Factors Predicting Recurrence of Clostridium difficile ...

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difficile–associated disease. Arch Intern Med. 2007;167:1092–1097. Abdelfatah et al. Journal of Investigative Medicine • Volume 63, Number 5, June 2015. 750.


Factors Predicting Recurrence of Clostridium difficile Infection (CDI) in Hospitalized Patients: Retrospective Study of More Than 2000 Patients Mohamed Abdelfatah, MD,* Rabih Nayfe, MD,* Ala Nijim, MD,* Kathleen Enriquez, MD,* Eslam Ali, MD,† Richard R. Watkins, MD, MS,‡§ and Hossam Kandil, MD, PhD†


increased colectomies.4 Recent estimates indicate approximately 250,000 hospitalizations and at least 14,000 deaths every year in the United States are associated with CDI,3 placing a significant financial constraint on the health care system with acute care direct costs estimated to range from US $3.2 billion to $4.8 billion.3,5–8 One factor contributing to recurrent CDI (RCDI) is impaired colonization resistance, allowing for proliferation of C. difficile and production of toxins and disease. Another factor may be impaired immune response as patients in a small series who developed RCDI had lower levels of immunoglobulins A and G to toxin B than did those who did not have a recurrence.9 Published risk factors for RCDI include older age,10 gastric acid suppression,10 antibiotics,10 and prior recurrences. Moreover, hospitalization in the previous 2 months and use of chemotherapy, proton-pump inhibitors (PPIs), and H2 blockers are associated with health care– associated C. difficile colonization.10 In addition to withdrawing the offending antibiotic, medical therapy for patients with mild to moderate CDI is metronidazole; severe CDI should be treated with vancomycin.5 Subtotal colectomy might be needed in severe CDI complicated with sepsis.5 Yet, up to 20% of patients will have recurrence despite successful treatment of the initial infection, with a risk of 65% for those who carry a prior history of CDI.11 Novel treatments with promising results are fidaxomicin or fecal microbiota transplantation.5 Recurrent CDI most commonly occurs within a week after treatment cessation,12 but recurrence can happen up to 8 weeks later.13 Most of the previous studies follow recurrence maximally for 2 months.14 Early identification of patients who are at high risk for severe CDI may help clinicians alter modifiable risk factors and hence improve outcomes. We conducted this study to determine the risk factors associated with recurrence of CDI.

From the *Department of Medicine, Akron General Medical Center, Cleveland Clinic Affiliate, Akron; †Division of Gastroenterology and Hepatology, East Carolina University, Greenville; ‡Division of Infectious Diseases, Akron General Medical Center, Akron; and §Department of Medicine, Northeast Ohio Medical University, Rootstown, OH. Received November 13, 2014, and in revised form January 13, 2015. Accepted for publication January 22, 2015. Reprints: Mohamed Abdelfatah, MD, 1st Akron General Ave, Akron, OH 44307. E-mail: [email protected] Copyright © 2015 by The American Federation for Medical Research ISSN: 1081-5589 DOI: 10.1097/JIM.0000000000000188

This was a retrospective case-control study of patients hospitalized at a single institution (Akron General Medical Center, Akron, OH) from January 2007 to December 2013 with CDI code 008.45. Data were collected from the electronic database at Akron General, a 532-bed tertiary academic medical center. After obtaining institutional review board approval, a total of 3020 patients with CDI were identified. Clostridium difficile infection was defined as more than 3 episodes of unformed stools within 24 hours with a positive C. difficile stool toxin assay A/B and/or polymerase chain reaction (PCR) and not attributable to any other cause. Clostridium difficile infection cure was defined as resolution of symptoms associated with the initial episodes of CDI completely and documentation of finishing the treatment prescribed. The primary outcome of the study was RCDI, defined as a new episode of diarrhea within 90 days and confirmed by a positive stool C. difficile toxin assay or PCR, after resolution of the initial CDI episode for at least 10 days and after discontinuation of the CDI therapy. Patients were excluded if (1) they did not receive or complete the course of treatment, (2) they were treated as outpatients or in emergency department and did not get admitted to the hospital,

Background: Clostridium difficile infection (CDI) has increased in incidence and severity worldwide, causing direct costs estimated to range from US $3.2 billion to $4.8 billion. The aim of this study was to investigate and identify factors that predict recurrence of CDI. Methods: This was a retrospective case-control study between 2007 and 2013 on patients admitted with CDI. Recurrent CDI is defined as a new episode of diarrhea within 90 days confirmed by a positive stool C. difficile toxin assay or polymerase chain reaction, after resolution of the initial CDI episode for at least 10 days and after discontinuation of the CDI therapy. Results: Three thousand twenty patients were diagnosed with CDI between January 2007 and December 2013. Two hundred nine of 2019 patients in the study had a recurrence of CDI within 90 days of the end of the initial CDI episode (10.3%). Multivariate analysis showed that most of the recurrences occurred in patients with comorbidities, particularly chronic kidney disease (odds ratio, 1.3; 95% confidence interval [CI], 1.0–2.4; P = 0.039). In addition, a higher percentage of patients in the recurrence group were prescribed proton-pump inhibitors (odds ratio, 1.65; 95% CI, 1.0–1.7; P = 0.002) and steroids (odds ratio, 1.65; 95% CI, 1.0–1.5; P = 0.047). Conclusions: Our data suggest that the use of glucocorticoids, use of proton-pump inhibitors, and having end-stage renal disease are significant risk factors associated with recurrent CDI. Key Words: Clostridium difficile infection (CDI), recurrent Clostridium difficile infection, statins, proton-pump inhibitors, antidepressants, steroids, renal disease, nursing home, diarrhea, CDI (J Investig Med 2015;63: 747–751)

lostridium difficile is an anaerobic, gram-positive, spore-forming noninvasive bacterium capable of causing symptoms ranging from moderate diarrhea to life-threatening pseudomembranous colitis. While historically the association between antibiotics and colitis was known, it was not until the late 1970s that its clinical identity as C. difficile–associated diarrhea (CDAD) was recognized.1 Recent data have shown that C. difficile infection (CDI) is responsible for approximately 20% to 25% of hospitalacquired diarrhea cases with increasing trends in morbidity and mortality noted since the beginning of the 21st century.2,3 According to data from the Centers for Disease Control and Prevention, there has been a significant increase not only in the incidence, but also in the recurrence and severity of CDI resulting in


Journal of Investigative Medicine • Volume 63, Number 5, June 2015

Copyright © 2015 American Federation for Medical Research. Unauthorized reproduction of this article is prohibited.


Journal of Investigative Medicine • Volume 63, Number 5, June 2015

Abdelfatah et al

TABLE 1. Characteristics of Patients Testing Positive for CDI C. difficile Recurrence

No C. difficile Recurrence


Age, mean ± SD, y Male, % (n) (n = 796) Female, % (n) (n = 1223) Mean WBC, billion/L, mean ± SD Total protein 8), % (n) (n = 83) PPI, % (n) (n = 981) Antidepressant, % (n) (n = 554) Statin use, % (n) (n = 674) Antibiotic use in the last 2 mo, % (n) (n = 345) Fluoroquinolones, % (n) (n = 150) Clindamycin, % (n) (n = 11) Penicillin/ampicillin/amoxicillin and clavulanate/ampicillin and sulbactam, % (n) (n = 110) Cephalosporin, % (n) (n = 126) Macrolides, % (n) (n = 42) Trimethoprim/sulfamethoxazole (TMP/SMX), % (n) (n = 21) Tetracycline, % (n) (n = 82) Aminoglycosides, % (n) (n = 7) Steroid use, % (n) (n = 255) % (n) Treated with vancomycin (n = 722) % (n) Treated with metronidazole (Flagyl) (n = 879) % (n) Treated with vancomycin plus Flagyl (n = 384) % (n) Treated with fidaxomicin (Dificid) (n = 34)

68.2 ± 16.5 10 (81) 10.4 (128) 12.9 ± 8.3 50.8 (96) 11.1 (174) 24.5 ± 15.7 9.7 (35) 44 (334) 7 (110) 10.3 (92) 9 (44) 8 (20) 18.4 (28) 6 (117) 135 ± 105 6 (31) 7.1 ± 2.4 8.8 (12) 12 (15) 9.6 (8) 13.3 (131) 11.5 (64) 12.8 (71) 9.8 (34) 13.3 (20) 0 10.9 (12)

69.32 ± 17.4 98.8 (715) 89.5 (1095) 13.2 ± 9.5 49.5 (800) 88.8 (1391) 23.9 ± 16.4 90 (324) 56 (430) 82.2 (1056) 89.6 (796) 90 (444) 91.9 (228) 81.5 (124) 46 (928) 124 ± 50 87.9 (227) 6.9 ± 2.0 91.2 (124) 88 (124) 90.3 (75) 86.6 (850) 24 (490) 89.4 (603) 90 (311) 86.6 (130) 100 (11) 5 (98)

0.366 0.834 0.834 0.67 0.706 0.309 0.808 0.002