進階搜尋


下載電子全文  
系統識別號 U0026-1108201521083700
論文名稱(中文) 困難梭狀桿菌感染: 台南地區醫院內流行病學研究及建立老鼠感染模型
論文名稱(英文) Clostridium difficile infection: hospital-based epidemiology in Tainan and establishment of an animal model
校院名稱 成功大學
系所名稱(中) 臨床醫學研究所
系所名稱(英) Institute of Clinical Medicine
學年度 103
學期 2
出版年 104
研究生(中文) 洪元斌
研究生(英文) Yuan-Pin Hung
電子信箱 yuebin16@yahoo.com.tw
學號 S98981149
學位類別 博士
語文別 英文
論文頁數 49頁
口試委員 指導教授-柯文謙
指導教授-蔡佩珍
召集委員-薛博仁
口試委員-陳彥旭
口試委員-謝奇璋
中文關鍵字 困難梭狀桿菌感染  Toll-like receptor  氫離子阻斷劑  toxinotype  ribotype 
英文關鍵字 Clostridium difficile infection  Toll-like receptor  proton pump inhibitor  toxinotype  ribotype 
學科別分類
中文摘要 困難梭狀桿菌感染是造成院內抗生素使用相關腹瀉的重要原因,發生率及死亡率正逐漸增加。台灣困難梭狀桿菌感染發生率仍未知。困難梭狀桿菌移生已知是困難梭狀桿菌相關腹瀉獨立危險因子;但困難梭狀桿菌移生對住院病患影響仍不清楚。對於困難梭狀桿菌感染病理機制的不了解,在訂定預防或治療政策時,面臨挑戰。
已知困難梭狀桿菌毒素會破壞腸壁,引起腸黏膜發炎及腸道破壞。除細菌毒素外,宿主免疫力缺失,也是困難梭狀桿菌感染增加的原因,因此宿主免疫防衛機制,也需要進一步研究。巨噬細胞如何辨識或吞噬困難梭狀桿菌的相關機制,仍未完全了解。Toll-like receptors (TLRs) 是先天性免疫重要組成,將研究TLRs 與困難梭狀桿菌關聯性。
獲得困難梭狀桿菌移生及感染的流行病學資料,將針對內科病房住院病患,以培養及毒素ELISA檢查糞便是否有困難梭狀桿菌移生。這些病人住院期間將持續追蹤,是否有發生困難梭狀桿菌感染的腸道炎及大腸炎。糞便中困難梭狀桿菌,將進一步做toxinotyping、 ribotyping。研究發現病患有困難梭狀桿菌移生,會有較高機會後續發生困難梭狀桿菌感染。氫離子阻斷劑和抗生素使用,都是困難梭狀桿菌移生或感染危險因子。另也證實台灣本土有高毒性困難梭狀桿菌菌株- 核糖核酸體分型126和027- 能造成嚴重感染;還發現特定TLRs基因多型性,與發生困難梭狀桿菌移生或感染有關。
為瞭解困難梭狀桿菌感染病理機制,將建立老鼠腸道感染模型。臨床上氫離子幫浦抑制劑使用,可能促成困難梭狀桿菌感染,藉由老鼠腸道感染模型,檢視氫離子幫浦抑制劑之角色與機轉,發現先前使用氫離子阻斷劑,將使老鼠的困難梭狀桿菌感染變得更嚴重。進一步以此老鼠模式,作為致病機制研究平台,探討TLR扮演的角色,用TLR2或 TLR4基因缺失老鼠,比較野生種老鼠及TLR2或 TLR4缺失老鼠,感染後腸道病理變化及發炎情況差異,結果發現TLR2或TLR4缺失老鼠發炎情形較嚴重, 因此推論TLRs在困難梭狀桿菌感染中,扮演保護性角色。
由醫院端的臨床流行病學研究,已獲得台灣困難梭狀桿菌移生及感染的第一手流病資料。從基礎研究,也瞭解困難梭狀桿菌感染時,宿主TLRs及相關發炎機制之角色。綜合研究結果,希望能喚起台灣醫界對困難梭狀桿菌感染之重視,更由鼠腸道感染模式研究平台之建立,能有助於未來困難梭狀桿菌感染的預防和治療藥物研發。
英文摘要 Clostridium difficile is a major cause of nosocomial antibiotic-associated diarrhea and has increasing incidence and fatality rates. The incidence of C. difficile infection (CDI) in Taiwan is unclear. C. difficile colonization is an independent risk factor for C. difficile-associated diarrhea. However, the impact of C. difficile colonization in hospitalized patients is not known. Gaps in our understanding of the pathogenesis of CDI present major challenges to the development of better preventive and therapeutic strategies against this problem.
C. difficile toxins breach the intestinal barrier and trigger musical inflammation and intestinal damage. In addition to the effects of bacterial toxins, impaired host immunity is also associated with increased risks of CDI, suggesting that the pathogenesis of CDI needs to be further characterized. The receptor-mediated mechanisms by which macrophages recognize and phagocytize bacteria, including clostridia, have not been well analyzed. Toll-like receptors (TLRs) are the major components of innate immunity. The relationship between TLRs and CDI was analyzed in this work.
An epidemiological study was performed in the medical wards of a regional hospital. Fecal culture and toxin ELISA tests were performed for C. difficile colonization in all hospitalized patients; during hospitalization, these patients were followed up for the development of CDI. All clinical C. difficile isolates were further characterized by toxinotyping and ribotyping. C. difficile colonization was noted to cause a higher risk of CDI. Prior exposure to proton pump inhibitors or antimicrobial agents was a risk factor for C. difficile colonization and infection. During the study period, some hypervirulent C. difficile strains, such as ribotype 126 and 027, were discovered in Tainan. Patients with a specific TLR polymorphism had a higher risk of C. difficile colonization and infection than those without the polymorphism.
To analyze the pathophysiology of CDI, a mouse model of CDI was designed to investigate the predisposing role of PPI in CDI. Mice developed severe CDI after PPI use. The mouse model of CDI could be used to analyze the contribution of innate immunity in CDI. To investigate the role of TLRs in the pathogenesis of CDI, Tlr2-/- or Tlr4-/- mice were infected by C. difficile. The mice then were examined for changes in the severity in clostridial colitis. Colon pathology findings in C. difficile-infected wild mice and Tlr2-/- or Tlr4-/- mice were compared. Tlr-/- mice presented more severe CDI than wild mice, indicative of a protective role of TLRs in CDI.
The first epidemiological information of C. difficile colonization and infection rates in Taiwan were obtained in the described clinical studies. In addition, basic research findings increased our understanding of TLRs and how they mediate the inflammatory responses against CDI. By combining these results, translational studies will likely draw the attention of medical professionals who deal with CDI. Furthermore, the described CDI mouse model can be utilized to develop preventive or therapeutic strategies for combating CDI.
論文目次 中文摘要 Ⅰ
English summary Ⅱ
Abbreviations Ⅵ
Table legends Ⅶ
Figure legends Ⅷ
Chapter 1. Introduction 1
Chapter 2. The epidemiology and clinical impact of Clostridium difficile colonization and infection 4
Introduction 4
Materials and methods 7
Results 9
Discussion 20
Chapter 3. Establishment of a mouse model of Clostridium difficile infection to investigate the role of a proton pump inhibitor and Toll-like receptors 25
Introduction 25
Materials and methods 27
Results 30
Discussion 38
Chapter 4. Summary and suggestions for future research 41
Clostridium difficile study- related publications 43
References 44

參考文獻 1. Kuijper EJ, van Dissel JT, Wilcox MH. Clostridium difficile: changing epidemiology and new treatment options. Curr Opin Infect Dis 2007; 376-83.
2. Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006; 758-64.
3. Kelly CP, LaMont JT. Clostridium difficile--more difficult than ever. N Engl J Med 2008; 1932-40.
4. Chung CH, Wu CJ, Lee HC, et al. Clostridium difficile infection at a medical center in southern Taiwan: incidence, clinical features and prognosis. J Microbiol Immunol Infect 2010; 119-25.
5. Lawrence SJ, Puzniak LA, Shadel BN, Gillespie KN, Kollef MH, Mundy LM. Clostridium difficile in the intensive care unit: epidemiology, costs, and colonization pressure. Infect Control Hosp Epidemiol 2007; 123-30.
6. DuPont HL, Garey K, Caeiro JP, Jiang ZD. New advances in Clostridium difficile infection: changing epidemiology, diagnosis, treatment and control. Curr Opin Infect Dis 2008; 500-7.
7. Borysiewicz E, Fil D, Konat GW. Rho proteins are negative regulators of TLR2, TLR3, and TLR4 signaling in astrocytes. J Neurosci Res 2009; 1565-72.
8. Texereau J, Chiche JD, Taylor W, Choukroun G, Comba B, Mira JP. The importance of Toll-like receptor 2 polymorphisms in severe infections. Clin Infect Dis 2005; S408-15.
9. Fekety R, Silva J, Toshniwal R, et al. Antibiotic-associated colitis: effects of antibiotics on Clostridium difficile and the disease in hamsters. Rev Infect Dis 1979; 386-97.
10. Czuprynski CJ, Johnson WJ, Balish E, Wilkins T. Pseudomembranous colitis in Clostridium difficile-monoassociated rats. Infect Immun 1983; 1368-76.
11. Knoop FC. Clindamycin-associated enterocolitis in guinea pigs: evidence for a bacterial toxin. Infect Immun 1979; 31-3.
12. Mitchell TJ, Ketley JM, Haslam SC, et al. Effect of toxin A and B of Clostridium difficile on rabbit ileum and colon. Gut 1986; 78-85.
13. Keel MK, Songer JG. The comparative pathology of Clostridium difficile-associated disease. Vet Pathol 2006; 225-40.
14. Pawlowski SW, Calabrese G, Kolling GL, et al. Murine model of Clostridium difficile infection with aged gnotobiotic C57BL/6 mice and a BI/NAP1 strain. J Infect Dis 2010; 1708-12.
15. Chen X, Katchar K, Goldsmith JD, et al. A mouse model of Clostridium difficile-associated disease. Gastroenterology 2008; 1984-92.
16. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011; 1693-703.
17. Garey KW, Jiang ZD, Ghantoji S, Tam VH, Arora V, Dupont HL. A common polymorphism in the interleukin-8 gene promoter is associated with an increased risk for recurrent Clostridium difficile infection. Clin Infect Dis 2010; 1406-10.
18. Hung YP, Tsai PJ, Hung KH, et al. Impact of Toxigenic Clostridium difficile Colonization and Infection among Hospitalized Adults at a District Hospital in Southern Taiwan. PLoS One 2012; 42415.
19. Songer JG, Jones R, Anderson MA, Barbara AJ, Post KW, Trinh HT. Prevention of porcine Clostridium difficile-associated disease by competitive exclusion with nontoxigenic organisms. Vet Microbiol 2007; 358-61.
20. Sambol SP, Merrigan MM, Tang JK, Johnson S, Gerding DN. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002; 1781-9.
21. Martirosian G, Szczesny A, Cohen SH, Silva J, Jr. Isolation of non-toxigenic strains of Clostridium difficile from cases of diarrhea among patients hospitalized in hematology/oncology ward. Pol J Microbiol 2004; 197-200.
22. Loo VG, Poirier L, Miller MA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005; 2442-9.
23. Labbe AC, Poirier L, Maccannell D, et al. Clostridium difficile infections in a Canadian tertiary care hospital before and during a regional epidemic associated with the BI/NAP1/027 strain. Antimicrob Agents Chemother 2008; 3180-7.
24. Hubert B, Loo VG, Bourgault AM, et al. A portrait of the geographic dissemination of the Clostridium difficile North American pulsed-field type 1 strain and the epidemiology of C. difficile-associated disease in Quebec. Clin Infect Dis 2007; 238-44.
25. Walk ST, Micic D, Jain R, et al. Clostridium difficile Ribotype Does Not Predict Severe Infection. Clin Infect Dis 2012; 1661-8.
26. Barbut F, Delmee M, Brazier JS, et al. A European survey of diagnostic methods and testing protocols for Clostridium difficile. Clin Microbiol Infect 2003; 989-96.
27. Barbut F, Mastrantonio P, Delmee M, Brazier J, Kuijper E, Poxton I. Prospective study of Clostridium difficile infections in Europe with phenotypic and genotypic characterisation of the isolates. Clin Microbiol Infect 2007; 1048-57.
28. Freeman J, Bauer MP, Baines SD, et al. The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 2010; 529-49.
29. Cheng VC, Yam WC, Chan JF, To KK, Ho PL, Yuen KY. Clostridium difficile ribotype 027 arrives in Hong Kong. Int J Antimicrob Agents 2009; 492-3.
30. Huang H, Fang H, Weintraub A, Nord CE. Distinct ribotypes and rates of antimicrobial drug resistance in Clostridium difficile from Shanghai and Stockholm. Clin Microbiol Infect 2009; 1170-3.
31. Liao CH, Ko WC, Lu JJ, Hsueh PR. Characterizations of clinical isolates of Clostridium difficile by toxin genotypes and by susceptibility to 12 antimicrobial agents, including fidaxomicin (OPT-80) and rifaximin: a multicenter study in Taiwan. Antimicrob Agents Chemother 2012; 3943-9.
32. Lin YC, Huang YT, Tsai PJ, et al. Antimicrobial susceptibilities and molecular epidemiology of clinical isolates of Clostridium difficile in taiwan. Antimicrob Agents Chemother 2011; 1701-5.
33. Hansson GK, Edfeldt K. Toll to be paid at the gateway to the vessel wall. Arterioscler Thromb Vasc Biol 2005; 1085-7.
34. Schwartz DA, Cook DN. Polymorphisms of the Toll-like receptors and human disease. Clin Infect Dis 2005; S403-7.
35. Karban AS, Okazaki T, Panhuysen CI, et al. Functional annotation of a novel NFKB1 promoter polymorphism that increases risk for ulcerative colitis. Hum Mol Genet 2004; 35-45.
36. Ackermann G, Tang YJ, Jang SS, Silva J, Rodloff AC, Cohen SH. Isolation of Clostridium innocuum from cases of recurrent diarrhea in patients with prior Clostridium difficile associated diarrhea. Diagn Microbiol Infect Dis 2001; 103-6.
37. Satomura H, Odaka I, Sakai C, Kato H. [Antibiotic-associated diarrhea due to Clostridium perfringens]. Kansenshogaku Zasshi 2009; 549-52.
38. Hunley TE, Spring MD, Peters TR, Weikert DR, Jabs K. Clostridium septicum myonecrosis complicating diarrhea-associated hemolytic uremic syndrome. Pediatr Nephrol 2008; 1171-5.
39. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 373-83.
40. Levey AS, Eckardt KU, Tsukamoto Y, et al. Definition and classification of chronic kidney disease: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2005; 2089-100.
41. Chen KH, Gu W, Zeng L, et al. Identification of haplotype tag SNPs within the entire TLR2 gene and their clinical relevance in patients with major trauma. Shock 2011; 35-41.
42. Zhang Q, Qian FH, Zhou LF, et al. Polymorphisms in toll-like receptor 4 gene are associated with asthma severity but not susceptibility in a Chinese Han population. J Investig Allergol Clin Immunol 2011; 370-7.
43. Hsieh YY, Wan L, Chang CC, Tsai CH, Tsai FJ. STAT2*C related genotypes and allele but not TLR4 and CD40 gene polymorphisms are associated with higher susceptibility for asthma. Int J Biol Sci 2009; 74-81.
44. Gao M, Wang CH, Sima X, Han XM. NFKB1 -94 insertion/deletion ATTG polymorphism contributes to risk of systemic lupus erythematosus. DNA Cell Biol 2012; 611-5.
45. Kyne L, Warny M, Qamar A, Kelly CP. Asymptomatic carriage of Clostridium difficile and serum levels of IgG antibody against toxin A. N Engl J Med 2000; 390-7.
46. Shim JK, Johnson S, Samore MH, Bliss DZ, Gerding DN. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998; 633-6.
47. Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difficile-associated disease. J Antimicrob Chemother 1998; C:21-7.
48. Pepin J, Saheb N, Coulombe MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005; 1254-60.
49. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003; 1339-50.
50. Hutin Y, Casin I, Lesprit P, et al. Prevalence of and risk factors for Clostridium difficile colonization at admission to an infectious diseases ward. Clin Infect Dis 1997; 920-4.
51. Riggs MM, Sethi AK, Zabarsky TF, Eckstein EC, Jump RL, Donskey CJ. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007; 992-8.
52. Shah K, Pass LA, Cox M, Lanham M, Arnold FW. Evaluating contemporary antibiotics as a risk factor for Clostridium difficile infection in surgical trauma patients. J Trauma Acute Care Surg 2012; 691-5.
53. Pultz NJ, Donskey CJ. Effect of antibiotic treatment on growth of and toxin production by Clostridium difficile in the cecal contents of mice. Antimicrob Agents Chemother 2005; 3529-32.
54. Gorbach SL. Antibiotics and Clostridium difficile. N Engl J Med 1999; 1690-1.
55. Merrigan MM, Sambol SP, Johnson S, Gerding DN. Prevention of fatal Clostridium difficile-associated disease during continuous administration of clindamycin in hamsters. J Infect Dis 2003; 1922-7.
56. Seal D, Borriello SP, Barclay F, Welch A, Piper M, Bonnycastle M. Treatment of relapsing Clostridium difficile diarrhoea by administration of a non-toxigenic strain. Eur J Clin Microbiol 1987; 51-3.
57. Baxter R, Ray GT, Fireman BH. Case-control study of antibiotic use and subsequent Clostridium difficile-associated diarrhea in hospitalized patients. Infect Control Hosp Epidemiol 2008; 44-50.
58. Dawson LF, Valiente E, Wren BW. Clostridium difficile--a continually evolving and problematic pathogen. Infect Genet Evol 2009; 1410-7.
59. Lee YC, Wang JT, Chen AC, Sheng WH, Chang SC, Chen YC. Changing incidence and clinical manifestations of Clostridium difficile-associated diarrhea detected by combination of glutamate dehydrogenase and toxin assay in Northern Taiwan. J Microbiol Immunol Infect 2012; 287-95.
60. Collins DA, Hawkey PM, Riley TV. Epidemiology of Clostridium difficile infection in Asia. Antimicrob Resist Infect Control 2013; 21.
61. Kim H, Jeong SH, Roh KH, et al. Investigation of toxin gene diversity, molecular epidemiology, and antimicrobial resistance of Clostridium difficile isolated from 12 hospitals in South Korea. Korean J Lab Med 2010; 491-7.
62. Huang H, Weintraub A, Fang H, Wu S, Zhang Y, Nord CE. Antimicrobial susceptibility and heteroresistance in Chinese Clostridium difficile strains. Anaerobe 2010; 633-5.
63. Wei HL, Wei SH, Huang CW, et al. Molecular typing and epidemiology of Clostridium difficile in respiratory care wards of central Taiwan. J Microbiol Immunol Infect 2013.
64. Hensgens MP, Goorhuis A, van Kinschot CM, Crobach MJ, Harmanus C, Kuijper EJ. Clostridium difficile infection in an endemic setting in the Netherlands. Eur J Clin Microbiol Infect Dis 2011; 587-93.
65. Bauer MP, Notermans DW, van Benthem BH, et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet 2011; 63-73.
66. Zidaric V, Pardon B, Dos Vultos T, et al. Different antibiotic resistance and sporulation properties within multiclonal Clostridium difficile PCR ribotypes 078, 126, and 033 in a single calf farm. Appl Environ Microbiol 2012; 8515-22.
67. Eckert C, Coignard B, Hebert M, et al. Clinical and microbiological features of Clostridium difficile infections in France: the ICD-RAISIN 2009 national survey. Med Mal Infect 2013; 67-74.
68. Schneeberg A, Neubauer H, Schmoock G, Grossmann E, Seyboldt C. Presence of Clostridium difficile PCR ribotype clusters related to 033, 078 and 045 in diarrhoeic calves in Germany. J Med Microbiol 2013; 1190-8.
69. Schneeberg A, Neubauer H, Schmoock G, et al. Clostridium difficile Genotypes in Piglet Populations in Germany. J Clin Microbiol 2013; 3796-803.
70. Alvarez-Perez S, Blanco JL, Pelaez T, et al. High prevalence of the epidemic Clostridium difficile PCR ribotype 078 in Iberian free-range pigs. Res Vet Sci 2013.
71. Pelaez T, Alcala L, Blanco JL, et al. Characterization of swine isolates of Clostridium difficile in Spain: A potential source of epidemic multidrug resistant strains? Anaerobe 2013.
72. Keessen EC, Hensgens MP, Spigaglia P, et al. Antimicrobial susceptibility profiles of human and piglet Clostridium difficile PCR-ribotype 078. Antimicrob Resist Infect Control 2013; 14.
73. Knight DR, Thean S, Putsathit P, Fenwick S, Riley TV. Cross-sectional study reveals high prevalence of Clostridium difficile non-PCR ribotype 078 strains in australian veal calves at slaughter. Appl Environ Microbiol 2013; 2630-5.
74. Nakamura I, Yamaguchi T, Tsukimori A, et al. Fulminant colitis from Clostridium difficile infection, the epidemic strain ribotype 027, in Japan. J Infect Chemother 2014; 380-3.
75. Tae CH, Jung SA, Song HJ, et al. The first case of antibiotic-associated colitis by Clostridium difficile PCR ribotype 027 in Korea. J Korean Med Sci 2009; 520-4.
76. Kim H, Lee Y, Moon HW, Lim CS, Lee K, Chong Y. Emergence of Clostridium difficile ribotype 027 in Korea. Korean J Lab Med 2011; 191-6.
77. Kim J, Seo MR, Kang JO, Choi TY, Pai H. Clinical and Microbiologic Characteristics of Clostridium difficile Infection Caused by Binary Toxin Producing Strain in Korea. Infection & chemotherapy 2013; 175-83.
78. Lim PL, Ling ML, Lee HY, et al. Isolation of the first three cases of Clostridium difficile polymerase chain reaction ribotype 027 in Singapore. Singapore Med J 2011; 361-4.
79. Wang P, Zhou Y, Wang Z, et al. Identification of Clostridium difficile ribotype 027 for the first time in Mainland China. Infect Control Hosp Epidemiol 2014; 95-8.
80. Huang H, Weintraub A, Fang H, Nord CE. Community acquired Clostridium difficile infection due to a moxifloxacin susceptible ribotype 027 strain. Scand J Infect Dis 2009; 158-9.
81. Ryan A, Lynch M, Smith SM, et al. A role for TLR4 in Clostridium difficile infection and the recognition of surface layer proteins. PLoS Pathog 2011; e1002076.
82. van der Velden AW, Thomas AA. The role of the 5' untranslated region of an mRNA in translation regulation during development. Int J Biochem Cell Biol 1999; 87-106.
83. Minmin S, Xiaoqian X, Hao C, et al. Single nucleotide polymorphisms of Toll-like receptor 4 decrease the risk of development of hepatocellular carcinoma. PLoS One 2011; e19466.
84. Reynolds CB, Emerson JE, de la Riva L, Fagan RP, Fairweather NF. The Clostridium difficile cell wall protein CwpV is antigenically variable between strains, but exhibits conserved aggregation-promoting function. PLoS Pathog 2011; e1002024.
85. Corthier G, Muller MC, Wilkins TD, Lyerly D, L'Haridon R. Protection against experimental pseudomembranous colitis in gnotobiotic mice by use of monoclonal antibodies against Clostridium difficile toxin A. Infect Immun 1991; 1192-5.
86. Vernet A, Corthier G, Dubos-Ramare F, Parodi AL. Relationship between levels of Clostridium difficile toxin A and toxin B and cecal lesions in gnotobiotic mice. Infect Immun 1989; 2123-7.
87. Persson S, Jensen JN, Olsen KE. Multiplex PCR method for detection of Clostridium difficile tcdA, tcdB, cdtA, and cdtB and internal in-frame deletion of tcdC. J Clin Microbiol 2011; 4299-300.
88. Stubbs SL, Brazier JS, O'Neill GL, Duerden BI. PCR targeted to the 16S-23S rRNA gene intergenic spacer region of Clostridium difficile and construction of a library consisting of 116 different PCR ribotypes. J Clin Microbiol 1999; 461-3.
89. Rupnik M, Avesani V, Janc M, von Eichel-Streiber C, Delmee M. A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates. J Clin Microbiol 1998; 2240-7.
90. Griffiths D, Fawley W, Kachrimanidou M, et al. Multilocus sequence typing of Clostridium difficile. J Clin Microbiol 2010; 770-8.
91. Versalovic J, Koeuth T, Lupski JR. Distribution of repetitive DNA sequences in eubacteria and application to fingerprinting of bacterial genomes. Nucleic Acids Res 1991; 6823-31.
92. Janvilisri T, Scaria J, Chang YF. Transcriptional profiling of Clostridium difficile and Caco-2 cells during infection. J Infect Dis 2010; 282-90.

論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2016-09-01起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2016-09-01起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw