Koenig Christina, Monogue Marguerite L, Shields Ryan K, Sakon Colleen M, Fratoni Andrew J, Roenfanz Hanna F, Finklea James D, Pope James S, Nicolau David P, Kuti Joseph L
Center for Anti-Infective Research & Development, Hartford Hospital, Hartford, Connecticut, USA.
Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Antimicrob Agents Chemother. 2025 Jan 31;69(1):e0153924. doi: 10.1128/aac.01539-24. Epub 2024 Dec 10.
Persons with CF (pwCF) present altered pharmacokinetics (PK) and are often infected with multidrug-resistant (MDR) bacteria. Herein, we describe the PK of cefiderocol, a siderophore cephalosporin with potent activity against MDR Gram-negative rods, in hospitalized adult pwCF with acute pulmonary exacerbation (APE). PwCF received ≥3 doses of 2 g cefiderocol (3 h infusion) with frequency determined according to their estimated glomerular filtration rate (eGFR). Blood sampling collected at steady state. Concentrations were fitted using the non-parametric adaptive grid algorithm in Pmetrics for R. Ten pwCF were enrolled; nine completed the study with six receiving 2 g q8 h and three 2 g q6 h. A two-compartment model best fitted the data. Mean (SD) PK parameters were clearance, 5.66 (1.28) L/h; volume of central compartment, 5.81 (3.52) L, and intercompartment transfer constants, k12, 4.29 (3.46) and k21, 2.25 (2.76) h. Protein binding was 48% (35-57). The 2 g q8 h regimen achieved a mean free time above the MIC (T >MIC) of 99% (94-99), 90% (69-100), and 64% (41-81) at MICs of 4 (susceptible), 8 (intermediate), and 16 (resistant) mg/L, respectively, with AUC of 1,191 (781-1,496) mg/Lh. In pwCF with eGFR >120 mL/min, 2 g q6 h attained 100% T >MIC up to 8 mg/L and 87% (83-92) at 16 mg/L, with AUC of 1,279 (1,054-1,590) mg/Lh. Among these nine pwCF with APE with normal or augmented renal clearance, cefiderocol using label prescribed dosing regimens according to eGFR was well tolerated and achieved optimal T >MIC exposure for pathogens up to MICs of 8 mg/L and AUC estimates similar to previously reported estimates in non-CF patients.
患有囊性纤维化（CF）的患者（pwCF）存在药代动力学（PK）改变，且常感染多重耐药（MDR）细菌。在此，我们描述了头孢地尔在患有急性肺部加重（APE）的住院成年pwCF中的PK情况，头孢地尔是一种对MDR革兰氏阴性杆菌具有强效活性的铁载体头孢菌素。pwCF接受≥3剂2g头孢地尔（3小时输注），给药频率根据其估计肾小球滤过率（eGFR）确定。在稳态时进行血样采集。使用R语言的Pmetrics中的非参数自适应网格算法对浓度进行拟合。纳入了10名pwCF；9名完成了研究，其中6名接受每8小时2g，3名接受每6小时2g。二室模型最能拟合数据。平均（标准差）PK参数为清除率5.66（1.28）L/h；中央室容积5.81（3.52）L，以及室间转运常数，k12为4.29（3.46），k21为2.25（2.76）h。蛋白结合率为48%（35 - 57）。每8小时2g的给药方案在4mg/L（敏感）、8mg/L（中介）和16mg/L（耐药）的MIC时，游离时间高于MIC（T>MIC）的平均值分别为99%（94 - 99）、90%（69 - 100）和64%（41 - 81），AUC为1191（781 - 1496）mg/Lh。在eGFR>120mL/min的pwCF中，每6小时2g的给药方案在高达8mg/L时T>MIC达到100%，在16mg/L时为87%（83 - 92），AUC为1279（1054 - 1590）mg/Lh。在这9名患有APE且肾清除率正常或增加的pwCF中，根据eGFR使用标签规定的给药方案的头孢地尔耐受性良好，对于高达8mg/L MIC的病原体实现了最佳的T>MIC暴露，且AUC估计值与先前在非CF患者中报道的估计值相似。
