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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.

Publication ,  Journal Article
Farrington, N; McEntee, L; Johnson, A; Unsworth, J; Darlow, C; Jimenez-Valverde, A; Hornik, C; Greenberg, R; Schwartz, J; Das, S; Hope, W
Published in: Antimicrob Agents Chemother
April 19, 2022

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.

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Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 19, 2022

Volume

66

Issue

4

Start / End Page

e0218121

Location

United States

Related Subject Headings

  • Tobramycin
  • Rabbits
  • Pseudomonas aeruginosa
  • Neonatal Sepsis
  • Microbiology
  • Microbial Sensitivity Tests
  • Meropenem
  • Meningoencephalitis
  • Drug Resistance, Bacterial
  • Anti-Bacterial Agents
 

Citation

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Chicago
ICMJE
MLA
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Farrington, N., McEntee, L., Johnson, A., Unsworth, J., Darlow, C., Jimenez-Valverde, A., … Hope, W. (2022). Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance. Antimicrob Agents Chemother, 66(4), e0218121. https://doi.org/10.1128/aac.02181-21
Farrington, Nicola, Laura McEntee, Adam Johnson, Jennifer Unsworth, Christopher Darlow, Ana Jimenez-Valverde, Christoph Hornik, et al. “Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.Antimicrob Agents Chemother 66, no. 4 (April 19, 2022): e0218121. https://doi.org/10.1128/aac.02181-21.
Farrington N, McEntee L, Johnson A, Unsworth J, Darlow C, Jimenez-Valverde A, et al. Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0218121.
Farrington, Nicola, et al. “Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance.Antimicrob Agents Chemother, vol. 66, no. 4, Apr. 2022, p. e0218121. Pubmed, doi:10.1128/aac.02181-21.
Farrington N, McEntee L, Johnson A, Unsworth J, Darlow C, Jimenez-Valverde A, Hornik C, Greenberg R, Schwartz J, Das S, Hope W. Pharmacodynamics of Meropenem and Tobramycin for Neonatal Meningoencephalitis: Novel Approaches to Facilitate the Development of New Agents to Address the Challenge of Antimicrobial Resistance. Antimicrob Agents Chemother. 2022 Apr 19;66(4):e0218121.

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 19, 2022

Volume

66

Issue

4

Start / End Page

e0218121

Location

United States

Related Subject Headings

  • Tobramycin
  • Rabbits
  • Pseudomonas aeruginosa
  • Neonatal Sepsis
  • Microbiology
  • Microbial Sensitivity Tests
  • Meropenem
  • Meningoencephalitis
  • Drug Resistance, Bacterial
  • Anti-Bacterial Agents