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Studies offer conflicting evidence on probiotics for CDI prevention

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Although guidelines do not recommend probiotics for the prevention of Clostridioides difficile infection, or CDI, researchers continue to study them as a potential solution.

“It is an exciting time in medicine as clinical researchers explore ways to prevent or mitigate diseases through alterations in the resident microbial population, primarily of the gut, but research is extending beyond the gut,” William Trick, MD, director of the collaborative research unit at Cook County Health in Chicago, told Infectious Diseases in Children. “Probiotics are one of the tools that will continue to be explored and used as the risks and benefits are better defined.”

The global market for probiotics was estimated to be around $48 billion in 2018 and is expected to rise consistently into the next decade, according to Grand View Research, a market research and consulting company based in the United States.

Studies examining varying doses and combinations of probiotics have produced contradictory results, raising questions about whether probiotics should be used or recommended for CDI prevention, especially in children. Infectious Diseases in Children spoke with numerous experts to gain insight on the subject.

Satish S.C. Rao, MD, PhD, FRCP, professor of medicine at the Medical College of Georgia, said he has found probiotics to be “beneficial and useful” in reducing C. difficile in his own practice. Source: Augusta University.

What the evidence says

Probiotics are primarily used to improve gut health, although their efficacy and usefulness is a topic of debate in the infectious disease community. Evidence has shown that some probiotics are helpful in preventing diarrhea caused by infections and antibiotics, but experts say more research is needed to determine which strains of probiotic are helpful and which are not.

“Since much of the single-project research has been underpowered to detect a statistically significant benefit, several meta-analyses have been performed,” Trick said. “Examples of conditions that may benefit from probiotics include antibiotic-associated diarrhea, prevention of necrotizing enterocolitis in neonates, and prevention of C. difficile.”

CDI is a primary focus of probiotic research. With the condition causing nearly 500,000 infections and an estimated 15,000 deaths per year in the U.S., according to the CDC, researchers and clinicians have turned to experimental probiotics to fight the bacteria.

Aaron E. Glatt

Many studies have explored using probiotics to prevent CDI, but they have not yielded conclusive, widely accepted results.

“Published literature is the only way that a society or professional, such as myself, could make a decision,” Aaron E. Glatt, MD, chairman of medicine, chief of infectious diseases and a hospital epidemiologist at South Nassau Communities Hospital, told Infectious Diseases in Children. “There are some papers suggesting that it is a good thing, some say there are no benefits, and there are so many formulations that it is almost impossible to compare the studies.

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“There are studies looking at a certain concentration of the saccharomyces or lactobacilli that are present in these probiotics, and others have different concentrations. Some will say it is somewhat effective and others will say it is not. Are they contradicting each other? Or are they just looking at two different concentrations or treatments? Nothing is standardized.”

Results of a meta-analysis of 18 randomized controlled trials conducted by Bradley C. Johnston, PhD, associate professor of community health and epidemiology at Dalhousie University in Canada, and colleagues offered what the authors deemed “moderate quality evidence” that probiotic prophylaxis can safely prevent CDI, especially in patients taking at least two antibiotics and in hospitals with a CDI incidence rate of at least 5%.

The findings, published last year in Infection Control & Hospital Epidemiology, determined that providing multistrain probiotics to pediatric and adult patients treated with antibiotics reduces their likelihood of CDI with no difference in serious adverse events compared with standard care. According to the analysis, the use of probiotic prophylaxis reduced the likelihood of infection in both the unadjusted (n = 6,645; OR = 0.37; 95% CI, 0.25-0.55) and adjusted models (n = 5,074; OR = 0.35; 95% CI, 0.23-0.55) and that an increased risk for infection was observed in patients who received two or more antibiotics (OR = 2.2; 95% CI, 1.11-4.37).

Another meta-analysis of 31 randomized controlled trials (n = 8,672) published in the Cochrane Review in 2017 found “moderate certainty evidence” that probiotics are effective at reducing C. difficile-associated diarrhea (CDAD). Overall, the incidence of CDAD was 1.5% among those given probiotics and 4% among placebo or control groups, with a risk ratio (RR) of 0.4 (95% CI, 0.3-0.52) — or a 60% risk reduction on average. The researchers observed a statistically significant difference in antibiotic-associated diarrhea outcomes when comparing children with adults (adult RR = 0.62; 95% CI, 0.51-0.76 vs. child RR = 0.38; 95% CI, 0.29-0.49) but not for other outcomes. Like the meta-analysis by Johnston and colleagues, the Cochrane Review meta-analysis showed that patients with a higher baseline risk for CDAD — exceeding 5% — would benefit the most from probiotic use. This group (n = 2,454) had an RR of 0.3 (95% CI, 0.21-0.42) — a statistically significant risk reduction of 70% on average, the researchers noted.

A single-center study by Trick and colleagues that evaluated a multispecies probiotic to prevent CDI found that there were similar results during baseline and intervention periods, with incidence rates of 6.9 vs. 7 CDIs per 10,000 patient-days, respectively, indicating no effect. Trick and colleagues noted in the study that there was a significant decrease in incidence during the last 6 months of the intervention, demonstrating a possible delayed benefit. They concluded that more studies are needed to validate any positive benefit.

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Findings from another study presented by Douglas Slain, PharmD, chair and professor of clinical pharmacy at West Virginia University, at IDWeek in 2017 showed that an automatic probiotic protocol at one community hospital did not protect against CDI in adults treated with antibiotics. Slain explained that the automatic protocol initiated probiotic treatment at the start of antibacterial therapy. After comparing CDI rates 3 years before and after the protocol was implemented, they found no change.

Probiotics for pediatric patients?

Jonathan Crews, MD, an assistant professor of pediatrics at Baylor College of Medicine, told Infectious Diseases in Children that the use of probiotics to prevent CDI is something that many pediatricians are interested in, “but we just do not have the data to use them routinely in children.”

Crews, who does not routinely use probiotics in his own practice, said families do ask about them. He believes that many are interested because probiotics are “generally safe” and readily available at local pharmacies and supermarkets.

“I think the primary question that families have is if probiotics will work,” he said. “That is the same question that we all have. At this point, we do not know if probiotics will prevent CDI in children. If they do, we do not know which products are best at preventing infection. We are still waiting for those studies to be done.”

Part of the problem, he suggested, is that most studies related to CDI prevention and probiotics have been conducted among immunocompetent adults.

“Finding out which patients would benefit the most is a really important piece, especially among children who, overall, are at low risk for CDI compared with adults,” Crews said.

Relying on clinical experience

Maggie J. Box

Maggie J. Box, PharmD, BCPS, and colleagues from Scripps Health published results of a large retrospective cohort study that found that probiotics did not decrease rates of facility-onset CDI among patients on antibiotics in their hospital outside San Diego. The team acknowledged that probiotics are not endorsed for CDI prevention, but that the hospital had added a commercially available combination of Lactobacillus acidophilus CL1285, L. casei LBC80R and L. rhamnosus CLR2 (Bio-K+) to its formulary based on a supplement published in 2015 in Clinical Infectious Diseases.

The study evaluated the outcomes of 1,576 patients treated with IV antibiotics. According to the results, hospital-onset CDI occurred in 1.8% of patients who also received probiotics and 0.9% in those who did not. Moreover, patients who received probiotics had longer lengths of stay, higher Charlson Comorbidity Index scores and were billed for more antibiotics.

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As a result of the study, the hospital removed all probiotics from the formulary, the researchers reported.

Additionally, Box said in an interview that quality control of probiotics can be an issue.

“Probiotics are regulated as a dietary supplement and are not required by the FDA to undergo rigorous evaluations for efficacy or safety,” she said. “Studies have shown that the contents of probiotic products may differ from the ingredients listed.”

Purna C. Kashyap, MBBS, scientific advisory board member at the American Gastroenterological Association Center for Gut Microbiome Research & Education and associate professor at the Mayo Clinic, cited the lack of conclusive evidence as reason to wait for better quality evidence before stocking formularies.

Purna Kashyap

“While conceptually attractive, we haven’t had much success with the currently available probiotics, and there are several reasons: lack of adequate science behind picking bacterial strains to use as probiotics, differences in design of study such as the choice of the type and number of bacteria, number of patients treated, duration of treatment and so on,” Kashyap said. “There has been low-level evidence supporting the use of probiotics in preventing infections such as C. difficile infection or treatment of certain forms of inflammatory bowel disease.”

However, some experts believe hospitals should stock probiotics. Trick, for one, thinks hospital formulary committees could help guide probiotic choices.

“There is general acceptance of probiotic use and substantial demand to use probiotic products. By selecting options for clinicians to choose, a hospital’s formulary committee can guide use to those probiotic products that have been most rigorously evaluated,” he explained. Additionally, he said infectious disease physicians should be knowledgeable to meet patient demands.

“Patients are aware of probiotic options and will expect their ID physicians to be knowledgeable about the possible uses of probiotics. The variability in the composition of product — different strains of organisms — and methods of use — indication, timing, and duration — requires familiarity with the literature.”

A lack of convincing evidence one way or the other may lead clinicians to rely on clinical experience. Satish S.C. Rao, MD, PhD, FRCP, professor of medicine at the Medical College of Georgia, said he has found probiotics to be “beneficial and useful” in reducing CDI in his own practice — the one situation in which he uses them.

“The challenge remains which probiotic [to use] and what dose and for how long. This remains unclear,” Rao told Infectious Diseases in Children.

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Rao believes hospitals should have at least two choices of broad-spectrum probiotics available in their formularies but also said “more concrete evidence” is needed to determine their benefit.

“At present there is no evidence that probiotics don’t work or cause harm for post-C. difficile diarrhea. There [are] some good animal data to back this, but it’s not so clear-cut in humans, though clinical observation supports their use,” Rao said. “Unfortunately, few hospitals stock them, and mostly we ask patients or relatives to get them over the counter. Therein lies the conundrum, as there is little proof or study as to which one is best.”

Using probiotics may come with side effects, which is why Rao believes they should be prescribed as drugs and not taken as health supplements.

“In fact, we found that probiotics can inadvertently colonize in the small bowel and cause harm,” he said.

In a study published last year in Clinical and Translational Gastroenterology, Rao and colleagues described what they called a “syndrome” of brain fog, gas and bloating in a small cohort of patients with an intact small bowel and colon that they said was possibly related to probiotic use and colonization of probiotic bacteria in the small bowel, causing D-lactic acidosis.

Box mentioned that bacteria found in probiotic forumulations may cause infections in hospitalized patients, particularly those with venous catheters.

The most common side effects reported by pediatric and adult patients who took part in the studies that were included in the Cochrane meta-analysis were abdominal cramping, nausea, fever, soft stools, flatulence and taste disturbance. However, the researchers wrote that taking probiotics does not increase the risk for side effects and that their use appears to be safe.

“People need to realize that probiotics have the potential to have side effects. It’s not just a [matter of using them and saying], ‘What’s the worst that can happen, it won’t work?’ No, there are potential concerns about using them, especially in immunocompromised patients,” Glatt said.

He added that the side effects are not severe enough to elicit a negative patient outcome. However, he advises against using them right away without “the right type of data.”

No official recommendations

Medical organizations like Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America do not recommend probiotics for CDI prevention in children or adults based on insufficient evidence, according to Erik R. Dubberke, MD, MSPH, professor of medicine at Washington University School of Medicine in St. Louis.

“The current research suggests there may be promise in using probiotics for prevention of primary and recurrent CDI, but many questions remain, including optimal probiotic formulation, duration of administration, and patient factors,” Dubberke, a co-author of the IDSA/SHEA guidelines on probiotic use, told Infectious Diseases in Children. “These and other questions should be the focus of future controlled clinical trials.”

“The key word is ‘promise,’ but there is no recommendation,” Glatt added. “We just don’t know.”

The CDC concurs, saying more conclusive results are needed to set standards for their use.

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The AAP released a clinical report in 2010 suggesting that, based on results from randomized clinical trials, probiotics are “modestly effective” at treating viral gastroenteritis-associated diarrhea and preventing antibiotic-associated diarrhea in otherwise healthy children. The authors stressed that probiotics should not be given to chronically or seriously ill children.

Currently, the CDC suggests taking preventive measures to avoid the spread of C. difficile. The agency recommends that doctors, nurses and other health care providers clean their hands before and after caring for patients with CDI while also using gowns and gloves.

The agency also reported that more than half of all hospitalized patients may receive an antibiotic at some point during their hospital stay, but 30% to 50% of antibiotics prescribed in hospitals are unnecessary or inappropriate. Experts recommend implementing antimicrobial stewardship practices as a preventive measure, being sure to not overuse antibiotics and prescribe antibiotics only when appropriate.

“People should certainly not rely on probiotics [to treat or prevent CDI],” Glatt said. “We will win the war against C. difficile by controlling inappropriate antibiotic usage and by improving antibiotic stewardship.”– by Caitlyn Stulpin and Katherine Bortz

Click here to read the , “Which probiotics or combination of probiotics hold the most promise for C. difficile prevention?”

References:

Box MJ et al. Open Forum Infect Dis. 2018;doi.org/10.1093/ofid/ofy192.

Ehrhardt S, et al. Open Forum Infect Dis. 2016;doi:10.1093/ofid/ofw011.

Goldenberg JZ, et al. Cochrane Database Syst Rev. 2017;doi:10.1002/14651858.CD006095.pub4.

Goldstein EJC, et al. Clin Infect Dis. 2015;doi: 10.1093/cid/civ142.

Grand View Research. Probiotics market size, share & trends analysis report by application (food & beverages, dietary supplements, animal feed) by end-use, by region, and segment forecast, 2018-2024. https://www.grandviewresearch.com/industry-analysis/probiotics-market. Accessed March 29, 2019.

Johnston BC, et al. Infect Control Hosp Epidemiol. 2018;doi:10.1017/ice.2018.84.

Rao SSC, et al. Clin Transl Gastroenterol. 2018; doi:10.1038/s41424-018-0030-7.

Slain D, et al. Abstract 80. Presented at: IDWeek; Oct. 4-8, 2017; San Diego.

Szajewska H, et al. Aliment Pharmacol Ther. 2015;doi:10.1111/apt.13404.

Thomas DW, et al. Pediatrics. 2010;doi:10.1542/peds.2010-2548.

Trick WE, et al. Infect Control Hosp Epidemiol. 2018; doi:10.1017/ice.2018.76.

For more information:

Maggie J. Box, PharmD, BCPS, can be reached at box.maggie@scrippshealth.org.

can be reached at box.maggie@scrippshealth.org. Jonathan Crews, MD, can be reached through Allison Mickey at allison.huseman@bcm.edu.

can be reached through Allison Mickey at allison.huseman@bcm.edu. Erik R. Dubberke, MD, MSPH, can be reached via 1 (314) 286-0100.

can be reached via 1 (314) 286-0100. Aaron E. Glatt, MD, can be reached at aglattmd@gmail.com.

can be reached at aglattmd@gmail.com. Purna Kashyap, MD, MBBS, can be reached at media@gastro.org.

can be reached at media@gastro.org. Satish Rao, MD, PhD, FRCP, can be reached at srao@augusta.edu.

can be reached at srao@augusta.edu. William Trick, MD, can be reached via 1 (312) 864-0950.

Disclosures: Box, Dubberke, Glatt, Rao and Trick report no relevant financial disclosures. Crews is a site investigator for a Merck product related to C. difficile. Kashyap reports being on the advisory board at uBiome and being a consultant for Salix.