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

Inclusion criteria:

1. Age ≥ 15 years
2. TBM defined as "definite", "probable" or "possible"
3. Signed Informed Consent

• Definite TBM = at least one of the following criteria: acid-fast bacilli seen inCSF 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 orcerebral imaging criteria).
• Possible TBM = total modified Marais 6-11 when neuroimaging is available, or 6-9when neuroimaging is not available.

Exclusion criteria:

• > 5 days of TB treatment
• 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.
• Clinical evidence of liver failure or decompensated cirrhosis.
• 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 NeuropathyScore (BPNS).
• Documented M. tuberculosis resistance to rifampicin.
• Positive gram-stain, bacterial culture or cryptococcal antigen in the Cerebral SpinalFluid.
• Evidence of active bleeding (hemoptysis, gastrointestinal bleeding, hematuria,intracranial bleeding).
• Inability to collect Cerebral Spinal Fluid, except for patients with confirmedtuberculosis (by rapid molecular test or culture) from another biological sample andclinical and/or CT scan evidence of meningitis.
• Major surgery within the last two weeks prior to inclusion.
• Ongoing chronic aspirin treatment (eg for cardiovascular risk).
• Current use of drugs contraindicated with study drugs and that cannot be safelystopped (see Appendix 1: Drugs contra-indicated with study drugs).
• 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.
• Any reason which at the discretion of the investigator would compromise safety andcooperation in the trial.