Clostridioides difficile infection (CDI) is the most common cause of health care–associated diarrhea, with the primary risk being the use of antibacterial drugs. Approximately 25% of first episodes of CDI are associated with a recurrence; recurrence rates increase with each episode and can be greater than 65%.1 There is no proven strategy to prevent recurrent CDI (rCDI) in patients requiring antimicrobial drugs for non-CDI indications. One strategy used is continuing or starting oral vancomycin with the use of antimicrobials to treat another bacterial infection. Prior studies of prophylaxis have been small and mostly retrospective, and results have been mixed when weighing the benefits with the risks.
The study by Keating et al2 attempts to address this question by performing a randomized, double-blinded, placebo-controlled clinical trial of prophylactic vancomycin vs placebo, with 2 well-defined end points: CDI recurrence and vancomycin-resistant Enterococcus species (VRE) colonization. They enrolled only 81 patients, 54% of the proposed sample size of 150 and just below the lowest number required by the power and sample size calculations.2 The patients could have 1 or more treated CDI episodes within the last 6 months and were being treated for a non-CDI infection. They chose the regimen recommended by the American College of Gastroenterology guidelines (vancomycin 125 mg orally daily).3 Most of the prior studies dosed the vancomycin differently, with 1 study using a higher dose of 250 mg twice daily.4 They used 2-step testing, using culture with the final diagnosis made by enzyme-linked immunoassay for both toxins A and B. If the enzyme-linked immunoassay was negative, stool was sent out for cell cytotoxicity. Positive stool cultures were tested by polymerase chain reaction, which was used to confirm the presence of the toxin B gene. The study demonstrated the benefit of daily vancomycin with a 13.5% decrease in recurrences.2 Although it did not reach statistical significance because the study was underpowered, the reduction appears to be a clinically meaningful result. What is striking, however, is how high the rates of recurrence were in both the treatment (43.6%) and placebo (57.1%) groups.2 There was no difference in rCDI outcomes when evaluating subgroups at particularly high risk of rCDI (ie, participants using higher-risk antibacterials, those with an immunocompromising condition, or those aged ≥65 years), although the numbers were small. The risk of recurrence increased with the number of episodes of CDI, so knowing the number of prior recurrences in the patients enrolled would be helpful in interpretation of the results. Those data were not reported. It is noted that the participants also provided a baseline stool sample or perirectal swab prior to randomization. It was not noted what percentage of patients had detectable C difficile colonization in the stool prior to initiation of the study. Follow-up of 8 weeks is sufficient to capture most, if not all, of the recurrent episodes.2
The secondary outcome was rates of VRE carriage.2 The rates of carriage were higher in the placebo group by rectal swab at the time of enrollment, but not significantly different. After vancomycin treatment, the rate of VRE colonization did not change in the vancomycin group but declined in the placebo group. After treatment, the vancomycin group had more VRE colonization.
One of the major risks of vancomycin use is the effect on the gut microbiota. A study by Isaac et al5 used high-throughput sequencing to analyze effects on fecal microbiota for up to 22 weeks after antibiotic cessation. Vancomycin induced persistent changes in the diversity and richness of the human microbiota. This may, in part, be a reason for increased colonization of VRE as the concentrations of vancomycin per gram of stool is very high. The overall effects on the fecal microbiota were not tested.
In addition, patients with obesity treated with vancomycin had reduction of the conversion of primary to secondary bile acids.5 Primary bile acids are associated with promotion of C difficile spore germination and growth, which may ultimately set up the patient for more recurrences.
There are 3 treatment guidelines for management of CDI: the American College of Gastroenterology guideline,3 which conditionally recommends vancomycin use; The European Society of Clinical Microbiology and Infectious Diseases guideline,6 which does not recommend routine prophylaxis but states that it may be useful in select patients; and the Infectious Diseases Society of America guideline,7 which found insufficient evidence to recommend use of vancomycin. The current study2 supports the use of vancomycin prophylaxis for prevention of rCDI in patients receiving antibacterial treatment for alternative indications within 180 days of the CDI episode. The small sample size limits the ability to provide conclusive evidence of efficacy. A large multicenter, double-blinded, randomized clinical trial will be necessary to answer this question definitively. It will also provide more evidence of the effects on the gut microbiota and allow clinicians to weigh the risks and benefits of vancomycin prophylaxis.
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2835889
2 Medical News 