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JAC Advance Access published online on March 29, 2007
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkm073
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Continuous administration of PBP-2- and PBP-3-specific ß-lactams causes higher cytokine responses in murine Pseudomonas aeruginosa and Escherichia coli sepsis

Jacqueline Buijs1,2,*, Anthonius S. M. Dofferhoff1,3, Johan W. Mouton1 and Jos W. M. van der Meer4,5

1 Department of Medical Microbiology and Infectious Diseases, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands 2 Department of Internal Medicine, Atrium Medical Centre, Heerlen, The Netherlands 3 Department of Internal Medicine, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands 4 Nijmegen University Centre for Infectious Diseases, University Medical Centre, Nijmegen, The Netherlands 5 Department of General Internal Medicine, University Medical Centre, Nijmegen, The Netherlands

Received 21 December 2006; returned 22 January 2007; revised 11 February 2007; accepted 12 February 2007

* Correspondence address. Atrium Medical Centre, PO Box 4446, 6401CX Heerlen, The Netherlands. Tel: +31-45-5766666; Fax: +31-45-5713360; E-mail: j.buijs{at}atriummc.nl/ jacqbuijs{at}hotmail.com

Objectives: Initial antibiotic treatment of severe infections can lead to clinical deterioration due to sudden endotoxin release and concomitant exaggerated inflammatory response. Antibiotic-induced morphological changes may contribute to this phenomenon. High-dose ceftazidime, which inhibits penicillin-binding protein (PBP)-1 in Gram-negative bacteria, causes quick bacteriolysis and low endotoxin release. Low-dose ceftazidime leads to PBP-3 inhibition, which causes bacterial filament formation, associated with high endotoxin releases. PBP-2-specific antibiotics induce spheroplasts, again associated with low endotoxin release. We hypothesized that antibiotic type, concentration and regimen influence bacterial morphology, endotoxin levels and inflammatory response.

Methods: Neutropenic mice with Escherichia coli or Pseudomonas aeruginosa sepsis were treated with ceftazidime or meropenem 10–320 mg/kg as an intravenous bolus or as continuous tail vein infusions of 0.1 mL/h. Four hours later, bacterial counts, morphology, plasma endotoxin, pro-inflammatory cytokines [tumour necrosis factor-{alpha} (TNF-{alpha}) and interleukin-6 (IL-6)] and antibiotic concentrations were measured.

Results: Continuous infusion of 80 mg/kg ceftazidime was the lowest dose preventing filaments in E. coli infections. Bolus treatment resulted in filament formation, irrespective of the dose. During continuous treatment, IL-6 and TNF-{alpha} concentrations were higher compared with bolus treatment and controls for both antibiotics and both strains. A clear relationship between cfu counts in muscle and circulating IL-6 was shown (r = – 0.579, P = 0.007), suggesting that plasma IL-6 is a valuable indicator of bacterial killing at the infection site.

Conclusions: Our findings show that not PBP affinity but the method of antibiotic administration is crucial during initial treatment of severe infections.

Key Words: ceftazidime , meropenem , TNF-{alpha} , IL-6 , endotoxin


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