Cerebrospinal Fluid Isoniazid Concentrations in Children With Tuberculous Meningitis: The Influence of Dosage and Acetylation Status

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Abstract
Cerebrospinal fluid (CSF) and plasma isoniazid (INH) concentrations were determined on 96 occasions in 38 children (median age 1.5 years) with tuberculous meningitis, and the effects of INH elimination status and test dosages of 10 mg/kg body weight and 20 mg/kg body weight was studied. Maximum cerebrospinal fluid INH concentrations were reached during the period 2 to 4 hours after dosing and cerebrospinal fluid and plasma INH concentrations did not differ significantly during this period. Cerebrospinal fluid INH concentrations following a dosage of 10 mg/kg (4.6 +/- 2.4 micrograms/mL) were, however, significantly lower than those following a dosage of 20 mg/kg (11.6 +/- 2.7 micrograms/mL). Cerebrospinal fluid INH concentrations in faster acetylators at a dosage of 10 mg/kg (3.2 +/- 1.1 micrograms/mL) were significantly lower than in slower acetylators (7.7 +/- 1.3 micrograms/mL), as was the case with a dosage of 20 mg/kg, where faster acetylators had cerebrospinal fluid INH concentrations of 10.5 +/- 2.5 micrograms/mL compared with 14.1 +/- 1.4 microgram/mL in slower acetylators. Following dosages of both 10 mg/kg and 20 mg/kg, INH concentrations in excess of the minimal inhibitory concentration for Mycobacterium tuberculosis persisted in the CSF 12 to 14 hours later. Despite the patients' being young and frequently malnourished, suffering from advanced forms of tuberculous meningitis, and receiving high dosages of INH, rifampicin, and pyrazinamide, none developed any clinical signs of hepatotoxicity and in only one child did the serum bilirubin level rise to 19 micrograms/mL.

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