title: Antimicrobial-induced release of endotoxin from Pseudomonas aeruginosa: comparison of in vitro and animal models.
abstract: This study was designed to compare the amount of lipopolysaccharide (LPS) induced following exposure to doripenem, imipenem/cilastatin, meropenem and ceftazidime in an in vitro computerized-simulation system (simulating the drug concentration pattern in human plasma after administration of a drug), with that induced by exposure to a drug at a constant concentration. When Pseudomonas aeruginosa was exposed to the test drugs at constant concentrations of 0.1 x, 1 x and 10 x MIC, differential relative induction of LPS was observed as follows: ceftazidime > meropenem, doripenem > imipenem/cilastatin. In the computerized-simulation system, however, the amount of LPS induced by treatment with ceftazidime (1 g) was similar to that by doripenem (250 mg), imipenem/cilastatin (500 mg) and meropenem (500 mg). In a rat model of P. aeruginosa bacteraemia, rates of eradication of bacteria from the blood were similar for carbapenems and ceftazidime except for 1 h post-administration of ceftazidime. Serum LPS levels induced by treatment with doripenem (30 mg/kg), imipenem/cilastatin (30 mg/kg), meropenem/cilastatin (30 mg/kg) and ceftazidime (50 mg/kg) were almost the same at 3 h after administration of each drug. Data obtained from computerized-simulation systems might be more applicable than those obtained from organisms exposed to constant drug concentrations for estimating the amount of LPS in the plasma of human patients infected with Gram-negative bacteria.
authors.affiliation: Department of Microbiology, Toho University School of Medicine, Omori-nishi 5-21-16, Ota-ku, Tokyo 143-8540, Japan. masakatsu.tsuji@shionogi.co.jp
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Tsuji
authors.forename: Hayato
authors.initials: H
authors.lastname: Matsuda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Miwa
authors.forename: Shuichi
authors.initials: S
authors.lastname: Miyazaki
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology; D002442:Ceftazidime / Q000493:pharmacokinetics / Q000494:pharmacology; D002511:Cephalosporins / Q000494:pharmacology; D015169:Colony Count, Microbial; D003198:Computer Simulation; D004731:Endotoxins / Q000378:metabolism*; D005260:Female; D008070:Lipopolysaccharides / Q000096:biosynthesis / Q000302:isolation & purification; D008858:Microscopy, Phase-Contrast; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D002511:Cephalosporins; D004731:Endotoxins; D008070:Lipopolysaccharides; D002442:Ceftazidime