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[Comparison of Epsilometer test and agar dilution method in detecting the sensitivity of Helicobacter pylori to metronidazole].

Author information

Affiliations

  • 1. Department of Gastroenterology, Peking University Third Hospital, Beijing 100191, China.
      Authors
    • Tian XL 1
    • Song ZQ 1
    • Suo BJ 1
    • Zhou LY 1
    • Li CL 1
    • Zhang YX 1
    (6 authors)

Beijing da xue xue bao. Yi xue ban = Journal of Peking University. Health Sciences, 01 Oct 2023, 55(5):934-938Language:chi
https://doi.org/10.19723/j.issn.1671-167x.2023.05.024 PMID: 37807751 PMCID: PMC10560899

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Abstract 

Objective

Agar dilution method (ADM) was used as the golden standard to evaluate the consistency of Epsilometer test (E-test) in detecting the sensitivity of Helicobacter pylori (H. pylori) to metronidazole.

Methods

From August 2018 to July 2020, patients with H. pylori infection treated for the first time in Peking University Third Hospital for gastroscopy due to dyspepsia were included in this study. Gastric mucosas were taken from the patients with H. pylori infection. H. pylori culture was performed. Both the ADM and E-test were applied to the antibiotic susceptibility of H. pylori to metro-nidazole, and the consistency and correlation between the two methods were validated.

Results

In the study, 105 clinical isolates of H. pylori were successfully cultured, and the minimum inhibitory concentration ≥ 8 mg/L was defined as drug resistance. Both ADM and the E-test showed high resistance rates to metronidazole, 64.8% and 62.9%, respectively. Among them, 66 drug-resistant strains were detected by ADM and E-test, and 37 were sensitive strains, so the consistency rate was 98.1%. Two strains were evaluated as drug resistance by ADM, but sensitive by the E-test, with a very major error rate of 1.9%. There was zero strain sensitive according to ADM but assessed as resistant by the E-test, so the major error rate was 0%. Taking ADM as the gold standard, the sensitivity of E-test in the detection of metronidazole susceptibility was 97.1% (95%CI: 0.888-0.995), and the specificity was 100% (95%CI: 0.883-1.000). Cohen's kappa analysis showed substantial agreement, and kappa coefficient was 0.959 (95%CI: 0.902-1.016, P < 0.001). Spearmans correlation analysis confirmed this correlation was significant (r=0.807, P < 0.001). The consistency evaluation of Bland-Altman method indicated that it was good, and there was no measured value outside the consistency interval. In this study, cost analysis, including materials and labor, showed a 32.2% higher cost per analyte for ADM as compared with the E-test (356.6 yuan vs. 269.8 yuan).

Conclusion

The susceptibility test of H. pylori to metronidazole by E-test presents better agreement with ADM. Because it is less expensive, less labor intensive, and more rapid, it is an easy and reliable method for H. pylori susceptibility testing.

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Logo of jpekinguhsLink to Publisher's site
Beijing Da Xue Xue Bao Yi Xue Ban. 2023 Oct 18; 55(5): 934–938.
Published online 2023 Aug 2. Chinese. https://doi.org/10.19723/j.issn.1671-167X.2023.05.024
PMCID: PMC10560899
PMID: 37807751

Language: Chinese | English

比较Epsilometer试验法和琼脂稀释法检测幽门螺杆菌对甲硝唑的敏感性

Comparison of Epsilometer test and agar dilution method in detecting the sensitivity of Helicobacter pylori to metronidazole

田 雪丽 (Xue-li TIAN), 宋 志强 (Zhi-qiang SONG),corresponding author* 索 宝军 (Bao-jun SUO), 周 丽雅 (Li-ya ZHOU), 李 彩玲 (Cai-ling LI), and 张 雨欣 (Yu-xin ZHANG)
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Abstract

目的

以琼脂稀释法为金标准, 评价Epsilometer试验(Epsilometer test, E-test)法检测幽门螺杆菌(Helicobacter pylori, H. pylori)对甲硝唑敏感性的一致性。

方法

纳入2018年8月至2020年7月因消化不良症状就诊于北京大学第三医院行胃镜检查的H. pylori感染初治患者, 取胃黏膜组织活检行H. pylori培养, 分别采用E-test法和琼脂稀释法检测H. pylori对甲硝唑的敏感性, 比较两种方法检测结果的一致性和相关性。

结果

成功培养105株H. pylori, 将最小抑菌浓度≥ 8 mg/L定义为耐药。琼脂稀释法检测甲硝唑耐药菌株68株, 耐药率64.8%, E-test法检测耐药菌株66株, 耐药率62.9%, 其中, 琼脂稀释法和E-test法检测均为耐药的菌株66株, 均为敏感的菌株37株, 两种方法的一致率为98.1%。2例菌株被琼脂稀释法评价为耐药, 而E-test法评价为敏感, 非常严重错误率为1.9%。没有菌株被琼脂稀释法评价为敏感, 而E-test法评价为耐药(严重错误率为0%)。以琼脂稀释法为金标准, E-test法检测甲硝唑耐药的灵敏度为97.1%(95%CI: 0.888~0.995), 特异度为100%(95%CI: 0.883~1.000)。Cohen’s kappa系数为0.959 (95%CI: 0.902~1.016, P < 0.001), Spearmans相关性检测r=0.807(P < 0.001)。采用Bland-Altman法进行一致性评价, 结果提示较好, 未出现一致性区间外的测值。E-test法比琼脂稀释法的成本更低, 平均完成1例试验两者的成本分别为269.8元和356.6元。

结论

E-test法检测H. pylori对甲硝唑的药敏试验与琼脂稀释法相比具有较强的一致性, E-test法省时、省力、价廉, 可以作为H. pylori药敏试验的优选检测方法。

Keywords: Epsilometer试验, 琼脂稀释计数, 幽门螺杆菌, 微生物敏感性试验

Abstract

Objective

Agar dilution method (ADM) was used as the golden standard to evaluate the consistency of Epsilometer test (E-test) in detecting the sensitivity of Helicobacter pylori (H. pylori) to metronidazole.

Methods

From August 2018 to July 2020, patients with H. pylori infection treated for the first time in Peking University Third Hospital for gastroscopy due to dyspepsia were included in this study. Gastric mucosas were taken from the patients with H. pylori infection. H. pylori culture was performed. Both the ADM and E-test were applied to the antibiotic susceptibility of H. pylori to metro-nidazole, and the consistency and correlation between the two methods were validated.

Results

In the study, 105 clinical isolates of H. pylori were successfully cultured, and the minimum inhibitory concentration ≥ 8 mg/L was defined as drug resistance. Both ADM and the E-test showed high resistance rates to metronidazole, 64.8% and 62.9%, respectively. Among them, 66 drug-resistant strains were detected by ADM and E-test, and 37 were sensitive strains, so the consistency rate was 98.1%. Two strains were evaluated as drug resistance by ADM, but sensitive by the E-test, with a very major error rate of 1.9%. There was zero strain sensitive according to ADM but assessed as resistant by the E-test, so the major error rate was 0%. Taking ADM as the gold standard, the sensitivity of E-test in the detection of metronidazole susceptibility was 97.1% (95%CI: 0.888-0.995), and the specificity was 100% (95%CI: 0.883-1.000). Cohen's kappa analysis showed substantial agreement, and kappa coefficient was 0.959 (95%CI: 0.902-1.016, P < 0.001). Spearmans correlation analysis confirmed this correlation was significant (r=0.807, P < 0.001). The consistency evaluation of Bland-Altman method indicated that it was good, and there was no measured value outside the consistency interval. In this study, cost analysis, including materials and labor, showed a 32.2% higher cost per analyte for ADM as compared with the E-test (356.6 yuan vs. 269.8 yuan).

Conclusion

The susceptibility test of H. pylori to metronidazole by E-test presents better agreement with ADM. Because it is less expensive, less labor intensive, and more rapid, it is an easy and reliable method for H. pylori susceptibility testing.

Keywords: Epsilometer test, Agar dilution count, Helicobacter pylori, Microbial sensitivity tests

随着对幽门螺杆菌(Helicobacter pylori，H. pylori)与人类疾病关系研究的深入，H. pylori感染已明确与消化性溃疡、慢性胃炎、消化不良等密切相关，更是胃癌的一级致病因子，因此H. pylori感染者应当给予积极的根除治疗[1-2]。然而，目前我国H. pylori感染的根除形势较为严峻，常用根除药物的耐药率明显升高，尤其是克拉霉素、甲硝唑及左氧氟沙星[3-5]。

抗生素敏感性检测方法是H. pylori感染的根除治疗和相关研究所需的重要工具和手段，对于有效、合理指导和选择根除方案非常必要[2, 6]。H. pylori菌株对甲硝唑敏感性的检测方法一直以来存在争议，美国临床实验室标准化协会(Clinical and Laboratory Standards Institute，CLSI)推荐采用琼脂稀释法(agar dilution method，ADM)作为H. pylori药敏试验的检测方法，认为其较为准确，但该方法耗时耗力，限制了其临床应用。

近年来，应用较多的Epsilometer试验(Epsilometer test，E-test)法因其易于掌握、省时省力、操作便捷，被临床医师和科研工作者青睐。但有研究显示，E-test法可能会高估H. pylori对甲硝唑的耐药性[7-8]，然而目前相关研究较少，尤其是较大样本和规范的研究。本研究旨在探讨ADM和E-test两种方法在检验H. pylori菌株对甲硝唑敏感性试验中，检测结果的一致性。

1. 材料与方法

1.1. 实验材料

本研究纳入2018年8月至2020年7月因消化不良症状就诊于北京大学第三医院行胃镜检查的H. pylori感染初治患者，取胃黏膜组织活检行H. pylori培养，成功培养了105例菌株，质控菌株是ATCC26695[9]。

1.2. 方法

1.2.1. 主要仪器

实验用仪器包括三气培养箱(4950E，NUAIRE公司，美国)、生物安全柜(NU-425-600E Class Ⅱ，NUAIRE公司，美国)、超净工作台(BCN-1800，北京东利哈尔仪器制造有限公司，中国)、超低温冰箱(Haier公司，中国)、比浊仪(Biomerieux，法国)等。

1.2.2. 主要试剂和材料

实验用试剂包括脑心浸液(CM1135)、Karmali弯曲菌琼脂基础(CM0935)和幽门螺杆菌选择添加剂(SR0147)(OXOID公司，英国)，脱纤维马血(奥科贝来得生物科技有限公司，中国)，甲硝唑E-test试纸(Biomerieux，法国)，甲硝唑(Sigma，M3761)，H. pylori质控菌株(ATCC 26695)等。

1.2.3. H. pylori的培养

冻存于-80 [degree celsius]的样本先在室温下放置30 min进行解冻，后研磨成匀浆，取出组织液接种于H. pylori选择培养基，将接种好的平皿置于37 [degree celsius]混合气体培养箱中(体积分数为5%的氧气、10%的二氧化碳、85%的氮气)，培养3~11 d，观察H. pylori菌株生长情况，长出针状半透明的菌落后进行显微镜检查及vacA基因聚合酶链式反应(polymerase chain reaction，PCR)鉴定，符合标准的判断为H. pylori。11 d无生长判断为阴性或培养失败。

1.2.4. ADM

将经72 h培养的H. pylori制成1×107~1×108菌落形成单位(colony forming units，CFU)/mL[10]的菌悬液，甲硝唑的药物质量浓度范围为0.125~256 mg/L，按照CLSI[10]制定的ADM步骤进行药敏试验，取2 μL菌悬液点种含抗生素的ADM平板，平行5次重复，于37 [degree celsius]微需氧培养72 h后读取最低抑菌浓度(minimal inhibitory concentration，MIC)值，MIC定义为完全抑制可见生长的最低抗生素浓度。在每个系列平板的开始和结束处接种无抗生素平板，以确认接种物的活性并观察有无污染菌的生长。

1.2.5. E-test法

用无菌棉拭子将所制菌悬液(100 μL)均匀涂布于Mueller-Hinton平板上[加入了7%(体积分数)脱纤维马血]，待菌液渗入培养基后，用无菌镊子夹取E-test试纸条放于琼脂表面，每个150 mm板上最多贴6条，每个试纸条均匀分布，最大刻度朝向平板边缘。于37 [degree celsius]微需氧培养72 h后读取MIC值，MIC值定义为E-test分级试纸条的椭圆形抑菌域交于试纸上的抗生素浓度。

1.3. 统计学分析

应用SPSS 22.0统计学软件和MedCalc软件分析数据，计数资料用样本量(百分数)描述，采用Cohen’s kappa系数和Bland-Altman法进行一致性分析，采用Spearmans法进行相关性检测，P<0.05为差异有统计学意义。

2. 结果

2.1. 培养的H. pylori菌株对甲硝唑的药敏试验结果

成功培养H. pylori菌株105株，将MIC ≥ 8 mg/L[6, 11]定义为耐药，ADM检测结果为甲硝唑耐药菌株68株，敏感菌株37株，耐药率为64.8%；E-test法检测结果为甲硝唑耐药菌株66株，敏感菌株39株，耐药率为62.9%。其中，ADM和E-test法检测均为耐药的菌株66株，均为敏感的菌株37株，两种方法的一致率为98.1%。

2.2. E-test法检测甲硝唑药敏试验的灵敏度和特异度

以ADM为金标准，E-test法检测甲硝唑药敏试验的灵敏度为97.1%(95%CI：0.888~0.995)，特异度为100%(95%CI：0.883~1.000)，阴性似然比为0.029。

2.3. E-test法检测甲硝唑药敏试验绝对一致性的非常严重错误率和严重错误率

以ADM为金标准，本研究中2例菌株被ADM评价为耐药，而被E-test法评价为敏感，非常严重错误率为1.9%；没有菌株被ADM评价为敏感，而被E-test法评价为耐药，严重错误率为0%。

2.4. 两种方法检测甲硝唑药敏试验的一致性和相关性分析

利用Cohen’s kappa系数分析判断两种检测方法的一致性，系数为0.959 (95%CI：0.902~1.016，P<0.001)，表明两种方法对于判断H. pylori菌株是否存在甲硝唑耐药具有较强的一致性。同时应用Bland-Altman法进行一致性评价(图 1)，显示两种方法测量结果的一致性很好，Spearmans相关性检测r=0.807(P<0.001)。

ADM, agar dilution method; E-test, Epsilometer test; MIC, minimal inhibitory concentration; SD, standard deviation.

Bland-Altman法评价ADM和E-test法检测甲硝唑MIC的一致性

Evaluation of the consistency of ADM and E-test in detecting MIC of metronidazole by Bland-Altman method

2.5. ADM和E-test法检测甲硝唑药敏试验的成本分析

如表 1所示，采用ADM和E-test法分别检测甲硝唑对H. pylori的药敏试验，E-test法所需的成本明显低于ADM，而且是在检测相对较大样本的情况下，ADM所用的抗生素已经降低了成本后所显示的价格，对于临床上检测几例样本的药敏试验，ADM的成本会更高。在准备平板和检测药敏结果的时间方面，ADM比E-test法明显更复杂和时间更长，因此在劳动力方面，ADM也比E-test成本高。

表 1

ADM和E-test法分别检测1例甲硝唑药敏试验的成本分析

Cost analysis of one case of metronidazole susceptibility test by ADM and E-test

E-testADM
Unit-price/yuan n Total/yuanUnit-price/yuan n Total/yuan
Others include cryopreservation tube, culture medium, inoculation ring, special glass tube for turbidimeter, special sterile cotton swab, etc. -, not applicable. ADM, agar dilution method; E-test, Epsilometer test.
E-test strip35.0135.0-
Agar dilution plate (11 gradients)-8.81196.8
Plate (containing antibiotics)12.0224.012.0224.0
Plate (without antibiotics)8.8435.28.8435.2
General culture plate25.0250.025.0250.0
Nitrogen, water and electricity60.0160.060.0160.0
Manual labor50.0150.075.0175.0
Others15.615.6
Total269.8356.6

3. 讨论

我国是H. pylori高感染率的国家，最新的meta分析显示，我国的H. pylori感染率高达55.8%，感染人口接近8亿[12]，是严重威胁国民健康的卫生健康问题。目前，根除H. pylori的抗生素耐药形式十分严峻，文献报道甲硝唑的耐药率高达63.8%，本研究结果与之相似(64.8%)。虽然甲硝唑的耐药率较高，但因其价格低廉、临床容易获得，在《第五次全国幽门螺杆菌感染处理共识报告》提出的7种方案中有2种方案仍涉及甲硝唑[13]，依然是临床常用的根除药物之一，所以，在用药前如果能明确其是否耐药，对于提高根除率是非常有益的。Thung等[5]根据药敏试验结果制定的根除方案结果显示，H. pylori的根除率提高了约20%(63.69%提高至85.99%)。

抗生素敏感性检测方法是H. pylori感染根除治疗和相关研究所需的重要工具和手段，对于有效、合理地指导和选择根除方案非常必要。E-test法作为简单、易于掌握的药敏试验检测方法，已在临床和科研中应用，但关于E-test法与ADM(CLSI推荐)检测H. pylori药敏试验一致性的研究并不多，限制了其广泛应用。总体上，两种检测方法用于H. pylori是否对阿莫西林、克拉霉素或左氧氟沙星耐药的一致性研究中，结果显示良好，而对甲硝唑药敏试验的一致性评价结果存在争议。在早些年的部分研究[7-8, 14]中，E-test法检测可能高估甲硝唑的耐药率约10%~20%，甚至有些研究达30%[15-16]，影响了对菌株耐药性的判断，而这种情况的发生机制并不明确，有文献分析其可能与H. pylori混合菌株、存在异质性耐药性亚群[17]、细菌接种浓度差异[15]、试验的可重复性差[15-16]等原因有关。Glupczynski等[15]的研究对试验参数进行了比较，发现较高浓度菌悬液、3 d培养期读取MIC值、Columbia或者Mueller-Hinton琼脂平板的试验结果稳定性较好，而这些重要试验参数与其他研究存在明显不一致。

当然也有一致性评价较好的研究，Miftahussurur等[9]分别用E-test、ADM检测来自临床的72例H. pylori培养菌株对甲硝唑的药敏，采用Cohen’s kappa分析两种检测方法的一致性，kappa系数为0.69(95%CI：0.52~0.85)。Ogata等[18]的研究中，Spearmans相关性检测分析显示，E-test和ADM检测甲硝唑药敏试验有较强的相关性(r=0.799, P<0.001)。Best等[19]严格控制标准试验条件，试验人员应用任何一种试验方法(E-test和ADM)均可以准确识别93%的甲硝唑耐药或敏感的H. pylori菌株(r=0.878)。上述研究与本研究的结果是一致的，以ADM作为金标准，E-test法检测甲硝唑耐药的灵敏度达97.1%，特异度达100%，Cohen’s kappa系数0.959(P<0.001)。我们采用Bland-Altman法做一致性分析，提示ADM和E-test法的数值在判断H. pylori菌株是否存在甲硝唑耐药上有强一致性，临床上对于两种检验方法数值符合的精准度要求不高，只要区分敏感和耐药菌株的一致性很好就达到了试验目的，所以一致性界限完全符合临床可接受的误差范围，Spearmans相关性检测结果也很好(r=0.807)。

本研究中，非常严重错误率和严重错误率分别为1.9%和0，比例非常低。与既往研究相比，本研究的优势在于：(1)样本均来自于临床菌株，极大还原了临床实际检测情况；(2)样本量较大，减少了抽样误差；(3)甲硝唑药敏试验检测时间较集中，减少了E-test试纸条的药物浓度受贮存温度等环境变化的影响。目前缺乏对于E-test法检测H. pylori药敏标准化试验条件的共识，但不难发现本研究及上述提示E-test法和ADM检测H. pylori对甲硝唑药敏试验一致性较好的研究中，选择的重点试验条件参数[包括菌悬液的浓度(1×107~1×108 CFU/mL)、读取MIC的时间(3 d)以及琼脂平板(Mueller-Hinton)等]均较为一致，保证了试验条件的稳定性[15]，获得了比较一致的结果。

E-test法检测药敏试验所需的时间、劳动力与ADM相比更有优势，尤其在检测标本量较少时，其优势更为突出，但以往极少有研究将其量化，尤其是对于H. pylori的药敏试验。Valdivieso-García等[20]的研究显示，将材料和劳动力成本都考虑在内，ADM的成本比E-test高39%，消耗时间方面，前者是后者的3.6倍，该研究是检测99例样本大肠弯曲杆菌(Campylobacter coli)和空肠弯曲杆菌(Campylobacter jejuni)药敏试验的结果，如果样本数少，差异会更大。本研究中，实验室条件和检测人员固定，方法成熟，为了更好地显示两种方法的成本差异，我们计算了平均检测1例标本时，ADM和E-test所需的成本，结果显示E-test所需的成本明显低于ADM，且是在检测样本量较大(105例)、我国劳动力成本相对较低的情况下。

本研究的局限性在于：(1)质控菌株选择了本实验室常用的敏感菌株ATCC26695，在进一步的研究中考虑调整为CLSI推荐的ATCC 43504；(2)本研究是单中心的实验室检测方法学研究，仅对甲硝唑的药敏试验进行了ADM和E-test检测方法的比较，在以后的研究中需扩展为多中心，对多种抗生素的药敏试验进行两种检测方法的比较，并增加实验室间的比较和实验室内方法的可重复性试验。

综上所述，E-test法在检测H. pylori对甲硝唑耐药率方面与ADM有很强的一致性和相关性，且耗时少、省力、价廉、易在临床上开展检查，值得在未来的H. pylori菌株检测和研究中广泛采用。

Funding Statement

国家自然科学基金(81670605)和北京大学第三医院院临床重点项目(BYSY2018008)

Funding Statement

Supported by the National Natural Science Foundation of China (81670605) and the Clinical Key Projects of Peking University Third Hospital (BYSY2018008)

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