Bollar Gretchen E, Shaffer Kendall M, Keith Johnathan D, Oden Ashley M, Dowell Alexander E, Ryan Kevin J, Acosta Edward P, Guimbellot Jennifer S, Kiedrowski Megan R, Birket Susan E
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, USA.
JAC Antimicrob Resist. 2024 Nov 20;6(6):dlae185. doi: 10.1093/jacamr/dlae185. eCollection 2024 Dec.
Ivacaftor exhibits anti-staphylococcal properties but does not clear from the lungs of people with cystic fibrosis (pwCF). We assessed whether exposure to therapeutic concentrations of ivacaftor could allow to form small colony variants (SCVs), a phenotype commonly associated with bacterial persistence.
Humanized G551D-CFTR (hG551D) rats were treated with ivacaftor for 7 days. Concentrations in the plasma, epithelial lining fluid and lung tissue lysate were measured using LC-MS/MS. Survival of during ivacaftor treatment was assessed in an hG551D rat model of lung infection. adaptation to therapeutic concentrations of ivacaftor was investigated by serial passage in the presence of 10 µM ivacaftor. Bacterial survival in the presence of antimicrobials was evaluated using growth curves and density assays.
Ivacaftor plasma concentrations of treated hG551D rats reached 3.488 ± 1.118 µM, with more variable concentrations in the epithelial lining fluid and lung tissue lysate. During infection, ivacaftor-treated hG551D rats returned similar numbers of bacteria from the lung, compared with vehicle-treated controls. Exposure of to ivacaftor led to the formation of ivacaftor-tolerant SCVs with an unstable phenotype and increased antibiotic tolerance.
Treatment with ivacaftor did not alter burden in the cystic fibrosis rat and led to the formation of tolerant SCVs , suggesting that development of an SCV phenotype may allow to persist in the cystic fibrosis lung during ivacaftor therapy.
依伐卡托具有抗葡萄球菌特性，但无法从囊性纤维化患者（pwCF）的肺部清除。我们评估了暴露于治疗浓度的依伐卡托是否会促使形成小菌落变异体（SCV），这是一种通常与细菌持续存在相关的表型。
用人源化G551D - CFTR（hG551D）大鼠接受依伐卡托治疗7天。使用液相色谱 - 串联质谱法（LC - MS/MS）测量血浆、上皮衬液和肺组织裂解物中的浓度。在hG551D大鼠肺部感染模型中评估依伐卡托治疗期间的生存率。通过在10 μM依伐卡托存在下连续传代研究对依伐卡托治疗浓度的适应性。使用生长曲线和密度测定法评估抗菌药物存在下的细菌存活率。
接受治疗的hG551D大鼠的依伐卡托血浆浓度达到3.488 ± 1.118 μM，上皮衬液和肺组织裂解物中的浓度变化更大。在感染期间，与载体治疗的对照组相比，依伐卡托治疗的hG551D大鼠从肺部排出的细菌数量相似。暴露于依伐卡托导致形成具有不稳定表型和增加抗生素耐受性的依伐卡托耐受SCV。
依伐卡托治疗并未改变囊性纤维化大鼠的细菌负荷，并导致形成耐受SCV，这表明SCV表型的发展可能使细菌在依伐卡托治疗期间在囊性纤维化肺部持续存在。
