Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets.
Antimicrob Agents Chemother
; 55(7): 3406-12, 2011 Jul.
Article
em En
| MEDLINE
| ID: mdl-21576431
ABSTRACT
Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Líquido da Lavagem Broncoalveolar
/
Tienamicinas
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Modelos Teóricos
Tipo de estudo:
Health_economic_evaluation
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Antimicrob Agents Chemother
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Estados Unidos