Randomized Clinical Trial of High-Dose Rifampicin With or Without Levofloxacin Versus Standard of Care for Pediatric Tuberculous Meningitis: The TBM-KIDS Trial.

BACKGROUND: Pediatric tuberculous meningitis (TBM) commonly causes death or disability. In adults, high-dose rifampicin may reduce mortality. The role of fluoroquinolones remains unclear. There have been no antimicrobial treatment trials for pediatric TBM. METHODS: TBM-KIDS was a phase 2 open-label randomized trial among children with TBM in India and Malawi. Participants received isoniazid and pyrazinamide plus: (i) high-dose rifampicin (30 mg/kg) and ethambutol (R30HZE, arm 1); (ii) high-dose rifampicin and levofloxacin (R30HZL, arm 2); or (iii) standard-dose rifampicin and ethambutol (R15HZE, arm 3) for 8 weeks, followed by 10 months of standard treatment. Functional and neurocognitive outcomes were measured longitudinally using Modified Rankin Scale (MRS) and Mullen Scales of Early Learning (MSEL). RESULTS: Of 2487 children prescreened, 79 were screened and 37 enrolled. Median age was 72 months; 49%, 43%, and 8% had stage I, II, and III disease, respectively. Grade 3 or higher adverse events occurred in 58%, 55%, and 36% of children in arms 1, 2, and 3, with 1 death (arm 1) and 6 early treatment discontinuations (4 in arm 1, 1 each in arms 2 and 3). By week 8, all children recovered to MRS score of 0 or 1. Average MSEL scores were significantly better in arm 1 than arm 3 in fine motor, receptive language, and expressive language domains (P < .01). CONCLUSIONS: In a pediatric TBM trial, functional outcomes were excellent overall. The trend toward higher frequency of adverse events but better neurocognitive outcomes in children receiving high-dose rifampicin requires confirmation in a larger trial. CLINICAL TRIALS REGISTRATION: NCT02958709.

Haemophilus influenzae type b and pneumococcal conjugate vaccination coverage in children aged 2-59 months in Malawi.

High vaccination coverage with Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines is critical to addressing childhood pneumonia's high mortality. The Innovative Treatments in Pneumonia project in Lilongwe, Malawi collected Hib and pneumococcal vaccination information from children's health passports and found the majority demonstrated inadequate and inconsistent documentation. We were unable to confidently assess the impact of Hib and pneumococcal vaccination on pneumonia treatment failure in our study population. Whether it be that enrolled children did not receive age-eligible vaccines or there was poor vaccination record-keeping, we do not know. A shift to an electronic data collection system may help ensure capture of essential vaccination data and provide more accurate records of both individual and population vaccination coverage in Malawi.

Malawian children with chest-indrawing pneumonia with and without comorbidities or danger signs.

BACKGROUND: Children with comorbidities or danger signs are often excluded from trials evaluating pneumonia treatment. METHODS: We sought to investigate whether the percentage of children with chest-indrawing pneumonia cured at Day 14 was lower among those with HIV infection or exposure, malaria, moderate or severe acute malnutrition, or anemia enrolled in a prospective observational cohort study than among children without these comorbidities enrolled in a concurrent prospective randomized controlled trial evaluating duration of amoxicillin treatment in Lilongwe, Malawi. RESULTS: Children with chest-indrawing pneumonia and comorbidities but without danger signs did not have statistically significant higher treatment failure rates by Day 6 than those in the chest-indrawing pneumonia clinical trial. However, children with chest-indrawing pneumonia and HIV infection or exposure, malaria, or moderate or severe acute malnutrition had higher rates of not being clinically cured at Day 14 when compared to children without these comorbidities (adjusted differences ranging from 7.7% to 17.0%). Furthermore, among children without danger signs at enrollment, but with HIV infection or HIV exposure or moderate or severe acute malnutrition, 12.5% and 15.6% respectively were not clinically cured at Day 14 even though they were without treatment failure by Day 6. CONCLUSIONS: More intensive follow-up of children with chest-indrawing pneumonia and comorbidities who do not have danger signs may be beneficial.