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Skorup, P. (2019). Antibacterial Effect and Inflammatory Response in Relation to Antibiotic Treatment of Sepsis. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Antibacterial Effect and Inflammatory Response in Relation to Antibiotic Treatment of Sepsis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Sepsis defines as life-threatening organ dysfunction caused by a dysregulated host response to infection. The importance of early administration of antibiotics in septic shock is undisputed, but the optimal antibiotic choice remains uncertain. Some national guidelines advocate single β-lactam antibiotic treatment while others recommend a combination of β-lactam and aminoglycoside. This thesis aimed to investigate the anti-bacterial properties and antibiotic-induced inflammatory responses of ß-lactam antibiotic compared with effects of the addition of an aminoglycoside in clinically relevant E. coli porcine intensive care sepsis/septic shock models. We also studied the host's antibacterial capacities in primary and secondary sepsis.

In Paper I the addition of an aminoglycoside, in comparison with single β-lactam antibiotic treatment,  caused decreased bacterial growth in the liver and greater antibiotic-induced blood killing activity ex vivo. The results thereby constitute possible mechanisms to the previously reported improved survival in the most critically ill sepsis patients receiving the β-lactam/aminoglycoside combination. Also observed in this paper was that individual blood bactericidal capacity may have significant effects on antimicrobial outcome.  

In Paper II we investigated endotoxin release in vivo after antibiotic treatment in comparison with no treatment. There were no differences, however, antibiotics did increase an inflammatory IL-6 response that was associated with leukocyte activation and pulmonary organ dysfunction. A secondary finding was that the addition of an aminoglycoside to a β-lactam induced trends towards less inflammation compared with β-lactam alone.

Paper III compared how challenge with different pre-killed E. coli activates the inflammatory response, resulting in higher cytokine responses, more leucocyte activation and inflammatory capillary leakage after single β-lactam compared with live or heat-killed bacteria. The addition of an aminoglycoside lowered the β-lactam-induced responses.

Paper IV demonstrated that animals with secondary sepsis exhibited an attenuated inflammatory response as expected; however, contrary to our hypothesis, the animals’ antibacterial capacities were intact and partly enhanced.

We conclude that there are likely several beneficial effects of the addition of an aminoglycoside to a β-lactam therapy regimen in septic shock. Because host antibacterial capacities in secondary sepsis are enhanced, the need for bactericidal antibiotic combinations is not greater in secondary than in primary sepsis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 78
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1524
Keywords
Sepsis, Septic shock, Antibiotics, Aminoglycoside, β-lactam, Bacteria, E. coli, Inflammation, Cytokines, Endotoxin, Porcine, ICU, Secondary sepsis, Endotoxin-tolerance.
National Category
Medical and Health Sciences Infectious Medicine Anesthesiology and Intensive Care
Research subject
Infectious Diseases
Identifiers
urn:nbn:se:uu:diva-366985 (URN)978-91-513-0533-2 (ISBN)
Public defence
2019-02-08, Gunnesalen, Ingång 10, Akademiska sjukhuset, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-01-18 Created: 2018-12-12 Last updated: 2019-02-18
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2019). The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis. Intensive Care Medicine Experimental, 7(1), Article ID 52.
Open this publication in new window or tab >>The impact of the systemic inflammatory response on hepatic bacterial elimination in experimental abdominal sepsis
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2019 (English)In: Intensive Care Medicine Experimental, ISSN 2197-425X, Vol. 7, no 1, article id 52Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Bacterial translocation from the gut has been suggested to induce a systemic inflammatory response syndrome (SIRS) and organ dysfunction. The liver has a pivotal role in eliminating circulating bacteria entering from the gut. We investigated whether pre-existing inflammation affects hepatic bacterial elimination.

METHODS: Fifteen anaesthetised piglets were infused with E. coli in the portal vein for 3 h. The naive group (n = 6) received the bacterial infusion without endotoxin exposure. SIRS (SIRS group, n = 6) was induced by endotoxin infusion 24 h before the bacterial infusion. For effects of anaesthesia, controls (n = 3) received saline instead of endotoxin for 24 h. Bacterial counts and endotoxin levels in the portal and hepatic veins were analysed during bacterial infusion.

RESULTS: The bacterial killing rate was higher in the naive group compared with the SIRS group (p = 0.001). The ratio of hepatic to portal venous bacterial counts, i.e. the median bacterial influx from the splanchnic circulation, was 0.06 (IQR 0.01-0.11) in the naive group and 0.71 (0.03-1.77) in the SIRS group at 3 h, and a magnitude lower in the naive group during bacteraemia (p = 0.03). Similar results were seen for hepatic endotoxin elimination. Peak log tumour necrosis factor alpha was higher in the naive 4.84 (4.77-4.89) vs. the SIRS group 3.27 (3.26-3.32) mg/L (p < 0.001).

CONCLUSIONS: Our results suggest that hepatic bacterial and endotoxin elimination is impaired in pigs with pre-existing SIRS while the inflammatory response to bacterial infusion is diminished. If similar mechanisms operate in human critical illness, the hepatic elimination of bacteria from the gut could be impaired by SIRS.

Keywords
Animal models, Bacterial translocation, Endotoxins, Escherichia coli, Mononuclear phagocyte system, Sepsis
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-392098 (URN)10.1186/s40635-019-0266-x (DOI)000483360800001 ()31456116 (PubMedID)
Funder
Swedish Society of Medicine, SLS-409831
Available from: 2019-08-29 Created: 2019-08-29 Last updated: 2019-10-18Bibliographically approved
Skorup, P., Maudsdotter, L., Tano, E., Lipcsey, M., Castegren, M., Larsson, A. & Sjölin, J. (2018). Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model. Critical Care Medicine, 46(7), e634-e641
Open this publication in new window or tab >>Dynamics of Endotoxin, Inflammatory Variables, and Organ Dysfunction After Treatment With Antibiotics in an Escherichia coli Porcine Intensive Care Sepsis Model
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2018 (English)In: Critical Care Medicine, ISSN 0090-3493, E-ISSN 1530-0293, Vol. 46, no 7, p. e634-e641Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: To investigate the dynamics of antibiotic-induced endotoxin liberation and inflammatory response in vivo in a clinically relevant large animal intensive care sepsis model and whether the addition of an aminoglycoside to a β-lactam antibiotic affects these responses.

DESIGN: Prospective, placebo-controlled interventional experimental study.

SETTING: University research unit.

SUBJECTS: Thirty-six healthy pigs administered Escherichia coli as a 3-hour infusion.

INTERVENTIONS: After 2 hours, during E. coli infusion, the animals were exposed to cefuroxime alone, the combination of cefuroxime and tobramycin, or saline.

MEASUREMENTS AND MAIN RESULTS: Plasma endotoxin, interleukin-6, tumor necrosis factor-α, leucocytes, and organ dysfunction were recorded for 4 hours after antibiotic treatment, and differences to the values before treatment were calculated. In vitro experiments were performed to ascertain whether endotoxin is released during antibiotic-induced bacterial killing of this E. coli strain. Despite differences between the treatment arms in vitro, no differences in plasma endotoxin were observed in vivo. Antibiotic-treated animals demonstrated a higher interleukin-6 response (p < 0.001), greater leucocyte activation (p < 0.001), and more pronounced deterioration in pulmonary static compliance (p < 0.01) over time than controls. Animals treated with the combination showed a trend toward less inflammation.

CONCLUSIONS: Treatment with antibiotics may elicit an increased inflammatory interleukin-6 response that is associated with leucocyte activation and pulmonary organ dysfunction. No observable differences were detected in plasma endotoxin concentrations. The reduction in cefuroxime-induced endotoxin release after the addition of an aminoglycoside in vitro could not be reproduced in this model.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-349226 (URN)10.1097/CCM.0000000000003139 (DOI)000435290400002 ()29595561 (PubMedID)
Available from: 2018-04-23 Created: 2018-04-23 Last updated: 2018-12-12Bibliographically approved
Hanslin, K., Sjölin, J., Skorup, P., Wilske, F., Frithiof, R., Larsson, A., . . . Lipcsey, M. (2016). Pre-existing systemic inflammation attenuates bacterial clearance by the liver in porcine abdominal sepsis. Intensive Care Medicine Experimental, 3(suppl. 1), A620
Open this publication in new window or tab >>Pre-existing systemic inflammation attenuates bacterial clearance by the liver in porcine abdominal sepsis
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2016 (English)In: Intensive Care Medicine Experimental, ISSN 1646-2335, E-ISSN 2197-425X, Vol. 3, no suppl. 1, p. A620-Article in journal, Meeting abstract (Refereed) Published
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-310602 (URN)10.1186/2197-425X-3-S1-A620 (DOI)
Available from: 2016-12-16 Created: 2016-12-16 Last updated: 2017-08-16Bibliographically approved
Skorup, P., Maudsdotter, L., Lipcsey, M., Castegren, M., Larsson, A., Jonsson, A.-B. & Sjölin, J. (2014). Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model.. PLoS ONE, 9(2), e90441
Open this publication in new window or tab >>Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model.
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 2, p. e90441-Article in journal (Refereed) Published
Abstract [en]

This study aimed to determine whether the addition of an aminoglycoside to a ß-lactam antibiotic increases the antimicrobial effect during the early phase of Gram-negative severe sepsis/septic shock. A porcine model was selected that considered each animal's individual blood bactericidal capacity. Escherichia coli, susceptible to both antibiotics, was given to healthy pigs intravenously during 3 h. At 2 h, the animals were randomized to a 20-min infusion with either cefuroxime alone (n = 9), a combination of cefuroxime+tobramycin (n = 9), or saline (control, n = 9). Blood samples were collected hourly for cultures and quantitative polymerase chain reaction (PCR). Bacterial growth in the organs after 6 h was chosen as the primary endpoint. A blood sample was obtained at baseline before start of bacterial infusion for ex vivo investigation of the blood bactericidal capacity. At 1 h after the administration of the antibiotics, a second blood sample was taken for ex vivo investigation of the antibiotic-induced blood killing activity. All animals developed severe sepsis/septic shock. Blood cultures and PCR rapidly became negative after completed bacterial infusion. Antibiotic-induced blood killing activity was significantly greater in the combination group than in the cefuroxime group (p<0.001). Growth of bacteria in the spleen was reduced in the two antibiotic groups compared with the controls (p<0.01); no difference was noted between the two antibiotic groups. Bacterial growth in the liver was significantly less in the combination group than in the cefuroxime group (p<0.05). High blood bactericidal capacity at baseline was associated with decreased growth in the blood and spleen (p<0.05). The addition of tobramycin to cefuroxime results in increased antibiotic-induced blood killing activity and less bacteria in the liver than cefuroxime alone. Individual blood bactericidal capacity may have a significant effect on antimicrobial outcome.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-220397 (URN)10.1371/journal.pone.0090441 (DOI)000332396200200 ()24587365 (PubMedID)
Available from: 2014-03-13 Created: 2014-03-13 Last updated: 2018-12-12Bibliographically approved
Castegren, M., Skorup, P., Lipcsey, M., Larsson, A. & Sjölin, J. (2013). Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction. PLoS ONE, 8(1), e53221
Open this publication in new window or tab >>Endotoxin tolerance variation over 24 h during porcine endotoxemia: association to changes in circulation and organ dysfunction
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 1, p. e53221-Article in journal (Refereed) Published
Abstract [en]

Endotoxin tolerance (ET), defined as reduced inflammatory responsiveness to endotoxin challenge following a first encounter with endotoxin, is an extensively studied phenomenon. Although reduced mortality and morbidity in the presence of ET has been demonstrated in animal studies, little is known about the temporal development of ET. Further, in acute respiratory distress syndrome ET correlates to the severity of the disease, suggesting a complicated relation between ET and organ dysfunction. Eighteen pigs were subjected to intensive care and a continuous endotoxin infusion for 24 h with the aim to study the time course of early ET and to relate ET to outcome in organ dysfunction. Three animals served as non-endotoxemic controls. Blood samples for cytokine analyses were taken and physiological variables registered every third hour. Production of TNF-α, IL-6, and IL-10 before and after endotoxin stimulation ex vivo was measured. The difference between cytokine values after and before ex vivo LPS stimulation (Δ-values) was calculated for all time points. ΔTNF-α was employed as the principal marker of ET and lower ΔTNF-α values were interpreted as higher levels of ET. During endotoxin infusion, there was suppression of ex vivo productions of TNF-α and IL-6 but not of IL-10 in comparison with that at 0 h. The ex vivo TNF-α values followed another time concentration curve than those in vivo. ΔTNF-α was at the lowest already at 6 h, followed by an increase during the ensuing hours. ΔTNF-α at 6 h correlated positively to blood pressure and systemic vascular resistance and negatively to cardiac index at 24 h. In this study a temporal variation of ET was demonstrated that did not follow changes in plasma TNF-α concentrations. Maximal ET occurred early in the course and the higher the ET, the more hyperdynamic the circulation 18 h later.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-149277 (URN)10.1371/journal.pone.0053221 (DOI)000313552400016 ()
Available from: 2011-03-16 Created: 2011-03-16 Last updated: 2017-12-11Bibliographically approved
Castegren, M., Lipcsey, M., Söderberg, E., Skorup, P., Eriksson, M., Larsson, A. & Sjölin, J. (2012). Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin. Shock, 37(5), 501-510
Open this publication in new window or tab >>Differences in Organ Dysfunction in Endotoxin Tolerant Pigs Under Intensive Care Exposed to a Second Hit of Endotoxin
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2012 (English)In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 37, no 5, p. 501-510Article in journal (Refereed) Published
Abstract [en]

Endotoxin tolerance is a well-studied phenomenon associated with a reduced inflammatory response. In the switch from an inflammatory to an anti-inflammatory response in clinical sepsis the concept of endotoxin tolerance is of obvious interest. However, only limited data exist regarding the effect of endotoxin tolerance on organ dysfunction and, therefore, this was investigated in a porcine intensive care sepsis model. Twenty-seven healthy pigs, including nine control animals, were included in the study. Twelve pigs pre-exposed to 24 h of intravenous endotoxin infusion and intensive care and six unexposed pigs were given either a high- or low-dose endotoxin challenge for 6 h. Inflammatory, circulatory, hypoperfusion and organ dysfunction parameters were followed. The inflammatory responses as well as parameters representing circulation, hypoperfusion, cardiac and renal function were all markedly attenuated in animals pre-exposed to endotoxin and intensive care as compared with animals not pre-exposed. In animals pre-exposed to endotoxin and given the high-dose of endotoxin challenge, deterioration in pulmonary function was equal to or even worse than in animals not pre-exposed.In contrast to the overall protective effect of endotoxin tolerance observed in other organ systems, the lungs of endotoxin tolerant animals demonstrated an increased responsiveness to high-dose endotoxin challenge.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-168692 (URN)10.1097/SHK.0b013e318249bb0d (DOI)000303010000009 ()22266970 (PubMedID)
Note

Previous title as submitted: "Compartmentalization of organ endotoxin tolerance in a porcine model of secondary sepsis"

Available from: 2012-02-15 Created: 2012-02-15 Last updated: 2017-12-07Bibliographically approved
Skorup, P., Wilske, F., Hanslin, K., Larsson, A., Lipcsey, M. & Sjölin, J.Enhanced Bacterial Clearance at a Secondary Sepsis Challenge in an Endotoxin-tolerant Porcine Intensive Care Model.
Open this publication in new window or tab >>Enhanced Bacterial Clearance at a Secondary Sepsis Challenge in an Endotoxin-tolerant Porcine Intensive Care Model
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(English)Manuscript (preprint) (Other academic)
Keywords
Secondary sepsis, Endotoxin-tolerance, Bacteria, E. coli, Porcine, ICU
National Category
Medical and Health Sciences Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-366977 (URN)
Note

P Skorup and F Wilske contributed equally to this work.

Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-12-12Bibliographically approved
Skorup, P., Maudsdotter, L., Lipcsey, M., Larsson, A. & Sjölin, J.Mode of Bacterial Killing Affects the Inflammatory Response and Associated Organ Dysfunctions in a Porcine E. coli Intensive Care Sepsis Model.
Open this publication in new window or tab >>Mode of Bacterial Killing Affects the Inflammatory Response and Associated Organ Dysfunctions in a Porcine E. coli Intensive Care Sepsis Model
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(English)Manuscript (preprint) (Other academic)
Keywords
Antibiotics, Bacteria, Sepsis, Cytokines, Inflammation, Porcine
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-366974 (URN)
Available from: 2018-11-27 Created: 2018-11-27 Last updated: 2018-12-12Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-5407-6612

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