CHICAGO – An investigational antibiotic was just as effective as ciprofloxacin at curing travelers’ diarrhea but was associated with a significantly lower rate of colonization with extended spectrum beta-lactam–resistant Escherichia coli, a phase III trial has determined.
“Rifamycin was noninferior to ciprofloxacin on every endpoint in this trial,” Robert Steffen, MD, said at the annual Digestive Disease Week. “However, there was no increase in extended spectrum beta-lactamase–producing Enterobacteriaceae (ESBL-E) associated with rifamycin, and significantly less new acquisition of these pathogens than in the ciprofloxacin group.”
Rifamycin is a poorly absorbed, broad-spectrum antibiotic in the same chemical family as rifaximin. It’s designed, both molecularly and in packaging, to become active only in the lower ileum and colon with limited systemic absorption. The drug is approved in Europe for infectious colitis, Clostridium difficile, diverticulitis, and also as supportive treatment of inflammatory bowel diseases and hepatic encephalopathy.
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Subjects were randomized to 3 days of rifamycin 800 mg, or ciprofloxacin 1,000 mg. Follow-up visits occurred on days 2, 5, and 6, with a final follow-up by mail 4 weeks later. The primary endpoint was time to last unformed stool from the first dose of study medication. Secondary endpoints were clinical cure (24 hours with no clinical symptoms, fever, or watery stools, or 48 hours with no fever; and either no stools or only formed stools), need for rescue therapy, treatment failure, pathogen eradication in posttreatment stool, and the rate of ESBL-E colonization.
The time to last unformed stool was 43 hours in the rifamycin group and 37 hours in the ciprofloxacin group, which were not significantly different. The results were similar when broken down by infective organism, by gender, and by study location.
Rifamycin was also noninferior to ciprofloxacin in several secondary endpoints, including clinical cure (85% each), treatment failure (15% each), and need for rescue therapy (1% vs. 2.6%). The drugs were also virtually identical in the number of unformed stools per 24-hour interval, which fell precipitously from 5.5 on day 1, to 1 by day 5, and in complete resolution of gastrointestinal symptoms, which were about 75% resolved in each group by day 5.
Rifamycin was equally effective in eradicating all of the pathogens identified in the cohort. This included all pathogens in the E. coli group, all in the potentially invasive group (Shigella, Campylobacter, Salmonella, and Aeromonas), norovirus, giardia, and Cryptosporidium.
Treatment-emergent adverse events occurred in 12% of each group; none were serious. About 8% of each group experienced an adverse drug reaction.
Where the drugs did differ, and sharply so, was in antibiotic resistance, said Dr. Steffen, of the University of Zürich and the University of Texas School of Public Health, Houston. At baseline, about 16% of the group was infected with ESBL–E coli. At last follow-up, those species were present in 16% of the rifamycin group, but in 21% of the ciprofloxacin group. Similarly, there was less new ESBL–E. coli colonization in patients who had been negative at baseline (10% vs. 17%).
The findings are particularly important in light of the increasing worldwide emergence of antibiotic-resistant bacteria, Dr. Steffen said. In fact, new guidelines released April 29 by the International Society of Travel Medicine recommend that antibiotics be reserved for moderate to severe cases of traveler’s diarrhea and not be used at all in milder cases (J Travel Med. 2017 Apr 29;24[suppl. 1]:S57-S74).
“The widespread use of ciprofloxacin and other antibiotics for travelers’ diarrhea has contributed to the rise of these resistant bacteria,” Dr. Steffen said in an interview. “We need to rethink the way we use these drugs and to focus instead on drugs that are not systemically absorbed. If rifamycin is eventually approved for this indication, it would be a good alternative to systemic antibiotics, curing the acute illness, and not contributing as much to the emergence of these worrisome pathogens.”
Digestive Disease Week® is jointly sponsored by the American Association for the Study of Liver Diseases (AASLD), the American Gastroenterological Association (AGA) Institute, the American Society for Gastrointestinal Endoscopy (ASGE), and the Society for Surgery of the Alimentary Tract (SSAT).
In a video interview at the meeting, Dr. Steffen spoke about the trial and concerns about antibiotic resistance that are addressed in the new guidelines and by this new study.
Dr. Falk Pharma GmbH of Freiburg, Germany, is developing rifamycin and conducted the study. Dr. Steffen has received consulting and travel fees from the company.
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