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Antimicrobial Agents and Chemotherapy, April 1998, p. 739-743, Vol. 42, No. 4
Department of Infectious Diseases, Leiden
University Medical Centre, 2300 RC Leiden, The Netherlands
Received 17 June 1997/Returned for modification 11 November
1997/Accepted 14 January 1998
It has been suggested that the antibiotic-induced release of
lipopolysaccharide (LPS) is an important cause of the development of
septic shock in patients treated for severe infections caused by
gram-negative bacteria.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Antibiotic-Induced Lipopolysaccharide (LPS) Release
from Salmonella typhi: Delay between Killing by Ceftazidime
and Imipenem and Release of LPS
-Lactam antibiotics change the integrity of
the bacterial cell envelope by binding to penicillin-binding proteins
(PBP) in the membrane and thus may affect the amount of LPS that is
released and the kinetics of that release. In this respect, ceftazidime
at intermediate concentrations binds with a high affinity to PBP 3 and
PBP 1a and thus can induce filament formation in addition to killing,
whereas imipenem preferentially binds to PBP 2 and PBP 1b, leading to
spheroplast formation and rapid cell lysis. We investigated the effects
of these antibiotics on the killing and the release of the
radioactively labelled LPS of Salmonella typhi Ty 21A. A
mathematical model was developed to calculate the delay between
bacterial killing and LPS release, designated the lag time. At
antibiotic concentrations inducing equal killing, the amount of LPS
released was the same for both antibiotics. Only after 6 h of
incubation at antibiotic concentrations above 0.5 µg/ml, the amount
of 3H-LPS released was slightly higher (~1.2-fold) in
incubations with ceftazidime than in those with imipenem, and the
maximum releases of the total label were 33.2% ± 0.89% and 27.1% ± 0.45%, respectively. Despite the clear concentration-dependent effect on the bacterial killing and subsequent LPS release, the lag time was
independent of the antibiotic concentration. For ceftazidime as well as
imipenem the lag time amounted to approximately 60 min. In conclusion,
our findings imply that the mechanism of antibiotic-induced LPS release
is independent of the PBP affinities for these
-lactam antibiotics.
Furthermore, once the organism is killed by either imipenem or
ceftazidime, the rate of LPS release from S. typhi does not
differ according to the antibiotic with which the organism is killed,
and there is little difference in the relative amount of LPS released.
*
Corresponding author. Mailing address: Department of
Infectious Diseases, Leiden University Medical Centre, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31-71-5262613. Fax:
31-71-5266758. E-mail:
J.Thompson{at}thuisnet.leidenuniv.nl.
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