替考拉宁是治疗囊性纤维化患者金黄色葡萄球菌感染的一种有前途的抗菌药物选择。
Tedizolid is a promising antimicrobial option for the treatment of Staphylococcus aureus infections in cystic fibrosis patients.
机构信息
Department of Pathology and Genomic Medicine, Center for Molecular and Translational Human Infectious Diseases Research, Houston Methodist Research Institute, Houston, TX, USA.
出版信息
J Antimicrob Chemother. 2020 Jan 1;75(1):126-134. doi: 10.1093/jac/dkz418.
BACKGROUND
Tedizolid is a protein synthesis inhibitor in clinical use for the treatment of Gram-positive infections. Pulmonary MRSA infections are a growing problem in patients with cystic fibrosis (CF) and the efficacy of tedizolid-based therapy in CF pulmonary infections is unknown.
OBJECTIVES
To evaluate the in vitro and in vivo activity of tedizolid and predict the likelihood of tedizolid resistance selection in CF-background Staphylococcus aureus strains.
METHODS
A collection of 330 S. aureus strains (from adult and paediatric patients), either of normal or small colony variant (SCV) phenotypes, gathered at three CF centres in the USA was used. Tedizolid activity was assessed by broth microdilution, Etest and time-kill analysis. In vivo tedizolid efficacy was tested in a murine pneumonia model. Tedizolid in vitro mutants were obtained by 40 days of exposure and progressive passages. Whole genome sequencing of clinical S. aureus strains with reduced susceptibility to tedizolid was performed.
RESULTS
MRSA strain MIC90s were tedizolid 0.12-0.25 mg/L and linezolid 1-2 mg/L; for MSSA strains, MIC90s were tedizolid 0.12 mg/L and linezolid 1-2 mg/L. Two strains, WIS 441 and Seattle 106, with tedizolid MICs of 2 mg/L and 1 mg/L, respectively, had MICs above the FDA tedizolid breakpoint (0.5 mg/L). Tedizolid at free serum concentrations exhibited a bacteriostatic effect. Mean bacterial burdens in lungs (log10 cfu/g) for WIS 423-infected mice were: control, 11.2±0.5; tedizolid-treated (10 mg/kg), 3.40±1.87; linezolid-treated (40 mg/kg), 4.51±2.1; and vancomycin-treated (30 mg/kg), 5.21±1.93. For WIS 441-infected mice the (log10 cfu/g) values were: control, 9.66±0.8; tedizolid-treated, 3.18±1.35; linezolid-treated 5.94±2.19; and vancomycin-treated, 4.35±1.7.
CONCLUSIONS
These results suggest that tedizolid represents a promising therapeutic option for the treatment of CF-associated MRSA/MSSA infections, having potent in vivo activity and low resistance potential.
背景
替加环素是一种临床用于治疗革兰氏阳性感染的蛋白质合成抑制剂。囊性纤维化（CF）患者的肺部耐甲氧西林金黄色葡萄球菌（MRSA）感染是一个日益严重的问题，替加环素为基础的治疗在 CF 肺部感染中的疗效尚不清楚。
目的
评估替加环素的体外和体内活性，并预测 CF 背景下金黄色葡萄球菌株中替加环素耐药选择的可能性。
方法
使用了在美国三个 CF 中心收集的 330 株金黄色葡萄球菌（来自成人和儿科患者），包括正常或小菌落变异（SCV）表型。通过肉汤微量稀释法、Etest 和时间杀伤分析评估替加环素的活性。在小鼠肺炎模型中测试替加环素的体内疗效。通过 40 天的暴露和连续传代获得替加环素体外突变株。对替加环素敏感性降低的临床金黄色葡萄球菌进行全基因组测序。
结果
MRSA 菌株 MIC90 为替加环素 0.12-0.25mg/L 和利奈唑胺 1-2mg/L；MSSA 菌株 MIC90 为替加环素 0.12mg/L 和利奈唑胺 1-2mg/L。两株具有替加环素 MIC 为 2mg/L 和 1mg/L 的 WIS 441 和西雅图 106 株，其 MIC 高于 FDA 替加环素折点（0.5mg/L）。替加环素在游离血清浓度下表现出抑菌作用。WIS 423 感染小鼠肺部的平均细菌负荷（log10cfu/g）为：对照组，11.2±0.5；替加环素治疗（10mg/kg）组，3.40±1.87；利奈唑胺治疗（40mg/kg）组，4.51±2.1；万古霉素治疗（30mg/kg）组，5.21±1.93。对于 WIS 441 感染的小鼠，（log10cfu/g）值为：对照组，9.66±0.8；替加环素治疗组，3.18±1.35；利奈唑胺治疗组 5.94±2.19；万古霉素治疗组，4.35±1.7。
结论
这些结果表明，替加环素代表了一种有前途的治疗 CF 相关 MRSA/MSSA 感染的治疗选择，具有强大的体内活性和低耐药潜力。
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