The in vivo significance of antibiotic-induced endotoxin release in experimental Gram-negative sepsis

Abstract

Considerable evidence now supports the experimental findings that penicillin-binding protein (PBP)-2 specific antimicrobial agents such as imipenem generate less endotoxin than PBP-3 specific agents such as ceftazidime during the process of bacteriolysis of Gram-negative bacteria. To determine if differences in endotoxin release have pathophysiologic significance in vivo, Sprague-Dawley rats were experimentally challenged with intraperitoneal injections of virulent, serum-resistant clinical strains of the following Gram-negative bacilli: Escherichia coli 018:K1, Klebsiella pneumoniae K2, and Pseudomonas aeruginosa 12.4.4 (immuno type 6). After intravenous administration of imipenem (25 mg/kg), ceftazidime (50 mg/kg) or saline control, imipenem and ceftazidime-treated animals had rapid reductions in the quantitative level of bacteremia from all three pathogens. Peritoneal fluid samples revealed spherical forms with imipenem and long, filamentous forms with ceftazidime. Circulating plasma endotoxin levels were consistently higher ( P < 0.05) with ceftazidime than imipenem for 6 h after administration of E. coli or P. aeruginosa intraperitoneal challenge. Endotoxin levels were unchanged to slightly higher with imipenem than ceftazidime following K. pneumoniae intraperitoneal challenge. TNF levels peaked 2 h post-therapy and were consistently higher with ceftazidime-treated animals ( P < 0.05). D-galactosamine-treated animals had LD50 values that were 0.5-2 log higher ( P < 0.001) with imipenem for E. coli and P. aeruginosa but did not differ from ceftazidime in animals challenged with the K. pneumoniae strain. These results indicate that the PBP-2 specific agent imipenem led to significantly less endotoxin release than did ceftazidime with its great affinity to PBP-3. Differential endotoxin release was found after antimicrobial therapy with the E. coli and P. aeruginosa strains but not with the K. pneumoniae strain tested in this study. The clinical relevance of these findings with treatment of systemic Gram-negative infections in humans will require further clinical investigation.

Differential modulation of the induction of inflammatory mediators by antibiotics in mouse macrophages in response to viable Gram-positive and Gram-negative bacteria

“…[22][23][24][25][26][27] The data presented here have shown that both ceftazidime and aztreonam treatment markedly enhanced LPS release from E. coli in comparison to imipenem treatment. In this respect, consistent with the observations reported here, previous reports from this laboratory and others have demonstrated that ceftazidime and aztreonam have greater ability than imipenem in vitro and ex vivo to induce LPS release, as well as production of cytokines such as TNF-a and IL-6.…”

Modulation of Release of Proinflammatory Bacterial Compounds by Antibacterials: Potential Impact on Course of Inflammation and Outcome in Sepsis and Meningitis

“…In D-galactosamine-sensitized mice infected with an LD 50 dose of P. aeruginosa, treatment with imipenem decreased mortality to 0%, whereas an equivalent dose of ceftazidime increased mortality in comparison to untreated animals (90). Similarly, in sepsis models of E. coli and P. aeruginosa infection in D-galactosamine-treated rats, imipenem therapy resulted in lower levels of circulating endotoxin and TNF and reduced mortality compared to ceftazidime treatment (127).…”

“…The potential of antibiotics to cause endotoxin release influenced the outcome of gram-negative sepsis in animal models (25,79,127). In mouse models of E. coli and P. aeruginosa peritonitis/sepsis, where bacteria, D-galactosamine (to sensitize mice for endotoxin), and antibiotics were given at the same time, 20 mg of the PBP-2 inhibitor imipenem per kg resulted in an approximately eightfold increase in the 50% lethal dose (LD 50 ) of bacteria.…”

Carbapenem-induced endotoxin release in Gram-negative bacterial sepsis rat models

“…PII: S 0 9 2 8 -8 2 4 4 ( 9 8 ) 0 0 0 8 4 -4 detrimental to the host with the Gram-negative bacterial infection [13,14]. Opal et al [11] showed a signi¢cant di¡erence between ceftazidime and imipenem in the plasma concentration of endotoxin released after antibiotic treatment in the Escherichia coli and Pseudomonas aeruginosa sepsis rat models. These results provided supportive evidence that differences in the plasma endotoxin concentration may re£ect the mode of antibacterial action of the antibiotics.…”

“…A number of in vivo studies have presented data indicating that antibiotic treatment can cause an increase in the plasma endotoxin concentration [3,5,8,11,13] and that released endotoxin may be 0928-8244 / 98 / $19.00 ß 1998 Federation of European Microbiological Societies. Published by Elsevier Science B.V. All rights reserved.…”