Abstract
BackgroundSepsis is often treated with penicillin-binding protein 3 (PBP-3) acting β-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response.MethodKilled or live Escherichia coli were administrated as a 3-h infusion to 16 healthy pigs in a prospective, randomized controlled interventional experimental study. Cefuroxime was chosen as the PBP-3-active antibiotic and tobramycin represented the aminoglycosides. The animals were randomized to receive (I) bacteria killed by cefuroxime, (II) live bacteria, (III) bacteria killed by heat, or (IV) bacteria killed by the combination of cefuroxime and tobramycin. Plasma endotoxin, tumor necrosis factor alpha, interleukin-6, interleukin-10, leukocytes, and organ function were recorded at the start of the experiment and then hourly for 6 h.ResultsDifferences in dynamics of concentration over time between the four treatment groups were found for the three cytokines (p < 0.001). Animals receiving cefuroxime-killed bacteria demonstrated higher responses than those receiving live (p < 0.05) or heat-killed bacteria (p < 0.01). The addition of tobramycin reduced the cefuroxime-induced responses (p < 0.001). The cytokine responses were associated with leucocyte activation that was further associated with pulmonary dysfunction and increases in lactate (p < 0.01).ConclusionsIn comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3-active antibiotic reduced that response.
Highlights
Sepsis is often treated with penicillin-binding protein 3 (PBP-3) acting β-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem
In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3-active antibiotic induced an increased inflammatory response that appears to be associated with deteriorated organ and cellular function
If variation in endotoxin levels after antibiotic treatment does not cause the differences in activation of the inflammatory response and clinical impairment in vivo, it may be hypothesized that other mechanisms such as antibiotic-induced structural alterations of the bacteria [13] may play an important role
Summary
Sepsis is often treated with penicillin-binding protein 3 (PBP-3) acting β-lactam antibiotics, such as piperacillin-tazobactam, cefotaxime, and meropenem. They cause considerable bacterial structural changes and have in vitro been associated with an increased inflammatory response. In a clinically relevant large animal sepsis model, our primary aim was to investigate whether bacteria killed by a PBP-3-active antibiotic has a greater effect on the early inflammatory response and organ dysfunction compared with corresponding amounts of live or heatkilled bacteria. In a recent study using a large animal Gram-negative sepsis model antibiotic-induced inflammation and organ impairment were observed but without any notable differences in plasma endotoxin concentrations compared with control animals [5]. If variation in endotoxin levels after antibiotic treatment does not cause the differences in activation of the inflammatory response and clinical impairment in vivo, it may be hypothesized that other mechanisms such as antibiotic-induced structural alterations of the bacteria [13] may play an important role
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