Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Nuffield Department of Medicine, University of Oxford, United Kingdom.
Clin Infect Dis. 2017 Jul 1;65(1):20-28. doi: 10.1093/cid/cix230.
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.
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.
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.
Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored.
ISRCTN61649292.
耐多药结核性脑膜炎（TBM）的诊断和治疗较为困难。该病死亡率高，目前尚无最佳治疗方法。我们比较了标准抗结核治疗与强化抗结核治疗对耐多药和敏感 TBM 患者的临床结局。
我们分析了结核分枝杆菌耐药性对纳入一项随机对照试验患者的结局的影响，该试验比较了标准 9 个月抗结核方案（含利福平 10 mg/kg/天）与强化方案（前 8 周用高剂量利福平 15 mg/kg/天和左氧氟沙星 20 mg/kg/天）治疗 TBM 的疗效。该试验的主要终点是 9 个月的生存率。在此亚组分析中，耐药类别被预先定义为耐多药（MDR）、异烟肼耐药、利福平敏感（INH-R）和异烟肼和利福平敏感（INH-S + RIF-S）。通过 Cox 回归比较了耐药类别和对强化治疗的反应，并进行了估计。
在 817 名随机患者中，有 322 名患者的耐药谱已知。86 例（26.7%）患者存在 INH-R，15 例（4.7%）患者存在 MDR，1 例（0.3%）患者存在利福平单耐药，220 例（68.3%）患者存在 INH-S + RIF-S。多变量回归显示，MDR（危险比[HR]，5.91[95%置信区间{CI}，3.00-11.6]，P<0.001）是死亡的独立预测因素。INH-R 与新发神经事件或死亡的联合结局显著相关（HR，1.58[95%CI，1.11-2.23]）。调整治疗调整后的校正 Cox 回归显示，强化治疗与 INH-R TBM 患者的生存改善显著相关（HR，0.34[95%CI，0.15-0.76]，P=0.01）。
早期强化治疗改善了 INH-R TBM 患者的生存。应进一步探索针对耐药 TBM 的靶向治疗方案。
ISRCTN61649292。
