Yasmine White

Background: Tuberculosis (TB) is the leading single bacterial cause of death worldwide. In 2023, approximately 400 000 people developed multidrug- and rifampicin-resistant TB (MDR/RR-TB), which complicates treatment. TB preventive treatment (TPT) is a critical strategy to prevent the progression from TB infection to TB disease among those at risk. In February 2024, based on data from 2 randomized controlled trials, levofloxacin was strongly recommended by the World Health Organization (WHO) as a TPT option in people of all ages exposed to MDR/RR-TB. There are uncertainties about the optimal dosing of levofloxacin in children and adolescents when using dispersible and solid formulations. We used pharmacokinetic modeling and simulations to determine the best dosing strategy in people aged up to 19 years for both formulations of levofloxacin. Methods: A previously developed population pharmacokinetic model of levofloxacin in children (0.2–16.8 years) was used and applied to new WHO harmonized weight bands. Simulations were conducted using demographic data from countries with the highest incidence of RR- or MDR-TB. Two currently available levofloxacin formulations (100 mg pediatric, dispersible tablets and 250 mg solid tablets) were considered. Results: A dosing regimen by weight band was developed for levofloxacin when used as TPT in people aged 0–19 years exposed to MDR/RR-TB. Doses correspond to 8–33 mg/kg for the 100 mg dispersible tablets and 10–42 mg/kg for 250 mg solid tablets. These doses achieve adequate adult target exposure levels. Conclusions: Pragmatic, weight-band dosing strategies help simplify the administration of MDR/RR-TB TPT and have been included in WHO guidance.

BACKGROUND: Hypoxic-ischemic brain injury/encephalopathy affects about 1.15 million neonates per year, 96% of whom are born in low- and middle-income countries. Therapeutic hypothermia is not effective in this setting, possibly because injury occurs significantly before birth. Here, we studied the pharmacokinetics, safety, and efficacy of perinatal azithromycin administration in near-term lambs following global ischemic injury to support earlier treatment approaches. METHODS: Ewes and their lambs of both sexes (n=34, 141–143 days) were randomly assigned to receive azithromycin or placebo before delivery as well as postnatally. Lambs were subjected to severe global hypoxia-ischemia utilizing an acute umbilical cord occlusion model. Outcomes were assessed over a 6-day period. RESULTS: While maternal azithromycin exhibited relatively low placental transfer, azithromycin-treated lambs recovered spontaneous circulation faster following the initiation of cardiopulmonary resuscitation and were extubated sooner. Additionally, peri- and postnatal azithromycin administration was well tolerated, demonstrating a 77-hour plasma elimination half-life, as well as significant accumulation in the brain and other tissues. Azithromycin administration resulted in a systemic immunomodulatory effect, demonstrated by reductions in proinflammatory IL-6 (interleukin-6) levels. Treated lambs exhibited a trend toward improved neurodevelopmental outcomes while histological analysis revealed that azithromycin supported white matter preservation and attenuated inflammation in the cingulate and parasagittal cortex. CONCLUSIONS: Perinatal azithromycin administration enhances neonatal resuscitation, attenuates neuroinflammation, and supports limited improvement of select histological outcomes in an ovine model of hypoxic-ischemic brain injury/encephalopathy.

Originally approved by the U.S. Food and Drug Administration (FDA) for its antihistamine properties, clemastine can also promote white matter integrity and has shown promise in the treatment of demyelinating diseases such as multiple sclerosis. Here, we conducted an in-depth analysis of the feasibility, safety, and neuroprotective efficacy of clemastine administration in near-term lambs (n = 25, 141–143 days) following a global ischemic insult induced via an umbilical cord occlusion (UCO) model. Lambs were randomly assigned to receive clemastine or placebo postnatally, and outcomes were assessed over a six-day period. Clemastine administration was well tolerated. While treated lambs demonstrated improvements in inflammatory scores, their neurodevelopmental outcomes were unchanged.