Drusano George Louis, Liu Weiguo, Fikes Steven, Cirz Ryan, Robbins Nichole, Kurhanewicz Stephanie, Rodriquez Jaime, Brown David, Baluya Dodge, Louie Arnold
Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida Research and Academic Center, Lake Nona.
Achaogen, San Francisco, California.
J Infect Dis. 2014 Oct 15;210(8):1319-24. doi: 10.1093/infdis/jiu237. Epub 2014 Apr 22.
Killing of bacterial pathogens by granulocytes is a saturable process, as previously demonstrated. There is virtually no quantitative information about how granulocytes interact with antimicrobial chemotherapy to kill bacterial cells.
We performed a dose-ranging study with the aminoglycoside plazomicin against Pseudomonas aeruginosa ATCC27853 in a granulocyte-replete murine pneumonia model. Plazomicin was administered in a humanized fashion (ie, administration of decrementing doses 5 times over 24 hours, mimicking a human daily administration profile). Pharmacokinetic profiling was performed in plasma and epithelial lining fluid. All samples were simultaneously analyzed with a population model. Mouse cohorts were treated for 24 hours; other cohorts treated with the same therapy were observed for another 24 hours after therapy cessation, allowing delineation of the therapeutic effect necessary to reduce the bacterial burden to a level below the half-saturation point.
The mean bacterial burden (±SD) at which granulocyte-mediated kill was half saturable was 2.45 × 10(6) ± 6.84 × 10(5) colony-forming units of bacteria per gram of tissue (CFU/g). Higher levels of plazomicin exposure reduced the bacterial burden to <5 log10 CFU/g, allowing granulocytes to kill an additional 1.0-1.5 log CFU/g over the subsequent 24 hours.
For patients with large bacterial burdens (eg, individuals with ventilator-requiring hospital-acquired pneumonia), it is imperative to kill ≥2 log10 CFU/g early after treatment initiation, to allow the granulocytes to contribute optimally to bacterial clearance.
如先前所示，粒细胞杀死细菌病原体是一个饱和过程。关于粒细胞如何与抗菌化疗相互作用以杀死细菌细胞，几乎没有定量信息。
我们在粒细胞充足的小鼠肺炎模型中，对氨基糖苷类药物普拉佐米星针对铜绿假单胞菌ATCC27853进行了剂量范围研究。普拉佐米星以人性化方式给药（即，在24小时内分5次给予递减剂量，模拟人类每日给药模式）。在血浆和上皮衬液中进行药代动力学分析。所有样本同时用群体模型进行分析。小鼠队列治疗24小时；接受相同治疗的其他队列在治疗停止后再观察24小时，从而确定将细菌负荷降低至半饱和点以下水平所需的治疗效果。
粒细胞介导的杀伤达到半饱和时的平均细菌负荷（±标准差）为每克组织2.45×10⁶±6.84×10⁵菌落形成单位的细菌（CFU/g）。更高水平的普拉佐米星暴露将细菌负荷降低至<5 log₁₀CFU/g，使粒细胞在随后24小时内能够额外杀死1.0 - 1.5 log CFU/g。
对于细菌负荷量大的患者（例如，需要使用呼吸机的医院获得性肺炎患者），在治疗开始后尽早杀死≥2 log₁₀CFU/g至关重要，以便粒细胞能够最佳地促进细菌清除。
