Erlendsdottir H, Knudsen J D, Odenholt I, Cars O, Espersen F, Frimodt-Møller N, Fuursted K, Kristinsson K G, Gudmundsson S
Departments of Microbiology, Landspitalinn (University Hospital), Reykjavík, Iceland.
Antimicrob Agents Chemother. 2001 Apr;45(4):1078-85. doi: 10.1128/AAC.45.4.1078-1085.2001.
Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 microg/ml and the other for which the penicillin MIC was 1.0 microg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (C(max)s) and times that the concentrations were greater than the MIC (T(>MIC)s). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T(>MIC) and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (approximately 6 log10 CFU/ml), followed by the thigh (approximately 3 log10 CFU/thigh), and being the lowest in the lung (approximately 1 log10 CFU/lung). In the rabbit model the maximal effect was approximately 6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T(>MIC) was > or =65% of the experimental time and C(max) was > or =15 times the MIC, and in the rabbit model bactericidal activity became marked when T(>MIC) was > or =35%, Cmax was > or =5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio and T(>MIC), the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.
临床和动物研究表明，在最佳给药剂量下，青霉素可能对青霉素不敏感肺炎链球菌（PNSP）仍有效。本研究通过在四种动物模型（小鼠腹膜炎、肺炎、大腿感染以及兔组织笼感染）中使用可比的青霉素给药方案，研究了相同的青霉素敏感肺炎链球菌（PSP）和PNSP菌株对青霉素的药效学反应是否存在差异。使用了两株6B型耐多药肺炎链球菌分离株，一株青霉素MIC为0.016μg/ml，另一株青霉素MIC为1.0μg/ml。另外在兔中研究了两株PNSP菌株。动物接受了五种不同的青霉素给药方案，这些方案导致血清中药物的最大浓度（C(max)s）以及浓度高于MIC的时间（T(>MIC)s）各不相同。终点指标是小鼠治疗6小时和兔治疗24小时后的细菌活力计数。在所有模型中均观察到相似的药效学效应。在小鼠模型中，杀菌活性取决于T(>MIC)，在较小程度上取决于Cmax/MIC和代时，但不取决于浓度 - 时间曲线下面积（AUC）/MIC。PSP和PNSP的最大杀菌活性相似，在腹膜和血液中最高（约6 log10 CFU/ml），其次是大腿（约3 log10 CFU/大腿），在肺部最低（约1 log10 CFU/肺）。在兔模型中，24小时后的最大效应约为6 log10 CFU/ml。在小鼠模型中，当T(>MIC)≥实验时间的65%且C(max)≥MIC的15倍时，杀菌活性变得显著；在兔模型中，当T(>MIC)≥35%、Cmax≥MIC的5倍且24小时的AUC/MIC超过25时，杀菌活性变得显著。通过优化Cmax/MIC比值和T(>MIC)，青霉素对肺炎链球菌的MIC可用于指导治疗，并在由PNSP引起的非脑膜感染中使治疗效果最大化。
