Differences in Therapeutic Efficacy among Cell Wall-Active Antibiotics in a Mouse Model of Gram-Negative Sepsis

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, Dgalactosamine, and saline intraperitoneally, an LD50 was achieved at an inoculum of ∼2 × 104 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 ∼3-fold increase in LD50 was observed with either meropenem or ceftazidime, whereas administration of imipenem resulted in an ∼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.