Xiao Alan J, Caro Luzelena, Popejoy Myra W, Huntington Jennifer A, Kullar Ravina
Merck & Co., Inc., Kenilworth, NJ, USA.
Infect Dis Ther. 2017 Mar;6(1):137-148. doi: 10.1007/s40121-016-0143-9. Epub 2016 Dec 24.
Ceftolozane/tazobactam is an antibacterial agent with potent in vitro activity against Gram-negative pathogens, including many extended-spectrum β-lactamase-producing Enterobacteriaceae and drug-resistant Pseudomonas aeruginosa. Because ceftolozane/tazobactam is primarily excreted renally, appropriate dose adjustments are needed for patients with renal impairment. Monte Carlo simulations were used to determine the probability of pharmacokinetic/pharmacodynamic target attainment for patients with varying degrees of renal function, including augmented renal clearance (ARC) and end-stage renal disease (ESRD) with hemodialysis.
Monte Carlo simulations were conducted for 1000 patients with ARC and normal renal function, mild renal impairment, moderate renal impairment, or severe renal impairment, and for 5000 patients with ESRD. Simulated dosing regimens were based on approved doses for each renal function category. Attainment targets for ceftolozane were 24.8% (bacteriostasis), 32.2% (1-log kill; bactericidal), and 40% (2-log kill) fT > minimum inhibitory concentration (MIC). The target for tazobactam was to achieve a 20% fT > minimum effective concentration (MEC) at an MEC of 1 mg/L, which was derived from a neutropenic mouse thigh infection model and was confirmed by efficacy data from clinical studies for complicated intraabdominal infections and complicated urinary tract infections.
In patients with ARC or normal renal function, ≥91% achieved bactericidal activity (32.2% fT > MIC) up to an MIC of 4 mg/L with a 1000-mg ceftolozane dose. In patients with renal impairment (mild, moderate, severe, ESRD), ≥93% achieved bactericidal activity up to an MIC of 8 mg/L. In patients of all renal function categories, the approved dosing regimens of tazobactam achieved ≥91% target attainment against a target of 20% fT > MEC.
At the approved dosing regimens for ceftolozane/tazobactam, ≥91% of patients in all renal function categories, including ARC (up to 200 mL/min) and ESRD, reached target attainment for bactericidal activity at MICs that correspond to susceptibility breakpoints for Enterobacteriaceae and P. aeruginosa.
头孢洛扎/他唑巴坦是一种抗菌药物，对革兰氏阴性病原体具有强大的体外活性，包括许多产超广谱β-内酰胺酶的肠杆菌科细菌和耐药铜绿假单胞菌。由于头孢洛扎/他唑巴坦主要经肾脏排泄，肾功能不全患者需要进行适当的剂量调整。采用蒙特卡洛模拟法来确定不同程度肾功能患者（包括增强肾清除率（ARC）和接受血液透析的终末期肾病（ESRD）患者）达到药代动力学/药效学目标的概率。
对1000例ARC患者、肾功能正常患者、轻度肾功能不全患者、中度肾功能不全患者或重度肾功能不全患者，以及5000例ESRD患者进行蒙特卡洛模拟。模拟给药方案基于每个肾功能类别批准的剂量。头孢洛扎的达标目标为fT＞最低抑菌浓度（MIC）的比例达到24.8%（抑菌）、32.2%（1个对数级杀灭；杀菌）和40%（2个对数级杀灭）。他唑巴坦的目标是在最低有效浓度（MEC）为1 mg/L时，fT＞MEC的比例达到20%，这一目标源自中性粒细胞减少小鼠大腿感染模型，并经复杂腹腔内感染和复杂尿路感染临床研究的疗效数据证实。
在ARC或肾功能正常的患者中，使用1000 mg头孢洛扎剂量时，MIC高达4 mg/L时≥91%的患者达到杀菌活性（fT＞MIC为32.2%）。在肾功能不全患者（轻度、中度、重度、ESRD）中，MIC高达8 mg/L时≥93%的患者达到杀菌活性。在所有肾功能类别的患者中，他唑巴坦的批准给药方案针对fT＞MEC达到20%的目标，达标率≥91%。
按照头孢洛扎/他唑巴坦的批准给药方案，所有肾功能类别（包括ARC（高达200 mL/min）和ESRD）中≥91%的患者在与肠杆菌科细菌和铜绿假单胞菌药敏折点对应的MIC水平上达到杀菌活性目标。
