Tsala Marilena, Vourli Sophia, Daikos George L, Tsakris Athanassios, Zerva Loukia, Mouton Johan W, Meletiadis Joseph
Clinical Microbiology Laboratory, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
First Department of Propaedeutic Medicine, Laikon Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
J Antimicrob Chemother. 2017 Jan;72(1):172-180. doi: 10.1093/jac/dkw354. Epub 2016 Sep 19.
In the absence of other therapeutic options, tigecycline is used to treat bloodstream infections and pneumonia caused by carbapenemase-producing Klebsiella pneumoniae (CP-Kp). In this study, the standard and high tigecycline dosing regimens were simulated and tested against different inocula of CP-Kp isolates in an in vitro pharmacokinetic (PK)/pharmacodynamic (PD) model.
Four susceptible isolates (EUCAST MICs of 0.125-1 mg/L) and two intermediately susceptible CP-Kp clinical isolates (MICs of 2 mg/L) were tested at three different inocula (10, 10 and 10 cfu/mL), simulating tigecycline serum and lung fC concentrations of 0.15 and 1.5 mg/L, respectively, of 50 mg tigecycline every 12 h for 48 h. The exposure-effect relationships were described and the probability of target attainment was calculated for each inoculum in order to determine PK/PD susceptibility breakpoints.
No cfu reduction was observed at serum concentrations. At lung concentrations and low inocula, a bacteriostatic and killing effect was found for isolates with MICs of 0.25 and 0.125 mg/L, respectively. The fAUC/MIC (tAUC/MIC) associated with half-maximal activity was 16 (150) with 10 cfu/mL, 28 (239) with 10 cfu/mL and 79 (590) with 10 cfu/mL. A PK/PD susceptibility breakpoint of ≤0.06 and ≤0.125 mg/L for bacteraemia with ≤10 cfu/mL and ≤0.25 and ≤0.5 mg/L for pneumonia with ≤10 cfu/g was determined for the standard tigecycline dose of 50 mg and the higher dose of 100 mg, respectively.
Tigecycline monotherapy with either 50 or 100 mg would not be sufficient for most patients with bacteraemia, though the higher dose of 100 mg could be effective for patients with pneumonia with low bacterial load.
在没有其他治疗选择的情况下，替加环素用于治疗由产碳青霉烯酶的肺炎克雷伯菌（CP-Kp）引起的血流感染和肺炎。在本研究中，在体外药代动力学（PK）/药效学（PD）模型中，对标准和高剂量替加环素给药方案针对不同接种量的CP-Kp分离株进行了模拟和测试。
对4株敏感分离株（欧洲抗菌药物敏感性试验委员会（EUCAST）最低抑菌浓度（MIC）为0.125 - 1mg/L）和2株中度敏感的CP-Kp临床分离株（MIC为2mg/L）在3种不同接种量（10⁴、10⁵和10⁶cfu/mL）下进行测试，模拟每12小时给予50mg替加环素，持续48小时后替加环素血清和肺组织游离浓度分别为0.15和1.5mg/L的情况。描述暴露-效应关系，并计算每种接种量下的达标概率，以确定PK/PD敏感性折点。
在血清浓度下未观察到cfu减少。在肺组织浓度和低接种量时，分别发现对MIC为0.25和0.125mg/L的分离株有抑菌和杀菌作用。与半数最大活性相关的fAUC/MIC（tAUC/MIC）在接种量为10⁴cfu/mL时为16（150），10⁵cfu/mL时为28（239），10⁶cfu/mL时为79（590）。对于标准剂量50mg和高剂量100mg的替加环素，分别确定了血流感染且接种量≤10⁴cfu/mL时PK/PD敏感性折点为≤0.06和≤0.125mg/L，肺炎且接种量≤10⁵cfu/g时为≤0.25和≤0.5mg/L。
对于大多数血流感染患者，50mg或100mg的替加环素单药治疗可能不足够，尽管100mg的高剂量对细菌载量低的肺炎患者可能有效。
