Cover Story

Probiotics: An unproven answer to prevent C. difficile infection

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

Results have varied, with some studies showing a protective effect and others finding no impact.

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.

“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 Disease News. “Probiotics are one of the tools that will continue to be explored and used as the risks and benefits are better defined.”

Studies examining varying doses and combinations of probiotics have produced contradictory results, raising questions about whether probiotics should be used or recommend for CDI prevention. Infectious Disease News spoke with several experts to gain insight on the subject.

What the evidence says

Primarily, probiotics are used to improve gut health, although their efficacy and usefulness is a topic of debate in the infectious disease community, experts said. Evidence has shown that some probiotics are helpful in preventing diarrhea caused by infections and antibiotics, but experts say more needs to be learned to determine which probiotics 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 United States, according to the CDC, researchers and clinicians have turned to probiotics to fight the bacteria.

The global market for probiotics was estimated to be around $36 billion in 2016 and expected to rise consistently into the next decade, according to Grand View Research, a market research and consulting company based in the U.S.

William Trick

Many studies have explored using probiotics for preventing CDI, but they have not yielded conclusive, widely accepted results, researchers said.

“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 Disease News. “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.

“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 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 the 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 an increased risk for infection was observed in patients who received two or more antibiotics (OR = 2.2; 95% CI, 1.11-4.37).

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.

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.

Maggie J. Box

More recently, 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 of San Diego. The team acknowledged that probiotics are not endorsed for CDI prevention but that the hospital had added a commercially available combination of L. 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.

Purna C. Kashyap

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

Should they be used?

Box noted that the 2017 Infectious Diseases Society of America clinical practice guidelines for CDI “state that there are insufficient data to recommend administration of probiotics for primary prevention of CDI.”

“In addition, there is also the potential for bacteria found in probiotic formulations to cause infections in hospitalized patients, particularly in those with central venous catheters,” Box told Infectious Disease News. “Finally, probiotics are regulated as a dietary supplement and are not required by the FDA to undergo rigorous evaluations for efficacy or safety. Studies have shown that the contents of probiotic products may differ from the ingredients listed, and quality control of these products can be an issue.”

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 a lack of conclusive evidence as a reason to wait for better quality evidence before stocking formularies.

“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 the design of studies, 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 Disease News.

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 from over the counter, and 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 describe 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.

“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.

“Now, I’m not saying side effects to the point that you shouldn’t use them and there will be a negative outcome — I’m saying that without the right type of data, I wouldn’t jump right to using them.”

No official recommendations

Erik R. Dubberke

The CDC and medical organizations like the IDSA have not recommended probiotics for CDI.

Current IDSA/Society for Healthcare Epidemiology clinical practice guidelines for CDI in adults and children “do not recommend the use of probiotics for the prevention of primary or recurrent CDI because of insufficient research showing a significant and reproducible impact on their use,” Erik R. Dubberke, MD, MSPH, professor of medicine at Washington University School of Medicine in St. Louis and an author of the guidelines, summarized.

“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 told Infectious Disease News. “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.

“There are currently no probiotics sold that are FDA-approved for either the prevention or treatment of C. diff. All probiotics sold in the United States are sold as nutritional supplements, none of which can make a claim beyond maintaining the ‘structure or function’ of the body,” L. Clifford McDonald, MD, associate director for science in the CDC’s Division of Healthcare Quality Promotion, told Infectious Disease News.

For example, the prevention or treatment of CDI would be a drug claim requiring a higher standard of scientific evidence, with studies proving that a certain probiotic, given at a specific dose, time and duration, effectively prevents or treats the condition.

“In addition, a drug claim would require additional documentation that a probiotic contains a specific strain of microorganism at a specific potency,” McDonald said. “Without this type of evidence, CDC does not recommend the use of probiotics for the prevention of C. diff and neither do our partners, as reflected in the recent IDSA/SHEA guideline.”

Current methods

Currently, the CDC suggests taking preventive measures to prevent 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.

Experts also recommend implementing antimicrobial stewardship practices as a preventive measure, being sure to not overuse antibiotics and only prescribe when appropriate.

According to the CDC, 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.

“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

Disclosures: Box, Dubberke, Glatt, McDonald, Rao and Trick report no relevant financial disclosures. Kashyap reports being on the advisory board at uBiome and being a consultant for Salix.

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

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

Results have varied, with some studies showing a protective effect and others finding no impact.

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.

“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 Disease News. “Probiotics are one of the tools that will continue to be explored and used as the risks and benefits are better defined.”

Studies examining varying doses and combinations of probiotics have produced contradictory results, raising questions about whether probiotics should be used or recommend for CDI prevention. Infectious Disease News spoke with several experts to gain insight on the subject.

What the evidence says

Primarily, probiotics are used to improve gut health, although their efficacy and usefulness is a topic of debate in the infectious disease community, experts said. Evidence has shown that some probiotics are helpful in preventing diarrhea caused by infections and antibiotics, but experts say more needs to be learned to determine which probiotics 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 United States, according to the CDC, researchers and clinicians have turned to probiotics to fight the bacteria.

The global market for probiotics was estimated to be around $36 billion in 2016 and expected to rise consistently into the next decade, according to Grand View Research, a market research and consulting company based in the U.S.

William Trick

Many studies have explored using probiotics for preventing CDI, but they have not yielded conclusive, widely accepted results, researchers said.

“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 Disease News. “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.

PAGE BREAK

“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 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 the 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 an increased risk for infection was observed in patients who received two or more antibiotics (OR = 2.2; 95% CI, 1.11-4.37).

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.

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.

Maggie J. Box

More recently, 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 of San Diego. The team acknowledged that probiotics are not endorsed for CDI prevention but that the hospital had added a commercially available combination of L. 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.

PAGE BREAK

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.

Purna C. Kashyap

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

Should they be used?

Box noted that the 2017 Infectious Diseases Society of America clinical practice guidelines for CDI “state that there are insufficient data to recommend administration of probiotics for primary prevention of CDI.”

“In addition, there is also the potential for bacteria found in probiotic formulations to cause infections in hospitalized patients, particularly in those with central venous catheters,” Box told Infectious Disease News. “Finally, probiotics are regulated as a dietary supplement and are not required by the FDA to undergo rigorous evaluations for efficacy or safety. Studies have shown that the contents of probiotic products may differ from the ingredients listed, and quality control of these products can be an issue.”

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 a lack of conclusive evidence as a reason to wait for better quality evidence before stocking formularies.

“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 the design of studies, 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.”

PAGE BREAK

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 Disease News.

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 from over the counter, and 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 describe 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.

“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.

“Now, I’m not saying side effects to the point that you shouldn’t use them and there will be a negative outcome — I’m saying that without the right type of data, I wouldn’t jump right to using them.”

PAGE BREAK

No official recommendations

Erik R. Dubberke

The CDC and medical organizations like the IDSA have not recommended probiotics for CDI.

Current IDSA/Society for Healthcare Epidemiology clinical practice guidelines for CDI in adults and children “do not recommend the use of probiotics for the prevention of primary or recurrent CDI because of insufficient research showing a significant and reproducible impact on their use,” Erik R. Dubberke, MD, MSPH, professor of medicine at Washington University School of Medicine in St. Louis and an author of the guidelines, summarized.

“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 told Infectious Disease News. “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.

“There are currently no probiotics sold that are FDA-approved for either the prevention or treatment of C. diff. All probiotics sold in the United States are sold as nutritional supplements, none of which can make a claim beyond maintaining the ‘structure or function’ of the body,” L. Clifford McDonald, MD, associate director for science in the CDC’s Division of Healthcare Quality Promotion, told Infectious Disease News.

For example, the prevention or treatment of CDI would be a drug claim requiring a higher standard of scientific evidence, with studies proving that a certain probiotic, given at a specific dose, time and duration, effectively prevents or treats the condition.

“In addition, a drug claim would require additional documentation that a probiotic contains a specific strain of microorganism at a specific potency,” McDonald said. “Without this type of evidence, CDC does not recommend the use of probiotics for the prevention of C. diff and neither do our partners, as reflected in the recent IDSA/SHEA guideline.”

Current methods

Currently, the CDC suggests taking preventive measures to prevent 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.

Experts also recommend implementing antimicrobial stewardship practices as a preventive measure, being sure to not overuse antibiotics and only prescribe when appropriate.

According to the CDC, 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.

“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

PAGE BREAK

Disclosures: Box, Dubberke, Glatt, McDonald, Rao and Trick report no relevant financial disclosures. Kashyap reports being on the advisory board at uBiome and being a consultant for Salix.

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