The time has come: sparing injectables in paediatric MDR-TB.

Proponents of critical thinking recount this fable: a daughter asks, “Mother, why do you cut the end off the holiday ham?” Her mother answers, “Because that’s the way Grandma always did it.” The daughter, an inquisitive sort, then asks her grandmother, “Grandma, why do you cut the end off of the holiday ham?” Her grandmother replies, “Because my pan is too small.” In matters of medicine, progress demands that clinicians and investigators continuously challenge practices that are more aligned with convention than with strong scientific rationale. Nowhere is this more imperative than in cases where treatment dictated by long-standing practice carries with it a high prevalence of permanent harm. And when irreversible toxicities affect children, they cast a long and terrible shadow, because children are affected for their entire lives. We argue that injectables should no longer be the standard of care for paediatric multidrug-resistant (MDR) tuberculosis, which is resistant to isoniazid and rifampicin. First, injectable anti-tuberculosis drugs are unacceptably toxic. Amikacin, kanamycin, and capreomycin are part of the backbone of current WHO recommended MDR tuberculosis regimens. Every medical student learns that the efficacy of aminoglycosides is concentration-dependent; what is less emphasised is that aspects of their toxicity are timedependent. Elegant studies in guinea pigs established that the cumulative area under the concentration–time curve of amikacin in perilymph strongly predicts ototoxicity. Animal studies show that once aminoglycosides have penetrated the inner ear, they take up to 38 days to clear. Emerging data in adults with MDR tuberculosis indicate a strong association of cumulative amikacin exposure with hearing loss. Considering the recommended treatment duration of injectables for MDR tuberculosis (≥4 months), this exposure is vastly higher than that experienced, for example, by neonates treated for sepsis with 2 weeks of gentamicin, where risk–benefit considerations are clearly different. Irreversible toxicities from injectables, such as hearing loss or vestibular damage, occur in at least 25% of children treated with these drugs. Impaired hearing, in turn, adversely affects neurocognitive and language development, psychosocial functioning, and school perform ance. Some of this damage can be arrested—but not reversed—if the injectable is stopped at the earliest signs of toxicity, if there is careful monitoring. However, this type of monitoring is resource intensive, infrequently available in settings where MDR tuberculosis is common, and challenging in young children. Daily intramuscular injections are programmatically challenging and painful, causing prolonged distress for children and their caregivers. Second, the evidence that injectables provide meaningful microbiological activity to MDR tuberculosis treat ment regimens is, at best, mixed. Given the high risk of serious permanent toxicity, the threshold for benefit should be high. However, in clinical studies of early bactericidal activity, amikacin as monotherapy at doses of 5–15 mg/kg per day had no measurable effect on sputum bacterial load, by contrast with all other tuberculosis drugs in use. Notably, there have been no randomised trials of injectablecontaining versus injectable-sparing regimens. A metaanalysis of adults with MDR tuberculosis showed that adults with tuberculosis resistant to aminoglycosides do not have worse outcomes than those without aminoglycoside resistance. In a meta-analysis of children programmatically treated for MDR tuberculosis, 119 of 842 children were treated without an injectable. Of these, 41 (72%) of 57 with culture-confirmed MDR tuberculosis and 58 (94%) of 62 with probable MDR tuberculosis had successful treatment outcomes. Indeed, paediatric tuberculosis generally has a low organism burden and better observed treatment response than adult tuberculosis; this paucibacillary nature makes childhood tuberculosis in some sense easier to treat from an efficacy perspective, and this paves the way for evaluating and implementing injectable-sparing treatment approaches. In 2016, WHO guidance, for the first time, states that paediatric MDR tuberculosis can be treated without injectables in many cases, based on the high risk of toxicity and favourable treatment outcomes. Third, though in the past there were no good alternatives to injectables for paediatric MDR tuberculosis, drugs are now available with better activity against the disease. Linezolid and clofazamine are recommended in the current WHO guidance for paediatric MDR tuberculosis; emerging paediatric pharmacokinetic and safety data will further inform their use in children. Delamanid has potent sterilising activity in pre-clinical studies, in addition to achieving highly favourable microbiological outcomes in phase 2 studies in adults. Delamanid also has a favourable safety profile when given to children in phase 1–2 clinical trials, with no cases of QTc prolongation greater than Ga ro /P ha ni e/ S cie nc e Ph ot o Li br ar y