Antimicrobial Drug Penetration Is Enhanced by Lung Tissue Inflammation and Injury

Abstract

Rationale: Pneumonia is a frequent and feared complication in intubated critically ill patients. Tissue concentrations of antimicrobial drugs need to be sufficiently high to treat the infection and also prevent development of bacterial resistance. It is uncertain whether pulmonary inflammation and injury affect antimicrobial drug penetration into lung tissue.Objectives: To determine and compare tissue and BAL fluid concentrations of ceftaroline fosamil and linezolid in a model of unilateral acute lung injury in pigs and to evaluate whether dose adjustment is necessary to reach sufficient antimicrobial concentrations in injured lung tissue.Methods: After induction of unilateral acute lung injury, ceftaroline fosamil and linezolid were administered intravenously. Drug concentrations were measured in lung tissue through microdialysis and in blood and BAL fluid samples during the following 8 hours. The primary endpoint was the tissue concentration area under the concentration curve in the first 8 hours (AUC_{0-8 h}) of the two antimicrobial drugs.Measurements and Main Results: In 10 pigs, antimicrobial drug concentrations were higher in inflamed and injured lung tissue compared with those in uninflamed and uninjured lung tissue (median ceftaroline fosamil AUC_{0-8 h} [and interquartile range] = 26.7 mg ⋅ h ⋅ L^-1 [19.7-39.0] vs. 16.0 mg ⋅ h ⋅ L^-1 [13.6-19.9], P = 0.02; median linezolid AUC_{0-8 h} 76.0 mg ⋅ h ⋅ L^-1 [68.1-96.0] vs. 54.6 mg ⋅ h ⋅ L-¹ [42.7-60.9], P = 0.01), resulting in a longer time above the minimal inhibitory concentration and in higher peak concentrations and dialysate/plasma ratios. Penetration into BAL fluid was excellent for both antimicrobials, but without left-to-right differences (ceftaroline fosamil, P = 0.78; linezolid, P = 1.00).Conclusions: Tissue penetration of two commonly used antimicrobial drugs for pneumonia is enhanced by early lung tissue inflammation and injury, resulting in longer times above the minimal inhibitory concentration. Thus, lung tissue inflammation ameliorates antimicrobial drug penetration during the acute phase.

Keywords: acute lung injury; animal model; antibacterial agents.