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Differences in therapeutic efficacy among cell wall-active antibiotics in a mouse model of gram-negative sepsis
1Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City 66160, USA.
Abstract:
The in vivo efficacy of three cell wall-active antibiotics, imipenem, meropenem, and ceftazidime, was compared in mice rendered hypersusceptible to the pathophysiologic effects of lipopolysaccharide by treatment with D-galactosamine. When CF-1 mice were administered Escherichia coli, D-galactosamine, and saline intraperitoneally, an LD50 was achieved at an inoculum of approximately 2 x 10(4) cfu. Administration of antibiotic at 20 mg/kg resulted in significant but widely variable protective efficacy from E. coli lethality among the three antibiotics. At this dose, an approximately 3-fold increase in LD50 was observed with either meropenem or ceftazidime, whereas administration of imipenem resulted in an approximately 8-fold increase in LD50 (P = .0053). When the dose of antibiotic was decreased to 2 mg/kg, neither meropenem nor ceftazidime could provide measurable protection, whereas imipenem was almost fully protective (P < .002). These differences in protective efficacy were also noted with experimental Pseudomonas aeruginosa but not Staphylococcus aureus infection.
Insights
Imipenem demonstrated superior in vivo efficacy against Escherichia coli and Pseudomonas aeruginosa infections in mice compared to meropenem and ceftazidime, especially at lower antibiotic doses. This highlights significant differences in protective capabilities among these cell wall-active antibiotics.
Area of Science:
- Pharmacology
- Infectious Diseases
- Microbiology
Background:
- Lipopolysaccharide (LPS) induces hypersusceptibility to infection.
- Cell wall-active antibiotics are crucial for treating bacterial infections.
Purpose of the Study:
- To compare the in vivo efficacy of imipenem, meropenem, and ceftazidime.
- To evaluate antibiotic protection against bacterial lethality in a hypersusceptible mouse model.
Main Methods:
- Mice were rendered hypersusceptible using D-galactosamine.
- Infection was induced with Escherichia coli or Pseudomonas aeruginosa.
- Antibiotic efficacy was assessed by determining the lethal dose 50 (LD50).
Main Results:
- Imipenem showed significantly greater protection than meropenem and ceftazidime against E. coli at 20 mg/kg (8-fold vs. 3-fold increase in LD50).
- At a lower dose (2 mg/kg), imipenem provided near-complete protection, while meropenem and ceftazidime offered no measurable protection.
- Similar efficacy differences were observed in Pseudomonas aeruginosa infections but not Staphylococcus aureus.
Conclusions:
- Imipenem exhibits superior in vivo protective efficacy compared to meropenem and ceftazidime in this hypersusceptible mouse model.
- Antibiotic dose significantly impacts protective efficacy, with imipenem maintaining effectiveness at lower concentrations.
- These findings suggest differential in vivo activity profiles for these beta-lactam antibiotics against specific Gram-negative pathogens.