Posts

The American College of Gastroenterology recommends against use of probiotics for primary or secondary prevention of C. difficile

By Prof. Daniel Merenstein MD, Georgetown University School of Medicine and Prof. Eamonn Quigley MD FRCP FACP MACG FRCPI,  Houston Methodist Hospital and Weill Cornell Medical College

The American College of Gastroenterology (ACG) recently published ACG Clinical Guidelines: Prevention, Diagnosis, and Treatment of Clostridioides difficile Infections. This review considers probiotics for prevention of CDI. The ACG’s recommendations regarding probiotics and C. difficile infection (CDI) are:

  1. We recommend against probiotics for the prevention of CDI in patients being treated with antibiotics (primary prevention) (conditional recommendation, moderate quality of evidence).
  2. We recommend against probiotics for the prevention of CDI recurrence (secondary prevention) (strong recommendation, very low quality of evidence).

The ACG guidelines take a different approach to the evidence relating to probiotics than that of the American Gastroenterological Association (AGA) or the Cochrane Collaboration. The most recent Cochrane review on prevention of C. difficile-associated diarrhea (CDAD) concluded in brief, “moderate certainty evidence suggests that probiotics are effective for preventing CDAD”. In the AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders, the recommendation was:

In adults and children on antibiotic treatment, we suggest the use of S. boulardii; or the 2-strain combination of L. acidophilus CL1285 and Lactobacillus casei LBC80R; or the 3-strain combination of L acidophilus, Lactobacillus delbrueckii subsp bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L. acidophilus, L. delbrueckii subsp bulgaricus, B. bifidum, and Streptococcus salivarius subsp thermophilus over no or other probiotics for prevention of C difficile infection. (Conditional recommendation, low quality of evidence.)

In both the AGA and ACG guidelines the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used. How, then, did they come to such different conclusions and recommendations?

The ACG guideline stated,  “a meta-analysis of 19 RCTs that concluded that probiotics were helpful at prevention of CDI in hospitalized patients if given close to start of antibiotics, with a 70% lower risk if probiotics were started within 2 days but falling to a 30% risk reduction if probiotics were started after 2 days of antibiotic therapy”. But then they did not take timing of probiotic administration into account as they assessed the evidence. Instead, they use the negative PLACIDE trial to override all other evidence for primary prevention. The PLACIDE trial was a well-done trial, but participants started their probiotic treatment 3- 7 days after antibiotics. Thus, it would seem that the ACG guideline’s conclusion could favor probiotics as long as they can be started within 2 days of the antibiotic and not recommend against probiotic use.

The ACG guideline objects to combining data on different probiotic strains in meta-analyses in order to provide evidence in favor of probiotics: “Evidence to support probiotics for this indication comes mainly from meta-analyses that pool data from small trials of different probiotic formulations and methodologies.” This is true, but the Cochrane review found thirty-nine studies (8,672 participants) that met their eligibility criteria and it is noteworthy that several different probiotics were found to be effective. The Cochrane number needed to treat (NNT) to prevent CDI is 42. However, if the ACG thought this was driven by too many negative trials, they could have qualified their recommendation. The Cochrane review found in subgroup analyses that probiotics are most effective (NNT=12) among trials with a CDI baseline risk >5%. But to conclude there is no benefit of probiotics for primary CDI is not supported by the evidence.

It is puzzling that ACG insists that the probiotic literature be pooled in a strain-specific manner, yet they support conclusions on fecal microbial transplant (FMT) even though FMT interventions are much more heterogeneous than probiotics in regard to composition and mode of administration. They recommend FMT for treatment of C. difficile based on only three double-blinded randomized clinical trials (here, here and here), only one of which was positive. The positive FMT study was conducted at two sites and compared donor stool (heterologous) versus patient’s own stool (autologous) administered by colonoscopy. Overall, 91% of patients in the FMT group achieved clinical cure compared with 63% in the control group. At site #1, the cure rate with donor FMT was 90.0% (CI, 51.8% to 98.7%) versus 42.9% with autologous FMT, whereas in site #2 the cure rate was essentially identical between the two groups. At site #2, donor FMT cure rate was 91.7% (CI, 57.2% to 98.9%) compared with 90.0% (CI, 51.8% to 98.7%) after autologous FMT. We mention this to question the consistency of evidence standards that the ACG guideline authors impose. They admonish pooled data from small trials of different probiotic formulations and methodologies yet ignore heterogeneity in FMT interventions. The data reviewed for probiotics was primarily from double-blinded randomized trials, while for FMT they rely on case series, uncontrolled studies or retrospective studies.

The authors go on to state, “… high quality evidence to support probiotics for most conditions is scarce.” How do they define “scarce” and “most conditions”? As mentioned, Cochrane found thirty-nine studies (8,672 participants) for prevention of CDAD. Under “summary of evidence”, the authors address issues such as size of the market, regulatory oversight, product cost and quality control problems with commercial products, all of which may reflect practical concerns with some probiotic products in the marketplace, but have nothing to do with available evidence. Furthermore, it is the only intervention where the financial value of the industry and cost of interventions is mentioned. Why are the size of the market or costs for FMT or drugs not just as relevant to this review? Cost is discussed throughout the recommendation but without performing or citing a formal cost analysis or cost-effectiveness analysis, even though there are approaches for doing so to inform evidence-based decision-making (here).

The authors indict probiotics for concerns about safety, citing not the thorough review sponsored by AHRQ and conducted by the RAND corporation that looked at 622 studies and found no statistically significant increased relative risk of the overall number of experienced adverse events (RR 1.00; 95% confidence interval [CI]: 0.93, 1.07, p=0.999), but by referring to a review article that cites case reports of blood infections and refers to one study with microbiota, not clinical, endpoints done in Israel on one commercial product. The data actually show that for well characterized, clinically tested probiotics with high levels of quality control the evidence for infectious complications in non-vulnerable populations is virtually nil. ACG does not mention that FMT was shut down due to safety concerns as soon as the pandemic started.

In summary, we are not convinced that the authors have justified their recommendation against the use of probiotics in relation to CDI prevention. They fail to clarify why the results of their GRADE evaluation of probiotic evidence for prevention of C. difficile resulted in totally different conclusions compared to the AGA document, which found evidence sufficient for conditional recommendation of four probiotic preparations. Further,  the review of evidence for probiotics, whether in terms of efficacy or safety, should be addressed in a manner consistent with other interventions considered and editorializing on issues such as market size, profits and product cost, in the absence of an objective approach using appropriate instruments, should be avoided.

Pharmacists as influencers of probiotic use

By Kristina Campbell, science writer

It’s not an uncommon scene in a pharmacy: someone standing in front of the shelf of probiotic products, picking up various bottles and reading the labels, looking uncertain. The person’s doctor may have recommended a certain brand of probiotic to prevent diarrhea with a prescribed course of antibiotics—but they’ve just noticed that the store-brand probiotic, with different strains, is half the price.

Dragana Skokovic-Sunjic

According to Dragana Skokovic-Sunjic, clinical pharmacist and author of the ‘Clinical Guide to Probiotic Products Available in Canada/US’, pharmacists can play an important and influential role helping patients make informed decisions about the available products. “Pharmacists provide a ‘last check validation’ before the patient actually decides to purchase a product,” she says. “And we proactively seek to assist those patients who need help.”

Nardine Nakhla

Nardine Nakhla, clinical pharmacist and Clinical Lecturer at the University of Waterloo School of Pharmacy, says pharmacists often have the knowledge and experience to zero in on which over-the-counter product(s) will or will not work for a certain individual. “Pharmacists have the knowledge and skills to individualize the recommendation based on patient-specific and disease-specific factors, and that is so very important with non-prescription and natural health products because there is no one-size-fits-all approach,” she says.

Can pharmacists apply their knowledge and skills to make specific probiotic recommendations? While it can be hard to narrow the evidence down on specific products, pharmacists can certainly play a role in helping patients understand the evidence for the products they encounter. In a recent interview with ISAPP, Skokovic-Sunjic and Nakhla explained why pharmacists in Canada and elsewhere have the potential to steer people’s choice of over-the-counter and natural health products – including probiotics.

Pharmacists have knowledge about the products on their shelves.

“Advising patients on self-care, which includes over-the-counter and natural health product use, is a key responsibility of Canadian pharmacists. We have North American survey data that shows, for patients who go out and buy non-prescription and natural health products, over 80% never read the label,” says Nakhla.

This means that having a pharmacist available at the point-of-purchase to answer questions can go a long way toward educating people about what’s actually in their hands and how to optimize use, if warranted.

“Having the pharmacist present lets you access somebody who can help inform your decisions—someone who can perhaps steer you away from products that may not be appropriate for you,” she says.

“Pharmacists need to be familiar with the products they are selling at their pharmacies,” adds Skokovic-Sunjic. “They are skilled at asking suitable questions to ensure the patient’s needs and wishes are understood and then to help them choose appropriate over-the-counter, ‘self-selection’ therapy.”

Pharmacists are unique in having non-prescription products within their standards of practice.

As a faculty member at the school of pharmacy, Nakhla emphasizes the requirement for pharmacists to know how to assess and manage patients seeking self-care in the community. She says, “We have a unique body of knowledge where we study non-prescription therapeutics and other self-care measures of disease management and health maintenance,” she says. “Pharmacists are trained to know about these and to recommend evidence-based and cost-effective measures individualized for each patient.”

“It’s explicitly stated under our Standards of Practice that we must be proficient in providing information on non-prescription products, natural health products, and on non-pharmacological measures to enable patients to receive the intended benefit of the therapies, whereas physicians are far more focused on the diagnosis and prescription therapies,” she says.

Pharmacists can identify patients who could benefit from probiotics

Both Nakhla and Skokovic-Sunjic emphasize that pharmacists frequently identify people who could potentially benefit from self-care products, even if they don’t come in looking for them.

Nakhla mentions the probiotic guide authored by Skokovic-Sunjic, and how it helps pharmacists provide helpful solutions to common problems that present in the community. “I think a good strategy is looking at the conditions listed in the probiotic guide and the subsequent products indicated for use for them, and then work backwards to try to identify patients who may benefit from the listed therapies, rather than just wait for them to present asking you questions.”

Pharmacists are in a position to encourage prevention.

“Pharmacy has historically focused on providing reactive healthcare rather than proactive or preventative care,” says Nakhla. But this has recently changed, with a growing emphasis on preventing chronic disease through ongoing health maintenance and self-care strategies. She cites pharmacists as qualified health professionals who encounter many generally healthy people throughout the course of their day, and who are therefore well-positioned to advise the public on how to remain healthy.

Skokovic-Sunjic gives some examples: “If the consumer will be travelling, we might suggest a specific probiotic to prevent traveller’s diarrhea. Or if we are coming to the cold and flu season, we may recommend a product they can take to reduce the risk of developing common infectious diseases.”

Pharmacists can conduct brief or lengthy assessments before providing recommendations.

Skokovic-Sunjic says, “A pharmacist can provide specific recommendations that could really make a big difference in the patient’s experience by quickly asking a few targeted questions. This strategy may save the patient time, money, frustration and sub-optimal health outcomes. When consumers self-select inappropriate products, they will not experience benefits they seek. Determined to choose a natural product, some consumers will try a second or even third product but will not get the symptom relief they are looking for. An unintended consequence of this is that the patient may dismiss the probiotics as ineffective not because they did not work, but because it was the wrong product for the desired effect.”

Brief assessment questions are especially important for probiotics, she adds, because specificity can ‘make or break’ how useful they are to an individual. “In my consultations with patients, I quite often include questions about bowel movements and I know they are questioning why I am asking. Understanding gut function can be extremely helpful in providing appropriate probiotic recommendations.”

Pharmacists can help people understand the concept of ‘evidence-based’.

Nakhla acknowledges it’s difficult for the average person to confront a shelf of probiotic products and delineate between the ones that have evidence backing their use, and the ones that do not. “That’s where I really think a pharmacist needs to intervene and to help them balance out the pros and the cons,” she says.

“If patients are looking for a probiotic to relieve a specific symptom, then looking for an evidence-based recommendation for that specific symptom is needed,” says Skokovic-Sunjic. “If they pick something that’s not supported by evidence, it may not provide symptom relief or the benefit they expect. This may be in addition to wasted funds and mounting frustration.”

Thus, pharmacists are in a unique position to contribute to enhanced awareness about efficacy and “evidence-based self-care” as they explain these concepts to consumers at the point of sale.

 

Given all the potential ways for pharmacists to guide consumer decisions about probiotics, both Skokovic-Sunjic and Nakhla agree that keeping up on the latest probiotic evidence is of high importance.

Through ISAPP’s new efforts to engage with pharmacists, the organization plans to gauge how pharmacists in various parts of the world approach probiotic recommendations, and to support the ‘best case scenario’ of pharmacists providing evidence-based information about probiotics directly to consumers.

Sign up here for ISAPP’s newsletter for pharmacists.

What’s a Clinician to do When the Probiotic Recommendations from Medical Organizations Do Not Agree?

By Prof. Hania Szajewska, MD, Department of Paediatrics, The Medical University of Warsaw, Poland

The scientific literature on probiotics is growing rapidly, with newly published studies continually adding to the sum of information about the probiotic strains that confer health benefits in specific populations.

In research, we make hypotheses. Eventually, they are resolved by collecting data or they are replaced by more refined, or entirely new, hypotheses. This process usually unfolds over an extended period of time. Along the way, medical and scientific organizations may decide to take ‘snapshots’ of the evidence to-date and develop guidelines based on available published studies. Unfortunately, disagreements can occur about the meaning of the data, sometimes leading to differences in the guidelines developed by various organizations.

But clinicians cannot always wait for the data to provide a crystal-clear picture. They want answers to guide their clinical practice. Hence the question: Should probiotics be used if guidelines do not agree on the use of probiotics for a certain indication, or on the strains to be used?

Take, for example, the current situation relevant to pediatric practice. Here I discuss two recommendation documents: one developed by the European Society of Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN), and another developed by the American Gastroenterological Association (AGA).

Acute diarrhea

In 2020, the ESPGHAN Working Group (WG) on Probiotics identified 16 systematic reviews and meta-analyses published since 2010, which included more than 150 RCTs. The WG made weak (also known as conditional) recommendations for (in descending order in terms of the number of trials evaluating any given strain):

  • S boulardii (low to very low certainty of evidence);
  • L rhamnosus GG (very low certainty of evidence); L reuteri DSM 17938 (low to very low certainty of evidence);
  • L rhamnosus 19070-2 & L reuteri DSM 12246 (very low certainty of evidence).

The WG made a strong recommendation against L helveticus R0052 & L rhamnosus R0011 (moderate certainty of evidence) and a weak (conditional) recommendation against Bacillus clausii strains O/C, SIN, N/R, and T (very low certainty of evidence)1.

In contrast, also in 2020, the AGA, based on the evaluation of 89 trials, made a conditional recommendation against the use of probiotics in children from North America with acute infectious gastroenteritis (moderate quality of evidence)2. The rationale for the negative AGA recommendation was that the majority of the studies were performed outside North America. Moreover, two large, high-quality null trials, performed in Canada and US, questioned the efficacy of the probiotics evaluated in these studies, for the management of children with acute gastroenteritis 3,4.

Prevention of necrotizing enterocolitis

Another example of discordant guidelines relates to necrotizing enterocolitis (NEC) in preterm infants. NEC is one of the most severe and life-threatening gastrointestinal diseases to occur in preterm infants, particularly those with a birth weight <1,000 g. The factors involved in the pathogenesis of NEC include formula feeding rather than breastfeeding, intestinal hypoxia–ischemia, and colonization of the gut with pathogenic microbiota5.

In 2020, both ESPGHAN6 and AGA2 published their recommendations on the use of probiotics for preventing NEC. While both were based on pair-wise systematic reviews and network meta-analyses7, their conclusions differed. The only probiotic strain that was recommended by both societies was L rhamnosus GG ATCC 53103. With regard to L reuteri DSM 17938, the ESPGHAN did not formulate a recommendation for or against it, while the AGA conditionally recommends it.

Why do guidelines differ?

Many factors contribute to the discrepancy in guidelines developed by various organizations. In the case of probiotics, they may be due to these differences:

  • Study methods. Although dozens of studies involving thousands of patients have been conducted in many indications, studies are subject to bias resulting from incorrect randomization, non-confidentiality, non-masking, or lack of intention-to-treat analysis.
  • Targeted population. The effectiveness of probiotics in different populations may vary, for example, due to differences diet or in microbiota at the start of treatment.
  • Probiotics are a heterogeneous intervention. Even if the rules for assessing individual strains, and not probiotics as a group, are followed, the effectiveness of probiotics is influenced by factors such as product quality, storage conditions, dose, timing of administration, and the duration of the intervention.
  • Outcome measures (endpoints). Studies use different outcomes to measure efficacy, and even if the same outcomes are used, their definition may differ (e.g. diarrhea duration may be defined as time to the last diarrheal stool or time to the first normal stool). Such heterogeneity in the reported outcomes, combined with the lack of standardized definitions, pose a challenge in meta-analyses and should be considered when interpreting the results.

What should clinicians do when the guidelines are not consistent?

Back to the question asked earlier: Should probiotics be routinely used if guidelines from the scientific or medical organizations do not agree on the use of probiotics?

One approach may not fit all. However, in the case of acute infectious diarrhea in children, both the AGA and ESPGHAN formulated a conditional recommendation: in the first case, it is negative; in the second, positive. It is important to note that the interpretation of a conditional recommendation for and a conditional recommendation against is similar. For clinicians, both mean that different choices will be appropriate for different people. Clinicians should help each patient make decisions consistent with the patient’s preferences. For patients, it means that the majority of individuals in this situation would want the suggested course of action, but many would not8.

Taken together, the recommendations communicate that probiotics may be beneficial, although not essential, in the treatment of acute diarrhea in young children.  The use of certain probiotics with documented efficacy may be considered in the management of acute diarrhea in young children.

With regard to the prevention of NEC, the AGA and ESPGHAN guidelines agree that certain probiotics reduce the risk of NEC in preterm infants. However, based on their analyses and the included / excluded studies they differ in the recommended strains; additionally, not all of the strain combinations are available everywhere. Therefore, it seems reasonable to choose a probiotic that is included in the recommendations of both societies (if available). One example is L. rhamnosus GG.

In general, organizations should be commended for taking on the daunting task of evaluating the probiotic evidence – both the quality of the studies and the positive or negative results – in order to generate recommendations. Until further well-conducted studies make the answer clearer, clinicians must live with some ambiguity and use the recommendations in the best way possible to inform their daily decisions with individual patients.

REFERENCES

  1. Szajewska H, Guarino A, Hojsak I, et al. Use of Probiotics for the Management of Acute Gastroenteritis in Children. An Update. J Pediatr Gastroenterol Nutr. 2020.
  2. Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020.
  3. Schnadower D, Tarr PI, Casper TC, et al. Lactobacillus rhamnosus GG versus Placebo for Acute Gastroenteritis in Children. The New England journal of medicine. 2018;379(21):2002-2014.
  4. Freedman SB, Williamson-Urquhart S, Farion KJ, et al. Multicenter Trial of a Combination Probiotic for Children with Gastroenteritis. The New England journal of medicine. 2018;379(21):2015-2026.
  5. Neu J, Walker WA. Necrotizing enterocolitis. The New England journal of medicine. 2011;364(3):255-264.
  6. van den Akker CHP, van Goudoever JB, Shamir R, et al. Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. Journal of pediatric gastroenterology and nutrition. 2020;70(5):664-680.
  7. van den Akker CHP, van Goudoever JB, Szajewska H, et al. Probiotics for Preterm Infants: A Strain-Specific Systematic Review and Network Meta-analysis. Journal of pediatric gastroenterology and nutrition. 2018;67(1):103-122.
  8. Andrews J, Guyatt G, Oxman AD, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations. J Clin Epidemiol. 2013;66(7):719-725.