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.