Multidrug-Resistant Tuberculosis Treatment Outcomes in Relation to Treatment and Initial Versus Acquired Second-Line Drug Resistance
Authors: Cegielski J. Peter , Kurbatova Ekaterina , van der Walt Martie , Brand Jeannette , Ershova Julia , Tupasi Thelma , Caoili Janice Campos , Dalton Tracy , Contreras Carmen , Yagui Martin , Bayona Jaime , Kvasnovsky Charlotte , Leimane Vaira , Kuksa Liga , Chen Michael P. , Via Laura E. , Hwang Soo Hee , Wolfgang Melanie , Volchenkov Grigory V. , Somova Tatiana , Smith Sarah E. , Akksilp Somsak , Wattanaamornkiet Wanpen , Kim Hee Jin , Kim Chang-ki , Kazennyy Boris Y. , Khorosheva Tatiana , Kliiman Kai , Viiklepp Piret , Jou Ruwen , Huang Angela Song-En , Vasilyeva Irina A. , Demikhova Olga V. ,   on behalf of the Global PETTS Investigators, Lancaster Joey , Odendaal Ronel , Diem Lois , Perez Therese C. , Gler Tarcela , Tan Kathrine , Bonilla Cesar , Jave Oswaldo , Asencios Luis , Yale Gloria , Suarez Carmen , Walker Allison Taylor , Norvaisha Inga , Skenders Girts , Sture Ingrida , Riekstina Vija , Cirule Andra , Sigman Erika , Cho Sang-Nae , Cai Ying , Eum Seokyong , Lee Jongseok , Park Seungkyu , Jeon Doosoo , Shamputa Isdore C. , Metchock Beverly , Kuznetsova Tatiana , Akksilp Rattanawadee , Sitti Wanlaya , Inyapong Jirapan , Kiryanova Elena V. , Degtyareva Irina , Nemtsova Evgenia S. , Levina Klavdia , Danilovits Manfred , Kummik Tiina , Lei Yung-Chao , Huang Wei-Lun , Erokhin Vladislav V. , Chernousova Larisa N. , Andreevskaya Sofia N. , Larionova Elena E. , Smirnova Tatyana G. 
Published: October 2015

Abstract
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 &lt; .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 &lt; .001 for trend), while acquired drug resistance decreased from 12% to 16% range, depending on the drug, down to 0%–2% (P &lt; .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.