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Paul Skorup
Section of infectious diseases
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5407-6612
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Background 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 heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response.
Method Killed or live Escherichia coli were administrated as a 3-hour (h) infusion to 16 healthy pigs in a prospective, placebo-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.
Results Differences 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 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).
Conclusions In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3 active antibiotic induced an increased inflammatory response associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3 active antibiotic reduced that response.
Keywords
Antibiotics, Bacteria, Sepsis, Cytokines, Inflammation, Porcine
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CURRENT STATUS: Published
View the published article at Critical Care.
No community comments so far
Editorial decision: Accept
On 19 Sep, 2020
Editor assigned
On 24 Aug, 2020
Submission checks complete
On 23 Aug, 2020
Editor invited
On 23 Aug, 2020
Version 1
Posted 04 Mar, 2020
No comments provided
Editorial decision: Minor revision
On 18 Jul, 2020
Review #3 received
Received 28 Jun, 2020
Review #2 received
Received 21 Jun, 2020
Reviewer #3 agreed
On 14 Jun, 2020
Reviewer #2 agreed
On 13 Jun, 2020
Review #1 received
Received 26 May, 2020
Reviewer #1 agreed
On 23 Apr, 2020
Reviewers invited
Invitations sent on 24 Mar, 2020
Editor assigned
On 03 Mar, 2020
Editor invited
On 02 Mar, 2020
Submission checks complete
On 29 Feb, 2020
First submitted
On 27 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
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A new preprint design is coming!
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See the published version of this preprint at Critical Care.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Paul Skorup
Section of infectious diseases
Corresponding Author
ORCiD: https://orcid.org/0000-0002-5407-6612
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Critical Care.
No community comments so far
Editorial decision: Accept
On 19 Sep, 2020
Editor assigned
On 24 Aug, 2020
Submission checks complete
On 23 Aug, 2020
Editor invited
On 23 Aug, 2020
Version 1
Posted 04 Mar, 2020
No comments provided
Editorial decision: Minor revision
On 18 Jul, 2020
Review #3 received
Received 28 Jun, 2020
Review #2 received
Received 21 Jun, 2020
Reviewer #3 agreed
On 14 Jun, 2020
Reviewer #2 agreed
On 13 Jun, 2020
Review #1 received
Received 26 May, 2020
Reviewer #1 agreed
On 23 Apr, 2020
Reviewers invited
Invitations sent on 24 Mar, 2020
Editor assigned
On 03 Mar, 2020
Editor invited
On 02 Mar, 2020
Submission checks complete
On 29 Feb, 2020
First submitted
On 27 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Critical Care & Emergency Medicine
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Critical Care.
Background 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 heat-killed bacteria. A secondary aim was to determine whether the addition of an aminoglycoside could mitigate the cefuroxime-induced response.
Method Killed or live Escherichia coli were administrated as a 3-hour (h) infusion to 16 healthy pigs in a prospective, placebo-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.
Results Differences 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 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).
Conclusions In comparison with live or heat-killed bacteria, bacteria killed by a PBP-3 active antibiotic induced an increased inflammatory response associated with deteriorated organ and cellular function. The addition of an aminoglycoside to the PBP-3 active antibiotic reduced that response.
Figure 1
Figure 2
This is a list of supplementary files associated with this preprint. Click to download.
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