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Variation in the propensity to release endotoxin after cefuroxime exposure in different gram-negative bacteria: Uniform and dose-dependent reduction by the addition of tobramycin
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
2003 In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, Vol. 35, no 1, 40-46 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2003. Vol. 35, no 1, 40-46 p.
URN: urn:nbn:se:uu:diva-92435OAI: oai:DiVA.org:uu-92435DiVA: diva2:165511
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
In thesis
1. Antibiotic-induced Bacterial Toxin Release – Inhibition by Protein Synthesis Inhibitors
Open this publication in new window or tab >>Antibiotic-induced Bacterial Toxin Release – Inhibition by Protein Synthesis Inhibitors
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Toxic products, such as endotoxin from the gram-negative and exotoxin from the gram-positive bacteria, are the most important initiators of the inflammatory host response in sepsis. In addition to antibacterial treatment, numerous attempts have been made to interfere with the exaggerated proinflammatory cascade initiated by the toxins. As most antitoxic and anti-inflammatory agents have shown no clear efficacy, an attractive alternative has been to prevent or minimise their release. Therefore, it was of interest to further study the antibiotic-induced release of toxins after exposure to antibiotics used for the treatment of the most severe infections, especially if protein synthesis inhibitors could reduce the release induced by PBP 3-specific β-lactam antibiotics.

There were significant reductions in endotoxin release from gram-negative bacteria when the combination of the PBP 3-specific β-lactam antibiotic, cefuroxime, and the protein synthesis inhibitor, tobramycin, was compared with cefuroxime alone. Increasing doses of tobramycin reduced endotoxin release and increased the killing rate. In a kinetic in vitro model the endotoxin release from E.coli was higher after the second dose of cefuroxime. Nevertheless, it was reduced after addition of tobramycin.

No binding of tobramycin to endotoxin was observed, either in vivo or in vitro. In a porcine sepsis model, a possible anti-inflammatory effect of ceftazidime and tobramycin, expressed as late cytokine inhibition, was seen.

The protein synthesis inhibitor, clindamycin, released less streptococcal pyrogenic exotoxin A (SpeA) from a group A streptococcus strain than penicillin, and addition of clindamycin to penicillin resulted in less toxin production than penicillin alone. The SpeA production was dependent on the bacterial number at the start of treatment. Higher doses of penicillin also led to less SpeA.

The choice of antibiotic class and dose may be important in the severely ill septic patient in whom an additional toxin release could be deleterious. A combination of a β-lactam antibiotic and a protein synthesis inhibitor seems beneficial but further investigations are needed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2004. 51 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1393
Communicable diseases, Endotoxin, LPS, exotoxin, SpeA, penicillin-binding protein, aminoglycosides, clindamycin, β-lactam antibiotics, severe sepsis, septic shock, Infektionssjukdomar
National Category
Infectious Medicine
urn:nbn:se:uu:diva-4692 (URN)91-554-6109-3 (ISBN)
Public defence
2004-12-17, Rosénsalen, ing 95/96 nbv, Akademiska sjukhuset, Uppsala, 13:15
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved

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