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Beneficial Antimicrobial Effect of the Addition of an Aminoglycoside to a β-Lactam Antibiotic in an E. coli Porcine Intensive Care Severe Sepsis Model.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD).
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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.

Place, publisher, year, edition, pages
2014. Vol. 9, no 2, p. e90441-
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-220397DOI: 10.1371/journal.pone.0090441ISI: 000332396200200PubMedID: 24587365OAI: oai:DiVA.org:uu-220397DiVA, id: diva2:704824
Available from: 2014-03-13 Created: 2014-03-13 Last updated: 2018-12-12Bibliographically approved
In thesis
1. Antibacterial Effect and Inflammatory Response in Relation to Antibiotic Treatment of Sepsis
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)
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Available from: 2019-01-18 Created: 2018-12-12 Last updated: 2019-02-18

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Skorup, PaulLipcsey, MiklósCastegren, MarkusLarsson, AndersSjölin, Jan

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