Drug TMC207 Cuts Response Time for Multidrug-resistant Tuberculosis
Tibotec's investigational drug TMC207, added to a 5-drug combination
regimen for 8 weeks, increased the cure rate for multidrug-resistant
tuberculosis (MDR-TB) and reduced response time by more than
half, according to study findings presented at the 50th Interscience
Conference on Antimicrobial Agents and Chemotherapy (ICAAC
2010) last month in Boston. A related report described
good outcomes using meropenem/clavulanate in a small group
of patients with extensively drug-resistant TB (XDR-TB).
is the leading cause of death for people
with HIV worldwide, and HIV positive individuals tend to experience
more aggressive disease and do not respond as well to treatment.
health officials are especially concerned about the now-widespread MDR-TB,
which is resistant to at least the 2 main first-line TB drugs, isoniazid
and rifampin, as well as the more recent emergence of XDR-TB, which
is also resistant to 3 or more second-line drugs, leaving patients "virtually
untreatable using currently available anti-TB drugs," according
to the World Health Organization.
Diacon from Stellenbosch University in South Africa and colleagues
reported results from the first stage of a Phase 2 trial that included
47 patients with newly diagnosed pulmonary MDR-TB. About 75% were men
and the median age was 33 years. Participants were either HIV negative
(88%) or, if HIV positive, had a CD4 count > 300 cells/mm3 and were
not on antiretroviral therapy.
were randomly assigned to receive either TMC207 (400 mg once-daily for
2 weeks, followed by 200 mg three times weekly) or placebo for 8 weeks,
added to a 5-drug MDR-TB background regimen taken for 18-24 months.
TMC207 works by inhibiting Mycobacterium tuberculosis synthesis of adenosine
were considered cured of TB if they had 2 consecutive negative sputum
cultures at least 28 days apart and no recurrence.
addition of TMC207 to the background regimen for 8 weeks resulted
in a 58% reduction in the median time to culture negativity.
in the TMC207 arm showed culture conversion after a median 11 weeks,
compared with 18 weeks for the placebo group.
of patients assigned to the TMC207 arm were culture negative at
the end of the trial or last observation, compared with 57% in the
of patients in the TMC207 arm and 43% in the placebo arm discontinued
the trial prematurely, primarily due to loss to follow-up or voluntary
and 21%, respectively, experienced moderate-to-severe (grade 3 and
4) adverse events.
serious adverse events attributable to the study drug were observed.
Based on these findings, the investigators concluded, "TMC207 administered
for 8 weeks with a standardized 5-drug MDR-TB regimen was generally well
tolerated and significantly increased the proportion of culture negative
subjects at weeks 8 and 24 compared to placebo."
they said, "The TMC207 group converted sputum more than twice as
fast as the placebo group."
from stage 2 of this trial, in which 161 patients are receiving TMC207
for 24 weeks, are expected soon.
In a second study, Marie-Christine Payen?from University Hospital Saint-Pierre
in Brussels and colleagues treated 4 patients with severe bilateral
pulmonary XDR-TB using meropenem/clavulanate combined with only 1 or
2 second-line anti-TB drugs that remained active according to drug susceptibility
They found that 3 patients -- including 1 who was HIV positive -- experienced
short-term favorable outcomes. Sputum culture negativity occurred after
8, 11, and 20 weeks. Clinical status improved and lung lesions visible
by X-rays decreased. All 3 were still on treatment at the time of the
Dr. Payen described one of these patients in more detail in a press
release issued by ICAAC. A 14-year old girl from Chechnya with extensive
bilateral pulmonary lesions and severe malnutrition had received first
and second-line anti-TB drugs in Chechnya without improvement. The Brussels
team treated her with a standard second-line regimen without success
until they received her drug susceptibility results, which showed that
her TB strain was only susceptible to capreomycin and linezolid. After
adding meropenem/clavulanate to these 2 drugs, her clinical status rapidly
improved and sputum culture conversion occurred after 11 weeks.
The remaining patient, who had a 7-year history of unsuccessful tuberculosis
treatment, extensive lung lesions, and only 1 remaining active drug
(capreomycin), failed to respond to meropenem/clavulanate. Therapy was
interrupted after 8 months and the patient died 3 months later.
"Given the poor prognostic factors of our patients," the researchers
concluded, adding meropenem/clavulanate "may have had a beneficial
impact on the favorable outcome of 3 of them."
"Further studies are needed to explore the real clinical benefit
of the combination of meropenem/clavulanate in the treatment of severe
XDR-tuberculosis," they continued. "Potential limitations
for its use include high cost, intravenous administration and lack of
drug susceptibility testing."
Abstract L1-521a: Stellenbosch Univ., Tygerberg, South Africa; Medical
Research Council, Durban, South Africa; Witwatersrand Univ., Johannesburg,
South Africa; Aurum Health Inst., Johannesburg, South Africa; Tibotec,
Inc., Titusville, NJ; Tibotec, Beerse, Belgium.
Abstract L1-517: CHU Saint-Pierre, Brussels, Belgium.
AH Diacon, A Pym, MP Grobusch, DF McNeeley, and others. Final Results
from Stage 1 of a Double-Blind, Placebo-Controlled Trial with TMC207
in Patients with Multi-Drug Resistant (MDR) Tuberculosis (TB). 50th
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC
2010). Boston, September 12-15, 2010. Abstract
C Martin, T Antoine-Moussiaux, and others. Four Cases of XDR-Tuberculosis
Treated with Meropenem-Clavulanate. 50th Interscience Conference on
Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September
12-15, 2010. Abstract
Experimental use of the combination of Meropenem-Clavulanate in severe
Extensively Drug-Resistant (XDR) pulmonary tuberculosis with few therapeutic
options. Media advisory. September 12, 2010.
World Health Organization. Emergence of XDR-TB. Press release. September