231例脊柱结核患者耐药情况分析
Analysis of drug resistance situation of Mycobacterium tuberculosis strains from 231 spinal tuberculosis patients
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责任编辑: 范永德
收稿日期: 2022-05-12
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目的: 分析231例脊柱结核患者的耐药特点,为临床医生制定脊柱结核治疗方案提供参考。 方法: 回顾性分析2016年1月至2021年12月首都医科大学附属北京胸科医院收治的231例脊柱结核住院患者信息,采用分枝杆菌微孔板药物敏感性检测技术测定来自231例脊柱结核患者的结核分枝杆菌对链霉素(Sm)、异烟肼(INH)、利福平(RFP)、乙胺丁醇(EMB)、利福喷丁(Rft)、左氧氟沙星(Lfx)、阿米卡星(Am)、卷曲霉素(Cm)、丙硫异烟胺(Pto)、对氨基水杨酸异烟肼(Pa)、莫西沙星(Mfx)、对氨基水杨酸(PAS)、克拉霉素(Clr)、利福布汀(Rfb)、卡那霉素(Km)和氯法齐明(Cfz)的敏感性。 结果: 脊柱结核患者对16种药物的总耐药率为34.63%(80/231), 复治患者的总耐药率(75.44%, 43/57)显著高于初治患者(21.26%, 37/174), 差异有统计学意义(χ2=55.660,P<0.001)。脊柱结核患者任一耐药率顺位为:Sm(24.68%, 57/231)>INH(22.51%,52/231)>Rft(19.05%, 44/231)>RFP(18.18%, 42/231)>Pa(15.58%, 36/231)>Rfb(13.85%, 32/231)>Lfx(7.79%, 18/231)>PAS(7.36%, 17/231)>Cm(5.63%, 13/231)>Km(4.76%, 11/231)=Cfz(4.76%, 11/231)>Pto(4.33%, 10/231)=Clr(4.33%,10/231)>EMB(3.90%, 9/231)>Am(3.46%,8/231)>Mfx(2.60%, 6/231)。脊柱结核患者多耐药率为11.69%(27/231), 复治患者的多耐药率(19.30%, 11/57)显著高于初治患者(9.20%, 16/174),差异有统计学意义(χ2=4.246, P=0.039); 耐多药率为15.58%(36/231),复治患者的耐多药率(52.63%, 30/57)显著高于初治患者(3.45%, 6/174), 差异有统计学意义(χ2=46.980, P<0.001)。 结论: 脊柱结核存在严重的耐药问题, 临床医生应根据患者药物敏感性试验结果制定有效的治疗方案。
关键词:
Objective: To analyze the drug resistance characteristics of 231 patients with spinal tuberculosis and to provide reference for clinicians to develop proper treatment regimens for spinal tuberculosis patients. Methods: The Mycobacterium tuberculosis strains and clinical data were collected from 231 culture-positive spinal tuberculosis patients, who were hospitalized in Beijing Chest Hospital from January 2016 to December 2021. Drug susceptibility test was performed for the following 16 drugs using ENCODE microplate methods: streptomycin (Sm), isoniazid (INH), rifampicin (RFP), ethambutol (EMB), rifapentine (Rft), levofloxacin (Lfx), amikacin (Am), capreomycin (Cm), prothionamide (Pto), isoniazid aminosalicylate (Pa), moxifloxacin (Mfx), p-aminosalicylic acid (PAS), clarithromycin (Clr), rifabutin (Rfb), kanamycin (Km) and clofazimine (Cfz). Results: The total drug resistance rate of those spinal tuberculosis patients to at least one of the 16 drugs was 34.63% (80/231), of which the drug resistance rate was significantly higher in previously treated patients (75.44%, 43/57) than in new patients (21.26%, 37/174), and the difference was statistically significant (χ2=55.660, P<0.001). The drug resistance rates of spinal tuberculosis patients to the 16 drugs from high to low were: Sm (24.68%, 57/231)>INH (22.51%, 52/231)>Rft (19.05%, 44/231)>RFP (18.18%, 42/231)>Pa (15.58%, 36/231)>Rfb (13.85%, 32/231)>Lfx (7.79%, 18/231)>PAS (7.36%, 17/231)>Cm (5.63%, 13/231)>Km (4.76%, 11/231)=Cfz (4.76%, 11/231)>Pto (4.33%, 10/231)=Clr (4.33%, 10/231)>EMB (3.90%, 9/231)>Am (3.46%, 8/231)>Mfx (2.60%, 6/231). The poly-drug resistance rate of spinal tuberculosis patients was 11.69% (27/231), of which the poly-drug resistance rate was significantly higher in previously treated patients (19.30%, 11/57) than in new patients (9.20%, 16/174),and the difference was statistically significant (χ2=4.246, P=0.039); The multidrug-resistance rate was 15.58% (36/231), of which the multidrug-resistance rate was significantly higher in previously treated patients (52.63%, 30/57) than in new patients (3.45%, 6/174),and the difference was statistically significant (χ2=46.980, P<0.001). Conclusion: There was serious epidemic of drug resistance in spinal tuberculosis patients. Effective treatment regimens should be developed according to the results of drug susceptibility tests.
Keywords:
本文引用格式
王潮虹, 孙晴, 廖鑫磊, 晏君, 王晨倩, 姜广路, 王芬, 薛毅, 黄海荣, 王桂荣.
Wang Chaohong, Sun Qing, Liao Xinlei, Yan Jun, Wang Chenqian, Jiang Guanglu, Wang Fen, Xue Yi, Huang Hairong, Wang Guirong.
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骨关节结核是肺外结核常见的表现形式,主要由结核分枝杆菌引起,通过呼吸道或消化道进入人体,经原发病灶如肺、肾和淋巴结等的血行播散进入骨关节,进而形成骨关节结核,发病率仅次于淋巴结结核和结核性胸膜炎[1-2]。脊柱结核是最常见最严重的骨关节结核[3],约占骨关节结核的50%[4]。脊柱结核早期通常无症状,随着病程进展由于骨骼破坏、脊椎塌陷、神经受压而出现疼痛、截瘫和畸形等症状[5⇓-7],从而造成患者预后不良和较高的病亡率[8]。2007—2008年全国结核病耐药性基线调查数据显示,中国肺结核患者中耐药结核病、多耐药结核病和耐多药结核病的发生率分别为37.79%、8.36%和8.32%[9]。结核分枝杆菌的高度耐药性,作为严重的公共卫生问题,很大程度上增加了临床治疗难度,越来越受到社会的广泛关注。脊柱结核也面临着耐药问题,由于脊柱结核具有起病时间长、病灶范围广、易复发等特点,因此脊柱结核患者在整个治疗过程中,除了彻底清创和稳定内固定等辅助治疗外,进行科学规范的抗结核药物治疗才是其治愈的关键和基础[10-11]。笔者通过分析231例脊柱结核患者的耐药情况,以期为临床医生制定脊柱结核患者合理的化疗方案提供理论依据。
对象和方法
一、 研究对象
选取2016年1月至2021年12月就诊于首都医科大学附属北京胸科医院的临床诊断脊柱结核住院患者231例。纳入标准:患者组织或脓液标本经分枝杆菌培养和菌种鉴定为结核分枝杆菌;患者标本进行了16种抗结核药物的药物敏感性试验(简称“药敏试验”)。
表1 不同社会学和临床特征在初治和复治脊柱结核患者中的分布
特征 | 初治患者 (174例) | 复治患者 (57例) | 合计 (231例) |
---|---|---|---|
性别 | |||
男性 | 101(58.05) | 28(49.12) | 129(55.84) |
女性 | 73(41.95) | 29(50.88) | 102(44.16) |
年龄组(岁) | |||
0~10 | 1(0.57) | 0(0.00) | 1(0.43) |
11~20 | 10(5.75) | 6(10.53) | 16(6.93) |
21~30 | 51(29.31) | 13(22.81) | 64(27.71) |
31~40 | 18(10.34) | 6(10.53) | 24(10.39) |
41~50 | 23(13.22) | 14(24.56) | 37(16.02) |
51~60 | 32(18.39) | 12(21.05) | 44(19.05) |
61~70 | 31(17.82) | 2(3.51) | 33(14.29) |
71~80 | 5(2.87) | 3(5.26) | 8(3.46) |
>80 | 3(1.72) | 1(1.75) | 4(1.73) |
职业 | |||
农民 | 77(44.25) | 21(36.84) | 98(42.42) |
工人 | 8(4.60) | 2(3.51) | 10(4.33) |
退(离)休人员 | 25(14.37) | 8(14.04) | 33(14.29) |
无业人员 | 17(9.77) | 8(14.04) | 25(10.82) |
学生 | 6(3.45) | 6(10.53) | 12(5.19) |
职员 | 22(12.64) | 8(14.04) | 30(12.99) |
其他a | 19(10.92) | 4(7.02) | 23(9.96) |
患病部位 | |||
颈椎 | 8(4.60) | 0(0.00) | 8(3.46) |
胸椎 | 60(34.48) | 14(24.56) | 74(32.03) |
腰椎 | 71(40.80) | 35(61.40) | 106(45.89) |
颈椎+胸椎 | 5(2.87) | 0(0.00) | 5(2.16) |
胸椎+腰椎 | 29(16.67) | 7(12.28) | 36(15.58) |
颈椎+胸椎+腰椎 | 1(0.57) | 1(1.75) | 2(0.87) |
基础疾病 | |||
营养不良 | 95(54.60) | 33(57.89) | 128(55.41) |
高血压 | 20(11.49) | 8(14.04) | 28(12.12) |
糖尿病 | 16(9.20) | 7(12.28) | 23(9.96) |
免疫性疾病 | 3(1.72) | 3(5.26) | 6(2.60) |
注 括号外数值为“患者例数”,括号内数值为“构成比(%)”; a:包括个体经营者、公务员、专业技术人员、厨师
二、 研究方法
1. 分枝杆菌培养:按照《结核病诊断实验室检查规程》[12]推荐的方法,脓液或组织标本采用改良罗氏培养法进行培养。
3. 药敏试验:应用分枝杆菌微孔板药敏检测试剂盒(培养法)(珠海银科医学工程股份有限公司)测定结核分枝杆菌对链霉素(Sm)、异烟肼(INH)、利福平(RFP)、乙胺丁醇(EMB)、利福喷丁(Rft)、左氧氟沙星(Lfx)、阿米卡星(Am)、卷曲霉素(Cm)、丙硫异烟胺(Pto)、对氨基水杨酸异烟肼(Pa)、莫西沙星(Mfx)、对氨基水杨酸(PAS)、克拉霉素(Clr)、利福布汀(Rfb)、卡那霉素(Km)和氯法齐明(Cfz)的敏感性。
三、 相关定义
单耐药指结核分枝杆菌经体外药敏试验证实对一种抗结核药物耐药;多耐药指结核分枝杆菌经体外药敏试验证实对一种以上的一线抗结核药物耐药但不包括同时对RFP和INH耐药;耐多药指结核分枝杆菌经体外药敏试验证实至少同时对RFP和INH耐药;交叉耐药是指结核分枝杆菌经体外药敏试验证实对一种抗结核药物耐药后,同时对另一种结构近似或作用性质相同的抗结核药物也发生耐药。
初治患者是指从未因结核病应用过抗结核药物治疗的患者,或使用抗结核药物治疗<1个月的患者;复治患者是指既往不规律使用抗结核药物治疗≥1个月,以及初治失败和复发的患者[16]。
四、 统计学处理
应用SPSS 24.0软件对数据进行统计学分析。计数资料以“例(株)”“率(%)”描述,各组间耐药率的比较采用卡方检验或Fisher精确概率检验,以P<0.05为差异有统计学意义。
结果
一、 脊柱结核患者总体耐药情况
1. 总耐药率:脊柱结核患者的231株结核分枝杆菌总耐药率为34.63%(80/231),复治患者的总耐药率(75.44%,43/57)显著高于初治患者(21.26%,37/174),差异有统计学意义(χ2=55.660,P<0.001)(表2)。
表2 不同任一耐药类型在初治和复治脊柱结核患者中的分布
耐药类型 | 合计(231例) | 初治患者(174例) | 复治患者(57例) | χ2值 | P值 |
---|---|---|---|---|---|
任一耐药 | 80(34.63) | 37(21.26) | 43(75.44) | 55.660 | <0.001 |
Sm | 57(24.68) | 24(13.79) | 33(57.89) | 44.930 | <0.001 |
INH | 52(22.51) | 13(7.47) | 39(68.42) | 91.440 | <0.001 |
RFP | 42(18.18) | 10(5.75) | 32(56.14) | 73.290 | <0.001 |
EMB | 9(3.90) | 0(0.00) | 9(15.79) | 28.590 | <0.001 |
Rft | 44(19.05) | 11(6.32) | 33(57.89) | 74.060 | <0.001 |
Lfx | 18(7.79) | 5(2.87) | 13(22.81) | 23.740 | <0.001 |
Am | 8(3.46) | 3(1.72) | 5(8.77) | 4.450 | 0.035 |
Cm | 13(5.63) | 7(4.02) | 6(10.53) | 2.300 | 0.129 |
Pto | 10(4.33) | 4(2.30) | 6(10.53) | 5.170 | 0.023 |
Pa | 36(15.58) | 8(4.60) | 28(49.12) | 64.701 | <0.001 |
Mfx | 6(2.60) | 1(0.57) | 5(8.77) | 8.393 | 0.004 |
PAS | 17(7.36) | 9(5.17) | 8(14.04) | 3.732 | 0.053 |
Clr | 10(4.33) | 5(2.87) | 5(8.77) | 2.232 | 0.127 |
Rfb | 32(13.85) | 6(3.45) | 26(45.61) | 63.967 | <0.001 |
Km | 11(4.76) | 4(2.30) | 7(12.28) | 7.360 | 0.007 |
Cfz | 11(4.76) | 4(2.30) | 7(12.28) | 7.360 | 0.007 |
注 括号外数值为“例数”,括号内数值为“率(%)”
2. 任一耐药率顺位: 231株结核分枝杆菌对16种抗结核药物任一耐药顺位为:Sm(24.68%,57/231)>INH(22.51%,52/231)>Rft(19.05%,44/231)>RFP(18.18%,42/231)>Pa(15.58%,36/231)>Rfb(13.85%,32/231)>Lfx(7.79%,18/231)>PAS(7.36%,17/231)>Cm(5.63%,13/231)>Km(4.76%,11/231)=Cfz(4.76%,11/231)>Pto(4.33%,10/231)=Clr(4.33%,10/231)>EMB(3.90%,9/231)>Am(3.46%,8/231)>Mfx(2.60%,6/231)(表2)。初治患者任一耐药顺位为:Sm(13.79%,24/174)>INH(7.47%,13/174)>Rft(6.32%,11/174)>RFP(5.75%,10/174)>PAS(5.17%,9/174)>Pa(4.60%,8/174)>Cm(4.02%,7/174)>Rfb(3.45%,6/174)>Lfx(2.87%,5/174)=Clr(2.87%,5/174)>Pto(2.30%,4/174)=Km(2.30%,4/174)=Cfz(2.30%,4/174)>Am(1.72%,3/174)>Mfx(0.57%,1/174)>EMB(0.00%,0/174)。复治患者任一耐药顺位为:INH(68.42%,39/57)>Sm(57.89%,33/57)=Rft(57.89%,33/57)>RFP(56.14%,32/57)>Pa(49.12%,28/57)>Rfb(45.61%,26/57)>Lfx(22.81%,13/57)>EMB(15.79%,9/57)>PAS(14.04%,8/57)>Km(12.28%,7/57)=Cfz(12.28%,7/57)>Cm(10.53%,6/57)=Pto(10.53%,6/57)>Am(8.77%,5/57)=Clr(8.77%,5/57)=Mfx(8.77%,5/57)(表2)。
二、 脊柱结核患者的耐药类型分布
1. 单耐药情况:231株结核分枝杆菌分离株中,对一种抗结核药物耐药的有17株,单耐药率为7.36%(17/231),其中初治患者单耐药率为8.62%(15/174),复治患者单耐药率为3.51%(2/57),初复治患者单耐药率差异无统计学意义。
2. 多耐药情况:231株结核分枝杆菌分离株中,共有多耐药菌株27株,多耐药率为11.69%(27/231),复治患者的多耐药率(19.30%, 11/57)显著高于初治患者(9.20%, 16/174),差异有统计学意义(χ2=4.246,P=0.039)(表3)。
表3 不同多耐药类型在初治和复治脊柱结核患者中的分布
耐药类型 | 合计(231例) | 初治患者(174例) | 复治患者(57例) | P值a | |||
---|---|---|---|---|---|---|---|
INH+Pa | 3(1.30) | 2(1.15) | 1(1.75) | 0.574 | |||
Sm+INH | 2(0.87) | 1(0.57) | 1(1.75) | 0.433 | |||
Sm+PAS | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
Cm+Clr | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
RFP+Rft | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
PAS+Clr | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
INH+PAS | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
INH+Pa+Cfz | 2(0.87) | 1(0.57) | 1(1.75) | 0.433 | |||
Lfx+Cm+Mfx | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
INH+Cm+Pa | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 | |||
耐药类型 | 合计(231例) | 初治患者(174例) | 复治患者(57例) | P值a | |||
Sm+INH+Rft | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 | |||
RFP+Rft+Rfb | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
Sm+RFP+Rft+Rfb | 2(0.87) | 1(0.57) | 1(1.75) | 0.433 | |||
INH+Rft+Cm+Pto+Rfb | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
Sm+Cm+PAS+Clr+Cfz | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
Sm+INH+Rft+PAS+Clr | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
INH+Cm+Pa+PAS+Clr+Km | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 | |||
Sm+RFP+Rft+PAS+Rfb+Cfz | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 | |||
INH+Cm+Pa+Clr+Rfb+Km | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 | |||
Sm+INH+Am+Pa+PAS+Km | 2(0.87) | 0(0.00) | 2(3.51) | 0.06 | |||
Sm+RFP+EMB+Rft+Lfx+Pa+Mfx+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 | |||
合计 | 27(11.69) | 16(9.20) | 11(19.30) | 0.039 |
注 a:采用Fisher精确概率检验;括号外数值为“例数”,括号内数值为“率(%)”
3. 耐多药情况:231株结核分枝杆菌分离株中,同时对INH和RFP耐药的菌株有36株,总耐多药率为15.58%(36/231),复治患者的耐多药率(52.63%, 30/57)显著高于初治患者(3.45%, 6/174),差异有统计学意义(χ2=46.980,P<0.001)(表4)。
表4 不同耐多药类型在初治和复治脊柱结核患者中的分布
耐多药类型 | 合计(231例) | 初治患者(174例) | 复治患者(57例) | P值a |
---|---|---|---|---|
INH+RFP+Rft | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Rft+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Rfb | 3(1.30) | 1(0.57) | 2(3.51) | 0.151 |
INH+RFP+Rft+Pa+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Pa | 2(0.87) | 0(0.00) | 2(3.51) | 0.060 |
INH+RFP+Sm+Rft+Pto | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Rft+Pa+PAS+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Pa+Rfb | 2(0.87) | 0(0.00) | 2(3.51) | 0.060 |
INH+RFP+Sm+EMB+Rft+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Lfx+Rfb | 2(0.87) | 0(0.00) | 2(3.51) | 0.060 |
INH+RFP+Sm+Rft+Lfx+Pto | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Am+Rfb+Km | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Lfx+Pa+Km | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 |
INH+RFP+Sm+Rft+Lfx+Pa+Rfb | 4(1.73) | 0(0.00) | 4(7.02) | 0.003 |
INH+RFP+Sm+Rft+Pa+Rfb+Cfz | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+EMB+Rft+Pa+Rfb | 2(0.87) | 0(0.00) | 2(3.51) | 0.060 |
INH+RFP+Sm+Rft+Pa+PAS+Rfb+Cfz | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Am+Cm+Pa+Km | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 |
INH+RFP+Sm+EMB+Rft+Lfx+Pa+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+EMB+Rft+Lfx+Pa+Mfx | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Lfx+Pto+Pa+Rfb | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+Rft+Lfx+Pa+PAS+Rfb | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 |
INH+RFP+Sm+Lfx+Am+Cm+Pto+Pa+PAS+Km | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 |
INH+RFP+Sm+Rft+Lfx+Am+Cm+Pto+Pa+PAS+Km | 1(0.43) | 1(0.57) | 0(0.00) | 1.000 |
INH+RFP+Sm+EMB+Rft+Cm+Pto+Pa+Mfx+PAS+Clr+Rfb+Cfz | 1(0.43) | 0(0.00) | 1(1.75) | 0.247 |
INH+RFP+Sm+EMB+Rft+Lfx+Am+Cm+Pto+Pa+Mfx+PAS+Clr+Km+Cfz | 2(0.87) | 0(0.00) | 2(3.51) | 0.060 |
合计 | 36(15.58) | 6(3.45) | 30(52.63) | <0.001 |
注 a:采用Fisher精确概率检验;括号外数值为“例数”,括号内数值为“率(%)”
4. 交叉耐药情况:RFP与Rfb、Rft的交叉耐药率分别为71.43%(30/42)和97.62%(41/42);Rfb与RFP、Rft的交叉耐药率分别为93.75%(30/32)和96.88%(31/32);Rft与RFP、Rfb的交叉耐药率分别为93.18%(41/44)和70.45%(31/44)。
三、 复治脊柱结核患者初治时抗结核治疗方案及其耐药情况
57例复治脊柱结核患者中,初治时48例为敏感患者,9例为耐药患者。48例敏感患者中,70.83%(34/48)的患者在初治采用了规范的HREZ抗结核治疗方案,29.17%(14/48)的患者在初治时采用HREZ联用氟喹诺酮类抗结核药物。初治采用规范HREZ抗结核治疗的脊柱结核复治患者中,本次药敏试验结果显示70.59%(24/34)的患者对一线抗结核药物任一耐药;采用HREZ联用氟喹诺酮类药物的复治患者中,78.57%(11/14)的患者对一线抗结核药物任一耐药,21.43%(3/14)的患者对任一氟喹诺酮类药物耐药。
讨论
本研究显示,231例脊柱结核患者的总耐药率、多耐药率和耐多药率分别为34.63%(80/231)、11.69%(27/231)和15.58%(36/231),初治患者分别为21.26%(37/174)、9.20%(16/174)和3.45%(6/174),复治患者分别为75.44%(43/57)、19.30%(11/57)和52.63%(30/57)。与2007—2008年全国结核病耐药性基线调查的最新数据相比,总耐药率略低于基线调查数据,多耐药率和耐多药率高于基线调查数据,且统计分析结果显示复治脊柱结核的耐药率明显高于初治患者[9]。可见,脊柱结核同肺结核一样存在着耐药问题,且形势不容乐观。数据显示初治脊柱结核的耐药情况仍处于一个较低水平,因此临床医生对其进行治疗时,有必要采取适当的策略来保证治疗的连续性,减少其复发的可能。
Rft、Rfb和RFP同属于利福霉素家族,利福霉素类药物主要是通过与结核分枝杆菌的RNA多聚酶结合,减少磷酸酯链形成,使结核分枝杆菌无法完成转录过程以及蛋白质合成过程,进而达到抑制结核分枝杆菌生长的效果[20]。RFP是敏感结核病治疗的核心药物之一,但会出现胃肠道症状、皮疹等不良反应,长期服用对肝功能有一定程度的损伤[21⇓-23]。Rft、Rfb对人体不良反应相对较小,经口服后会广泛分布在机体血液及组织中,随后进入肝细胞后会加速代谢,充分发挥治疗作用,该药物不易被胃肠道吸收,对胃肠道刺激较小,可以减少其不良反应的发生[24]。因此,患者对RFP不耐受的情况下,临床上可以考虑选择其家族成员进行代替治疗。本研究结果显示,脊柱结核患者中RFP与Rfb、Rft的交叉耐药率分别为71.43%(30/42)和97.62%(41/42),与国内文献报道的利福霉素类药物之间有交叉耐药现象吻合,RFP和Rft之间为完全交叉耐药,RFP和Rfb之间为非完全耐药[25]。约有30%的RFP耐药株对Rfb仍然敏感,对于这类患者,可以选择Rfb作为联合治疗的有效药之一[26]。
本研究的231例脊柱结核患者中,年龄最小的9岁,最大的83岁,其中21~30岁和51~60岁的患者所占比例较高,分别为27.71%和19.05%,与国内外其他学者研究结果一致[17,27],21~30岁患者所占比例高可能与该年龄段的人群学习、工作、生活压力大有关。本研究的231例脊柱结核患者主要职业是农民,占总数的42.42%(98/231)。分析原因可能是农民从事耕种活动,劳动强度大易损伤骨骼,且农民健康意识薄弱,对结核病的重视度低,从而增加了其患脊柱结核的概率。本研究的231例脊柱结核患者中,最常见的受累部位是腰椎,占45.89%(106/231),其次是胸椎,占32.03%(74/231),腰椎合并胸椎结核占15.58%(36/231),与国内其他学者的研究结果一致[17]。分析原因可能是该病主要通过血行传播,而脊柱血供缓慢充沛,当椎体感染发生后容易随血流扩散到邻近组织,使相邻椎体受累造成合并感染。
对于57例复治脊柱结核患者,初治采用规范HREZ方案抗结核治疗的脊柱结核患者中,本次药敏试验结果显示70.59%(24/34)的患者对一线抗结核药物任一耐药;采用HREZ联用氟喹诺酮类药物治疗的患者中,78.57%(11/14)的患者对一线抗结核药物任一耐药,21.43%(3/14)的患者对任一氟喹诺酮类药物耐药,可见复治脊柱结核患者的耐药情况与初次治疗方案存在一定的相关性。
综上所述,脊柱结核耐药形势严峻,耐多药的发生率较高,临床上应重视脊柱结核初治患者,对脓液或组织标本培养阳性的患者积极进行药敏试验,根据不同的耐药特点定制个体化的治疗方案,保证治疗的连续性,减少继发性耐药的产生,降低耐多药结核病发生的风险。期望本次对脊柱结核患者耐药情况的研究分析为结核病的治疗工作提供科学的参考。
利益冲突 所有作者均声明不存在利益冲突
作者贡献 王潮虹:采集数据、统计分析、论文撰写和修改;孙晴、廖鑫磊、晏君和王晨倩:采集数据和统计分析;姜广路、王芬和薛毅:数据录入;黄海荣:获取科研经费和行政、技术或材料支持;王桂荣:酝酿和设计实验、文章修改和指导
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利福霉素类药物治疗结核病的临床应用研究进展
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Multi-drug resistant spinal tuberculosis-epidemiological characteristics of in-patients: a multicentre retrospective study
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