title: Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial.
abstract: BACKGROUND
  Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting.
  
  
  METHODS
  In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755.
  
  
  RESULTS
  60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03).
  
  
  CONCLUSIONS
  These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease.
  
  
  BACKGROUND
  Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.
authors.affiliation: Department of Pharmacology and Therapy, Faculty of Medicine, Universitas Padjadjaran/Hasan Sadikin Hospital, Bandung, Indonesia.
authors.forename: Rovina
authors.initials: R
authors.lastname: Ruslami
authors.forename: A Rizal
authors.initials: AR
authors.lastname: Ganiem
authors.forename: Sofiati
authors.initials: S
authors.lastname: Dian
authors.forename: Lika
authors.initials: L
authors.lastname: Apriani
authors.forename: Tri Hanggono
authors.initials: TH
authors.lastname: Achmad
authors.forename: Andre J
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: George
authors.initials: G
authors.lastname: Borm
authors.forename: Rob E
authors.initials: RE
authors.lastname: Aarnoutse
authors.forename: Reinout
authors.initials: R
authors.lastname: van Crevel
mesh_terms: D000293:Adolescent; D000328:Adult; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination / Q000009:adverse effects / Q000379:methods; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D006801:Humans; D007214:Indonesia; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D011804:Quinolines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012293:Rifampin / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000890:Anti-Infective Agents; D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D000077266:Moxifloxacin; D012293:Rifampin