Irritable bowel syndrome (IBS) is a functional disorder affecting up to 20% of the general population in Western countries, with an estimated incidence of 1–2% per year and high social costs [1]. The pathophysiology of IBS has been attributed to impaired intestinal motility, immunologic dysfunction, and an atypical psychological background. IBS management is mainly tailored to the treatment of the principal and most troublesome symptoms.

The largest available studies investigating IBS treatment efficacy and safety include patients with diarrhea as predominant symptom (IBS-D), which accounts for about one-third of the affected population [1]. Two identically designed phase 3, double-blind, placebo-controlled trials, the TARGET-1 and the TARGET-2, have reported that rifaximin at the dose of 550 mg tid for 2 weeks is superior to placebo in improving IBS-D symptoms such as bloating, abdominal pain, and altered stool consistency over the 10-week study period, with a good safety profile [2]. Thus, in 2015 rifaximin was approved by the US Food and Drug Administration (FDA) for the treatment of IBS-D.

IBS is associated with dysbiosis, a condition in which the composition of the intestinal microbiota is altered in that the abundance of bacterial strains associated with disease is increased, whereas the abundance of strains associated with health is decreased [3]. Although the beneficial effects of the use of rifaximin in a disorder not classically considered infectious such as IBS may be quite surprising, the broad antimicrobial activity and eubiotic properties of rifaximin may account for its success in the management of gastrointestinal conditions associated with dysbiosis.

Several studies have demonstrated the positive effects of rifaximin on the composition of the gut microbial community, and in particular the increase in the abundance of bacteria associated with health such as Bifidobacterium, F. prausnitzii, and Lactibacillus, in the absence of significant alterations of the overall composition, lasting up to 1 month after treatment completion [4,5,6].

In most cases, IBS is a chronic disorder with relapsing symptoms. As a consequence, patients often need prolonged or repeat treatment during their life. This is a crucial issue when an antibiotic is used in clinical practice, as the development of mechanisms of resistance among bacteria may affect clinical efficacy.

To untangle this knot, a third trial, the TARGET-3 [7], has investigated the efficacy of rifaximin re-treatment in IBS-D patients who experienced symptomatic relapse after an initial successful treatment with rifaximin. Among 1074 patients who initially responded to rifaximin 550 mg tid for two weeks in the open-label phase, 692 relapsed during the observation phase and 636 of them were randomly assigned to receive a second course of rifaximin (328) or placebo (308). The percentage of responders was significantly higher with rifaximin than placebo (38.1 vs 31.5%; p = 0.03), especially in those with relief of abdominal pain (50.6 vs 42.2%; p = 0.018). Significant improvements were also achieved for several outcomes such as the prevention of symptom recurrence, achievement of a durable response, and bowel movement urgency, but not for stool consistency. The TARGET-3 has therefore demonstrated that re-treatment is effective in IBS patients who initially respond to rifaximin and experience relapsing symptoms. Although one can deduce that the effect of rifaximin on gut bacteria may persist over time due to the lack of outbreaks resistant organisms, this hypothesis needs confirmation, in particular in “real-world” clinical practice. Furthermore, in patients with IBS receiving rifaximin, there is a possibility that bacterial species cross-resistant to other antibiotics may be emerge, with obvious risks of significant comorbidity.

In this issue of Digestive Diseases and Sciences, Pimentel et al. [8] reported on the absence of clinically meaningful bacterial resistance after short-term repeat treatment with rifaximin in patients with IBS-D. In this study, stools from 103 patients participating in the open-label phase of the TARGET-3 study were collected for fecal culture and susceptibility testing prior to and after a 2-week course of rifaximin 550 mg tid. Seventy-three out of the 103 patients participated in the double-blind phase, 37 in the rifaximin group and 36 in the placebo group. Among the 1429 bacterial and yeast isolates, the major bacterial families included Bacteroidaceae (36.7%) and Enterobacteriaceae (33.9%), whereas Clostridiaceae (1.5%), Pseudomonadaceae (0.3%), and yeasts (1.2%) were less represented.

Overall, the analysis of rifaximin susceptibility revealed an increase in rifaximin minimum inhibitory concentration (MIC)50 and MIC90 from baseline, although susceptible isolates were still observed at week 2 and weeks 7–32. Enterobacteriaceae and Staphylococcaceae were the two bacterial families exhibiting significant changes in their resistance profile after rifaximin treatment (Fig. 1). In particular, Enterobacteriaceae isolates MIC50 and MIC90 values for rifaximin increased from baseline to week 2 and remained higher until weeks 19–22 and then decreased for the rest of the study. At week 2, rifaximin MIC50 and MIC90 of Staphylococcaceae increased; MIC50 recovered to baseline levels at week 7 and MIC90 recovered to baseline levels at week 23. C. difficile and Enterococcaceae isolates were susceptible to rifaximin throughout the open-label phase. Similar results were reported in the double-blind rifaximin group, whereas in the double-blind placebo group microbial isolates remained susceptible to rifaximin in samples collected during all visits.

Fig. 1
figure 1

Minimum inhibitory concentration (MIC) 50 and 90 for Enterobacteriaceae and Staphylococcaceae reported by Pimentel et al. OL open-label study, DB double-blind study

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These observations are in line with previous studies reporting the broad antimicrobial effect of rifaximin, demonstrating that aerobic Gram-positive cocci are more prone to develop resistance compared to anaerobic and Gram-negative organisms [9]. Nonetheless, rifaximin is a poorly absorbed antibiotic reaching intestinal concentrations that are far above the MIC of tested bacteria, limiting the selection of resistant isolates. Furthermore, the recovery of bacterial sensitiveness several weeks after stopping treatment reflects the specific mechanism of bacterial resistance elicited by rifaximin, requiring chromosomal mutation of the drug target mediated by DNA-dependent RNA polymerase. Therefore, genes of resistance are rarely transmitted to other bacteria, and after the death of resistant microbes, rifaximin sensitivity is rapidly restored [10].

The study from Pimentel et al. also supports the evidence that has been emerged so far that the occurrence of infections from resistant C. difficile strains related to rifaximin treatment is extremely rare and is attributable to non-IBS-related predisposing conditions such as hospitalization or multiple and prolonged antibiotic use [10]. Another important finding of the present study is the absence of cross-resistance of Bacteroidaceae, Enterobacteriaceae, and Enterococcaceae to non-rifamycin-based antibiotics after rifaximin exposure. Therefore, the repeat use of rifaximin does not reduce the efficacy of other antibiotics and may be considered without such concerns when needed.

There is growing evidence regarding the increase in abundance of health-associated bacteria, which may mediate the beneficial effects of rifaximin in several gastrointestinal diseases. The development of resistance induced by rifaximin among Bifidobacteria has already been described [11], and similar changes may also happen for F. prausnitzii and Lactobacilli. Further studies are needed to specifically address these findings that are crucial in the personalized management of IBS treatment.

Doubtless, the detection of progressive clinical improvements that occur in a already mild entity in a large proportion of patients may limit the accurate quantification of the response after multiple treatments, as already discussed by the authors of the TARGET-3 study. From the microbiological point of view, changes in the antimicrobial sensitivity of gut bacteria may be an important component of tailored management, especially in the setting of multiple relapses. Unfortunately, the effect of repeat rifaximin treatment on other constituents of the gut microbiota remains unknown.

In summary, short-term repeat treatment with rifaximin is not associated with the emergence of significant bacterial resistance, which is limited to Enterobacteriaceae and Staphylococcaceae and is rapidly reversible. These findings may help answer the question of whether or not repeat rifaximin treatment may be worthwhile in IBS-D patients with relapsing symptoms, although prediction of which patients may obtain clinical benefit after several treatments remains difficult.