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Clinical Crossroads | Clinician's Corner

A 76-Year-Old Man With Recurrent Clostridium difficile–Associated Diarrhea:  Review of C difficile Infection

Ciarán P. Kelly, MD, Discussant
JAMA. 2009;301(9):954-962. doi:10.1001/jama.2009.171.
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Clostridium difficile infection (CDI) is a common and increasingly severe nosocomial infectious disease. The case of Mr S, a 76-year-old man with multiple recurrences of CDI, illustrates the difficulties in treating recurrent disease and the way it complicates the management of other medical conditions. Risk factors for CDI include antimicrobial use, hospital admission, advancing age, and severe underlying disease. A clinical diagnosis of CDI is usually confirmed by identifying C difficile toxins in a stool sample. Evidence supports metronidazole, 500 mg every 6 hours for 10 to 14 days, as the treatment of choice for mild to moderately severe CDI. Oral vancomycin, 125 mg every 6 hours for 10 to 14 days, is recommended for severe CDI, for which it is more effective than metronidazole. Recurrent CDI occurs in more than 20% of patients when metronidazole or vancomycin treatment is discontinued. Few studies have evaluated treatment options for recurrent CDI, but a prolonged, tapering, and pulse-dosed regimen of oral vancomycin is commonly used. Careful attention to antimicrobial stewardship and infection control practices is essential to curb this nosocomial, iatrogenic disease.

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The burden of recurrent Clostridium difficile infections
Posted on February 19, 2009
Els van Nood, M.D.
Academic Medical Center, department of Internal Medicine, Amsterdam, The Netherlands
Conflict of Interest: None Declared
Prolonged and persistent Clostridium difficile Infections (CDI) have a tremendous impact on quality of life. As Mr S illustrates, the chronicity, the uncertainty and the diarrhea lead to a deteriorating state, with apparently no prospects for improvement or cure. In this case, difficulties regarding the management of recurrent CDI already begin at diagnosis. The sensitivity of various toxin tests, the most commonly used diagnostic tool for the detection of CDI, range between 55 and 97%.(1-2) Some clinicians therefore advocate repeated testing, which in turn may lead to false positive outcomes. The cytotoxicity cell test is the gold standard, and should be performed in difficult cases, even though it takes 2-3 days to complete the test.(2) Colonoscopy can be valuable in this particular case, by showing either signs of CDI (pseudomembranous colitis or typical volcano lesions in biopsies) or an alternative explanation contributing to the recurrent diarrhea (microscopic colitis, inflammatory bowel disease or malignancy). In general, restricted use of antibiotics, in particular quinolones, cephalosporins and clindamycin is considered a preventive measure.(3) Glove wearing, hand washing and cleaning with chlorine-based detergents all are effective infection control measures to prevent re-infection or transmission to other patients.(4) Initial CDI that requires antibiotic treatment is cured in 80% of patients, with metronidazole and vancomycin being equally effective for mild to moderate disease.(5) Oral vancomycin is the drug of choice in severe and recurrent disease. For a first recurrence, a response rate of 67% is reported for antibiotic treatment.(6) However, the efficacy of antibiotics for a second, third or next recurrence is not known, and may be substantially lower.(7) Alternative antibiotic therapy may include prolonged tapered and/or pulsed vancomycin schedules, although evidence regarding efficacy is lacking. Additional therapies include immunoglobulins, cholestyramine, rifaximin, or teicoplanin. Empirical therapy, although tempting, should be avoided where possible; longstanding vancomycin therapy, although not systemically absorbed, and therefore considered as save, increases the risk for vancomycin resistant enterococci, whereas prolonged courses of metronidazol can lead to neurotoxic side effects. Persistent disturbed intestinal flora is considered a prerequisite for Clostridium difficile to grow and produce toxins, leading to diarrhea. It is often not clear whether a recurrence or a new infection has taken place, up to 56% of recurrences may in fact reflect reinfection.(8) Cure of recurrent CDI by infusion of feces from (thoroughly screened) healthy donors has been described in over 150 patients. The overall reported success rate is about 90%, but a prospective randomised trial is lacking. Feces mixed with saline can be infused either in the colon (ie, as an enema) or by duodenal tube.(9) We have been treating patients with donor feces for 2 years, with excellent results, and a randomised trial has been initiated, comparing the efficacy of vancomycin with fecal infusions.(10) Awaiting the results of this study, donor feces infusion is tolerated well, with promising results. If recurrent C.difficile can be demonstrated in Mr S’ case, it could be very rewarding to offer this somewhat “unaesthetic treatment approach”.(quote of John Bartlett) Reference list (1)Planche T, Aghaizu A, Holliman R, Riley P, Poloniecki J, Breathnach A, et al. Diagnosis of Clostridium difficile infection by toxin detection kits: a systematic review. Lancet Infect Dis 2008 Dec;8(12):777-84. (2)Turgeon DK, Novicki TJ, Quick J, Carlson L, Miller P, Ulness B, et al. Six rapid tests for direct detection of Clostridium difficile and its toxins in fecal samples compared with the fibroblast cytotoxicity assay. J Clin Microbiol 2003 Feb;41(2):667-70. (3)Pepin J, Saheb N, Coulombe MA, Alary ME, Corriveau MP, Authier S, 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 Nov 1;41(9):1254-60. (4)Fawley WN, Underwood S, Freeman J, Baines SD, Saxton K, Stephenson K, et al. Efficacy of hospital cleaning agents and germicides against epidemic Clostridium difficile strains. Infect Control Hosp Epidemiol 2007 Aug;28(8):920-5. (5)Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile- associated diarrhea, stratified by disease severity. Clin Infect Dis 2007 Aug 1;45(3):302-7. (6)Pepin J, Routhier S, Gagnon S, Brazeau I. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis 2006 Mar 15;42(6):758-64. (7)McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002 Jul;97(7):1769-75. (8)Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection--relapse or reinfection? J Hosp Infect 1998 Feb;38(2):93-100. (9)Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol 2004 Jul;38(6):475-83. (10)Nieuwdorp M, van NE, Speelman P, van Heukelem HA, Jansen JM, Visser CE, et al. [Treatment of recurrent Clostridium difficile-associated diarrhoea with a suspension of donor faeces]. Ned Tijdschr Geneeskd 2008 Aug 30;152(35):1927-32.

Financial disclosure: The FECAL trial is sponsored by a grant from ZonMW, The Netherlands Organisation for Health Research and Development
Tres Difficile
Posted on February 11, 2009
Nick Daneman, MD, MSc, FRCPC
Sunnybrook Health Sciences Centre, University of Toronto
Conflict of Interest: None Declared
Mr S embodies the growing suffering generated by Clostridium difficile colitis. Superimposed upon a doubling in incidence over the last decade,(1) there have been dramatic increases in the acute severity of C.difficile infections, characterized by more intensive care unit admissions and colectomies and a four-fold rise in attributable mortality.(2) One of the most common and difficult complications of C.difficile colitis is disease recurrence. Traditionally, 1 in 4 patients with C.difficile infection have experienced recurrent disease following their initial treatment, and this risk appears to be increasing in recent years, especially among elderly patients.(3, 4) Mr. S's protracted course of recurrences and altered quality of life are unfortunately typical of the broader clinical experience with C.difficile.(4) A substantial fraction of C.difficile recurrences result from reinfection with the bacteria from its hospital reservoir (other colonized and infected patients and their immediate environments).(5) However, many recurrences relate to persistent infection with antibiotic-impermeable C.difficile spores, which can then germinate (usually within 6 weeks of initial infection) to produce the vegetative form of the organism. Although a recent randomized controlled trial demonstrated vancomycin to be superior to metronidazole in the treatment of acute severe C.difficile infections,(6) it offers no advantage in preventing relapses.(4, 6)
Therefore, multiple treatment strategies have emerged to counter relapsing C.difficile colitis; all supported by intriguing theoretic rationales, none supported by rigorous evidence. Should we choose combination therapy with rifaximin, to overcome potentially unmeasured resistance to first line agents?(7) Should we taper or pulse vancomycin therapy to allow time for spores to germinate to their virulent but vulnerable form?(8) Adding or prolonging antibiotic therapy may worsen our crisis of antibiotic resistance, so instead maybe we should replenish patients' microbial flora with nonpathogenic organisms (eg, Saccharomyces boulardii) to outcompete C.difficile?(9) If Mr. S is truly "going out of [his] mind", and if he has a loving (or perhaps begrudging) family member, his best bet to definitively restore his intestinal flora is via stool transplantation.(10) Of course, he may find the idea of donor stool a lot less palatable than a donor kidney. While we await clinical trials to inform our treatment choices, it is clear that none of these strategies offers a panacea for recurrent C.difficile colitis.
Therefore, as with other hospital-acquired infections, our greatest emphasis must be on prevention. We must prevent acquisition of C.difficile by implementing best infection control practices, such as contact isolation for patients with diarrhea, strict hand hygiene adherence, aggressive environmental cleaning, and outbreak surveillance. More importantly we must minimize inappropriate antibiotic exposure among all hospitalized patients, and in particular those with a recent diagnosis of C.difficile colitis. One of the most important maneuvers in Mr. S's care, for example, was the removal of his foley cathether, to reduce his risk of recurrent urinary tract infections and need for repeat antibiotic treatments. Treatment of asymptomatic bacteriuria in this patient population represents another common avoidable cause of C.difficile recurrence. Mr. S has not accepted his C.difficile colitis as an expected part of his healthcare experience. Nor should we.
No financial disclosures.
Reference List
1. McDonald LC, Owings M, Jernigan DB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis 2006; 12(3):409-415. 2. Gravel D, Miller M, Simor A et al. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: a Canadian Nosocomial Infection Surveillance Program Study. Clin Infect Dis 2009; 48(5):568-576. 3. Pepin J, Alary ME, Valiquette L et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005; 40(11):1591-1597. 4. McFarland LV, Surawicz CM, Rubin M, Fekety R, Elmer GW, Greenberg RN. Recurrent Clostridium difficile disease: epidemiology and clinical characteristics. Infect Control Hosp Epidemiol 1999; 20(1):43-50. 5. Wilcox MH, Fawley WN, Settle CD, Davidson A. Recurrence of symptoms in Clostridium difficile infection--relapse or reinfection? J Hosp Infect 1998; 38(2):93-100. 6. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile- associated diarrhea, stratified by disease severity. Clin Infect Dis 2007; 45(3):302-307. 7. Johnson S, Schriever C, Galang M, Kelly CP, Gerding DN. Interruption of recurrent Clostridium difficile-associated diarrhea episodes by serial therapy with vancomycin and rifaximin. Clin Infect Dis 2007; 44(6):846- 848. 8. McFarland LV, Elmer GW, Surawicz CM. Breaking the cycle: treatment strategies for 163 cases of recurrent Clostridium difficile disease. Am J Gastroenterol 2002; 97(7):1769-1775. 9. McFarland LV. Meta-analysis of probiotics for the prevention of antibiotic associated diarrhea and the treatment of Clostridium difficile disease. Am J Gastroenterol 2006; 101(4):812-822. 10. 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(5):580-585.
Probiotics and C. Difficile
Posted on February 3, 2009
Harvey F Carroll, PhD
retired from City University of NY
Conflict of Interest: None Declared
I would consider probiotics such as Saccharomyces boulardii along with antibiotic therapy. Long term use of the probiotics might prevent the recurrence of the C. difficile after the antibiotics have eradicated it.
References: Surawicz CM, McFarland LV, Greenberg RN, et al. The search for a better treatment for recurrent Clostridium difficile disease: use of high-dose vancomycin combined with Saccharomyces boulardii. Clin Infect Dis 2000;31:1012-1017.
Pochapin M. The effect of probiotics on Clostridium difficile diarrhea. Am J Gastroenterol 2000;95:S11-S13.
Marteau PR, de Vrese M, Cellier CJ, Schrezenmeir J. Protection from gastrointestinal diseases with the use of probiotics. Am J Clin Nutr 2001;73:430S-436S.
Jeanne A. Drisko, Cheryl K. Giles, Bette J. Bischoff. Probiotics in Health Maintenance and Disease Prevention. Altern Med Rev 2003;8(2):143-155)
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