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Clostridium difficile in adults: Epidemiology, microbiology, and pathophysiology

Author
J Thomas Lamont, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Elinor L Baron, MD, DTMH

INTRODUCTION

Clostridium difficile is the causative organism of antibiotic-associated colitis. Colonization of the intestinal tract occurs via the fecal-oral route and is facilitated by disruption of normal intestinal flora due to antimicrobial therapy. The organism is capable of elaborating exotoxins that bind to receptors on intestinal epithelial cells, leading to inflammation and diarrhea (figure 1). (See "Clostridium difficile infection in adults: Clinical manifestations and diagnosis".)

Our understanding of C. difficile microbiology and epidemiology is changing rapidly. Issues related to C. difficile microbiology and epidemiology will be reviewed here. Clinical manifestations, diagnosis, and prevention and treatment of C. difficile are discussed separately. (See "Clostridium difficile infection in adults: Clinical manifestations and diagnosis" and "Clostridium difficile infection: Prevention and control" and "Clostridium difficile in adults: Treatment".)

EPIDEMIOLOGY

Overview — Antibiotic-associated diarrhea and colitis were well established soon after widespread use of antibiotics [1]. In 1978, C. difficile was identified as the causative pathogen in the majority of cases, and the earliest cases of C. difficile were attributed largely to clindamycin [1,2]. Increasing use of penicillins and cephalosporins subsequently led to the implication of these antibiotic classes, although clindamycin remains an important culprit. Between 1989 and 1992, a strain of C. difficile highly resistant to clindamycin (the "J strain") was implicated in large outbreaks of diarrhea in four hospitals in the United States [3]. The use of clindamycin is a specific risk factor for this strain, and colonization with the clindamycin-resistant strain increases the risk for developing C. difficile–associated diarrhea (CDAD).

From 2003 to 2006, C. difficile infections were observed to be more frequent, severe, refractory to standard therapy, and likely to relapse than previously described [1]. These observations have occurred throughout North America and Europe and have been attributed to a new strain designated BI, NAP1, or ribotype 027 (these designations are based on different methods for strain typing and all refer to the same strain, known as strain NAP1/BI/027). This strain appears to be more virulent than other strains [4], which may be attributable to increased toxin production compared with conventional strains. Fluoroquinolone use has strongly correlated with the emergence of this strain [5], and acquisition of fluoroquinolone resistance by outbreak strains appears to have contributed to the increasing frequency of CDAD outbreaks [6]. (See 'Hypervirulent strain: NAP1/BI/027' below.)

In Quebec, Canada, an increase in the frequency and severity of CDAD was observed in the early 2000s [7,8]. A retrospective review of 1771 cases from this region demonstrated that, in 2003, the incidence of CDAD per 100,000 had increased fourfold since 1991; the incidence had risen 10-fold for individuals over 65 years of age [8]. Among hospitalized patients, the incidence increased from 3 to 12 per 1000 persons (1991 to 2002) to 25 to 43 per 1000 persons (2003 to 2004). These cases were more serious and refractory to therapy, with significant rates of toxic megacolon and disease requiring colectomy. Ten percent of cases required admission to an intensive care, and 2.5 percent underwent an emergency colectomy; the mortality was 16 percent [9].

                

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References
Top
  1. Bartlett JG. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann Intern Med 2006; 145:758.
  2. Bartlett JG, Moon N, Chang TW, et al. Role of Clostridium difficile in antibiotic-associated pseudomembranous colitis. Gastroenterology 1978; 75:778.
  3. Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med 1999; 341:1645.
  4. Miller M, Gravel D, Mulvey M, et al. Health care-associated Clostridium difficile infection in Canada: patient age and infecting strain type are highly predictive of severe outcome and mortality. Clin Infect Dis 2010; 50:194.
  5. Pépin 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; 41:1254.
  6. He M, Miyajima F, Roberts P, et al. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat Genet 2013; 45:109.
  7. 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; 353:2442.
  8. Pépin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004; 171:466.
  9. Pépin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005; 173:1037.
  10. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med 2005; 353:2433.
  11. Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005; 26:273.
  12. Goorhuis A, Van der Kooi T, Vaessen N, et al. Spread and epidemiology of Clostridium difficile polymerase chain reaction ribotype 027/toxinotype III in The Netherlands. Clin Infect Dis 2007; 45:695.
  13. Kuijper EJ, Coignard B, Tüll P, et al. Emergence of Clostridium difficile-associated disease in North America and Europe. Clin Microbiol Infect 2006; 12 Suppl 6:2.
  14. Hall AJ, Curns AT, McDonald LC, et al. The roles of Clostridium difficile and norovirus among gastroenteritis-associated deaths in the United States, 1999-2007. Clin Infect Dis 2012; 55:216.
  15. Goorhuis A, Bakker D, Corver J, et al. Emergence of Clostridium difficile infection due to a new hypervirulent strain, polymerase chain reaction ribotype 078. Clin Infect Dis 2008; 47:1162.
  16. Hensgens MP, Goorhuis A, Dekkers OM, et al. All-cause and disease-specific mortality in hospitalized patients with Clostridium difficile infection: a multicenter cohort study. Clin Infect Dis 2013; 56:1108.
  17. Belmares J, Johnson S, Parada JP, et al. Molecular epidemiology of Clostridium difficile over the course of 10 years in a tertiary care hospital. Clin Infect Dis 2009; 49:1141.
  18. Walk ST, Micic D, Jain R, et al. Clostridium difficile ribotype does not predict severe infection. Clin Infect Dis 2012; 55:1661.
  19. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372:825.
  20. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis. Infect Control Hosp Epidemiol 1995; 16:459.
  21. Kim KH, Fekety R, Batts DH, et al. Isolation of Clostridium difficile from the environment and contacts of patients with antibiotic-associated colitis. J Infect Dis 1981; 143:42.
  22. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989; 320:204.
  23. Samore MH, Venkataraman L, DeGirolami PC, et al. Clinical and molecular epidemiology of sporadic and clustered cases of nosocomial Clostridium difficile diarrhea. Am J Med 1996; 100:32.
  24. Freedberg DE, Salmasian H, Cohen B, et al. Receipt of Antibiotics in Hospitalized Patients and Risk for Clostridium difficile Infection in Subsequent Patients Who Occupy the Same Bed. JAMA Intern Med 2016.
  25. Curry SR, Muto CA, Schlackman JL, et al. Use of multilocus variable number of tandem repeats analysis genotyping to determine the role of asymptomatic carriers in Clostridium difficile transmission. Clin Infect Dis 2013; 57:1094.
  26. Eyre DW, Cule ML, Wilson DJ, et al. Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013; 369:1195.
  27. Zacharioudakis IM, Zervou FN, Pliakos EE, et al. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis. Am J Gastroenterol 2015; 110:381.
  28. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the infectious diseases society of America (IDSA). Infect Control Hosp Epidemiol 2010; 31:431.
  29. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis 2006; 12:409.
  30. Gravel D, Miller M, Simor A, et al. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48:568.
  31. Reveles KR, Lee GC, Boyd NK, Frei CR. The rise in Clostridium difficile infection incidence among hospitalized adults in the United States: 2001-2010. Am J Infect Control 2014; 42:1028.
  32. Riggs MM, Sethi AK, Zabarsky TF, et al. 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; 45:992.
  33. Alasmari F, Seiler SM, Hink T, et al. Prevalence and risk factors for asymptomatic Clostridium difficile carriage. Clin Infect Dis 2014; 59:216.
  34. Blossom DB, McDonald LC. The challenges posed by reemerging Clostridium difficile infection. Clin Infect Dis 2007; 45:222.
  35. Shim JK, Johnson S, Samore MH, et al. Primary symptomless colonisation by Clostridium difficile and decreased risk of subsequent diarrhoea. Lancet 1998; 351:633.
  36. Hirschhorn LR, Trnka Y, Onderdonk A, et al. Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994; 169:127.
  37. Dial S, Delaney JA, Barkun AN, Suissa S. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA 2005; 294:2989.
  38. Dial S, Delaney JA, Schneider V, Suissa S. Proton pump inhibitor use and risk of community-acquired Clostridium difficile-associated disease defined by prescription for oral vancomycin therapy. CMAJ 2006; 175:745.
  39. Khanna S, Pardi DS, Aronson SL, et al. The epidemiology of community-acquired Clostridium difficile infection: a population-based study. Am J Gastroenterol 2012; 107:89.
  40. Chitnis AS, Holzbauer SM, Belflower RM, et al. Epidemiology of community-associated Clostridium difficile infection, 2009 through 2011. JAMA Intern Med 2013; 173:1359.
  41. Centers for Disease Control and Prevention (CDC). Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep 2005; 54:1201.
  42. Hecker MT, Riggs MM, Hoyen CK, et al. Recurrent infection with epidemic Clostridium difficile in a peripartum woman whose infant was asymptomatically colonized with the same strain. Clin Infect Dis 2008; 46:956.
  43. Gould LH, Limbago B. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin Infect Dis 2010; 51:577.
  44. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003; 51:1339.
  45. Wiström J, Norrby SR, Myhre EB, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47:43.
  46. Loo VG, Bourgault AM, Poirier L, et al. Host and pathogen factors for Clostridium difficile infection and colonization. N Engl J Med 2011; 365:1693.
  47. Kyne L, Sougioultzis S, McFarland LV, Kelly CP. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol 2002; 23:653.
  48. Bliss DZ, Johnson S, Savik K, et al. Acquisition of Clostridium difficile and Clostridium difficile-associated diarrhea in hospitalized patients receiving tube feeding. Ann Intern Med 1998; 129:1012.
  49. Kamthan AG, Bruckner HW, Hirschman SZ, Agus SG. Clostridium difficile diarrhea induced by cancer chemotherapy. Arch Intern Med 1992; 152:1715.
  50. Bishara J, Farah R, Mograbi J, et al. Obesity as a risk factor for Clostridium difficile infection. Clin Infect Dis 2013; 57:489.
  51. Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review. Clin Infect Dis 1993; 17:109.
  52. D'Agostino RB Sr, Collins SH, Pencina KM, et al. Risk estimation for recurrent Clostridium difficile infection based on clinical factors. Clin Infect Dis 2014; 58:1386.
  53. Abou Chakra CN, McGeer A, Labbé AC, et al. Factors Associated With Complications of Clostridium difficile Infection in a Multicenter Prospective Cohort. Clin Infect Dis 2015; 61:1781.
  54. Centers for Disease Control and Prevention (CDC). Surveillance for community-associated Clostridium difficile--Connecticut, 2006. MMWR Morb Mortal Wkly Rep 2008; 57:340.
  55. Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology 2014; 146:1547.
  56. Johnson S, Clabots CR, Linn FV, et al. Nosocomial Clostridium difficile colonisation and disease. Lancet 1990; 336:97.
  57. Gurwith MJ, Rabin HR, Love K. Diarrhea associated with clindamycin and ampicillin therapy: preliminary results of a cooperative study. J Infect Dis 1977; 135 Suppl:S104.
  58. Tedesco FJ, Barton RW, Alpers DH. Clindamycin-associated colitis. A prospective study. Ann Intern Med 1974; 81:429.
  59. Deshpande A, Pasupuleti V, Thota P, et al. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013; 68:1951.
  60. Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother 2013; 57:2326.
  61. Kelly CP, Pothoulakis C, LaMont JT. Clostridium difficile colitis. N Engl J Med 1994; 330:257.
  62. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998; 40:1.
  63. Stevens V, Dumyati G, Fine LS, et al. Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011; 53:42.
  64. Geric B, Rupnik M, Gerding DN, et al. Distribution of Clostridium difficile variant toxinotypes and strains with binary toxin genes among clinical isolates in an American hospital. J Med Microbiol 2004; 53:887.
  65. Hensgens MP, Goorhuis A, Dekkers OM, Kuijper EJ. Time interval of increased risk for Clostridium difficile infection after exposure to antibiotics. J Antimicrob Chemother 2012; 67:742.
  66. Carignan A, Allard C, Pépin J, et al. Risk of Clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis 2008; 46:1838.
  67. Doernberg SB, Winston LG, Deck DH, Chambers HF. Does doxycycline protect against development of Clostridium difficile infection? Clin Infect Dis 2012; 55:615.
  68. Brown KA, Jones M, Daneman N, et al. Importation, Antibiotics, and Clostridium difficile Infection in Veteran Long-Term Care: A Multilevel Case-Control Study. Ann Intern Med 2016; 164:787.
  69. Falsen E, Kaijser B, Nehls L, et al. Clostridium difficile in relation to enteric bacterial pathogens. J Clin Microbiol 1980; 12:297.
  70. Campbell RR, Beere D, Wilcock GK, Brown EM. Clostridium difficile in acute and long-stay elderly patients. Age Ageing 1988; 17:333.
  71. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med 2010; 170:772.
  72. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med 2010; 170:784.
  73. Morrison RH, Hall NS, Said M, et al. Risk factors associated with complications and mortality in patients with Clostridium difficile infection. Clin Infect Dis 2011; 53:1173.
  74. Kwok CS, Arthur AK, Anibueze CI, et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107:1011.
  75. Tleyjeh IM, Abdulhak AB, Riaz M, et al. The association between histamine 2 receptor antagonist use and Clostridium difficile infection: a systematic review and meta-analysis. PLoS One 2013; 8:e56498.
  76. http://www.fda.gov/Drugs/DrugSafety/ucm290510.htm (Accessed on February 14, 2012).
  77. Barletta JF, El-Ibiary SY, Davis LE, et al. Proton Pump Inhibitors and the Risk for Hospital-Acquired Clostridium difficile Infection. Mayo Clin Proc 2013; 88:1085.
  78. Freedberg DE, Salmasian H, Friedman C, Abrams JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection among inpatients. Am J Gastroenterol 2013; 108:1794.
  79. Hall IC, O'Toole E. Intestinal flora in newborn infants with a description of a new pathogenic anaerobe Bacillus difficilis. Am J Dis Child 1935; 49:390.
  80. George RH, Symonds JM, Dimock F, et al. Identification of Clostridium difficile as a cause of pseudomembranous colitis. Br Med J 1978; 1:695.
  81. Price SB, Phelps CJ, Wilkins TD, Johnson JL. Cloning of the carbohydrate-binding portion of the toxin a gene of Clostridium difficile. Curr Microbiol 1987; 16:55.
  82. Just I, Selzer J, Wilm M, et al. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 1995; 375:500.
  83. Riegler M, Sedivy R, Pothoulakis C, et al. Clostridium difficile toxin B is more potent than toxin A in damaging human colonic epithelium in vitro. J Clin Invest 1995; 95:2004.
  84. Brito GA, Sullivan GW, Ciesla WP Jr, et al. Clostridium difficile toxin A alters in vitro-adherent neutrophil morphology and function. J Infect Dis 2002; 185:1297.
  85. Hecht G, Koutsouris A, Pothoulakis C, et al. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 1992; 102:416.
  86. Akerlund T, Svenungsson B, Lagergren A, Burman LG. Correlation of disease severity with fecal toxin levels in patients with Clostridium difficile-associated diarrhea and distribution of PCR ribotypes and toxin yields in vitro of corresponding isolates. J Clin Microbiol 2006; 44:353.
  87. Lima AA, Innes DJ Jr, Chadee K, et al. Clostridium difficile toxin A. Interactions with mucus and early sequential histopathologic effects in rabbit small intestine. Lab Invest 1989; 61:419.
  88. Sears CL, Kaper JB. Enteric bacterial toxins: mechanisms of action and linkage to intestinal secretion. Microbiol Rev 1996; 60:167.
  89. Castagliuolo I, Riegler M, Pasha A, et al. Neurokinin-1 (NK-1) receptor is required in Clostridium difficile- induced enteritis. J Clin Invest 1998; 101:1547.
  90. Mahida YR, Makh S, Hyde S, et al. Effect of Clostridium difficile toxin A on human intestinal epithelial cells: induction of interleukin 8 production and apoptosis after cell detachment. Gut 1996; 38:337.
  91. Melo Filho AA, Souza MH, Lyerly DM, et al. Role of tumor necrosis factor and nitric oxide in the cytotoxic effects of Clostridium difficile toxin A and toxin B on macrophages. Toxicon 1997; 35:743.
  92. Warny M, Keates AC, Keates S, et al. p38 MAP kinase activation by Clostridium difficile toxin A mediates monocyte necrosis, IL-8 production, and enteritis. J Clin Invest 2000; 105:1147.
  93. Pothoulakis C, Sullivan R, Melnick DA, et al. Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes. J Clin Invest 1988; 81:1741.
  94. Souza MH, Melo-Filho AA, Rocha MF, et al. The involvement of macrophage-derived tumour necrosis factor and lipoxygenase products on the neutrophil recruitment induced by Clostridium difficile toxin B. Immunology 1997; 91:281.
  95. Lyras D, O'Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009; 458:1176.
  96. Alfa MJ, Kabani A, Lyerly D, et al. Characterization of a toxin A-negative, toxin B-positive strain of Clostridium difficile responsible for a nosocomial outbreak of Clostridium difficile-associated diarrhea. J Clin Microbiol 2000; 38:2706.
  97. Moncrief JS, Zheng L, Neville LM, Lyerly DM. Genetic characterization of toxin A-negative, toxin B-positive Clostridium difficile isolates by PCR. J Clin Microbiol 2000; 38:3072.
  98. Limaye AP, Turgeon DK, Cookson BT, Fritsche TR. Pseudomembranous colitis caused by a toxin A(-) B(+) strain of Clostridium difficile. J Clin Microbiol 2000; 38:1696.
  99. Kuehne SA, Cartman ST, Heap JT, et al. The role of toxin A and toxin B in Clostridium difficile infection. Nature 2010; 467:711.
  100. Hung YP, Lin HJ, Wu TC, et al. Risk factors of fecal toxigenic or non-toxigenic Clostridium difficile colonization: impact of Toll-like receptor polymorphisms and prior antibiotic exposure. PLoS One 2013; 8:e69577.
  101. McFarland LV, Elmer GW, Stamm WE, Mulligan ME. Correlation of immunoblot type, enterotoxin production, and cytotoxin production with clinical manifestations of Clostridium difficile infection in a cohort of hospitalized patients. Infect Immun 1991; 59:2456.
  102. Cloud J, Noddin L, Pressman A, et al. Clostridium difficile strain NAP-1 is not associated with severe disease in a nonepidemic setting. Clin Gastroenterol Hepatol 2009; 7:868.
  103. Spigaglia P, Mastrantonio P. Molecular analysis of the pathogenicity locus and polymorphism in the putative negative regulator of toxin production (TcdC) among Clostridium difficile clinical isolates. J Clin Microbiol 2002; 40:3470.
  104. Popoff MR, Rubin EJ, Gill DM, Boquet P. Actin-specific ADP-ribosyltransferase produced by a Clostridium difficile strain. Infect Immun 1988; 56:2299.
  105. McEllistrem MC, Carman RJ, Gerding DN, et al. A hospital outbreak of Clostridium difficile disease associated with isolates carrying binary toxin genes. Clin Infect Dis 2005; 40:265.
  106. Barbut F, Decré D, Lalande V, et al. Clinical features of Clostridium difficile-associated diarrhoea due to binary toxin (actin-specific ADP-ribosyltransferase)-producing strains. J Med Microbiol 2005; 54:181.
  107. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005; 366:1079.
  108. Rupnik M, Avesani V, Janc M, et al. A novel toxinotyping scheme and correlation of toxinotypes with serogroups of Clostridium difficile isolates. J Clin Microbiol 1998; 36:2240.
  109. Petrella LA, Sambol SP, Cheknis A, et al. Decreased cure and increased recurrence rates for Clostridium difficile infection caused by the epidemic C. difficile BI strain. Clin Infect Dis 2012; 55:351.
  110. Marsh JW, Arora R, Schlackman JL, et al. Association of relapse of Clostridium difficile disease with BI/NAP1/027. J Clin Microbiol 2012; 50:4078.
  111. Walker AS, Eyre DW, Wyllie DH, et al. Relationship between bacterial strain type, host biomarkers, and mortality in Clostridium difficile infection. Clin Infect Dis 2013; 56:1589.
  112. See I, Mu Y, Cohen J, et al. NAP1 strain type predicts outcomes from Clostridium difficile infection. Clin Infect Dis 2014; 58:1394.
  113. Rao K, Micic D, Natarajan M, et al. Clostridium difficile ribotype 027: relationship to age, detectability of toxins A or B in stool with rapid testing, severe infection, and mortality. Clin Infect Dis 2015; 61:233.
  114. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372:1539.
  115. 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; 342:390.
  116. Kyne L, Warny M, Qamar A, Kelly CP. Association between antibody response to toxin A and protection against recurrent Clostridium difficile diarrhoea. Lancet 2001; 357:189.
  117. Leung DY, Kelly CP, Boguniewicz M, et al. Treatment with intravenously administered gamma globulin of chronic relapsing colitis induced by Clostridium difficile toxin. J Pediatr 1991; 118:633.
  118. Warny M, Vaerman JP, Avesani V, Delmée M. Human antibody response to Clostridium difficile toxin A in relation to clinical course of infection. Infect Immun 1994; 62:384.
  119. Jiang ZD, Garey KW, Price M, et al. Association of interleukin-8 polymorphism and immunoglobulin G anti-toxin A in patients with Clostridium difficile-associated diarrhea. Clin Gastroenterol Hepatol 2007; 5:964.
  120. Kelly CP. Immune response to Clostridium difficile infection. Eur J Gastroenterol Hepatol 1996; 8:1048.
  121. Sambol SP, Merrigan MM, Tang JK, et al. Colonization for the prevention of Clostridium difficile disease in hamsters. J Infect Dis 2002; 186:1781.
  122. Jiang ZD, DuPont HL, Garey K, et al. A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am J Gastroenterol 2006; 101:1112.
  123. El Feghaly RE, Stauber JL, Deych E, et al. Markers of intestinal inflammation, not bacterial burden, correlate with clinical outcomes in Clostridium difficile infection. Clin Infect Dis 2013; 56:1713.
  124. Tedesco FJ, Gordon D, Fortson WC. Approach to patients with multiple relapses of antibiotic-associated pseudomembranous colitis. Am J Gastroenterol 1985; 80:867.
  125. Aboudola S, Kotloff KL, Kyne L, et al. Clostridium difficile vaccine and serum immunoglobulin G antibody response to toxin A. Infect Immun 2003; 71:1608.
  126. Eglow R, Pothoulakis C, Itzkowitz S, et al. Diminished Clostridium difficile toxin A sensitivity in newborn rabbit ileum is associated with decreased toxin A receptor. J Clin Invest 1992; 90:822.
  127. Jangi S, Lamont JT. Asymptomatic colonization by Clostridium difficile in infants: implications for disease in later life. J Pediatr Gastroenterol Nutr 2010; 51:2.
  128. Mårdh PA, Helin I, Colleen I, et al. Clostridium difficile toxin in faecal specimens of healthy children and children with diarrhoea. Acta Paediatr Scand 1982; 71:275.
  129. Viscidi R, Laughon BE, Yolken R, et al. Serum antibody response to toxins A and B of Clostridium difficile. J Infect Dis 1983; 148:93.
  130. Kelly CP, Pothoulakis C, Orellana J, LaMont JT. Human colonic aspirates containing immunoglobulin A antibody to Clostridium difficile toxin A inhibit toxin A-receptor binding. Gastroenterology 1992; 102:35.