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


RESULTS
Serum and pleural fluid specimens were serially collected at 5, 10, 15, 30, 60, 90, 120, 180, 240, 300, and 360 min 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 Cmax 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 AUC0-360 (1594.8+/-510.3 microg min/ml), and the highest pleural fluid AUC0-360/plasma AUC0-360 ratio (0.79+/-0.04). BIPM/CS had the highest plasma AUC0-360 (3040.1+/-1525.9 microg min/ml). In pleural fluid AUC0-360/plasma AUC0-360 ratio MEPM/CS was significantly higher than those for the remaining agents. In pleural fluid AUC0-360 and plasma AUC0-360 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.
Department of Internal Medicine and Bioregulation, Nagoya City University Graduate School of Medical Sciences, Mizuho-ku, Nagoya 467-8602, Japan. toniwa@med.nagoya-cu.ac.jp
Toshiaki
T
Niwa
Atsushi
A
Nakamura
Takashi
T
Kato
Takeo
T
Kutsuna
Ken
K
Katou
Hiroki
H
Morita
Yasuhiro
Y
Kojima
Makoto
M
Itoh
D000818:Animals; D019540:Area Under Curve; D001826:Body Fluids / Q000378:metabolism*; D015780:Carbapenems / Q000493:pharmacokinetics*; D016724:Empyema, Pleural / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D035422:Pleural Cavity / Q000378:metabolism*; D010998:Pleurisy / Q000188:drug therapy* / Q000378:metabolism; D011817:Rabbits
D015780:Carbapenems