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Antibiotic-induced Bacterial Toxin Release – Inhibition by Protein Synthesis Inhibitors
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Sciences.
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. , p. 51
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1393
Keywords [en]
Communicable diseases, Endotoxin, LPS, exotoxin, SpeA, penicillin-binding protein, aminoglycosides, clindamycin, β-lactam antibiotics, severe sepsis, septic shock
Keywords [sv]
Infektionssjukdomar
National Category
Infectious Medicine
Identifiers
URN: urn:nbn:se:uu:diva-4692ISBN: 91-554-6109-3 (print)OAI: oai:DiVA.org:uu-4692DiVA, id: diva2:165515
Public defence
2004-12-17, Rosénsalen, ing 95/96 nbv, Akademiska sjukhuset, Uppsala, 13:15
Opponent
Supervisors
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
List of papers
1. Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release
Open this publication in new window or tab >>Endotoxin release from Escherichia coli after exposure to tobramycin: dose-dependency and reduction in cefuroxime-induced endotoxin release
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2000 In: Clinical Microbiology and Infectious Diseases, ISSN 1198-743, Vol. 6, no 2, p. 74-81Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92434 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
2. 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
Open this publication in new window or tab >>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
2003 In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, Vol. 35, no 1, p. 40-46Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92435 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
3. Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock
Open this publication in new window or tab >>Endotoxin neutralization and anti-inflammatory effects of tobramycin and ceftazidime in porcine endotoxin shock
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2004 In: Critical Care, ISSN 1466-609, Vol. 8, no 1, p. R35-R41Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-92436 (URN)
Available from: 2004-11-26 Created: 2004-11-26Bibliographically approved
4. Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: Higher release after the second dose
Open this publication in new window or tab >>Propensity to release endotoxin after two repeated doses of cefuroxime in an in vitro kinetic model: Higher release after the second dose
2007 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 60, no 2, p. 328-333Article in journal (Refereed) Published
Abstract [en]

Objectives: To study endotoxin release from two strains of Escherichia coli after exposure to two repeated doses of cefuroxime in an in vitro kinetic model.

Methods: Cefuroxime in concentrations simulating human pharmacokinetics was added to the bacterial solution with a repeated dose after 12 h. In another experiment, tobramycin was given concomitantly with the second dose of cefuroxime. Samples for viable counts and endotoxin analyses were drawn before the addition of antibiotics and at 2 and 4 h after each dose.

Results: The propensity to release endotoxin, expressed as log10 endotoxin release (EU)/log10 killed bacteria, was higher after the second than after the first dose, 0.80 ± 0.04 and 0.65 ± 0.01, respectively, in the ATCC strain and 0.80 ± 0.04 and 0.65 ± 0.02, respectively, in the clinical strain (P < 0.001). Endotoxin was released earlier after the second dose (P < 0.001). Addition of tobramycin at the second dose reduced the endotoxin release in comparison with that of cefuroxime alone (P < 0.001).

Conclusions: The propensity to liberate endotoxin is higher after the second dose of cefuroxime than after the first, resulting in a higher release of endotoxin than expected from bacterial count. The release after the second dose can be reduced by the addition of tobramycin.

Keywords
aminoglycosides, Escherichia coli, morphology
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-92437 (URN)10.1093/jac/dkm190 (DOI)000248986500017 ()17567631 (PubMedID)
Available from: 2004-11-26 Created: 2004-11-26 Last updated: 2017-12-14Bibliographically approved
5. Release of streptococcal SpeA after exposure to penicillin; dependency on dose and inhibition by clindamycin
Open this publication in new window or tab >>Release of streptococcal SpeA after exposure to penicillin; dependency on dose and inhibition by clindamycin
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-92438 (URN)
Available from: 2004-11-26 Created: 2004-11-26 Last updated: 2010-01-13Bibliographically approved

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