Search

BACKGROUND Resistance to second-line drugs develops during treatment of multidrug-resistant (MDR) tuberculosis, but the impact on treatment outcome has not been determined. METHODS Patients with MDR tuberculosis starting second-line drug treatment were enrolled in a prospective cohort study. Sputum cultures were analyzed at a central reference laboratory. We compared subjects with successful and poor treatment outcomes in terms of (1) initial and acquired resistance to fluoroquinolones and second-line injectable drugs (SLIs) and (2) treatment regimens. RESULTS Of 1244 patients with MDR tuberculosis, 973 (78.2%) had known outcomes and 232 (18.6%) were lost to follow-up. Among those with known outcomes, treatment succeeded in 85.8% with plain MDR tuberculosis, 69.7% with initial resistance to either a fluoroquinolone or an SLI, 37.5% with acquired resistance to a fluoroquinolone or SLI, 29.3% with initial and 13.0% with acquired extensively drug-resistant tuberculosis (P < .001 for trend). In contrast, among those with known outcomes, treatment success increased stepwise from 41.6% to 92.3% as the number of drugs proven effective increased from ≤1 to ≥5 (P < .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%-2% (P < .001 for trend). In multivariable analysis, the adjusted odds of treatment success decreased 0.62-fold (95% confidence interval, .56-.69) for each increment in drug resistance and increased 2.1-fold (1.40-3.18) for each additional effective drug, controlling for differences between programs and patients. Specific treatment, patient, and program variables were also associated with treatment outcome. CONCLUSIONS Increasing drug resistance was associated in a logical stepwise manner with poor treatment outcomes. Acquired resistance was worse than initial resistance to the same drugs. Increasing numbers of effective drugs, specific drugs, and specific program characteristics were associated with better outcomes and less acquired resistance.

(See the Editorial Commentary by Daley and Horsburgh on pages 1064–5.) Microbial drug resistance has become a major public health concern worldwide. In the case of tuberculosis, the first global drug resistance survey, published in 1997, reported multidrug-resistant (MDR) tuberculosis (ie, resistant to at least isoniazid and rifampicin) in virtually every participating country [1]. Shortly thereafter, the World Health Organization (WHO) and many other partners launched the DOTS (directly observed treatment, short course)–Plus initiative for the programmatic management of MDR tuberculosis in middle- and low-income countries [2–4] because only a small fraction of MDR tuberculosis cases were diagnosed and treated worldwide [5]. Initially, this initiative focused on the availability, affordability, quality, and control of second-line drugs (SLDs) needed to treat MDR tuberculosis [6]. To the extent that the level of MDR tuberculosis in a country was a barometer for the strength of its basic tuberculosis control program, the partners recognized the risk of generating more highly drug-resistant tuberculosis [4]. Suddenly providing access to relatively obscure and toxic SLDs for treatment of MDR tuberculosis would likely lead to the development of widespread resistance to these same drugs. Indeed, in 2010, WHO estimated that 94 000 of 440 000 (21.4%) MDR tuberculosis cases worldwide may be the consequence of recently acquired resistance [5]. Therefore, WHO and its partners planned to introduce second-line treatment for MDR tuberculosis through an expanding series of pilot and demonstration projects [3, 4, 7]. These projects had to meet specific criteria that were developed to maximize cure rates and minimize the extent to which further drug resistance would develop [7, 8]. These criteria included, as examples, robust political commitment and leadership, a strong basic DOTS program, documented proficiency in phenotypic drug susceptibility testing (DST), strong individualized treatment regimens, 100% direct observation of MDR tuberculosis treatment, assiduous management of drug toxicities, and operational infection control measures. To increase access to SLDs and make them affordable, the Green Light Committee (GLC) established a pooled procurement mechanism consolidating demand into larger, more frequent, more predictable purchases [5, 6]. In turn, major pharmaceutical manufacturers offered 60%–90% price reductions for their brands of quality-assured antituberculosis drugs [6, 7, 9, 10]. Projects procured drugs through this mechanism. To prevent acquired resistance, self-selected programs in middle- and low-income countries applied to the GLC, which evaluated, assisted, approved, and monitored applicants. To evaluate whether programs met the criteria for access to SLDs, the GLC ensured that applicants (1) had strong basic DOTS programs and (2) met the criteria established by WHO's Scientific Panel on MDR Tuberculosis [7, 8]. Under these circumstances, the programs would be granted access to procure high-quality, reduced-price SLDs. From 1 January 2000 to 30 June 2011, the GLC approved 138 projects in 90 countries, representing 131 262 patients with MDR tuberculosis [11]. The GLC Secretariat tracked the procurement, distribution, and utilization of drugs, but there was no built-in mechanism to track acquired SLD resistance. To determine whether this GLC process, in the broad sense, could potentially reduce the frequency of acquired drug resistance, we launched the Preserving Effective TB Treatment Study (PETTS) to quantify the emergence of further resistance to SLD in GLC-approved MDR tuberculosis treatment programs, compared concurrently with non-GLC programs in 2 middle-income and 2 high-income countries.