It has no current market, not even a prescription
price. Its makers stopped commercial
production years ago because demand was so low. But an
antibiotic long abandoned as a weak low-dose
treatment for tuberculosis may have found renewed purpose,
this time as a potent high-dose fighter
against the most common and actively contagious form of the
lung disease.
"Rifapentine is back," said Johns Hopkins infectious
disease specialist Eric Nuermberger,
whose studies in mice, published in the Public Library of
Science journal PLoS Medicine online Dec. 17,
have found it so promising as an initial treatment for
active TB that clinical trials are scheduled to
begin next year in at least eight countries.
The mouse studies showed that substituting higher and
daily doses of rifapentine for another
antibiotic, rifampin, cured mice two to three times faster
than the much older standard regimen of
drugs that includes rifampin. Researchers say if tests in
people confirm the findings in mice, the
average time to clear the potentially fatal bacterial
infection could be reduced from six months to
three months or less.
"People infected with TB are desperate for better
therapies to combat the infection, therapies
that can work more quickly and thus limit its chances to
spread," said Nuermberger, who headed the
team of researchers from Johns Hopkins and elsewhere. "And
having the ability to more effectively
treat the most common form of the disease, so-called
drug-susceptible TB, is a key step in holding off
multidrug-resistant strains from developing, too.
"It's a huge advantage to have a drug that's already
government-approved, and an equally great
surprise to know that it was there all the while," said
Nuermberger, an assistant professor at the
School of Medicine. He said that Phase 2 clinical trials
will begin as quickly as possible, by mid-2008,
to gauge the effectiveness of rifapentine as a key
component to daily anti-TB drug regimens.
The nonprofit Global Alliance for TB Drug Development
estimates that worldwide more than 9
million people are infected with the highly contagious and
active form of TB, caused by Mycobacterium
tuberculosis; experts say another 424,000 are infected with
the more dangerous, multidrug-resistant
form of the disease.
Most of the antibiotics currently used to treat TB,
Nuermberger notes, were developed in the
1950s or 1960s, and few new medications have appeared
since.
Rifapentine, approved by the Food and Drug
Administration in 1998 for treating widespread
drug-susceptible TB, was initially developed as a less
cumbersome once-weekly tablet. But the drug
"was never really considered effective in low doses when
compared to the gold standard, daily high-
dose regimens with rifampin," said Nuermberger. Rifampin
(sold as Rifadin and Rimactane) was FDA-
approved in 1968.
The potential for shortened treatment times follows an
advance in October by the team's top
scientist, Richard Chaisson, director of Johns Hopkins' Center
for TB Research. Chaisson and his
group showed that another antibiotic, moxifloxacin
(Avelox), when substituted for ethambutol
(Myambutol), may cut treatment times from six months to
four.
Nuermberger and his team investigated the high-dose
potential of rifapentine because the drug
was in the same class of drugs as rifampin, which is part
of the standard antibiotic cocktail of
rifampin, pyrazinamide and isoniazid, a triple-drug combo
sold as Rifater, or with moxifloxacin in place
of isoniazid.
Given as part of a treatment known as "directly
observed therapy short-course," or DOTS,
because the drugs are usually given in direct view of a
caregiver to ensure compliance, the regimen
requires several daily doses for six to nine months. DOTS
cures 95 percent of those treated, but the
lengthy treatment period has proved a problem for patients,
who sometimes miss taking their drugs on
time, minimizing the therapy's effectiveness.
In the new study, Nuermberger and his team tested
seven different combinations of antibiotic
drugs in hundreds of mice infected with active TB. Some
were treated with the standard DOTS
regimen, daily Rifater, while others took rifapentine in
place of rifampin. Rifapentine, in daily amounts
similar to what an adult human would take (600 milligrams),
was also tested separately in combination
with moxifloxacin- or isoniazid-based DOTS regimens.
Blood and tissue testing were done over a six-month
period to see how quickly each drug
combination rid the body of active TB. Treated mice were
also tested three months later to check
against any potential for relapse.
After 10 weeks of drug therapy, mice taking
rifapentine and moxifloxacin tested negative for
active TB and remained so when retested three months later.
Those treated with rifapentine and
isoniazid also tested clear of the bacterium by 10 weeks
but were at least 10 percent more likely to
relapse unless treatment persisted for another month.
Meanwhile, the traditional DOTS regimen
mostly took the full six months to work.
Results showed a distinct advantage in using
rifapentine over rifampin, with rifapentine having
remained in the blood in three times higher concentrations
throughout treatment, indicating the
drug's "longer-lasting action," Nuermberger said.
Two clinical trials are scheduled to study high-dose
and daily combinations with rifapentine. The
first is being spearheaded by Chaisson and will take place
in Brazil. The second will be led by Johns
Hopkins researcher Susan Dorman and scientists from the
Centers for Disease Control and Prevention
and will study those infected in 40 cities in six countries
around the world.
Nuermberger and colleagues conducted their research
with funding from the National Institute
of Allergy and Infectious Diseases, a member of the
National Institutes of Health. Bayer donated
supplies of moxifloxacin, and Sanofi Aventis donated
supplies of rifapentine for the study, which
started in early 2006 and took nearly a year to finish.
In addition to Nuermberger and Chaisson, researchers
from Johns Hopkins involved in this
study, led by Ian Rosenthal, were Ming Zhang, Kathy
Williams, Sandeep Tyagi, William Bishai and
Jacques Grosset. Bishai has previously received research
support from Bayer and has a grant pending
with Schering-Plough, which markets moxifloxacin; he also
previously received grants from Hoechst
Marion Rousel, now owned by Sanofi Aventis. Chaisson has
received study funding from Bayer and
Sanofi Aventis for this and other studies.
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