Children: WHO recommendations on longer MDR-TB regimens apply to children as well as adults. Most medicines in longer regimens have been part of MDR-TB regimens for many years, in similar combinations, for both adults and children. The WHO consolidated guidelines recommend the use of bedaquiline in children aged 6 years and above¹⁵, and delamanid in children aged 3 years and above (1). Delamanid exposure is achieved with the dispersible 25 mg tablet tested in the trial in children aged 3–5 years; the preparation is also available for children under compassionate use. Bioavailability of delamanid may be altered when the 50 mg tablet is split, crushed or dissolved. There are also concerns with some oral medicines (e.g. delamanid, linezolid and ethionamide) that the adult tablet may shatter if attempts are made to split it, and its contents are exceedingly bitter and unpalatable. The tablets are normally susceptible to oxidation and heat; thus, retaining pill fragments for use at any time other than the time of administration is likely to result in the delivery of lower than expected active compound and unspecified oxidation byproducts. The avoidance of an injectablecontaining regimen is particularly desirable in children. Shortening the total treatment duration to less than 18 months may be considered in the case of children without extensive disease.
Severe forms of extrapulmonary TB and TB meningitis: The WHO recommendations on longer MDR-TB regimens apply also to patients with extrapulmonary disease. Adjustments may be required, depending on the specific location of disease. Treatment of MDR/RR-TB meningitis is best guided by DST of the infecting strain and by the ability of TB medicines to cross the blood–brain barrier. Group A fluoroquinolones (e.g. levofloxacin, moxifloxacin and linezolid) have good penetration across the blood–brain barrier (i.e. the CNS), as do ethionamide (or prothionamide), cycloserine (or terizidone), and imipenem-cilastatin (87–89). Seizures may be more common in children with meningitis treated with imipenem, and meropenem is preferred for cases of TB meningitis and in children (90–92). Highdose isoniazid and pyrazinamide can also reach therapeutic levels in the CSF, and may be useful if the strains are susceptible. PAS and ethambutol do not penetrate the CNS well and should not be counted on as effective agents for MDR-TB meningitis. Amikacin and streptomycin only penetrate the CNS in the presence of meningeal inflammation. There are few data on the CNS penetration of clofazimine, bedaquiline or delamanid.
Pregnancy: Knowledge about the safety of bedaquiline and delamanid in pregnancy and during breastfeeding is still sparse. However, new evidence from an observational study in South Africa included information on 58 mothers who received bedaquiline during pregnancy. The results of this study indicated that fetal exposure to bedaquiline in utero was associated with low birth weight (<2500 g), with no other significant differences in infant outcomes, pregnancy outcomes or maternal treatment outcomes, including weight gain in the infants until 1 year of age. It is recommended that, in pregnancy, a longer regimen be individualized to include components with an established safety profile. The outcomes of treatment and pregnancy, and postpartum surveillance for congenital anomalies, should be documented to help inform future recommendations for MDR-TB treatment during pregnancy (1, 93). Amikacin, streptomycin, prothionamide and ethionamide are usually contraindicated during pregnancy.
HIV infection: The composition of an MDR-TB treatment regimen does not usually differ substantially for people living with HIV. Some drug–drug interactions may be avoided with careful attention (e.g. bedaquiline and efavirenz, or bedaquiline and ritonavir) (see Table 6.2) (52–54).
¹⁴ Data used for analysis to support these recommendations were from patients who did not receive two or more group A medicines. However, a small proportion of patients included in the analysis were on all-oral regimens, and in these patients the same optimal treatment duration was observed using identical parameters.
¹⁵ Based on the results of an RCT conducted by the manufacturer, the US FDA has extended approval for the use of bedaquiline for children aged 5 years and above (32). However, these data have not yet been assessed by WHO.