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

Summary

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.

Findings

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).

Interpretation

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.

Funding

Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Introduction

Meningitis is the most severe form of tuberculosis, resulting in death or neurological disability in 50% of patients.1, 2 The treatment in patients with tuberculous meningitis follows the model for short-course chemotherapy in patients with pulmonary tuberculosis, but the optimum drug regimen and duration have not been established.

Rifampicin is important in the treatment of tuberculous meningitis as shown by the high mortality in patients with rifampicin-resistant tuberculous meningitis.3, 4 However, the dose used is at the low end of the dose-response curve,5, 6 and the penetration of rifampicin into cerebrospinal fluid is low.⁷ Higher doses of rifampicin for pulmonary tuberculosis have been assessed in several clinical trials reported before 1985.8, 9 Until now, no data were available for the use of high-dose rifampicin in tuberculous meningitis, although one clinical trial is underway in Vietnam.¹⁰ Apart from a higher dose of rifampicin, intravenous rather than oral administration might improve the drug penetration into the plasma and cerebrospinal fluid.

Penetration of other standard drugs for tuberculosis, isoniazid and pyrazinamide, into the cerebrospinal fluid is good and they are important for treatment of tuberculous meningitis. By contrast, neither ethambutol nor streptomycin, both commonly used drugs, show good penetration into the cerebrospinal fluid in the absence of inflammation. Fluoroquinolones might be good alternatives to these drugs. Of the fluoroquinolones, moxifloxacin has the highest activity against Mycobacterium tuberculosis in vitro and in mice.11, 12 The combination of rifampicin and moxifloxacin has been assessed in clinical trials with the aim of shortening the treatment in patients with tuberculosis.13, 14, 15 Moxifloxacin has a good penetration in cerebrospinal fluid¹⁶ and in patients with tuberculous meningitis.¹⁷ Of note, data from in-vitro studies and those in animals suggest that the optimum dose of moxifloxacin for tuberculosis could be higher than the standard dose of 400 mg once daily18, 19 particularly because rifampicin lowers the plasma concentrations of moxifloxacin by about 30%.²⁰

Therefore, in view of the high morbidity and mortality associated with tuberculous meningitis, we have assessed intensified treatment regimens containing high-dose rifampicin and moxifloxacin.