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Clostridioides Difficile Infection: Is There a Role for Diet and Probiotics?

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Clostridioides Difficile Infection: Is There a Role for Diet and Probiotics? NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202 NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202 Carol Rees Parrish, MS, RDN, Series Editor Clostridioides difficile Infection: Is There a Role for Diet and Probiotics? Christopher Ward Colleen R. Kelly Clostridioides difficile is a spore forming bacterium leading to significant morbidity and mortality amongst hospitalized as well as non-hospitalized patients in the United States. While hospital acquired infections have reduced, in recent years we have seen an increase in community acquired infections. With the focus on antimicrobial therapies and fecal microbiota transplantation, it is important to understand the evidence behind probiotics and nutrition in the management of C. difficile infections. There is an abundance of new literature regarding the $40 billion a year probiotic industry, meanwhile patients require dietary advice following an infection. In this review, we aim to give the non-specialty clinician some clarity regarding these issues. INTRODUCTION lostridioides difficile is an anaerobic, of CDI, as many cases occur without a history of gram positive, spore forming bacterium antibiotic use.2 There was a significant increase in Cthat causes a spectrum of gastrointestinal CDI between 2000-2010, which has been attributed symptoms ranging from mild diarrhea to colitis, to increased detection with use of nucleic acid toxic megacolon, intestinal perforation, and amplification testing, more virulent strains, and death. It is spread via the fecal-oral route and increased community antibiotic use. Since then, is frequently encountered in hospitals, affecting we have seen a reduction in healthcare associated 1% of US hospital stays1 and nursing homes CDI, though there are still almost half a million where antibiotic use is common. Concerningly, cases per year within the United States.3 Infection community-acquired infections are common, and control measures, decreased fluroquinolone use, recent research suggests other undefined causes and improved antibiotic stewardship have been credited with these results.4 Christopher Ward1 1Department of Medicine, In recent years there has been an abundance Warren Alpert Medical School of Brown University, of new literature on C. difficile with regards to Providence, RI Colleen R. Kelly1,2 1Department of management and prevention options. For the non- Medicine, Warren Alpert Medical School of Brown specialty clinician, it is challenging to determine University, Providence, RI 2Lifespan Physician which data is high quality and what can be applied to Group Gastroenterology Practice, Providence, RI their patients. With the spotlight on fecal microbiota 26 PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2020 Clostridioides difficile Infection: Is There a Role for Diet and Probiotics? NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202 NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202 transplantation (FMT) and other non-antibiotic ill patients leading to the recommendation that therapies for CDI, it is understandable that both they be used with caution in immunocompromised clinicians and patients are seeking preventative patients and those with structural heart disease or options such as probiotics and nutrition. Here we central venous catheters.11 Microbiome analyses evaluate the current evidence for these therapies have shown that they may actually impede in the prevention of CDI. normal recolonization in the gut after a course of antibiotics.12 Despite this, probiotics are widely Probiotics recommended by physicians to prevent CDI in Probiotics are defined as live microorganisms that, patients being treated with antibiotics (primary when administered in adequate amounts, confer a prevention) or in patients being treated for CDI to health benefit on the host.5 The literal translation prevent recurrences (secondary prevention). Costs is “for-life”, which conveys that they are good, range from $30 to $100 per month for the most natural, and beneficial to biological functions. commonly recommended formulations, which are Proposed mechanisms for beneficial effects include frequently taken for extended courses and typically modification of the gut microbiota, competitive not covered by insurance. Given these costs, the adherence to the mucosa and epithelium, desire to provide reliable health information to our strengthening of the gut epithelial barrier, and patients, and the potential for harm, it is important modulation of the immune system to convey an to critically appraise data supporting the use of advantage to the host.6 Probiotics are marketed probiotics in CDI. as dietary supplements with colourful labels and Evidence to support probiotics in the vague claims of “friendly bacteria” to “improve gut management of CDI comes mainly from meta health.” This 40 billion dollar a year industry,7 while analyses, which pool data from smaller trials of extremely appealing to patients and healthcare variable probiotic formulations and methodologies. professionals, operates without the strict oversight There is a paucity of high-quality clinical trial by the U.S. Food and Drug Administration that is data of probiotics in CDI, and most studies are required of drugs. A quick internet search reveals underpowered, with CDI as a secondary outcome a plethora of websites recommending various in studies done to assess prevention of antibiotic probiotics as a means to improve one’s health for associated diarrhea (AAD). A 2016 global review various indications, including after CDI. A 2010 of guidelines, strategies, and recommendations survey of gastroenterologists found that 98% of for CDI prevention4 labelled probiotics as an respondents believed probiotics have a role in area of research, but were unable to recommend treating gastrointestinal illnesses or symptoms, their use. There is currently insufficient evidence despite the paucity of data to support their use. to recommend any probiotic for the primary or Sixty percent believed that the literature supported secondary prevention of CDI. the use of probiotics in the treatment of CDI.8 Due to the lack of regulation and freedom to make The Literature general health claims on product labels, there The PLACIDE trial is the largest double-blind is little incentive for manufacturers to conduct clinical primary prevention randomized controlled clinical trials to support specific indications for trial (RCT) to date.13 This multicenter trial in the their products.9 United Kingdom enrolled nearly 3000 elderly The trouble with many of the available inpatients who were at high risk of contracting products is that quality control is often sub-optimal CDI. Patients >65 years old receiving antibiotics with inconsistencies and deviations from the were randomized to treatment with a multi-strain information provided on the product label including preparation composed of bifidobacterium and misidentified, misclassified or non-viable strains, Lactobacillus acidophillus strains or placebo for contaminated products, or diminished functional 21 days. AAD including CDI occurred in 10·8% of properties.10 The belief that probiotics “can’t hurt” the microbial preparation group and 10·4% of those has been challenged by case reports of bloodstream treated with placebo. CDI was an uncommon cause infections with probiotic organisms in critically of AAD and occurred in just 0·8% of the microbial PRACTICAL GASTROENTEROLOGY • SEPTEMBER 2020 27 Clostridioides difficile Infection: Is There a Role for Diet and Probiotics? NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #202#202 preparation group and 1·2% of the placebo group. Saccharomyces Boulardii The authors concluded that probiotics were of no Hope for Recurrent CDI? benefit in prevention of AAD or CDI. There were several publications in the 1990s Many nutritional websites and magazines involving Saccharomyces boulardii that showed broadly claim “high quality evidence” for promise regarding CDI secondary prevention.20 S. probiotics in CDI, most citing the Cochrane boulardii is a yeast that grows on lychee fruit. It was Review in 2017 by Golbenberg et al, which looked discovered by a French pharmacist who observed at probiotics for primary prevention of CDI in South-East Asian natives chewing the skins of the adults and children, enrolling 8672 participants.14 fruit to lessen the symptoms of cholera. It produces It is important to highlight that 27 of the 31 studies a protease that inactivates the receptor site for C. analysed were felt to be of unclear or high risk of difficile toxin A, lending biologic plausibility to bias and more than half had missing data. The its use in CDI.21 incidence of CDI was 1.5% in the treatment group A 1994 multicenter RCT showed decreased and 4% in the control groups, a 60% risk reduction. CDI recurrence in patients treated with S. They concluded a modest benefit of probiotics boulardii in addition to either metronidazole or (number needed to benefit=42). However, in post- vancomycin in those who had already suffered hoc subgroup analysis these benefits only held a recurrence (34.6% with S. boulardii vs 64.7% up in trials enrolling participants with baseline with placebo).22 There was no benefit over placebo CDI risk >5%, which is higher than the average in patients with primary infection. A follow up risk in American hospitals and therefore has study published in 2000 enrolled 168 recurrent questionable clinical application. The conclusions CDI patients who were treated with a 28 day course of this Cochrane review have been criticized as of S. boulardii or placebo
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