Probiotics for GI Disorders and Antibiotic-Associated Diarrhea in Children

By Bradley C. Johnston, ND, MSc Cand, and Sunita Vohra, MD, FRCPC, MSc

Probiotics refer to "friendly" non-pathogenic microorganisms intended to benefit the host by improving the properties of indigenous microflora.1 The rationale behind probiotic administration is based on re-inoculation and normalization of unbalanced indigenous microflora using specific probiotic strains. These friendly microorganisms have been shown to improve microbial balance in the intestinal tract and display both antibacterial and immune regulatory effects in humans.2,3 They have been administered both prophylactically and therapeutically in an attempt to modify intestinal activity as well as mucosal, epithelial, and systemic immune activity.4

Background

It is hypothesized that many children and adults may have inadequate indigenous microflora because of exposure to overly sterile environmental conditions that result in the development of gastrointestinal (GI) and immunological problems.5 Compared to a diet that once contained several thousand times more bacteria, today’s food is highly processed, pasteurized, and sterilized, resulting in limited exposure to bacteria.6 The overly hygienic environment in which most children in developed countries reside lacks microbial stimulation, and this may result in an impaired gut barrier that in turn may cause autoimmune, infectious, and inflammatory conditions.6 This situation also may be associated with various GI disorders such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), infectious diarrhea, Clostridium difficile colitis, and antibiotic-associated diarrhea (AAD).

Probiotics for GI Disorders in Children

One of the primary areas of probiotic research in children is for the treatment and prevention of GI disorders. Small uncontrolled trials using Lactobacillus GG (Lactobacillus casei spp. rhamnosus) for the treatment of C. difficile-associated diarrhea, which can occur after antibiotic therapy, have demonstrated positive results. Although a number of uncontrolled and controlled trials of Lactobacillus GG for C. difficile-associated diarrhea in adults have been reviewed,7 only one small uncontrolled pediatric trial has been reported: In this open label case series of four pediatric patients with recurrent C. difficile, Lactobacillus GG demonstrated positive results in preventing relapses.8 In addition, Saccharomyces boulardii has demonstrated benefit in adults with C. difficile and AAD.9,10

Probiotics for the treatment of acute diarrheas, specifically virally induced diarrhea in children, have been extensively studied in randomized controlled trials (RCTs). These trials include a number of probiotic species, both alone and in combination, and have demonstrated decreased severity and duration of diarrhea in a range of socioeconomic populations when administered individually or as part of oral rehydration therapy.11 A recent meta-analysis of nine RCTs concluded that lactobacillus interventions, including Lactobacillus acidophilus, Lactobacillus bulgaris, Lactobacillus GG, and Lactobacillus reuteri, reduced the duration of acute infectious diarrhea by approximately one day in children, with trials of Lactobacillus GG making the most substantial contribution to the overall results.12 For example, of the nine trials, four used the probiotic Lactobacillus GG in the treatment groups. However, in a recent RCT, Lactobacillus GG was ineffective in children with severe diarrhea admitted to the hospital. The authors hypothesized that prior intestinal colonization from probiotic use may be important, resulting in greater benefits with regard to prevention of virally induced diarrhea rather than treatment.13 Large RCTs of Lactobacillus GG and S. boulardii for the prevention of traveler’s diarrhea (of viral origin) have demonstrated effectiveness in adults.14,15

The prevention of acute diarrhea using probiotics also has been studied in RCTs in infants. Of note, there are safety concerns with exposing neonates and infants to probiotics (see the Safety section). Bifidobacterium bifidum, together with Streptococcus thermophilus and Lactobacillus GG, has demonstrated benefit in preventing nosocomial diarrheas.11,16 In uncontrolled trials, Bifidobacterium lactis and L. reuteri (as well as RCTs of Lactobacillus GG) have demonstrated a reduction in the incidence of acute diarrhea in children.11,17

Diarrhea also is a well-known sequelae of IBD and IBS. The efficacy of probiotics in IBD and IBS has previously been reviewed;4,18 however, no trials of probiotics for IBS have been reported in children. Two small but promising trials of probiotics for the treatment of children with Crohn’s disease have been reported.19,20 In both open label trials, 10 billion Lactobacillus GG colony-forming units (CFUs) were administered twice daily. Malin et al reported that orally administered Lactobacillus GG has the potential to increase gut IgA immune response and promote the gut immunological barrier.19 Gupta et al reported a significant improvement in the Crohn’s disease activity index.20

Probiotics for Pediatric Antibiotic-Associated Diarrhea

Most antibiotic treatments disturb the colonization resistance of GI flora, resulting in a range of clinical symptoms, of which diarrhea is the most frequent. Specifically, antibiotics that act on anaerobes are most often associated with diarrhea, with aminopenicillins, cephalosporins, and clindamycins resulting in the highest risk of diarrheal side effects.21 Although the overgrowth of many enteropathogens has been demonstrated in AAD, C. difficile overgrowth has become known as the bacterial agent most associated with AAD.22 Reports in the general population indicate that AAD occurs in approximately 5%-39% of patients between initiation of antibiotic therapy and up to two months after the end of treatment.21,22 The incidence of diarrhea in children receiving broad-spectrum antibiotics ranges from 20% to 40%.23

Two recent meta-analyses on probiotics provide evidence to suggest probiotics prevent AAD in the general population.24,25 Results strongly favored probiotic co-administration with antibiotics for the prevention of diarrheal side effects.

There are more than 30 strains of probiotics commonly used, yet little is known about the strains or doses that yield the most beneficial results for the prevention of AAD (see Table). Lactobacillus GG, one probiotic strain that has been extensively studied for many GI disorders, has demonstrated benefit in two pediatric randomized controlled trials for AAD. Lactobacillus GG has been the focus of probiotic research because of its proven safety, its resistance to stomach acid and bile, and its ability to temporarily colonize the human intestine.26 To date, a systematic review of probiotics for pediatric AAD has not been conducted. To address this need the authors of this article published a protocol in the Cochrane Database of Systematic Reviews to assess probiotics as an adjunct to antibiotics for the prevention of AAD in children.27

A systematic search of MEDLINE identified two RCTs that evaluate Lactobacillus GG for the prevention of AAD in children.28,29 These two studies (n = 307) provide evidence that 10-20 billion CFUs of Lactobacillus GG per day significantly decrease the incidence of diarrhea in children. Furthermore, both studies indicate that children administered Lactobacillus GG who became ill had diarrhea (> 2 loose bowel movements per day) for a significantly shorter duration of time, approximately three quarters of a day less than those administered placebo. However, clinical heterogeneity was apparent and larger rigorous trials are needed.

Safety

The safest forms of probiotic bacteria are found in many common fermented foods, including yogurt, buttermilk, kefir, tempeh, miso, and sauerkraut.30 The trials of probiotics for treating pediatric diarrhea reviewed in this article investigate supplemental forms of probiotics. Supplemental forms provide a substantially higher dose of probiotic and appear to be more effective than fermented foods in treating GI disorders. These studies have investigated a wide spectrum of probiotic supplementation doses, ranging from 1 million to 300 billion CFUs per day, usually taken in powder or capsule form and combined with food or drink.

In a review of 143 trials of the use of several different probiotic strains and doses for a host of health concerns in otherwise healthy individuals, no significant adverse events were reported.31 Although safety does not appear to be a concern in healthy individuals, case reports of bacteremia with clinical features ranging from septicemia, pneumonia, and meningitis infections have been documented in immunocompromised and severely debilitated individuals using probiotics.32,33 For example, 82% of 89 cases of adult lactobacillus bacteremia patients in Finland had severe comorbidities.32 There has been one reported case of meningitis caused by bifidobacterium in an immunocompromised infant and one case report of meningitis caused by Bifidobacterium breve in an otherwise healthy neonate.33,34

Few reports or controlled trials specifically document the safety of feeding large amounts of probiotics to healthy infants or children for extended periods of time (longer than 1-2 weeks). The most rigorous of the reports, a prospective, double-blind, randomized, placebo-controlled trial of 180 healthy infants 3-24 months of age demonstrated long-term consumption (mean 210 days) of B. lactis and S. thermophilus (100,000 CFUs per day) was well tolerated and safe.35 Administration of Lactobacillus GG (1-2 billion CFUs per day) has also been evaluated in double-blind placebo-controlled trials in pregnancy and postnatally for six months.36,37 Although no adverse events were reported in these trials, they did not investigate the effectiveness or potential safety concerns of probiotics in patients with severe debilitating disease or altered immune function. Given the limited amount of information, probiotic use in these populations needs to be closely monitored or avoided until further studies have been conducted.

Conclusion

Re-inoculation and normalization of unbalanced indigenous microflora using specific probiotic strains underlies the rationale of probiotic administration in children. Lactobacillus GG has been widely studied in adults and children and possesses the characteristics needed to provide benefits to the host (e.g., resistance to acid and bile, colonization in human intestinal tract). Lactobacillus GG at a dose of 10-20 billion CFUs per day appears to be safe and clinically effective at preventing AAD and C. difficile-associated diarrhea in otherwise healthy children. Although Lactobacillus GG alone or in combination with oral rehydration therapy for traveller’s diarrhea has been demonstrated to be effective in adults, trials in children are still needed. Lactobacillus GG for the treatment of acute diarrhea in healthy children has repeatedly demonstrated significant results, whereas other probiotic strains such as L. acidophilus, L. bulgaris, and L. reuteri have demonstrated great promise. Meanwhile for the prevention of acute diarrhea, RCTs in healthy infants using B. bifidum, together with S. thermophilus, as well as RCTs employing Lactobacillus GG, have demonstrated benefit in preventing nosocomial diarrheas. Probiotic use in severely debilitated and immunocompromised children and adults should be avoided. Neonates administered probiotics, in particular Bifidobacterium breve, should be closely monitored.

Recommendation

Advantages of probiotic co-administration with antibiotics include ease of administration, the potential for increasing the probability of the child completing the antibiotic prescription vs. premature discontinuation of the antibiotic due to diarrheal side effects, and maintenance/restoration of the gut microflora. Lactobacillus GG is a novel and apparently worthwhile therapy for the prevention of pediatric AAD. A one-month supply of Lactobacillus GG is available in most health food stores and many pharmacies for approximately $20.

Clinicians and parents wishing to prevent AAD in healthy children may consider a strict Lactobacillus GG probiotic or a probiotic cocktail that contains up to 20 billion CFUs of Lactobacillus GG co-administered with the antibiotic. Larger rigorous trials of Lactobacillus GG and other microbes for pediatric AAD are still needed before making wide public health and clinical recommendations for routine use.

Mr. Johnston is a graduate student, and Dr. Vohra is the Director of the Complementary and Alternative Research and Education (CARE) program, Stollery Children’s Hospital, Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.

References

1. Havenaar R, Huis In’t Veld JHS. Probiotics: A general view. In: Wood BJB, ed. The Lactic Acid Bacteria in Health and Disease. 1st ed. Amsterdam: Elsevier; 1992:1-200.

2. Gismondo MR, et al. Review of probiotics available to modify gastrointestinal flora. Int J Antimicrob Agents 1999;12:287-292.

3. Goldin BR. Health benefits of probiotics. Br J Nutr 1998;80: S203-S207.

4. Fedorak RN, Madsen KL. Probiotics and prebiotics in gastrointestinal disorders. Curr Opin Gastroenterol 2004; 20:146-155.

5. Favier CF, et al. Molecular monitoring of succession of bacterial communities in human neonates. Appl Environ Microbiol 2002;68:219-226.

6. Isolauri E. Probiotics in human disease. Am J Clin Nutr 2001;73:1142S-1146S.

7. Surawicz CM. Probiotics, antibiotic-associated diarrhoea and Clostridium difficile diarrhoea in humans. Best Pract Res Clin Gastroenterol 2003;17:775-783.

8. Biller JA, et al. Treatment of recurrent Clostridium difficile colitis with Lactobacillus GG. J Pediatr Gastroenterol Nutr 1995;21:224-226.

9. Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95(1 Suppl):S11-S13.

10. Lewis SJ, et al. The lack of therapeutic effect of Saccharomyces boulardii in the prevention of antibiotic-related diarrhoea in elderly patients. J Infect 1998;36:171-174.

11. Szajewska H, Mrukowicz JZ. Probiotics in the treatment and prevention of acute infectious diarrhea in infants and children: A systematic review of published randomized, double-blind, placebo-controlled trials. J Pediatr Gastroenterol Nutr 2001; 33(Suppl 2):S17-S25.

12. Van Niel CW, et al. Lactobacillus therapy for acute infectious diarrhea in children: A meta-analysis. Pediatrics 2002;109: 678-684.

13. Costa-Ribeiro H, et al. Limitations of probiotic therapy in acute, severe dehydrating diarrhea. J Pediatr Gastroenterol Nutr 2003;36:112-115.

14. DuPont HL. Prevention of diarrhea by the probiotic, Lactobacillus GG. J Pediatr 1999;134:1-2.

15. Hilton E, et al. Efficacy of Lactobacillus GG as a diarrheal preventive in travelers. J Travel Med 1997;4:41-43.

16. Saavedra JM, et al. Feeding of Bifidobacterium bifidum and Streptococcus thermophilus to infants in hospital for prevention of diarrhoea and shedding of rotavirus. Lancet 1994;344: 1046-1049.

17. Duggan C, et al. Protective nutrients and functional foods for the gastrointestinal tract. Am J Clin Nutr 2002;75:789-808.

18. Hart AL, et al. Use of probiotics in the treatment of inflammatory bowel disease. J Clin Gastroenterol 2003;36:111-119.

19. Malin M, et al. Promotion of IgA immune response in patients with Crohn’s disease by oral bacteriotherapy with Lactobacillus GG. Ann Nutr Metab 1996;40:137-145.

20. Gupta P, et al. Is Lactobacillus GG helpful in children with Crohn’s disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr 2000;31:453-457.

21. Wistrom J, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: A prospective study. J Antimicrob Chemother 2001;47:43-50.

22. McFarland LV. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998;16:292-307.

23. Elstner CL, et al. Lack of relationship of Clostridium difficile to antibiotic-associated diarrhea in children. Pediatr Infect Dis 1983;2:364-366.

24. D’Souza A, et al. Probiotics in prevention of antibiotic associated diarrhea: Meta-analysis. BMJ 2002;324:1361.

25. Cremonini F, et al. Meta-analysis: The effect of probiotic administration on antibiotic associated diarrhea. Aliment Pharmacol Ther 2002;16:1461-1467.

26. Saxelin M. LGG-Summatim: Lactobacillus GG and its health effects. 2002. Available at: www.valio.com. Accessed on June 20, 2004.

27. Johnston BC, et al. Probiotics for the prevention of antibiotic-associated diarrhea in children (Protocol for a Cochrane Review). The Cochrane Library 2004;(3).

28. Arvola T, et al. Prophylactic Lactobacillus GG reduces antibiotic-associated diarrhea in children with respiratory infections: A randomized study. Pediatrics 1999;104:e64.

29. Vanderhoof JA, et al. Lactobacillus GG in the prevention of antibiotic-associated diarrhea in children. J Pediatr 1999;135: 564-568.

30. Dixon S. News Archive—Progress Newsletter Spring 2002 Online. Available at: www.cancer.med.umich.edu/news/pro09spr02.htm. Accessed on June 20, 2004.

31. Salminen S, et al. Demonstration of safety of probiotics—A review. Int J Food Microbiol 1998;44:93-106.

32. Salminen MK, et al. Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clin Infect Dis 2004;38:62-69.

33. Hata D, et al. Meningitis caused by bifidobacterium in an infant. Pediatr Infect Dis J 1988;7:669-671.

34. Nakazawa T, et al. Neonatal meningitis caused by Bifidobacterium breve. Brain Dev 1996;18:160-162.

35. Saavedra JM, et al. Long-term consumption of infant formulas containing live probiotic bacteria: Tolerance and safety. Am J Clin Nutr 2004;79:261-267.

36. Rautava S, et al. Probiotics during preganancy and breastfeeding might confer immunomodulatory protection against atopic disease in the infant. J Allergy Clin Immunol 2002;109:119-121.

37. Kalliomaki M, et al. Probiotics in the primary prevention of atopic disease: A randomized placebo-controlled trial. Lancet 2001:357:1076-1079.