Schentag J J
State University of New York, Buffalo School of Pharmacy, New York.
Scand J Infect Dis Suppl. 1990;74:218-34.
In vitro, antibiotics are known to kill bacteria in predictable relationships to their broth concentrations. It was our hypothesis that serum concentration was an important determinant of the rate of bacterial eradication in patients. This contention was reinforced by animal studies, which have clearly demonstrated concentration-related antibacterial activity. The animal models rely on reduction of bacterial colony counts as an endpoint of effect, and demonstrate that colony count reductions are related to antibiotic dose and probably to serum concentration. We adapted these methods for use in intubated patients with Gram-negative pneumonia. Briefly, each patient had extensive staging of the pneumonic process, and the Gram-negative organism was isolated and its minimal inhibitory concentration (MIC) was determined. In each patient measurement of the antibiotic serum concentrations in the interval between two doses of the drug was also performed. The pharmacokinetic profile of the drug was then superimposed on the bacterial MIC, and we then derived the patients individual peak to MIC ratio, area above MIC, and time above MIC. Each of these pharmacokinetic parameters was then related to the time required to eradicate the bacterial pathogens in the patient. For beta-lactams and quinolones, time above MIC was the most predictive of bacterial eradication times. Clearly, these methods can be used to develop dosing strategies for patients, as well as to determine clinically relevant doses and dosing strategies in clinical trials. Further work is needed, however, to assess whether these concepts hold for other types of bacteria (such as Gram-positive) or apply as accurately to other infection sites in addition to pneumonia.
在体外，已知抗生素可按照与肉汤浓度的可预测关系杀死细菌。我们的假设是，血清浓度是患者体内细菌清除率的一个重要决定因素。动物研究强化了这一观点，这些研究清楚地证明了与浓度相关的抗菌活性。动物模型将细菌菌落计数的减少作为效应终点，并表明菌落计数的减少与抗生素剂量以及可能与血清浓度有关。我们将这些方法应用于患有革兰氏阴性肺炎的插管患者。简要来说，每位患者都对肺炎进程进行了广泛分期，分离出革兰氏阴性菌并测定其最低抑菌浓度（MIC）。在每位患者中，还对两剂药物给药间隔期间的抗生素血清浓度进行了测量。然后将药物的药代动力学曲线叠加在细菌MIC上，进而得出患者个体的峰浓度与MIC之比、高于MIC的面积以及高于MIC的时间。然后将这些药代动力学参数中的每一个与患者体内根除细菌病原体所需的时间相关联。对于β-内酰胺类和喹诺酮类药物，高于MIC的时间对细菌清除时间的预测性最强。显然，这些方法可用于为患者制定给药策略，以及在临床试验中确定临床相关剂量和给药策略。然而，还需要进一步开展工作，以评估这些概念是否适用于其他类型的细菌（如革兰氏阳性菌），或者除肺炎外是否能同样准确地应用于其他感染部位。
