Cerebrospinal fluid concentrations of antituberculosis agents in adults and children

doi:10.1016/j.tube.2010.07.002

Tuberculosis

Volume 90, Issue 5, September 2010, Pages 279-292

https://doi.org/10.1016/j.tube.2010.07.002 Get rights and content

Summary

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.

Section snippets

Introduction and methodology

Tuberculous meningitis (TBM) is the most destructive complication of tuberculosis causing considerable mortality and morbidity despite the availability of antituberculosis agents that successfully treat pulmonary and other forms of tuberculosis. Although the stage of disease when treatment is commenced is a critical determinant of outcome, even patients at an early disease stage may deteriorate, despite apparently appropriate management.¹ It is, thus, essential that optimal use be made of

Isoniazid

INH has a low MIC in liquid media of 0.02–0.04 μg/ml,⁴ excellent pharmacokinetics and is easily absorbed and distributed throughout the body and has the highest early bactericidal activity (EBA) of all current antituberculosis agents⁵ and, for this reason, is the best agent to protect companion drugs against resistance⁶; conversely it is usually the first agent to which a population of Mycobacterium tuberculosis will become resistant.

Clinical experience in pulmonary tuberculosis patients

Discussion

During the last two decades, based on considerable experience with pulmonary tuberculosis, the chemotherapy of all forms of tuberculosis has become standardized to a six-month regimen incorporating the “essential” drugs INH, RMP, PZA, EMB for two months followed by INH and RMP for four months or INH and EMB for six months. In the 2003 Guidelines for National Programmes WHO recommended this regimen for TBM, but suggested that EMB should be replaced by SM.⁶⁷ None the less this regimen has not

Acknowledgements

I am greatly indebted to the librarians of the Medical Library of the Faculty of Health Sciences, Stellenbosch University for their assistance in finding many papers that were not available in South Africa. PRD is supported by the National Research Foundation of South Africa.

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ReviewCerebrospinal fluid concentrations of antituberculosis agents in adults and children

Summary

Section snippets

Introduction and methodology

Isoniazid

Discussion

Acknowledgements

Tuberculosis

Lancet

Dis Chest

Chest

Tubercle Lung Dis

Clin Microbiol Infect

Tubercle

Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults

N Eng J Med

Pharmacokinetic aspects of the treatment of infections of the central nervous system

J Antimicrob Chemothr

Pharmacokinetic optimization of the treatment of bacterial central nervous system infections

Clin Pharmacokin

In vitro activities of fourteen antimicrobial agents against drug susceptible and resistant clinical isolates of Mycobacterium tuberculosis and comparative intracellular activities against virulent H37 Rv strain in human macrophages

Curr Microbiol

Role of individual drugs in the chemotherapy of tuberculosis

Int J Tuberc Lung Dis

Clinical implications of isoniazid blood levels in pulmonary tuberculosis

N Eng J Med

The influence of human N-acetyltransfearase genotype on the early bactericidal activity of isoniazid

Clin Infect Dis

The influence of dose and N-acetyltransferase genotype and phenotype on the pharmacokinetics and pharmacodynamics of isoniazid

Eur J Clin Pharmacol

A concurrent comparison of isoniazid plus PAS with three regimens of isoniazid alone in the domiciliary treatment of pulmonary tuberculosis in South India

Bull Wld Hlth Org

Therapeutic drug monitoring: principles and applications in mycobacterial infections

Drug Ther

The absorption, distribution, excretion, and short-term toxicity of isonicotinic acid hydrazide (nydrazid) in man

Am Rev Tuberc

Distribution and excretion of radioactive isoniazid in tuberculosis patients

JAMA

Concentrations of active isoniazid in serum and cerebrospinal fluid of patients with tuberculosis treated with isoniazid

Pediatrics

Pyrazinamide and other drugs in tuberculosis meningitis

Lancet

Kinetics of isoniazid transfer into cerebrospinal fluid in patients with tuberculous meningitis

J Korean Med Sci

Effect of steroids on cerebrospinal fluid penetration of antituberculosis drugs in tuberculosis meningitis

Clin Pharmacol Ther

Cerebrospinal fluid isoniazid concentrations in children with tuberculous meningitis: the influence of dosage and acetylation status

Pediatrics

Cerebrospinal fluid drug concentrations and the treatment of tuberculosis meningitis

Am Rev Respir Dis

Le concentrazioni dell’isoniazide nel sangue e nel liquor in rapporto a varie dosi orali

Minerva Med

The genetics of acetylation

Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary tuberculosis. Third report

Lancet

Controlled trial of 2, 4 & 6 months of pyrazinamide in a 6-month, 3-times weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin and pyrazinamide

Am Rev Resp Dis

Kinetic studies on rifampicin

Chemotherapy

Rifampicin: a new rifamycin

Arzneimittelforschung

Ricerche sull’assorbimento orale e sulla eliminaxione urinaria della rifampicina

Gaz Intern Med Chirurg

Binding of rifampicin by human plasma proteins

Eur J Clin Pharmacol

Comparative pharmacokinetics and pharmacodynamics of rifamycin antibacterials

Clin Pharmacokin

Roles of rifampicin in drug–drug interactions: underlying molecular mechanisms involving the nuclear pregnane X receptor

Ann Clin Microb Antimicrob

Serum rifampicin levels in patients with tuberculosis

Clin Drug Invest

U.S. Public Health Service trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis

Am Rev Respir Dis

The early bactericidal activity of drugs in patients with pulmonary tuberculosis

Am Rev Respir Dis

The early bactericidal activity of rifabutin in patients with pulmonary tuberculosis measured by sputum viable counts: a new method of drug assessment

J Antimicrob Chemother

The early bactericidal activities of rifampin and rifapentine in pulmonary tuberculosis

Am J Respir Crit Care Med

Basic concepts in the chemotherapy of tuberculosis

Review
Cerebrospinal fluid concentrations of antituberculosis agents in adults and children