The Emerging Nightmare of C. difficile
Special Feature
By Uday Nanavaty, MD, Pulmonary and Critical Care Medicine, Rockville, MD. Dr. Nanavaty reports no financial relationships related to this field of study.
This article originally appeared in the April 2006 issue of Critical Care Alert. It was edited by David J. Pierson, MD, and peer reviewed by William Thompson, MD. Dr. Pierson is Professor, Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, and Dr. Thompson is Staff Pulmonologist, VA Medical Center, Associate Professor of Medicine, University of Washington. Dr. Pierson and William Thompson report no financial relationships relevant to this field of study.
Nosocomial infections are unfortunately common in intensive care units all across the United States. Although a wide variety of guidelines and treatment options exist for common types of nosocomial infections, such as catheter-related bloodstream infections or the ventilator-associated pneumonia, much less importance is given in critical care to Clostridium difficile infections. Although infection with this organism is not necessarily nosocomial, it is more often acquired during hospitalization. Several reports of severe C. difficile-associated disease (CDAD) due to a hyper-virulent strain have appeared recently,1-3 including the report from Canada in which CDAD was associated with high short- and long-term mortality and approximately 10 extra days of hospitalization per case.4 Therefore, I review the literature on this existing infection, as I am certain that the readers are much more likely to see and treat a case of severe CDAD in the future than any of the emerging infections that we hear about from the scientific and lay press.
The Organism
C. difficile is a Gram-positive bacillus that can form spores. Although it is uncommon to find the organism in the stool of healthy adults (< 3%), carriage rates increase with increasing age, with antibiotic therapy, and with hospitalization or hematological malignancies. The organism can live in spore form in the hospital room from weeks to months after the infected patient has been discharged. It produces toxins that cause severe inflammation and cell death in the colonic mucosa. Although the organism was first described in 1930s, its pathogenic role in pseudomembranous colitis was established only in the 1970s.
The organism is difficult to culture, hence the name difficile. Enzyme assay to detect C. difficile's toxin A or toxin B is the most rapid way to make a clinical diagnosis. The assays have high sensitivity and specificity, although a negative test does not necessarily rule out an infection. Care must be taken to submit the specimen within 2 hours of collection, as the toxin rapidly degenerates at room temperature, giving rise to a false-negative test. Tests based on C. difficile's ability to induce cytotoxicity are very specific but take longer time and, hence, are not routinely used in clinical practice.
Spores of this organism are ingested and, when bowel flora is altered in susceptible individuals, the organism assumes a vegetative form in the colonic mucosa. The organism can exist in both forms in the colonic mucosa. In recurrent CDAD, it is often difficult to assess if the organism grew from the colonic mucosa (relapse) or if a new organism was acquired (recurrence).
The Epidemiology
Antibiotic exposure is clearly the most important factor in the development of CDAD. Although practically any antibiotic can cause CDAD, cases and outbreaks have been reported more frequently after clindamycin, third-generation cephalosporins, broad-spectrum penicillins, and fluoroquinolone use. CDAD accounts for approximately 15-25% of antibiotic-associated diarrhea, and the majority of cases of pseudomembranous colitis.
The incidence of CDAD is clearly on the rise. As estimated by the Centers for Disease Control and Prevention,1 CDAD as a diagnosis during hospital stay was reported at an estimated rate of 31 cases per 100,000 population in 1996, which subsequently doubled to an estimated rate of 61/100,000. The highest rate of infection occurs in the age group older than 65 years. This age group tends to get affected about 7 times as much as the next age group of 45-64 years. Thus, age seems to be an important risk factor in development of CDAD. The majority of cases occur in patients who have received antibiotics, although cases have been reported as long as 3 months after stopping antibiotics. Hematological malignancy and prolonged hospital stay are also associated with increased risk of CDAD.
CDAD is associated with variable mortality. In one of the largest outbreaks reported from Quebec, Pepin and colleagues reported a mortality rate of 23% at 30 days in patients who had CDAD, compared to 7% among matched controls.3 In the most severe cases where surgery is considered an option, mortality may be as high as 50%. It is estimated that each case of nosocomial CDAD caused 10.7 additional days of hospitalization. It is also estimated that CDAD costs $1.1 billion dollars in annual healthcare costs in the United States alone.
The Clinical Spectrum of CDAD in Critical Care
In most cases, CDAD presents as mild diarrhea. In the majority of the cases that I have seen personally in critical care settings, patients present with severe watery diarrhea associated with a peculiar smell and dehydration. Abdominal pain is not typical unless colonic perforation develops. Abdominal distension is often seen in patients presenting with CDAD. Diarrhea may be absent, and patients may present with toxic megacolon or an ileus-type picture. Sepsis and septic shock are often the presenting diagnosis, sometimes developing before the obvious diarrhea that raises suspicion for CDAD. Laboratory tests are characterized by elevated leukocyte counts, often in the leukemoid range. Renal failure develops in severe cases. Abdominal exam should be carefully followed in the ICU, as patients may develop toxic megacolon or colonic perforation days after starting appropriate treatment.
The clinical diagnosis is often suspected with the peculiar smell of CDAD and the previous history of antibiotic therapy. A freshly collected stool specimen should be sent for C. difficile toxin assay. Bedside sigmoidoscopy or colonoscopy is also often helpful, especially if the toxin assay is negative, as it can demonstrate the pseudomembrane formation and show patchy necrosis or colitis. Rarely, only the right side of the colon may be involved. If this is suspected, a more complete endoscopic examination may be necessary. CT scan often demonstrates thickened bowel wall and colonic dilatation, and can help rule out perforation or alternative diagnosis.
Treatment of CDAD
Patients with severe CDAD require rapid volume resuscitation for severe dehydration. Septic shock may require vasopressor therapy. If patients are on antibiotics, careful attention needs to be given to limiting the duration of antibiotics as much as possible. Stopping of the offending agent(s) is one of the first steps toward improving the chances of clearing this organism. Patients who continue to stay on the antibiotics that resulted in CDAD have higher chances of developing recurrence and severe CDAD.
Most cases of CDAD respond initially to antibiotic therapy. Oral metronidazole, in a dose of 250 to 500 mg every 8 hours for 10 to 14 days, is the most preferred therapy. If the patient is unable to take this agent (eg, pregnancy) or to tolerate it, oral vancomycin is equally effective at 125 mg 4 times a day dosing. Increasing the dose of oral vancomycin does not offer any additional advantage and, in general, the cost of this drug is substantially higher than that of metronidazole. I am not aware of any randomized, controlled trial of the combination of vancomycin and metronidazole. The intravenous form of metronidazole has been shown to be effective. However, vancomycin is not very well secreted in colonic mucosa to be effective via the intravenous route.
A novel concept, especially in patients with recurrent or relapsing CDAD, is to use pulse doses of oral vancomycin or metronidazole. The antibiotic is given in usual doses but at increasing intervals, with the hope that as the interval of antibiotic administration increases, the remaining spores will germinate and be killed by the next dose. Such regimens are continued for up to 3 weeks.4
Additional antibiotics have been tried but are not commonly used. Teicoplanin, fusidic acid, and bacitracin have been tried in one or more randomized studies. Rifampicin has been reported to help patients with recurrent or relapsing CDAD, but only in a total of 8 patients in the literature. Similarly, very limited case series data exist for use of intravenous gamma globulin (IVIg), a very expensive and limited resource, in CDAD.
Patients with CDAD should be isolated to prevent the spread of the organisms. Gloves should be worn while touching the patient or any surface in the patient's room, as they may have the spores of organism on them. If close contact with the patient's bed is expected, gowns should be worn as well. Although an alcohol hand wash is often adequate, if the institution is experiencing a high rate of CDAD, hand washing is often recommended after taking care of CDAD patients, as the spores may not be eradicated with alcohol-based hand sanitizers.
Probiotics are cultures of microorganisms that are administered orally to populate the colonic mucosa to reduce the severity or prevent development of CDAD. Saccharomyces boulardii and Lactobacillus species have been used, more often for prevention of CDAD.5 The role of probiotics in severe CDAD is not clear but, in my opinion, they are worth trying. Rare case series have reported use of human stool enemas to populate the colonic mucosa as a treatment of severe CDAD. Severe cases may require total parenteral nutrition to provide nutritional support until resolution of diarrhea. In the reported literature, diarrhea due to recurrence or relapse can last for as many as 55 days.
Role of Surgery in Severe CDAD
If the patient presents with an acute abdomen or develops toxic megacolon, or has refractory diarrhea and does not seem to respond in 4-5 days of conservative treatment, total colectomy with ileostomy may be a life saving option. In one of the largest reported series, Longo and colleagues reported 67 cases from a Department of Veterans Affairs database that required colectomy as therapy of CDAD.6 Of these cases, 54% had acquired CDAD in the hospital, whereas 46% had acquired it in community settings. Thirty-seven percent of cases did not have diarrhea, and 64% presented as a surgical abdomen. Eighteen percent of cases had negative stool studies for C. difficile, but all had pathological changes of CDAD in colon. Perforation and infarction were found in 58 out of 67 cases. Overall mortality was 48% in this case series. Thus, surgery is often the last resort in the most severe cases of CDAD.
Conclusion
Overall, severe CDAD is a life-threatening nosocomial infection that requires careful contact isolation, judicious use of antibiotics, and close monitoring for development of complications. Although there are not many reports of severe CDAD in hospital medicine literature, mortality is high, especially if complications develop that require surgical intervention. As more and more care gets bundled, careful unbundling of the broad spectrum antibiotics will be required to reduce the incidence and to prevent further spread of this fastidious organism.
References
1. McDonald LC, et al. Clostridium difficile Infection in Patients Discharged from US Short-stay Hospitals, 1996-2003. Emerg Infect Dis. [serial on the Internet]. March 2006. Accessed 03/01/2006. Available at www.cdc.gov/ncidod/EID/vol12no03/05-1064.htm.
2. McDonald LC, et al. An Epidemic, Toxin Gene-Variant Strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441.
3. Pepin J, et al. Mortality Attributable to Nosocomial Clostridium difficile-Associated Disease During an Epidemic Caused by a Hypervirulent Strain in Quebec. CMAJ. 2005;173:1037-1042.
4. McFarland LV. Alternative Treatments for Clostridium difficile Disease: What Really Works? J Med Microbiol. 2005;54:101-111.
5. Dendukuri N, et al. Probiotic Therapy for the Prevention and Treatment of Clostridium difficile-Associated Diarrhea: A Systematic Review. CMAJ. 2005;173:167-170. Erratum in: CMAJ. 2005;173:345.
6. Longo WE, et al. Outcome after Colectomy for Clostridium difficile Colitis. Dis Colon Rectum. 2004;47:1620-1626.
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