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

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)20-28
Number of pages9
JournalClinical Infectious Diseases
Volume65
Issue number1
DOIs
Publication statusPublished - 1 Jul 2017
Externally publishedYes

Keywords

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

Cite this

Heemskerk, A. D., Nguyen, M. T. H., Dang, H. T. M., Vinh Nguyen, C. V., Nguyen, L. H., Do, T. D. A., ... Thwaites, G. E. (2017). Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen. Clinical Infectious Diseases, 65(1), 20-28. https://doi.org/10.1093/cid/cix230
Heemskerk, A. Dorothee ; Nguyen, Mai Thi Hoang ; Dang, Ha Thi Minh ; Vinh Nguyen, Chau Van ; Nguyen, Lan Huu ; Do, Thu Dang Anh ; Nguyen, Thuong Thuy Thuong ; Wolbers, Marcel ; Day, Jeremy ; Le, Thao Thi Phuong ; Nguyen, Bang Duc ; Caws, Maxine ; Thwaites, Guy E. / Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen. In: Clinical Infectious Diseases. 2017 ; Vol. 65, No. 1. pp. 20-28.
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title = "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.",
keywords = "drug-resistance, isoniazid, levofloxacin, tuberculosis, Tuberculous meningitis",
author = "Heemskerk, {A. Dorothee} and Nguyen, {Mai Thi Hoang} and Dang, {Ha Thi Minh} and {Vinh Nguyen}, {Chau Van} and Nguyen, {Lan Huu} and Do, {Thu Dang Anh} and Nguyen, {Thuong Thuy Thuong} and Marcel Wolbers and Jeremy Day and Le, {Thao Thi Phuong} and Nguyen, {Bang Duc} and Maxine Caws and Thwaites, {Guy E.}",
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Heemskerk, AD, Nguyen, MTH, Dang, HTM, Vinh Nguyen, CV, Nguyen, LH, Do, TDA, Nguyen, TTT, Wolbers, M, Day, J, Le, TTP, Nguyen, BD, Caws, M & Thwaites, GE 2017, 'Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen', Clinical Infectious Diseases, vol. 65, no. 1, pp. 20-28. https://doi.org/10.1093/cid/cix230

Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen. / Heemskerk, A. Dorothee; Nguyen, Mai Thi Hoang; Dang, Ha Thi Minh; Vinh Nguyen, Chau Van; Nguyen, Lan Huu; Do, Thu Dang Anh; Nguyen, Thuong Thuy Thuong; Wolbers, Marcel; Day, Jeremy; Le, Thao Thi Phuong; Nguyen, Bang Duc; Caws, Maxine; Thwaites, Guy E.

In: Clinical Infectious Diseases, Vol. 65, No. 1, 01.07.2017, p. 20-28.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Clinical Outcomes of Patients with Drug-Resistant Tuberculous Meningitis Treated with an Intensified Antituberculosis Regimen

AU - Heemskerk, A. Dorothee

AU - Nguyen, Mai Thi Hoang

AU - Dang, Ha Thi Minh

AU - Vinh Nguyen, Chau Van

AU - Nguyen, Lan Huu

AU - Do, Thu Dang Anh

AU - Nguyen, Thuong Thuy Thuong

AU - Wolbers, Marcel

AU - Day, Jeremy

AU - Le, Thao Thi Phuong

AU - Nguyen, Bang Duc

AU - Caws, Maxine

AU - Thwaites, Guy E.

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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.

AB - 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.

KW - drug-resistance

KW - isoniazid

KW - levofloxacin

KW - tuberculosis

KW - Tuberculous meningitis

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U2 - 10.1093/cid/cix230

DO - 10.1093/cid/cix230

M3 - Article

VL - 65

SP - 20

EP - 28

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

IS - 1

ER -