Cerebrospinal fluid concentrations of antituberculosis agents in adults and children

Abstract

Tuberculous meningitis (TBM) causes a devastating morbidity and mortality in adults and children. Even in patients presenting at an early stage of disease, deterioration may occur despite apparently adequate therapy. The literature relating to cerebrospinal fluid penetration of antituberculosis agents is reviewed. Amongst the essential antituberculosis agents isoniazid has the best CSF pharmacokinetics reaching peak concentrations (C(max)) only slightly less than in blood. Pyrazinamide also has good CSF penetration and in children receiving dosages of 40 mg/kg the CSF C(max) exceeds the proposed minimal inhibitory concentration of 20 μg/ml. Streptomycin other aminoglycosides and ethambutol have poor CSF penetration and cannot be agents of first choice for TBM treatment. Rifampicin at dosages used in adults seldom reaches CSF concentrations exceeding MIC, but does so more frequently in children when dosages of up to 20 mg/kg are used. The non-essential agents ethionamide, the fluoroquinolones, with the exception of ciprofloxacin, and cycloserine (terizadone) have relatively good CSF penetration and are recommended for TBM treatment. The dosages of the essential agents recommended for the treatment of TBM in children are INH 10 mg/kg (range 6-15 mg/kg bodyweight), rifampicin 15 mg/kg (range 10-20 mg/kg), pyrazinamide 35 mg/kg (range 30-40 mg/kg), ethambutol 20 mg/kg (range 15-25 mg/kg) and streptomycin 15 mg/kg (range 12-18 mg/kg). Amongst second-line agents ofloxacin, levofloxacin and moxifloxacin should be used in dosages of 15-20 mg/kg, ethionamide 20 mg/kg in a single dose, if tolerated, and for cycloserine (terizadone) 15 mg/kg. Antituberculous chemotherapy should be started as soon as the diagnosis of TBM is considered.