Greisman S E, DuBuy J B, Woodward C L
Infect Immun. 1979 Aug;25(2):538-57. doi: 10.1128/iai.25.2.538-557.1979.
Outbred Swiss mice were inoculated intraperitoneally or intravenously with one 90 to 100% lethal dose of Escherichia coli O:18, Proteus mirabilis, or Klebsiella pneumoniae. After carefully timed intervals, aminoglycoside antibiotics were begun at dosages nnd intervals predetermined to constitute optimal therapy. With progressive increases in delay of antibiotic therapy, mortality rates increased progressively from 0% to 90 to 100%. Standardized models of infection were developed by selecting delay periods before initiating antibiotic therapy such that 50 to 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. The following were observed: (i) adrenal corticosteroids prevented mortality that was no longer preventable by optimal aminoglycoside antibiotics alone. The following were preventable by optimal aminoglycoside antibiotic therapy alone; (ii) specific antisera also did so, provided anaphylaxis was circumvented; (iii) in one model (P. mirabilis), such protection by adrenal corticosteroids and specific antiserum could be additive; (iv) adrenal corticosteroids and specific antiserum acted synergistically with the aminoglycoside antibiotics--no protection was achieved by delayed administration of the steroids or antiserum alone; (v) timing was crucial--the synergistic protective activity of adrenal corticosteroids and of specific antiserum with aminoglycosides declined rapidly as infection progressed; (vi) cyclophosphamide pretreatment markedly impaired the synergistic protective activity of specific antiserum and of adrenal corticosteroids with aminoglycosides; (vii) 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, Rd, and Re chemotypes, anticoagulants (heparin), ascorbic acid, antiproteolytic agents (aprotinin), alpha adrenergic blockers (phenoxybenzamine), prostaglandin synthetase inhibitors (acetylsalicylic acid, sodium salicylate, indomethacin), nicotinamide, glucose, and insulin-glucose-potassium mixtures.
将远交系瑞士小鼠通过腹腔内或静脉内接种1个90%至100%致死剂量的大肠杆菌O:18、奇异变形杆菌或肺炎克雷伯菌。在经过精心设定的时间间隔后，开始以预先确定的剂量和间隔给予氨基糖苷类抗生素，以构成最佳治疗方案。随着抗生素治疗延迟时间的逐渐增加，死亡率从0%逐渐上升至90%至100%。通过选择开始抗生素治疗前的延迟时间，建立了标准化感染模型，使得死亡率达到50%至70%。利用这些模型，在延迟抗生素治疗的同时给予具有抗内毒素活性的药物，以确定是否有任何药物能够预防革兰氏阴性菌败血症导致的死亡率，而这是仅靠抗生素无法预防的。观察到以下情况：(i) 肾上腺皮质类固醇可预防仅靠最佳氨基糖苷类抗生素无法预防的死亡率。以下情况仅靠最佳氨基糖苷类抗生素治疗即可预防；(ii) 特异性抗血清也可预防，前提是避免过敏反应；(iii) 在一个模型（奇异变形杆菌）中，肾上腺皮质类固醇和特异性抗血清的这种保护作用可能具有相加性；(iv) 肾上腺皮质类固醇和特异性抗血清与氨基糖苷类抗生素协同作用——单独延迟给予类固醇或抗血清无法实现保护作用；(v) 时间很关键——随着感染进展，肾上腺皮质类固醇和特异性抗血清与氨基糖苷类抗生素的协同保护活性迅速下降；(vi) 环磷酰胺预处理显著损害特异性抗血清和肾上腺皮质类固醇与氨基糖苷类抗生素的协同保护活性；(vii) 除肾上腺皮质类固醇和特异性抗血清外，没有其他所谓的抗内毒素药物能够预防仅靠氨基糖苷类抗生素无法预防的死亡率。这些药物包括针对Rc、Rd和Re化学型粗糙突变肠杆菌科细菌的抗血清、抗凝剂（肝素）、抗坏血酸、抗蛋白水解剂（抑肽酶）、α肾上腺素能阻滞剂（酚苄明）、前列腺素合成酶抑制剂（乙酰水杨酸、水杨酸钠、吲哚美辛）、烟酰胺、葡萄糖以及胰岛素-葡萄糖-钾混合物。
