Table 2. A scoring system to select drugs for inclusion in experimental regimens.

	Anti-TB activity	Clinical efficacy data in TBM	Site of disease exposure	Safety/tolerability	Drug-drug interactions	Access
3	Potent bactericidal sterilising activity in vivo		Potentially therapeutic concentrations in brain parenchyma from animal models and/or non-invasive human studies at human-equivalent doses
2	Moderate in vivo activity, mainly related to EBA	Benefit in RCT	Detectable concentrations in brain parenchyma but possibly below therapeutic thresholds	Well- tolerated at optimised doses with low toxicity potential		Affordable and available in target countries, oral administration
1	Weak in vivo activity at tolerable doses	Benefit in non- randomised studies, sub- groups in RCT, or case reports/series	Detectable in CSF only or not yet studied in brain parenchyma	Generally well-tolerated but may have treatment- limiting AE	No clinically relevant DDI	Affordable and available in target countries, IV administration
0	In vitro data only	No data from trials or case reports	Insufficient / no data to judge	Poorly tolerated but acceptable safety profile	Clinically important DDI	Expensive and/or not registered in target countries
No go	No in vivo activity (EBA) attolerable doses	RCT data shows no effect	Undetectable in brain parenchyma at human- equivalent doses	Poorly tolerated and/or frequent treatment- limiting AE	Precludes use in TBM regimens	Not currently manufactured

Individual drugs are ranked by adding points from each parameter; the higher number of points the higher the priority for inclusion in experimental TBM regimens. Extra weighting is applied to anti-TB activity and site of disease exposure by creating categories for higher point allocation. Lower weighting is applied to clinical efficacy in TBM because new agents are less likely to have been evaluated in clinical trials. Similarly, safety/tolerability is weighted less because drug efficacy is prioritised for this condition with high early mortality. Drug-drug interactions and access are assigned fewer available points because of limited categories. AE=adverse events. DDI=drug-drug interactions. EBA=early bactericidal activity. IV=intravenous. RCT=randomised controlled trial. TBM=tuberculous meningitis.