Salkind, Alan R. MD
* Both the incidence and severity of Clostridium difficile infection (CDI) are increasing.
* Patients with community-acquired infection may not have traditional risk factors.
* A hypervirulent strain of C difficle that produces excess toxins has been isolated.
* Patients with mild disease can progress to severe CDI while receiving treatment.
* Oral vancomycin should be the initial antibiotic choice for patients with severe disease.
Clostridium difficile (C difficile) is a spore-forming, toxin-producing, Gram-positive anaerobic bacterium that is widely distributed in nature. It was first described in 1935, but was not recognized as a cause of gastrointestinal disease until 1978.1 Approximately 3% of adults are asymptomatically colonized with C difficile. The frequency of adults colonized increases to 20%–30% in acute care hospitals1 and may be as high as 50% in long-term care facilities.2 C difficile can cause mild diarrhea or fulminate disease such as megacolon, pseudomembranous colitis, and perforation, mainly in hospitalized patients exposed to antibiotics.1,3 The number of deaths from C difficile infection (CDI) exceeds that of all other intestinal infections.4 Nosocomial infection increases the cost of hospitalization by 54% and the length of stay by 3.6 days.5 One study estimated that the annual cost for management of CDI in the United States was $3.2 billion.6
The incidence and severity of CDI have been increasing. Review of US hospital discharge data revealed that the frequency of patients discharged in 1993 with a principle diagnosis of CDI was 24/1000 discharges. By 2005, that frequency jumped to 76/1000 discharges, a 3.2-fold increase.7 During the same period, the number of hospital discharges, which included CDI as one of all listed diagnoses, showed a 3.5-fold increase.7 Mortality rates from C difficile disease in the US increased from 5.7/1,000,000 population in 1999 to 23.7/1,000,000 population in 2004.4 The incidence of CDI in Canada rose 4.3-fold from 1991 to 2003, associated with a threefold increase in CDI-related deaths.8 Potential factors contributing to the increased frequency and severity of CDI are an aging population, hospitalized patients with numerous comorbidities, excess antibiotic use, and emergence of a more virulent strain of C difficile.
While most cases of CDI occur in hospitalized patients, community-acquired infections are recognized. Antibiotic exposure and age >65 years are common risk factors for the acquisition of CDI in the hospitalized patient,3,9 but these factors may be absent in individuals with community-acquired CDI (CA-CDI).10 In one study, 32% of CA-CDI patients had not taken an antibiotic during the 90 days preceding symptoms, and 25% of patients had no recent underlying conditions or healthcare exposures. Twenty-eight percent of the patients were <45 years old.11 Another study showed that only 65% of patients with CA-CDI were exposed to antibiotics in the 42 days preceding symptoms. The median age of these patients was 37 years.12 Dial et al reported that among patients >65 years old admitted to the hospital with CA-CDI, 53% had no exposure to antibiotics in the 45 days before disease onset. For those exposed to antibiotics, clindamycin and gatifloxacin were associated with the highest risk.13 Use of proton pump inhibitors and concurrent diagnoses of renal failure, inflammatory bowel disease, and irritable bowel disease were also related to an increased risk of CA-CDI.13 Recently, ten cases of CDI occurring in peripartum women were reported.14 Nine of 10 patients reported antibiotic use within three months of CDI.14 Peripartum women may be an emerging at-risk population for CDI. Possible community sources for C difficile are soil, household pets, food, and exposure to recently hospitalized patients.10
Factors predisposing to the development of CDI are listed in Table 1. An essential occurrence leading to CDI is disturbance of the normal, protective flora of the colon.1,15 Ingested toxigenic spores germinate to vegetative forms in the small intestine. In the colon, C difficile produce toxins A and B. Both toxins can induce intestinal permeability and cytoskeletal changes, but toxin B is ten times more potent than toxin A.1 Toxin B was identified as the virulence factor necessary for full expression of CDI.16
A strain of C difficile associated with severe disease was identified in 2005. This strain was isolated from patients in the US, Canada and Europe.17,18 The strain was characterized as belonging to restriction endonuclease analysis group BI, North American pulsed-field gel electrophoresis type 1 (NAP1), and ribotype 027. Based on these molecular characteristics, the strain was named BI/NAP1/027.17,18 Analyses revealed at least three factors unique to BI/NAP1/027: high-level fluoroquinolone resistance; a mutation at the site of the proposed negative regulator of toxin A and B production, leading to a 16 to 23-fold increase of their levels; and production of a third toxin called binary toxin.17,18 Isolates with molecular characteristics similar to BI/NAP1/027 have also caused disease in outpatients.14 Emergence of the BI/NAP1/027 hypervirulent strain may explain, at least in part, the rise in both the incidence and severity of CDI.19
Diseases caused by CDI can vary from a mild diarrheal illness to fulminate colitis, perforation or megacolon.1,3 CDI should be considered in patients with predisposing factors (Table 1) for the disease who present with loose or watery stools.1 The frequency of diarrhea may range from a few episodes daily to 15–30 bowel movements per day.1 Disease onset may occur shortly after or as long as two months postexposure to antibiotics.3 Abdominal pain (∼22%), fever (∼28%), leukocytosis (∼50%), and fecal leukocytes (∼50%) are presenting characteristics. Abdominal pain may be localized to the lower quadrants. Gross blood in the stools is rare. Hypoalbuminemia, when present, may occur early in the disease process.3
Clinicians should be aware that mild disease can progress rapidly. White blood cell (WBC) counts, usually in the range of 15,000 cells/mm3, may approach 50,000 cells/mm3. Wanahita et al reported that about 25% of patients with proven CDI had WBC counts >30,000 cells/mm3. The leukocytosis may precede diarrhea and abdominal pain.20 Severe cases of CDI may be marked by paralytic ileus that can evolve into megacolon, accompanied by systemic toxicity. Diarrhea may be absent in patients with ileus, and administration of narcotic analgesics may be a risk for this complication. Symptoms of unexplained fever, leukocytosis, and abdominal pain in a patient with recent antibiotic or antineoplastic exposure or surgical or nonsurgical gastrointestinal interventions should raise a suspicion of CDI,1,21,22 even if diarrhea is absent.3,20
Most patients with CDI have clinically significant diarrhea, defined as ≥3 loose or watery stools per day for at least one to two days.23 Testing for CDI should be reserved for patients with the greatest likelihood of having the disease. An enzyme immunoassay (EIA) detecting toxins A and B is used by the vast majority of clinical laboratories. It has the advantage of same-day results and ease of performance.3,23 While these assays are highly specific (>97%), their sensitivities are in the neighborhood of 70%, when compared to the gold standard, the tissue culture cytotoxicity assay.23 However, that assay is not feasible for clinical laboratories because of its technical difficulty and long turn-around time (≥ 48 hours). Because of the low sensitivity of the EIA, false negative results are common. A negative assay should not dissuade consideration of CDI when there is a strong clinical suspicion of the disease. A repeat EIA, if negative, reduces the positive predictive value to about 50% and increases the negative predictive value to >95%.23 Further EIA testing adds little to the diagnostic yield, while increasing costs. Repeat EIA testing during or after treatment is not indicated, as patients may shed C difficile toxin in their stools for weeks after successful treatment.24 Endoscopy and/or CT imaging of the abdomen should be considered for patients with a high suspicion of CDI who are not responding to therapy.
Polymerase chain reaction (PCR) assays for the detection of toxigenic C difficile have been developed, demonstrating sensitivities of about 90% and specificities of >97%.23,25 The US Food and Drug Administration (FDA) recently approved a commercial PCR assay for C difficile.26 Although more expensive than the EIA, PCR assays may eliminate unnecessary repeat testing and result in earlier laboratory diagnosis and treatment of CDI.23,25 Clinical laboratory testing to identify the B1/NAP1/027 strain is not yet widely available.
Treatment recommendations are presented in Table 2. Historically, stopping the antibiotic treatment alone has resulted in resolution of symptoms in about 20% of patients. This strategy should only be used in the mildest of cases and with close observation because mild disease can rapidly become severe.24,27,28
Intravenous vancomycin should never be prescribed to treat CDI. Oral vancomycin is the only antibiotic treatment approved by the FDA for symptomatic C difficile. However, because of its low cost (compared to oral vancomycin) and concerns about the development of vancomycin-resistant bacteria, metronidazole has been the preferred treatment for most cases of initial CDI.24,27 The results of recent studies have caused re-examination of that strategy, especially for patients with severe CDI.
Zar et al29 stratified patients with CDI as having mild or severe disease based on clinical characteristics. One point was given for age >60 years, temperature >38.3°C, albumin level <2.5 mg/dL, or peripheral WBC count ≥15,000 cells/mm3. Two points were given if the patient had endoscopic evidence of pseudomembranous colitis or treatment in the intensive care unit. For patients considered to have mild disease (<2 points), there was no significant difference (P = 0.36) in cure rates between metronidazole (90%) and vancomycin (98%). In contrast, for patients with severe CDI (≥2 points), there was a significant difference (P = 0.02) in cure rates between metronidazole (76%) and vancomycin (97%). The precise mechanism of vancomycin superiority was not elucidated. A recent narrative review also emphasized the equivalence of metronidazole and vancomycin for mild, but not severe, disease.30 Another study showed that vancomycin significantly reduced complications from CDI by 2.2-fold (P = 0.02) compared to metronidazole.8
Patients with fulminate CDI may have a rapid progression to pseudomembranous colitis, ileus, megacolon or perforation. Diarrhea may be absent in patients with ileus or megacolon.3 Intravenous metronidazole plus vancomycin given orally, by nasogastric tube or enema, should be considered for those patients, although no randomized trials of this approach have been reported.24,27
In summary, the weight of evidence indicates that oral vancomycin should be considered as initial treatment for patients with severe disease, while metronidazole should be used for patients with mild disease.24,27,28 However, clinicians should be aware that there is no widely accepted set of clinical characteristics to define disease severity.29,30 Severity indices should not replace clinical judgment.
Recurrent CDI occurs in about 20% of cases initially treated with vancomycin or metronidazole.27 Most recurrences occur within one to two weeks after completion of therapy.24 The mechanism of recurrences may involve continued exposure to organisms through reinfection, relapse from germination of C difficile spores in the gastrointestinal tract, or inadequate levels of antitoxin antibodies in response to initial infection.24 Most patients with a first recurrence should be retreated with the same drug used to treat the first episode.24,27 Vancomycin therapy should be considered if the patient has severe CDI and was initially treated with metronidazole.24,28
Some patients will develop repeated recurrences of CDI over a period of months to years.24 For these patients, vancomycin should be administered. In a study of 163 patients with recurrent CDI, tapering or pulsed dosing of oral vancomycin was more effective than metronidazole therapy.28 Oral vancomycin and rifampin for seven days or a ten-day course of vancomycin followed by a two-week course of rifaximin may be effective for patients failing vancomycin tapering or pulsed dosing.24 Use of rifaximin for this indication has not been approved by the FDA.
Nonantimicrobial treatments for patients with recurrent CDI have been evaluated. A recent systematic literature review did not find convincing evidence to support the use of probiotics, such as Lactobacillus sp. and Saccharomyces boulardii.31 A small trial of Lactobacillus rhamnosus for prevention of recurrent CDI showed no benefit.32 Anion exchange resins given to bind C difficile toxins have demonstrated limited efficacy and carry the potential to bind antimicrobials used to treat CDI.24,28 Intravenous immunoglobulin (IVIG) can be considered in refractory cases, but its cost and uncertain efficacy are disadvantages.24,27,33,34 Stool infusion therapy, whereby fecal flora from a healthy donor is infused by nasogastric tube or rectally, has been associated with a high success rate. In a brief review describing patients with recurrent CDI, 60 (90%) of 67 patients who received stool infusion therapy were reported as cured.35 Resolution of recurrent CDI was documented in 15 of 16 patients who received stool infusion through a nasogastric tube.36 Randomized controlled trials of stool infusion have not been reported.
Treatment failures with metronidazole and lack of consistently effective therapies for recurrent CDI have led investigators to search for new, more effective treatments. Nitazoxanide, an antiparasitic drug, was shown in small studies to be as effective as metronidazole and possibly as effective as vancomycin.37,38 Nitazoxanide is not currently approved by the FDA for treatment of CDI. The exchange resin, tolevamer, was shown to be noninferior to vancomycin in a phase 2 trial,24 but it was not more effective than vancomycin or metronidazole in a phase 3 trial,39 making its use for treatment of CDI uncertain.
Because hospitalized patients with C difficile are a reservoir for the organism,2 good hand hygiene and contact isolation are essential in the care of any patient with CDI. Alcohol-containing hand-sanitizing agents are not sporicidal, and they should not be used as the sole agent for hand hygiene when caring for patients with C difficile. Handwashing with soap and water is recommended.27 Restricted antibiotic utilization can decrease the incidence of CDI. In particular, reducing fluoroquinolone use may be an important factor for controlling emergence of the BI/NAP1/027 strain.9 Two recent studies found that compliance with institutional antimicrobial prescribing guidelines decreased the incidence of CDI by 50–70%.40,41
Recent changes in the epidemiology, pathogenesis, and treatment of CDI have renewed attention to this pathogen. Emergence of the BI/NAP1/027 hypervirulent strain has been associated with increases in the incidence and severity of CDI. In addition, CA-CDI is increasingly recognized. In contrast to hospitalized patients, CA-CDI may cause disease in younger adults and may not be associated with antibiotic exposure. Peripartum women may be a newly indentified risk population. Patients suspected of having CDI should be carefully evaluated to determine the severity of infection. Oral metronidazole remains appropriate first-line treatment for patients with mild-to-moderate disease, while oral vancomycin should be administered to patients with severe disease. Selecting the best treatment of patients with multiple recurrences is hampered by the lack of a robust database. Stool infusion therapy may be an option for patients with recalcitrant disease. Contact isolation, handwashing with soap and water, and prudent use of antibiotics are three everyday interventions that clinicians can use to reduce the emergence and spread of CDI.
1. Bartlett JG. Historical perspectives on studies of Clostridium difficile and C. difficile infection. Clin Infect Dis 2008;46(suppl 1):S4–S11.
2. Riggs MM, Sethi AK, Zabarsky TF, et al. Asymptomatic carriers are a potential source for transmission of epidemic and nonepidemic Clostridium difficile strains among long-term care facility residents. Clin Infect Dis 2007;45:992–998.
3. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. [Review.] Clin Infect Dis 2008;46(suppl 1):S12–S18.
4. Redelings MD, Sorvillo F, Mascola L. Increase in Clostridium difficile-related mortality rates, United States, 1999–2004. Emerg Infect Dis 2007;13:1417–1419.
5. 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.
6. O'Brien JA, Lahue BJ, Caro JJ, et al. The emerging infectious challenge of Clostridium difficile-associated disease in Massachusetts hospitals: clinical and economic consequences. Infect Control Hosp Epidemiol 2007;28:1219–1227.
7. Elixhauser A, Jhung M. Clostridium difficile
-associated disease in U.S. Hospitals, 1993–2005. Healthcare cost and utilization project. Statistical brief #50 2008. Search: Clostridium difficile
. Available at: www.hcup-us.ahrq.gov
. Accessed January 5, 2009.
8. Pépin J, Valiquette L, Alary ME, et al. Clostridium difficile-associated diarrhea in a region of Quebec from 1991 to 2003: a changing pattern of disease severity. CMAJ 2004;171:466–472.
9. Pépin 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.
10. Pituch H. Clostridium difficile is no longer just a nosocomial infection or an infection of adults. Int J Antimicrob Agents 2009;33(suppl 1):S42–S45.
11. Surveillance for community-associated Clostridium difficile–Connecticut, 2006. Mor Mortal Wkly Rep 2008;57:340–343.
12. Hirschhorn LR, Trnka Y, Onderdonk A, et al. Epidemiology of community-acquired Clostridium difficile-associated diarrhea. J Infect Dis 1994;169:127–133.
13. Dial S, Kezouh A, Dascal A, et al. Patterns of antibiotic use and risk of hospital admission because of Clostridium difficile infection. CMAJ 2008;179:767–772.
14. Centers for Disease Control and Prevention (CDC). Severe Clostridium difficile-associated disease in populations previously at low risk—four states, 2005. MMWR Morb Mortal Wkly Rep 2005;54:1201–1205.
15. Bartlett JG, Onderdonk AB, Cisneros RL, et al. Clindamycin-associated colitis due to a toxin-producing species of Clostridium in hamsters. J Infect Dis 1977;136:701–705.
16. Lyras D, O'Connor JR, Howarth PM, et al. Toxin B is essential for virulence of Clostridium difficile. Nature 2009;458:1176–1179.
17. 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.
18. Warny M, Pepin J, Fang A, et al. Toxin production by an emerging strain of Clostridium difficile associated with outbreaks of severe disease in North America and Europe. Lancet 2005;366:1079–1084.
19. Pépin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ 2005;173:1037–1042.
20. Wanahita A, Goldsmith EA, Musher DM. Conditions associated with leukocytosis in a tertiary care hospital, with particular attention to the role of infection caused by Clostridium difficile. Clin Infect Dis 2002;34:1585–1592.
21. Anand A, Glatt AE. Clostridium difficile infection associated with antineoplastic chemotherapy: a review [review]. Clin Infect Dis 1993;17:109–113.
22. Pierce PF Jr, Wilson R, Silva J Jr, et al. Antibiotic-associated pseudomembranous colitis: an epidemiologic investigation of a cluster of cases. J Infec Dis 1982;145:269–274.
23. Peterson LR, Robicsek A. Does my patient have Clostridium difficile infection? Ann Intern Med 2009;151:176–179.
24. Gerding D, Muto C, Owens RJ. Treatment of Clostridium difficile infection. Clin Infect Dis 2008;46(suppl 1):S32–S42.
25. Stamper PD, Alcabasa R, Aird D, et al. 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 2009;47:373–378.
26. FDA approves rapid DNA test to detect Clostridium difficile
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28. McFarland LV. Alternative treatments for Clostridium difficile disease: what really works? J Med Microbiol 2005;54:101–111.
29. 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.
30. Pepin J. Vancomycin for the treatment of Clostridium difficile infection: for whom is this expensive bullet really magic? Clin Infect Dis 2008;46:1493–1498.
31. Dendukuri N, Costa V, McGregor M, et al. Probiotic therapy for the prevention and treatment of Clostridium difficile-associated diarrhea: a systematic review. CMAJ 2005;173:167–170.
32. Lawrence SJ, Korzenik JR, Mundy LM. Probiotics for recurrent Clostridium difficile disease. J Med Microbiol 2005;54:905–906.
33. Juang P, Skledar SJ, Zgheib NK, et al. Clinical outcomes of intravenous immune globulin in severe Clostridium difficile-associated diarrhea. Am J Infect Control 2007;35:131–137.
34. McPherson S, Rees CJ, Ellis R, et al. Intravenous immunoglobulin for the treatment of severe, refractory, and recurrent Clostridium difficile diarrhea. Dis Colon Rectum 2006;49:640–645.
35. Borody TJ. “Flora power”—fecal bacteria cure chronic C. difficile diarrhea. Am J Gastroenterol 2000;95:3028–3029.
36. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis 2003;36:580–585.
37. Musher DM, Logan N, Hamill RJ, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis 2006;43:421–427.
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Product Code: SMJ09-10A
Clostridium difficile: An Update for the Primary Care Clinician
September 2010 CME Questions
1. Which of the following is not a characteristic of the BI/NAP1/027 strain of C difficile?
A. Increased toxin A but not toxin B production
B. Fluoroquinolone resistance
C. Production of binary toxin
D. Associated with severe disease
2. From 1993 to 2005, the frequency of patients discharged from US hospitals with a principle diagnosis of C difficile infection (CDI) increased by:
3. Patients with severe CDI should be treated with:
A. Intravenous vancomycin
B. Oral metronidazole
C. Oral vancomycin
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CME Questions - Answer Key
1. A, 2. C, 3. D