GSK656与克拉霉素、阿奇霉素体外协同抗脓肿分枝杆菌的活性研究

doi:10.3969/j.issn.1000-6621.2021.02.010

中国防痨杂志 ›› 2021, Vol. 43 ›› Issue (2): 153-158.doi: 10.3969/j.issn.1000-6621.2021.02.010

GSK656与克拉霉素、阿奇霉素体外协同抗脓肿分枝杆菌的活性研究

郭海萍, 陈磊, 霍凤敏, 逄宇, 李姗姗()

101149 首都医科大学附属北京胸科医院细菌免疫室[郭海萍(研究生)、霍凤敏、逄宇、李姗姗];山东省潍坊市第二人民医院检验科(陈磊)
101149 首都医科大学附属北京胸科医院细菌免疫室[郭海萍(研究生)、霍凤敏、逄宇、李姗姗];101149 首都医科大学附属北京胸科医院细菌免疫室[郭海萍(研究生)、霍凤敏、逄宇、李姗姗];山东省潍坊市第二人民医院检验科(陈磊)
101149 首都医科大学附属北京胸科医院细菌免疫室[郭海萍(研究生)、霍凤敏、逄宇、李姗姗];山东省潍坊市第二人民医院检验科(陈磊)

收稿日期:2020-09-14 出版日期:2021-02-10 发布日期:2021-02-03
通信作者: 郭海萍,李姗姗 E-mail:lss9011@126.com
基金资助:
北京市医院管理中心“登峰”人才培养计划(DFL20191601);北京市医院管理中心“扬帆”专业建设(ZYLX202122)

The study of in vitro synergistic activities of GSK656 with clarithromycin or azithromycin against Mycobacterium abscessus

GUO Hai-Ping, CHEN Lei, HUO Feng-min, PANG Yu, LI Shan-Shan()

^*Department of Bacteriology and Immunology, Beijing Chest Hospital, Capital Medical University, Beijing 101149, China

Received:2020-09-14 Online:2021-02-10 Published:2021-02-03
Contact: GUO Hai-Ping,LI Shan-Shan E-mail:lss9011@126.com

摘要/Abstract

摘要：

目的评价3-氨甲基-4-卤代苯并恶唑类化合物GSK656与大环内酯类药物克拉霉素、阿奇霉素联合用药对脓肿分枝杆菌的体外抗菌活性。方法收集2016—2018年期间首都医科大学附属北京胸科医院菌株库保存的非结核分枝杆菌共80株,包括脓肿分枝杆菌30株,堪萨斯分枝杆菌7株,胞内分枝杆菌37株,鸟分枝杆菌5株和偶发分枝杆菌1株;将30株脓肿分枝杆菌纳入本研究。用微孔阿尔玛蓝检测法(MABA法)测定GSK656、克拉霉素和阿奇霉素对脓肿分枝杆菌的体外最低抑菌浓度(MIC),并采用棋盘稀释法检测GSK656分别与克拉霉素、阿奇霉素联合用药时的体外抗菌作用。结果克拉霉素对脓肿分枝杆菌的MIC为0.031~16mg/L, 其耐药率为10.0%(3/30)。阿奇霉素对脓肿分枝杆菌的MIC为0.125~64mg/L,其耐药率为30.0%(9/30)。GSK656对脓肿分枝杆菌分离株的MIC₅₀和MIC₉₀分别为0.25mg/L和2mg/L。在GSK656-克拉霉素联合中,6株(20.0%,6/30)表现为协同作用,23株(76.7%,23/30)为无关,1株(3.3%,1/30)为拮抗;在GSK656-阿奇霉素联合中,3株(10.0%,3/30)为协同,18株(60.0%,18/30)为无关,9株(30.0%,9/30)为拮抗,GSK656联合克拉霉素组与GSK656联合阿奇霉素组的联合效应差异有统计学意义(χ²=8.010,P=0.018)。结论 GSK656具有良好的体外抗脓肿分枝杆菌的活性。GSK656联合克拉霉素组与GSK656联合阿奇霉素组的联合效应有差异,其中拮抗效应在GSK656与阿奇霉素联合用药时更多见。

关键词: GSK656, 抗菌药, 分枝杆菌,非典型性, 药物评价

Abstract:

Objective The purpose of this study was to assess in vitro drug susceptibility of M.abscessus against the combinations of the 3-aminomethyl 4-halogen benzoxaboroles compound GSK656 with macrolides, including clarithromycin (Clr) and azithromycin (Azm). Methods Eighty nontuberculous mycobacteria isolates were stored the biobank of Beijing Chest Hospital, Capital Medical University between 2016 and 2018, consisting of 30 isolates of M.abscessus, 7 isolates of Mycobacterium kansasii,37 isolates of Mycobacterium intracellulare, 5 isolates of Mycobacterium avium and 1 isolates of Mycobacterium fortuitum. The minimal inhibitory concentrations (MICs) were determined using Microporous Alamar-Blue Assay (MABA). Additionally, the checkerboard titration method was used to determine the synergistic effect between GSK656 and other antimicrobial agents. Results For Clr, the MIC values of M.abscessus isolates ranged from 0.031 mg/L to 16 mg/L. The proportion of Clr resistance was 10.0% (3/30) for M.abscessus. For Azm, the MIC values of M.abscessus isolates ranged from 0.125 to 64 mg/L. The Azm resistance was noted in 30.0% (9/30) of M.abscessus isolates. Additionally, GSK656 also exhibited the potent activity against M.abscessus isolates, the MIC₅₀ and MIC₉₀ of which were 0.25 and 2 mg/L, respectively. In the GSK656-Clr combination, 6 (20.0%,6/30) were synergistic, 23 (76.7%,23/30) were indifferent,1 (3.3%,1/30) was antagonistic. For the GSK656-Azm combination, 3 (10.0%,3/30) was synergistic, 18 (60.0%,18/30) were indifferent, and 9(30.0%,9/30)were antagonistic. Chi-square test results revealed that there was a statistically significant difference in synergistic distribution between GSK-Clr and GSK-Azm group (χ²=8.010,P=0.018). Conclusion Our data demonstrate that GSK656 has promising activity against M.abscessus in vitro. The synergistic distribution between GSK-Clr group and GSK-Azm group is statistically significant. The antagonistic effect is more frequent for GSK-Azm combination than GSK-Clr combination.

Key words: GSK656, Antimicrobial agent, Mycobacteria,atypical, Drug evaluation

郭海萍, 陈磊, 霍凤敏, 逄宇, 李姗姗. GSK656与克拉霉素、阿奇霉素体外协同抗脓肿分枝杆菌的活性研究[J]. 中国防痨杂志, 2021, 43(2): 153-158. doi: 10.3969/j.issn.1000-6621.2021.02.010

GUO Hai-Ping, CHEN Lei, HUO Feng-min, PANG Yu, LI Shan-Shan. The study of in vitro synergistic activities of GSK656 with clarithromycin or azithromycin against Mycobacterium abscessus[J]. Chinese Journal of Antituberculosis, 2021, 43(2): 153-158. doi: 10.3969/j.issn.1000-6621.2021.02.010

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关系	MIC范围 (mg/L)				FICI范围	菌株数
关系	单药 GSK656	单药 Azm	联合 GSK656	联合 Azm	FICI范围	菌株数
协同	2~8	0.25~1	0.5~2	0.063~0.25	0.375~0.5	3
无关	0.125~4	0.125~64	0.063~2	0.063~32	0.75~2	18
拮抗	0.063~0.5	0.125~1	0.063~1	0.25~4	3~8.5	9

关系	MIC范围 (mg/L)				FICI范围	菌株数
关系	单药 GSK656	单药 Clr	联合 GSK656	联合 Clr	FICI范围	菌株数
协同	0.25~4	0.031~0.125	0.063~1	0.008~1	0.3125~0.5	6
无关	0.063~8	0.031~16	0.063~2	0.008~4	0.625~2	23
拮抗	0.125	0.031	0.125	0.125	5	1

关系	菌株[株(构成比,%)]		χ²值	P值
关系	GSK656-Clr	GSK656-Azm	χ²值	P值
协同	6(20.0)	3(10.0)	8.010	0.018
无关	23(76.7)	18(60.0)
拮抗	1(3.3)	9(30.0)

GSK656与克拉霉素、阿奇霉素体外协同抗脓肿分枝杆菌的活性研究

The study of in vitro synergistic activities of GSK656 with clarithromycin or azithromycin against Mycobacterium abscessus

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药物	MIC值范围 (mg/L)	MIC₅₀ 值 (mg/L)	MIC₉₀ 值 (mg/L)	MIC值菌株分布(株)
药物	MIC值范围 (mg/L)	MIC₅₀ 值 (mg/L)	MIC₉₀ 值 (mg/L)	0.031 mg/L	0.063 mg/L	0.125 mg/L	0.25 mg/L	0.5 mg/L	1 mg/L	2 mg/L	4 mg/L	8 mg/L	16 mg/L	32 mg/L	64 mg/L
GSK656	0.063~8	0.25	2	0	1	6	10	6	1	4	1	1	0	0	0
Azm	0.125~64	1	32	0	0	4	2	2	11	0	2	1	4	3	1
Clr	0.031~16	0.125	4	6	3	9	4	0	0	1	4	1	2	0	0

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