Antibiotic treatment for small intestinal bacterial overgrowth: Is a cocktail better than a single?

Small intestinal bacterial overgrowth (SIBO) is being recognized to be associated with several digestive and extra-digestive diseases increasingly by the clinicians due to the fact that the technique to diagnose this condition by invasive quantitative culture of upper gut aspirate is being replaced by popular glucose and lactulose hydrogen breath tests (GHBT, LHBT) despite the low sensitivity and specificity of the breath tests.1 Several conditions are associated with SIBO; these include disorders of gut–brain interaction such as irritable bowel syndrome (IBS), particularly the diarrhea-predominant (IBS-D) subtype, anatomical abnormalities such as small bowel stricture, diverticula, fistula, blind loop syndrome, primary or secondary visceral neuromyopathy, malabsorption syndrome due to various causes, acquired and inherited immune deficiency syndromes, obesity and its surgical treatment, cirrhosis, particularly in the presence of its complications, non-alcoholic fatty liver disease, chronic pancreatitis, particularly in the presence of uncontrolled diabetes mellitus, proton pump inhibitor therapy, inflammatory bowel disease, particularly Crohn disease, and primary biliary cholangitis, etc.1-3 There has been a paradigm shift in the treatment of SIBO after a non-absorbable broad-spectrum antibiotic, rifaximin, was approved by the Food and Drug Administration, USA, for IBS after a landmark study in 2011.4 However, that study did not evaluate the efficacy of rifaximin in the presence of SIBO. Three subsequent studies showed greater efficacy of rifaximin in patients with IBS in the presence of SIBO.5-7 Several other studies evaluated the efficacy of rifaximin as a single agent in the treatment of SIBO.2 A pooled eradication rate of SIBO with rifaximin as a single agent was 71% on intention-to-treat and 73% on per-protocol analyses.2 Moreover, recurrence of SIBO following successful treatment with rifaximin is common. In the current issue of the United European Gastroenterology Journal, Richard N et. al. from France evaluated the efficacy of a single antibiotic (quinolone or azole) and rotating antibiotics (quinolone and azole, one after the other) for ten days every month for three months on 223 patients with SIBO diagnosed using 75-g GHBT in a retrospective study.8 Resolution of SIBO diagnosed using negative GHBT was achieved more often with rotating than single antibiotic (70% vs. 51%). Negative GHBT, indicating resolution of SIBO, was associated with improvement in quality of life and abdominal bloating.8 Though this study is important considering that there is paucity of data on the comparison of single antibiotics and rotating antibiotics in the treatment of SIBO, the study has a few limitations in its design, methods, and data interpretation. The most important among these is the use of antibiotics other than the broad-spectrum non-absorbable antibiotic rifaximin, which is the drug of choice for treatment of SIBO. The Azole group of drugs are associated with side effects such as nausea, vomiting, metallic taste and are, therefore, not preferred currently in the treatment of SIBO. The other limitations include a non-randomized retrospective design and the choice of the group based on physicians' preference, which could introduce bias; this is evidenced by the fact that the number of patients in different groups was discordant and systemic sclerosis and cholecystectomy, both of which are more frequently associated with gut microbiota dysbiosis including SIBO,1, 9 were commoner in rotating than a single antibiotic group. Sample size has not been calculated by appropriate statistical technique. The patients included in the final analysis might have recruitment bias as of the 710 patients, 223 (31%) were finally included, as a large proportion of the other patients did not undergo a second GHBT.8 Is it possible that the treating physician's decision to undertake a second GHBT had a selection bias? As two-thirds of the patients were not included in the final data analysis, generalizing the result to clinical practice may have limitations. The other limitations include lack of data on compliance to therapy, which is particularly important with drugs commonly associated with adverse effects such as azoles and the long interval between first and second GHBT (mean 150 days). Recurrence of SIBO following successful treatment with an antibiotic is not uncommon during 3–6 months follow-up,1 which could underestimate the frequency of resolution of SIBO, particularly in the single antibiotic arm. Another limitation is the criteria used to diagnose SIBO on GHBT. A high fasting breath hydrogen or methane has been used to diagnose SIBO. However, this criterion has not been validated.10 Despite all the limitations mentioned above, the study is important to clinicians and researchers as it raises lots of questions that need further investigations. It is worthy re-iterating what Curtis Tyrone Jones, a German musical artist, said “Perspectives are like batteries. You can see the positive or the negative, and they'll keep you charged up if you replace them often enough.” The author has no conflict of interest to declare.