title: beta-Lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime.
abstract: The relative effects of two beta-lactam antibiotics, penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime, upon in vitro induction of lipopolysaccharide (LPS) release were investigated against smooth- and rough-LPS mutant isolates of Pseudomonas aeruginosa. Free LPS liberated from both isolates are 10- to 40-fold higher for ceftazidime-exposed cultures than control or imipenem-treated cultures after 4-8 h at 35 degrees C despite equivalent MICs. Lethalities of filtrates in mice correlated with in vitro endotoxin assay results. Sub-MIC levels of ceftazidime induced filamentation and LPS release without significant bacterial lysis. Amounts released not only matched the quantities achieved at inhibitory concentrations (e.g., 1-, 2-, and 50-times MIC) of ceftazidime but significantly exceeded levels of LPS liberated by exposure to imipenem, less than or equal to 100 times its MIC. Sub-MIC levels of imipenem released relatively small amounts of free LPS while reducing colony counts approximately 2 logs more than equivalent amounts of ceftazidime after 2 h. Data suggest that ceftazidime-induced filamentation releases larger quantities of bioreactive LPS than nonfilamentous fast-lysing imipenem.
authors.affiliation: Merck Institute for Therapeutic Research, Rahway, New Jersey 07065.
authors.forename: J J
authors.initials: JJ
authors.lastname: Jackson
authors.forename: H
authors.initials: H
authors.lastname: Kropp
mesh_terms: D000818:Animals; D001426:Bacterial Proteins; D002352:Carrier Proteins; D002442:Ceftazidime / Q000378:metabolism / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology; D005260:Female; D006602:Hexosyltransferases / Q000378:metabolism*; D015378:Imipenem / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000187:drug effects / Q000378:metabolism* / Q000633:toxicity; D051379:Mice; D008826:Microbial Sensitivity Tests; D009097:Multienzyme Complexes / Q000378:metabolism*; D002267:Muramoylpentapeptide Carboxypeptidase; D009154:Mutation; D046915:Penicillin-Binding Proteins; D010458:Peptidyl Transferases / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D009097:Multienzyme Complexes; D046915:Penicillin-Binding Proteins; D015378:Imipenem; D004492:Edetic Acid; D002442:Ceftazidime; D010458:Peptidyl Transferases; D006602:Hexosyltransferases; D002267:Muramoylpentapeptide Carboxypeptidase