New research 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 appropriate.
“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.”
Drug-resistant 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.
Susceptibility to 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 treatment outcome.
For the most part, the association between susceptibility and drug effect did not vary importantly between studies.
The findings 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.”
Bastos ML et al. Treatment outcomes of patients with multidrug- and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis. Clin Infect Dis, online edition, 2014.