JAC Advance Access published online on January 6, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg042
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Department of Microbiology,
Toho University School of Medicine, Omori-nishi 5-21-16, Ota-ku,
Tokyo 143-8540; Antimicrobial
Program, Discovery Research Laboratories, Shionogi & Co.
Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan
* Corresponding author. E-mail: masakatsu.tsuji{at}shionogi.co.jp.
Received 29 July 2002
; revised 28 August 2002
; accepted 10 October 2002
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.
Keywords: lipopolysaccharide, antibiotics, carbapenems,
computerized-simulation system
Antimicrobial-induced release of endotoxin from Pseudomonas aeruginosa: comparison of in
vitro and animal models
2 Antimicrobial
Program, Discovery Research Laboratories, Shionogi & Co.
Ltd, 3-1-1 Futaba-cho, Toyonaka, Osaka 561-0825, Japan
3 Department of Microbiology,
Toho University School of Medicine, Omori-nishi 5-21-16, Ota-ku,
Tokyo 143-8540
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