Pharmacokinetic study of pleural fluid penetration of carbapenem antibiotic agents in chemical pleurisy

Summary Study objectives We investigated pleural fluid penetration of carbapenem antibiotic agents [imipenem (IPM), panipenem (PAPM), meropenem (MEPM), and biapenem (BIPM)] using an experimental rabbit pleuritis model to clarify the usefulness of the carbapenem agents for the treatment of bacterial pleurisy or pyothorax. Measurements and results Serum and pleural fluid specimens were serially collected at 5, 10, 15, 30, 60, 90, 120, 180, 240, 300, and 360min after antibiotic administration for measurement of antibiotic levels. We investigated each agent alone as well as drug solutions containing each agent and a dehydropeptidase-I-specific inhibitor, cilastatin (CS), to remove the influence of dehydropeptidase-I-related hydrolysis. Groups of animals \( n = 3 \) received each carbapenem agent with or without CS. Serum and pleural fluid antibiotic levels were measured by high-performance liquid chromatography (HPLC). Because C max is not useful for evaluating the antimicrobial effects of carbapenem antibiotic agents due to their dose-dependent antimicrobial activity, we also investigated the AUC, which is correlated with the total drug levels in vivo. Among the drug solutions containing CS, MEPM/CS had the highest pleural fluid AUC 0–360 (1594.8±510.3μgmin/ml), and the highest pleural fluid AUC 0–360 /plasma AUC 0–360 ratio (0.79±0.04). BIPM/CS had the highest plasma AUC 0–360 (3040.1±1525.9μgmin/ml). In pleural fluid AUC 0–360 /plasma AUC 0–360 ratio MEPM/CS was significantly higher than those for the remaining agents. In pleural fluid AUC 0–360 and plasma AUC 0–360 there were no significant differences among these mixed solutions. Conclusions MEPM had the most favorable pleural fluid penetration. Pleural fluid penetration should be examined in infection models and in clinical trials.