Prescribing an Antibiotic? Pair It With Probiotics

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.

PRACTICE CHANGER
Recommend that patients taking antibiotics also take probiotics, which have been found to be effective both for the prevention and treatment of antibiotic-associated diarrhea (AAD).¹

STRENGTH OF

RECOMMENDATION
A: Based on a systematic review and meta-analysis of randomized controlled trials (RCTs).

ILLUSTRATIVE CASE
When you prescribe an antibiotic for a 45-year-old patient with Helicobacter pylori, he worries that the medication will cause diarrhea. Should you recommend that he take probiotics?

More than a third of patients taking antibiotics develop AAD,² and in 17% of cases, AAD is fatal.^3,4 Although the diarrhea may be the result of increased gastrointestinal (GI) motility in some cases, a disruption of the GI flora that normally acts as a barrier to infection and aids in the digestion of carbohydrates is a far more common cause.

Morbidity and mortality are high
AAD is associated with several pathogens, including Clostridium difficile, Clostridium perfringens, Klebsiella oxytoca, and Staphylococcus aureus,² and varies widely in severity. Pseudomembranous colitis secondary to C difficile is the main cause of AAD-related mortality, which more than doubled from 2002 to 2009.^3,4 C difficile infections cost the US health care system up to $1.3 billion annually.⁵ With such high rates of morbidity and mortality and high health care costs associated with AAD, even a small reduction in the number of cases would have a big impact.

Probiotics replenish the natural GI flora with nonpathogenic organisms. A 2006 meta-analysis of 31 RCTs assessing the efficacy of probiotics for both the prevention of AAD and treatment of C difficile found a pooled relative risk (RR) of 0.43 for AAD in the patients taking probiotics.⁶ However, many of the studies included in that meta-analysis were small. As a result, in 2010, the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA) recommended against the use of probiotics for the prevention of primary C difficile infection, citing a lack of high-quality evidence.⁷

Nonetheless, that same year, 98% of gastroenterologists surveyed expressed a belief that probiotics had a role in the treatment of GI illness.⁸ And in 2011, the Third Yale Working Group on Probiotic Use published recommendations for probiotic use based on expert opinion.⁹ The meta-analysis detailed in this PURL, which included more than 30 trials published since the 2006 meta-analysis, addressed the efficacy of probiotics for prevention and treatment of AAD.

STUDY SUMMARY
Probiotics significantly reduce AAD
Hempel et al reviewed 82 studies and pooled data from 63 RCTs (N = 11,811) to identify the RR of AAD among patients who received probiotics during antibiotic treatment, compared with those who received no probiotics or were given a placebo.¹ The studies encompassed a variety of antibiotics, taken alone or in combination, and several probiotics, including Lactobacillus, Bifidobacterium, Saccharomyces, and some combinations.

The outcome: The pooled RR for AAD in the probiotics groups was 0.58, with a number needed to treat of 13. Although the authors reported that the overall quality of the included trials was poor, a sensitivity analysis of the higher-quality studies yielded similar results.

Subgroup analyses by type of probiotic and duration of antibiotic treatment were also consistent with the overall pooled RR. In subgroup analysis by age, a similar decrease in AAD was found among the youngest patients (ages 0 to 17) and those between the ages of 17 and 65. Among patients older than 65—for whom there were just three studies—a nonsignificant decrease in risk was found. Twenty-three of the studies assessed adverse outcomes, of which none were reported.

WHAT'S NEW
A reason to pair antibiotics and probiotics
This meta-analysis reached a similar conclusion to the 2006 meta-analysis: Probiotics appear to be effective in preventing and treating AAD in children and adults receiving a wide variety of antibiotics for a number of conditions. The results were also consistent with those of a new meta-analysis that looked specifically at one pathogen—and found a reduction of 66% in C difficile–associated diarrhea in patients taking probiotics with their antibiotics.¹⁰

CAVEATS
Limited data on the safety

of probiotics exist
There was some heterogeneity among the studies in the meta-analysis by Hempel et al,¹ and some of the studies were of poor quality. Because of this, the authors used subgroup and sensitivity analysis, which supported their initial conclusion.

Probiotics have generally been considered safe; however, there have been rare reports of sepsis and fungemia associated with probiotic use, especially in immunosuppressed patients.¹ Fifty-nine of the included studies did not assess adverse events, which limited the ability of this meta-analysis to assess safety.¹ Patients taking probiotics should be monitored for adverse effects.

CHALLENGES TO IMPLEMENTATION
Lack of guidance on dosing and duration
Since probiotics are considered food supplements, health insurance will not cover the cost (which will likely be more than $20 per month). No single probiotic strain has high-quality evidence; however, most of the RCTs included in the meta-analysis used combinations of Lactobacillus species, which are usually found in OTC antidiarrheal probiotic supplements. No standard dose exists, but dose ranges in RCTs are 107 to 1010 colony-forming units per capsule (taken one to three times daily);¹ however, product labels have variable accuracy.¹¹ The duration of treatment ranges from one to three weeks—or as long as the patient continues to take antibiotics. .

REFERENCES
1. Hempel S, Newberry S, Maher A, et al. Probiotics for the prevention and treatment of antibiotic-associated diarrhea. JAMA. 2012; 307:1959-1969.

2. McFarland LV. Antibiotic-associated diarrhea: epidemiology, trends and treatment. Future Microbiol. 2008;3:563-578.

3. Pepin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile–associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.

4. Perry A, Dellon E, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 Update. Gastroenterology. 2012;143: 1179-1187.

5. Dubberke E, Wertheimer A. A review of current literature on the economic burden of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2009;30:57-66.

6. McFarland L. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol. 2006;101:

812-822.

7. Cohen S, Gerding D, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Infect Control Hosp Epidemiol. 2010;31: 431-455.

8. Williams M, Ha C, Ciorba M. Probiotics as therapy in gastroenterology. J Clin Gastroenterol. 2010;44:631-636.

9. Floch M, Walker A, Madsne K, et al. Recommendations for probiotic use—2011 update. J Clin Gastroenterol. 2011;45(suppl):S168-S171.

10. Johnston BC, Ma SS, Goldenberg JZ, et al. Probiotics for the prevention of Clostridium difficile–associated diarrhea: a systematic review and meta-analysis. Ann Intern Med. 2012;157:878-888.

11. Hamilton-Miller J, Shah S. Deficiencies in microbiological quality and labeling of probiotic supplements. Int J Food Microbiol. 2002; 72:175-176.

Acknowledgement
The PURLs Surveillance System was developed with support from Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2012. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2012;61:673-674.