first-line drugs (although not in all countries). Standard treatment for children is usually effective with better treatment success rates compared with adults [38]. Home-based treatment is always preferred, if possible. Treatment of drug-susceptible TB The WHO currently recommends two shorter 4-month regimens for children and adolescents with drug-susceptible TB (DS-TB) [27]. The first regimen was informed by the SHINE trial (Shorter treatment for minimal tuberculosis (TB) in children), which showed that for children with nonsevere TB using standard first-line drugs, a 4-month regimen was noninferior to a standard 6-month regimen. The 4-month regimen, using rifampicin, isoniazid and pyrazinamide, with or without ethambutol, is indicated for children aged 3 months to 16 years with nonsevere TB [27, 39]. The second regimen was informed by another trial in individuals aged ⩾12 years, which compared a rifapentine- and moxifloxacin-containing 4-month regimen with a standard 6-month regimen for both severe and nonsevere TB, finding that the shorter regimen was noninferior [39, 40]. Neither of these regimens can be used in those with EPTB, such as TBM, disseminated TB, osteoarticular TB or abdominal TB [27, 40]. Although TB treatment outcomes in children are excellent, optimal anti-TB drug dosing is required for certain subgroups at risk of subtherapeutic drug concentrations [41]. Suboptimal exposures have been observed in smaller children and in those weighing ⩾25 kg (who receive mg·kg−1 doses as for adults) when dosed according to the current WHO paediatric dosing recommendation using fixed-dose combination drugs [42]. Children living with HIV and those suffering from severe acute malnutrition may also experience suboptimal exposures [41–43]. Treatment of TBM The evidence for TBM treatment is limited and is mostly extrapolated from PTB. Treatment outcomes for children with TBM are often poor, with high mortality and neurological disabilities, especially when disease is advanced [44–46]. The WHO recommends a 2-month regimen of rifampicin, isoniazid, pyrazinamide and ethambutol, followed by 10 months of rifampicin and isoniazid at standard doses [27]. Pharmacokinetic modelling suggests that higher rifampicin doses are required in children to achieve adequate rifampicin exposures [47], and in a paediatric TBM trial that recruited 37 children, neurocognitive outcomes in children receiving high-dose rifampicin (30 mg·kg−1) were better than those who received the standard dose [48]. A pharmacokinetic and safety study of children with PTB (Opti-Rif trial: Pharmacokinetics and safety of high-dose rifampicin in children with TB) demonstrated that rifampicin dosages of up to 60–75 mg·kg−1 were needed to achieve target exposure and were safe. These higher dosages could contribute to improving TBM outcomes in children [49]. An alternative treatment regimen of 6 months using higher-dose rifampicin and isoniazid given with pyrazinamide and ethionamide has been conditionally recommended by the WHO, based on observational cohorts from South Africa [50]. Ethionamide is preferred as the fourth drug because of better cerebrospinal fluid penetration compared with ethambutol [51]. The SURE trial (Short intensive treatment for children with tuberculous meningitis), which is currently underway, will assess the efficacy of a modified shorter intensified 6-month regimen with optimised doses of rifampicin, isoniazid and pyrazinamide with levofloxacin in place of ethionamide (ISRCTN identifier ISRCTN40829906). The neurological sequelae observed in TBM are attributed to the pathological impact of the host immune response and hypercoagulability [52]. Standard adjunctive therapy with corticosteroids for TBM reduces mortality risk in patients without HIV infection but does not prevent 224 https://doi.org/10.1183/2312508X.10025322 ERS MONOGRAPH |THE CHALLENGE OF TB IN THE 21ST CENTURY