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

J Antimicrob Chemother. 2007 May;59(5):926-33. doi: 10.1093/jac/dkm073. Epub 2007 Mar 29.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacokinetics
  • Ceftazidime / administration & dosage
  • Ceftazidime / pharmacokinetics
  • Ceftazidime / pharmacology
  • Ceftazidime / therapeutic use
  • Colony Count, Microbial
  • Cytokines / immunology*
  • Endotoxins / blood
  • Escherichia coli / cytology
  • Escherichia coli / drug effects
  • Escherichia coli Infections / blood
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / immunology
  • Escherichia coli Infections / microbiology
  • Female
  • Meropenem
  • Mice
  • Penicillin-Binding Proteins / metabolism*
  • Pseudomonas Infections / blood
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas Infections / immunology
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / cytology
  • Pseudomonas aeruginosa / drug effects
  • Sepsis / blood
  • Sepsis / drug therapy*
  • Sepsis / immunology
  • Thienamycins / administration & dosage
  • Thienamycins / pharmacology
  • Thienamycins / therapeutic use

Substances

  • Anti-Bacterial Agents
  • Cytokines
  • Endotoxins
  • Penicillin-Binding Proteins
  • Thienamycins
  • Ceftazidime
  • Meropenem