Original Article

Is It Clostridium difficile Infection or Something Else? A Case-control Study of 352 Hospitalized Patients With New-onset Diarrhea

Authors: Farrin A. Manian, MD, MPH, Sangita Aradhyula, MD, MPH, Sandy Greisnauer, RN, Diane Senkel, RN, Janice Setzer, RN, Michele Wiechens, RN, P Lynn Meyer, RN, MPH


Background: Clostridium difficile-associated diarrhea (CDAD) is a leading cause of nosocomial diarrhea in the United States, and may be associated with significant morbidity and occasional mortality. Diarrhea is also very common among hospitalized patients and is often related to a variety of factors not related to C difficile infection.

Methods: We performed a retrospective case-control study at a tertiary care community medical center to delineate factors that are predictive of CDAD among hospitalized patients with new-onset diarrhea (ie, not present at the time of admission). Controls were selected based on negative C difficile toxin test(s) (CDTTs) (>95% by cytotoxic assay), presence on the same ward as the patients with first positive CDTT, and hospitalization around the same period as the positive cases.

Results: The study involved 352 patients (88 cases and 264 controls). In univariate analysis, age 75 years or greater, exposure to cefazolin or levofloxacin during the 4-week period preceding CDTT, and hospitalization for 7 days or greater before CDTT were significantly associated with a positive test; male gender and prior ceftriaxone exposure nearly reached statistical significance. Multivariate logistic regression analysis revealed age 75 years or greater (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.3–3.7), hospitalization for 7 days or more (OR 2.3, 95% CI 1.3–3.8], and prior exposure to cefazolin (OR 3.5, 95% CI 1.6–7.5) or levofloxacin (OR 2.1, 95% CI 1.2–3.7) as independent predictors of a positive CDTT; male gender nearly achieved statistical significance (OR 1.6, 95% CI 0.9–2.7).

Conclusions: Among hospitalized patients with diarrhea who underwent testing for C difficiletoxin, age 75 years or older, hospitalization for 7 days or greater, and recent exposure to cefazolin or levofloxacin were important predictors of a positive CDTT. These findings may help in the initiation of early presumptive treatment for CDAD, and appropriate isolation of higher risk patients before results become available. In addition, consideration of these risk factors may help in deciding whether a CDTT should be repeated when the first test is negative. Our study also supports more judicious use of antibiotics, particularly cefazolin and levofloxacin, in reducing the risk of CDAD in hospitalized patients.

Key Points

* Important predictors for Clostridium difficile-associated diarrhea include age greater than 75 years, hospitalization of 7 days or greater, and prior exposure to cefazolin or levofloxacin.

* Male gender and prior ceftriaxone exposure nearly reached statistical significance as a predictor for C difficile-associated diarrhea.

* More judicious use of antibiotics, particularly cefazolin and levofloxacin, may help reduce the risk of C difficile-associated diarrhea among hospitalized patients.

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1. Johnson S, Gerding DN. Clostridium difficile-associated diarrhea. Clin Infect Dis 1998;26:1027–1036.
2. Gorbach SL. Antibiotics and Clostridium difficle. N Engl J Med 1999;341:1690–1691.
3. Gerding DN, Johnson S, Peterson LR, et al. Clostridium difficile-associated diarrhea and colitis.Infect Control Hosp Epidemiol 1995;16:459–477.
4. Bartlett JG. Antibiotic-associated diarrhea. N Engl J Med 2002;346:334–339.
5. Hurley BW, Nguyen CC. The spectrum of pseudomembranous enterocolitis and antibiotic-associated diarrhea. Arch Intern Med 2002;162:2177–2184.
6. Kyne L, Hamel MB, Polavaram R, et al. Health care costs and mortality associated with nosocomial diarrhea due to Clostridium difficile. Clin Infect Dis 2002;34:346–353.
7. McFarland LV, Surawicz CM, Stamm WE. Risk factors for Clostridium difficile carriage and C difficile-associated diarrhea in a cohort of hospitalized patients. J Infect Dis 1990;162:678–674.
8. Modena S, Bearelly D, Swartz K, et al. Clostridium difficile among hospitalized patients receiving antibiotics: a case-control study. Infect Control Hosp Epidemiol 2005;26:685–690.
9. Gerding DN, Olson MM, Peterson LR, et al. Clostridium difficile associated diarrhea and colitis in adults: a prospective case-controlled epidemiologic study. Arch Intern Med 1986;146:95–100.
10. Brown E, Talbot GH, Axelrod P, et al. Risk factors for Clostridium difficile toxin-associated diarrhea.Infect Control Hosp Epidemiol 1990;11:283–290.
11. Vesta KS, Wells PG, Gentry CA, et al. Specific risk factors for Clostridium difficile-associated diarrhea: a prospective, multicenter, case control evaluation. Am J Infect Control 2005;33:469–472.
12. Cooper GS, Lederman MM, Salata RA. A predictive model to identify Clostridium difficile toxin in hospitalized patients with diarrhea. Am J Gastroenterol 1996;91:80–84.
13. Kroker PB, Bower M, Azadian B. Clostridium difficile infection, hospital geography and time-space clustering. QJM 2001;94:223–225.
14. McDonald LC. Clostridium difficile: responding to a new threat from an old enemy. Infect Control Hosp Epidemiol 2005;26:672–675.
15. Bignardi GE. Risk factors for Clostridium difficile infection. J Hosp Infect 1998;40:1–15.
16. Simor AE, Yake SL, Tsimidis K. Infection due to Clostridium difficile among elderly residents of a long-term-care facility. Clin Infect Dis 1993;17:672–678.
17. Barbut F, Petit JC. Epidemiology of Clostridium difficile-associated infections. Clin Microbiol Infect2001;7:405–410.
18. Borriello SP, Wilcox MH. Clostridium difficile infections of the gut: the unanswered questions. J Antimicrob Chemother 1998;41(Suppl C):67–69.
19. Forward LJ, Tompkins DS, Brett MM. Detection of Clostridium difficile cytotoxin and Clostridium perfringens enterotoxin in cases of diarrhea in the community. J Med Microbiol 2003;52:753–757.
20. Palmore TN, Sohn S, Malak SE, et al. Risk factors for acquisition of Clostridium difficile-associated diarrhea among outpatients at a cancer hospital. Infect Control Hosp Epidemiol 2005;26:680–684.
21. Johnson S, Clabots CR, Linn FV, et al. Nosocomial Clostridium difficile colonisation and disease.Lancet 1990;336:97–100.
22. Clabots CR, Johnson S, Olson MM, et al. Acquisition of Clostridium difficile by hospitalized patients: evidence for colonized new admissions as a source of infection. J Infect Dis 1992;166:561–567.
23. McFarland LV, Mulligan ME, Kwok RY, et al. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med 1989;320:204–210.
24. Borrielo SP. The influence of the normal flora on Clostridium difficile colonization of the gut. Ann Med1990;22:61–67.
25. Wilson KH. The microecology of Clostridium difficile. Clin Infect Dis 1993;16(Suppl 4):S214–S218.
26. Nelson DE, Auerbach SB, Baltch AL, et al. Epidemic Clostridium difficile- associated diarrhea: role of second- and third-generation cephalosporins. Infect Control Hosp Epidemiol 1994;15:88–94.
27. Zimmerman RK. Risk factors for Clostridium difficile cytotoxin-positive diarrhea after control for horizontal transmission. Infect Control Hosp Epidemiol 1991;12:96–100.
28. Golledge CL, McKenzie T, Riley TV. Extended spectrum cephalosporins and Clostridium difficile. J Antimicrob Chemother 1989;23:929–931.
29. 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;353:2442–2449.
30. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene- variant strain of Clostridium difficile. N Engl J Med 2005;353:2433–2441.
31. Osler T, Lott D, Bordley J, et al. Cefazolin-induced pseudomembranous colitis resulting in perforation of the sigmoid colon. Dis Colon Rectum 1986;29:140–143.
32. McNeeley SG, Anderson GD, Sibai BM. Clostridium difficile colitis associated with single-dose cefazolin prophylaxis. Obstet Gynecol 1985;66:737–738.
33. Privitera G, Scarpellini P, Ortisi G, et al. Prospective study of Clostridium difficile intestinal colonization and disease following single-dose antibiotic prophylaxis in surgery. J Antimicrob Chemother 1991;35:208–210.
34. Muto CA, Pokrywka M, Shutt K, et al. A large outbreak of Clostridium difficile-asociated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect Control Hosp Epidemiol 2005;26:273–280.
35. 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;41:1254–1260.
36. McCusker ME, Harris AD, Perencevich E, et al. Fluoroquinolone use and Clostridium difficile-associated diarrhea. Emerg Infect Dis 2003;9:730–733.
37. Ozawa TT, Valadez T. Clostridium difficile infection associated with levofloxacin treatment. Tenn Med 2002;95:113–115.
38. Yip C, Loeb M, Salama S, et al. Quinolone use as a risk factor for nosocomial Clostridium difficile-associated diarrhea. Infect Control Hosp Epidemiol 2001;22:572–575.
39. Mendez MN, Gibbs L, Jacobs RA, et al. Impact of a piperacillin-tazobactam shortage on antimicrobial prescribing and the rate of vancomycin-resistant enterococci and Clostridium difficile infections. Pharmacotherapy 2006;26:61–67.
40. Khan R, Cheesebrough J. Impact of changes in antibiotic policy on Clostridium difficile-associated diarrhea (CDAD) over a five-year period in a district general hospital. J Hosp Infect 2003;54:104–108.
41. Al-Eidan FA, McElnay JC, Scott MG, et al. Clostridium difficile-associated diarrhoea in hospitalized patients. J Clin Pharm Ther 2000;25:101–109.
42. 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;129:1012–1019.
43. Snell H, Ramos M, Longo S, et al. 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 2004;42:4863–4865.
44. Vanpoucke H, De Baere T, Claeys G, et al. Evaluation of six commercial assays for the rapid detection of Clostridium difficile toxin and/or antigen in stool specimens. Clin Microbiol Infect2001;7:55–64.
45. Borek AP, Aird DZ, Carroll KC. Frequency of sample submission for optimal utilization of the cell culture cytotoxicity assay for detection of Clostridium difficile toxin. J Clin Microbiol 2005;43:2994–2995.