劉雪芳， 馬嵐青

昆明醫(yī)科大學(xué)第一附屬醫(yī)院消化內(nèi)科，云南 昆明 650032

幽門螺旋桿菌對(duì)克拉霉素、甲硝唑、左氧氟沙星耐藥的研究進(jìn)展

劉雪芳， 馬嵐青

昆明醫(yī)科大學(xué)第一附屬醫(yī)院消化內(nèi)科，云南 昆明 650032

幽門螺旋桿菌(Helicobacter pylori，H.pylori)感染可導(dǎo)致慢性胃炎、消化性潰瘍、胃癌和胃黏膜相關(guān)淋巴組織(mucosa-associated lymphoid tissue, MALT)淋巴瘤。而H.pylori根除治療失敗與克拉霉素、甲硝唑及左氧氟沙星高的耐藥率有關(guān)?，F(xiàn)已證實(shí)這些抗生素的耐藥機(jī)制與H.pylori基因突變有關(guān)。提高對(duì)這些抗生素耐藥機(jī)制的了解對(duì)發(fā)展和證實(shí)以活檢組織為基礎(chǔ)的耐藥性檢測(cè)方法很有必要?？焖贆z測(cè)H.pylori耐藥的基因突變有助于H.pylori根除治療方案的選擇。

幽門螺旋桿菌；抗生素耐藥；基因突變；克拉霉素；甲硝唑；左氧氟沙星

幽門螺旋桿菌(Helicobacter pylori，H.pylori)是革蘭氏陰性微需氧細(xì)菌。H.pylori感染普遍出現(xiàn)在各個(gè)國(guó)家，發(fā)展中國(guó)家的感染率超過(guò)70%,發(fā)達(dá)國(guó)家感染率20%～50%。H.pylori感染可以導(dǎo)致慢性胃炎、消化性潰瘍、胃癌和胃黏膜相關(guān)淋巴組織(mucosa-associated lymphoid tissue, MALT)淋巴瘤。根除H.pylori可以降低胃癌的發(fā)病率。

三聯(lián)療法曾被推薦作為一線治療H.pylori感染的方法，這種治療方法包括質(zhì)子泵抑制劑和兩種抗生素。然而隨著這種治療方法根除H.pylori失敗率的增加，許多研究人員發(fā)現(xiàn)H.pylori對(duì)抗生素耐藥是導(dǎo)致這種方法根除失敗的主要原因。目前含有鉍劑的四聯(lián)療法被推薦為根除H.pylori的首選方法。克拉霉素、甲硝唑、左氧氟沙星作為根除H.pylori最常選用的抗生素，H.pylori對(duì)其的耐藥直接影響根除率。所以了解耐藥機(jī)制和快速檢測(cè)H.pylori在H.pylori感染根除治療中有重要意義。本文就H.pylori對(duì)克拉霉素、甲硝唑及左氧氟沙星的耐藥機(jī)制和檢測(cè)方法作一概述。

1 克拉霉素

1.1 耐藥機(jī)制H.pylori對(duì)克拉霉素耐藥受多種因素影響，研究表明H.pylori23S rRNA肽基轉(zhuǎn)移酶彎曲部分基因2143和2144腺嘌呤突變?yōu)轼B(niǎo)嘌呤，2142腺嘌呤突變?yōu)榘奏1]。突變A2143G和A2144G是被確認(rèn)為H.pylori耐克拉霉素的原因[2]，韓國(guó)科學(xué)家Kim等[3]研究發(fā)現(xiàn)T2182C突變，同時(shí)報(bào)道了基因突變可以同時(shí)出現(xiàn)2～3個(gè)。但是Moder等[4]研究T2182C突變與克拉霉素耐藥并無(wú)關(guān)聯(lián)。有報(bào)道[3]指出A2115G、C2694A也與克拉霉素耐藥有關(guān)，西班牙科學(xué)家Agudo等[5]研究并未發(fā)現(xiàn)以上突變，但是指出H.pylori對(duì)克拉霉素的抵抗可能與人種、地區(qū)、年齡、性別有關(guān)。H.pylori對(duì)克拉霉素耐藥率存在明顯地域差異：伊朗的耐藥率為45.2%[6]，巴西的耐藥率為8.0%[7]，意大利的耐藥率為9.9%[8]。H.pylori對(duì)克拉霉素耐藥率存在年齡及性別的差異：Boyanova等[9]研究發(fā)現(xiàn)65歲以上的耐藥率低于65歲以下，且男性耐藥率高于女性。同時(shí)還發(fā)現(xiàn)非消化性潰瘍患者克拉霉素的耐藥率高于消化性潰瘍患者。服用非甾體類抗炎藥的患者對(duì)克拉霉素的耐藥率高于未服用患者；H.pylori耐藥率與出生地、是否吸煙、飲食習(xí)慣等有關(guān)。而O’Connor等[10]研究發(fā)現(xiàn)有根除治療經(jīng)驗(yàn)患者耐藥率高于未進(jìn)行根除治療患者(32.4%vs9.3%)。因此，克拉霉素對(duì)H.pylori的耐藥率是受多種因素影響。

1.2 檢測(cè)方法H.pylori耐克拉霉素檢測(cè)方法主要是基于PCR技術(shù)的分子診斷技術(shù)，這些技術(shù)都是建立在與H.pylori耐藥相關(guān)基因突變的基礎(chǔ)上。熒光定量PCR(Light Cycle)可以在1 h內(nèi)檢測(cè)出23S rRNA上的點(diǎn)突變[1]。Nasted PCR可以快速、準(zhǔn)確地檢測(cè)出H.pylori耐克拉霉素23S rRNA的突變[11]。Schabereiter-Gurtner等[12]研究表明通過(guò)Biprones 技術(shù)聯(lián)合Real-time PCR可成為精確的非創(chuàng)傷性檢測(cè)H.pylori感染的方法，提高Real-time PCR特異性檢測(cè)H.pylori感染及對(duì)克拉霉素耐藥的23S rRNA上的點(diǎn)突變，同時(shí)雙探針熒光能量轉(zhuǎn)移(FRET)聯(lián)合Real-time PCR技術(shù)，其擴(kuò)增產(chǎn)物通過(guò)溶解曲線進(jìn)行分析，在幾個(gè)小時(shí)內(nèi)能夠同時(shí)檢測(cè)H.pylori感染及大環(huán)內(nèi)酯類耐藥性[13]。van Doorn等[14]通過(guò)線性探針?lè)聪螂s交技術(shù)(PCR-LiPA)能夠快速、準(zhǔn)確地檢測(cè)出H.pylori耐大環(huán)內(nèi)酯類藥物的23S rRNA的突變。Moder等[4]也證明了焦磷酸測(cè)序技術(shù)是一種可靠、快速、高度準(zhǔn)確的檢測(cè)H.pylori對(duì)克拉霉素耐藥的方法。此外，比色法DNA芯片能夠檢測(cè)野生株和任何位置單個(gè)點(diǎn)突變，對(duì)檢測(cè)H.pylori耐藥基因有高度特異性，且不要求昂貴的設(shè)備，花費(fèi)低、操作簡(jiǎn)單，具有高流通量和在臨床上應(yīng)用的技術(shù)可行性[15]，尤其適用于發(fā)展中國(guó)家的小型和中等規(guī)模的醫(yī)院。因此，比色法DNA芯片也是一種可靠、快速、準(zhǔn)確地檢測(cè)有關(guān)H.pylori克拉霉素耐藥的方法。

2 甲硝唑

2.1 耐藥機(jī)制H.pylori對(duì)甲硝唑耐藥最根本的原因是H.pylori基因突變。早在1998年Goodwin等[16]報(bào)道對(duì)氧敏感的NADPH硝基還原酶活性與H.pylori對(duì)甲硝唑敏感性有關(guān)。突變的H.pylori的rdxA基因可以鈍化對(duì)氧敏感的NADPH硝基還原酶基因的編碼和表達(dá)。大量研究調(diào)查顯示H.pylori耐甲硝唑與H.pylori的基因rdxA或frxA基因突變有關(guān)[17-19]。而H.pylori對(duì)甲硝唑的高耐藥率與rdxA基因低突變率[20]，提示H.pylori對(duì)甲硝唑耐藥還存在其他機(jī)制。Kaakoush等[21]認(rèn)為H.pylori耐甲硝唑不僅涉及rdxA或frxA基因突變，更多的是涉及復(fù)雜新陳代謝的改變。Tsugawa等[22]研究發(fā)現(xiàn)不是所有對(duì)甲硝唑耐藥的H.pylori都具有硝基還原酶活性，只有少部分菌株具有此酶活性。并指出多數(shù)對(duì)甲硝唑耐藥的H.pylori是由于鐵吸收蛋白調(diào)節(jié)器(fur)上的兩個(gè)氨基酸類突變(C78Y，P114S)。同時(shí)Choi等[23]報(bào)道fur基因產(chǎn)物可能與其他細(xì)胞成分、新陳代謝線路相互作用，在胃小凹內(nèi)形成有利于H.pylori生存的特殊環(huán)境。此外，RND流出泵過(guò)度表達(dá)增加H.pylori對(duì)甲硝唑的耐藥率[24]，不含cagA基因的H.pylori菌株相對(duì)于含cagA基因的H.pylori更易對(duì)甲硝唑產(chǎn)生耐藥[25]。愛(ài)爾蘭O’Connor 等[10]報(bào)道H.pylori對(duì)甲硝唑與性別有關(guān)，女性耐藥率為35.4%，男性耐藥率為28.5%。

2.2 檢測(cè)方法H.pylori耐甲硝唑是基于多種因素，檢測(cè)甲硝唑耐藥菌株方法也涉及多方面。Singh等[26]重復(fù)共有基因序列(repetitive intergenic consensus sequences，ERIC)結(jié)合隨機(jī)擴(kuò)增基因多態(tài)性PCR技術(shù)(random amplified polymorphic DNA-PCR，RAPD-PCR)識(shí)別耐甲硝唑菌株。Jenks等[17]、Tankovic等[18]采用PCR技術(shù)特意性擴(kuò)增H.pylorirdxA基因片段，然后對(duì)該片段進(jìn)行核苷酸序列測(cè)定，以檢測(cè)出耐藥菌株。Mehrabadi等[24]通過(guò)RT-PCR方法和同源分析法檢測(cè)出RND流出泵過(guò)度表達(dá)，從而鑒別H.pylori耐甲硝唑菌株。Morimoto等[27]采用重復(fù)序列PCR(rep-PCR)聯(lián)合高級(jí)微生物基因分型系統(tǒng)(DiversiLab Microbial Typing System DL)快速、高敏感地識(shí)別耐甲硝唑、克拉霉素菌株及克拉霉素同時(shí)耐藥的菌株。高分辨率溶解曲線分析技術(shù)(high resolution melting analysis，HRM)利用溶解溫度和變性程度之間關(guān)系進(jìn)行基因片段分析，完全基于核酸物理性質(zhì)進(jìn)行分析，無(wú)需序列特異性探針，不受突變堿基類型和位點(diǎn)局限，在PCR結(jié)束后直接運(yùn)行HRM既可以對(duì)未知突變進(jìn)行篩查、掃描，又可以對(duì)已知突變進(jìn)行分析，也可用于短片段重復(fù)序列的分析[28]。

3 左氧氟沙星

3.1 耐藥機(jī)制H.pylori對(duì)氟喹諾酮類藥物耐藥99%是由于H.pylorigyrA基因的喹諾酮類藥物耐藥決定區(qū)(quinolone resistance determining region，QRDR)突變導(dǎo)致[29]。已有13種突變被檢測(cè)出，它們位于基因gyrA的86、87、88和91位點(diǎn)[30-32]。有研究表明83.8%的H.pylori對(duì)左氧氟沙星耐藥是由于H.pylori上的基因gyrA在Asn87或是Asp91位點(diǎn)上點(diǎn)突變[31]。且H.pylori的基因gyrA在Asn87位點(diǎn)上的突變對(duì)左氧氟沙星耐藥率高于H.pylori的基因gyrA在Asp91位點(diǎn)上點(diǎn)突變。而gyrB基因在463位點(diǎn)上點(diǎn)突變是H.pylori對(duì)氟喹諾酮類藥物耐藥的新機(jī)制。可能由于不同地區(qū)對(duì)抗生素的使用劑量與適應(yīng)證制定標(biāo)準(zhǔn)不同，H.pylori對(duì)左氧氟沙星耐藥出現(xiàn)地域、年齡差異。Megraud等[33]研究調(diào)查中顯示H.pylori對(duì)左氧氟沙星耐藥率在成人與兒童中是不同的：成人耐藥率為14.1%，兒童為8.0%；不同地區(qū)對(duì)左氧氟沙星的耐藥率也是不同的：北歐為7.7%，南/中歐為18.6%，西歐為13.1%，馬來(lái)西亞為0[34]；O’Connor等[35]發(fā)現(xiàn)H.pylori耐左氧氟沙星存在年齡差異：45歲以下耐藥率為2.8%，45歲以上耐藥率為19.1%。

3.2 檢測(cè)方法H.pylori耐左氧氟沙星檢測(cè)主要是檢測(cè)突變的基因，這些方法主要是基于PCR技術(shù)的分子診斷技術(shù)。大多檢測(cè)H.pylori耐左氧氟沙星都是采用PCR技術(shù)特意性擴(kuò)增H.pylorigyrA基因的QRDR片段，然后對(duì)該片段進(jìn)行核苷酸序列測(cè)定[29-31]。德國(guó)學(xué)者Glocker等[36]利用Real-time PCR結(jié)合熒光共振能量轉(zhuǎn)換技術(shù)(fluorescence resonance energy transfer-based real-time PCR)檢測(cè)出不同突變類型基因突變菌株的熔解溫度，通過(guò)熔解溫度鑒別耐喹諾酮類藥物的H.pylori。Nishizawa等[37]構(gòu)建等位基因特異性PCR(Allele-specific PCR，AS-PCR)，在3～5 h內(nèi)檢測(cè)出H.pylorigyrA基因上的突變，是一種快速、可靠地識(shí)別耐氟喹諾酮類藥物的菌株方法。Rajper等[38]利用反向雜交PCR線性探針測(cè)定快速測(cè)定耐左氧氟沙星的H.pylorigyrA基因上的突變。此外，GenoType HelicoDR測(cè)試是依賴DNA條帶方法學(xué)檢測(cè)出耐左氧氟沙星的H.pylorigyrA基因上的突變及耐克拉霉素H.pylori的23S rRNA的突變，也可檢測(cè)出對(duì)克拉霉素和左氧氟沙星同時(shí)耐藥的菌株[39]，這種方法操作簡(jiǎn)單便于在臨床使用。

隨著抗生素在根除H.pylori感染治療中的廣泛應(yīng)用，耐藥菌株也不斷出現(xiàn)，H.pylori根除治療面臨著嚴(yán)峻的考驗(yàn)。因此，設(shè)計(jì)一種快速、準(zhǔn)確、高敏感性及操作簡(jiǎn)便的檢測(cè)對(duì)抗生素耐藥菌株的方法，對(duì)指導(dǎo)臨床用藥有著深遠(yuǎn)的意義。近年來(lái)，基因芯片技術(shù)逐漸趨于成熟，HRM因其快速、低成本、高敏感性、特異性好、重復(fù)性好及操作簡(jiǎn)便，在國(guó)外興起一種用于突變掃描和基因分型的最新遺傳學(xué)分析方法，成為國(guó)外新興的遺傳學(xué)、方法學(xué)研究和應(yīng)用熱點(diǎn)。二者均具有較高的臨床應(yīng)用價(jià)值及推廣意義。

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堪誤：本刊2015年第12期第1494頁(yè)第一作者王銳的文章《危險(xiǎn)因素對(duì)胃黏膜癌前病變中血管內(nèi)皮生長(zhǎng)因子表達(dá)的影響》左下角基金項(xiàng)目：全軍“十二五”課題面上項(xiàng)目(CWS11J005),標(biāo)注有誤，本文無(wú)基金項(xiàng)目，特此更正。

Advances in research of Helicobacter pylori resistance to Clarithromycin, Metronidazole, Levofloxacin

LIU Xuefang, MA Lanqing

Department of Gastroenterology, the First Affilicated Hospital of Kunming Medical University, Kunming 650032, China

Infection with Helicobacter pylori (H.pylori) is associated with chronic gastritis and peptic ulceration and the bacterium. It is also considered as a risk factor for the development of gastric adenocarcinoma and mucosa-associated lymphoid tissue (MALT) lymphoma. High resistance rates of Clarithromycin, Metronidazole, and Levofloxacin are associated withH.pylorieradication failure. It is widely accepted that the resistance to these antimicrobial is related with mutations ofH.pylorigene. Improving the understanding of the mechanisms of antimicrobial resistance inH.pyloriis essential for the development and validation of biopsy-based tests for detection of resistance. Rapid detection of mutations gene ofH.pyloricontributes to the selection of suitable eradication therapies for patients.

Helicobacter pylori; Antimicrobial resistance; Gene mutations; Clarithromycin; Metronidazole; Levofloxacin

10.3969/j.issn.1006-5709.2016.01.028

云南省聯(lián)合專項(xiàng)基金(2012FB027)

劉雪芳，碩士在讀，研究方向：消化系統(tǒng)疾病。E-mail：532180042@qq.com

馬嵐青，博士，研究生導(dǎo)師，副主任醫(yī)師，研究方向：消化系統(tǒng)疾病。E-mail：malanqing@aliyun

R37

A

1006-5709(2016)01-0101-04

2014-12-25