A Randomized, Double-Blind, Placebo-Controlled Trial of Rifaximin, a Nonabsorbable Antibiotic, in the Treatment of Tropical Enteropathy

Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri, USA.
The American Journal of Gastroenterology (Impact Factor: 10.76). 06/2009; 104(9):2326-33. DOI: 10.1038/ajg.2009.270
Source: PubMed


Tropical enteropathy is characterized by an increased urinary lactulose-to-mannitol (L:M) ratio on a site-specific sugar absorption test and is associated with increased intestinal permeability and decreased nutrient absorptive capacity. The etiology of tropical enteropathy is postulated to be intestinal bacterial overgrowth. This study tested the hypothesis that treatment with a nonabsorbable, broad-spectrum antibiotic, rifaximin, reduces the L:M ratio in rural Malawian children, among whom tropical enteropathy is common.
All children aged 3-5 years from one village were enrolled in a randomized, double-blind, placebo-controlled trial of treatment with rifaximin for 7 days. The L:M ratio was measured before and after treatment, and the change in the L:M ratio was the primary outcome. Secondary outcomes were changes in the urinary sucrose-to-lactulose (SUC:L) and sucralose-to-lactulose (SCL:L) ratios, as well as changes in the fractions of each test sugar recovered in the urine.
A total of 144 children participated in this study, of whom 76% had an elevated L:M ratio on enrollment (L:M > or = 0.10). Children who received rifaximin did not show an improvement in their L:M ratio compared with those who received placebo (-0.01+/-0.12 vs. 0.02+/-0.16, respectively, P=0.51, mean+/-s.d.), nor were there significant differences between the two groups in excretion of lactulose, mannitol, sucralose, or sucrose, or in the SUC:L and SCL:L ratios.
Rifaximin had no effect on the tropical enteropathy of 3-5-year-old Malawian children, suggesting that small-bowel bacterial overgrowth is not an important etiological factor in this condition.

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Available from: Kenneth Maleta, Dec 29, 2014
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    • "There is no established therapy to reverse the changes of EE. Antibiotics [8], probiotics [9], glutamine supplementation [10] and long chain fatty acid supplements [11] have been tried without success. Multiple micronutrient (MM) supplementation is an attractive potential therapy as micronutrients such as zinc [12,13] and vitamin A [14] have previously been shown to reduce morbidity and mortality from infectious diarrhoeal illnesses, hinting at an immunological role in the intestine. "
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    ABSTRACT: Environmental enteropathy (EE) is an asymptomatic abnormality of small bowel structure and function, which may underlie vaccine inefficacy in the developing world. HIV infection co-exists in many of these populations. There is currently no effective treatment. We conducted a secondary analysis of a randomised controlled trial of high dose multiple micronutrient (MM) supplementation on small bowel architecture in EE in participants with or without HIV infection. In a double-blind parallel-group trial of the effect of MM on innate immune responses to oral vaccines, consenting Zambian adults were randomised to receive 6 weeks of 24 micronutrients as a daily capsule or placebo. HIV status was established after randomisation. Proximal jejunal biopsies were obtained after the supplementation period. Villous height, crypt depth, villous width, villous perimeter per 100 mum muscularis mucosa (a measure of epithelial surface area), and villous cross sectional area per 100 mum muscularis mucosa (a measure of villous compartment volume) were measured in orientated biopsy sections using semi-automated image analysis. Analysis was by intention to treat. 18 patients received MM and 20 placebo. 6/18 MM and 9/20 placebo patients had HIV. In HIV negative patients given MM compared to placebo, mean villous height was 24.0% greater (293.3 v. 236.6 mum; 95% CI of difference 17.7-95.9 mum; P = 0.006), mean villous area was 27.6% greater (27623 v. 21650 mum2/100 mum; 95% CI of difference 818-11130 mum2/100 mum; P = 0.03), and median villous perimeter was 29.7% greater (355.0 v. 273.7 mum/100 mum; 95% CI of difference 16.3-146.2 mum/100 mum; P = 0.003). There was no significant effect on crypt depth or villous width. No effect was observed in HIV positive patients. There were no adverse events attributable to MM. MM improved small bowel villous height and absorptive area, but not crypt depth, in adults with EE without HIV. Nutritional intervention may therefore selectively influence villous compartment remodelling. In this small study, there was a clear difference in response depending on HIV status, suggesting that EE with superimposed HIV enteropathy may be a distinct pathophysiological condition.
    BMC Gastroenterology 01/2014; 14(1):15. DOI:10.1186/1471-230X-14-15 · 2.37 Impact Factor
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    • "Researchers have attempted to treat EE in human children with antibiotics but with little success. In fact, in one study, provision of antibiotics led to an increased incidence of diarrhoea, perhaps due to a negative effect of antibiotics on the 'good' bacteria in the gut (Trehan et al. 2009). Short-term antibiotic therapy may fail because of re-exposure to fecal bacteria soon after treatment. "
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    ABSTRACT: It is well known that the relationship between child nutrition and infection is bidirectional, i.e. frequent illness can impair nutritional status and poor nutrition can increase the risk of infection. What is less clear is whether infection reduces the effectiveness of nutrition interventions or, vice versa, whether malnutrition lessens the impact of infection control strategies. The objective of this paper is to review the evidence regarding this interaction between nutrition and infection with respect to child growth in low-income populations. Even when there are no obvious symptoms, physiological conditions associated with infections can impair growth by suppressing appetite, impairing absorption of nutrients, increasing nutrient losses and diverting nutrients away from growth. However, there is little direct evidence that nutrition interventions are less effective when infection is common; more research is needed on this question. On the other hand, evidence from four intervention trials suggests that the adverse effects of certain infections (e.g. diarrhoea) on growth can be reduced or eliminated by improving nutrition. Interventions that combine improved nutrition with prevention and control of infections are likely to be most effective for enhancing child growth and development.
    Maternal and Child Nutrition 10/2011; 7 Suppl 3(s3):129-42. DOI:10.1111/j.1740-8709.2011.00357.x · 3.06 Impact Factor
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    • "Other studies revealed that two-thirds of adult patients with Crohn's disease entered remission after rifaximin therapy (Shafran and Burgunder, 2010). A retrospective review revealed a well tolerated and favorable role for rifaximin in pediatric IBD (Muniyappa et al., 2009; Trehan et al., 2009). However, the role of rifaximin in irritable bowel syndrome and IBD therapy and its mechanisms of action are not understood. "
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    ABSTRACT: Human pregnane X receptor (PXR) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in Crohn's disease and active ulcerative colitis. In the current study, the protective and therapeutic role of rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with rifaximin in the dextran sulfate sodium (DSS)-induced and trinitrobenzene sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of rifaximin ameliorated the clinical hallmarks of colitis in DSS- and TNBS-treated hPXR mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. In addition, higher survival rates and recovery from colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when rifaximin was administered after the onset of symptoms. Nuclear factor κB (NF-κB) target genes were markedly down-regulated in hPXR mice by rifaximin treatment. In vitro NF-κB reporter assays demonstrated inhibition of NF-κB activity after rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of rifaximin on IBD through human PXR-mediated inhibition of the NF-κB signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD.
    Journal of Pharmacology and Experimental Therapeutics 10/2010; 335(1):32-41. DOI:10.1124/jpet.110.170225 · 3.97 Impact Factor
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