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.