结核分枝杆菌临床分离株对四种注射用抗结核药物耐药及交叉耐药分析

摘要/Abstract

摘要： 目的探讨链霉素（S）、卡那霉素(Km)、阿米卡星(Am)和卷曲霉素(Cm)对结核分枝杆菌的耐药及交叉耐药情况，为耐药结核病的化学治疗提供理论依据。方法对首都医科大学附属北京胸科医院2004年1月至2010年12月间4247株临床分离株的药物敏感试验结果进行分析。采用绝对浓度法进行药物敏感试验。4种药物之间总耐药率的差异采用配对χ²检验及χ²分割法，以P<0.007 14为差异有统计学意义。4种药物之间交叉耐药率的差异采用两个样本率比较的χ²检验，以P<0.05为差异具有统计学意义。结果 4247份临床分离株标本中，S的耐药率为45.11%(1916/4247)，Km的耐药率为17.93%(718/4005)，Am的耐药率为19.02%(792/4164)，Cm的耐药率为9.44%(401/4247)。经配对χ²检验，Cm与S、Am、Km之间耐药率差异有统计学意义，χ²值分别为1349.34、281.54、193.16，P值均小于0.007 14。经配对χ²检验，S与Am、Km之间耐药率差异有统计学意义，χ²值分别为821.10、869.28，P值均小于0.007 14。经配对χ²检验， Am与Km之间耐药率差异有统计学意义，χ²值为13.98，P值小于0.007 14，耐药率从高到低依次为S、Am、Km和Cm。S在其他3种药物的耐药株中的耐药率分别为82.59%（耐Km株，593/718）、77.78%（耐Am株，616/792）、76.81%（耐Cm株，308/401），χ²值分别为502.959、453.911、626.654，P值均小于0.05。Km在另外3种药物耐药株中的耐药率分别为33.13%（耐S株，593/1790）、83.31%（耐Am株，634/761）、67.89%（耐Cm株，260/383），χ²值分别为502.959、12.079、100.536，P值均小于0.05。Am在另外3种药物耐药株的耐药率分别为32.78%（耐S株，616/1879）、89.55%（耐Km株，634/708）、77.95%（耐Cm株，304/390），χ²值分别为453.911、12.079、163.761，P值均小于0.05。Cm在其他3种药物的耐药株中的耐药率分别为16.08%（耐S株，308/1916）、36.21%（耐Km株，260/718）和38.38%（耐Am株，304/792），χ²值分别为626.654、100.536、163.761，P值均小于0.05。结论 4种注射用抗结核药物的耐药率从高到低依次为S、Am、Km和Cm。4种药物之间均表现出交叉耐药，但程度不同。S与其他3种药物之间为单向耐药，Km和Am两个药物之间近似完全交叉耐药，Cm是其他3种药物耐药时的选择药物。

关键词: 分枝杆菌, 结核, 链霉素, 卡那霉素, 阿米卡星, 卷曲霉素硫酸盐, 抗药性, 细菌

Abstract: Objective To investigate the drug resistance and the cross resistance of Mycobacterium tuberculosis isolated from clinical samples to streptomycin (S), kanamycin (Km), amikacin (Am) and capreomycin (Cm) and to provide scientific evidences for clinical treatment of drug resistance tuberculosis. Methods A retrospective study was adopted to analyze the results of drug susceptibility testing(DST) with absolute concentration method of 4247 isolates from patients with tuberculosis in Beijing Chest Hospital from Jan. 2004 to Dec. 2010. Mathed Chi-square test and partition of chi-square were applied for the overall drug resistant rate analysis, while chi-square test was applied to compare the cross resistance to 4 injectable antituberculous drugs. Results The drug resistant rates to the four drugs were 45.11%(S, 1916/4247), 17.93%(Km, 718/4005), 19.02%(Am,792/4164) and 9.44%(Cm, 401/4247) among 4247 resistant isolates respectively. The differences were statistically significant by matched χ²test and partitions of χ² method. The values of χ² were 1349.34 (Cm/S), 281.54 (Cm/Am) and 193.16 (Cm/Km) (P<0.007 14) respectively. For the drug resistant rates of S/Am and S/Km, the values of χ² were 821.10 (S/Am) and 869.28 (S/Km) (P<0.007 14) respectively. The value of χ² was 13.98 (Am/Km) (P<0.007 14). The drug resistant rates sequencing from up to down were S, Am, Km and Cm. The drug resistant rates to S among the other 3 drug-resistance isolates were 82.59%(Km resistant isolates, 593/718), 77.78%(Am resistant isolates, 616/792) and 76.81%(Cm resistant isolates, 308/401) respectively. The values of χ² were 502.959, 453.911 and 626.654 (P<0.05). The drug resistant rates to Km among the other 3 drug-resistance isolates were 33.13%(S resistant isolates, 593/1790), 83.31%(Am resistant isolates, 634/761) and 67.89%(Cm resistant isolates, 260/383) respectively. The values of χ² were 502.959, 12.079 and 100.536 (P<0.05). The drug resistant rates to Am among the other 3 drug-resistance isolates were 32.78%(S resistant isolates, 616/1879), 89.55%(Km resistant isolates, 634/708) and 77.95%(Cm resistant isolates, 304/390) respectively. The values of χ² were 453.911, 12.079 and 163.761 (P<0.05). The drug resistant rates to Cm among the other three drug resistance isolates were 16.08%(S resistant isolates, 308/1916), 36.21%(Km resistant isolates, 260/718) and 38.38%(Am resistant isolates, 304/792) respectively. The values of χ² were 626.654, 100.536 and 163.761(P<0.05). Conclusion The drug resistant rates sequencing from up to down of four injectable antituberculous drugs are streptomycin, amikacin, kanamycin and capreomycin. There are cross resistances among these four drugs with different levels. Streptomycin is unidirectional resistant to the other three drugs. Kanamycin and amikacin are almost full cross-resistant. Capreomycin is the candidate drug when the other three drugs are resistant.

Key words: Mycobacterium tuberculosis, Streptomycin, Kanamycin, Amikacin, Capreomycin sulfate, Drug resistance, bacterial

常珊付育红李琦卜建玲黄海荣马玙陈效友. 结核分枝杆菌临床分离株对四种注射用抗结核药物耐药及交叉耐药分析[J]. 中国防痨杂志, 2013, 35(1): 37-40.

CHANG Shan, FU Yu-hong, LI Qi, BU Jian-ling, HUANG Hai-rong, MA Yu, CHEN Xiao-you. Analysis on drug resistance and cross resistance of Mycobacterium tuberculosis isolated from clinical samples to four injectable antituberculous drugs[J]. Chinese Journal of Antituberculosis, 2013, 35(1): 37-40.

参考文献

［1］WHO.耐药结核病临床医生使用指南.2版.北京：中国疾病预防控制中心结核病防治中心， 2010.

［2］中华人民共和国卫生部. 全国结核病耐药性基线调查报告（2007—2008年）.北京：人民卫生出版社，2010.

［3］全国第五次结核病流行病学抽样调查技术指导组，全国第五次结核病流行病学抽样调查办公室.2010年全国第五次结核病流行病学抽样调查报告.中国防痨杂志，2012，34(8)：485-508.

［4］中国防痨协会.结核病诊断细菌学检验规程.中国防痨杂志，1996，18(1)：28-33.

［5］王生伟，张侠.1996—2006年南京地区结核病耐药状况分析.中国防痨杂志，2008， 30(5):408-410.

［6］施旭东，王雷. 卷曲霉素对结核分枝杆菌体外抑菌作用的研究.江苏大学学报医学版，2004，14(2)：100-102.

［7］肖和平.唐神结.耐药结核病防治手册.北京：人民卫生出版社，2009.

［8］岛尾忠难.结核病学.北京：人民卫生出版社，1987.

［9］倪正义，熊建刚，凡毅.丁胺卡那与卡那霉素对结核杆菌的交叉耐药情况分析.医师进修杂志，2000，23(7)：10.

［10］曹广云，肖和平，闫丽萍，等. 三种注射用抗结核药物对结核分枝杆菌的耐药情况分析.中国防痨杂志，2010，32(4):227-230.

［11］Krüüner A，Jureen P， Levina K， et al. Discordant resistance to kanamycin and amikacin in drug-resistant Mycobacterium tuberculosis. Antimicrob Agents Chemother，2003，47(9):2971-2973.

［12］Maus CE，Plikaytis BB，Shinnick TM.Molecular analysis of cross-resistance to capreomycin， kanamycin，amikacin，and viomycin in Mycobacterium tuberculosis. Antimicrob Agents Chemother，2005，49(8):3192-3197.

［13］Jugheli L，Bzekalava N，de Rijk P，et al.High level of cross-resistance between kanamycin，amikacin，and capreomycin among Mycobacterium tuberculosis isolates from Georgia and a close relation with mutations in the rrs gene.Antimicrob Agents Chemother，2009，53(12):5064-5068.

［14］WHO.耐药结核病规划管理指南. 2008年紧急修订版.北京：中国疾病预防控制中心结核病防治中心，2008.

［15］吴雪琼.结核分支杆菌耐链霉素分子机制的研究进展.微生物学免疫学进展，1998，26(3)：83-85.

［16］Via LE，Cho SN，Hwang S， et al. Polymorphisms associated with resistance and cross-resistance to aminoglycosides and capreomycin in Mycobacterium tuberculosis isolates from South Korean patients with drug-resistant tuberculosis.J Clin Microbiol，2010，48(2):402-411.

［17］Sirgel FA，Tait M，Warren RM，et al.Mutations in the rrs A1401G gene and phenotypic resistance to amikacin and capreomycin in Mycobacterium tuberculosis. Microb Drug Resist，2012，18(2):193-197.

［18］Georghiou SB，Magana M，Garfein RS，et al. Evaluation of genetic gutations associated with Mycobacterium tuberculosis resistance to amikacin，kanamycin and capreomycin: a systematic review.PLoS One，2012，7(3):e33275.

[1]	邓国防,张培泽,杨敏,付亮. 二线注射剂治疗耐多药结核病的现状与思考[J]. 中国防痨杂志, 2019, 41(6): 604-608.
[2]	李可维,赵薇,刘思洁,杨修军,申莉,刘昕,齐鹏. MTB对阿米卡星和卡那霉素耐药相关rrs与eis基因突变的研究[J]. 中国防痨杂志, 2018, 40(10): 1141-1143.
[3]	袁小亮张天托朱家馨郑文争雷建平涂少华罗一钧刘惟优. 江西省结核分枝杆菌耐二线抗结核药的分子学特征[J]. 中国防痨杂志, 2013, 35(9): 649-654.
[4]	江勇钱明王威陈涛李海成陈燕梅卓文基郭卉欣周琳钟球. 卷曲霉素在罗氏培养基中的稳定性研究[J]. 中国防痨杂志, 2013, 35(8): 562-565.
[5]	何秀云朱传智逄宇黄香玉蒋丽气赵雁林庄玉辉. 耐异烟肼和链霉素的结核分枝杆菌临床分离株与敏感株差异蛋白表达研究[J]. 中国防痨杂志, 2013, 35(3): 173-178.
[6]	李同心崔振玲汪小黎陆俊梅王洁胡忠义. 噬菌体生物扩增法检测结核分枝杆菌阿米卡星耐药性方法的建立及应用评价[J]. 中国防痨杂志, 2011, 33(3): 158-162.
[7]	张廷梅, 熊敏, 蔡翠, 骆科文, 龙应林. 9例广泛耐药肺结核患者临床分析[J]. 中国防痨杂志, 2010, 32(5): 19-20.
[8]	胡远莲, 何广学, 刘志敏, 郑建礼, 邢超. 我国二线抗结核药物使用现状调查研究[J]. 中国防痨杂志, 2010, 32(3): 123-128.
[9]	贾琼, 石大伟, 赵玉玲, 李辉, 陈彦丞, 李亮, 朱国峰. 河南省耐多药结核分枝杆菌链霉素耐药相关基因rpsL和rrs突变分析[J]. 中国防痨杂志, 2010, 32(11): 760-762.
[10]	曹广云, 肖和平, 闫丽萍, 景玲杰, 杨华. 三种注射用抗结核药物对结核分枝杆菌的耐药情况分析[J]. 中国防痨杂志, 2010, 32(04): 227-230.
[11]	曾丹,于德禄,田荆芳. 硫酸卷曲霉素超声雾化吸入联合抗结核药物治疗复治菌阳肺结核的近期疗效观察[J]. 中国防痨杂志, 2009, 31(1): 3-5.
[12]	陆宇,赵伟杰,郑梅琴,王彬,M.Weisspapir,H.Gao,J.Schwarz. 纳米链霉素在小鼠结核病模型中治疗作用的研究[J]. 中国防痨杂志, 2008, 30(6): 502-505.
[13]	李洪敏,梁建琴,王巍,陈红兵,苗青,张霞,. 结核分枝杆菌Km基因突变与耐卡那霉素药物的研究[J]. 中国防痨杂志, 2008, 30(1): 37-39.
[14]	高春荣,袁东运,徐立江,. 含阿米卡星及左氧氟沙星方案治疗耐多药肺结核近期疗效观察[J]. 中国防痨杂志, 2004, 26(3): 165-167.