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

Abstract

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.

Clinical trials registration: ISRCTN61649292.

Keywords: drug-resistance; isoniazid; levofloxacin; tuberculosis; tuberculous meningitis.

Figure 1.

Study flow diagram. *Nine patients who had isoniazid resistance detected and were randomized to intensified treatment received treatment adjustment with the addition of at least a fluoroquinolone. ^†Fifteen patients who had isoniazid resistance detected and were randomized to standard treatment received treatment adjustment with the addition of at least a fluoroquinolone. ^‡Four patients who had rifampicin resistance detected and were randomized to intensified treatment received treatment adjustment with at least a fluoroquinolone. For 3 patients, this was part of a second-line treatment schedule and 1 patient received levofloxacin and amikacin added to first-line drugs. ^§Two patients who had rifampicin resistance detected and were randomized to standard treatment received treatment adjustment with at least a fluoroquinolone. One patient with rifampicin monoresistance received this as part of second-line therapy. The other patient had multidrug resistance and received only additional levofloxacin and no other second-line agents. Abbreviations: CSF, cerebrospinal fluid; EMB, ethambutol; FQN, fluoroquinolone; INH, isoniazid; mono, monoresistance; RIF, rifampicin; STR, streptomycin.

Figure 2.

Time-to-event analysis by resistance category and human immunodeficiency virus (HIV) status. A, Kaplan-Meier (KM) estimates of survival during 9 months by resistance category. B, KM estimates of combined endpoint of time to new neurological event or death by resistance category. C, KM estimates of survival by resistance category of HIV-uninfected patients. D, KM estimates of survival by resistance category of HIV-infected patients. The light gray line represents patients with tuberculous meningitis (TBM) with no isoniazid (INH) or rifampicin (RIF) resistance. The darker gray line represents patients with TBM with INH resistance, but no RIF resistance. The black line represents patients with TBM with RIF resistance or multidrug resistance. Abbreviations: INH, isoniazid; MDR, multidrug resistance; RIF, rifampicin.

Figure 3.

Time-to-event analysis by randomized treatment. A, Overall 9-month survival by randomized arm of 86 patients in the isoniazid-resistant, rifampicin-susceptible (INH-R) category. B, Overall 9-month survival by randomized treatment arm of 16 patients in the rifampicin multidrug resistance category. C, Time to new neurological event or death by randomized treatment of 86 patients in the INH-R category. D and E, Overall 9-month survival by randomized treatment of 39 human immunodeficiency virus (HIV)–uninfected (D) and 47 HIV-infected (E) patients in the INH-R category. Cox regression was stratified by tuberculous meningitis severity grade and HIV status. Abbreviations: CI, confidence interval; HR, hazard ratio.