title: Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis.
abstract: BACKGROUND
  Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients.
  
  
  METHODS
  We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization.
  
  
  RESULTS
  A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08).
  
  
  CONCLUSIONS
  Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).
authors.affiliation: From the Oxford University Clinical Research Unit (A.D.H., N.D.B., N.T.H.M., T.T.H.C., N.H.P., T.T.H., N.T.B.Y., D.T.M.H., J.N.D., L.M., T.T.V.T., M.W., G.E.T., J.J.F.), Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease (N.D.B., N.H.D., N.T.N.L., N.H.L., N.N.L., L.T.P., N.N.V., N.Q.H., N.T.B.Y., D.T.M.H.), and Hospital for Tropical Diseases (N.H.P., P.P.L., N.V.V.C.) - all in Ho Chi Minh City, Vietnam; and the Nuffield Department of Medicine, University of Oxford, Oxford (A.D.H., J.N.D., L.M., M.W., G.E.T., J.J.F.), and Liverpool University, Liverpool (M.C.) - both in the United Kingdom.
authors.forename: A Dorothee
authors.initials: AD
authors.lastname: Heemskerk
authors.forename: Nguyen D
authors.initials: ND
authors.lastname: Bang
authors.forename: Nguyen T H
authors.initials: NT
authors.lastname: Mai
authors.forename: Tran T H
authors.initials: TT
authors.lastname: Chau
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Phu
authors.forename: Pham P
authors.initials: PP
authors.lastname: Loc
authors.forename: Nguyen V V
authors.initials: NV
authors.lastname: Chau
authors.forename: Tran T
authors.initials: TT
authors.lastname: Hien
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Dung
authors.forename: Nguyen T N
authors.initials: NT
authors.lastname: Lan
authors.forename: Nguyen H
authors.initials: NH
authors.lastname: Lan
authors.forename: Nguyen N
authors.initials: NN
authors.lastname: Lan
authors.forename: Le T
authors.initials: le T
authors.lastname: Phong
authors.forename: Nguyen N
authors.initials: NN
authors.lastname: Vien
authors.forename: Nguyen Q
authors.initials: NQ
authors.lastname: Hien
authors.forename: Nguyen T B
authors.initials: NT
authors.lastname: Yen
authors.forename: Dang T M
authors.initials: DT
authors.lastname: Ha
authors.forename: Jeremy N
authors.initials: JN
authors.lastname: Day
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
authors.forename: Laura
authors.initials: L
authors.lastname: Merson
authors.forename: Tran T V
authors.initials: TT
authors.lastname: Thinh
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.forename: Guy E
authors.initials: GE
authors.lastname: Thwaites
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Farrar
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000328:Adult; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D024881:Drug Resistance, Bacterial; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications; D006801:Humans; D053208:Kaplan-Meier Estimate; D064704:Levofloxacin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D016016:Proportional Hazards Models; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects; D014390:Tuberculosis, Meningeal / Q000150:complications / Q000188:drug therapy* / Q000401:mortality
chemical_list: D000995:Antitubercular Agents; D064704:Levofloxacin; D012293:Rifampin