Intensified antibiotic treatment of tuberculosis meningitis

ABSTRACT

Introduction

Meningitis is the most severe manifestation of tuberculosis, resulting in death or disability in over 50% of those affected, with even higher morbidity and mortality among patients with HIV or drug resistance. Antimicrobial treatment of Tuberculous meningitis (TBM) is similar to treatment of pulmonary tuberculosis, although some drugs show poor central nervous system penetration. Therefore, intensification of antibiotic treatment may improve TBM treatment outcomes.

Areas covered

In this review, we address three main areas: available data for old and new anti-tuberculous agents; intensified treatment in specific patient groups like HIV co-infection, drug-resistance, and children; and optimal research strategies.

Expert commentary

There is good evidence from preclinical, clinical, and modeling studies to support the use of high-dose rifampicin in TBM, likely to be at least 30 mg/kg. Higher dose isoniazid could be beneficial, especially in rapid acetylators. The role of other first and second line drugs is unclear, but observational data suggest that linezolid, which has good brain penetration, may be beneficial. We advocate the use of molecular pharmacological approaches, physiologically based pharmacokinetic modeling and pharmacokinetic-pharmacodynamic studies to define optimal regimens to be tested in clinical trials. Exciting data from recent studies hold promise for improved regimens and better clinical outcomes in future.

KEYWORDS:

• Tuberculous meningitis
• TB meningitis
• antituberculous therapy
• intensified

Declaration of interest

FV Creswell is supported through a Wellcome Trust Clinical PhD Fellowship (210772/Z/18/Z) and is an honorary fellow of the MUII-plus which is supported through the DELTAS Africa Initiative (Grant no. 107743). K Dooley is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD/NIH: R01HD074944). FV Cresswell, L te Brake, R Ruslami, R Aarnoutse and R van Crevel will receive support from Medical Research Council UK for a phase III RCT “High Dose Oral Rifampicin to Improve Survival from Adult TB Meningitis - (HARVEST) Trial” to be conducted in Uganda, South Africa and Indonesia (MR/S004963/1).The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplemental data

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Additional information

Funding

This paper was not funded.