ICAAC: Mice Fare Better Than Men In Novel TB Regimen

CHICAGO, Sept. 19 -- When it comes to curing TB quickly, it may be better to be a mouse than a man.
Researchers have shown that a course of antibiotics that substitutes moxifloxacin (Avelox) for isoniazid (Nydrazid) in the standard tuberculosis regimen can dramatically shorten the time to a cure -- at least for mice with TB.
But the same approach doesn't seem to work as well in people, Susan Dorman, M.D., of Johns Hopkins, told attendees at the Interscience Conference on Anti-microbial Agents and Chemotherapy here.
In a large international study, there was a trend toward better performance with moxifloxacin but it wasn't statistically significant, Dr. Dorman said.
The study, organized by the CDC's Tuberculosis Trials Consortium, involved more than 400 patients with sputum-positive TB who were randomized to the gold standard TB regimen or to a regimen that used moxifloxacin instead of isoniazid.
The gold standard regimen includes rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol), as well as isoniazid.
A positive sputum culture means a patient is infectious and the time to convert the sputum culture from positive to negative is seen as a measure of how long a complete cure will take, Dr. Dorman said.
Eight weeks into her study, 60% of those in the moxifloxacin arm had negative sputum cultures, compared with 55% of those in the standard isoniazid arm. But that the difference was not statistically significant.
"It's a trend in the right direction," Dr. Dorman said, "but that's all."
She said that she and her colleagues are still analyzing data, but the result appears to be clear.
On the other hand, Dr. Dorman said, the new combination was safe and well tolerated, so it offers clinicians another treatment option.
"There's a discordance," said Jacques Grosset, M.D., also of Johns Hopkins and a leader in the search for new, shorter TB regimens. His research team has found that mice can be cured more rapidly by using moxifloxacin.
"I am surprised the result was not better than that," he said. But, he theorized, it's possibly because mice are easier to experiment on than people.
Dr. Grosset and colleagues argue that isoniazid is antagonistic to rifampin, one of the two major TB drugs, while moxifloxacin is not. In mice, he said, the substitution "significantly increased the bactericidal activity and reduced the time to culture conversion by two months."
But the idea of tweaking the standard regimen of TB treatment has some human evidence on its side.
In a smaller randomized trial in Brazil -- involving just 170 patients -- using moxifloxacin did speed up the culture conversion rate, reported Richard Chaisson, M.D., also of Johns Hopkins, and an investigator with Dr. Dorman on the larger trial.
But in that trial, the drug was substituted for ethambutol, rather than isoniazid and the culture conversion rate was 85% at eight weeks in the moxifloxacin arm, compared with 68% with ethambutol. The difference was significant at P=0.02.
Dr. Chaisson described the findings as "the most compelling evidence in nearly 25 years that a novel antibiotic drug combination works better than the current gold standard."
Dr. Dorman's study was supported by the CDC, the Global Alliance for TB Drug Development, and Bayer. Dr. Chaisson's work was supported by the FDA, the Global Alliance, and Bayer. Drs. Dorman, Grosset and Chaisson reported no financial conflicts.Primary source: ICAACSource reference: Grosset JHE et al. "Short-Course Treatment of Active TB with FDA Approved Agents: Predictions from Animal Models." Presentation 1961. Additional source: ICAACSource reference: Dorman S et al. "Moxifloxacin vs. Isoniazid in the First 2 Months of Treatment for Pulmonary Tuberculosis." Presentation L376b. Additional source: ICAACSource reference: Chaisson RE et al. "A Randomized, Placebo-Controlled Trial of Moxifloxacin vs. Ethambutol in the Initial Phase of Tuberculosis Therapy in Brazil." Presentation L736a