Small intestinal bacterial overgrowth (SIBO) is an intestinal microflora imbalance with abnormally high bacterial counts in the small intestine, which may be associated with a wide clinical spectrum ranging from the absence of clinical features or mild and unspecific intestinal symptoms to severe malabsorption (1,2) (3,4) (5) (2,6–8) (9–12) (13,14)
The mainstay of SIBO treatment is antibiotic therapy, and a variety of antibiotics have been used (1,2) (1,12,15,16) (17) (17,18)
The aim of this study was to evaluate the effectiveness of trimethoprim-sulfamethoxazole (TMP-SMT) and metronidazole (MTZ) in the treatment of children with SIBO who were diagnosed using an LBT.
METHODS
This noncontrolled open clinical trial evaluated the effectiveness of TMP-SMT and MTZ in the treatment of SIBO. SIBO was diagnosed using the LBT. Twenty children (ages between 6 and 10 years) with SIBO, who had not experienced diarrhea for at least 30 days, were included in this study. The exclusion criteria included chronic diseases, such as heart disease, nephropathy, neuropathy, congenital abnormalities, and the use of antibiotics up to 15 days before the LBT.
These 20 patients with SIBO were enrolled during a community-based cross-sectional survey that was performed in a slum in the municipality of Osasco, state of São Paulo, Brazil. One of the aims of the project was to evaluate the prevalence of SIBO in asymptomatic schoolchildren living in the slum. The sample was composed of 84 children whose families lived under poor socioeconomic and environmental conditions. This slum was located in the vicinity of a landfill. SIBO was diagnosed in 20 (23.8%) of 84 children, who were subsequently included in the evaluation of the effectiveness of TMP-SMT and MTZ in the treatment of SIBO. The demographic and socioeconomic data of these children with and without SIBO were previously published (14)
The children with SIBO were treated with TMP-SMT (30 mg kg−1 d−1 ) and MTZ (20 mg kg−1 d−1 ) in 2 daily doses for 14 days (6–8)
Breath samples were collected before and 15, 30, 45, 60, 90, 120, and 180 minutes after the ingestion of 10 g lactulose. The levels of H2 and CH4 in the samples were measured by gas chromatography using a QuinTron MicroLyzer model SC (QuinTron Instrument Company, Milwaukee, WI). SIBO was diagnosed if the H2 level was ≥20 ppm above baseline in samples that were collected up to 60 minutes after the lactulose administration (13,9,10,16) 4 concentration was also evaluated (10,11,18)
This project was evaluated and approved by the research ethics committee of the Federal University of São Paulo. A signed informed consent form was obtained from the parents or guardians of each of the participants at the time of admission into the study.
RESULTS
One month after treatment with TMP-SMT and MTZ, 19 (95.0%) of the 20 children showed a negative LBT for SIBO (McNemar test, P < 0.001). The H2 and CH4 concentrations obtained during the LBT were analyzed for both the areas under the individual curve (Table 1 ) and the mean concentration in each sample (Fig. 1 ).
TABLE 1: Areas under the curves of hydrogen and methane (ppm) in breath samples collected from children between 0 and 60 minutes, and 60 and180 minutes in a breath test after lactulose ingestion before treatment and after antibiotic treatment (n = 20)
FIGURE 1: The mean concentrations of hydrogen (ppm) and methane (ppm) in breath samples collected from children after fasting and at 15, 30, 60, 90, 120, 150, and 180 minutes after lactulose ingestion before treatment and after antibiotic treatment (n = 20). Paired t test: P < 0.05 when comparing the H2 samples before and after treatment at 15, 30, 45, 60, and 90 minutes; P > 0.05 when comparing all CH4 samples before and after treatment.
Considering the areas under the individual curves, children with SIBO exhibited higher H2 production before treatment in both the first hour (H2 presumably produced in the small intestine) and between 60 and 180 minutes (H2 presumably produced in the colon) of the test as compared with the H2 production posttreatment (Table 1 ). The areas under the curves indicated a small increase in CH4 production, both during the first 60 minutes of the LBT and at minutes 60 to 180; however, the paired t test did not show a statistically significant difference (Table 1 ).
Figure 1 shows the mean H2 and CH4 concentrations (parts per million per minute) that were obtained from each sample during the breath tests before and after treatment. The H2 concentrations in each sample were lower after treatment in the first 60 minutes of the test and between 60 and 180 minutes. The CH4 concentration remained at similar levels in all collected samples. Although the mean CH4 concentrations of each sample were higher after the antibiotic treatment, there was no significant difference.
DISCUSSION
This study showed the effectiveness of TMP-SMT and MTZ administered for 2 weeks in 2 daily doses for the treatment of SIBO in asymptomatic schoolchildren living in a slum. Additionally, TMP-SMT and MTZ did not reduce the CH4 production. It is important to emphasize that this study was not a controlled trial because the treatment of SIBO was a healthcare action included in a community research project that aimed to evaluate the prevalence of malnutrition and SIBO in children living in the slum (14) (7,8)
The success rate of our study disagreed with the results of an article published in 2011 (12) (12) 2 >90 minutes after the ingestion of the lactulose, with a peak H2 concentration <20 ppm in 180 minutes. An abnormal LBT was based on a profile that failed to meet this operational definition. SIBO was identified in >90% of the patients studied (12) 2 production in both the small intestine and the colon. In contrast, in our study, the diagnostic criterion for diagnosing SIBO was a H2 level ≥20 ppm above the baseline within 60 minutes, which has been widely used (13,9,10,16)
Two studies in adults with SIBO associated with digestive functional disorders also found a lower eradication rate (approximately 50%) using rifaximin (15) (16) (15,16) (13) (15,16)
Another important issue is the recent inclusion of the breath CH4 concentration in the diagnostic criteria of SIBO in infancy (10,11) 4 concentration was not included in the diagnosis of SIBO because the data were collected before this new proposal. In the pediatric age group, high breath CH4 was previously associated with slow-transit colonic and rectal fecal impaction (10,18,19) (20) 4 production found in these children may be associated with poor environmental and sanitation conditions (14)
The decreased H2 production before and 60 minutes after the administration of the lactulose showed that TMP-SMT and MTZ acted against bacteria in both the small and large intestine. In contrast, TMP-SMT and MTZ did not reduce CH4 production. Although there was no significant difference, the CH4 production was higher after treatment with TMP-SMT and MTZ. One probable explanation for this difference could be a decrease in the number of H2 -producing bacteria, which favors the growth of methanogenic bacteria. It appears that the TMP-SMT and MTZ combination acts against bacteria that produce H2 , but not against methanogenic bacteria. This is an interesting finding because although methanogenic bacteria are highly resistant to a large number of antibiotics (21) (21–23)
Therefore, we conclude that the combination of TMP-SMT and MTZ was effective in treating asymptomatic Brazilian children living in a slum who presented SIBO. TMP-SMT and MTZ did not decrease intestinal CH4 production.
Acknowledgment
The authors thank Health Department of the City of Osasco for assistance in the study.
REFERENCES
1. Dukowicz A, Lacy BA, Levine GM. Small intestinal overgrowth: a comprehensive review.
Gastroenterol Hepatol 2007; 3:112–122.
2. Malik BA, Xie YY, Wine E, et al. Diagnosis and pharmacological management of small intestinal bacterial overgrowth in children with intestinal failure.
Can J Gastroenterol 2011; 25:41–45.
3. Dahstrom KA, Danielson L, Kalin M, et al. Chronic non-specific diarrhea of infancy successfully treated with trimethoprim-sulfamethoxazole.
Scand J Gastroenterol 1989; 24:589–592.
4. De Boissieu D, Chaussain M, Badoual J, et al. Small-bowel bacterial overgrowth in children with chronic diarrhea, abdominal pain or both.
J Pediatr 1996; 128:203–207.
5. Heikens GT, Schofield WN, Dawson S, et al. The effects of high energy supplement and metronidazole on malnourished children rehabilitated in the community: anthropometry.
Eur J Clin Nutr 1993; 47:160–173.
6. Vanderhoof JA, Young RJ, Murray N, et al. Treatment strategies for small bowel bacterial overgrowth in short bowel syndrome.
J Pediatr Gastroenterol Nutr 1998; 27:155–160.
7. Vanderhoof JA. Walker WA, Durie PR, Hamilton JR, et al. Short-bowel syndrome and intestinal adaptation.
Pediatric Gastrointestinal Disease 3rd ed.Hamilton, Ontario:BC Decker; 2000. 583–602.
8. Goulet O, Ruemelle F. Causes and management of intestinal failure in children.
Gastroenterology 2006; 130 (2 suppl 1):S16–S28.
9. Peralta S, Cottone C, Doveri T, et al. Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms: experience with rifaximin.
World J Gastroenterol 2009; 15:2628–2631.
10. Leiby A, Mehta D, Gopalareddy V, et al. Bacterial overgrowth and methane production in children with encopresis.
J Pediatr 2010; 156:766–770.
11. Morais MB, Soares AC, Tahan S. Constipation, breath methane and orocecal transit time for a bean meal test.
J Pediatr 2011; 159:171–172.
12. Collins BC, Lin HC. Double-blind, placebo controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain.
J Pediatr Gastroenterol Nutr 2011; 52:382–386.
13. Reis JC, Morais MB, Oliva CA, et al. Breath hydrogen test in the diagnosis of environmental enteropathy in children living in an urban slum.
Dig Dis Sci 2007; 52:1253–1258.
14. Mello CS, Tahan S, Melli LC, et al. Methane production and small intestinal bacterial overgrowth in children living in a slum.
World J Gastroenterol 2012; 18:5932–5939.
15. Pimentel M, Chow EJ, Lin HC. Normalization of lactulose breath testing correlates with symptom improvement in irritable bowel syndrome: a double-blind, randomized controlled study.
Am J Gastroenterol 2003; 98:412–419.
16. Pimentel M, Chow EJ, Lin HC. Eradication of small intestinal bacterial overgrowth reduces symptoms of irritable bowel syndrome.
Am J Gastroenterol 2000; 95:3503–3506.
17. Gasbarrini A, Corazza GR, Gasbarrini G, et al. Methodology and indications of H2-breath testing in gastrointestinal diseases: the Rome Consensus Conference.
Aliment Pharmacol Ther 2009; 29 (Suppl. 1):1–49.
18. Soares ACF, Lederman HM, Fagundes-Neto U, et al. Breath methane associated with slow colonic transit time in children with chronic constipation.
J Clin Gastroenterol 2005; 39:512–515.
19. Attaluri A, Jackson M, Valestin J, et al. Methanogenic flora is associated with altered colonic transit but not stool characteristics in constipation without IBS.
Am J Gastroenterol 2010; 105:1407–1411.
20. Lewis J, Heaton KW. Stool form scale as a useful guide to intestinal transit time.
Scand J Gastroenterol 1997; 32:920–924.
21. Dridi B, Fardeau ML, Ollivier B, et al. The antimicrobial resistance pattern of cultured human methanogens reflects the unique phylogenetic position of archaea.
J Antimicrob Chemother 2011; 66:2038–2044.
22. Dermouni HL, Ansorg RA. Isolation and antimicrobial susceptibility testing of fecal strains of the archaeon
Methanobrevibacter smithii .
Chemotherapy 2001; 47:177–183.
23. Ansorg R, Rath PM, Runde V, et al. Influence of intestinal decontamination using metronidazole on the detection of methanogenic archae in bone marrow transplant recipients.
Bone Marrow Transplant 2003; 31:117–119.
