Original Articles: Gastroenterology
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). SIBO may be associated with diverse clinical conditions, such as chronic diarrhea (3,4), malnutrition (5), intestinal failure (2,6–8), and functional gastrointestinal disorders (9–12), and with children living in areas with poor sanitation, such as in urban slums (13,14).
The mainstay of SIBO treatment is antibiotic therapy, and a variety of antibiotics have been used (1,2), including rifaximin, which is a nonabsorbable antibiotic (1,12,15,16). The gold standard for diagnosing SIBO is culture of the intestinal fluid, which is an invasive and expensive method. In contrast, breath testing is an effective method of evaluating patients for potential SIBO. The lactulose hydrogen breath test (LBT) has been widely used for diagnosing SIBO because of its simplicity, low cost, safety, and lack of invasiveness (17). Breath testing may also be used to evaluate intestinal methane production (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.
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). One month after the end of the treatment period, these children underwent a second LBT. The treatment was considered effective when this second test was negative for SIBO.
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). The effect of the antibiotic treatment on the breath CH4 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.
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).
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.
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). Therefore, considering the negative effect of symptomatic and asymptomatic SIBO on health and ethical principles, all of the children with SIBO were treated. The choice of the TMP-SMT and MTZ combination was based on the classical recommendation for the treatment of SIBO (7,8) and the availability of these drugs in the public health system in Brazil.
The success rate of our study disagreed with the results of an article published in 2011 (12), which found that only 20% of children treated with rifaximin achieved a normalized LBT after treatment; however, the diagnostic criterion in that study (12) was as follows: a normal LBT was operationally defined as a clear peak of H2 >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). We believe that this diagnostic criterion overestimated the rate of SIBO and underestimated the efficacy of the antibiotic because it accounted for H2 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) and other antibiotics (16). In these studies (15,16), SIBO was diagnosed based on an LBT, using the same diagnostic criterion used in our study. This diagnostic criterion has been widely used in the literature for both children (13) and adults (15,16).
Another important issue is the recent inclusion of the breath CH4 concentration in the diagnostic criteria of SIBO in infancy (10,11). In the present study, the CH4 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). None of the children included in the present study presented intestinal constipation according to information collected on their intestinal habits complemented by the use of the Bristol scale (20). Therefore, we believe that the higher CH4 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), they are susceptible to MTZ (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.
The authors thank Health Department of the City of Osasco for assistance in the study.
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Keywords:© 2013 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,
antibiotic; children; hydrogen/methane breath test; small intestinal bacterial overgrowth