Summary auto-generated
Researchers established a mouse model of endogenous septicemia caused by multi-resistant Klebsiella pneumoniae and Escherichia coli. Using conventional mice treated with immunosuppressive agents, cyclophosphamide (CY) induced 70% mortality primarily from Pseudomonas aeruginosa, while fluorouracil (5-FU) caused 100% mortality from Enterobacteriaceae including K. pneumoniae. To create a more clinically relevant model, specific-pathogen-free mice were decontaminated with ampicillin and ceftazidime, then orally inoculated with antibiotic-resistant K. pneumoniae or E. coli strains carrying an extended-spectrum β-lactamase plasmid. Subsequent 5-FU treatment induced lethal septicemia in most mice (70-100% mortality) caused by the inoculated organisms, while CY was less effective. Mice given a cured strain lacking the resistance plasmid did not develop septicemia. The 5-FU model more closely resembles human nosocomial infections following broad-spectrum antibiotic use and bowel decontamination, making it valuable for investigating pathophysiology and therapeutic strategies against antibiotic-resistant Enterobacteriaceae septicemia.
Key findings
- Fluorouracil (5-FU) is superior to cyclophosphamide for inducing endogenous Enterobacteriaceae septicemia in mice, achieving 100% mortality with K. pneumoniae CF514
- A novel model combining bowel decontamination, oral inoculation of specific antibiotic-resistant strains, and 5-FU immunosuppression successfully reproduces clinically relevant endogenous septicemia
- The antibiotic resistance plasmid CAZ-1/TEM-5 is essential for disease induction; cured strains lacking this plasmid did not cause septicemia
- The 5-FU model closely mimics human nosocomial infections where broad-spectrum antibiotic use precedes septicemia from enteric pathogens
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Abstract
Multi-resistant Klebsiella pneumoniae have recently occurred in several nosocomial outbreaks of septicaemia. An animal model resembling the pathophysiology of these infections in man would be very useful. A new model of endogenous septicaemia caused by K. pneumoniae and Escherichia coli strains in mice has been established. The mortality rate of conventional ddY mice given cyclophosphamide (CY) or fluorouracil (5-FU), each 200 mg/kg intraperitoneally, every other day was 70 and 100%, respectively. Pseudomonas aeruginosa septicaemia was observed in all dead mice treated with CY, whereas Enterobacteriaceae, including K. pneumoniae, were isolated from 90% of mice given 5-FU. Specific-pathogen-free mice, decontaminated with ampicillin and ceftazidime, were given multi-resistant K. pneumoniae CF504, CF514 or E. coli CF604, or CF614 carrying CAZ-1/TEM-5 plasmid by oral inoculation. Subsequent dosing with 5-FU induced lethal septicaemia caused by the inoculated strains in most of these mice, whereas CY did not regularly induce septicaemia. This model with 5-FU is considered to resemble closely the situation observed in man and to be beneficial for investigating pathophysiology and therapeutic strategies.