Probiotics and the Treatment of Infectious Diarrhea

Jonathan E. Teitelbaum, MD

Pediatr Infect Dis J. 2005;24(3):267-268. 

Introduction

Research efforts have focused on the various mechanisms by which pathogenic bacteria achieve their detrimental effects. Recently attention has turned to the indigenous nonpathogenic microorganisms and ways in which they benefit the host. This is particularly relevant as microorganisms have developed resistance to antibiotics, thus prompting the need for alternative treatments for gastrointestinal diseases. Probiotics, an emerging alternative therapy popularized in 1908 by Metchnikoff as a link between fermented foods and longevity, are intestinal bacteria that promote health by stimulating optimal mucosal immune responses and by preventing gastrointestinal infections.

Although probiotics are considered benign and without pathologic potential, there are case reports of bacteremia or fungemia, most often in immunocompromised hosts. The Food and Drug Administration has no authority to establish a formal regulatory category for functional foods, including probiotics. There is great variability among products; in some studies, preparations contained no viable bacteria.[1] There is a common, but largely untrue, belief that American yogurts provide probiotic effects; low colony counts of bacteria survive the pasteurization process, and the specific strains of bacteria used in the culturing process have not been shown to be therapeutic.

Some of the best evidence of probiotics efficacy has been in the treatment of diarrheal illnesses. The mechanisms by which probiotics prevent or ameliorate diarrhea are stimulation of the immune system, competition for binding sites on intestinal epithelial cells and elaboration of bacteriocins. Efficacy depends on the type of diarrhea and differs in viral, antibiotic-associated and traveler's diarrhea.

Viral Diarrhea

The effect of probiotics on shortening episodes of acute infectious diarrhea has been well-documented. Enterococcus faecium , Streptococcus faecium SF68 and certain lactobacillus strains have proven efficacy. A metaanalysis of previously published randomized, controlled studies of lactobacillus therapy reveals that the duration of diarrhea in hospitalized children is shortened by an average of 0.7 days.[2] Similarly a randomized, placebo-controlled trial in a cohort of nonhospitalized children attending day-care centers also reduced the mean duration of diarrhea.[3] The underlying mechanism by which probiotics produce their clinical effect is likely multifactorial and has led to much speculation. Some theorize that lactobacilli enhance the expression and elaboration of intestinal mucins. These glycoproteins appear to be protective during intestinal infections. However, protective qualities may be overcome by mucinase-producing bacteria. Others hypothesize that rotavirus causes biphasic diarrhea, the first osmotic and the second due to overgrowth of urease-producing bacteria; probiotics prevent bacterial overgrowth.

In studies of the immunomodulating effects of probiotics, 49 children with acute rotavirus diarrhea were randomized to receive Lactobacillus GG (LGG), Lactobacillus casei subsp. rhamnosus ( Lactophilus ) or a combination of Streptococcus thermophilus and Lactobacillus delbruckii (Yalacta). Mean duration of diarrhea was 1.8 days for children in the LGG group, 2.8 in the Lactophilus group and 2.6 in the Yalacta group. Only LGG significantly increased the number of rotavirus-specific IgA-secreting cells and serum IgA level in the convalescent stage.[4] This and similar studies suggest that the humoral immune system is significant in the effect of probiotics. However, enhanced humoral response does not fully explain the clinical effect of probiotics as evidenced by a study comparing the efficacy of heat-inactivated LGG against viable bacteria in the treatment of rotaviral diarrhea. Reduction in the duration of diarrhea was the same for both groups, but significantly fewer infants receiving the heat-inactivated strains had detectable IgA responses.[5]

Antibiotic-Associated Diarrhea

A metaanalysis of studies involving probiotic administration to prevent antibiotic-associated diarrhea found a strong benefit.[6] The studies support the role of various probiotics such as Lactobacillus GG, Saccharomyces boulardii , E faecium , Lactobacillus acidophilus and Lactobacillus bulgaris coadministered with a variety of antibiotics. A study of 16 healthy volunteers taking erythromycin for 1 week found that coadministration of LGG yogurt not only reduced the number of days with diarrhea from 8 to 2 but also decreased associated side effects such as abdominal pain from 39% to 23%.[7] In a large pediatric study, 188 children taking a 10-day course of antibiotics were enrolled in a double blind placebo-controlled study with LGG. In the LGG group, the incidence of diarrhea decreased from 26% to 8%, and the duration of diarrhea decreased from 5.88 days to 4.7 days. Furthermore the consistency of the stool, based on a visual score, was looser in the placebo group.[8]

Clostridium difficile- Related Diarrhea

The use of probiotics for treatment of C difficile diarrhea is a logical step, particularly given the success of fecal enemas for relapsing cases. An early case report described 4 children with relapsing C difficile who responded to supplement with LGG. C difficile toxins A and B are cytotoxins; toxin A also acts as an enterotoxin. S. boulardii inhibits toxin A and B enteritis by releasing a 54-kDa protease that cleaves these toxins and their receptor for the brush border membrane.[9]

The ability of probiotics to prevent C difficile -associated diarrhea is supported by a study of 138 hospitalized adults receiving antibiotics who were randomized to receive probiotics or placebo. Of those who developed diarrhea, 2.9% of the probiotic group were positive for C difficile toxins, compared with 7.25% of the placebo group. When all stool samples were tested, only 46% of the probiotic group were toxin-positive versus 78% of the placebo group.[10]

The use of probiotics as adjuvant therapy in prevention of recurrent C difficile diarrhea has been demonstrated. S. boulardii was used in conjunction with standard antimicrobial treatment in a placebo-controlled study of 124 adult patients with C difficile diarrhea. Sixty-four patients were infected from their initial presentation, whereas 60 had a prior episode of disease. In those with an initial episode, there was no difference in recurrence rate; however, in patients with prior C difficile disease, the recurrence rate was significantly less in the group receiving the probiotic.[11]

Bacterial Diarrhea, Including Traveler's Diarrhea

Overall results of studies of probiotics for use in treatment or prevention of bacterial diarrhea, other than C difficile , are mixed. Many studies have evaluated the efficacy of probiotics in preventing traveler's diarrhea. In a study of 820 travelers to 2 resorts in Turkey, LGG failed to affect the overall rate of diarrhea (43% of controls versus 38% in the LGG). However, in 1 resort, the diarrhea rate was 40% for controls compared with 24% of the LGG-treated travelers.[12] In a second study, travelers were monitored by a hospital-based Travel and Immunization Center. Destinations varied and compliance with the study drug (placebo or LGG) was good in 245 participants. Overall the incidence of traveler's diarrhea averaged 7.4%/d for the placebo group and 3.9%/d for the probiotic group.[13] In a study of healthy volunteers fed enterotoxigenic Escherichia coli , there was no benefit from concurrent administration of lactobacilli.[14] Results of other studies of probiotics alone or in combination for prevention of traveler's diarrhea are conflicting. Cost-benefit analysis studies are needed to determine whether a marginal reduction in traveler's diarrhea warrants treatment of all travelers.

The effects of probiotics for other pathogenic bacteria are variable. A study of E faecium in 183 Bangladeshi adults with acute diarrhea caused by Vibrio cholera , enterotoxigenic Escherichia coli or unknown organisms did not shown efficacy.[15] Although some studies with L. acidophilus have shown an effect against bacterial causes of enteritis and Bifidobacterium breve has been somewhat effective against Campylobacter , most studies of probiotics for treatment of patients with bloody diarrhea have not shown a benefit.

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