Aside from bedaquiline, the medicines that compose the 9-month all-oral regimen have been part of MDR/RR-TB regimens for many years, in similar combinations, for both adults and children. The associated adverse drug reactions have been widely described and the drug dosages established (Annex). Child-friendly formulations are now available for all second-line drugs and should be provided to children whenever possible. When these are not available, practical instructions for use of adult formulations for administration are available, so lack of formulation should not be a hindrance to treating children of all ages. This must be addressed as a priority by treatment programmes that include management of children with MDR/RR-TB. Now that dosing and safety data are available for bedaquiline in children aged below 6 years, the removal of the age restriction for the use of bedaquiline means that children of all ages with MDR/RR-TB may be offered the 9-month all-oral regimen if they meet the eligibility criteria (47). Extent of disease is defined slightly differently for children than for adults, and most children with TB have less severe forms of the disease than adults. The term “adults” in this chapter refers to individuals aged 15 years and older and “children” refers to those aged below 15 years; thus, the adult population includes older adolescents.
Evidence from the SHINE trial (Shorter Treatment for Minimal Tuberculosis in Children), which was the first and only large Phase 3 trial to evaluate the duration of TB treatment in children with nonsevere drug-susceptible TB (DS-TB), suggests that pulmonary TB disease should be classified as severe (which may include extensive, advanced and complicated disease) or nonsevere in children (47). Despite the lack of comparable data among children with MDR/RR-TB disease specifically, the same definitions for severity of disease are likely to be appropriate when considering the use of a shorter regimen for children with MDR/RR-TB. Nonsevere disease in children is defined as peripheral lymph node TB; intrathoracic lymph node TB without airway obstruction; uncomplicated TB pleural effusion (without empyema or pneumothorax); or paucibacillary, noncavitary disease confined to one lobe of the lungs and without a miliary pattern (evaluated on chest X-ray) (47).
Bacteriological confirmation of MDR/RR-TB disease in younger children is relatively uncommon, and the decision to treat for MDR/RR-TB may rely on clinical signs and symptoms, radiological findings and significant exposure to someone with microbiologically confirmed MDR/RR-TB. In children without microbiological confirmation of TB disease or rifampicin resistance, the choice of regimen relies partly on the drug-resistance pattern of the isolate obtained from the most likely index case. Although only six children aged below 14 years were included in the analysis of the shorter regimen dataset from South Africa, the evidence supporting the use of this regimen in adults may be extrapolated to children, provided the implementation considerations are followed. The benefits of a shorter regimen for a child with MDR/RR-TB should be weighed against the high pill burden and the difficulties of administering each of the seven drugs in this regimen, particularly if child-friendly formulations of the drugs are not available. Bedaquiline is relatively well tolerated and easy to administer to children; adultformulation bedaquiline tablets suspended in water have been shown to have the same bioavailability as tablets swallowed whole (Annex).
For most second-line TB drugs, adverse effects appear to be less frequent in children than in adults; however, close monitoring is still warranted in children, regardless of the regimen. Before a shorter regimen containing linezolid is offered to a child, the clinician must consider the feasibility of close monitoring, particularly for haematological side-effects, which requires repeated blood draws for at least the first 2 months of treatment. Visual acuity and colour vision are more difficult to monitor in younger children than in older children and adults. Ethionamide might be considered a safer alternative for children in some settings, but this should be balanced against the lower efficacy of the drug compared with linezolid, and the poor gastrointestinal tolerability and need to monitor for hypothyroidism.