Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections in the United States with nearly 500,000 cases diagnosed annually.1 Amplifying this burden is the high rate of recurrent CDI (rCDI), which occurs in ~25% of patients treated with metronidazole or vancomycin and at even higher rates, up to 40-60%, in patients following a first recurrence.2-4 Compared to patients without recurrence, patients with rCDI are more likely to require hospitalization and have a 33% increased risk of 6-month mortality.5 With such a heavy burden, it is no wonder that we as clinicians are tempted to do what we can to prevent rCDI.
Antibiotic prophylaxis is routinely used to prevent a variety of infectious diseases, ranging from surgical site infections to viral infections. So why wouldn’t we also use it for C. difficile infection? Although appealing, high quality evidence supporting its use is lacking and routine CDI prophylaxis may walk a fine line between helpful and harmful for our patients. A true understanding of the risks and benefits first requires a basic knowledge of how CDI develops and the role of the gut microbiome.
The gut microbiome: a primer for clinicians
Between 90-99% of a healthy human’s gut microbiome is composed of two bacteria phyla, Bacteroidetes and Firmicutes, while Actinobacteria, Cyanobacteria, Proteobacteria, and Verrucomicrobia make up the remainder.6-7 This balanced ecosystem provides colonization resistance against a variety of pathogenic organisms, including C. difficile, by secreting natural antimicrobials and bacteriophages, competing for nutrients, and maintaining gut barrier integrity.8-9 When a disrupting force such as antibiotics is introduced, we lose our microbiome diversity and allow for C. difficile colonization and infection.
Antibiotics with broad spectra of activity are highest risk for causing CDI since they kill much of our gut microbiota.10 This killing causes a state of dysbiosis, including both loss of diversity and quantitative reductions in bacterial organisms. This dysbiosis also places patients at highest risk of CDI development in the first three months after antibiotics are discontinued although the microbiome can take a year or longer to fully restore.11 It is also extremely important to note that the antibiotics we use to treat CDI are not C. difficile-specific and cause additional microbiome disruptions.12,13 This is especially true with use of oral vancomycin, which causes profound shifts in the gut microbiome.12 This collateral damage is well-worth the benefit of killing C. difficile in patients with CDI, but the line between benefit and harm is a lot thinner when using the antibiotics in patients to prevent CDI.
Caution and concerns with current evidence
More than twenty studies over the past three decades have studied the use of CDI prophylaxis.14,15 At first glance, the body of literature as a whole appears to support the use of prophylaxis, with the majority of the studies demonstrating significantly lower rates of CDI with prophylaxis use. However, we should be cautious in our interpretation of this literature for several reasons.
As of this writing, only one study of CDI prophylaxis is a randomized, double-blind, trial.16 The vast majority are unblinded and retrospective, which likely suffer from selection biases since those patients chosen to receive prophylaxis were likely at a higher risk of developing CDI than those not receiving it. Providers were also unblinded and may have been less likely to order a C. difficile diagnostic test in those that received antibiotic prophylaxis. Both of these effects hinder our ability to interpret these studies.
Another large concern I have in the interpretation of these trials is the rate and duration of patient follow up. Armed with our knowledge of the microbiome, we know that dysbiosis from these prophylactic antibiotics can put patients at risk for CDI for up to three months following discontinuation. We should therefore view trials with a skeptical eye that only follow patients to hospital discharge or until prophylaxis is discontinued. Similarly, the follow-up in many of the studies are based on chart review, which risks missing outpatient CDI diagnoses. Since the overall occurrence of CDI in these trials is relatively low in either arm, any missed outcomes in either group may be more likely to affect the statistical significance of the findings.
The heterogeneity in the trials also presents a challenge in recommending widespread use of CDI prophylaxis. A variety of patient populations and high-risk conditions were considered for trial inclusion, making it difficult to discern which patients may benefit from prophylaxis. Although the majority of studies utilize vancomycin as prophylaxis, many did not specify the dose used. In those that do, dosing regimens range from 125 mg daily up to a full treatment dose of 125 mg every six hours. Furthermore, the duration of prophylaxis is variable amongst studies. Once taking these biases and uncertainties into account, I find it difficult to find strong supporting evidence for the routine use of CDI prophylaxis.
Which patients should be considered to receive CDI prophylaxis?
Despite these limitations, there is one randomized, double-blinded, placebo-controlled trial which we can use to inform our current recommendations for prophylaxis.16 In this trial, which included neutropenic, hematopoietic stem cell transplant recipients receiving fluoroquinolone prophylaxis, fidaxomicin 200 mg administered once daily demonstrated a 6% reduction in CDI occurrence. Notably this trial studied fidaxomicin, which is known to cause less dysbiosis than vancomycin and may therefore be expected to serve as a safer prophylaxis option.17 Outside of this specific patient population, I agree with several other experts that more high-quality studies are needed before adopting more widespread use of CDI prophylaxis.18,19
- Centers for Disease Control and Prevention (CDC). Antibiotic resistance threats in the United States (U.S.). Atlanta: Department of Health and Human Services, CDC; 2019.
- Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014; 59(3):345–54.
- Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011; 364(5):422–31.
- Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Inf Secur. 2009; 58:403–10.
- Olsen MA, Yan Y, Reske KA, et al. Impact of Clostridium difficile recurrence on hospital readmissions. Am J Infect Control. 2015; 43(4):318–22.
- Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science. 2005; 308(5728):1635–8.
- Ley RE, Peterson DA, Gordon JI. Review ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell. 2006; 124(4):837–48.
- Theriot CM, Young VB. Interactions between the gastrointestinal microbiome and Clostridium difficile. Annu Rev Microbiol. 2015; 69:445–61.
- Ducarmon QR, Zwittink RD, Hornung BVH, et al. Gut microbiota and colonization resistance against bacterial enteric infection. Microbiol Mol Biol Rev. 2019; 83(3):e00007–19.
- Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother. 2014; 69:881-91.
- Hensgens MP, Goorhuis A, Dekkers OM, et al. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother. 2012; 67(3):742–8.
- Thorpe CM, Kane AV, Chang J, et al. Enhanced preservation of the human intestinal microbiota by ridinilazole, a novel Clostridium difficile targeting antibacterial, compared to vancomycin. PLoS One. 2018; 13(8):e0199810.
- 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; 212:1656-64.
- Carlson TJ, Gonzales-Luna, AJ. Utilizing antibiotics to prevent Clostridioides difficile infection: Does exposure to a risk factor decrease risk? J Antimicrob Chemother. 2020; 75(10):2735-42.
- 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):1302-9.
- Mullane KM, Winston DJ, Nooka A et al. A randomized, placebo-controlled trial of fidaxomicin for prophylaxis of Clostridium difficile-associated diarrhea in adults undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2019; 68:196–203.
- Louie TJ, Cannon K, Byrne B et al. Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI. Clin Infect Dis. 2012; 55:S132–42.
- Garey KW. Perils, pitfalls, and promise of primary prophylaxis for Clostridioides difficile infection. Clin Infect Dis. 2020; 71(5):1140–1.
- McCreery R, Cawcutt K, Cortes-Penfield N, Van Schooneveld T. Oral vancomycin prophylaxis for Clostridioides difficile in high-risk patients receiving systemic antibiotics: what exactly are we preventing? Clin Infect Dis. 2020; 71(7):1798.