臺灣博碩士論文加值系統

背景及目的: 對於幽門&;#63761;旋桿菌的除菌治&;#63937;，以氫&;#63978;子幫浦抑制劑為根基的三合一藥物是專家共&;#63996;為第一線治&;#63937;方法。然而，因世界各國菌種抗藥性逐漸增強，導致除菌失敗&;#63841;也隨之增加。因此，學者們嘗試運用第二線或第三線的救援治&;#63937;方法或提出新的其他第一線治&;#63937;&;#63789;改進成功&;#63841;。在本研究中，我們試著去&;#63930;解近期十二&;#63886;南台灣醫學中心幽門&;#63761;旋桿菌抗藥性增加的傾向，第一至三線治&;#63937;中抗藥性與除菌&;#63841;相關性，觀察是否有影響抗藥性的因子，並分析&;#63847;同藥物抗藥
性是否有關&;#63895;性影響。
材&;#63934;及方法: 我們將南臺灣高雄醫學大學醫院2003 &;#63886;九月到2014 &;#63886;七月就診病患，蒐集就醫資&;#63934;建&;#63991;成四個&;#63847;同的資&;#63934;庫，包含??1.2004 &;#63886;至2011 &;#63886;接受第一線治&;#63937;無細菌培養病患群2.2008 &;#63886;至2013 &;#63886;接受第一線治&;#63937;有細菌培養病患群3.2003 &;#63886;至2014 &;#63886;接受第二線治&;#63937;有細菌培養病患群4.2005 &;#63886;至2012 &;#63886;接受第三線治&;#63937;有細菌培養病患群。收案的標準包括必須做過胃鏡及碳-13 &;#63933;素呼氣法確診為幽門&;#63761;旋桿菌感染的患者。運用胃鏡下取得病患組織檢體培養幽門&;#63761;旋桿菌，&;#63860;存在則&;#63965;用濃&;#64001;梯&;#64001;試紙條(Ｅ-test)&;#63789;偵測細
菌抗藥性有無，且針對常用於幽門&;#63761;旋桿菌除菌的五種抗生素藥物，分別是Metronidazole, Clarithromycin, Tetracycline, Levofloxacin 和Amoxicillin。各線治&;#63937;病人經抗生素治&;#63937;後
再接受胃鏡追蹤檢查併&;#64000;片及碳-13 &;#63933;素呼氣法確認是否成
功&;#63856;菌。&;#63965;用統計方法分析抗藥性的增加是否會影響除菌成
功&;#63841;。另外在各線的治&;#63937;中，&;#63965;用多因子迴歸分析找出可能
會影響抗藥性的危險因子。
結果: 接受第一線&;#63937;法未做細菌培養有1227 個病患，除菌成
功&;#63841;從2004~2007 &;#63886;86% &;#64009;到2008~2011 &;#63886;75%。接受第一線&;#63937;法有做細菌培養有154 個病患，除菌成功&;#63841;從2010~2011 &;#63886;96.1% &;#64009;到2012~2013 &;#63886;95.1%，細菌抗藥性分別為: Metronidazole: 28.8% 升到34.8%， Clarithromycin:5.8% 保持5 %， Tetracycline: 0% 升到4.3%， Levofloxacin:13.5% 升到30.4% 及Amoxicillin 0% 升到4.3%。接受第二線&;#63937;法有做細菌培養有237 個病患，除菌成功&;#63841;從2009~2011&;#63886;79.7% &;#64009;到 2012~2014 &;#63886;60% ， 抗藥性分別為Metronidazole: 47.8% 升到53.3%， Clarithromycin:58% 升
到66.7 %， Tetracycline: 0% 升到6.7%， Levofloxacin: 26.1%
升到40% 及 Amoxicillin 0 % 保持0%。接受第三線&;#63937;法有做細菌培養有39 個病患，除菌成功&;#63841;從2005-2008 &;#63886;68% &;#64009;到2009-2012 &;#63886;68.4%，細菌抗藥性分別為: Metronidazole:76% &;#64009;到64.3%， Clarithromycin:64.5% &;#64009;到32.5 %，Tetracycline: 0% 升到7.1%，Levofloxacin: 50% 保持50% 及Amoxicillin: 0 % 保持0%。除此外，從我們的研究中發現 ，抗藥性將會影響除菌&;#63841;，特別是Clarithromycin 抗藥性增加會使第一線和三線治&;#63937;治&;#63937;成功&;#63841;下&;#64009;;Metronidazole 抗藥性增加會使第二線治&;#63937;成功&;#63841;下&;#64009;，Levofloxacin 抗藥性增加會使第二和三線治&;#63937;成功&;#63841;下&;#64009;。除&;#63930;性別是Metronidazole 抗藥性的危險因子(&;#63873;性>男性)，其它並無特定
因子影響抗藥性的增加。
結&;#63809;: 綜合以上結果，Metronidazole 和 Clarithromycin 的抗
藥性在第一和二線治&;#63937;前&;#64038;有上升，雖在第三線下&;#64009;，但仍至少超過30%。Levofloxacin 在第一和二線治&;#63937;前則有明顯上升，在第三線則維持至少50%。Tetracycline 和Amoxicillin&;#63847;管在第一二三線，抗藥性皆很低。

Background: PPI-based triple therapy is the gold standard for Helicobacter pylori (H. pylori) first-line eradication. However,successful eradication is falling due to increasing antibioticsresistance worldwide. Therefore, many people have been referred for the secondary and third-line salvage therapies or newly designed first-line therapies to improve eradication success rate. Aim to this study, we attempt to analyze the trend of antibiotics resistance of H. pylori, impact of antibiotics resistance on the eradication rate from first-line to third-line treatment, independence factors for the resistance in single medical center in southern Taiwan.
Materials and Methods: We retrospectively investigated the
chart records of patients in Kaohsiung Medical University from September 2003 to July 2014 and separated the participants in four different groups including first-line treatment without culture and first-line to third-line treatment with culture. The inclusion criteria included those who had received esophagogastroduodenoscopy (EGD) examination and 13C-urea breathe test (UBT) to confirm the status of H. pylori. Then tissue sample biopsied by EGD were cultured and antibiotics resistance was detected by E-test if culture is positive. Five drugs were studied, including Metronidazole, Clarithromycin, Tetracycline, Levofloxacin and Amoxicillin. All people had received any line treatment were confirmed if eradication is successful under follow EGD and UBT. In addition, we also observed the impact of antibiotics resistance on the eradication rate by statistics method. We also survey independent risk factors for antibiotics resistance in different line treatment with
lone antibiotics.
Results: 1227 case had first-line treatment without H.pylori
culture was recruited and eradication success rate from 86% to 75 %. 154 cases had first-line treatment with H. pylori culture and eradication success rate reduced from 2010~2011 96.1% to 2012~2013 95.1 % and different antibiotics resistance includes Metronidazole: 28.8% to 34.8%, Clarithromycin: 5.8% to 0%, Tetracycline: 0% to 4.3 %, Levofloxacin: 13.5% to 30.4% and Amoxicillin: 0% to 4.3%. 237 cases had second-line treatment with H. pylori culture and eradication success rate reduced from 2009~2011 79.7% to 2012~2013 60 % and different antibiotics resistance includes Metronidazole: 47.8% to 53.3%, Clarithromycin: 58% to 66.7%, Tetracycline: 0% to 6.7 %,Levofloxacin: 26.1% to 40% and Amoxicillin: 0% to 0%. 39 cases had third-line treatment with H. pylori culture and eradication success rate reduced from 2005~2008 68% to 2009~2012 68.4 % and different antibiotics resistance includes Metronidazole: 76% to 64.3%, Clarithromycin: 64.5% to 32.5%, Tetracycline: 0% to 7.1%, Levofloxacin: 50% to 50% and Amoxicillin: 0% to 0%. We also found antibiotics resistance effects eradication rate especially increasing Clarithromycin
resistance reduces eradication rate of first-line and third
treatment, Metronidazole resistance reduces it of first-line and second-line treatment and Levofloxacin reduced it of second-line and third-line treatment. Sex has been a risk factor to Metronidazole resistance and no other factors are found to affect other antibiotics resistance.
Conclusion: In our retrospective study, we could find emerging resistance to antibiotics rate has affected the eradication success rate in 12 years. Resistance to Metronidazole and Clarithromycin increased in first-line and second-line treatment, although decreased in third-line treatment, remained as least 30%. Levofloxacin increased dominantly in first-line and second-line treatment and maintains as high as 50 % in third-line treatment. Resistance to Tetracycline and Amoxicillin resistance was nearly 0 % across the board indifferent line treatment. Specific antibiotics resistance influence alternative line treatment and no obvious risk factor was survey except forsex for Metronidazole.

目次
&;#63809;文指導教授及口試委員之畢業&;#63809;文通過證明書
授權書: 高雄醫學大學紙本&;#63809;文授權書
中文摘要 3
英文摘要 6
致謝辭 9
前言 10
研究材&;#63934;與方法 15
研究結果 21
討&;#63809; 26
結&;#63809;
&;#63851;考文獻 32
附&;#63807;(圖表) 40

1.Warren, J.R., and B. J. Marshall, Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet, 1983. 1(8336): p. 1273-5.
2.McColl, K.E., Clinical practice. Helicobacter pylori infection. N Engl J Med, 2010. 362(17): p. 1597-604.
3.Kusters, J.G., A.H. van Vliet, and E.J. Kuipers, Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev, 2006. 19(3): p. 449-90.
4.Talley, N.J. and R.H. Hunt, What role does Helicobacter pylori play in dyspepsia and nonulcer dyspepsia? Arguments for and against H. pylori being associated with dyspeptic symptoms. Gastroenterology, 1997. 113(6 Suppl): p. S67-77.
5.Kuipers, E.J., J.C. Thijs, and H.P. Festen, The prevalence of Helicobacter pylori in peptic ulcer disease. Aliment Pharmacol Ther, 1995. 2: p. 59-69.
6.Parsonnet, J., et al., Helicobacter pylori infection and gastric lymphoma. N Engl J Med, 1994. 330(18): p. 1267-71.
7.Graham, D.Y. and W.A. Qureshi, Antibiotic-resistant H. pylori infection and its treatment. Curr Pharm Des, 2000. 6(15): p. 1537-44.
8.Peek, R.M., Jr., C. Fiske, and K.T. Wilson, Role of innate immunity in Helicobacter pylori-induced gastric malignancy. Physiol Rev, 2010. 90(3): p. 831-58.
9.Vakil, N., H. pylori treatment: new wine in old bottles?: Am J Gastroenterol. 2009 Jan;104(1):26-30. doi: 10.1038/ajg.2008.91.
10.Malfertheiner, P., et al., Management of Helicobacter pylori infection--the Maastricht IV/ Florence Consensus Report. Gut, 2012. 61(5): p. 646-64.
11.Torres, J., et al., A community-based seroepidemiologic study of Helicobacter pylori infection in Mexico. J Infect Dis, 1998. 178(4): p. 1089-94.
12.Lin, J.T., et al., Helicobacter pylori infection in a randomly selected population, healthy volunteers, and patients with gastric ulcer and gastric adenocarcinoma. A seroprevalence study in Taiwan. Scand J Gastroenterol, 1993. 28(12): p. 1067-72.
13.De Francesco, V., et al., Worldwide H. pylori antibiotic resistance: a systematic review. J Gastrointestin Liver Dis, 2010. 19(4): p. 409-14.
14.Abadi, A.T., et al., Frequency of antibiotic resistance in Helicobacter pylori strains isolated from the northern population of Iran. J Microbiol, 2011. 49(6): p. 987-93.
15.Rajper, S., et al., Macrolide and fluoroquinolone resistance in Helicobacter pylori isolates: an experience at a tertiary care centre in Pakistan. J Pak Med Assoc, 2012. 62(11): p. 1140-4.
16.Saracino, I.M., et al., High prevalence of primary antibiotic resistance in Helicobacter pylori isolates in Italy. J Gastrointestin Liver Dis, 2012. 21(4): p. 363-5.
17.Talebi Bezmin Abadi, A., et al., Primary resistance of Helicobacter pylori to levofloxacin and moxifloxacine in Iran. Intern Emerg Med, 2012. 7(5): p. 447-52.
18.An, B., et al., Antibiotic resistance in Helicobacter pylori strains and its effect on H. pylori eradication rates in a single center in Korea. Ann Lab Med, 2013. 33(6): p. 415-9.
19.Hsiang, J., et al., Increasing primary antibiotic resistance and ethnic differences in eradication rates of Helicobacter pylori infection in New Zealand--a new look at an old enemy. N Z Med J, 2013. 126(1384): p. 64-76.
20.Kupcinskas, L., et al., Evolution of Helicobacter pylori susceptibility to antibiotics during a 10-year period in Lithuania. APMIS, 2013. 121(5): p. 431-6.
21.Megraud, F., et al., Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut, 2013. 62(1): p. 34-42.
22.Seck, A., et al., Primary antibiotic resistance and associated mechanisms in Helicobacter pylori isolates from Senegalese patients. Ann Clin Microbiol Antimicrob, 2013. 12: p. 3.
23.Selgrad, M., et al., Antibiotic susceptibility of Helicobacter pylori in central Germany and its relationship with the number of eradication therapies. Eur J Gastroenterol Hepatol, 2013. 25(11): p. 1257-60.
24.Su, P., et al., Antibiotic resistance of Helicobacter pylori isolated in the Southeast Coastal Region of China. Helicobacter, 2013. 18(4): p. 274-9.
25.Vekens, K., et al., Primary antimicrobial resistance of Helicobacter pylori in Belgium. Acta Clin Belg, 2013. 68(3): p. 183-7.
26.Vilaichone, R.K., et al., Nationwide survey of Helicobacter pylori antibiotic resistance in Thailand. Diagn Microbiol Infect Dis, 2013. 77(4): p. 346-9.
27.Vilaichone, R.K., et al., Antibiotics resistance rate of Helicobacter pylori in Bhutan. World J Gastroenterol, 2013. 19(33): p. 5508-12.
28.Camargo, M.C., et al., The problem of Helicobacter pylori resistance to antibiotics: a systematic review in Latin America. Am J Gastroenterol, 2014. 109(4): p. 485-95.
29.Picoli, S.U., et al., Resistance to amoxicillin, clarithromycin and ciprofloxacin of Helicobacter pylori isolated from Southern Brazil patients. Rev Inst Med Trop Sao Paulo, 2014. 56(3): p. 197-200.
30.Yang, J.C., et al., A multicenter study on eradication of Helicobacter pylori infection in patients with duodenal ulcer by lansoprazole-antibiotics combined therapy. J Microbiol Immunol Infect, 1999. 32(): p. 1-8.
31.Chang, W.L., et al., Resistance to metronidazole, clarithromycin and levofloxacin of Helicobacter pylori before and after clarithromycin-based therapy in Taiwan. J Gastroenterol Hepatol, 2009. 24(7): p. 1230-5.
32.Wu, D.C., et al., Sequential and concomitant therapy with four drugs is equally effective for eradication of H pylori infection. Clin Gastroenterol Hepatol, 2010. 8(1): p. 36-41.
33.Hu, C.T., et al., Resistance rate to antibiotics of Helicobacter pylori isolates in eastern Taiwan. J Gastroenterol Hepatol, 2007. 22(5): p. 720-3.
34.Villoria, A., [Acid-related diseases: are higher doses of proton pump inhibitors more effective in the treatment of Helicobacter pylori infection?]. Gastroenterol Hepatol, 2008. 31(8): p. 546-7.
35.Calvet, X., et al., A meta-analysis of short versus long therapy with a proton pump inhibitor, clarithromycin and either metronidazole or amoxycillin for treating Helicobacter pylori infection. Aliment Pharmacol Ther, 2000. 14(5): p. 603-9.
36.Tseng, Y.S., et al., Amoxicillin resistance with beta-lactamase production in Helicobacter pylori. Eur J Clin Invest, 2009. 39(9): p. 807-12.
37.Gerrits, M.M., et al., 16S rRNA mutation-mediated tetracycline resistance in Helicobacter pylori. Antimicrob Agents Chemother, 2002. 46(9): p. 2996-3000.
38.Poon, S.K., et al., Primary resistance to antibiotics and its clinical impact on the efficacy of Helicobacter pylori lansoprazole-based triple therapies. Aliment Pharmacol Ther, 2002. 16(2): p. 291-6.
39.Marais, A., et al., Cag negative status of Helicobacter pylori is a risk factor for failure of PPI-based triple therapies in non-ulcer dyspepsia. Gastroenterology. 114: p. A214.
40.Horiki, N., et al., Annual change of primary resistance to clarithromycin among Helicobacter pylori isolates from 1996 through 2008 in Japan. Helicobacter, 2009. 14(5): p. 86-90.
41.Huang, A.H., et al., Impact of Helicobacter pylori antimicrobial resistance on the outcome of 1-week lansoprazole-based triple therapy. J Formos Med Assoc, 2000. 99(9): p. 704-9.
42.Lee, J.W., et al., Prevalence of primary and secondary antimicrobial resistance of Helicobacter pylori in Korea from 2003 through 2012. Helicobacter, 2013. 18(3): p. 206-14.
43.Liou, J.M., et al., Levofloxacin-based and clarithromycin-based triple therapies as first-line and second-line treatments for Helicobacter pylori infection: a randomised comparative trial with crossover design. Gut, 2010. 59(5): p. 572-8.
44.Ndip, R.N., et al., Helicobacter pylori isolates recovered from gastric biopsies of patients with gastro-duodenal pathologies in Cameroon: current status of antibiogram. Trop Med Int Health, 2008. 13(6): p. 848-54.
45.Seck, A., et al., Antibiotic susceptibility of Helicobacter pylori isolates in Dakar, Senegal. J Infect Dev Ctries, 2009. 3(2): p. 137-40.
46.Lin, C.W., et al., Helicobacter pylori in gastric biopsies of Taiwanese patients with gastroduodenal diseases. Jpn J Med Sci Biol, 1998. 51(1): p. 13-23.
47.Graham, D.Y., et al., Factors influencing the eradication of Helicobacter pylori with triple therapy. Gastroenterology, 1992. 102(2): p. 493-6.
48.Peretz, A., et al., Resistance of Helicobacter pylori to tetracycline, amoxicillin, clarithromycin and metronidazole in Israeli children and adults. J Antibiot (Tokyo), 2014. 67(8): p. 555-7.