A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with Gram-negative urosepsis

Abstract

Evidence from in vitro experiments and animal and human studies indicate that antibiotic therapy may induce the release of endotoxin from the outer membrane of Gram-negative bacteria. Antibiotics that bind preferentially to penicillin-binding protein-2 (PBP-2) —such as imipenem — are associated with little release of endotoxin, while antibiotics that preferentially bind to PBP-3 — such as ceftazidime — are associated with far greater release of endotoxin. We conducted a randomized, multicenter, double-blind study comparing imipenem to ceftazidime in patients with urinary tract infections caused by Gram-negative bacilli associated with signs and symptoms of systemic inflammation. A total of 33 patients were randomized to receive either imipenem (n = 14) or ceftazidime (n = 19) for initial treatment for urosepsis. No differences in plasma endotoxin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) or urine endotoxin, IL-6 or IL-8 levels were found between the two treatment groups within the first 8 h after antibiotic administration. We conclude that, if differences exist with respect to endotoxin release by these two antimicrobial agents, these differences are not readily demonstrable in this clinical study with carefully defined patients with Gram-negative urinary tract infections.

References

Dofferhoff AS , Nijland JH , de Vries Hospers HG , Mulder PO , Weits J. , Bom VJ Effects of different types and combinations of antimicrobial agents on endotoxin release from Gram-negative bacteria: an in vitro and in vivo study. Scand J Infect Dis 1991; 23: 745—754.

Jackson JJ , Kropp H. β-Lactam antibiotic-induced release of free endotoxin: in vitro comparison of penicillin-binding protein (PBP) 2-specific imipenem and PBP 3-specific ceftazidime. J Infect Dis 1992; 165: 1033—1041.

Dofferhoff AS , Esselink MT , de Vries Hospers HG et al. The release of endotoxin from antibiotic-treated Escherichia coli and the production of tumour necrosis factor by human monocytes. J Antimicrob Chemother 1993; 31: 373—384.

Arditi M. , Kabat W. , Yogev R. Antibiotic-induced bacterial killing stimulates tumor necrosis factor-alpha release in whole blood. J Infect Dis 1993; 167: 240—244.

Mustafa MM , Mertsola J. , Ramilo O. , Saez Llorens X , Risser RC , McCracken Ghj. Increased endotoxin and interleukin-1 beta concentrations in cerebrospinal fluid of infants with coliform meningitis and ventriculitis associated with intraventricular gentamicin therapy. J Infect Dis 1989; 160: 891—895.

Mustafa MM , Ramilo O. , Mertsola J. et al. Modulation of inflammation and cachectin activity in relation to treatment of experimental Hemophilus influenzae type b meningitis. J Infect Dis 1989; 160: 818—825.

Odio CM , Faingezicht I. , Paris M. et al. The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis. N Engl J Med 1991; 324: 1525—1531.

Bucklin SE , Morrison DC Differences in therapeutic efficacy among cell wall-active antibiotics in a mouse model of Gram-negative sepsis. J Infect Dis 1995; 172: 1519—1527.

Prins JM , van Agtmael MA , Kuijper EJ , van Deventer SJ , Speelman P. Antibiotic-induced endotoxin release in patients with Gram-negative urosepsis: a double-blind study comparing imipenem and ceftazidime. J Infect Dis 1995; 172: 886—891.

10.

Suffredini AF , Fromm RE , Parker MM et al. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med 1989; 321: 280—287.

11.

Knaus WA , Draper EA , Wagner DP , Zimmerman JE APACHE II: a severity of disease classification system. Crit Care Med 1985; 13: 818—829.

12.

Simpson AJ , Opal SM , Prins JM , White J. , Palardy J. Differential antibiotic-induced endotoxin release in acute septicemic melioidosis . Abstracts of the 38th ICAAC 1998 ; 597.

13.

Maury E. , Barakett V. , Blanchard H. et al. Circulating endotoxin during initial antibiotic treatment of severe gram-negative bacteremic infections. J Infect Dis 1998; 178: 270—273.