Antibiotic Aims at IBS Bloating and Global Symptoms

LOS ANGELES, Oct. 19 -- The traveler's diarrhea antibiotic Xifaxan (rifaximin) appears to improve global symptoms and bloating of irritable bowel syndrome, according to researchers here.

A single course of the oral nonsystemic antibiotic cut global IBS symptoms by more than a third for the duration of a 10 week study, reported Mark Pimentel, M.D., of Cedars-Sinai Medical Center in Los Angeles, and colleagues, in the Oct. 17 issue of the Annals of Internal Medicine.

Although the study is the first to suggest a sustained benefit of antibiotics for IBS symptoms after treatment is stopped, an accompanying editorial by Douglas A. Drossman, M.D., of the University of North Carolina at Chapel Hill said the study design may hamper the usefulness of the "novel and important" findings.

Xifaxan recipients had a 36.4% (standard deviation 31.46%) improvement in global symptoms averaged over the 10-week study compared with 21.00% (SD 22.08%) for the placebo group.

However, this primary outcome measure "is unique in the spectrum of IBS trials in the last decade and makes comparisons with other trials difficult," cautioned Dr. Drossman, and responders were not defined beforehand so it is unclear whether the response rate is clinically meaningful relative to the placebo response rate.

He also noted that site recruitment differed markedly between the two study sites (83 participants versus three participants). He also pointed out that "since the global measure includes pain, the imbalance in baseline pain scores is important to note. The imbalance (higher baseline pain scores in the rifaximin group) favors the reduction in the global measure with rifaximin."

In addition he wrote that "although lactulose breath test studies were done before and after treatment, data relating to the prevalence of the abnormal test results in each group and the correlation of clinical response to reduction in test scores were not reported."

The Xifaxan group also reported significantly less bloating on a visual analog scale compared to the placebo group (P=0.010), a difference that persisted after controlling for differences between groups in baseline pain scores (P=0.001).

Besides bloating, none of the secondary end points improved with treatment compared to placebo on the visual analog scale:

• Abdominal pain (P=0.32),
• Diarrhea (P=0.67), and
• Constipation (P=0.069).

This suggests Xifaxan "may be targeted more for bloating," Dr. Drossman wrote.

While the cause of irritable bowel syndrome is uncertain, there is some evidence suggesting that it is caused by an abnormal growth of bacteria in the small intestine.

Xifaxan is a gut-selective antibiotic derived from the rifamycin family that may reduce bacterial overgrowth due to its broad-spectrum activity in vitro against gram-positive, gram-negative, aerobic, anaerobic, and microaerophilic bacteria. It is FDA approved for treating traveler's diarrhea.

The double-blind trial included adults who met Rome I criteria for IBS. Forty-three were randomized to 400 mg of Xifaxan three times daily for 10 days and 44 were randomized to placebo. This was just shy of the 44 per group needed to detect a difference of 35% (SD 50%) with a power of 90%.

Patients completed a seven-day stool diary before initiation of the study, for the week following completion of treatment, and during the last week of the study. They also completed a questionnaire on symptoms before starting treatment, after completing treatment, weekly at home during the study, and at the clinic visit at the end of the study.

Global improvement percentage "varied widely across week for most individuals," which may have been the impetus for averaging the results for all 10 weeks. This percentage was significant as a function of group (P=0.020) but not as a function of week (P=0.78) or group-by-week (P=0.96), which means "being in the rifaximin group was the main factor associated with the improvement," the researchers wrote.

Abdominal pain was higher at baseline in the Xifaxan group (severity score 52.4 (SD 28.8) versus 36.8 (SD 29.8) placebo), which would tend to bias the global scores in favor of Xifaxan. However, the researchers noted that abdominal pain did not affect the global improvement outcome in a fixed-effects model.

After controlling for abdominal pain, diarrhea score on the visual analog scale were still not significantly better than placebo (P=0.151).

Exclusion criteria included the presence of underlying conditions that are known to predispose to bacterial overgrowth, such as diabetes, previous bowel resection, inflammatory bowel disease, or any known chronic gastroenterological disease. Individuals taking tegaserod and antidepressants were excluded as well as those who reported taking an oral antibiotic within the previous three months.

Two patients withdrew due to side effects, but both were in the placebo group. The most common side effects with Xifaxan were abdominal pain, diarrhea, and a bad taste in the mouth but they occurred rarely and at a similar rate in both groups.

The investigators noted that the study was limited by the "modest" number of participants and by a duration that was too short to identify recurrence of symptoms, which is expected if bacterial overgrowth is assumed to be the mechanism by which the drug works in this setting.

Dr. Drossman suggested the following strategy for patients with irritable bowel syndrome based on the results:

• Determine whether the patient may have bacterial overgrowth based on symptoms of postprandial abdominal discomfort, bloating, and possibly loose stools.
• If these clinical features are present and the subsequent lactulose H₂ breath study results are positive, consider a course of a broad-spectrum antibiotic.
• Then try a probiotic to add "good" bacteria.
• If the stool normalizes or becomes more constipated, consider adding a prokinetic agent.
• If symptoms recur and a second lactulose H₂ breath test is positive, retreat with antibiotics.
• If lactulose testing is not available, take a conservative approach and do not repeat treatments unless there is a clear and sustained benefit for at least several months.

The study was funded by a grant from Salix Pharmaceuticals, which makes Xifaxan. Some of the authors reported financial disclosures for Novartis, Chugai Pharmaceutical, Promethus, Romark, and Salix Pharmaceuticals. Cedars-Sinai Medical Center has a licensing agreement with Salix Pharmaceuticals.