Clostridium difficile infection (CDI) is a common and costly bacterial illness in hospitalized patients, involving 1% of U.S. hospital stays with an aggregate cost of $8.2 billion annually.1 The spore-forming, gram-positive bacillus is spread by the fecal-oral route; in health-care settings, it is often transmitted by hand carriage and contamination of environmental surfaces. C. diff produces toxins that can cause a spectrum of diseases, including asymptomatic carriage, mild to severe diarrhea, colitis, and pseudomembranous colitis, which in severe cases can lead to sepsis, colectomy, or death.
CDI is defined as the acute onset of diarrhea in a patient with documented toxigenic C. diff or C. diff toxin, without any other clear cause of diarrhea.2 In the past decade, CDI has increased in frequency and severity, with most experts thinking it is related to a particularly virulent strain known as BI/NAP1/027.3 Antibiotic exposure is the most significant and modifiable risk factor for CDI, with increasing age, gastric acid suppression, and immunocompromised states also placing patients at increased risk for developing infection.
In February, the American College of Gastroenterology (ACG) released guidelines for diagnostic testing and pharmacologic therapy for CDI, management of complicated and recurrent disease, and infection control and prevention.2 Previous recommendations for the prevention, diagnosis, and treatment of CDI have been provided by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and a collaboration of the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA).4,5 Recommendations addressing CDI in infants and children are also available.6 The 2013 ACG guidelines are the first from this group to address CDI and are intended to supplement previously published guidelines.
Diagnostic testing. The ACG guidelines emphasize that only stools from patients with diarrhea be tested for C. diff and/or its toxin. Colonization with C. diff is common, and performing tests in asymptomatic patients may complicate clinical care. Rarely, patients with CDI will develop ileus, and in those cases, rectal swab may be performed, but in nearly all circumstances, only diarrheal stools warrant testing. The authors also strongly discourage repeat testing after a negative test and testing for cure following treatment and resolution of symptoms. All of these recommendations are consistent with the SHEA-IDSA guidelines and reflect moderate- to high-quality evidence.
Recognizing that diagnostic testing for C. diff continues to evolve, the ACG makes specific recommendations regarding the use of newer tests, such as nucleic acid amplification and glutamate dehydrogenase detection. These are favored over toxin A and B enzyme immunoassay testing due to higher sensitivity.
Management of mild, moderate, and severe CDI. As with prior guidelines, the 2013 ACG guidelines stratify treatment recommendations by disease severity. Mild to moderate disease, which includes diarrhea only (mild) or diarrhea with signs and symptoms not meeting criteria for severe or complicated CDI (moderate), should be treated with metronidazole 500 mg orally three times daily for 10 days. Oral vancomycin should only be used in patients with mild to moderate disease who fail to respond after five to seven days of metronidazole or in those who are intolerant to metronidazole, or pregnant or breastfeeding. Although fidaxomicin is FDA-approved to treat mild to moderate CDI, the ACG does not make a formal recommendation on its use, given its high cost and limited data to support its effectiveness.
The ACG defines severe disease as CDI in patients with albumin <3 g/dL, and either WBC ≥15,000 cells/mm3 or abdominal tenderness. Though this definition of severe disease differs from the ESCMID and SHEA-IDSA definitions, which include elevated creatinine (>50% greater than premorbid level) instead of low albumin, the treatment recommendation is the same: vancomycin 125 mg orally four times daily for 10 days. While vancomycin and metronidazole are equally effective in mild to moderate CDI, there is some evidence to suggest that vancomycin is more effective in severe disease.7
Regardless of disease severity, one of the strongest recommendations is to discontinue any inciting antibiotics. This point, along with the recommendation to avoid anti-peristaltic agents, has also been emphasized in prior guidelines. Additionally, the authors note that although providers commonly prescribe treatment for 14 days, there is no evidence to suggest that a 14-day treatment course is more efficacious than a 10-day course for either metronidazole or vancomycin.
Management of severe and complicated CDI. Severe and complicated disease refers to CDI in patients meeting at least one of the following criteria: admission to the ICU, hypotension, fever ≥38.5°C, ileus or significant abdominal distention, mental status changes, WBC ≥35,000 or <2,000 cells/mm3, serum lactate >2.2 mmol/L, or end-stage organ failure. This definition is more specific than the SHEA-IDSA guidelines, which categorize severe and complicated disease as situations where shock, ileus, or megacolon are present. The recommended treatment is combined therapy with oral vancomycin 125 mg four times daily, plus intravenous metronidazole 500 mg three times daily. Surgical consultation should be obtained in all patients with complicated CDI. Colectomy should be considered in patients with evidence of severe sepsis, leukocytosis of ≥50,000, lactate ≥5 mmol/L, and failure to improve with medical therapy.
Patients with ileus or history of bowel surgery in whom oral antibiotics may not reach the colon should have vancomycin per rectum (enema of 500 mg in 100 mL to 500 mL of normal saline every six hours) added to the above treatments, regardless of disease severity.
Management of recurrent CDI. Consistent with previously published guidelines, the ACG recommends that the first recurrence of CDI be treated with the same regimen that was used for the initial episode. Second recurrences should be treated with a pulsed oral vancomycin regimen. Data are lacking regarding specific taper regimens, but the ACG suggests vancomycin 125 mg four times daily for 10 days, followed by a 125 mg dose every three days for 10 doses. For additional recurrences, fecal microbiota transplant may be considered. Reports suggest that this practice is safe and effective, but data from randomized controlled trials are lacking.
There is limited evidence to support the use of other antibiotics (e.g. rifampin, rifamixin), probiotics, or immunotherapy in the prevention of recurrent CDI.
Management of CDI in patients with comorbid conditions. A unique feature of the 2013 ACG guidelines is the incorporation of recommendations for patient groups who are at elevated risk for developing CDI or associated complications. Patients with inflammatory bowel disease (IBD) are one such group, as they often have underlying colonic inflammation and ongoing immunosuppression. The authors recommend that patients presenting with IBD flares be tested for C. diff. Other immunocompromised populations, including patients with malignancy, exposure to chemotherapy or corticosteroids, organ transplantation, and cirrhosis, should also be tested for CDI when presenting with diarrheal illness. Similarly, pregnant and peripartum women are considered high-risk and should undergo early testing and prompt initiation of treatment for CDI in the setting of diarrhea.
Infection control and prevention. Like SHEA-IDSA, the ACG recommends a hospital-based infection control program, antibiotic stewardship, and strict use of contact precautions for patients with known or suspected CDI. Contact precautions should be continued at minimum for the duration of diarrhea. Patients should be placed in private rooms and disposable equipment should be used, when possible. Disinfection of environmental surfaces is critical, as the environment is a common source of nosocomial infection. Disinfectants should have an Environmental Protection Agency-registered C. diff sporicidal label claim or contain a minimum concentration of chlorine solution. Important: Hand-washing with soap and water is required, as alcohol-based antiseptics are not active against C. diff spores.
The 2013 ACG guidelines for the diagnosis, treatment, and prevention of CDI are generally consistent with previously published guidelines from ESCMID and SHEA-IDSA. Ongoing points of emphasis are the following:
- Only test patients with diarrhea;
- Do not repeat testing after a negative test or after completion of treatment;
- Promptly discontinue any inciting antibiotics;
- Avoid use of anti-peristaltic agents; and
- Treat based on disease severity.
Hospitalists should be aware of criteria that place patients into the severe and complicated category, and understand that initial treatment should be provided for a 10-day course. These guidelines also highlight the need for a high index of suspicion and low threshold for empiric treatment in immunocompromised patients.
Finally, hospitalists should be attentive to antibiotic stewardship and strictly adhere to contact precautions and hand hygiene with soap and water, as these behaviors have been shown to prevent and control CDI.
Dr. Cunningham Sponsler is a hospitalist in the section of hospital medicine at Vanderbilt University in Nashville, Tenn.
References 1. Lucado J, Gould C, Elixhauser A. Clostridium difficile infections (CDI) in hospital stays, 2009. Healthcare Cost and Utilization Project website. Available at: http://www.hcup-us.ahrq.gov/reports/statbriefs/sb124.pdf. Accessed June 17, 2013.
2. Surawicz CM, Brandt LJ, Binion DJ, et al. Guidelines for diagnosis, treatment and prevention of Clostridium difficile infections. Am J Gastroenterol. 2013;108:478-498.
3. Freeman J, Bauer MP, Baines SD, et al. The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev. 2010;23:529-549.
4. Bauer MP, Kuijper EJ, van Dissel JT. European Society of Clinical Microbiology and Infectious Diseases (ESCMID): treatment guidance for Clostridium difficile infection (CDI). Clin Microbiol Infect. 2009;15:1067-1079.
5. 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 and Hosp Epidemiol. 2010;31:431-455.
6. Committee on Infectious Diseases. Clostridium difficile infection in infants and children. Pediatrics. 2013;131:196-200.
7. Zar FA, Bakkanagari SR, Moorthi KM, et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.