Higher daily doses of rifampin, a cornerstone
of tuberculosis treatment, killed more TB bacteria in sputum cultures,
and the higher doses did so without increasing the adverse effects of
treatment, according to a randomized controlled trial published online
in the American Thoracic Society's American Journal of Respiratory and
Critical Care Medicine.
In "Efficacy and Safety of High-Dose Rifampin in Pulmonary
Tuberculosis: A Randomized Controlled Trial," Gustavo E. Velásquez, MD,
MPH, associate physician in the Division of Infectious Diseases at
Brigham and Women's Hospital in Boston, and co-authors report on a phase
2 trial conducted in Lima, Peru, with 180 adults with new,
drug-susceptible TB. Previous studies looking at whether intermittent
delivery of higher doses of rifampin were effective in killing the TB
bacterium found intermittent higher doses were more toxic than lower
doses.
The authors of the current trial said that the findings were
particularly encouraging because they suggest that at a high enough dose
of daily rifampin, a treatment period of less than the standard six
months may be possible.
"Six months of treatment with four drugs -- often delivered with
support and supervision -- represents a substantial burden on the health
care system, as well as on the patient," Dr. Velásquez said. "Patients
who cannot complete the full regimen may not be cured, which permits
ongoing transmission and the development of drug-resistant TB."
The authors wrote that optimization of rifampin dosing is a priority
because it has the most potent sterilizing effect of the four first-line
agents, is available throughout the world, and costs only pennies per
capsule.
Trial participants were randomized equally to receive a standard dose
of 10 mg/kg/day of rifampin or higher doses of 15 and 20 mg/kg/day,
along with standard doses of the other first-line anti-TB drugs
(isoniazid, pyrazinamide, ethambutol), during the first eight weeks of
intensive therapy. After that, participants in all three trial arms
received standard doses of rifampin and isoniazid during four months of
continuation therapy.
The trial found that each five mg/kg/day increase in rifampin
increased the elimination rate of TB bacteria from sputum. The trial
also looked at rifampin concentrations in plasma and found that
elimination rates of TB bacteria were significantly related to higher
rifampin concentrations. All findings were true even after adjusting for
age, sex and extent of disease.
Importantly, the increased efficacy of higher doses did not appear to
result in more grade two or higher rifampin-related adverse events. Two
commonly reported adverse events of rifampin are liver toxicity and
flu-like syndrome. Flu-like syndrome was not observed in this trial.
The trial did not find that rates of culture conversion, a milestone
in TB therapy indicating that bacteria are no longer detectable in
culture, differed among the three trial arms after the eight-week
intensive treatment phase. The authors said the trial was not powered to
make that determination.
"The difference was too modest at the tested doses for successful
treatment shortening," Dr. Velásquez said. "However, these results,
taken together with other recently published reports, support efforts to
increase doses of rifampin to 35 mg/kg/day and possibly higher until
the maximum tolerable dose is identified."
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