This randomized clinical trial examines whether prophylactic oral vancomycin vs placebo reduces recurrent Clostridioides difficile infection in adults receiving antibiotics for another indication.
Key Points
Question
Is oral vancomycin prophylaxis effective for recurrent Clostridioides difficile infection (CDI) during antibiotic treatment for non-CDI indications?
Findings
In this randomized clinical trial of 81 participants who had completed treatment for a CDI and were taking systemic antibiotics for a non-CDI indication, recurrent CDI occurred in 43.6% of participants in the oral vancomycin group vs 57.1% in the placebo group at 8 weeks. However, the study was underpowered and this difference did not reach statistical significance.
Meaning
Other interventions should be investigated for their effectiveness in preventing CDI recurrence after non–CDI-indicated antibiotic therapy.
Abstract
Importance
Systemic antibiotic use for patients with a non–Clostridioides difficile infection (CDI) is a major risk factor for recurrent CDI. Increasing use of oral vancomycin for secondary prophylaxis against recurrent CDI in this context has uncertain efficacy.
Objective
To evaluate whether oral vancomycin prophylaxis compared with placebo is effective against recurrent CDI during and 8 weeks after the end of study treatment.
Design, Setting, and Participants
This phase 2, placebo-controlled, double-blind randomized clinical trial was conducted in 4 large health systems across the upper Midwest US. Adults who had completed treatment for CDI within the past 180 days and were taking a systemic antibiotic for a non-CDI indication were enrolled between May 21, 2018, and March 30, 2023, and followed up for 8 weeks after the end of study treatment.
Intervention
Participants were randomized 1:1 to 125 mg of oral vancomycin or placebo once daily during antibiotic use for a non-CDI plus 5 days following cessation of those antibiotics.
Main Outcomes and Measures
The primary outcome was recurrent CDI incidence during treatment and the 8-week follow-up period. The secondary outcome was vancomycin-resistant Enterococcus carriage in stool.
Results
Among 81 randomized participants (median age, 59 years [IQR, 50-67 years]), all were included in the primary as-randomized analysis (39 in the vancomycin group; 42 in the placebo group). Sixty patients (74.1%) completed 8-week follow-up and were included in the secondary as–completed treatment analysis (31 in the vancomycin group; 29 in the placebo group). Recurrent CDI occurred in 17 of 39 participants in the oral vancomycin group (43.6%) and 24 of 42 in the placebo group (57.1%; absolute difference in percentage, −13.5% [95% CI, −35.1% to 8.0%]). Adverse events occurred in 27 of 39 participants in the oral vancomycin group (69.2%) and 27 of 42 in the placebo group (64.3%). Vancomycin-resistant Enterococcus carriage was found in 15 of 30 patients in the oral vancomycin group (50.0%) and 6 of 25 in the placebo group (24.0%) (P = .048) 8 weeks after treatment.
Conclusions and Relevance
In this randomized clinical trial, the incidence of recurrent CDI was lower (though did not reach significance) in participants taking oral vancomycin compared with those taking placebo. Because the study was underpowered, it was unable to reveal firm conclusions about the efficacy (or lack thereof) of vancomycin prophylaxis with respect to recurrent CDI.
Trial Registration
ClinicalTrials.gov Identifier: NCT03462459
Introduction
Clostridioides difficile infection (CDI) is the most common cause of health care–associated diarrhea.1,2 Over one-third of patients who develop CDI will develop 1 or more recurrences; recurrence risk increases with each episode.3,4 The main risk factor for CDI is antibiotic use.5 Following therapy and resolution of initial CDI, recurrent CDI may be triggered when antibiotics are given for other indications.2,6 Prevention is essential to reduce the myriad medical, social, and psychological consequences of recurrent CDI.7,8 Interventions to prevent recurrent CDI during exposure to systemic antibiotics in a person with prior but not current CDI are needed in clinical practice.9
Oral vancomycin for prophylaxis against recurrent CDI has been used in clinical practice based on retrospective cohort studies showing possible favorable outcomes.10,11 However, their observational designs precluded assessing efficacy because of confounding, heterogeneity in data availability, inclusion criteria, study populations, and uncertainty regarding the magnitude of the effect.12,13,14,15,16 In a prospective trial in asymptomatic patients colonized with C difficile, oral vancomycin was effective in eliminating fecal C difficile during and immediately after treatment, but most participants began to shed C difficile again within approximately 3 weeks of completing oral vancomycin treatment.17
Whether oral vancomycin prophylaxis is effective against recurrent CDI remains unanswered. Furthermore, most studies have looked primarily at benefits of treatment without evaluating potential risks.12,13,14,15,16,18 This is a critical gap in the field, as oral vancomycin is not without risk (particularly, vancomycin-resistant Enterococcus [VRE] gut proliferation).19,20,21,22
We conducted a prospective randomized clinical trial to assess the effect of oral vancomycin prophylaxis on recurrent CDI incidence and VRE carriage of the gut in patients with a recent CDI who were taking systemic antibiotics for a non-CDI indication. This study aimed to evaluate whether a low dose of oral vancomycin administered during and immediately following non–CDI-indicated antibiotic treatment was effective in preventing recurrent CDI.
Methods
Trial Design
We conducted a phase 2, double-blind, placebo-controlled randomized clinical trial of adult patients with a recent CDI who were prescribed systemic antibiotics for non-CDI indications (NCT03462459). This was a multicenter study with participants enrolled at 4 large health systems: University of Wisconsin (UW) Health (Madison, Wisconsin) from May 21, 2018, through March 30, 2023; Medical College of Wisconsin (MCW; Milwaukee, Wisconsin) from February 1, 2019, through December 31, 2022; Henry Ford Hospital (Detroit, Michigan) from October 1, 2020, through December 31, 2021; and Mayo Clinic (Rochester, Minnesota) from November 1, 2021, through October 31, 2022. Three health systems (including UW Health and MCW) were initially included, with 1 dropping out without enrolling. Henry Ford Hospital was added in October 2020 and Mayo Clinic was added in November 2021 to increase enrollment. The trial protocol and statistical analysis plan are available in Supplement 1. The protocol was approved by the UW-Madison institutional review board, which served as the institutional review board of record for all study sites. All participants provided written informed consent via paper or electronic form. This study followed the Consolidated Standards of Reporting Trials (CONSORT) 2010 reporting guideline.
Participants
Adults were eligible to participate if they had a documented diagnosis of 1 or more CDIs within the past 180 days, had completed CDI treatment, and were receiving non–CDI-indicated systemic antibiotics for 2 weeks or less. Participants could not have received more than 72 hours of systemic antibiotics at enrollment. Individuals were ineligible to participate if they had a contraindication to vancomycin use, were currently using oral vancomycin, or were using metronidazole or tetracycline monotherapy. Individuals were also ineligible if they had suspected CDI or other relevant gastrointestinal conditions, such as bacterial gastrointestinal infection, at enrollment; recent major gastrointestinal surgery; or history of total colectomy or bariatric surgery. A full list of inclusion and exclusion criteria is available in the trial protocol (Supplement 1).
Study coordinators (included K.H.) and investigators (physicians or advanced practice practitioners; included M.B.G., M.R., S.K., C.S., N.S.) reviewed inpatients’ and outpatients’ electronic medical records (EMRs) to determine their eligibility (positive C difficile test result within the past 180 days and a new antibiotic prescription for a non-CDI indication). Eligible individuals were approached and invited to attend an enrollment visit (visit 1), during which participants provided informed consent and underwent a clinical assessment to collect demographics, medical history, dietary information, baseline bowel movement measures (via the Bristol Stool Scale23), and current medications. Participants’ race and ethnicity data were required to be collected by the funding agency and were determined from EMR data. Racial groups participants could select were American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or Other Pacific Islander, White, and multiracial, and ethnic groups were Hispanic and non-Hispanic. Participants also provided a baseline stool sample or perirectal swab sample prior to beginning study treatment or placebo. Participants were then randomized to a study group and were provided the study intervention or placebo.
Patients had weekly telephone calls from their first study treatment dose through 8 weeks after completing treatment to monitor for adverse events and recurrent CDI. Patients had 2 visits after enrollment: visit 2 occurred within 1 week after the patient took their last study capsule, and visit 3 occurred 8 weeks after the patient took their last study capsule.
Recruitment and enrollment procedures were impacted by the COVID-19 pandemic, as nonessential clinical procedures, study enrollment, and in-person contact with patients and study participants were suspended in March 2020. The coordinating site received an exemption to continue the study after June 2020.
Randomization
Participants were randomized in a 1:1 block scheme to the intervention (oral vancomycin) or placebo arm. A randomization schedule was created by the study biostatistician using random number generation software, and randomization was stratified by site. The randomization schedule was provided to site pharmacists, who distributed intervention or placebo materials directly to participants and/or clinical staff. Participants and study staff were blinded to study group assignment. Patients who had excess vancomycin or placebo doses after completing their treatment schedule were asked to return or dispose of the excess doses.
Interventions
The intervention was 125 mg of oral vancomycin (Akorn). The placebo was 125 mg of lactose national formulary grade monohydrate powder encapsulated in empty size-1 gelatin (blue and white) capsules (both from Fagron). Sites purchased supplies and encapsulated study drug and/or placebo. Site investigational pharmacies could purchase a different generic from alternative sources if preferred materials were not available. Vancomycin and gelatin capsules that most closely resembled each other were selected.
Hospitalized patients received the study capsules from clinical staff, and treatment administration was scheduled during the stay. Outpatients self-administered capsules. Capsules were taken orally once per day for the duration of antibiotic use plus 5 days following cessation of non–CDI-indicated antibiotics. Participants recorded the dates of capsule ingestion on a medication diary.
Outcomes
The primary objective was to evaluate the efficacy of oral vancomycin prophylaxis for recurrent CDI. The primary end point was incidence of recurrent CDI in participants using oral vancomycin compared with incidence in participants taking placebo during treatment and through 8 weeks following completion of treatment. Incidence of recurrent CDI was collected via weekly telephone calls with participants. Participants reporting 3 or more type-5 to type-7 stools (via the Bristol Stool Scale23) above their baseline bowel movements in a 24-hour period provided stool samples to the coordinating site laboratory for 2-step testing to confirm recurrent CDI. Stool samples were cultured for C difficile, with toxigenic polymerase chain reaction confirmation for positive culture results. A combined C difficile toxin A and B enzyme-linked immunoassay (ELISA) (TECHLAB Inc) conducted by the coordinating site laboratory followed by a cytotoxin cell culture assay (if ELISA results were negative) at ARUP Laboratories was used to identify toxigenic C difficile for the recurrent CDI outcome.
The secondary objective was comparing gut VRE carriage in patients taking oral vancomycin vs placebo. Patients self-collected stool samples (and/or perirectal swab samples if stool could not be produced) at enrollment, visit 2, and visit 3 and shipped them to the coordinating site laboratory. The presence of VRE was identified through broth enrichment following culture onto selective agar.
Sample Size
Power and sample size were based on the primary outcome (recurrent CDI incidence). Previous research showed an absolute decrease of 22% in the proportion of patients with CDI recurrence (h = 0.66) between those receiving oral vancomycin and those receiving placebo.11 We estimated that using a 1:1 random allocation ratio with 80% power and 2-tailed P < .05, a sample size between 84 and 144 total participants would be needed depending on the level of attrition. We proposed a total sample size of 150 participants, anticipating no more than a 20% attrition rate, to detect effects as low as h = 0.57, or a 20.5% decrease in recurrence.
Statistical Analysis
Statistical analyses are primarily reported for the population randomized in the study (as-randomized group). The secondary statistical analyses are reported for the population that completed all 3 visits (as–completed treatment group). Proportional tests were conducted to compare the episodes of CDI recurrence in the 8 weeks following the completion of the study intervention in patients receiving vancomycin vs patients receiving placebo using the χ2 test. Log-rank tests were conducted to compare the proportions without recurrence within the 8-week period between patients receiving vancomycin and those receiving placebo with the Kaplan-Meier method. A nonparametric Wilcoxon rank sum test was used to compare distributions of the number of days to the first recurrence of CDI after starting oral vancomycin or placebo. The χ2 test was also conducted to compare the proportions of patients who had positive VRE results. The significance level was set to 2-sided P ≤ .05. All statistical analyses were conducted in R, version 4.4.0 (R Project for Statistical Computing).24
Results
Participants
Between May 21, 2018, and March 30, 2023, 4054 individuals were assessed for eligibility via EMR, and 553 eligible individuals were approached. Of those, 470 declined participation, including 185 (39.4%) who were already taking oral vancomycin and did not wish to discontinue (156 of the 185 [84.3%] were at a single site). A total of 83 individuals enrolled, and 81 were randomized (39 to oral vancomycin and 42 to placebo) (Figure 1). Table 1 displays baseline characteristics including demographics and medical history within each treatment group (oral vancomycin or placebo). Median age of the participants was 59 years (IQR, 50-67 years); 49 (60.5%) were female, and 32 (39.5%) were male. One participant (1.2%) was American Indian or Alaska Native, 1 (1.2%) was Asian, 9 (11.1%) were Black or African American, none were Native Hawaiian or Other Pacific Islander, 68 (84.0%) were White, none were multiracial, and 2 (2.5%) had unknown race. Of 80 participants with ethnicity data, 2 (2.5%) were Hispanic and 78 (97.5%) were non-Hispanic. Demographic factors and baseline comorbid conditions were evenly distributed across study groups.
Figure 1. Participant Selection and Flow in the Trial of Oral Vancomycin for the Prevention of Recurrent Clostridioides difficile Infection (CDI).
GI indicates gastrointestinal; SOC, standard of care.
aOther clinical reasons for exclusion included current diarrhea; pregnancy or lactation; life expectancy under 6 months; died after screening but before being approached by study team; other known (non-CDI) bacterial infection, toxic megacolon, or small bowel ileus; known to be colonized with C difficile; or other complex medical history or inappropriate for study per clinician (eg, total colectomy or bariatric surgery, allergy to oral vancomycin, or inability to swallow capsules).
Table 1. Baseline Participant Demographics and Medical History.
| Characteristic | Patientsa | |
|---|---|---|
| Oral vancomycin (n = 39) | Placebo (n = 42) | |
| Age, median (IQR), y | 58 (49-67) | 59 (50-66) |
| Sex | ||
| Female | 24 (61.5) | 25 (59.5) |
| Male | 15 (38.5) | 17 (40.5) |
| Race | ||
| American Indian or Alaskan Native | 0 | 1 (2.4) |
| Asian | 1 (2.6) | 0 |
| Black or African American | 3 (7.7) | 6 (14.3) |
| Native Hawaiian or Other Pacific Islander | 0 | 0 |
| White | 34 (87.2) | 34 (81.0) |
| Multiracial | 0 | 0 |
| Unknown | 1 (2.6) | 1 (2.4) |
| Ethnicity | ||
| Hispanic | 1/39 (2.6) | 1/41 (2.4) |
| Non-Hispanic | 38/39 (97.4) | 40/41 (97.6) |
| Smoking status | ||
| Have not smoked within 6 mo | 32/33 (97.0) | 35/38 (92.1) |
| Smoked within 6 mo | 1/33 (3.0) | 3/38 (7.9) |
| Fecal microbiota transplant history | ||
| Yes | 1/39 (2.6) | 0 |
| No | 38/39 (97.4) | 41/41 (100) |
| Medical history | ||
| Head, ears, nose, throat | 26 (66.7) | 29 (61.9) |
| Respiratory | 28 (71.8) | 22 (52.4) |
| Cardiovascular | 32 (82.1) | 30 (71.4) |
| Gastrointestinal | 33 (84.6) | 36 (85.7) |
| Genitourinary | 34 (87.2) | 35 (83.3) |
| Musculoskeletal | 28 (71.8) | 35 (83.3) |
| Neurologic | 16 (41.0) | 21 (50.0) |
| Endocrine or metabolic | 30 (76.9) | 32 (76.2) |
| Lymphatic | 17 (43.6) | 10 (23.8) |
| Dermatologic | 17 (43.6) | 13 (31.0) |
| Psychiatric | 23 (59.0) | 24 (57.1) |
| Other | 22 (56.4) | 26 (61.9) |
| Major surgery | 2 (5.1) | 4 (9.5) |
| Unknown or not reported | 0 | 2 (4.7) |
Data are presented as number or number/total number (percentage) of participants unless otherwise indicated.
Because of COVID-19 pandemic impacts and lack of funding for project extensions, enrollment ended at 81 participants. Overall, 55 (67.9%) were enrolled at UW Health, 18 (22.2%) at MCW, 6 (7.4%) at Henry Ford Hospital, and 2 (2.5%) at Mayo Clinic. A total of 60 participants (74.1%), with 29 in the placebo group (69.0%) and 31 in the oral vancomycin group (79.5%), completed all study activities through visit 3 and were included in the secondary as–completed treatment analysis (eTable 1 in Supplement 2).
Primary Outcome
Eight weeks after completing treatment, 17 of 39 patients in the oral vancomycin group (43.6%) and 24 of 42 in the placebo group (57.1%) experienced a CDI recurrence (absolute difference in percentage, −13.5%; 95% CI, −35.1% to 8.0%; P = .22) (Table 2). There was no statistically significant difference in nonrecurrence probability over time (from start of oral vancomycin or placebo treatment) between treatment groups (Figure 2A). We also did not find a difference in the distribution of the number of days to first recurrence of CDI between treatment groups (Figure 2B and C). Similar results were observed in the as–completed treatment analysis (eAppendixes 1 and 2, eTable 1, and eFigure 1 in Supplement 2). There was a slight difference between curves when comparing CDI recurrence between study sites (eAppendix 2, eTable 2, and eFigure 2 in Supplement 2). There was no difference in recurrent CDI outcomes when evaluating subgroups at particularly high risk of recurrent CDI (use of high-risk antibiotics, having an immunocompromised condition, or age ≥65 years) (eAppendixes 3-5, eTables 3-5, and eFigures 3-5 in Supplement 2).25,26
Table 2. As-Randomized Analysis of Primary and Secondary Outcomesa.
| Outcome | Patients, No. (%) | Absolute difference in percentage, % (95% CI) | P value | |
|---|---|---|---|---|
| Oral vancomycin | Placebo | |||
| Primary outcome | ||||
| CDI recurrence within 8 wk | 17/39 (43.6) | 24/42 (57.1) | −13.5 (−35.1 to 8.0) | .22 |
| Secondary outcomeb | ||||
| VRE carriage at visit 1 | 20/37 (54.1) | 27/40 (67.5) | −13.4 (−35.1 to 8.2) | .23 |
| VRE carriage at visit 3 | 15/30 (50.0) | 6/25 (24.0) | 26.0 (1.5 to 50.5) | .048 |
Abbreviations: CDI, Clostridioides difficile infection; VRE, vancomycin-resistant enterococcus.
The primary and secondary outcomes were analyzed using a χ2 test without continuity correction.
Stool samples to measure VRE carriage were collected within 14 days of 8 weeks following the end of treatment. VRE carriage results were missing from 9 patients in the oral vancomycin group (23.1%) and 17 patients in the placebo group (40.5%) at visit 3.
Figure 2. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the As-Randomized Population and Distribution of Number of Days to First Recurrence of Clostridioides difficile Infection After Beginning Oral Vancomycin or Placebo.
Day 0 corresponds to the first day of oral vancomycin or placebo use as part of this study.
Secondary Outcome
There was no difference in VRE carriage between treatment groups at enrollment (visit 1) (Table 2). Participants taking oral vancomycin had marginally more VRE carriage 8 weeks after completing treatment (visit 3) (15 of 30 [50.0%]) than participants taking placebo (6 of 25 [24.0%]) (absolute difference in percentage, 26.0%; 95% CI, 1.5%-50.5%; P = .048). However, in the placebo group, there was a significant reduction in participants with VRE carriage between visit 1 (27 of 40 [67.5%]) and visit 3 (6 of 25 [24.0%]) (absolute difference in percentage, 43.5%; 95% CI, 21.3%-65.7%; P < .001). There was no difference in VRE carriage between visit 1 (20 of 37 [54.1%]) and visit 3 (15 of 30 [50.0%]) in the oral vancomycin group (absolute difference in percentage, 4.1%; 95% CI, −20.0% to 28.1%; P = .74).
Adverse Events
In the as-randomized population, 27 participants in the oral vancomycin group (69.2%) and 27 participants in the placebo group (64.3%) reported 1 or more adverse events (Table 3). Of all 88 adverse events, 85 (96.6%) were deemed to be unrelated or unlikely to be related to the study treatment. The most common adverse event was gastrointestinal disorders, reported in 20 participants taking oral vancomycin (51.3%) and 20 participants taking placebo (47.6%).
Table 3. Adverse Events During the 8 Weeks Following Treatment.
| Adverse event | Patients, No. (%) | |
|---|---|---|
| Vancomycin arm (n = 39) | Placebo arm (n = 42) | |
| Any | 27 (69.2) | 27 (64.3) |
| Blood and lymphatic system disorders | 1 (2.6) | 0 |
| Cardiac system disorders | 2 (5.1) | 0 |
| Ear and labyrinth disorders | 0 | 1 (2.4) |
| Endocrine disorders | 1 (3.3) | 0 |
| Gastrointestinal disorders | 20 (51.3) | 20 (47.6) |
| General disorders and administration site conditions | 3 (7.7) | 3 (7.1) |
| Infections and infestations | 8 (20.5) | 6 (14.3) |
| Injury, poisoning, and procedural complications | 0 | 2 (4.8) |
| Investigations | 0 | 1 (2.4) |
| Metabolism and nutrition disorders | 1 (2.6) | 1 (2.4) |
| Musculoskeletal and connective tissue disorders | 4 (10.3) | 1 (2.4) |
| Nervous system disorders | 1 (2.6) | 2 (4.8) |
| Psychiatric disorders | 1 (2.6) | 1 (2.4) |
| Kidney and urinary disorders | 4 (10.3) | 0 |
| Reproductive system and breast disorders | 0 | 1 (2.4) |
| Respiratory, thoracic, and mediastinal disorders | 1 (2.6) | 1 (2.4) |
| Skin and subcutaneous tissue disorders | 2 (5.1) | 2 (4.8) |
| Surgical and medical procedures | 2 (5.1) | 2 (4.8) |
| Vascular disorders | 0 | 4 (9.5) |
Discussion
In this double-blind, placebo-controlled randomized clinical trial, patients who had CDI in the previous 180 days who took 125 mg of prophylactic oral vancomycin during and for 5 days after a course of non–CDI-indicated antibiotic therapy had lower rates of recurrent CDI than patients taking a placebo; however, this study was underpowered to find a statistically significant difference. There were high rates of recurrent CDI in both the treatment (43.6%) and the placebo (57.1%) groups. However, the study population was at particularly high risk for recurrent CDI given that all participants had a recent CDI and used systemic antibiotics.26,27 The median age of participants was 59 years, and older age is also a risk factor for recurrent CDI.26
Previous prospective randomized clinical trials have had mixed findings on the effectiveness of oral vancomycin prophylaxis. A trial in asymptomatic patients with C difficile colonization found that oral vancomycin was temporarily effective in reducing C difficile shedding during and immediately after treatment, but most patients receiving oral vancomycin returned to shedding C difficile within approximately 3 weeks of completing treatment.17 Another randomized trial of oral vancomycin to prevent initial CDI in high-risk patients receiving systemic antibiotics found a significant reduction in health care facility–onset CDI in patients receiving oral vancomycin prophylaxis compared with no prophylaxis.18 However, the follow-up period was limited. We had a longer follow-up period of 8 weeks to measure recurrent CDI incidence after completion of treatment.
In the absence of clear evidence, use of oral vancomycin prophylaxis has remained an unresolved issue among leading health organizations. Oral vancomycin prophylaxis during non–CDI-indicated systemic antibiotic therapy has been conditionally recommended for patients at high risk of CDI recurrence by the American College of Gastroenterology (ACG), which notes that this recommendation is supported by low-quality evidence and that there is a need for prospective clinical trials.28 The Infectious Diseases Society of America found insufficient evidence to make a recommendation in its 2017 clinical practice guidelines and did not address the question in its 2021 update.29,30 The European Society of Clinical Microbiology and Infectious Diseases 2021 update did not recommend routine prophylaxis during antibiotic treatment but suggested prophylaxis may be appropriate in select patients with recurrent CDI after antibiotic use and with careful consideration of risks and benefits.31
Our clinical trial used the ACG dosage and treatment duration for prophylactic oral vancomycin (125 mg of oral vancomycin once per day for the duration of non–CDI-indicated antibiotic therapy plus 5 days after the course of antibiotics was completed). Previous studies have evaluated different dosages and durations of oral vancomycin treatment.17,18 We selected a low dosage to reduce the risk of gut dysbiosis. A meta-analysis of oral vancomycin prophylaxis in a variety of patient populations found recurrent CDI to be less likely in patients taking oral vancomycin.32 In addition, recent meta-analyses found the lower dosage and longer duration that we used in our study to be associated with protective effects against CDI.32,33 However, nearly all prior studies on this topic have been retrospective.9,32 A strength of our study was its design as a placebo-controlled, double-blind randomized clinical trial, allowing for prospective analyses of the effectiveness of oral vancomycin in reducing recurrent CDI outcomes compared with placebo. Because our study was underpowered, we were not able to confirm these previous findings10,11,32,33; we did not find a significant reduction in recurrent CDI in patients prospectively assigned to use of oral vancomycin compared with those receiving placebo.
Vancomycin use has been associated with VRE colonization.34 While other studies have not found an increase in VRE infections after oral vancomycin treatment,32 our study evaluated carriage of VRE in the gut, a risk factor for future VRE infection.34 We found that in patients taking placebo, there was a significant reduction in the proportion with VRE carriage from visit 1 (27 of 40 [67.5%]) to visit 3 (6 of 25 [24.0%]) (P < .001), but VRE carriage did not change in patients taking oral vancomycin.
Prior to and during our study, clinical oral vancomycin prophylaxis use at participating sites was often based on institutional and practice preferences rather than clinical trial evidence to show benefit. Many patients were prescribed oral vancomycin prophylaxis prior to being identified for possible enrollment in this study. During recruitment, we noted many participants who did not wish to participate because they were already taking oral vancomycin prophylaxis and did not wish to discontinue use due to the possibility of being randomized to the placebo group. Of the 470 eligible patients who were approached but declined participation, 185 (39.4%) cited this concern. Of these 185 patients, 156 (84.3%) were located at 1 site. Given the difference in protocols for preventing recurrent CDI across different sites and the impact of this on potential patient populations, maintaining equipoise will be a consideration in any future studies.
Limitations
This study has limitations. We did not reach our target enrollment of 150 participants, ultimately randomizing 81 participants. While we have reported the trends and findings in this population, the study was underpowered, which precludes drawing conclusions from findings.
Our study also did not evaluate broader effects on the gut microbiome that may be impacted by systemic antibiotic and oral vancomycin use. Vancomycin alters the gut microbiome, including reducing baseline commensals, which may allow C difficile to colonize and establish.35,36 Additional research on patient populations, dosages, and dosing schedules may be needed to determine whether oral vancomycin may provide a greater protective effect within specific parameters while maintaining a low risk profile for patients.
Conclusions
In this randomized clinical trial, among patients with a recent CDI and taking a subsequent non–CDI-indicated antibiotic course, patients taking oral vancomycin had reduced rates of recurrent CDI compared with patients taking a placebo. However, our study was underpowered to identify a statistically significant difference. There was a marginal but significant difference in VRE carriage in stool samples at 8 weeks after treatment between patients taking oral vancomycin and patients taking a placebo; however, participants taking placebo had a decrease in VRE carriage after completing treatment that was not observed in participants taking oral vancomycin. While this study was underpowered due to enrollment challenges, these findings suggest that other interventions should be investigated for their effectiveness in preventing CDI recurrence after non–CDI-indicated antibiotic therapy.
Trial Protocol
eAppendix 1. Secondary As-Completed-Treatment Analyses Results
eTable 1. As-Completed-Treatment Analysis of Primary and Secondary Outcomes
eFigure 1. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the As-Completed-Treatment Population
eAppendix 2. Comparison of Primary Outcome, Stratified by Study Sites
eFigure 2. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the As-Randomized Population, Stratified by Study Sites
eTable 2. Comparison of Recurrence Rates Between Intervention Group and Placebo Group at 10-Day Intervals After the Intervention, Stratified by Study Sites
eAppendix 3. Primary and Secondary Outcomes in Participants Taking Higher-Risk Antibiotics
eTable 3. Primary and Secondary Outcomes in Participants Taking High-Risk Antibiotics
eFigure 3. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants Taking High-Risk Antibiotics
eAppendix 4. Primary and Secondary Outcomes in Immunocompromised Participants
eTable 4. Primary and Secondary Outcomes in Immunocompromised Participants
eFigure 4. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants With an Immunocompromising Condition
eAppendix 5. Primary and Secondary Outcomes in Participants Aged 65 Years or Older
eTable 5. Primary and Secondary Outcomes in Participants Aged 65 Years or Older
eFigure 5. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants Aged 65 Years or Older
Data Sharing Statement
References
- 1.Pacheco SM, Johnson S. Important clinical advances in the understanding of Clostridium difficile infection. Curr Opin Gastroenterol. 2013;29(1):42-48. doi: 10.1097/MOG.0b013e32835a68d4 [DOI] [PubMed] [Google Scholar]
- 2.Evans CT, Safdar N. Current trends in the epidemiology and outcomes of Clostridium difficile infection. Clin Infect Dis. 2015;60(suppl 2):S66-S71. doi: 10.1093/cid/civ140 [DOI] [PubMed] [Google Scholar]
- 3.Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med. 2008;359(18):1932-1940. doi: 10.1056/NEJMra0707500 [DOI] [PubMed] [Google Scholar]
- 4.O’Horo JC, Jindai K, Kunzer B, Safdar N. Treatment of recurrent Clostridium difficile infection: a systematic review. Infection. 2014;42(1):43-59. doi: 10.1007/s15010-013-0496-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med. 2015;372(16):1539-1548. doi: 10.1056/NEJMra1403772 [DOI] [PubMed] [Google Scholar]
- 6.Song JH, Kim YS. Recurrent Clostridium difficile infection: risk factors, treatment, and prevention. Gut Liver. 2019;13(1):16-24. doi: 10.5009/gnl18071 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Zellmer C, De Wolfe TJ, Van Hoof S, Blakney R, Safdar N. Patient perspectives on fecal microbiota transplantation for Clostridium difficile infection. Infect Dis Ther. 2016;5(2):155-164. doi: 10.1007/s40121-016-0106-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Garey KW, Aitken SL, Gschwind L, et al. Development and validation of a Clostridium difficile health-related quality-of-life questionnaire. J Clin Gastroenterol. 2016;50(8):631-637. doi: 10.1097/MCG.0000000000000473 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Reigadas E, van Prehn J, Falcone M, et al. ; European Society of Clinical Microbiology and Infectious Diseases Study Group on Clostridioides difficile (ESGCD) and Study Group for Host and Microbiota Interaction (ESGHAMI) . How to: prophylactic interventions for prevention of Clostridioides difficile infection. Clin Microbiol Infect. 2021;27(12):1777-1783. doi: 10.1016/j.cmi.2021.06.037 [DOI] [PubMed] [Google Scholar]
- 10.Carignan A, Poulin S, Martin P, et al. Efficacy of secondary prophylaxis with vancomycin for preventing recurrent Clostridium difficile infections. Am J Gastroenterol. 2016;111(12):1834-1840. doi: 10.1038/ajg.2016.417 [DOI] [PubMed] [Google Scholar]
- 11.Van Hise NW, Bryant AM, Hennessey EK, Crannage AJ, Khoury JA, Manian FA. Efficacy of oral vancomycin in preventing recurrent Clostridium difficile infection in patients treated with systemic antimicrobial agents. Clin Infect Dis. 2016;63(5):651-653. doi: 10.1093/cid/ciw401 [DOI] [PubMed] [Google Scholar]
- 12.Knight EM, Schiller DS, Fulman MK, Rastogi R. Long-term efficacy of oral vancomycin prophylaxis for the prevention of Clostridium difficile recurrence. J Pharm Pract. 2020;33(5):633-639. doi: 10.1177/0897190019825994 [DOI] [PubMed] [Google Scholar]
- 13.Connor KA, Conn KM. Analysis of the impact of secondary prophylaxis on Clostridioides difficile recurrence in critically ill adults. SAGE Open Med. Published online June 12, 2020. doi: 10.1177/2050312120930898 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ganetsky A, Han JH, Hughes ME, et al. Oral vancomycin prophylaxis is highly effective in preventing Clostridium difficile infection in allogeneic hematopoietic cell transplant recipients. Clin Infect Dis. 2019;68(12):2003-2009. doi: 10.1093/cid/ciy822 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zacharioudakis IM, Zervou FN, Dubrovskaya Y, Phillips MS. Oral vancomycin prophylaxis against recurrent Clostridioides difficile infection: efficacy and side effects in two hospitals. Infect Control Hosp Epidemiol. 2020;41(8):908-913. doi: 10.1017/ice.2020.176 [DOI] [PubMed] [Google Scholar]
- 16.Caroff DA, Menchaca JT, Zhang Z, et al. Oral vancomycin prophylaxis during systemic antibiotic exposure to prevent Clostridiodes difficile infection relapses. Infect Control Hosp Epidemiol. 2019;40(6):662-667. doi: 10.1017/ice.2019.88 [DOI] [PubMed] [Google Scholar]
- 17.Johnson S, Homann SR, Bettin KM, et al. Treatment of asymptomatic Clostridium difficile carriers (fecal excretors) with vancomycin or metronidazole: a randomized, placebo-controlled trial. Ann Intern Med. 1992;117(4):297-302. doi: 10.7326/0003-4819-117-4-297 [DOI] [PubMed] [Google Scholar]
- 18.Johnson SW, Brown SV, Priest DH. Effectiveness of oral vancomycin for prevention of healthcare facility-onset Clostridioides difficile infection in targeted patients during systemic antibiotic exposure. Clin Infect Dis. 2020;71(5):1133-1139. doi: 10.1093/cid/ciz966 [DOI] [PubMed] [Google Scholar]
- 19.Almyroudis NG, Lesse AJ, Hahn T, et al. Molecular epidemiology and risk factors for colonization by vancomycin-resistant Enterococcus in patients with hematologic malignancies. Infect Control Hosp Epidemiol. 2011;32(5):490-496. doi: 10.1086/659408 [DOI] [PubMed] [Google Scholar]
- 20.Banach DB, Peaper DR, Fortune BE, Emre S, Dembry LM. The clinical and molecular epidemiology of pre-transplant vancomycin-resistant enterococci colonization among liver transplant recipients. Clin Transplant. 2016;30(3):306-311. doi: 10.1111/ctr.12690 [DOI] [PubMed] [Google Scholar]
- 21.de Bruin MA, Riley LW. Does vancomycin prescribing intervention affect vancomycin-resistant enterococcus infection and colonization in hospitals? a systematic review. BMC Infect Dis. 2007;7:24. doi: 10.1186/1471-2334-7-24 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Fridkin SK, Edwards JR, Courval JM, et al. ; Intensive Care Antimicrobial Resistance Epidemiology (ICARE) Project and the National Nosocomial Infections Surveillance (NNIS) System Hospitals . The effect of vancomycin and third-generation cephalosporins on prevalence of vancomycin-resistant enterococci in 126 US adult intensive care units. Ann Intern Med. 2001;135(3):175-183. doi: 10.7326/0003-4819-135-3-200108070-00009 [DOI] [PubMed] [Google Scholar]
- 23.O’Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ. 1990;300(6722):439-440. doi: 10.1136/bmj.300.6722.439 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.R: a language and environment for statistical computing. Version 4.4.0. R Foundation for Statistical Computing. 2024. Accessed October 28, 2024. https://www.R-project.org/
- 25.Webb BJ, Subramanian A, Lopansri B, et al. Antibiotic exposure and risk for hospital-associated Clostridioides difficile infection. Antimicrob Agents Chemother. 2020;64(4):e02169-e19. doi: 10.1128/AAC.02169-19 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Deshpande A, Pasupuleti V, Thota P, et al. Risk factors for recurrent Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2015;36(4):452-460. doi: 10.1017/ice.2014.88 [DOI] [PubMed] [Google Scholar]
- 27.Drekonja DM, Amundson WH, Decarolis DD, Kuskowski MA, Lederle FA, Johnson JR. Antimicrobial use and risk for recurrent Clostridium difficile infection. Am J Med. 2011;124(11):1081.e1-1081.e7. doi: 10.1016/j.amjmed.2011.05.032 [DOI] [PubMed] [Google Scholar]
- 28.Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021;116(6):1124-1147. doi: 10.14309/ajg.0000000000001278 [DOI] [PubMed] [Google Scholar]
- 29.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;66(7):e1-e48. doi: 10.1093/cid/cix1085 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.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 [DOI] [PubMed] [Google Scholar]
- 31.van Prehn J, Reigadas E, Vogelzang EH, et al. ; Guideline Committee of the European Study Group on Clostridioides difficile . European Society of Clinical Microbiology and Infectious Diseases: 2021 update on the treatment guidance document for Clostridioides difficile infection in adults. Clin Microbiol Infect. 2021;27(suppl 2):S1-S21. doi: 10.1016/j.cmi.2021.09.038 [DOI] [PubMed] [Google Scholar]
- 32.Babar S, El Kurdi B, El Iskandarani M, et al. Oral vancomycin prophylaxis for the prevention of Clostridium difficile infection: a systematic review and meta-analysis. Infect Control Hosp Epidemiol. 2020;41(11):1302-1309. doi: 10.1017/ice.2020.277 [DOI] [PubMed] [Google Scholar]
- 33.Maraolo AE, Mazzitelli M, Zappulo E, et al. Oral vancomycin prophylaxis for primary and secondary prevention of Clostridioides difficile infection in patients treated with systemic antibiotic therapy: a systematic review, meta-analysis and trial sequential analysis. Antibiotics (Basel). 2022;11(2):183. doi: 10.3390/antibiotics11020183 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Meschiari M, Kaleci S, Monte MD, et al. Vancomycin resistant enterococcus risk factors for hospital colonization in hematological patients: a matched case-control study. Antimicrob Resist Infect Control. 2023;12(1):126. doi: 10.1186/s13756-023-01332-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Lewis BB, Buffie CG, Carter RA, et al. Loss of microbiota-mediated colonization resistance to Clostridium difficile infection with oral vancomycin compared with metronidazole. J Infect Dis. 2015;212(10):1656-1665. doi: 10.1093/infdis/jiv256 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Vrieze A, Out C, Fuentes S, et al. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity. J Hepatol. 2014;60(4):824-831. doi: 10.1016/j.jhep.2013.11.034 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol
eAppendix 1. Secondary As-Completed-Treatment Analyses Results
eTable 1. As-Completed-Treatment Analysis of Primary and Secondary Outcomes
eFigure 1. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the As-Completed-Treatment Population
eAppendix 2. Comparison of Primary Outcome, Stratified by Study Sites
eFigure 2. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the As-Randomized Population, Stratified by Study Sites
eTable 2. Comparison of Recurrence Rates Between Intervention Group and Placebo Group at 10-Day Intervals After the Intervention, Stratified by Study Sites
eAppendix 3. Primary and Secondary Outcomes in Participants Taking Higher-Risk Antibiotics
eTable 3. Primary and Secondary Outcomes in Participants Taking High-Risk Antibiotics
eFigure 3. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants Taking High-Risk Antibiotics
eAppendix 4. Primary and Secondary Outcomes in Immunocompromised Participants
eTable 4. Primary and Secondary Outcomes in Immunocompromised Participants
eFigure 4. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants With an Immunocompromising Condition
eAppendix 5. Primary and Secondary Outcomes in Participants Aged 65 Years or Older
eTable 5. Primary and Secondary Outcomes in Participants Aged 65 Years or Older
eFigure 5. Estimated Nonrecurrence Probability Over Time Between Treatment Groups for the Randomized Participants Aged 65 Years or Older
Data Sharing Statement