Question:  Please clarify the use of probiotics with concomitant antibiotic therapy. I see this combination in practice and am unclear whether it has clinical benefit for preventing antibiotic-associated diarrhea.

Response from Darrell Hulisz, PharmD Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

Probiotics are live microorganisms which when administered in controlled amounts may confer health benefits to patients by improving microbial balance, primarily in the gastrointestinal (GI) tract.
Probiotics may contain a single isolate or a mixture of isolates, such as Lactobacillus, Bifidobacterium, or Saccharomyces species. These preparations are regulated as dietary supplements or foods and are available as tablets, capsules, powders, or in fermented foods such as yogurt.
Probiotics have been studied in a variety of GI conditions, such as infectious diarrhea, irritable bowel syndrome, inflammatory bowel disease, antibiotic-associated diarrhea, and Clostridium difficile infection.
This review focuses on the use of probiotics with concurrent antibiotic treatment for the prevention of antibiotic-associated diarrhea. The reader is referred elsewhere for information regarding probiotics for the treatment of C difficile.
Probiotic formulations are similar to the beneficial microorganisms found in the human gut.
However, the beneficial effects of probiotics in some cases tend to be strain specific (eg, Lactobacillus species strain GG); thus, not all the positive results of one preparation can be generalized to other preparations.
It is well known that antibiotic therapy can disrupt the homeostatic balance in the gut flora, causing an overgrowth of pathogenic microbes relative to beneficial flora. This allows pathogenic bacteria to colonize the gut and gain access to the GI mucosa, precipitating diarrhea and predisposing patients to fluid and electrolyte disturbances. Probiotics with specific strains of beneficial bacteria and yeast aim to restore that balance.
The most commonly used probiotic microbes include Saccharomyces species (yeast) and lactic acid bacteria, specifically Lactobacillus and Bifidobacterium species. These bacteria liberate acid in the gut and lower luminal pH, which suppresses the growth of pathogenic flora.
Probiotics also decrease colonization of pathogenic organisms in the gut by secreting hydrogen peroxide and organic acids that are locally toxic to pathogenic bacteria and may competitively block microbial adhesion to the gut epithelium.
Certain probiotic strains may have immunomodulating effects such as increasing cytokine activity and stimulating lymphocyte and macrophage phagocytosis in the intestine.
Numerous controlled studies investigating the use of probiotics to prevent antibiotic-associated diarrhea have been included in several meta-analyses.  A meta-analysis by Cremonini and colleagues examined 7 homogenous, placebo-controlled trials (n = 881) of probiotic efficacy in preventing antibiotic-associated diarrhea. Results showed a combined relative risk (RR) of 0.3966 (95% confidence interval [CI], 0.27-0.57) favoring a beneficial effect of probiotics (Saccharomyces boulardii and Lactobacillus species) for reducing the risk for antibiotic-induced diarrhea.
In 2002, D'Souza and coworkers conducted a meta-analysis of 9 studies in which study groups received probiotics with antibiotics and control groups received placebo with antibiotics. The odds ratio in favor of probiotics for preventing diarrhea associated with antibiotics was 0.39 (95% CI, 0.25-0.62; P < .001) for S boulardii (yeast) and 0.34 (95% CI, 0.19-0.61; P < .01) for Lactobacillus species. The combined odds ratio was 0.37 (95% CI, 0.26-0.53; P < .001) in support of probiotic treatment over placebo.
A subsequent 2005 meta-analysis evaluated the effectiveness of S boulardii in preventing antibiotic-associated diarrhea in children and adults. Only 5 randomized controlled trials (n = 1076) met criteria for review. Treatment with S boulardii compared with placebo reduced the risk for antibiotic-associated diarrhea from 17.2% to 6.7% (RR, 0.43; 95% CI, 0.23-0.78). The number needed to treat to prevent 1 case of antibiotic-associated diarrhea was 10 (95% CI, 7-16).
The probiotic dosage and combinations that have shown efficacy for antibiotic-associated diarrhea are as follows

• S boulardii 4 × 10⁹ to 2 × 10¹⁰ colony forming units (CFU) daily for 1-4 weeks;
• Lactobacillusrhamnosus strain GG 6 × 10⁹ to 4 × 10¹⁰ CFU daily for 1-2 weeks;
• L acidophilus and L bulgaricus 2 × 10⁹ CFU daily for 5-10 days;
• L acidophilus and Bifidobacterium longum 5 × 10⁹ CFU daily for 7 days; and
• L acidophilus and B lactis 1 × 10¹¹ CFU daily for 21 days.

The adverse effects of probiotics are minimal and generally confined to the GI tract. These include flatulence, constipation, and bloating.
Rare cases of probiotic-related bacteremia and fungemia have been reported.
Because probiotics contain live microorganisms, patients who are immunocompromised, have severe underlying comorbidities, are critically ill, or have short bowel syndrome may be more susceptible to probiotic sepsis and should not receive them
Preparations containing Lactobacillus species preparations are contraindicated in patients with a hypersensitivity to lactose or milk.
Products containing S boulardii are contraindicated in patients with a yeast allergy.

Conclusion

Some probiotic formulations appear to be safe and modestly effective for preventing antibiotic-associated diarrhea. However, many unanswered questions remain regarding the use of probiotics for this indication. There are no evidence-based guidelines or consensus statements regarding probiotics for this use. However, the American Academy of Pediatrics issued a Clinical Report on the use of probiotics and prebiotics in children in 2010 that discussed a wide variety of conditions for which these agents have been used, including antibiotic-associated diarrhea. Additionally, the optimal dose, duration, and mode of delivery for probiotics has not been fully elucidated.
Although various probiotics are marketed, only those formulations evaluated in controlled clinical trials should be recommended. Patient selection criteria would at a minimum include immunocompetent patients with a history of antibiotic-associated diarrhea. Further studies should delineate which patients benefit most from probiotics.