After our summer break, I’m looking forward to our first Journal Club of the Autumn tomorrow (register here). I’ve written this post in preparation for the Journal Club, which is hosted by IPC Partners in partnership with IPC Launch, ID Watch, and the Healthcare Hygiene magazine on the topic “Optimizing prevention and treatment of gastrointestinal and urinary tract infections”. The paper that I’ll be covering is a randomised controlled trial of oral vancomycin to prevent recurrent C. difficile infection.

Why I chose this article:

• Whilst C. difficile infection (CDI) is less of an issue than it once was in the UK, there is recent evidence of an increase in the UK. Also, prevalence of C. difficile is an remains high elsewhere in the world, and to compound this, surveillance systems are far from adequate meaning that under-reporting is probably considerable.
• Around 1/3 of patients who develop CDI will develop one or more recurrences.
• Faecal colonisation with C. difficle is complex and our understanding is limited, mainly because patients are rarely tested for asymptomatic colonisation with C. difficile.
• All antibiotics have a downside (for patients, healthcare systems, and society), so I’d need to see very convincing evidence to convince me that antibiotic prophylaxis should be widely used to prevent recurrent CDI.   

Design and methods:

• This study was a prospective placebo-controlled 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 was a multicentre study undertaken in the US, involving adult patients.
• The primary outcome was the incidence of CDI in patients receiving oral vancomycin vs. placebo.
• The secondary outcome was the incidence of VRE (via self-collected stool samples) in patients receiving oral vancomycin vs. placebo.

Key findings:

• A total of 81 patients were randomised (fewer than intended because of issues due to COVID-19 and funding).
• Eight weeks after completing treatment, 17/39 patients in the oral vancomycin group (43.6%) and 24/42 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)
• There was also no significant difference in recurrence probability by day over time (although this was close to significance!) or in the distribution of the number of days to recurrence if there was one.
• Various sub-analyses didn’t find anything significant either (in terms of intention-to-treat population, high-risk patient groups, or different study sites).
• There was a statistically significant difference in VRE carriage between patients in the vancomycin group vs. placebo at the end of the study (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).  

Strengths and limitations:

• This was a placebo controlled RCT, so right up there in terms of study design.
• Comprehensive inclusion / exclusion criteria were applied.
• The study only evaluated one dose / duration of therapy.
• Incomplete recruitment (80 vs. 150 target).
• Did not evaluate wider impact on gut microbiome (although did evaluate impact on VRE carriage).  

Points for discussion:

• The rate of recurrence was high in both arms of the study (44% for vanc and 57% for placebo). This was probably because these patients were selected on the basis of being on systemic antibiotics for an infection.
• The national / international guideline position on the use of antibiotic prophylaxis to prevent recurrent CDI reflects the lack of evidence – the ESCMID guidance on C. difficile treatment suggested considering it for high risk patients, but most guidelines don’t go there. In fact, the latest NICE guidance recommends against antibiotics to prevent CDI.
• Despite this guideline position, there is some evidence from the study that vanc prophylaxis to prevent CDI is already common, in that 40% of the 470 eligible patients were excluded on the basis of already being on vanc and not wanting to be randomised off it!
• The findings on VRE carriage in this study are rather equivocal, but there is a suggestion that the antibiotic prophylaxis selected for VRE carriage. The prevalence of VRE carriage reduced in the placebo arm rather than increasing in the vanc arm – but this still supports the idea that vanc use selected for VRE.
• There are other approaches that we can look at to prevent recurrent CDI, especially FMT but also probiotics / prebiotics.

What this means for IPC:

• Reinforces that antibiotic usage drives antibiotic resistance.
• Not strong enough evidence to recommend vancomycin prophylaxis to prevent recurrent CDI.

I’ll be presenting this paper at Journal Club tomorrow (register here). Hope you can join us!