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Sequential in vitro effects and analysis using simulators of in vivo blood and urinary antimicrobial concentrations on the endotoxin release from bacteria exposed to carbapenem antibiotics


Endotoxin release fromPseudomonas aeruginosa exposed to an antimicrobial agent was examined using cytotoxicity assays and simulators of blood and urinary antimicrobial concentrations. The antibiotics included imipenem (IPM), panipenem (PAPM), meropenem (MEPM), biapenem (BIPM), BO-2727, and ceftazidime (CAZ). Washed bacterial cell suspensions were directly exposed to various concentrations of the drugs, and measurements of the endotoxin levels and sequential morphological changes were observed using scanning electron microscopy (SEM). Also, using a simulator of blood and urine concentrations, changes in viable cell counts and endotoxin levels were measured using PAO-1, a standardP. aeruginosa strain, and 2 clinical isolates. Compared with the control endotoxin level of PAO-1, the endotoxin level increased over time after CAZ administration using subMIC concentrations, but were lower when treated with the other drugs. At concentrations greater than the MIC, endotoxin levels increased after treatment with MEPM, BO-2727, and CAZ. These endotoxin levels were different by 1 hour after administration, and continued to increase for 6 hours after administration. Bacteria which released large amounts of endotoxin showed a tendency to elongate their bodies. Simulating a clinical situation using MEPM, BO-2727, and CAZ, the endotoxin levels occasionally exceeded pretreatment levels immediately after administration in both the blood and urine. Bacteria releasing increased amounts of endotoxin tended to elongate their bodies as an effect of the administered drug. Blood and urinary endotoxin levels may increase due to the administration of an antibiotic, which suggests that such increases may cause shock or pyrexia at the time of drug administration.

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Matsui, T., Nakano, Y., Higuchi, A. et al. Sequential in vitro effects and analysis using simulators of in vivo blood and urinary antimicrobial concentrations on the endotoxin release from bacteria exposed to carbapenem antibiotics. J Infect Chemother 3, 139–145 (1997).

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Key words

  • endotoxin
  • Pseudomonas aeruginosa
  • carbapenems
  • drug autosimulator