Millar B C, Rendall J C, Downey D G, Moore J E
Northern Ireland Public Health Laboratory, Department of Bacteriology, Belfast City Hospital, Belfast, UK.
School of Biomedical Sciences, Ulster University, Coleraine, UK.
J Clin Pharm Ther. 2018 Dec;43(6):836-843. doi: 10.1111/jcpt.12722. Epub 2018 Jun 29.
Ivacaftor is a novel potentiator of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein, which corrects the gating defect and increases ion-function of activated cell-surface CFTR. Bacteria also regulate their physiology through ion channels. However, little is known about the potential effects of ivacaftor on bacterial ion channels, which, in turn, may have a potential effect on transport across the bacterial cell membrane. Therefore, any change in the ability to transport molecules across cell membranes in bacteria could have an important impact on bacterial transport physiology. One area where this could be particularly important is in the movement of antibiotics, both into and out of the bacterial cell. An in vitro study was therefore performed to examine the influence of ivacaftor at therapeutic concentration on antibiotic susceptibility of 11 commonly used anti-pseudomonal antibiotics against a population of clinical Pseudomonas aeruginosa [PA], from CF and non-CF sources.
Pseudomonas aeruginosa (n = 80; including 70 ivacaftor-naïve clinical PA from sputa from adult CF patients and 10 control PA from non-CF clinical blood culture sources) were examined. Antibiotic susceptibility was determined by standard disc diffusion assay using CLSI criteria and measuring zone size (mm), against four classes of anti-pseudomonal antibiotics, including beta-lactams (temocillin, ceftazidime, piperacillin/tazobactam, imipenem, meropenem and aztreonam), aminoglycosides (gentamicin, tobramycin, amikacin), fluoroquinolone (ciprofloxacin) and polymyxin (colistin), in the absence and presence of ivacaftor (5 μmol/L), as previously determined. In addition, all CF and non-CF PA were examined phenotypically in vitro, as previously described, for changes linked to bacterial virulence, including (i) growth density (ii) pigmentation, (iii) presence of adhesins and (iv) change to mucoidy, in the presence/absence of ivacaftor at therapeutic concentration.
Antibiotic susceptibility did not decrease significantly with any of the antibiotics examined with CF PA isolates or with non-CF PA control organisms. There was a statistically significant increase in zone size (CF PA and amikacin, gentamicin, temocillin and ciprofloxacin; Non-CF PA and amikacin, gentamicin and aztreonam). However, at a population level, this did not translate into a shift in CLSI category to a more susceptible phenotype. None of the PA isolates examined were susceptible to ivacaftor alone, and additionally, no changes were noted with the four phenotypic parameters examined in the presence of ivacaftor.
This study showed that antibiotic susceptibility of commonly used anti-pseudomonal antibiotics was not negatively affected by ivacaftor, in a population of ivacaftor-naive P. aeruginosa.
依伐卡托是一种新型的针对缺陷型囊性纤维化跨膜传导调节因子（CFTR）蛋白的增效剂，可纠正门控缺陷并增强活化的细胞表面CFTR的离子功能。细菌也通过离子通道调节其生理功能。然而，关于依伐卡托对细菌离子通道的潜在影响知之甚少，而这反过来可能会对细菌细胞膜的转运产生潜在影响。因此，细菌跨细胞膜转运分子能力的任何变化都可能对细菌转运生理学产生重要影响。在一个特别重要的领域是抗生素进出细菌细胞的转运。因此，进行了一项体外研究，以考察治疗浓度的依伐卡托对11种常用抗铜绿假单胞菌抗生素针对来自囊性纤维化（CF）和非CF来源的临床铜绿假单胞菌（PA）群体的药敏性的影响。
检测了铜绿假单胞菌（n = 80；包括70株来自成年CF患者痰液的未接触过依伐卡托的临床PA和10株来自非CF临床血培养来源的对照PA）。根据CLSI标准，通过标准纸片扩散法测定抗生素敏感性，并测量抑菌圈大小（mm），针对四类抗铜绿假单胞菌抗生素，包括β-内酰胺类（替莫西林、头孢他啶、哌拉西林/他唑巴坦、亚胺培南、美罗培南和氨曲南）、氨基糖苷类（庆大霉素、妥布霉素、阿米卡星）、氟喹诺酮类（环丙沙星）和多粘菌素类（黏菌素），分别在有和没有依伐卡托（5 μmol/L）的情况下进行检测，依伐卡托浓度如前所述。此外，如前所述，对所有CF和非CF PA进行体外表型检测，以观察与细菌毒力相关的变化，包括（i）生长密度（ii）色素沉着，（iii）黏附素的存在情况以及（iv）在治疗浓度的依伐卡托存在/不存在的情况下向黏液样转变的情况。
对于CF PA分离株或非CF PA对照菌株所检测的任何一种抗生素，药敏性均未显著降低。抑菌圈大小有统计学意义的增加（CF PA与阿米卡星、庆大霉素、替莫西林和环丙沙星；非CF PA与阿米卡星、庆大霉素和氨曲南）。然而，在群体水平上，这并未转化为CLSI分类向更敏感表型的转变。所检测的PA分离株中没有一个对单独的依伐卡托敏感，此外，在依伐卡托存在的情况下，所检测的四个表型参数均未观察到变化。
本研究表明，在未接触过依伐卡托的铜绿假单胞菌群体中，常用抗铜绿假单胞菌抗生素的药敏性不受依伐卡托的负面影响。
