Pustaka Ilmiah Universitas Padjadjaran

Abstrak

Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial

Background Intensifi ed antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefi t of several treatment regimens containing high-dose rifampicin and moxifl oxacin 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 moxifl oxacin 400 mg, moxifl oxacin 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 fl uid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. Findings 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifl oxacin, ten moxifl oxacin 400 mg, and nine moxifl oxacin 800 mg) and high dose (ten no moxifl oxacin, nine moxifl oxacin 400 mg, and ten moxifl oxacin 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 ; 78•7 mg.h/L [95% CI 71•0–87•3] vs 26•0 mg.h/L[19•0–35•6]), maximum plasma concentrations (Cmax0–6; 22•1 mg/L [19•9–24•6] vs 6•3 mg/L [4•9–8•3]), and concentrations in cerebrospinal fl uid (0•60 mg/L [0•46–0•78] vs 0•21 mg/L [0•16–0•27]). Doubling the dose of moxifl oxacin resulted in a proportional increase in plasma AUC (31•5 mg.h/L [24•1–41•1] vs 15•1 mg.h/L [12•8–17•7]),Cmax 0–6(7•4 mg/L [5•6–9•6] vs 3•9 mg/L [3•2–4•8]), and drug concentrations in the cerebrospinal fl uid (2•43 mg/L[1•81–3•27] vs 1•52 mg/L [1•28–1•82]). Intensifi ed 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). Interpretation These data suggest that treatment containing a higher dose of rifampicin and standard-dose or highdose moxifloxac in during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefi t in patients with severe disease. Funding Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientifi c Research, and Padjadjaran University, Bandung, Indonesia.