Diagnosis of clostridium difficile infection: An ongoing conundrum for clinicians and for clinical laboratories

Clinical Microbiology Reviews

Volumn 26, Issue 3, 2013, Pages 604-630

  Burnham, Carey Ann D ^a   Carroll, Karen C ^b  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b JOHNS HOPKINS UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBIOTIC AGENT; BACTERIAL TOXIN; CALGRANULIN; CEPHALOSPORIN; CLINDAMYCIN; GLUCOSYLTRANSFERASE; GLUTAMATE DEHYDROGENASE; GLYCOPROTEIN GP 96; INTERLEUKIN 1BETA; INTERLEUKIN 8; LACTOFERRIN; METRONIDAZOLE; STREPTOMYCIN; TUMOR NECROSIS FACTOR ALPHA; VANCOMYCIN;

ANTIBIOTIC SENSITIVITY; ARTICLE; BACTERIUM CULTURE; CELL CULTURE; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM DIFFICILE INFECTION; DISEASE SEVERITY; ENTERITIS; ENZYME IMMUNOASSAY; HEMATOPOIETIC STEM CELL TRANSPLANTATION; HUMAN; IMMUNE RESPONSE; LOOP MEDIATED ISOTHERMAL AMPLIFICATION; MULTILOCUS SEQUENCE TYPING; NONHUMAN; NUCLEIC ACID AMPLIFICATION; PATHOPHYSIOLOGY; POLYMERASE CHAIN REACTION; PULSED FIELD GEL ELECTROPHORESIS; RIBOTYPING; SENSITIVITY AND SPECIFICITY; SERODIAGNOSIS; SINGLE NUCLEOTIDE POLYMORPHISM; VARIABLE NUMBER OF TANDEM REPEAT;

ANIMALS; BACTERIOLOGICAL TECHNIQUES; CLOSTRIDIUM DIFFICILE; CLOSTRIDIUM INFECTIONS; CROSS INFECTION; HUMANS;

CLOSTRIDIUM DIFFICILE;

EID: 84879764131     PISSN: 08938512     EISSN: 10986618     Source Type: Journal    
DOI: 10.1128/CMR.00016-13     Document Type: Article

References (272)

1. Voth DE, Ballard JD. 2005. Clostridium difficile toxins: mechanism of action and role in disease. Clin. Microbiol. Rev. 18:247-263.
2. Figueroa I, Johnson S, Sambol SP, Goldstein EJ, Citron DM, Gerding DN. 2012. Relapse versus reinfection: recurrent Clostridium difficile infection following treatment with fidaxomicin or vancomycin. Clin. Infect. Dis. 55(Suppl 2):S104-S109. doi:10.1093/cid/cis357.
3. Hall IC, O'Toole E. 1935. Intestinal flora in newborn infants: with a description of a new pathogenic anaerobe, Bacillus difficilis. Am. J. Dis. Child. 49:390-402.
4. Bartlett JG. 2009. Clostridium difficile infection: historic review. Anaerobe 15:227-229.
5. Synder MD. 1937. Further studies on Bacillus difficilis. J. Infect. Dis. 60:223.
6. Finney JMT. 1893. Gastroenterostomy for cicatrizing ulcer of the pylorus. Bull. Johns Hopkins Hosp. 4:53-55.
7. Tedesco FJ, Barton RW, Alpers DH. 1974. Clindamycin-associated colitis. A prospective study. Ann. Intern. Med. 81:429-433.
8. Laughon BE, Viscidi RP, Gdovin SL, Yolken RH, Bartlett JG. 1984. Enzyme immunoassays for detection of Clostridium difficile toxins A and B in fecal specimens. J. Infect. Dis. 149:781-788.
9. Chang T-W, Bartlett JG, Gorbach SL, Onderdonk AB. 1978. Clindamycin- induced enterocolitis in hamsters as a model of pseudomembranous colitis in patients. Infect. Immun. 20:526-529.
10. Bartlett JG, Chang TW, Gurwith M, Gorbach SL, Onderdonk AB. 1978. Antibiotic-associated pseudomembranous colitis due to toxinproducing clostridia. N. Engl. J. Med. 298:531-534.
11. Sebaihia M, Wren BW, Mullany P, Fairweather NF, Minton N, Stabler R, Thomson NR, Roberts AP, Cerdeno-Tarraga AM, Wang H, Holden MT, Wright A, Churcher C, Quail MA, Baker S, Bason N, Brooks K, Chillingworth T, Cronin A, Davis P, Dowd L, Fraser A, Feltwell T, Hance Z, Holroyd S, Jagels K, Moule S, Mungall K, Price C, Rabbinowitsch E, Sharp S, Simmonds M, Stevens K, Unwin L, Whithead S, Dupuy B, Dougan G, Barrell B, Parkhill J. 2006. The multidrugresistant human pathogen Clostridium difficile has a highly mobile, mosaic genome. Nat. Genet. 38:779-786.
12. Rupnik M. 2010. Clostridium difficile toxinotyping. Methods Mol. Biol. 646:67-76.
13. Brouwer MS, Allan E, Mullany P, Roberts AP. 2012. Draft genome sequence of the nontoxigenic Clostridium difficile strain CD37. J. Bacteriol. 194:2125-2126.
14. Britton RA, Young VB. 2012. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 20:313-319.
15. Kelly CP, Kyne L. 2011. The host immune response to Clostridium difficile. J. Med. Microbiol. 60:1070-1079.
16. Loo VG, Bourgault AM, Poirier L, Lamothe F, Michaud S, Turgeon N, Toye B, Beaudoin A, Frost EH, Gilca R, Brassard P, Dendukuri N, Beliveau C, Oughton M, Brukner I, Dascal A. 2011. Host and pathogen factors for Clostridium difficile infection and colonization. N. Engl. J. Med. 365:1693-1703.
17. Kelly CP. 2012. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin. Microbiol. Infect. 18(Suppl 6):21-27.
18. Wilson KH, Silva J, Fekety FR. 1981. Suppression of Clostridium difficile by normal hamster cecal flora and prevention of antibioticassociated cecitis. Infect. Immun. 34:626-628.
19. Wilson KH, Freter R. 1986. Interaction of Clostridium difficile and Escherichia coli with microfloras in continuous-flow cultures and gnotobiotic mice. Infect. Immun. 54:354-358.
20. Freter R. 1955. The fatal enteric cholera infection in the guinea pig, achieved by inhibition of normal enteric flora. J. Infect. Dis. 97:57-65.
21. Jakobsson HE, Jernberg C, Andersson AF, Sjolund-Karlsson M, Jansson JK, Engstrand L. 2010. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS One 5:e9836. doi:10.1371/journal.pone.0009836.
22. Dethlefsen L, Huse S, Sogin ML, Relman DA. 2008. The pervasive effects of an antibiotic on the human gut microbiota, as revealed by deep 16S rRNA sequencing. PLoS Biol. 6:e280. doi:10.1371/journal.pbio.0060280.
23. Dethlefsen L, Relman DA. 2011. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proc. Natl. Acad. Sci. U. S. A. 108(Suppl 1):4554-4561.
24. Gough E, Shaikh H, Manges AR. 2011. Systematic review of intestinal microbiota transplantation (fecal bacteriotherapy) for recurrent Clostridium difficile infection. Clin. Infect. Dis. 53:994-1002.
25. van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, Keller JJ. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368:407-415.
26. Carroll KC, Bartlett JG. 2011. Biology of Clostridium difficile: implications for epidemiology and diagnosis. Annu. Rev. Microbiol. 65:501-521.
27. Deneve C, Janoir C, Poilane I, Fantinato C, Collignon A. 2009. New trends in Clostridium difficile virulence and pathogenesis. Int. J. Antimicrob. Agents 33(Suppl 1):S24-S28. doi:10.1016/S0924-8579(09)70012-3.
28. Matamouros S, England P, Dupuy B. 2007. Clostridium difficile toxin expression is inhibited by the novel regulator TcdC. Mol. Microbiol. 64:1274-1288.
29. Pruitt RN, Lacy DB. 2012. Toward a structural understanding of Clostridium difficile toxins A and B. Front. Cell. Infect. Microbiol. 2:28. doi: 10.3389/fcimb.2012.00028.
30. McDonald LC, Killgore GE, Thompson A, Owens RC, Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN. 2005. An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 353:2433-2441.
31. Rupnik M. 2008. Heterogeneity of large clostridial toxins: importance of Clostridium difficile toxinotypes. FEMS Microbiol. Rev. 32:541-555.
32. Dineen SS, Villapakkam AC, Nordman JT, Sonenshein AL. 2007. Repression of Clostridium difficile toxin gene expression by CodY. Mol. Microbiol. 66:206-219.
33. Dawson LF, Valiente E, Wren BW. 2009. Clostridium difficile-a continually evolving and problematic pathogen. Infect. Genet. Evol. 9:1410-1417.
34. Freeman J, Bauer MP, Baines SD, Corver J, Fawley WN, Goorhuis B, Kuijper EJ, Wilcox MH. 2010. The changing epidemiology of Clostridium difficile infections. Clin. Microbiol. Rev. 23:529-549.
35. Kim H, Riley TV, Kim M, Kim CK, Yong D, Lee K, Chong Y, Park JW. 2008. Increasing prevalence of toxin A-negative, toxin B-positive isolates of Clostridium difficile in Korea: impact on laboratory diagnosis. J. Clin. Microbiol. 46:1116-1117.
36. Shin BM, Kuak EY, Yoo SJ, Shin WC, Yoo HM. 2008. Emerging toxin A-B+variant strain of Clostridium difficile responsible for pseudomembranous colitis at a tertiary care hospital in Korea. Diagn. Microbiol. Infect. Dis. 60:333-337.
37. Albesa-Jove D, Bertrand T, Carpenter EP, Swain GV, Lim J, Zhang J, Haire LF, Vasisht N, Braun V, Lange A, von Eichel-Streiber C, Svergun DI, Fairweather NF, Brown KA. 2010. Four distinct structural domains in Clostridium difficile toxin B visualized using SAXS. J. Mol. Biol. 396:1260-1270.
38. Ho JG, Greco A, Rupnik M, Ng KK. 2005. Crystal structure of receptorbinding C-terminal repeats from Clostridium difficile toxin A. Proc. Natl. Acad. Sci. U. S. A. 102:18373-18378.
39. Giesemann T, Egerer M, Jank T, Aktories K. 2008. Processing of Clostridium difficile toxins. J. Med. Microbiol. 57:690-696.
40. Shen A. 2012. Clostridium difficile toxins: mediators of inflammation. J. Innate Immun. 4:149-158.
41. Sundriyal A, Roberts AK, Ling R, McGlashan J, Shone CC, Acharya KR. 2010. Expression, purification and cell cytotoxicity of actinmodifying binary toxin from Clostridium difficile. Protein Expr. Purif. 74:42-48.
42. Geric B, Carman RJ, Rupnik M, Genheimer CW, Sambol SP, Lyerly DM, Gerding DN, Johnson S. 2006. Binary toxin-producing, large clostridial toxin-negative Clostridium difficile strains are enterotoxic but do not cause disease in hamsters. J. Infect. Dis. 193:1143-1150.
43. Schwan C, Stecher B, Tzivelekidis T, van Ham M, Rohde M, Hardt WD, Wehland J, Aktories K. 2009. Clostridium difficile toxin CDT induces formation of microtubule-based protrusions and increases adherence of bacteria. PLoS Pathog. 5:e1000626. doi:10.1371/journal.ppat.1000626.
44. Dingle KE, Griffiths D, Didelot X, Evans J, Vaughan A, Kachrimanidou M, Stoesser N, Jolley KA, Golubchik T, Harding RM, Peto TE, Fawley W, Walker AS, Wilcox M, Crook DW. 2011. Clinical Clostridium difficile: clonality and pathogenicity locus diversity. PLoS One 6:e19993. doi:10.1371/journal.pone.0019993.
45. He M, Miyajima F, Roberts P, Ellison L, Pickard DJ, Martin MJ, Connor TR, Harris SR, Fairley D, Bamford KB, D'Arc S, Brazier J, Brown D, Coia JE, Douce G, Gerding D, Kim HJ, Koh TH, Kato H, Senoh M, Louie T, Michell S, Butt E, Peacock SJ, Brown NM, Riley T, Songer G, Wilcox M, Pirmohamed M, Kuijper E, Hawkey P, Wren BW, Dougan G, Parkhill J, Lawley TD. 2013. Emergence and global spread of epidemic healthcare-associated Clostridium difficile. Nat. Genet. 45:109-113.
46. Akerlund T, Persson I, Unemo M, Noren T, Svenungsson B, Wullt M, Burman LG. 2008. Increased sporulation rate of epidemic Clostridium difficile type 027/NAP1. J. Clin. Microbiol. 46:1530-1533.
47. Lanis JM, Barua S, Ballard JD. 2010. Variations in TcdB activity and the hypervirulence of emerging strains of Clostridium difficile. PLoS Pathog. 6:e1001061. doi:10.1371/journal.ppat.1001061.
48. Stabler RA, Gerding DN, Songer JG, Drudy D, Brazier JS, Trinh HT, Witney AA, Hinds J, Wren BW. 2006. Comparative phylogenomics of Clostridium difficile reveals clade specificity and microevolution of hypervirulent strains. J. Bacteriol. 188:7297-7305.
49. Warny M, Pepin J, Fang A, Killgore G, Thompson A, Brazier J, Frost E, McDonald LC. 2005. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 366:1079-1084.
50. Carter GP, Douce GR, Govind R, Howarth PM, Mackin KE, Spencer J, Buckley AM, Antunes A, Kotsanas D, Jenkin GA, Dupuy B, Rood JI, Lyras D. 2011. The anti-sigma factor TcdC modulates hypervirulence in an epidemic BI/NAP1/027 clinical isolate of Clostridium difficile. PLoS Pathog. 7:e1002317. doi:10.1371/journal.ppat.1002317.
51. Bartlett JG, Gerding DN. 2008. Clinical recognition and diagnosis of Clostridium difficile infection. Clin. Infect. Dis. 46(Suppl 1):S12-S18. doi:10.1086/521863.
52. Cohen SH, Gerding DN, Johnson S, Kelly CP, Loo VG, McDonald LC, Pepin J, Wilcox MH. 2010. 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. 31:431-455.
53. McCollum DL, Rodriguez JM. 2012. Detection, treatment, and prevention of Clostridium difficile infection. Clin. Gastroenterol. Hepatol. 10: 581-592.
54. Welfare MR, Lalayiannis LC, Martin KE, Corbett S, Marshall B, Sarma JB. 2011. Co-morbidities as predictors of mortality in Clostridium difficile infection and derivation of the ARC predictive score. J. Hosp. Infect. 79:359-363.
55. Lyerly DM, Krivan HC, Wilkins TD. 1988. Clostridium difficile: its disease and toxins. Clin. Microbiol. Rev. 1:1-18.
56. Planche T, Wilcox M. 2011. Reference assays for Clostridium difficile infection: one or two gold standards? J. Clin. Pathol. 64:1-5.
57. Barbut F, Braun M, Burghoffer B, Lalande V, Eckert C. 2009. Rapid detection of toxigenic strains of Clostridium difficile in diarrheal stools by real-time PCR. J. Clin. Microbiol. 47:1276-1277.
58. Eastwood K, Else P, Charlett A, Wilcox M. 2009. Comparison of nine commercially available Clostridium difficile toxin detection assays, a real-time PCR assay for C. difficile tcdB, and a glutamate dehydrogenase detection assay to cytotoxin testing and cytotoxigenic culture methods. J. Clin. Microbiol. 47:3211-3217.
59. Peterson LR, Manson RU, Paule SM, Hacek DM, Robicsek A, Thomson RB, Jr, Kaul KL. 2007. Detection of toxigenic Clostridium difficile in stool samples by real-time polymerase chain reaction for the diagnosis of C. difficile-associated diarrhea. Clin. Infect. Dis. 45:1152-1160.
60. Stamper PD, Alcabasa R, Aird D, Babiker W, Wehrlin J, Ikpeama I, Carroll KC. 2009. Comparison of a commercial real-time PCR assay for tcdB detection to a cell culture cytotoxicity assay and toxigenic culture for direct detection of toxin-producing Clostridium difficile in clinical samples. J. Clin. Microbiol. 47:373-378.
61. de Jong E, de Jong AS, Bartels CJ, van der Rijt-van den Biggelaar C, Melchers WJ, Sturm PD. 2012. Clinical and laboratory evaluation of a real-time PCR for Clostridium difficile toxin A and B genes. Eur. J. Clin. Microbiol. Infect. Dis. 31:2219-2225.
62. Murray PR, Weber CJ. 1983. Detection of Clostridium difficile cytotoxin in HEp-2 and CHO cell lines. Diagn. Microbiol. Infect. Dis. 1:331-333.
63. Doern GV, Coughlin RT, Wu L. 1992. Laboratory diagnosis of Clostridium difficile-associated gastrointestinal disease: comparison of a monoclonal antibody enzyme immunoassay for toxins A and B with a monoclonal antibody enzyme immunoassay for toxin A only and two cytotoxicity assays. J. Clin. Microbiol. 30:2042-2046.
64. Ota KV, McGowan KL. 2012. Clostridium difficile testing algorithms using glutamate dehydrogenase antigen and C. difficile toxin enzyme immunoassays with C. difficile nucleic acid amplification testing increase diagnostic yield in a tertiary pediatric population. J. Clin. Microbiol. 50:1185-1188.
65. Kvach EJ, Ferguson D, Riska PF, Landry ML. 2010. Comparison of BD GeneOhm Cdiff real-time PCR assay with a two-step algorithm and a toxin A/B enzyme-linked immunosorbent assay for diagnosis of toxigenic Clostridium difficile infection. J. Clin. Microbiol. 48:109-114.
66. Riley TV, Brazier JS, Hassan H, Williams K, Phillips KD. 1987. Comparison of alcohol shock enrichment and selective enrichment for the isolation of Clostridium difficile. Epidemiol. Infect. 99:355-359.
67. Hink T, Burnham CA, Dubberke ER. 2013. A systematic evaluation of methods to optimize culture-based recovery of Clostridium difficile from stool specimens. Anaerobe 19:39-43.
68. Marler LM, Siders JA, Wolters LC, Pettigrew Y, Skitt BL, Allen SD. 1992. Comparison of five cultural procedures for isolation of Clostridium difficile from stools. J. Clin. Microbiol. 30:514-516.
69. Mundy LS, Shanholtzer CJ, Willard KE, Gerding DN, Peterson LR. 1995. Laboratory detection of Clostridium difficile. A comparison of media and incubation systems. Am. J. Clin. Pathol. 103:52-56.
70. Peterson LR, Kelly PJ, Nordbrock HA. 1996. Role of culture and toxin detection in laboratory testing for diagnosis of Clostridium difficileassociated diarrhea. Eur. J. Clin. Microbiol. Infect. Dis. 15:330-336.
71. George WL, Sutter VL, Citron D, Finegold SM. 1979. Selective and differential medium for isolation of Clostridium difficile. J. Clin. Microbiol. 9:214-219.
72. Wren M. 2010. Clostridium difficile isolation and culture techniques. Methods Mol. Biol. 646:39-52.
73. Bliss DZ, Johnson S, Clabots CR, Savik K, Gerding DN. 1997. Comparison of cycloserine-cefoxitin-fructose agar (CCFA) and taurocholate- CCFA for recovery of Clostridium difficile during surveillance of hospitalized patients. Diagn. Microbiol. Infect. Dis. 29:1-4.
74. Arroyo LG, Rousseau J, Willey BM, Low DE, Staempfli H, McGeer A, Weese JS. 2005. Use of a selective enrichment broth to recover Clostridium difficile from stool swabs stored under different conditions. J. Clin. Microbiol. 43:5341-5343.
75. Wilcox MH, Fawley WN, Parnell P. 2000. Value of lysozyme agar incorporation and alkaline thioglycollate exposure for the environmental recovery of Clostridium difficile. J. Hosp. Infect. 44:65-69.
76. She RC, Durrant RJ, Petti CA. 2009. Evaluation of enzyme immunoassays to detect Clostridium difficile toxin from anaerobic stool culture. Am. J. Clin. Pathol. 131:81-84.
77. Thonnard J, Carreer F, Avesani V, Delmee M. 1996. Toxin A detection on Clostridium difficile colonies from 24-h cultures. Clin. Microbiol. Infect. 2:50-54.
78. Kundrapu S, Sunkesula VC, Jury LA, Sethi AK, Donskey CJ. 2012. Utility of perirectal swab specimens for diagnosis of Clostridium difficile infection. Clin. Infect. Dis. 55:1527-1530.
79. Eckert C, Burghoffer B, Lalande V, Barbut F. 2013. Evaluation of the chromogenic agar chromID C. difficile. J. Clin. Microbiol. 51:1002-1004.
80. Perry JD, Asir K, Halimi D, Orenga S, Dale J, Payne M, Carlton R, Evans J, Gould FK. 2010. Evaluation of a chromogenic culture medium for isolation of Clostridium difficile within 24 hours. J. Clin. Microbiol. 48:3852-3858.
81. Hill KA, Collins J, Wilson L, Perry JD, Gould FK. 2013. Comparison of two selective media for the recovery of Clostridium difficile from environmental surfaces. J. Hosp. Infect. 83:164-166.
82. Bouza E. 2009. Clostridium difficile infection: same incidence and worse prognosis? Clin. Infect. Dis. 48:577-579.
83. Bayardelle P. 2009. Importance of culture for detection of Clostridium difficile toxin from stool samples to report true incidence and mortality related to C. difficile in hospitals. Clin. Infect. Dis. 49:1134-1135.
84. Kim J, Pai H, Seo MR, Kang JO. 2012. Clinical and microbiologic characteristics of tcdA-negative variant Clostridium difficile infections. BMC Infect. Dis. 12:109. doi:10.1186/1471-2334-12-109.
85. Elliott B, Squire MM, Thean S, Chang BJ, Brazier JS, Rupnik M, Riley TV. 2011. New types of toxin A-negative, toxin B-positive strains among clinical isolates of Clostridium difficile in Australia. J. Med. Microbiol. 60:1108-1111.
86. Goorhuis A, Legaria MC, van den Berg RJ, Harmanus C, Klaassen CH, Brazier JS, Lumelsky G, Kuijper EJ. 2009. Application of multiple-locus variable-number tandem-repeat analysis to determine clonal spread of toxin A-negative Clostridium difficile in a general hospital in Buenos Aires, Argentina. Clin. Microbiol. Infect. 15:1080-1086.
87. Novak-Weekley SM, Marlowe EM, Miller JM, Cumpio J, Nomura JH, Vance PH, Weissfeld A. 2010. Clostridium difficile testing in the clinical laboratory by use of multiple testing algorithms. J. Clin. Microbiol. 48: 889-893.
88. van den Berg RJ, Bruijnesteijn van Coppenraet LS, Gerritsen HJ, Endtz HP, van der Vorm ER, Kuijper EJ. 2005. Prospective multicenter evaluation of a new immunoassay and real-time PCR for rapid diagnosis of Clostridium difficile-associated diarrhea in hospitalized patients. J. Clin. Microbiol. 43:5338-5340.
89. Le Guern R, Herwegh S, Grandbastien B, Courcol R, Wallet F. 2012. Evaluation of a new molecular test, the BD Max Cdiff, for detection of toxigenic Clostridium difficile in fecal samples. J. Clin. Microbiol. 50: 3089-3090.
90. Chapin KC, Dickenson RA, Wu F, Andrea SB. 2011. Comparison of five assays for detection of Clostridium difficile toxin. J. Mol. Diagn. 13:395-400.
91. Sharp SE, Ruden LO, Pohl JC, Hatcher PA, Jayne LM, Ivie WM. 2010. Evaluation of the C. Diff Quik Chek Complete Assay, a new glutamate dehydrogenase and A/B toxin combination lateral flow assay for use in rapid, simple diagnosis of Clostridium difficile disease. J. Clin. Microbiol. 48:2082-2086.
92. Planche T, Aghaizu A, Holliman R, Riley P, Poloniecki J, Breathnach A, Krishna S. 2008. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect. Dis. 8:777-784.
93. Massey V, Gregson DB, Chagla AH, Storey M, John MA, Hussain Z. 2003. Clinical usefulness of components of the Triage immunoassay, enzyme immunoassay for toxins A and B, and cytotoxin B tissue culture assay for the diagnosis of Clostridium difficile diarrhea. Am. J. Clin. Pathol. 119:45-49.
94. Musher DM, Manhas A, Jain P, Nuila F, Waqar A, Logan N, Marino B, Graviss EA. 2007. Detection of Clostridium difficile toxin: comparison of enzyme immunoassay results with results obtained by cytotoxicity assay. J. Clin. Microbiol. 45:2737-2739.
95. Polage CR, Chin DL, Leslie JL, Tang J, Cohen SH, Solnick JV. 2012. Outcomes in patients tested for Clostridium difficile toxins. Diagn. Microbiol. Infect. Dis. 74:369-373.
96. Dubberke ER, Han Z, Bobo L, Hink T, Lawrence B, Copper S, Hoppe-Bauer J, Burnham CA, Dunne WM, Jr. 2011. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J. Clin. Microbiol. 49:2887-2893.
97. Han Z, McMullen KM, Russo AJ, Copper SM, Warren DK, Dubberke ER. 2012. A Clostridium difficile infection "intervention": change in toxin assay results in fewer C difficile infection cases without changes in patient outcomes. Am. J. Infect. Control 40:349-353.
98. Arnold A, Pope C, Bray S, Riley P, Breathnach A, Krishna S, Planche T. 2010. Prospective assessment of two-stage testing for Clostridium difficile. J. Hosp. Infect. 76:18-22.
99. Humphries RM, Uslan DZ, Rubin Z. 2013. Performance of Clostridium difficile toxin enzyme immunoassay and nucleic acid amplification tests stratified by patient disease severity. J. Clin. Microbiol. 51:869-873.
100. Carroll KC. 2011. Tests for the diagnosis of Clostridium difficile infection: the next generation. Anaerobe 17:170-174.
101. Crobach MJ, Dekkers OM, Wilcox MH, Kuijper EJ. 2009. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): data review and recommendations for diagnosing Clostridium difficileinfection (CDI). Clin. Microbiol. Infect. 15:1053-1066.
102. Doing KM, Hintz MS, Keefe C, Horne S, LeVasseur S, Kulikowski ML. 2010. Reevaluation of the Premier Clostridium difficile toxin A and B immunoassay with comparison to glutamate dehydrogenase common antigen testing evaluating Bartels cytotoxin and Prodesse ProGastro Cd polymerase chain reaction as confirmatory procedures. Diagn. Microbiol. Infect. Dis. 66:129-134.
103. Goldenberg SD, Cliff PR, Smith S, Milner M, French GL. 2010. Two-step glutamate dehydrogenase antigen real-time polymerase chain reaction assay for detection of toxigenic Clostridium difficile. J. Hosp. Infect. 74:48-54.
104. Larson AM, Fung AM, Fang FC. 2010. Evaluation of tcdB real-time PCR in a three-step diagnostic algorithm for detection of toxigenic Clostridium difficile. J. Clin. Microbiol. 48:124-130.
105. Quinn CD, Sefers SE, Babiker W, He Y, Alcabasa R, Stratton CW, Carroll KC, Tang YW. 2010. C. Diff Quik Chek complete enzyme immunoassay provides a reliable first-line method for detection of Clostridium difficile in stool specimens. J. Clin. Microbiol. 48:603-605.
106. Sloan LM, Duresko BJ, Gustafson DR, Rosenblatt JE. 2008. Comparison of real-time PCR for detection of the tcdC gene with four toxin immunoassays and culture in diagnosis of Clostridium difficile infection. J. Clin. Microbiol. 46:1996-2001.
107. Swindells J, Brenwald N, Reading N, Oppenheim B. 2010. Evaluation of diagnostic tests for Clostridium difficile infection. J. Clin. Microbiol. 48:606-608.
108. Zheng L, Keller SF, Lyerly DM, Carman RJ, Genheimer CW, Gleaves CA, Kohlhepp SJ, Young S, Perez S, Ye K. 2004. Multicenter evaluation of a new screening test that detects Clostridium difficile in fecal specimens. J. Clin. Microbiol. 42:3837-3840.
109. Reller ME, Alcabasa RC, Lema CA, Carroll KC. 2010. Comparison of two rapid assays for Clostridium difficile common antigen and a C difficile toxin A/B assay with the cell culture neutralization assay. Am. J. Clin. Pathol. 133:107-109.
110. Reyes RC, John MA, Ayotte DL, Covacich A, Milburn S, Hussain Z. 2007. Performance of TechLab C. DIFF QUIK CHEK and TechLab C. DIFFICILE TOX A/B II for the detection of Clostridium difficile in stool samples. Diagn. Microbiol. Infect. Dis. 59:33-37.
111. Samra Z, Luzon A, Bishara J. 2008. Evaluation of two rapid immunochromatography tests for the detection of Clostridium difficile toxins. Dig. Dis. Sci. 53:1876-1879.
112. Sharp SE, Ivie WM, Buckles MR, Coover DM, Pohl JC, Hatcher PA. 2009. A simple 3-step algorithm for improved laboratory detection of Clostridium difficile toxin without the need for tissue culture cytotoxicity neutralization assays. Diagn. Microbiol. Infect. Dis. 64:344-346.
113. Fenner L, Widmer AF, Goy G, Rudin S, Frei R. 2008. Rapid and reliable diagnostic algorithm for detection of Clostridium difficile. J. Clin. Microbiol. 46:328-330.
114. Shetty N, Wren MW, Coen PG. 2011. The role of glutamate dehydrogenase for the detection of Clostridium difficile in faecal samples: a metaanalysis. J. Hosp. Infect. 77:1-6.
115. Kawada M, Annaka M, Kato H, Shibasaki S, Hikosaka K, Mizuno H, Masuda Y, Inamatsu T. 2011. Evaluation of a simultaneous detection kit for the glutamate dehydrogenase antigen and toxin A/B in feces for diagnosis of Clostridium difficile infection. J. Infect. Chemother. 17:807-811.
116. Snell H, Ramos M, Longo S, John M, Hussain Z. 2004. Performance of the TechLab C. DIFF CHEK-60 enzyme immunoassay (EIA) in combination with the C. difficile Tox A/B II EIA kit, the Triage C. difficile panel immunoassay, and a cytotoxin assay for diagnosis of Clostridium difficile- associated diarrhea. J. Clin. Microbiol. 42:4863-4865.
117. Ticehurst JR, Aird DZ, Dam LM, Borek AP, Hargrove JT, Carroll KC. 2006. Effective detection of toxigenic Clostridium difficile by a two-step algorithm including tests for antigen and cytotoxin. J. Clin. Microbiol. 44:1145-1149.
118. Tenover FC, Novak-Weekley S, Woods CW, Peterson LR, Davis T, Schreckenberger P, Fang FC, Dascal A, Gerding DN, Nomura JH, Goering RV, Akerlund T, Weissfeld AS, Baron EJ, Wong E, Marlowe EM, Whitmore J, Persing DH. 2010. Impact of strain type on detection of toxigenic Clostridium difficile: comparison of molecular diagnostic and enzyme immunoassay approaches. J. Clin. Microbiol. 48:3719-3724.
119. Carman RJ, Wickham KN, Chen L, Lawrence AM, Boone JH, Wilkins TD, Kerkering TM, Lyerly DM. 2012. Glutamate dehydrogenase is highly conserved among Clostridium difficile ribotypes. J. Clin. Microbiol. 50:1425-1426.
120. Goldenberg SD, Gumban M, Hall A, Patel A, French GL. 2011. Lack of effect of strain type on detection of toxigenic Clostridium difficile by glutamate dehydrogenase and polymerase chain reaction. Diagn. Microbiol. Infect. Dis. 70:417-419.
121. Tenover FC, Baron EJ, Peterson LR, Persing DH. 2011. Laboratory diagnosis of Clostridium difficile infection: can molecular amplification methods move us out of uncertainty? J. Mol. Diagn. 13:573-582.
122. Selvaraju SB, Gripka M, Estes K, Nguyen A, Jackson MA, Selvarangan R. 2011. Detection of toxigenic Clostridium difficile in pediatric stool samples: an evaluation of Quik Check Complete Antigen assay, BD GeneOhm Cdiff PCR, and ProGastro Cd PCR assays. Diagn. Microbiol. Infect. Dis. 71:224-229.
123. Culbreath K, Ager E, Nemeyer RJ, Kerr A, Gilligan PH. 2012. Evolution of testing algorithms at a university hospital for detection of Clostridium difficile infections. J. Clin. Microbiol. 50:3073-3076.
124. Vasoo S, Stevens J, Portillo L, Barza R, Schejbal D, Wu MM, Chancey C, Singh K. Cost-effectiveness of a modified two-step algorithm using a combined glutamate dehydrogenase/toxin enzyme immunoassay and real-time PCR for the diagnosis of Clostridium difficile infection. J. Microbiol. Immunol. Infect., in press.
125. Wren B, Clayton C, Tabaqchali S. 1990. Rapid identification of toxigenic Clostridium difficile by polymerase chain reaction. Lancet 335:423.
126. Kato N, Ou CY, Kato H, Bartley SL, Brown VK, Dowell VR, Jr, Ueno K. 1991. Identification of toxigenic Clostridium difficile by the polymerase chain reaction. J. Clin. Microbiol. 29:33-37.
127. Gumerlock PH, Tang YJ, Meyers FJ, Silva J, Jr. 1991. Use of the polymerase chain reaction for the specific and direct detection of Clostridium difficile in human feces. Rev. Infect. Dis. 13:1053-1060.
128. Gumerlock PH, Tang YJ, Weiss JB, Silva J, Jr. 1993. Specific detection of toxigenic strains of Clostridium difficile in stool specimens. J. Clin. Microbiol. 31:507-511.
129. Belanger SD, Boissinot M, Clairoux N, Picard FJ, Bergeron MG. 2003. Rapid detection of Clostridium difficile in feces by real-time PCR. J. Clin. Microbiol. 41:730-734.
130. Stamper PD, Babiker W, Alcabasa R, Aird D, Wehrlin J, Ikpeama I, Gluck L, Carroll KC. 2009. Evaluation of a new commercial TaqMan PCR assay for direct detection of the Clostridium difficile toxin B gene in clinical stool specimens. J. Clin. Microbiol. 47:3846-3850.
131. Terhes G, Urban E, Soki J, Nacsa E, Nagy E. 2009. Comparison of a rapid molecular method, the BD GeneOhm Cdiff assay, to the most frequently used laboratory tests for detection of toxin-producing Clostridium difficile in diarrheal feces. J. Clin. Microbiol. 47:3478-3481.
132. Knetsch CW, Bakker D, de Boer RF, Sanders I, Hofs S, Kooistra-Smid AM, Corver J, Eastwood K, Wilcox MH, Kuijper EJ. 2011. Comparison of real-time PCR techniques to cytotoxigenic culture methods for diagnosing Clostridium difficile infection. J. Clin. Microbiol. 49:227-231.
133. Zidaric V, Kevorkijan BK, Oresic N, Janezic S, Rupnik M. 2011. Comparison of two commercial molecular tests for the detection of Clostridium difficile in the routine diagnostic laboratory. J. Med. Microbiol. 60:1131-1136.
134. Viala C, Le Monnier A, Maataoui N, Rousseau C, Collignon A, Poilane I. 2012. Comparison of commercial molecular assays for toxigenic Clostridium difficile detection in stools: BD GeneOhm Cdiff, XPert C. difficile and Illumigene C. difficile. J. Microbiol. Methods 90:83-85.
135. Goldenberg SD, Dieringer T, French GL. 2010. Detection of toxigenic Clostridium difficile in diarrheal stools by rapid real-time polymerase chain reaction. Diagn. Microbiol. Infect. Dis. 67:304-307.
136. Shin S, Kim M, Kim M, Lim H, Kim H, Lee K, Chong Y. 2012. Evaluation of the Xpert Clostridium difficile assay for the diagnosis of Clostridium difficile infection. Ann. Lab. Med. 32:355-358.
137. Pancholi P, Kelly C, Raczkowski M, Balada-Llasat JM. 2012. Detection of toxigenic Clostridium difficile: comparison of the cell culture neutralization, Xpert C. difficile, Xpert C. difficile/Epi, and Illumigene C. difficile assays. J. Clin. Microbiol. 50:1331-1335.
138. Babady NE, Stiles J, Ruggiero P, Khosa P, Huang D, Shuptar S, Kamboj M, Kiehn TE. 2010. Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital. J. Clin. Microbiol. 48: 4519-4524.
139. Kok H, Wang Q, Thomas LC, Gilbert GL. 2011. Presumptive identification of Clostridium difficile strain 027/NAP1/BI on Cepheid Xpert: interpret with caution. J. Clin. Microbiol. 49:3719-3721.
140. Ylisiurua P, Koskela M, Vainio O, Tuokko H. 2013. Comparison of antigen and two molecular methods for the detection of Clostridium difficile toxins. Scand. J. Infect. Dis. 45:19-25.
141. Lalande V, Barrault L, Wadel S, Eckert C, Petit JC, Barbut F. 2011. Evaluation of a loop-mediated isothermal amplification assay for diagnosis of Clostridium difficile infections. J. Clin. Microbiol. 49:2714-2716.
142. Bruins MJ, Verbeek E, Wallinga JA, Bruijnesteijn van Coppenraet LE, Kuijper EJ, Bloembergen P. 2012. Evaluation of three enzyme immunoassays and a loop-mediated isothermal amplification test for the laboratory diagnosis of Clostridium difficile infection. Eur. J. Clin. Microbiol. Infect. Dis. 31:3035-3039.
143. Focus Diagnostics. June 2012. Focus Diagnostics Inc product package insert. Focus Diagnostics Inc, Cypress, CA.
144. Hicke B, Pasko C, Groves B, Ager E, Corpuz M, Frech G, Munns D, Smith W, Warcup A, Denys G, Ledeboer NA, Lindsey W, Owen C, Rea L, Jenison R. 2012. Automated detection of toxigenic Clostridium difficile in clinical samples: isothermal tcdB amplification coupled to arraybased detection. J. Clin. Microbiol. 50:2681-2687.
145. Quidel. December 2012. Quidel Molecular AmpliVue C difficile product package insert. Quidel Molecular, San Diego, CA.
146. Nanosphere. December2012. Nanosphere Verigene Clostridium difficile Nucleic Acid Test (CDF) package insert. Nanosphere Inc, Northbrook, IL.
147. Bomers MK, van Agtmael MA, Luik H, van Veen MC, Vandenbroucke- Grauls CM, Smulders YM. 2012. Using a dog's superior olfactory sensitivity to identify Clostridium difficile in stools and patients: proof of principle study. BMJ 345:e7396. doi:10.1136/bmj.e7396.
148. Peterson LR, Robicsek A. 2009. Does my patient have Clostridium difficile infection? Ann. Intern. Med. 151:176-179.
149. Fong KS, Fatica C, Hall G, Procop G, Schindler S, Gordon SM, Fraser TG. 2011. Impact of PCR testing for Clostridium difficile on incident rates and potential on public reporting: is the playing field level? Infect. Control Hosp. Epidemiol. 32:932-933.
150. Goldenberg SD. 2011. Public reporting of Clostridium difficile and improvements in diagnostic tests. Infect. Control Hosp. Epidemiol. 32: 1231-1232.
151. Williamson DA, Basu I, Freeman J, Swager T, Roberts SA. 2013. Improved detection of toxigenic Clostridium difficile using the Cepheid XpertCdifficile assay and impact onCdifficile infection rates in a tertiary hospital: a double-edged sword. Am. J. Infect. Control 41:270-272.
152. Longtin Y, Trottier S, Brochu G, Paquet-Bolduc B, Garenc C, Loungnarath V, Beaulieu C, Goulet D, Longtin J. 2013. Impact of the type of diagnostic assay on Clostridium difficile infection and complication rates in a mandatory reporting program. Clin. Infect. Dis. 56:67-73.
153. Catanzaro M, Cirone J. 2012. Real-time polymerase chain reaction testing for Clostridium difficile reduces isolation time and improves patient management in a small community hospital. Am. J. Infect. Control 40:663-666.
154. Sydnor ER, Lenhart A, Trollinger B, Avdic E, Maragakis LL, Carroll KC, Cosgrove SE. 2011. Antimicrobial prescribing practices in response to different Clostridium difficile diagnostic methodologies. Infect. Control Hosp. Epidemiol. 32:1133-1136.
155. Louie TJ, Miller MA, Mullane KM, Weiss K, Lentnek A, Golan Y, Gorbach S, Sears P, Shue YK. 2011. Fidaxomicin versus vancomycin for Clostridium difficile infection. N. Engl. J. Med. 364:422-431.
156. Ashraf H, Beltinger J, Alam NH, Bardhan PK, Faruque AS, Akter J, Salam MA, Gyr N. 2007. Evaluation of faecal occult blood test and lactoferrin latex agglutination test in screening hospitalized patients for diagnosing inflammatory and non-inflammatory diarrhoea in Dhaka, Bangladesh. Digestion 76:256-261.
157. Sherwood RA. 2012. Faecal markers of gastrointestinal inflammation. J. Clin. Pathol. 65:981-985.
158. van Langenberg DR, Gearry RB, Wong HL, Ward M, Gibson PR. 2010. The potential value of faecal lactoferrin as a screening test in hospitalized patients with diarrhoea. Intern. Med. J. 40:819-827.
159. Guerrant RL, Araujo V, Soares E, Kotloff K, Lima AA, Cooper WH, Lee AG. 1992. Measurement of fecal lactoferrin as a marker of fecal leukocytes. J. Clin. Microbiol. 30:1238-1242.
160. Miller JR, Barrett LJ, Kotloff K, Guerrant RL. 1994. A rapid test for infectious and inflammatory enteritis. Arch. Intern. Med. 154:2660-2664.
161. Steiner TS, Flores CA, Pizarro TT, Guerrant RL. 1997. Fecal lactoferrin, interleukin-1beta, and interleukin-8 are elevated in patients with severe Clostridium difficile colitis. Clin. Diagn. Lab. Immunol. 4:719-722.
162. Pawlowski SW, Archbald-Pannone L, Carman RJ, Alcantara-Warren C, Lyerly D, Genheimer CW, Gerding DN, Guerrant RL. 2009. Elevated levels of intestinal inflammation in Clostridium difficile infection associated with fluoroquinolone-resistant C. difficile. J. Hosp. Infect. 73: 185-187.
163. LaSala PR, Ekhmimi T, Hill AK, Farooqi I, Perrotta PL. 2013. Quantitative fecal lactoferrin in toxin-positive and toxin-negative Clostridium difficile specimens. J. Clin. Microbiol. 51:311-313.
164. Shastri YM, Bergis D, Povse N, Schafer V, Shastri S, Weindel M, Ackermann H, Stein J. 2008. Prospective multicenter study evaluating fecal calprotectin in adult acute bacterial diarrhea. Am. J. Med. 121: 1099-1106.
165. Enocksson A, Lundberg J, Weitzberg E, Norrby-Teglund A, Svenungsson B. 2004. Rectal nitric oxide gas and stool cytokine levels during the course of infectious gastroenteritis. Clin. Diagn. Lab. Immunol. 11:250-254.
166. Jiang ZD, DuPont HL, Garey K, Price M, Graham G, Okhuysen P, Dao-Tran T, LaRocco M. 2006. A common polymorphism in the interleukin 8 gene promoter is associated with Clostridium difficile diarrhea. Am. J. Gastroenterol. 101:1112-1116.
167. Wilcox MH. 2012. Overcoming barriers to effective recognition and diagnosis of Clostridium difficile infection. Clin. Microbiol. Infect. 18(Suppl 6):13-20.
168. Wilcox MH. 2012. Policy development for Clostridium difficile. J. Antimicrob. Chemother. 67(Suppl 1):i19-i22. doi:10.1093/jac/dks203.
169. Oka K, Osaki T, Hanawa T, Kurata S, Okazaki M, Manzoku T, Takahashi M, Tanaka M, Taguchi H, Watanabe T, Inamatsu T, Kamiya S. 2012. Molecular and microbiological characterization of Clostridium difficile isolates from single, relapse, and reinfection cases. J. Clin. Microbiol. 50:915-921.
170. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. 2007. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile- associated diarrhea, stratified by disease severity. Clin. Infect. Dis. 45:302-307.
171. Bartlett JG. 2008. The case for vancomycin as the preferred drug for treatment of Clostridium difficile infection. Clin. Infect. Dis. 46:1489-1492.
172. Brazier JS, Fawley W, Freeman J, Wilcox MH. 2001. Reduced susceptibility of Clostridium difficile to metronidazole. J. Antimicrob. Chemother. 48:741-742.
173. Wong SS, Woo PC, Luk WK, Yuen KY. 1999. Susceptibility testing of Clostridium difficile against metronidazole and vancomycin by disk diffusion and Etest. Diagn. Microbiol. Infect. Dis. 34:1-6.
174. Baines SD, O'Connor R, Freeman J, Fawley WN, Harmanus C, Mastrantonio P, Kuijper EJ, Wilcox MH. 2008. Emergence of reduced susceptibility to metronidazole in Clostridium difficile. J. Antimicrob. Chemother. 62:1046-1052.
175. Pelaez T, Alcala L, Alonso R, Rodriguez-Creixems M, Garcia-Lechuz JM, Bouza E. 2002. Reassessment of Clostridium difficile susceptibility to metronidazole and vancomycin. Antimicrob. Agents Chemother. 46: 1647-1650.
176. Clinical and Laboratory Standards Institute. 2007. Methods for antimicrobial susceptibility testing of anaerobic bacteria; approved standard. CLSI, Wayne, PA.
177. Erikstrup LT, Danielsen TK, Hall V, Olsen KE, Kristensen B, Kahlmeter G, Fuursted K, Justesen US. 2012. Antimicrobial susceptibility testing of Clostridium difficile using EUCAST epidemiological cut-off values and disk diffusion correlates. Clin. Microbiol. Infect. 18:E266-E272. doi:10.1111/j.1469-0691.2012.03907.x.
178. Citron DM, Ostovari MI, Karlsson A, Goldstein EJ. 1991. Evaluation of the E test for susceptibility testing of anaerobic bacteria. J. Clin. Microbiol. 29:2197-2203.
179. Poilane I, Cruaud P, Torlotin JC, Collignon A. 2000. Comparison of the E test to the reference agar dilution method for antibiotic susceptibility testing of Clostridium difficile. Clin. Microbiol. Infect. 6:155-156.
180. Bartlett JG. 2006. Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann. Intern. Med. 145:758-764.
181. Pepin J, Valiquette L, Alary ME, Villemure P, Pelletier A, Forget K, Pepin K, Chouinard D. 2004. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 171:466-472.
182. Dupuy B, Govind R, Antunes A, Matamouros S. 2008. Clostridium difficile toxin synthesis is negatively regulated by TcdC. J. Med. Microbiol. 57:685-689.
183. Morgan OW, Rodrigues B, Elston T, Verlander NQ, Brown DF, Brazier J, Reacher M. 2008. Clinical severity of Clostridium difficile PCR ribotype 027: a case-case study. PLoS One 3:e1812. doi:10.1371/journal.pone.0001812.
184. Walk ST, Micic D, Jain R, Lo ES, Trivedi I, Liu EW, Almassalha LM, Ewing SA, Ring C, Galecki AT, Rogers MA, Washer L, Newton DW, Malani PN, Young VB, Aronoff DM. 2012. Clostridium difficile ribotype does not predict severe infection. Clin. Infect. Dis. 55:1661-1668.
185. Burns DA, Heap JT, Minton NP. 2010. The diverse sporulation characteristics of Clostridium difficile clinical isolates are not associated with type. Anaerobe 16:618-622.
186. Burns DA, Heeg D, Cartman ST, Minton NP. 2011. Reconsidering the sporulation characteristics of hypervirulent Clostridium difficile BI/ NAP1/027. PLoS One 6:e24894. doi:10.1371/journal.pone.0024894.
187. Lessa FC, Gould CV, McDonald LC. 2012. Current status of Clostridium difficile infection epidemiology. Clin. Infect. Dis. 55(Suppl 2):S65-S70. doi:10.1093/cid/cis319.
188. Kuijper EJ, Coignard B, Brazier JS, Suetens C, Drudy D, Wiuff C, Pituch H, Reichert P, Schneider F, Widmer AF, Olsen KE, Allerberger F, Notermans DW, Barbut F, Delmee M, Wilcox M, Pearson A, Patel BC, Brown DJ, Frei R, Akerlund T, Poxton IR, Tull P. 2007. Update of Clostridium difficile-associated disease due toPCRribotype 027 in Europe. Euro Surveill. 12(6):E1-E2. http://www.eurosurveillance.org/images/dynamic/EM/V12N06/art714.pdf.
189. Dallal RM, Harbrecht BG, Boujoukas AJ, Sirio CA, Farkas LM, Lee KK, Simmons RL. 2002. Fulminant Clostridium difficile: an underappreciated and increasing cause of death and complications. Ann. Surg. 235:363-372.
190. Elliott B, Reed R, Chang BJ, Riley TV. 2009. Bacteremia with a large clostridial toxin-negative, binary toxin-positive strain of Clostridium difficile. Anaerobe 15:249-251.
191. Limbago BM, Long CM, Thompson AD, Killgore GE, Hannett GE, Havill NL, Mickelson S, Lathrop S, Jones TF, Park MM, Harriman KH, Gould LH, McDonald LC, Angulo FJ. 2009. Clostridium difficile strains from community-associated infections. J. Clin. Microbiol. 47: 3004-3007.
192. Khanna S, Pardi DS. 2012. Community-acquired Clostridium difficile infection: an emerging entity. Clin. Infect. Dis. 55:1741-1742.
193. Khanna S, Pardi DS. 2010. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Rev. Gastroenterol. Hepatol. 4:409-416.
194. Lambert PJ, Dyck M, Thompson LH, Hammond GW. 2009. Population- based surveillance of Clostridium difficile infection in Manitoba, Canada, by using interim surveillance definitions. Infect. Control Hosp. Epidemiol. 30:945-951.
195. Eyre DW, Golubchik T, Gordon NC, Bowden R, Piazza P, Batty EM, Ip CL, Wilson DJ, Didelot X, O'Connor L, Lay R, Buck D, Kearns AM, Shaw A, Paul J, Wilcox MH, Donnelly PJ, Peto TE, Walker AS, Crook DW.2012.Apilot study of rapid benchtop sequencing of Staphylococcus aureus and Clostridium difficile for outbreak detection and surveillance. BMJ Open 2(3):e001124. doi:10.1136/bmjopen-2012-001124.
196. Gould LH, Limbago B. 2010. Clostridium difficile in food and domestic animals: a new foodborne pathogen? Clin. Infect. Dis. 51:577-582.
197. Limbago B, Thompson AD, Greene SA, Maccannell D, MacGowan CE, Jolbitado B, Hardin HD, Estes SR, Weese JS, Songer JG, Gould LH. 2012. Development of a consensus method for culture of Clostridium difficile from meat and its use in a survey of U.S. retail meats. Food Microbiol. 32:448-451.
198. Weese JS, Avery BP, Rousseau J, Reid-Smith RJ. 2009. Detection and enumeration of Clostridium difficile spores in retail beef and pork. Appl. Environ. Microbiol. 75:5009-5011.
199. Metcalf D, Avery BP, Janecko N, Matic N, Reid-Smith R, Weese JS. 2011. Clostridium difficile in seafood and fish. Anaerobe 17:85-86.
200. Metcalf DS, Costa MC, Dew WM, Weese JS. 2010. Clostridium difficile in vegetables, Canada. Lett. Appl. Microbiol. 51:600-602.
201. Cohen SH, Tang YJ, Silva J, Jr. 2001. Molecular typing methods for the epidemiological identification of Clostridium difficile strains. Expert Rev. Mol. Diagn. 1:61-70.
202. Grundmann H, Hori S, Tanner G. 2001. Determining confidence intervals when measuring genetic diversity and the discriminatory abilities of typing methods for microorganisms. J. Clin. Microbiol. 39:4190-4192.
203. Hunter PR, Gaston MA. 1988. Numerical index of the discriminatory ability of typing systems: an application of Simpson's index of diversity. J. Clin. Microbiol. 26:2465-2466.
204. Knetsch C, Lawley T, Hensgens M, Corver J, Wilcox M, Kuijper E. 2013. Current application and future perspectives of molecular typing methods to study Clostridium difficile infections. Euro Surveill. 18(4):pii=20381. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=20381.
205. Killgore G, Thompson A, Johnson S, Brazier J, Kuijper E, Pepin J, Frost EH, Savelkoul P, Nicholson B, van den Berg RJ, Kato H, Sambol SP, Zukowski W, Woods C, Limbago B, Gerding DN, McDonald LC. 2008. Comparison of seven techniques for typing international epidemic strains of Clostridium difficile: restriction endonuclease analysis, pulsedfield gel electrophoresis, PCR-ribotyping, multilocus sequence typing, multilocus variable-number tandem-repeat analysis, amplified fragment length polymorphism, and surface layer protein A gene sequence typing. J. Clin. Microbiol. 46:431-437.
206. Kristjansson M, Samore MH, Gerding DN, DeGirolami PC, Bettin KM, Karchmer AW, Arbeit RD. 1994. Comparison of restriction endonuclease analysis, ribotyping, and pulsed-field gel electrophoresis for molecular differentiation of Clostridium difficile strains. J. Clin. Microbiol. 32:1963-1969.
207. Stubbs SL, Brazier JS, O'Neill GL, Duerden BI. 1999. 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. 37:461-463.
208. Bidet P, Barbut F, Lalande V, Burghoffer B, Petit JC. 1999. Development of a new PCR-ribotyping method for Clostridium difficile based on ribosomal RNA gene sequencing. FEMS Microbiol. Lett. 175:261-266.
209. Westblade LF, Chamberland RR, MacCannell D, Collins R, Dubberke ER, Dunne WM, Jr, Burnham CA. 2013. Development and evaluation of a novel, semiautomated Clostridium difficile typing platform. J. Clin. Microbiol. 51:621-624.
210. Manzoor SE, Tanner HE, Marriott CL, Brazier JS, Hardy KJ, Platt S, Hawkey PM. 2011. Extended multilocus variable-number tandemrepeat analysis of Clostridium difficile correlates exactly with ribotyping and enables identification of hospital transmission. J. Clin. Microbiol. 49:3523-3530.
211. Indra A, Huhulescu S, Schneeweis M, Hasenberger P, Kernbichler S, Fiedler A, Wewalka G, Allerberger F, Kuijper EJ. 2008. Characterization of Clostridium difficile isolates using capillary gel electrophoresisbased PCR ribotyping. J. Med. Microbiol. 57:1377-1382.
212. Health Protection Agency. 2011. Clostridium difficile Ribotyping Network (CDRN) for England and Northern Ireland 2010/2011 annual report. Health Protection Agency, London, United Kingdom. http://www.hpa.org.uk/webc/HPAwebFile/HPAweb_C/1317133396963.
213. Valiente E, Dawson LF, Cairns MD, Stabler RA, Wren BW. 2012. Emergence of new PCR ribotypes from the hypervirulent Clostridium difficile 027 lineage. J. Med. Microbiol. 61:49-56.
214. Marsh JW, O'Leary MM, Shutt KA, Pasculle AW, Johnson S, Gerding DN, Muto CA, Harrison LH. 2006. Multilocus variable-number tandem- repeat analysis for investigation of Clostridium difficile transmission in hospitals. J. Clin. Microbiol. 44:2558-2566.
215. van den Berg RJ, Schaap I, Templeton KE, Klaassen CH, Kuijper EJ. 2007. Typing and subtyping of Clostridium difficile isolates by using multiple-locus variable-number tandem-repeat analysis. J. Clin. Microbiol. 45:1024-1028.
216. Hardy K, Manzoor S, Marriott C, Parsons H, Waddington C, Gossain S, Szczepura A, Stallard N, Hawkey PM. 2012. Utilizing rapid multiplelocus variable-number tandem-repeat analysis typing to aid control of hospital-acquired Clostridium difficile infection: a multicenter study. J. Clin. Microbiol. 50:3244-3248.
217. Marsh JW, O'Leary MM, Shutt KA, Sambol SP, Johnson S, Gerding DN, Harrison LH. 2010. Multilocus variable-number tandem-repeat analysis and multilocus sequence typing reveal genetic relationships among Clostridium difficile isolates genotyped by restriction endonuclease analysis. J. Clin. Microbiol. 48:412-418.
218. Wei HL, Kao CW, Wei SH, Tzen JT, Chiou CS. 2011. Comparison of PCR ribotyping and multilocus variable-number tandem-repeat analysis (MLVA) for improved detection of Clostridium difficile. BMC Microbiol. 11:217. doi:10.1186/1471-2180-11-217.
219. Maiden MC. 2006. Multilocus sequence typing of bacteria. Annu. Rev. Microbiol. 60:561-588.
220. Maiden MC, Bygraves JA, Feil E, Morelli G, Russell JE, Urwin R, Zhang Q, Zhou J, Zurth K, Caugant DA, Feavers IM, Achtman M, Spratt BG. 1998. Multilocus sequence typing: a portable approach to the identification of clones within populations of pathogenic microorganisms. Proc. Natl. Acad. Sci. U. S. A. 95:3140-3145.
221. Lemee L, Dhalluin A, Pestel-Caron M, Lemeland JF, Pons JL. 2004. Multilocus sequence typing analysis of human and animal Clostridium difficile isolates of various toxigenic types. J. Clin. Microbiol. 42:2609-2617.
222. Lemee L, Bourgeois I, Ruffin E, Collignon A, Lemeland JF, Pons JL. 2005. Multilocus sequence analysis and comparative evolution of virulence- associated genes and housekeeping genes of Clostridium difficile. Microbiology 151:3171-3180.
223. Griffiths D, Fawley W, Kachrimanidou M, Bowden R, Crook DW, Fung R, Golubchik T, Harding RM, Jeffery KJ, Jolley KA, Kirton R, Peto TE, Rees G, Stoesser N, Vaughan A, Walker AS, Young BC, Wilcox M, Dingle KE. 2010. Multilocus sequence typing of Clostridium difficile. J. Clin. Microbiol. 48:770-778.
224. Harris SR, Cartwright EJ, Torok ME, Holden MT, Brown NM, Ogilvy- Stuart AL, Ellington MJ, Quail MA, Bentley SD, Parkhill J, Peacock SJ. 2013. Whole-genome sequencing for analysis of an outbreak of meticillin- resistant Staphylococcus aureus: a descriptive study. Lancet Infect. Dis. 13:130-136.
225. Koser CU, Holden MT, Ellington MJ, Cartwright EJ, Brown NM, Ogilvy-Stuart AL, Hsu LY, Chewapreecha C, Croucher NJ, Harris SR, Sanders M, Enright MC, Dougan G, Bentley SD, Parkhill J, Fraser LJ, Betley JR, Schulz-Trieglaff OB, Smith GP, Peacock SJ. 2012. Rapid whole-genome sequencing for investigation of a neonatal MRSA outbreak. N. Engl. J. Med. 366:2267-2275.
226. Chan JZ, Pallen MJ, Oppenheim B, Constantinidou C. 2012. Genome sequencing in clinical microbiology. Nat. Biotechnol. 30:1068-1071.
227. Jolley KA, Maiden MC. 2010. BIGSdb: scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 11:595. doi:10.1186/1471-2105-11-595.
228. Loman NJ, Constantinidou C, Chan JZ, Halachev M, Sergeant M, Penn CW, Robinson ER, Pallen MJ. 2012. High-throughput bacterial genome sequencing: an embarrassment of choice, a world of opportunity. Nat. Rev. Microbiol. 10:599-606.
229. Didelot X, Eyre D, Cule M, Ip C, Ansari A, Griffiths D, Vaughan A, O'Connor L, Golubchik T, Batty E, Piazza P, Wilson D, Bowden R, Donnelly P, Dingle K, Wilcox M, Walker S, Crook D, Peto T, Harding R. 2012. Microevolutionary analysis of Clostridium difficile genomes to investigate transmission. Genome Biol. 13:R118. doi:10.1186/gb-2012 -13-12-r118.
230. Surawicz CM, Brandt LJ, Binion DG, Ananthakrishnan AN, Curry SR, Gilligan PH, McFarland LV, Mellow M, Zuckerbraun BS. 2013. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections. Am. J. Gastroenterol. 108:478-498.
231. Ferguson JK, Cheng AC, Gilbert GL, Gottlieb T, Korman T, McGregor A, Richards M, Roberts S, Robson J, Van Gessel H, Riley TV. 2011. Clostridium difficile laboratory testing in Australia and New Zealand: national survey results and Australasian Society for Infectious Diseases recommendations for best practice. Pathology 43:482-487.
232. Manabe YC, Vinetz JM, Moore RD, Merz C, Charache P, Bartlett JG. 1995. Clostridium difficile colitis: an efficient clinical approach to diagnosis. Ann. Intern. Med. 123:835-840.
233. Debast SB, van Kregten E, Oskam KM, van den Berg T, van den Berg RJ, Kuijper EJ. 2008. Effect on diagnostic yield of repeated stool testing during outbreaks of Clostridium difficile-associated disease. Clin. Microbiol. Infect. 14:622-624.
234. Deshpande A, Pasupuleti V, Patel P, Pant C, Pagadala M, Hall G, Hu B, Jain A, Rolston DD, Sferra TJ, Atreja A. 2012. Repeat stool testing for Clostridium difficile using enzyme immunoassay in patients with inflammatory bowel disease increases diagnostic yield. Curr. Med. Res. Opin. 28:1553-1560.
235. Cardona DM, Rand KH. 2008. Evaluation of repeat Clostridium difficile enzyme immunoassay testing. J. Clin. Microbiol. 46:3686-3689.
236. Renshaw AA, Stelling JM, Doolittle MH. 1996. The lack of value of repeated Clostridium difficile cytotoxicity assays. Arch. Pathol. Lab. Med. 120:49-52.
237. Borek AP, Aird DZ, Carroll KC. 2005. Frequency of sample submission for optimal utilization of the cell culture cytotoxicity assay for detection of Clostridium difficile toxin. J. Clin. Microbiol. 43:2994-2995.
238. Nistico JA, Hage JE, Schoch PE, Cunha BA. 2013. Unnecessary repeat Clostridium difficile PCR testing in hospitalized adults with C. difficilenegative diarrhea. Eur. J. Clin. Microbiol. Infect. Dis. 32:97-99.
239. Aichinger E, Schleck CD, Harmsen WS, Nyre LM, Patel R. 2008. Nonutility of repeat laboratory testing for detection of Clostridium difficile by use of PCR or enzyme immunoassay. J. Clin. Microbiol. 46: 3795-3797.
240. Garimella PS, Agarwal R, Katz A. 2012. The utility of repeat enzyme immunoassay testing for the diagnosis of Clostridium difficile infection: a systematic review of the literature. J. Postgrad. Med. 58:194-198.
241. Rousseau C, Poilane I, De Pontual L, Maherault AC, Le Monnier A, Collignon A. 2012. Clostridium difficile carriage in healthy infants in the community: a potential reservoir for pathogenic strains. Clin. Infect. Dis. 55:1209-1215.
242. Larson HE, Barclay FE, Honour P, Hill ID. 1982. Epidemiology of Clostridium difficile in infants. J. Infect. Dis. 146:727-733.
243. Sandora TJ, Fung M, Flaherty K, Helsing L, Scanlon P, Potter-Bynoe G, Gidengil CA, Lee GM. 2011. Epidemiology and risk factors for Clostridium difficile infection in children. Pediatr. Infect. Dis. J. 30:580-584.
244. Matsuki S, Ozaki E, Shozu M, Inoue M, Shimizu S, Yamaguchi N, Karasawa T, Yamagishi T, Nakamura S. 2005. Colonization by Clostridium difficile of neonates in a hospital, and infants and children in three day-care facilities of Kanazawa, Japan. Int. Microbiol. 8:43-48.
245. Benno Y, Sawada K, Mitsuoka T. 1984. The intestinal microflora of infants: composition of fecal flora in breast-fed and bottle-fed infants. Microbiol. Immunol. 28:975-986.
246. Kim J, Smathers SA, Prasad P, Leckerman KH, Coffin S, Zaoutis T. 2008. Epidemiological features of Clostridium difficile-associated disease among inpatients at children's hospitals in the United States, 2001-2006. Pediatrics 122:1266-1270.
247. Nylund CM, Goudie A, Garza JM, Fairbrother G, Cohen MB. 2011. Clostridium difficile infection in hospitalized children in the United States. Arch. Pediatr. Adolesc. Med. 165:451-457.
248. Zilberberg MD, Tillotson GS, McDonald C. 2010. Clostridium difficile infections among hospitalized children, United States, 1997-2006. Emerg. Infect. Dis. 16:604-609.
249. Klein EJ, Boster DR, Stapp JR, Wells JG, Qin X, Clausen CR, Swerdlow DL, Braden CR, Tarr PI. 2006. Diarrhea etiology in a children's hospital emergency department: a prospective cohort study. Clin. Infect. Dis. 43:807-813.
250. Toltzis P, Kim J, Dul M, Zoltanski J, Smathers S, Zaoutis T. 2009. Presence of the epidemic North American pulsed field type 1 Clostridium difficile strain in hospitalized children. J. Pediatr. 154:607-608.
251. Bryant K, McDonald LC. 2009. Clostridium difficile infections in children. Pediatr. Infect. Dis. J. 28:145-146.
252. Luna RA, Boyanton BL, Jr, Mehta S, Courtney EM, Webb CR, Revell PA, Versalovic J. 2011. Rapid stool-based diagnosis of Clostridium difficile infection by real-time PCR in a children's hospital. J. Clin. Microbiol. 49:851-857.
253. Toltzis P, Nerandzic MM, Saade E, O'Riordan MA, Smathers S, Zaoutis T, Kim J, Donskey CJ. 2012. High proportion of false-positive Clostridium difficile enzyme immunoassays for toxin A and B in pediatric patients. Infect. Control Hosp. Epidemiol. 33:175-179.
254. Schutze GE, Willoughby RE. 2013. Clostridium difficile infection in infants and children. Pediatrics 131:196-200.
255. Chopra T, Alangaden GJ, Chandrasekar P. 2010. Clostridium difficile infection in cancer patients and hematopoietic stem cell transplant recipients. Expert Rev. Anti Infect. Ther. 8:1113-1119.
256. Schalk E, Bohr UR, Konig B, Scheinpflug K, Mohren M. 2010. Clostridium difficile-associated diarrhoea, a frequent complication in patients with acute myeloid leukaemia. Ann. Hematol. 89:9-14.
257. Gifford AH, Kirkland KB. 2006. Risk factors for Clostridium difficileassociated diarrhea on an adult hematology-oncology ward. Eur. J. Clin. Microbiol. Infect. Dis. 25:751-755.
258. Stewart DB, Yacoub E, Zhu J. 2012. Chemotherapy patients with C. difficile colitis have outcomes similar to immunocompetent C. difficile patients. J. Gastrointest. Surg. 16:1566-1572.
259. Boutros M, Al-Shaibi M, Chan G, Cantarovich M, Rahme E, Paraskevas S, Deschenes M, Ghali P, Wong P, Fernandez M, Giannetti N, Cecere R, Hassanain M, Chaudhury P, Metrakos P, Tchervenkov J, Barkun JS. 2012. Clostridium difficile colitis: increasing incidence, risk factors, and outcomes in solid organ transplant recipients. Transplantation 93:1051-1057.
260. Pant C, Anderson MP, O'Connor JA, Marshall CM, Deshpande A, Sferra TJ. 2012. Association of Clostridium difficile infection with outcomes of hospitalized solid organ transplant recipients: results from the 2009 Nationwide Inpatient Sample database. Transpl. Infect. Dis. 14: 540-547.
261. Avery R, Pohlman B, Adal K, Bolwell B, Goldman M, Kalaycio M, Hall G, Andresen S, Mossad S, Schmitt S, Mason P, Longworth D. 2000. High prevalence of diarrhea but infrequency of documented Clostridium difficile in autologous peripheral blood progenitor cell transplant recipients. Bone Marrow Transplant. 25:67-69.
262. Bobak D, Arfons LM, Creger RJ, Lazarus HM. 2008. Clostridium difficile-associated disease in human stem cell transplant recipients: coming epidemic or false alarm? Bone Marrow Transplant. 42:705-713.
263. Dubberke ER, Reske KA, Srivastava A, Sadhu J, Gatti R, Young RM, Rakes LC, Dieckgraefe B, DiPersio J, Fraser VJ. 2010. Clostridium difficile-associated disease in allogeneic hematopoietic stem-cell transplant recipients: risk associations, protective associations, and outcomes. Clin. Transplant. 24:192-198.
264. Chakrabarti S, Lees A, Jones SG, Milligan DW. 2000. Clostridium difficile infection in allogeneic stem cell transplant recipients is associated with severe graft-versus-host disease and non-relapse mortality. Bone Marrow Transplant. 26:871-876.
265. Alonso CD, Treadway SB, Hanna DB, Huff CA, Neofytos D, Carroll KC, Marr KA. 2012. Epidemiology and outcomes of Clostridium difficile infections in hematopoietic stem cell transplant recipients. Clin. Infect. Dis. 54:1053-1063.
266. Issa M, Vijayapal A, Graham MB, Beaulieu DB, Otterson MF, Lundeen S, Skaros S, Weber LR, Komorowski RA, Knox JF, Emmons J, Bajaj JS, Binion DG. 2007. Impact of Clostridium difficile on inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 5:345-351.
267. Rodemann JF, Dubberke ER, Reske KA, Seo DH, Stone CD. 2007. Incidence of Clostridium difficile infection in inflammatory bowel disease. Clin. Gastroenterol. Hepatol. 5:339-344.
268. Tremaine WJ. 2007. Inflammatory bowel disease and Clostridium difficile- associated diarrhea: a growing problem. Clin. Gastroenterol. Hepatol. 5:310-311.
269. Ananthakrishnan AN. 2012. Detecting and treating Clostridium difficile infections in patients with inflammatory bowel disease. Gastroenterol. Clin. North Am. 41:339-353.
270. Powell N, Jung SE, Krishnan B. 2008. Clostridium difficile infection and inflammatory bowel disease: a marker for disease extent? Gut 57:1183-1184.
271. Nguyen GC, Kaplan GG, Harris ML, Brant SR. 2008. A national survey of the prevalence and impact of Clostridium difficile infection among hospitalized inflammatory bowel disease patients. Am. J. Gastroenterol. 103:1443-1450.
272. Redding W, Avdic E, Carroll K, Cosgrove S. 2012. Gut check: an antimicrobial stewardship intervention to improve clinician ordering and prescribing behaviors surrounding Clostridium difficile testing with PCR, abstr 760. ID Week 2012, San Diego, CA.