Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance

Neonatal sepsis is an underrecognized burden on health care systems throughout the world. Antimicrobial drug resistance (AMR) is increasingly prevalent and compromises the use of currently recommended first-line agents. The development of new antimicrobial agents for neonates and children is mandated by regulatory agencies. However, there remains uncertainty about suitable development pathways, especially because of the propensity of premature babies to develop meningoencephalitis as a complication of neonatal sepsis and difficulties studying this disease in clinical settings. We developed a new platform and approach to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis using Pseudomonas aeruginosa as the challenge organism. We defined the pharmacodynamics of meropenem and tobramycin in these models. The percentage of partitioning of meropenem and tobramycin into the cerebrospinal fluid was comparable at 14.3 and 13.7%, respectively. Despite this similarity, there were striking differences in their pharmacodynamics. Meropenem resulted in bactericidal activity in both the cerebrospinal fluid and cerebrum, whereas tobramycin had minimal antibacterial activity. A hollow fiber infection model (HFIM) using neonatal CSF concentration time profiles yielded pharmacodynamics comparable to those observed in the rabbit model. These new experimental models can be used to estimate the pharmacodynamics of currently licensed agents and those in development and their potential efficacy for neonatal bacterial meningoencephalitis.

Automated summary

Neonatal sepsis is a burden on healthcare systems worldwide, and the increasing prevalence of antimicrobial drug resistance compromises the use of recommended first-line agents. However, the development of new antimicrobial agents for neonatal bacterial meningoencephalitis is still uncertain due to the challenges of studying this disease in clinical settings, particularly in premature infants. In this study, a new platform and approach were developed to accelerate the development of antimicrobial agents for neonatal bacterial meningoencephalitis, using Pseudomonas aeruginosa as the challenge organism. The pharmacodynamics of meropenem and tobramycin were defined in these models, and the results showed significant differences in their antibacterial activities. The developed experimental models can be used to estimate the pharmacodynamics and potential efficacy of currently licensed agents and those in development for neonatal bacterial meningoencephalitis.