published in the online edition of Clinical
Infectious Diseases supports World Health Organization (WHO)
recommendations for the use of drug susceptibility testing to select drugs for
the treatment of drug-resistant tuberculosis. Drug susceptibility testing for
ethambutol, pyrazinamide and second-line anti-tuberculosis (TB) treatment was shown to
provide clinically useful information for the selection of treatment regimens
for multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB).
The chances of treatment success were increased between 1.7 and 4.6-fold when
susceptibility testing showed that the use of an individual agent was
“For all drugs
tested, use of that drug was associated with higher odds of treatment success
compared to failure and relapse, or compared to failure, relapse and death if
the isolate was susceptible rather than resistant to that drug,” comment the
authors. “These findings suggest that DST [drug susceptibility testing]
results, using current methods, can be useful for the selection of TB drugs in
individualized treatment of patients with MDR-TB.”
is a growing global health problem. MDR-TB is defined as TB with resistance to
the key first-line drugs isoniazid and rifampin, whereas XDR-TB involves resistance
to isoniazid and rifampin, at least one drug in the fluoroquinolone class and
one or more injectable second-line drugs.
WHO recommend that people with MDR- or XDR-TB should receive individualised treatment with
regimens selected on the basis of drug susceptibility testing. However, such
tests are performed for only 5% of TB cases and susceptibility
tests have not been validated against treatment outcomes.
Members of an
expert group convened by WHO to develop guidance for the treatment of
drug-resistant TB therefore conducted an analysis of treatment outcomes in
8955 people with MDR- or XDR-TB according to drug susceptibility results.
Information on the
patients was gathered from 31 previously published cohort studies; these were
conducted in all world regions.
the following drugs was analysed: the
first-line drugs ethambutol and pyrazinamide and also drugs from classes used
in second-line therapy – injectable drugs (streptomycin, kanamycin, amikacin
and capreomycin), fluoroquinolones
(ofloxacin, levofloxacin and later-generation quinolones) and drugs from group
4 agents (ethionamide/prothionamide, cycloserine or para-aminosalicylic acid).
Data were also
obtained on individual patient demographics, clinical features of TB disease, culture
results, chest X-ray, sputum smear results, HIV infection status and use of
antiretroviral therapy (ART).
The patients had a
mean age of 39 years, 68% were male, 60% had received previous first-line TB
therapy and 11% treatment with second-line TB agents. Overall, 12% of patients were living with
HIV but only 1.3% of these patients received ART during TB therapy.
Of the 31 studies
included in the analysis, 27 reported in results of drug susceptibility testing
for ethambutol and pyrazinamide with 26 studies reporting on the results of
susceptibility testing for second-line drugs.
For each of the
drugs analysed, the odds of treatment success (versus failure/relapse) were
significantly higher when the agent was susceptible rather than resistant to that
specific drug. Results were similar when death was included as an unsuccessful
For the most part,
the association between susceptibility and drug effect did not vary importantly
remained robust in a series of sensitivity analyses that adjusted for patient
characteristics, availability of treatment options and resistance to other
second-line drugs. The adjusted odds of treatment success after susceptibility
testing for ethambutol, pyrazinamide and drugs in group 4 ranged from 1.7 to
2.3. For second-line injectables and fluoroquinolones, the odds ranged from
2.4 to 4.6.
“To our knowledge
this is the first evidence of the association of DST results for second line
drugs and treatment outcomes,” write the investigators. “These findings should
be generalizable, since patients were treated at 31 different centres – located
in all WHO regions, including some very resource-limited settings.”
They conclude that
drug sensitivity testing for ethambutol, pyrazinamide and second-line TB drugs
provides useful information for the selection of drugs for the therapy of
MDR-TB. However, the authors call for further studies to “improve, standardize
and validate laboratory methods and critical concentrations for these tests.”