New Rifamycin Formulation Curtails Traveler's Diarrhea

Laird Harrison

October 10, 2013

SAN FRANCISCO — An experimental formulation of rifamycin under development by Santarus shortens the duration of symptoms of traveler's diarrhea by about a day, a new study shows.

The formulation appears "to be effective in the invasive forms of the disease and is extremely effective in the noninvasive forms that are actually more common," said study author Herbert DuPont, MD, director of the Center for Infectious Diseases at the University of Texas in Houston.

Dr. DuPont, who is working on the drug with Santarus, presented the study results here at IDWeek 2013.

About 15% to 40% of travelers to Africa, Latin America, and South Asia suffer from traveler's diarrhea, he noted. Of these, about 5% develop irritable bowel syndrome after the diarrhea resolves.

"Antibiotics shorten the disease dramatically, and we hope to be able to shorten the duration of postdiarrhea complications," he said.

Currently, 2 antibiotics are licensed in the United States for the treatment of traveler's diarrhea: ciprofloxacin and rifaximin. But each of these leaves something to be desired, according to Dr. DuPont.

Ciprofloxacin can cause serious adverse reactions, and rifaximin does not work against the most invasive organisms that cause the disease because it doesn't penetrate the mucosa where they hide out, he explained.

The researchers designed the multimatrix (MMX) delivery system with the hope that they could minimize adverse effects from the drug's activity on the saprophytic flora of the upper intestinal tract. The enteric coating on rifamycin MMX dissolves as the tablet reaches the cecum, allowing the gradual diffusion of the agent into the colonic lumen.

To test the drug, the researchers recruited travelers in Mexico and Guatemala who were suffering from traveler's diarrhea.

They analyzed data from 178 patients randomly assigned to treatment with oral rifamycin MMX 400 mg twice a day, and 65 patients randomly assigned to placebo.

Patients kept a diary of their symptoms. The researchers prescribed other antibiotics, such as another fluoroquinolone, as rescue therapy if the symptoms worsened or failed to improve after 2 days.

Outcomes were assessed 2 to 3 days after the end of treatment. Patients were considered cured if they passed no more than 2 soft stools and no watery stools, had no fever, and had no signs or symptoms of enteric infection other than mild excess gas for 2 days. They were also considered cured if they passed no stools or only formed stools and had no fever for 2 days, with or without other signs or symptoms of enteric infection.

Table. Outcomes in Patients With Traveler's Diarrhea

Treatment Median Time to Last Unformed Stool Clinical Cure Rate P Value
Rifamycin MMX 46.0 hours 81.4% <.001
Placebo 68.0 hours 56.9% <.001

 

The time to last unformed stool was shorter in the treatment group than in the placebo group for patients diagnosed with invasive pathogens such as Shigella spp., Salmonella, and Campylobacter. However, the sample size was small and the results were not statistically significant.

Adverse events were less common with rifamycin MMX than with placebo (29.6% vs 38.5%). In addition, fewer patients in the rifamycin MMX group experienced severe adverse events or withdrew from the study because of adverse events than in the placebo group.

The researchers did not consider the severe adverse events seen in the rifamycin group, abdominal pain, or neuroblastoma to be related to the drug.

Although there was some acquired resistance to rifamycin MMX, Dr. DuPont said that this should not pose a barrier to using the drug for traveler's diarrhea.

"These are travelers, and they are a drop in the bucket of the local population," he said. "They are such a small fraction of the people in an international site, it's not a worry. However, it is a perplexing point."

Dr. DuPont said his group is undertaking a similar study in India.

Stephen Calderwood, MD, chief of infectious diseases at Massachusetts General Hospital in Boston, called this formulation of rifamycin "a very reasonable approach," and noted that it would be welcomed by people suffering from traveler's diarrhea.

However, he wondered whether the new drug, if approved, would be more expensive than currently approved agents, which are available in generic form.

Dr. Calderwood noted that head-to-head trial could best determine if rifamycin MMX has fewer adverse effects or drug interactions.

This study was funded by Santarus. Dr. DuPont reports receiving research support from Santarus. Dr. Calderwood has disclosed no relevant financial relationships.

IDWeek 2013: Abstract 1306. Presented October 5, 2013.

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