Experimental gram-negative bacterial sepsis: prevention of mortality not preventable by antibiotics alone

Publisher Website
Google Scholar
Abstract
Outbred Swiss mice were inoculated i.p. or i.v. with 1 LD90-100 of Escherichia coli 0:18, Proteus mirabilis or Klebsiella pneumoniae. After carefully timed intervals, aminoglycoside antibiotics were begun at dosages and intervals pre-determined to constitute optimal therapy. With progressive increases in delay of antibiotic therapy, mortality rates increased progressively from 0% to 90-100%. Standardized models of infection were developed by selecting delay periods before initiating antiboitic therapy such that 50-70% mortalities resulted. Utilizing these models, agents with reputed anti-endotoxin activity were administered concomitantly with the delayed antibiotic therapy to determine if any could prevent gram-negative septic mortality no longer preventable by the antibiotics alone. Adrenal corticosteroids prevented mortality that was no longer preventable by optimal aminoglycoside antibiotic therapy alone. Specific antisera prevented mortality provided anaphylaxis was circumvented. In 1 model (P. mirabilis), such protection by adrenal corticosteroids and specific antiserum could be additive. Adrenal corticosteroids and specific antiserum acted synergistically with the aminoglycoside antibiotics; no protection was achieved by delayed administration of the steroids or antiserum alone. Timing was crucial; the synergistic protective activity of adrenal corticosteroids and of specific antiserum with aminoglycosides declined rapidly as infection progressed. Cyclophosphamide pre-treatment markedly impaired the synergistic protective activity of specific antiserum and of adrenal corticosteroids with aminoglycosides. No reputed anti-endotoxin agents other than adrenal corticosteroids and specific antiserum proved capable of preventing mortality not preventable by aminoglycoside antibiotics alone. These included antisera to rough mutant Enterobacteriaceae of Rc, Fd and Re chemotypes, anti-coagulants (heparin), ascorbic acid, anti-proteolytic agents (aprotinin), .alpha.-adrenergic blockers (phenoxybenzamine), prostaglandin synthetase inhibitors (acetylsalicylic acid, sodium salicylate, indomethacin), nicotinamide, glucose and insulin-glucose-K mixtures.