Experimental Gram-Negative Bacterial Sepsis: Optimal Methylprednisolone Requirements for Prevention of Mortality Not Preventable by Antibiotics Alone

Abstract

Outbed ICR mice were inoculated ip with one LD_90-100 Escherichia coli 0:18, Proteus mirabilis, or Klebsiella pneumoniae. After carefully timed intervals, aminoglycoside antibiotics were begun at dosages and intervals predetermined to constitute optimal therapy. With progressive delay of antibiotic therapy, mortality rates increased progressively from 0 to 90-100%. Standardized models of infection were obtained by selecting delay periods before initiating antibiotic therapy such that 50 to 70% mortality rates resulted. In these models, 30 mg/kg methylprednisolone (MP) given prior to or concomitantly with the delayed antibiotic therapy and repeated 4 hr later was previously shown capable of preventing gram-negative septic mortality not preventable by the optimal antibiotic therapy alone. The present studies quantitate the optimal quantities of MP required for such protection. It was found that (1) in the absence of aminoglycoside antibiotics, MP consistently failed to reduce mortality; (2) in the antibiotic-treated animals, a single im injection of 30 mg/kg MP provided definite protection. A second and a third injection of 30 mg/kg of MP at 4-hr intervals provided additional, but decremental, increments of protection; (3) decreasing the dose of MP to 10 mg/kg or less consistently reduced its protective activity; (4) increasing the dose of MP to 60 mg/kg or greater consistently reduced its protective activity; (5) short additional increments in delay in initiating antibiotic and MP therapy annulled the protective activity of MP. The findings indicate that the ability of MP to reduce murine mortality from gram-negative bacterial sepsis is not only critically restricted by the requirements for its early administration in conjunction with appropriate antibiotics, but also by its relatively narrow optimal dose-response range and the decremental increments in its effectiveness upon repetitive administration.