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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

Abstract

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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References

  1. Cohen J, McConnel JS. Release of endotoxin from bacteria exposed to ciprofloxacin and its prevention with polymyxin B. Eur J Clin Microbiol 1986;5:13–17.

    PubMed  CAS  Article  Google Scholar 

  2. Hurley JC, Louis WJ, Tosolini FA, Carlin JB. Antibiotic-induced release of endotoxin in chronically bacteriuric patients. Antimicrob Agents Chemother 1991;35:2388–2394.

    PubMed  CAS  Google Scholar 

  3. Rokke O, Revhaug A, Osterud B, Giercksky KE. Increased plasma levels of endotoxin and corresponding changes in circulatory performance in a porcine sepsis model: the effect of antibiotic administration. Prog Clin Biol Res 1988;272:247–262.

    PubMed  CAS  Google Scholar 

  4. Goto H, Nakamura S. Liberation of endotoxin from Escherichia coli by addition of antibiotics. Jpn J Exp Med 1980;50:35–43.

    PubMed  CAS  Google Scholar 

  5. Shenep JL, Barton RP, Mogan KA. Role of antibiotic class in the rate of liberation of endotoxin during therapy for experimental gram-negative bacterial sepsis. J Infect Dis 1985;151:1012–1018.

    PubMed  CAS  Google Scholar 

  6. Shenep JL, Mogan KA. Kinetics of endotoxin release during antibiotic therapy for experimental gram-negative bacterial sepsis. J Infect Dis 1984;150:380–388.

    PubMed  CAS  Google Scholar 

  7. Ohya S and Sekine N. Bacterial activity of cefpodoxime evaluated with an in vitro pharmacokinetic simulation system. Annu Rep Sankyo Res Lab 1990;42:75–86.

    CAS  Google Scholar 

  8. Nishimura M, Kumamoto Y, Shibuya A, Hirose T, Tsukamoto T. An in vitro study on treatment of complicated cystitis using an automatic simulator. JJA Inf D 1990;64:1004–1012.

    CAS  Google Scholar 

  9. Jackson JJ, Kropp H. Beta-lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP3-specific ceftazidime. J Infect Dis 1992;165:1033–1041.

    PubMed  CAS  Google Scholar 

  10. Dofferhoff ASM, Nijland JH, de Vries Hospers HG, Mulder POM, Weits J, Bom VJJ. Effects of different types and combinations of antimicrobial agents on endotoxin release from gram-negative bacteria: in vitro and in vivo. J Infect Dis 1991;23:745–754.

    CAS  Article  Google Scholar 

  11. Yokota T, et al. Imipenem (MK-087): its in vitro antibiotic activity, inactivation of beta-lactamase, affinity to penicillin-binding proteins (PBP) of bacteria, and stability to homogenates of the kidney and brain of mice. Chemotherapy 1985;33(suppl 4):43–53.

    CAS  Google Scholar 

  12. Yokota T, Sekiguchi R. Ceftazidime (SN401): the penetrability through the outer membrane and the affinity for penicillin-binding proteins of gram-negative bacteria. Chemotherapy 1981;31 (suppl 3):17–21.

    Google Scholar 

  13. Matsuda K, et al. Comparative effect of imipenem and other antibiotics on the release of endotoxin from gram-negative bacteria. Chemotherapy 1993;41:345–350.

    CAS  Google Scholar 

  14. Yokota T, Kanda K and Suzuki E. Panipenem, its in vitro antibacterial activity, binding affinity to bacterial PBPs, inactivation of beta-lactamases, stability to DHP-I, and synergy in bactericidal effect with complement or mouse cultured macrophages. Chemotherapy 1991;39(suppl 43): 14–23.

    CAS  Google Scholar 

  15. Kuwahara K, Yokota T. A new carbapenem, biapenem: its in vitro activity and biological affinity to bacterial PBPs, and stability to dehydropeptidase-I. Chemotherapy 1994;42(suppl 4):26–36.

    CAS  Google Scholar 

  16. Yokota T, Suzuki E and Arai K. Meropenem: its in vitro antibacterial activity and biological stability. Chemotherapy 1992;40(suppl 1):30–40.

    CAS  Google Scholar 

  17. Miyara T, Ishimine T, Saito A. Antibiotic-induced endotoxin release fromPseudomonas aeruginosa: effects of imipenem and ceftazidime. Chemotherapy 1994;43:351–356.

    Google Scholar 

  18. Buijs J, Dofferhoff ASM. Antibiotic-induced endotoxin release: type, dose, and dosing schedule. Abstracts of 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, p 147.

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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). https://doi.org/10.1007/BF02491503

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  • DOI: https://doi.org/10.1007/BF02491503

Key words

  • endotoxin
  • Pseudomonas aeruginosa
  • carbapenems
  • drug autosimulator