Intensified Tuberculosis Treatment to Reduce the Mortality of Patients With Tuberculous Meningitis

Prior treatment

• Major surgery within the last two weeks prior to inclusion.
• Current use of drugs contraindicated with study drugs and that cannot be safely stopped (see Appendix 1: Drugs contra-indicated with study drugs).

Other illness

• Clinical evidence of liver failure or decompensated cirrhosis.
• Documented M. tuberculosis resistance to rifampicin.
• Evidence of active bleeding (hemoptysis, gastrointestinal bleeding, hematuria, intracranial bleeding).
• Inability to collect Cerebral Spinal Fluid, except for patients with confirmed tuberculosis (by rapid molecular test or culture) from another biological sample and clinical and/or CT scan evidence of meningitis.
• In available history from patients:
  • Evidence of past intracranial bleeding.
  • Evidence of past of peptic ulceration.
  • Evidence of recent (\< 3 month) gastrointestinal bleeding.
  • Known hypersensitivity contraindicating the use of study drugs .
  • Evidence of porphyria.
  • Evidence of hyperuricemia or gout.

Lab values

• Renal failure (eGFR\<30 ml/min, CKD-EPI formula).
• Neutrophil count \< 0.6 x 109/L.
• Hemoglobin concentration \< 8 g/dL.
• Total bilirubin \> 2.6 times the Upper Limit of Normal
• Platelet count \< 50 x 109/L.
• ALT \> 5 times the Upper Limit of Normal.

Other

• \> 5 days of TB treatment
• For women: more than 17 weeks pregnancy or breastfeeding.
• For patients without decrease level of consciousness (Glasgow Coma Scale = 15): Peripheral neuropathy scoring Grade 3 or above on the Brief Peripheral Neuropathy Score (BPNS).
• Positive gram-stain, bacterial culture or cryptococcal antigen in the Cerebral Spinal Fluid.
• Ongoing chronic aspirin treatment (eg for cardiovascular risk).
• Any reason which at the discretion of the investigator would compromise safety and cooperation in the trial.

• Age ≥ 15 years
• TBM defined as "definite", "probable" or "possible"
• Signed Informed Consent
  • Definite TBM = at least one of the following criteria: acid-fast bacilli seen in CSF microscopy, positive CSF M. tuberculosis culture, or positive CSF M. tuberculosis commercial nucleic acid amplification test.
  • Probable TBM = total modified Marais score ≥12 when neuroimaging is available, or ≥10 when neuroimaging is not available (at least 2 points should come from CSF or cerebral imaging criteria).
  • Possible TBM = total modified Marais 6-11 when neuroimaging is available, or 6-9 when neuroimaging is not available.