Is &lt;i&gt;C difficile&lt;/i&gt; to blame for your patient’s diarrhea?

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Applied Evidence

Is C difficile to blame for your patient’s diarrhea?

J Fam Pract. 2011 March;60(3):128-134

By

Tracy L. Lemonovich, MD

Richard R. Watkins, MD, MS

Once viewed almost exclusively as a nosocomial infection, C difficile is increasingly common in outpatient settings, making it imperative that FPs be proficient in detection and treatment.

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References

1. Gerding DN. Global epidemiology of Clostridium difficile infection in 2010. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S32-S34.

2. Cohen SH, Gerding DH, 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 Hosp Epidemiol. 2010;31:431-455.

3. Bartlett JG. Detection of Clostridium difficile infection. Infect Control Hosp Epidemiol. 2010;31(suppl 1):S35-S37.

4. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.

5. Dial S, Delaney JA, Barkun AN, et al. Use of gastric acid-suppressive agents and the risk of community-acquired Clostridium difficile-associated disease. JAMA. 2005;294:2989-2995.

6. Cunningham R, Dale B, Undy B, et al. Proton pump inhibitors as a risk factor for Clostridium difficile diarrhoea. J Hosp Infect. 2003;54:243-245.

7. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.

8. Shah S, Lewis A, Leopold D, et al. Gastric acid suppression does not promote clostridial diarrhoea in the elderly. QJM. 2000;93:175-181.

9. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis. 2008;46(suppl 1):S12-S18.

10. Henrich TJ, Krakower D, Bitton A, et al. Clinical risk factors for severe Clostridium difficile-associated disease. Emerg Infect Dis. 2009;15:415-422.

11. Kutty PK, Woods CW, Sena AC, et al. Risk factors for and estimated incidence of community-associated Clostridium difficile infection, North Carolina, USA. Emerg Infect Dis. 2010;16:197-204.

12. 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.

13. Mohan SS, McDermott BP, Parchuri S, et al. Lack of value of repeat stool testing for Clostridium difficile toxin. Am J Med. 2006;119:356.e7-e8.

14. Bryant K, McDonald LC. Clostridium difficile infections in children. Pediatr Infect Dis J. 2009;28:145-146.

15. 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.

16. Belmares J, Gerding DN, Parada JP, et al. Outcome of metronidazole therapy for Clostridium difficile disease and correlation with a scoring system. J Infect. 2007;55:495-501.

17. Hickson M, D’Souza AL, Muthu N, et al. Use of probiotic Lactobacillus preparation to prevent diarrhoea associated with antibiotics: randomised double blind placebo controlled trial. BMJ. 2007;335:80.-

18. Ledoux D, Labombardi VJ, Karter D. Lactobacillus acidophilus bacteraemia after use of a probiotic in a patient with AIDS and Hodgkin’s disease. Int J STD AIDS. 2006;17:280-282.

19. Hammerman C, Bin-Nun A, Kaplan M. Safety of probiotics: comparison of two popular strains. BMJ. 2006;333:1006-1008.

20. Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.

21. Nair S, Yadav D, Corpuz M, et al. Clostridium difficile colitis: factors influencing treatment failure and relapse—a prospective evaluation. Am J Gastroenterol. 1998;93:1873-1876.

22. Garey KW, Sethi S, Yadav Y, et al. Meta-analysis to assess risk factors for recurrent Clostridium difficile infection. J Hosp Infect. 2008;70:298-304.

23. Das R, Feuerstadt P, Brandt LJ. Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with Clostridium difficile-associated disease. Am J Gastroenterol. 2010;105:2040-2049.

24. Cadena J, Thompson GR, 3rd, Patterson JE, et al. Clinical predictors and risk factors for relapsing Clostridium difficile infection. Am J Med Sci. 2010;339:350-355.

25. Linsky A, Gupta K, Lawler EV, et al. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010;170:772-778.

26. Johnson S, Schriever C, Galang M, et al. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis. 2007;44:846-848.

PRACTICE RECOMMENDATIONS

• A C difficile diagnosis should be made by one of several widely available testing protocols, including a 2-step method using the common antigen assay to determine whether C difficile is present, followed by an enzyme immunoassay for toxins A and B to improve specificity. B

• Oral metronidazole should be used for initial treatment of mild to moderate C difficile infection, and oral vancomycin and possibly intravenous metronidazole for severe cases. A

• Metronidazole should not be used after an initial recurrence or for long-term therapy because of the risk of neurotoxicity. A

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

CASE Mary S, an 82-year-old patient you recently treated for bronchitis with a 3-day course of levofloxacin, calls your office complaining of diarrhea and abdominal cramps. She describes the diarrhea as nonbloody and particularly foul smelling and asks if she can take loperamide for her symptoms.

If Mary S were your patient, what would you tell her?

The incidence of Clostridium difficile infection (CDI) has been on the rise since 2000, when a common epidemic strain began circulating in North America.¹ Although hospitalization or residency in a long-term care facility remains a classic risk factor for CDI, physicians in out-patient settings are increasingly likely to see patients with community-acquired CDI.

Recently updated guidelines from the Society for Health-care Epidemiology of America (SHEA) and the Infectious Diseases Society of America define CDI as the presence of diarrhea (≥3 unformed stools in 24 hours) and either a positive stool test for toxigenic C difficile or its toxins or colonoscopic or histopathologic findings demonstrating pseudomembranous colitis.² That said, the clinical features of CDI are nonspecific and many patients do not fit the classic profile. So diagnosing CDI requires a high index of suspicion.

The text and tables that follow detail some surprising things about who is likely to develop CDI and which treatment options to employ (and, in some cases, avoid).

Is it CDI? Looking beyond the obvious

Antibiotic use and advanced age, like hospitalization, are classic risk factors for CDI.³ Diarrhea typically begins during or shortly after a course of antibiotics, but may develop as long as 8 weeks after treatment is completed. While any antibiotic, including metronidazole, can precipitate CDI, clindamycin, cephalosporins, extended-spectrum penicillins, and quinolones are most frequently implicated.⁴ Epidemiologic studies have suggested an association between gastric acid-reducing agents—primarily proton-pump inhibitors—and CDI.^4-7 But this link remains controversial, as other investigations have not found a clear relationship.⁸

FAST TRACK

In a recent study of patients with CDI, almost half had no exposure to antibiotics and 20% of the cases were community-acquired.

In addition to diarrhea, approximately 28% of patients with CDI develop a fever (as high as 104°F); 50% develop leukocytosis (up to 50,000 cells/mcL); and 22% develop abdominal pain, usually localized to the lower quadrants.⁹ These symptoms, however, are not specific to C difficile, and could be due to a different enteric pathogen, intra-abdominal sepsis, inflammatory bowel disease, or adverse effects of medication, among other causes.⁹

Markers for severe CDI include age >70 years, leukocyte count >20,000 cells/mcL, albumin level <2.5 g/dL, small-bowel obstruction or ileus, and a computed tomography (CT) scan showing colorectal inflammation.¹⁰ Severe CDI can lead to toxic megacolon, bowel perforation, sepsis, and even death.

In addition to considering CDI in patients with nonspecific symptoms, it is important to include it in the differential diagnosis of patients who do not fit the classic profile. In a recent study of patients with CDI at 4 Veterans Affairs facilities, almost half (49%) of those studied had no exposure to antimicrobial drugs. The researchers further found that the median age of patients with CDI was 61 years—younger than that found in previous studies—and that 20% of the cases were community-acquired.¹¹

Consider CDI in children, too. Risk factors for CDI in pediatric patients include disruption of the normal microflora of the gastrointestinal tract, compromised immune status, poor diet, underlying health conditions, concurrent infections, and cancer.¹²

Diagnostic testing: Consider a 2-step assay

Patients with symptoms suggestive of CDI should undergo laboratory testing to confirm the diagnosis. TABLE 1 lists the tests that are widely available in the United States.³ Only liquid stools should be tested and just one sample should be sent to the lab, as multiple samples do not increase the diagnostic yield.¹³ In addition, tests should be used only for diagnosis, and not as a “test of cure.” This is because patients can shed C difficile toxin and spores for several weeks after completing treatment, and there are wide variations in the sensitivity of toxin assays.