Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen

A. Dorothee Heemskerk, Mai Thi Hoang Nguyen, Ha Thi Minh Dang, Chau Van Vinh Nguyen, Lan Huu Nguyen, Thu Dang Anh Do, Thuong Thuy Thuong Nguyen, Marcel Wolbers, Jeremy Day, Thao Thi Phuong Le, Bang Duc Nguyen, Maxine Caws, Guy E. Thwaites

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Background. Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and-susceptible TBM treated with either standard or intensified antituberculosis treatment. Methods. We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression. Results. Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P <.001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI,.15-.76], P =.01) in INH-R TBM. Conclusions. Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored.

Original languageEnglish
Pages (from-to)20-28
Number of pages9
JournalClinical Infectious Diseases
Issue number1
Publication statusPublished - 1 Jul 2017
Externally publishedYes


  • drug-resistance
  • isoniazid
  • levofloxacin
  • tuberculosis
  • Tuberculous meningitis

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