PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 1 5 Number 7 July 20 09 Sa ccharomyces boulardii as a Probiotic for Children Marcia L. Buck, Pharm.D., FCCP accharomyces boulardii ( S. boulardii ) has allowing increased carbohydrate degradation and S been used as a probiotic agent since the absorption in patients with diarrhea , a nd restor es 1950s . It has been shown to be useful in the normal levels of sh ort chain fatty acids in the treatment of acute infectious diarrhea , the colon which are necessary for absorption of prevention or treatment of diarrhea associated water and electrolytes. In addition, S. boulardii with antibiotic use , and as an adjunctive therapy may reduce inflammation in the GI tract by for Helicobacter pylori infection. It has also stimulating regula to ry T ce lls and in hibit ing been suggested as a formula suppl ement for mitogen -activating protein (MAP) kinase and premature infants. 1-4 This issue of Pediatric nuclear factor -kappa B ( NF -B) signal Pharmacotherapy will describe the studies transduction pathways, resulting in decreased published to date on S. boulardii in infants and secretion of interleukin (IL -8) and tumor necrosis children and provide an overview of the adverse factor alpha (TNF ). S boulardii also decreases effects and dosing recommendations for this inducible nitric oxide synthase (NOS) activity agent in infants , children , and adults . and up -regulates proliferators -activated receptor - ga mma (PPAR -), leading to a reduction in Mechanism of Action intestinal inflammation .1-4 Probiotics are live non -pathogenic micro - organisms that are taken orally to aid in the Pharmacokinetics and Pharmacodynamics maintenance and/or restoration of healthy Daily administration of lyophilized S. boulardii gastrointestinal (GI) micro flora. In addition to S. at standard doses results in detectable levels of boulardii , other probiotics include Lactobacillus live yeast throughout the GI tract. S. boulardi i rhamnosus strain GG (formerly L. casei GG) , L. does not attach to the mucosa of the intestine. A re uteri , L. acidophilus , Bifidobacterium spp., and stable concentration is reached within 3 days in Streptococcus spp. preparations. 1,2 While most adults. A week after discontinuing treatment, S. probiotic s are bacteria, S. boulardii is a non - boulardii can no longer be detected in the bowel colonizing, non -systemic yeast . It was first lumen . Several investigators have documented a isolated in 1923 from lychee fruit in Indonesia by correla tion between the concentration of the Fren ch scientis t Henri Boulard who not ed that yeast in GI tract and the degree of symptomatic natives of the area used the skin of the fruit to improvement following C. difficile infection in treat symptoms of cholera. 2, 5,6 both animal models and clinical trials .3 While the mechanisms by which probiotics exert Clinical Trials in Infants and Children their benefit are not fully understood, it has been suggested that they improve host barrier function, Treatment of Acute Infectious Diarr hea produce competitive inhibition of pathogenic Since the mid -1980s , several case series , open bacteria , and bolster immune function. S. prospective studies, and randomized controlled boulardii secretes enzymatic proteins, including trials have evaluated the efficacy of S. boulardii a protease that degrades Clostridium difficile in the treatment of acute diarrhea associated with toxins and a phosphatase that inactivates gastroenteritis in children. In 2007, Szajewska endotoxins such as t he lipopolysaccharide and col leagues conducted a meta -analysis of the produced by E. coli . It also strengthens tight results from five studies comparing S. boulardii junctions between enterocytes (reducing chloride to placebo or no intervention. 7 A total of 619 secretion) , promote s maturation of the inte stinal children were enrolled in these trials , with S. brush border membrane and stimulates boulardii doses of 250 to 600 mg/day or placebo production of glycoproteins (including secretory given for 4 to 6 days . Four studies included the IgA) . S. boulard ii also promotes production of duration of diarrhea as an outcome, with all dis accharidases su ch as lactase, sucrase, maltase , demonstrating a significant reduction with and N -amin opeptidase in the brush border treatment. The combined data from these studies provided a pooled weighted mean Persistent C. difficile infection ha s also been difference of -1.1 days (95% CI : -1.3 to -0.8) . found to improve with S. boulardii therapy. 10 Single stu dies used in this analysis also Buts and colleagues treated 19 infants (average documented a reduction in the risk of diarrhea age 8 months) with persistent intestinal lasting more than 7 days, as well as a reduction in symptoms related to C. difficile overgrowth. The length of hospital stay. The authors concluded patients were treated with S. boulardii 250 mg that treatment with S. boulardii had a moderate given two to four times per day for 15 days. clinical benefit in the treatm ent of acute diarrhea Within 1 week of starting therapy, 95% had in otherwise healthy children. improvement in symptoms with a significant reduction in stool frequency (p<0.001). In 85% An additional randomized controlled trial was of the cases, toxin B was cleared by the end of published by H twe and colleagues in 2008. 8 The treatment, while eradication of C. diffi cile was authors enrolled 100 Myanmar children between complete in 14 patients (73%) by one month. 3 months and 10 years of age with acute diarrhea. Two patients relapsed after the end of treatment, The childre n received oral rehydration solution but responded to a second 15 -day course. with or without S. boulardii 250 mg given twice Additional research, with larger sample sizes, is daily for a period of 5 days. The mean duration needed to substantiate these early studies. of diarrhea was 3.08 days in the S. boulardii group compared to 4.68 days in the controls Prevention of Antibiotic -associated Diarrhea (p<0.05). On the second day, 27 (54%) of the Two randomized controlled studies have found a treatment group were having less than 3 stools beneficial effect of S. boulardi i in the prevention per day, compared to only 15 (30%) of the of antibiotic -associated diarrhea , including that controls (p=0.19). Stool consistency was no caused by C. difficile .11,1 2 In 2004, Erdeve and different between the groups on day 2 ; h owever colleagues enrolled 653 chil dren between 1 and by day 3 , stool consistency has retu rned to 15 years of age in a study evaluating the efficacy normal in 38 (76% ) of the treatment group versus of S. boulardii during treatment with 12 (24%) of the controls (p=0.019) . The authors ampicillin/sulbactam or azithromycin. 11 Four concluded that treatment resulted in a shortened hundred sixty -six children completed the study. duration of acute diarrhea, which could produce Antibiotic -associated diarrhea was observed in significant societal and economic benefits. 14 (5. 7%) of the 244 children given S. boulardii during their antibiotic course, compared to 42 Treatment of Chronic Diarrhe a (19%) of the 222 controls (p<0.05). When In addition to the treatment of acute diarrhea, S. separated by drug, the effect of S. boulardii was boulardii has also been found to be beneficial in statistically significant only for the children with chronic diarrhea. Castaneda ampicillin/sulbactam group (5.9% in cidence in Guillot and colleagues conducted a randomized, the treatment group compared to 25.6% in the double -blind, placebo -controlled trial in 40 controls, p<0.05) and was most pronounced in infants and childr en (ages 6 to 36 months) with children less than 6 years of age. chronic diarrhea. 9 The study patients included 35 children with Giardia lamblia , 4 with The following year, Kotowska and colleagues Shigella, and one patient with chronic diarrhea of published a second randomized controlled trial an undetermined etiology. The 39 patients with with S. boulardii in 269 c hildren (6 months to 14 known infections had undergone standar d years of age). 12 All of the children were treated treatment with an appropriate antimicrobial or with antibiotics after diagnosis of otitis media or antiparasitic. The patients were randomized to a respiratory tract infection. The most frequently receive either S. boulardii 250 mg or placebo used antibiotics in the study were amoxicillin, orally twice daily for one month. Prior to cefuroxime, clarithromycin, penicillin, and initiation of the study, the average number of roxithromycin. The patients were randomized to stools was 4 -6 per day . At the end of the study, receive either S. boulardii 250 mg or placebo 65% of the patients in the S. boulardii group twice daily for the duration of antibiotic therapy. were having normal stool frequency, defined as The i ncidence of antibiotic -associated diarrhea 1-3 stools/day, compared to only 15% of the (including C. difficile diarrhea) in the treat ment controls (p=0.006). Histiologic improvement group was only 3.4% compared to 17.3% in the was also found in the S. boulardii group ; the controls (RR 0.2, 95% CI: 0.07 -0.5). No ne of number of patients with normal jejunal mucosa the patients required discontinuation of increas ed from 15% at baseline to 35% by the antibiotic s or hospitalization, and no adverse end of the study. In comparison, there was no events were reported. The results of these two change in the controls. There were no adverse studies are similar to a number of clinical trials in events reported. adults demonstrating the utility of S. boulardii in preventing antibiotic -associated diarrhea. Use in H. pylori Infection Adverse Effects Probiotics, including S.