Witowski Andrea, Palmowski Lars, Minichmayr Iris K, Zeitlinger Markus, Dorn Christoph, Lier Constantin, Adamzik Michael, Nowak Hartmuth, Rahmel Tim
Klinik für Anästhesiologie, Intensivmedizin und Schmerztherapie, Universitätsklinikum Knappschaftskrankenhaus Bochum, D-44892 Bochum, Germany.
Department of Clinical Pharmacology, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria.
J Antimicrob Chemother. 2024 Dec 2;79(12):3297-3302. doi: 10.1093/jac/dkae361.
The rise in carbapenem-resistant bacteria and the limited number of effective antibiotics pose a major health-care threat. The combination of ceftazidime (CAZ) and avibactam (AVI) represents an approved treatment option for carbapenem-resistant intra-abdominal infections. However, data on the pharmacokinetic profile of AVI in the hepatobiliary compartment is lacking.
To provide clinical in vivo data on the concentration of AVI in bile fluid as a surrogate for hepatobiliary excretion.
A single dose of 2000/500 mg CAZ/AVI was administered prolonged over 2 h to 10 patients prior to abdominal surgery, with bile samples available in nine patients in this phase IIb study (DRKS-ID: DRKS00023533). Antibiotic concentrations in plasma (0-8 h), bile (after resection) and pharmacodynamic parameters were determined.
The mean concentration across individuals in bile was 33.5 mg/L (±20.5 mg/L) for CAZ and 7.1 mg/L (±3.5 mg/L) for AVI, resulting in bile/plasma ratios of 0.58 (±0.26) and 0.61 (±0.18). The Cmax in plasma was 87.2 mg/L (±25.0 mg/L) for CAZ and 18.6 mg/L (±6.29 mg/L) for AVI, with AUC0-∞ values of 351 h·mg/L (±104 h·mg/L) and 72.1 h·mg/L (±32.1 h·mg/L), respectively. Plasma concentrations of both CAZ and AVI remained more than 50% of the dosing interval above the minimum inhibitory concentrations (T>MIC > 50%; MICCAZ = 8 mg/L, MICAVI = 1 mg/L) in all patients. No antibiotic-associated side effects were reported during the 30-day follow-up.
The concentrations of CAZ and AVI in bile suggest their potential as a valuable therapeutic option for multi-resistant biliary infections.
耐碳青霉烯类细菌的增加以及有效抗生素数量有限对医疗保健构成了重大威胁。头孢他啶（CAZ）和阿维巴坦（AVI）联合用药是耐碳青霉烯类腹腔内感染的一种已获批治疗方案。然而，缺乏关于AVI在肝胆系统药代动力学特征的数据。
提供AVI在胆汁中的浓度这一反映肝胆排泄情况的临床体内数据。
在腹部手术前，对10例患者进行2小时的2000/500mg CAZ/AVI单剂量延长给药，在这项IIb期研究（DRKS-ID：DRKS00023533）中，9例患者可获得胆汁样本。测定血浆（0 - 8小时）、胆汁（切除后）中的抗生素浓度以及药效学参数。
CAZ在胆汁中的个体平均浓度为33.5mg/L（±20.5mg/L），AVI为7.1mg/L（±3.5mg/L），胆汁/血浆比值分别为0.58（±0.26）和0.61（±0.18）。CAZ在血浆中的Cmax为87.2mg/L（±25.0mg/L），AVI为18.6mg/L（±6.29mg/L），AUC0-∞值分别为351h·mg/L（±104h·mg/L）和72.1h·mg/L（±32.1h·mg/L）。在所有患者中，CAZ和AVI的血浆浓度在给药间隔期间均保持在最低抑菌浓度以上50%以上（T>MIC>50%；MICCAZ = 8mg/L，MICAVI = 1mg/L）。在30天的随访期间未报告与抗生素相关的副作用。
CAZ和AVI在胆汁中的浓度表明它们有可能成为多重耐药性胆道感染的一种有价值的治疗选择。
