Xie Rujia, Rogers Halley, Chow Joseph W, Soto Elena, Raber Susan R
Pfizer Ltd, Singapore, Singapore.
Pfizer Inc, New York, New York, USA.
Antimicrob Agents Chemother. 2025 Aug 6;69(8):e0195024. doi: 10.1128/aac.01950-24. Epub 2025 Jun 18.
Aztreonam-avibactam, a fixed-ratio (3:1) β-lactam/β-lactamase inhibitor combination, was approved in Europe in 2024 for adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection, hospital-acquired/ventilator-associated pneumonia, and other infections due to aerobic gram-negative organisms with limited treatment options. Pharmacokinetic data from two phase 3 trials were added to previous data to develop a simultaneous aztreonam and avibactam population pharmacokinetic model. The final model was used to simulate exposures by infection type and renal function and estimate the joint probability of pharmacodynamic target attainment (PTA) for phase 3 patients (aztreonam 60% T >MIC of 8 mg/L and avibactam 50% T >C of 2.5 mg/L). Additional simulations evaluated simplified loading doses, regimens for end-stage renal disease, and ceftazidime-avibactam + aztreonam regimens. The final model included 4,914 aztreonam plasma samples (431 subjects) and 18,222 avibactam plasma samples (2,635 subjects). A two-compartment model with zero-order infusion and first-order elimination best fit the data. Time-varying creatinine clearance was a key covariate on clearance for both drugs, whereas infection type was a key covariate on clearance and volume, with the lowest exposures observed in patients with cIAI. Final aztreonam-avibactam dose regimens achieved joint PTA 89% to >99% at steady state across renal function groups. Ceftazidime-avibactam + aztreonam dose regimens proposed by the Infectious Diseases Society of America (IDSA) achieved joint PTA <85% due to insufficient avibactam exposures. Approved aztreonam-avibactam dose regimens (single loading dose and regular maintenance doses, all 3 h intravenous infusions) are optimized for joint PTA across renal function groups and infection types.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03329092 and NCT03580044.
氨曲南-阿维巴坦是一种固定比例（3:1）的β-内酰胺/β-内酰胺酶抑制剂组合，于2024年在欧洲获批用于患有复杂性腹腔内感染（cIAI）、复杂性尿路感染、医院获得性/呼吸机相关性肺炎以及因需氧革兰氏阴性菌引起的其他感染且治疗选择有限的成人患者。来自两项3期试验的药代动力学数据被添加到先前的数据中，以建立一个同时包含氨曲南和阿维巴坦的群体药代动力学模型。最终模型用于按感染类型和肾功能模拟暴露情况，并估计3期患者达到药效学靶点（PTA）的联合概率（氨曲南60%T>MIC为8mg/L，阿维巴坦50%T>C为2.5mg/L）。额外的模拟评估了简化负荷剂量、终末期肾病的给药方案以及头孢他啶-阿维巴坦+氨曲南给药方案。最终模型包括4914份氨曲南血浆样本（431名受试者）和18222份阿维巴坦血浆样本（2635名受试者）。具有零级输注和一级消除的二室模型最符合数据。随时间变化的肌酐清除率是两种药物清除率的关键协变量，而感染类型是清除率和血容量的关键协变量，在cIAI患者中观察到的暴露量最低。最终的氨曲南-阿维巴坦给药方案在各肾功能组稳态时实现了89%至>99%的联合PTA。美国传染病学会（IDSA）提出的头孢他啶-阿维巴坦+氨曲南给药方案因阿维巴坦暴露不足而导致联合PTA<85%。获批的氨曲南-阿维巴坦给药方案（单次负荷剂量和常规维持剂量，均为3小时静脉输注）针对各肾功能组和感染类型的联合PTA进行了优化。临床试验本研究已在ClinicalTrials.gov注册，注册号为NCT03329092和NCT03580044。
