Linezolid is increasingly important for multidrug-resistant tuberculosis (MDR-TB) treatment. However, among children with MDR-TB, there are no linezolid pharmacokinetic data, and its adverse effects have not yet been prospectively described. We characterised the pharmacokinetics, safety, and optimal dose of linezolid in children treated for MDR-TB. Children routinely treated for MDR-TB in 2 observational studies (2011–2015, 2016–2018) conducted at a single site in Cape Town, South Africa, underwent intensive pharmacokinetic sampling after either a single dose or multiple doses of linezolid (at steady state). Linezolid pharmacokinetic parameters, and their relationships with covariates of interest, were described using nonlinear mixed-effects modelling. Children receiving long-term linezolid as a component of their routine treatment had regular clinical and laboratory monitoring. Adverse events were assessed for severity and attribution to linezolid. The final population pharmacokinetic model was used to derive optimal weight-banded doses resulting in exposures in children approximating those in adults receiving once-daily linezolid 600 mg. Forty-eight children were included (mean age 5.9 years; range 0.6 to 15.3); 31 received a single dose of linezolid, and 17 received multiple doses. The final pharmacokinetic model consisted of a one-compartment model characterised by clearance (CL) and volume (V) parameters that included allometric scaling to account for weight; no other evaluated covariates contributed to the model. Linezolid exposures in this population were higher compared to exposures in adults who had received a 600 mg once-daily dose. Consequently simulated, weight-banded once-daily optimal doses for children were lower than those currently used for most weight bands. Ten of 17 children who were followed long term had a linezolid-related adverse event, including 5 with a grade 3 or 4 event, all anaemia. Adverse events resulted in linezolid dose reductions in 4, temporary interruptions in 5, and permanent discontinuation in 4 children. Limitations of the study include the lack of very young children (none below 6 months of age), the limited number who were HIV infected, and the modest number of children contributing to long-term safety data. Linezolid-related adverse effects were frequent and occasionally severe. Careful linezolid safety monitoring is required. Compared to doses currently used in children in many settings for MDR-TB treatment, lower doses may approximate current adult target exposures, might result in fewer adverse events, and should therefore be evaluated.

Moxifloxacin is currently recommended at a dose of 7.5-10 mg/kg for children with multidrug-resistant (MDR) tuberculosis, but pharmacokinetic and long-term safety data of moxifloxacin in children with tuberculosis are lacking. An area under the curve (AUC) of 40-60 µg × h/mL following an oral moxifloxacin dose of 400 mg has been reported in adults. In a prospective pharmacokinetic and safety study, children 7-15 years of age routinely receiving moxifloxacin 10 mg/kg daily as part of multidrug treatment for MDR tuberculosis in Cape Town, South Africa, for at least 2 weeks, underwent intensive pharmacokinetic sampling (predose and 1, 2, 4, 8, and either 6 or 11 hours) and were followed for safety. Assays were performed using liquid chromatography-tandem mass spectrometry, and pharmacokinetic measures calculated using noncompartmental analysis. Twenty-three children were included (median age, 11.1 years; interquartile range [IQR], 9.2-12.0 years); 6 of 23 (26.1%) were human immunodeficiency virus (HIV)-infected. The median maximum serum concentration (Cmax), area under the curve from 0-8 hours (AUC0-8), time until Cmax (Tmax), and half-life for moxifloxacin were 3.08 (IQR, 2.85-3.82) µg/mL, 17.24 (IQR, 14.47-21.99) µg × h/mL, 2.0 (IQR, 1.0-8.0) h, and 4.14 (IQR, 3.45-6.11), respectively. Three children, all HIV-infected, were underweight for age. AUC0-8 was reduced by 6.85 µg × h/mL (95% confidence interval, -11.15 to -2.56) in HIV-infected children. Tmax was shorter with crushed vs whole tablets (P = .047). Except in 1 child with hepatotoxicity, all adverse effects were mild and nonpersistent. Mean corrected QT interval was 403 (standard deviation, 30) ms, and no prolongation >450 ms occurred. Children 7-15 years of age receiving moxifloxacin 10 mg/kg/day as part of MDR tuberculosis treatment have low serum concentrations compared with adults receiving 400 mg moxifloxacin daily. Higher moxifloxacin dosages may be required in children. Moxifloxacin was well tolerated in children treated for MDR tuberculosis.

Multidrug-resistant (MDR) tuberculosis (TB) presents a challenge for global TB control. Treating individuals with MDR-TB infection to prevent progression to disease could be an effective public health strategy. Young children are at high risk of developing TB disease following infection and are commonly infected by an adult in their household. Identifying young children with household exposure to MDR-TB and providing them with MDR-TB preventive therapy could reduce the risk of disease progression. To date, no trials of MDR-TB preventive therapy have been completed and World Health Organization guidelines suggest close observation with no active treatment. The tuberculosis child multidrug-resistant preventive therapy (TB-CHAMP) trial is a phase III cluster randomised placebo-controlled trial to assess the efficacy of levofloxacin in young child contacts of MDR-TB cases. The trial is taking place at three sites in South Africa where adults with MDR-TB are identified. If a child aged < 5 years lives in their household, we assess the adult index case, screen all household members for TB disease and evaluate any child aged < 5 years for trial eligibility. Eligible children are randomised by household to receive daily levofloxacin (15–20 mg/kg) or matching placebo for six months. Children are closely monitored for disease development, drug tolerability and adverse events. The primary endpoint is incident TB disease or TB death by one year after recruitment. We will enrol 1556 children from approximately 778 households with an average of two eligible children per household. Recruitment will run for 18–24 months with all children followed for 18 months after treatment. Qualitative and health economic evaluations are embedded in the trial. If the TB-CHAMP trial demonstrates that levofloxacin is effective in preventing TB disease in young children who have been exposed to MDR-TB and that it is safe, well tolerated, acceptable and cost-effective, we would expect that that this intervention would rapidly transfer into policy. ISRCTN Registry, ISRCTN92634082 . Registered on 31 March 2016.

With growing attention globally to the childhood tuberculosis epidemic after decades of neglect, and with the burden of severe acute malnutrition (SAM) remaining unacceptably high worldwide, the co...

Limited data on fluoroquinolone pharmacokinetics and cardiac effects in children exist. Among 22 children receiving drug-resistant tuberculosis prophylaxis or treatment, serum concentrations following oral doses of levofloxacin (15 mg/kg of body weight) and ofloxacin (20 mg/kg) were lower than those expected from existing pediatric data, possibly due to differences in the formulations (crushed tablets). Drug exposures were lower than those in adults following standard doses and below the proposed pharmacodynamic targets, likely due to more rapid elimination in children. No QT prolongation was observed.