical Outcomes

Figure 2. Figure 2. Rates of Primary and Secondary End Points.

For the primary outcome of clinical cure, the lower boundary of the 97.5% confidence interval for the difference in cure rates between fidaxomicin and vancomycin was −3.1 percentage points in the modified intention-to-treat (mITT) analysis and −2.6 percentage points in the per-protocol (PP) analysis.

Table 2. Table 2. Rates of Clinical Cure at the End of Therapy, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.

The overall outcomes are shown in Figure 2. The criterion for noninferiority with respect to the primary end point of clinical cure was met in both the modified intention-to-treat and per-protocol populations. In the modified intention-to-treat population, 88.2% of patients in the fidaxomicin group (253 of 287 patients) and 85.8% of those in the vancomycin group (265 of 309) met the criteria for clinical cure (with a lower boundary of the 97.5% confidence interval [CI] for the difference in cure rates of −3.1 percentage points). In the per-protocol population, 92.1% of the patients in the fidaxomicin group (244 of 265 patients) and 89.8% of the patients in the vancomycin group (254 of 283) were considered to have met the criteria for clinical cure (with a lower boundary of the 97.5% CI of −2.6 percentage points). Subgroup analyses of the rates of clinical cure according to the patients' age, inpatient versus outpatient status, prior occurrence of C. difficile infection versus no prior occurrence, treatment for C. difficile infection versus no treatment within 24 hours before the start of the study, baseline severity of the disease, infecting strain type, no response versus response to previous metronidazole therapy, and use versus nonuse of concomitant systemic antimicrobial therapy showed no significant differences between treatments in both the modified intention-to-treat and per-protocol populations (Table 2).

Table 3. Table 3. Rates of Recurrence of C. difficile Infection, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.

Treatment with fidaxomicin was associated with a significantly lower rate of recurrence than was treatment with vancomycin in both the modified intention-to-treat population (15.4% [39 of 253 patients] vs. 25.3% [67 of 265]; a reduction with fidaxomicin of 9.9 percentage points; 95% CI, −16.6 to −2.9; P=0.005) and the per-protocol population (13.3% [28 of 211 patients] vs. 24.0% [53 of 221]; a reduction with fidaxomicin of 10.7 percentage points; 95% CI, −17.9 to −3.3; P=0.004). Fidaxomicin treatment was also associated with lower rates of recurrence when the analysis was performed according to subgroups in both the modified intention-to-treat and per-protocol populations (Table 3). The rates of recurrence in the fidaxomicin and vancomycin groups were similar among patients with the NAP1/BI/027 strain: 24.4% (11 of 45 patients) and 23.6% (13 of 55), respectively (P=0.93). Among patients with other strains, however, the rate of recurrence was lower with fidaxomicin: 7.8% (8 of 103 patients), versus 25.5% (27 of 106) with vancomycin (a reduction with fidaxomicin of 17.7 percentage points; 95% CI, −27.5 to −7.9; P<0.001). This represents a 69% relative reduction in recurrences with fidaxomicin as compared with vancomycin in the subgroup of patients with non–NAP1/BI/027 strains. The relative risk of recurrence for patients with a non–NAP1/BI/027 strain was approximately 3.3 times as high (95% CI, 1.6 to 6.9) among patients receiving vancomycin as among patients receiving fidaxomicin. At the time a recurrence occurred, the same REA strain type as that in the initial occurrence was recovered in 12 of 14 patients in the fidaxomicin group and in 27 of 33 patients in the vancomycin group.

Treatment with fidaxomicin resulted in significantly higher rates of resolution of diarrhea without recurrence than did treatment with vancomycin: 74.6% (214 of 287 patients) versus 64.1% (198 of 309) in the modified intention-to-treat population (an increase with fidaxomicin of 10.5 percentage points; 95% CI, 3.1 to 17.7; P=0.006) and 77.7% (206 of 265 patients) versus 67.1% (190 of 283) in the per-protocol population (an increase with fidaxomicin of 10.6 percentage points; 95% CI, 3.1 to 17.9; P=0.006).

The median time to resolution of diarrhea was shorter in the fidaxomicin group than in the vancomycin group (58 hours vs. 78 hours in the modified intention-to-treat population and 55 hours vs. 69 hours in the per-protocol population) among both inpatients (91 hours vs. 120 hours and 72 hours vs. 78 hours in the two populations, respectively) and outpatients (47 hours vs. 61 hours and 47 hours vs. 60 hours in the two populations, respectively). None of these differences were significant.

Safety

There were no significant differences between the fidaxomicin group and the vancomycin group in the rates of adverse events or serious adverse events (see Table 1 and Table 2 in the Supplementary Appendix, available at NEJM.org). The occurrence of any adverse event during the treatment period until 7 days after treatment was reported in 62.3% of the patients in the fidaxomicin group and 60.4% of the patients in the vancomycin group; the occurrence of any serious adverse event was reported in 25.0% and 24.1% of the patients in the two groups, respectively. Adverse events possibly or definitely related to the study treatment were mild gastrointestinal and nonspecific symptoms; the rate of these events was similar in the two groups (9.7% and 9.0% in the fidaxomicin and vancomycin groups, respectively). Significantly more serious adverse events related to laboratory test results occurred in the fidaxomicin group than in the vancomycin group (4.7% vs. 1.2%, P=0.01), without an obvious pattern (Table 2 in the Supplementary Appendix). No subjects discontinued the study as a result of intolerance or allergy to the study medications.

Microbiologic Evaluation

Measurement of in vitro antimicrobial activity against C. difficile showed minimum inhibitory concentrations at or below 0.25 μg per milliliter for 90% of isolates in the case of fidaxomicin and 2.0 μg per milliliter in the case of vancomycin. There was no relationship between the minimum inhibitory concentration of baseline clinical isolates and the clinical outcome (cure or recurrence). No shifts in susceptibility to fidaxomicin or vancomycin occurred during the study.

Pharmacokinetic Evaluation

The mean (±SD) plasma level of fidaxomicin after administration of the drug on day 1 was 22.8±26.5 ng per milliliter (range, 0.4 to 185.0). In addition, no plasma accumulation was found between day 1 and the end of therapy. The mean end-of-therapy fecal concentration of fidaxomicin was 1225.1±759.0 μg per gram (range, 31.7 to 4640.0), which is 4900 times as high as the minimum inhibitory concentration of 0.25 μg per milliliter for 90% of isolates against C. difficile.

Discussion

During the past decade, the clinical profile of C. difficile infection has worsened, with increased numbers of cases, greater morbidity, an increased incidence of complications requiring colectomy, and rising mortality. These worsening disease markers have occurred in parallel with the emergence of the new and more virulent BI/NAP1/027 C. difficile strain, although efforts to link a poor outcome of infection to the hypervirulent strain have not been uniformly successful.4,25-29 Regardless of the cause, C. difficile infection has become a more serious disease in North America and Europe, even in countries with a relatively low incidence of the BI/NAP1/027 strain.

The initial therapeutic approach to a diagnosed case of C. difficile infection is to discontinue the antibiotic that precipitated the infection. Although a minority of cases will resolve with cessation of antibiotic selection pressure, the risk of worsening disease mandates that treatment be directed against the pathogen. The standard treatments are metronidazole and vancomycin. Both drugs have liabilities. Metronidazole is efficiently absorbed, so that only small quantities reach the colon,30 which is a pharmacodynamic disadvantage in a primarily mucosal or luminal infection. In addition, it has systemic side effects, such as nausea, headache, taste perversion, and peripheral neuropathy. Furthermore, several studies have shown that metronidazole therapy, as compared with vancomycin therapy, is associated with more failures and higher rates of recurrence, especially among severely ill patients.31,32 Concern has been expressed that oral administration of metronidazole or vancomycin may induce the emergence of vancomycin-resistant enterococci.33

One of the most problematic aspects of C. difficile infection is the rate of recurrence. After successful initial treatment with metronidazole or vancomycin, 20 to 30% of patients have a recrudescence of illness within 60 days — but usually within the first 2 weeks.34 Retreatment with metronidazole or vancomycin resolves the condition in most patients, but approximately one third (or more) of patients have one or more additional recurrences. Severe illness and deaths associated with relapses have been reported at approximately the same rate as those associated with the primary event.

This was a phase 3 trial of fidaxomicin, a macrocyclic antibiotic that has a narrow antimicrobial spectrum, with activity against C. difficile and most strains of staphylococci and enterococci but negligible activity against gram-negative organisms and fungi. Fidaxomicin is poorly absorbed from the intestinal tract and is associated with the same low incidence of systemic side effects as oral vancomycin. The major benefits of fidaxomicin in this comparative study with vancomycin were a 45% relative reduction in recurrences and a correspondingly improved rate of global cure, an outcome that is termed “symptomatic cure” by Nelson.35 For the 35.9% of patients with the BI/NAP1/027 strain, the rates of cure and recurrence in the per-protocol analysis were the same as those with vancomycin, but for the 64.1% of patients with other strain types, the recurrence rate was 7.8% with fidaxomicin as compared with 25.5% with vancomycin (a 69% relative reduction). Besides the obvious benefit to the patient, the prevention of recurrence would eliminate the costs of treating additional episodes of C. difficile infection and should reduce the rate of person-to-person transmission.

Certain microbiologic characteristics may explain the favorable results with respect to recurrence. Fidaxomicin rapidly kills C. difficile (i.e., it is bactericidal), whereas vancomycin inhibits growth (i.e., it is bacteriostatic). Along with its narrow antimicrobial spectrum,15-18 fidaxomicin also has a prolonged postantibiotic effect against C. difficile, which is not observed in the case of vancomycin. Vancomycin treatment results in the suppression of organisms of the bacteroides group in the fecal flora, which are considered to be markers of normal anaerobic microflora,21 whereas fidaxomicin preserves these organisms in the flora of patients.36 The anaerobic bowel flora maintains “colonization resistance,” which prevents the introduction or persistence of pathogens and may inhibit the reemergence of C. difficile. Preservation of the intestinal flora should also theoretically reduce the likelihood of selection for overgrowth of vancomycin-resistant enterococci. In conclusion, fidaxomicin and vancomycin have similar effectiveness with respect to the clinical resolution of acute diarrheal disease due to C. difficile infection, but more sustained or durable resolution of disease (i.e., improved global cure) is achieved with fidaxomicin — a finding that may be attributable to lesser impairment of the intestinal microbiome during treatment of the infection.

Funding and Disclosures

Drs. Louie, Miller, Mullane, Weiss, Lentnek, and Golan report that their respective institutions received per-case funding from Optimer Pharmaceuticals to support patient expenses. Drs. Louie, Miller, Mullane, and Golan report receiving support from Optimer Pharmaceuticals for travel to meetings for the conduct of the clinical trial or presentation of the results of the clinical trial, and Drs. Louie, Miller, and Mullane report receiving honoraria from Optimer Pharmaceuticals for participation in additional meetings related to investigative planning for fidaxomicin. In addition, Dr. Louie reports receiving honoraria or consulting fees from Merck, Cubist Pharmaceuticals, ViroPharma, Cempra, and Iroko Pharmaceuticals, and being listed on a fidaxomicin patent; Dr. Miller, receiving honoraria or consulting fees from Merck, Iroko Pharmaceuticals, and Salix Pharmaceuticals; Dr. Weiss, receiving honoraria or consulting fees from Abbott, Bayer, Pfizer, and Genzyme; Dr. Shue, being an employee of and owning stock options in Optimer Pharmaceuticals; Dr. Sears, being an employee of and owning stock options in Optimer Pharmaceuticals and being listed as an inventor on a fidaxomicin patent; and Dr. Gorbach, being a part-time employee of Optimer Pharmaceuticals, receiving honoraria from and owning stock options in Cempra, and holding a patent on lactobacillus GG probiotic and β-glucan.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

No other potential conflict of interest relevant to this article was reported.

This article (10.1056/NEJMoa0910812) was updated on September 15, 2011, at NEJM.org.

Author Affiliations

From the University of Calgary, Calgary, AB, Canada (T.J.L.); McGill University (M.A.M.) and the University of Montreal (K.W.) — both in Montreal; the University of Chicago, Chicago (K.M.M.); Wellstar Infectious Disease, Marietta, GA (A.L.); Tufts Medical Center, Boston (Y.G., S.G.); and Optimer Pharmaceuticals, San Diego, CA (S.G., P.S., Y.-K.S.).

Address reprint requests to Dr. Louie at the Division of Infectious Diseases, Departments of Medicine and Microbiology and Infectious Diseases, University of Calgary, Foothills Hospital, 1403 29 St. NW, Calgary, AB T2N 4J8, Canada, or at .

Additional investigators in the OPT-80-003 Clinical Study Group are listed in the Supplementary Appendix, available at NEJM.org.

Supplementary Material

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Citing Articles (1065)

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    Letters

    Figures/Media

    1. Figure 1. Randomization and Follow-up.
      Figure 1. Randomization and Follow-up.
    2. Table 1. Demographic and Baseline Clinical Characteristics of the Patients in the Modified Intention-to-Treat and Per-Protocol Populations.
      Table 1. Demographic and Baseline Clinical Characteristics of the Patients in the Modified Intention-to-Treat and Per-Protocol Populations.
    3. Figure 2. Rates of Primary and Secondary End Points.
      Figure 2. Rates of Primary and Secondary End Points.

      For the primary outcome of clinical cure, the lower boundary of the 97.5% confidence interval for the difference in cure rates between fidaxomicin and vancomycin was −3.1 percentage points in the modified intention-to-treat (mITT) analysis and −2.6 percentage points in the per-protocol (PP) analysis.

    4. Table 2. Rates of Clinical Cure at the End of Therapy, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.
      Table 2. Rates of Clinical Cure at the End of Therapy, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.
    5. Table 3. Rates of Recurrence of C. difficile Infection, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.
      Table 3. Rates of Recurrence of C. difficile Infection, According to Subgroups, in the Modified Intention-to-Treat and Per-Protocol Populations.

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