Cerebrospinal Fluid Drug Concentrations and the Treatment of Tuberculous Meningitis

Abstract

Tuberculous meningitis is a very serious form of tuberculosis. In the absence of randomized controlled trials of alternative treatment regimens, its management depends on employing potent drugs that penetrate well into the cerebrospinal fluid (CSF). The penetration of isoniazid, rifampin, and streptomycin into the CSF of 27 Chinese patients was studied using fluorimetric and microbiologic procedures. Isoniazid rapidly diffused into the CSF, peak concentrations in excess of 3 mg/L, or over 30 times its minimal inhibitory concentration (MIC) against Mycobacterium tuberculosis being attained within 4 hr. In contrast, rifampin and streptomycin penetrated very slowly across the meninges, and CSF levels only slightly in excess of their MICs against M. tuberculosis were achieved. The penetration of the drugs into the CSF correlated poorly with differences in their partitioning between octanol/water and cyclohexane/water but could be predicted using a simple model based on their renal clearance rates and plasma protein binding. It is recommended that patients with tuberculous meningitis should be treated for at least 9 months with a combination of isoniazid, rifampin, and pyrazinamide, which may be supplemented in the first 2 mo with streptomycin.

Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects

“…Some have advocated for longer treatment (64,66), while others have supported a short course of 6 to 9 months (50, 74, 156, 228). Both isoniazid and pyrazinamide pass easily across the BBB (54,55,84,155), and isoniazid remains the backbone of TBM treatment. Rifampin and ethambutol have significantly less penetration into the CNS (54, 84), although they still play an important role in the treatment of CNS tuberculosis (139).…”

Tuberculosis of Central Nervous System

“…Rifampicin's contribution to the treatment of TBM is relatively modest and significantly less than that in pulmonary disease. 61 The failure to demonstrate a beneficial contribution of PZA to the treatment of TBM despite excellent CSF penetration could be due to long treatment duration, which essentially precluded chances of demonstrating its sterilizing capability. There is no conclusive evidence to demonstrate the improvement in the outcome with the use of pyrazinamide.…”

Meningitis tuberculosa: claves para su diagnóstico y propuestas terapéuticas

“…En la elección del esquema anti-TBC se debe preferir fármacos con buena penetración al SNC (Tabla 9). Isoniacida, que posee un excelente efecto bactericida, junto con pirazinamida y etionamida, son fármacos de libre paso por la barrera hemato-encefálica; a consecuencia de ello, su concentración en el LCR es prácticamente similar a la sanguínea [45][46][47] . Otros fármacos tienen penetración intermedia a SNC, como moxifl oxacina y levofl oxacina 48,49 .…”

“…Otros fármacos tienen penetración intermedia a SNC, como moxifl oxacina y levofl oxacina 48,49 . Rifampicina, por otro lado, tiene baja penetración a SNC, el paso de este antimicrobiano ocurre en fase temprana de la MTBC y se asocia a la infl amación inicial meníngea siendo su concentración en LCR < 10% respecto de la sérica 46 ; sin embargo, ya que la fracción libre no ligada a proteínas que corresponde al 20% de la rifampicina total 50 es la que actúa sobre M. tuberculosis, esta condición de baja penetración es relativa desde el punto de vista terapéu-tico. Además, dado que más de la mitad de los casos de MTBC tienen una TBC diseminada o de otra ubicación no se puede prescindir de este fármaco en el esquema inicial 47 .…”

“…Además, dado que más de la mitad de los casos de MTBC tienen una TBC diseminada o de otra ubicación no se puede prescindir de este fármaco en el esquema inicial 47 . Etambutol y los aminoglucosidos, incluyendo estreptomicina, también penetran en fases tempranas infl amatorias del tratamiento; la concentración en el LCR de este último fármaco representa ~20% de su fracción sérica 46,47 de modo que su acción es marginal y posiblemente debe replantearse la indicación de estreptomicina dentro del esquema de las guías chilenas para MTBC 51 .…”