Project Details
Early Career
Status: Funded - Closed
Optimal Antibiotic Dosing for Pediatric Bacterial Meningitis
Porter Hunt, PhD
Summary
BACKGROUND: Bacterial meningitis can be cured if sufficient antibiotic rapidly reaches the cerebrospinal fluid (CSF). Yet, the extent to which most drugs reach the CSF of children is unknown because serial lumbar punctures to collect CSF are invasive and rarely advisable. GAP: Vancomycin (VAN) and cefepime (CPM) are commonly used to treat meningitis, but CSF exposure and optimal dosing are currently unknown. Incorrect dosing may result in dangerous toxicities, resistant pathogens, and treatment failure. HYPOTHESIS: I hypothesize that physiologically based pharmacokinetic (PBPK) models and rich pharmacokinetic data from the CSF of children with external ventricular drains (EVDs) will enable optimized VAN and CPM dosing for children with bacterial meningitis. METHODS: I will conduct a single-center, observational CSF PK study in children with EVDs who are receiving VAN or CPM per standard of care. I will use data from this study to parameterize CSF compartments of PBPK models to predict VAN and CPM exposure in CSF and to optimize antibiotic dosing. RESULTS: The vancomycin PBPK model predicts both plasma and CSF concentrations well. Predicted CSF VAN concentrations remain low and relatively constant over the dosing interval, with plasma:CSF AUC ratios of about 10. These low CSF vancomycin exposures suggest that plasma vancomycin exposures should remain as high as safely possible to treat CNS infections in most children. IMPACT: This study will provide optimal, model-informed VAN and CPM dosing to enable best outcomes for children with bacterial meningitis. Furthermore, the research platform created by this study will facilitate optimal dosing strategies for additional central nervous system drugs in children.
Publications:
Hunt, J. P.; McKnite, A. M.; Green, D. J.; Whelan, A. J.; Imburgia, C. E.; Watt, K. M. Interaction of Ceftazidime and Clindamycin with Extracorporeal Life Support. Journal of Infection and Chemotherapy 2023. https://doi.org/10.1016/j.jiac.2023.08.007.
Honeycutt, C. C.; McDaniel C. G.; McKnite, A. M.; Hunt, J. P.; Whelan, A. J.; Green, D. J.; Watt, K. M. Meropenem Extraction by Ex Vivo Extracorporeal Life Support Circuits. Journal of ExtraCorporeal Technology 2023.
Hunt, J. P.; Dubinsky, S.; McKnite, A. M.; Cheung K. W. K.; van Groen, B. D.; Giacomini, K. M.; de Wildt, S.N.; Edginton, A. N.; Watt, K. M. Maximum Likelihood Estimation of Renal Transporter Ontogeny Profiles for Pediatric PBPK Modeling. CPT: Pharmacometrics & Systems Pharmacology 2023. https://doi.org/10.1002/psp4.13102.
Dubinsky, S.; Watt, K. M.; Imburgia, C. E.; McKnite, A. M.; Hunt, J. P.; Rice, C.; Rower, J. E.; Edginton, A. N. Anakinra Removal by Continuous Renal Replacement Therapy: An Ex Vivo Analysis. Critical Care Explorations 2023. DOI: 10.1097/CCE.0000000000001010.