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Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Apr 19; Vol. 66 (4), pp. e0218121. Date of Electronic Publication: 2022 Mar 22. - Publication Year :
- 2022
-
Abstract
- 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.
- Subjects :
- Animals
Anti-Bacterial Agents pharmacology
Anti-Bacterial Agents therapeutic use
Drug Resistance, Bacterial
Meropenem pharmacology
Microbial Sensitivity Tests
Pseudomonas aeruginosa
Rabbits
Tobramycin pharmacology
Tobramycin therapeutic use
Meningoencephalitis drug therapy
Neonatal Sepsis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 66
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 35315689
- Full Text :
- https://doi.org/10.1128/aac.02181-21