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The Changing Face of Clostridium difficile Diarrhea (CDAD) Herbert L. DuPont, M.D. Director, Center for Infectious Diseases, University of Texas – Houston.

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Presentation on theme: "The Changing Face of Clostridium difficile Diarrhea (CDAD) Herbert L. DuPont, M.D. Director, Center for Infectious Diseases, University of Texas – Houston."— Presentation transcript:

1 The Changing Face of Clostridium difficile Diarrhea (CDAD) Herbert L. DuPont, M.D. Director, Center for Infectious Diseases, University of Texas – Houston School of Public Health Chief of Internal Medicine, St. Luke’s Episcopal Hospital Vice-Chairman Department of Medicine, Baylor College of Medicine

2 Topics Covered C. difficile (CD) the organism Importance in the hospital Changing epidemiology Diagnosis Risk factors Treatment: first bouts and recurrent disease Hospital infection control Future research questions

3 Microbiology Ubiquitous anaerobic, Gram-positive, spore-forming rod When the normal gastrointestinal (GI) flora is disrupted, exposure to C. difficile may result in C. difficile–associated diarrhea (CDAD) 3%–5% of healthy adults and 16%–35% of inpatients might be colonized Aslam S et al. Lancet Infect Dis. 2005;5: Bouza E et al. Med Clin North Am. 2006;90:

4 Scope of the Problem Leading identified cause of infectious nosocomial diarrhea, million cases/yr Occurrence of diarrhea in hospitalized patients who receive antibiotics: 3%– 29% 1 Mortality due to CDAD ranges from 6%– 30% when pseudomembranous colitis is shown to be present 1 Hospital costs attributable to C. difficile are an estimated $1,200 per day 2 The average length of stay is prolonged by 8.7 days Recurrences typically occur 3-21 d after recovery from first bout (mean 6 d) with rate of subsequent recurrence rate of > 50% often over years Annual cost $1.1 billion/yr 1. Aslam S et al. Lancet Infect Dis. 2005;5: Weinberg E et al. Am J Gastroenterol. 2006;101:S196.

5 Changing Epidemiology New epidemic strain of C. difficile 1 –Increased virulence –Antimicrobial resistance Possible causes 1,2 –Changes in Antimicrobial use Other drug prescribing practices Infection control practices –Aging of the hospital inpatient population More CDAD in non-hospital populations; other drugs implicated including proton pump inhibitors 1.McDonald LC. Infect Control Hosp Epidemiol. 2005;26: US Department of Health and Human Services. healthworkforce/reports/changedemo/aging.htm. Accessed December 21, 2007.

6 McDonald LC, et al. Emerg Infect Dis. 2006;12: , and unpublished CDC data. Rates of CDI Tripled in US Hospitals between 2000 and Year Discharges per 100,000 Population x x x xx x x x x x Any diagnosis Primary diagnosis x

7 Pittsburgh, –Life-threatening disease increased from 1.6% to 3.2% –44 colectomies and 20 deaths Sherbrooke, Quebec, –16.7% attributable mortality –Average of 10.7 extra hospital days St. Louis, –12.3% attributable mortality –2.7 times more likely to be discharged to LTCF Increasing Severity 1. Dallal RM, et al. Ann Surg. 2002;235: Pépin J, et al. Can Med Assoc J. 2005;173: Dubberke ER, et al. SHEA

8 Epidemic Strain Produces greater quantities of toxins A and B in vitro 1,2 Has a tcdC gene deletion 2 Binary toxin genes are present 2 Classified using various methods 2,3 –Toxinotype III [restriction fragment-length polymorphism polymerase chain reaction (RFLP-PCR)] –BI (restriction-endonuclease analysis [REA]) –NAP1 (pulsed-field gel electrophoresis [PFGE]) –Ribotype 027 (PCR) –Pulsovar A (PFGE; Quebec) Is highly resistant to fluoroquinolones 4,5 1.CDC Fact Sheet. July Warny M, et al. Lancet. 2005;366: Hubert B, et al. Clin Infect Dis. 2007;44: McDonald LC, et al. 42nd Annual Meeting of IDSA; Abstract LB-2. 5.McDonald LC, et al. N Engl J Med. 2005;353:

9 Possible Virulence Factors: Epidemic Strain Hypothesis Major genes in pathogenicity locus (PaLoc) of C. difficile and relation to binary toxin genes Adapted from McDonald LC, et al. N Engl J Med. 2005;353: ; with permission.

10 The Diagnosis How do you make the diagnosis of C. difficile associated diarrhea (CDAD)?

11 Diagnostic Tools Advantages and Disadvantages TestAdvantage(s)Disadvantage(s) Toxin testing Enzyme immunoassay Same-day test; detects toxin A, or A and B Less sensitive than tissue culture cytotoxicity assay Tissue culture cytotoxicity More sensitive than enzyme immunoassay Detects toxin B primarily; labor intensive; requires 24–48 hours for a final result Detection of glutamate dehydrogenase Rapid tests (<1 hour), very sensitive Not specific, toxin testing required to verify diagnosis; may prove useful as screening tool Stool cultureMost sensitive test available when performed appropriately May be associated with false- positive results if isolate is not tested for toxin*; labor-intensive; requires 48–96 hours for results * Due to presence of nontoxigenic strains. CDC Fact Sheet, August 2004 (updated 7/22/05).

12 Host Factors Am I at risk for the disease? Is it just antibiotic therapy and hospitalization? What will you do when you Experience Diarrhea?

13 Diarrhea is hereditary “It runs in your Genes (Jeans!)” IL-8 gene polymorphism increases host susceptibility and is associated a defective immune (IgG) response to toxin A Jiang Z-D, DuPont HL, et al. Amer J Gastroenterol 2006;101:1-5 Jiang Z-D, DuPont HL, et al. Clin Gastroenterol Hepatol 2007;5:964-8 C. difficile Diarrhea and Colitis is not A Random Occurrence

14 Relative Risk for Developing C. difficile Diarrhea/Colitis in Controlled Studies Odds Ratio Modena S, et al. Infect Control Hosp Epi 2005;26: Dial S, JAMA 2005;294: Kyne L, et al. Infect Control Hosp Epi 2002;23:653-9 Jiang Z-D, et al. Amer J Gastroenterol 2006; in press

15 Risk of C. difficile Diarrhea According to Antibiotic Class Loo VG, et al. N Engl J Med. 2005;353: Odds Ratio CephalosporinsFluoroquinolonesClindamycinMacrolides

16 Immune Response in C. difficile Infection and Diarrhea Antitoxin A IgG levels in serum rise higher in those without symptoms than in those with illness (probable protective amnestic response in those previously exposed) Serum IgG and IgM antibody responses predict those who will not relapse Work is needed to characterize sIgA responses and associations with recovery and relapse Kyne L, et al. N Engl J Med 2000;342:390-7 Kyne L, et al. Lancet 2001;357:189-93

17 Treatment Drugs for C. difficile-associated disease: Are they OK for Mom? Gerding, DN. Clin Infect Dis 2005;40:

18 Objective of CDAD Therapy Inhibition of growth of Clostridium difficile (vegetative forms) Preservation or re-establishment of gut flora

19 Initial Treatment Options Metronidazole 1-3 Oral preferred 500 mg 3 times a day for 10–14 days Historical first-line agent Do not use for more than 14 days or beyond first recurrence because of toxicity 4 Vancomycin 1-3 Effective orally or rectally, not intravenously 125 mg orally 4 times a day for 10–14 days Recently shown to be superior to metronidazole for severe disease 5 1.Fekety R. Am J Gastroenterol. 1997;92: Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: ASHP. Am J Health-Syst Pharm. 1998;55: Cohen SH, et al. 45th Annual Meeting of the Infectious Diseases Society of America (IDSA); October 4-7, 2007, San Diego, CA. 1.Zar FA, et al. Clin Infect Dis. 2007;45: Metronidazole (Flagyl) Vancomycin (Oral)

20 Oral Vancomycin vs Metronidazole in Mild and Severe Disease 172 patients enrolled and 150 completed the trial Clinical Cure in Mild Disease (n=81) Clinical Cure in Severe Disease (n=69) Zar FA, et al. Clin Infect Dis. 2007;45: MetronidazoleVancomycin P = NS Percent of Patients 100 MetronidazoleVancomycin P = Percent of Patients 100

21 Treatment Strategies for Recurrent CDAD Repeat treatment with metronidazole or vancomycin is recommended for first recurrence Oral vancomycin in tapering or pulse dosing if multiple recurrences –125 mg every other day for 4–6 weeks –Tapered dose over a mean of 21 days –125–500 mg every 3 days over a mean of 27 days Fecal transplant (30–50 g fresh stool from healthy donor in normal saline delivered by enema or nasogastric tube) Intravenous immunoglobulin (IVIG) (400 mg/kg ± repeat in 3 weeks)—supporting data are anecdotal but positive Bartlett JG. Ann Intern Med. 2006;145: McFarland LV et al. Am J Gastroenterol. 2002;97: Tedesco FJ et al. Am J Gastroenterol. 1985;80: Metronidazole (Flagyl) Vancomycin (Oral)

22 Other Approaches to Treat Relapses of C. difficile Diarrhea Rifaximin 400 mg tid for 14 d followed by 200 mg tid for 14 d 1 Vancomycin 500 mg mg qid for 10 d plus S. boulardii (500 mg bid x 14 d after stopping antibiotics) Rifaximin (Xifaxan) Saccharomyces 1 DuPont HL, et al. DDW, Washington, DC May 2007

23 Rifaximin Treatment of Recurrent CDAD Garey KW, et al. J Clin Gastroenterol (in press) M = metronidazole; V = vancomycin; N = nitazoxanide, R = rifaximin Rifaximin 400 mg tid X 14 d Then 200 mg tid 1 DuPont HL, et al. DDW, Washington, DC May 2007

24 Infection Control Measures Glove use Hand hygiene Private room/barrier precautions/Isolation (until ≥2 days after diarrhea ceases Handwashing Single use rectal thermometer, dedicated equipment when possible Environmental disinfection with 1:10 hypochlorite Antimicrobial stewardship/restriction

25 Use of Alcohol-Based Hand Rubs (ABHRs) and Incidence No outbreaks occurred from 2001–2003 Despite a significant, progressive increase in use of alcohol- based hand rubs (ABHRs), no evidence of increased incidence was found Boyce JM, et al. Infect Control Hosp Epidemiol. 2006;27: Soap and waterABHRs Hand-hygiene method 2001 End of Use as percentage (%) 100

26 C. difficile Diarrhea and Colitis Directions of Future Research What is the optimal treatment of CDAD leading to clinical cure without recurrence? How can we prevent infection and disease in high-risk patients? Potential prevention strategies: - improved infection control methods; - changing pattern of antibiotic and other drug utilization in the hospital; - identification of hosts at risk with development of targeted prevention strategy (drugs, biologic agents and vaccines) How should recurrences best be managed?

27 The Hopeless Conflicts of Herbert L. DuPont, MD U.S. Companies: Norwich Pharmacal Company and Norwich- Eaton Pharmaceuticals; Burroughs Wellcome Company; Merrell Dow Pharmaceuticals, Inc; Merck Sharp and Dohme; A.H. Robins Company; Upjohn Company; Hoffmann-LaRoche, Inc; Janssen Pharmaceutica; Procter & Gamble Company; Ortho Pharmaceuticals; Otsuka Pharmaceuticals; Bristol-Myers Squibb; Shaman Pharmaceuticals, Inc; International Companies: Ciba-Geigy Ltd, Basel, Switzerland; Zyma SA, Nyon, Switzerland; SmithKline Beecham Biologicals, Rixensart, Belgium; and Alfa Wassermann SpA, Bologna, Italy *Salix Pharmaceuticals; Romark Institute for Medical Research; Optimer Pharmaceuticals; IOMAI Corporation; McNeil Consumer Products; University of Massachusetts Biologics; Merck Vaccine Division * Important recent conflicts

28 Risk of CDAD With Specific Antimicrobials Characteristic Adjusted Hazard Ratio (95% CI) Fluoroquinolones Any Levofloxacin Ciprofloxacin Gatifloxacin Moxifloxacin 3.44 (2.65–4.47)* 2.52 (1.68–3.79) 3.74 (2.81–4.97) 6.10 (2.22–16.74) 2.04 (0.50–8.31) Cephalosporins First generation Second generation Third generation 1.78 (1.25–2.46) † 1.89 (1.45–2.46)* 1.65 (1.15–2.12) † Macrolides1.65 (1.15–2.39) † Clindamycin1.77 (1.06–2.96) † Intravenous  -lactam/  -lactamase inhibitor 1.88 (1.35–2.63) † *P< † P<0.05. CI = confidence interval. Pepin J et al. Clin Infect Dis. 2005;41:

29 Hospital-Associated C. difficile Diarrhea and Colitis Major Risk Factors 1.Antibiotics 2.Advanced age and comorbidity 3.Hospitalization Other Risk Factors 1.Surgery 2.Immunosuppression 3.Nasogastric tube feedings 4.Genetics 5.Defective immune response to toxin A 6.PPIs Bartlett JG. Ann Intern Med. 2006;145: Surowiec D et al. Ann Pharmacother. 2006;40:

30 Severe C. difficile Colitis Epidemic in U.S., Canada & Europe Showing  frequency Epidemics occurring due to a clone of toxinotype III C. difficile that produces binary toxin with tcdC deletion (hypervirulent strain producing times more toxin A and B with increased rate of sporulation*), resistant to fluoroquinolones Relapses occurring in approximately half Metronidazole showing  effectiveness Pepin J et al. Clin Infect Dis 2005;41:1254 McEllistrem MC, et al. Clin Infect Dis 2005;40:265 McDonald LC, et al. N Engl J Med 2005;353:2433 Warny M et al. Lancet 2005;366:1079 *referred to as BI/NAP1/027

31 The C. difficile MegaBug We are seeing more CDAD illness and more severe cases resulting in fever, leukemoid reactions, colectomy or death Why?

32 New Epidemic Recent reports of more frequent, more severe, and more refractory C. difficile disease that results in –Toxic megacolon –Leukemoid reactions –Severe hypoalbuminemia –Requirement for colectomy –Shock –Death Complications are most common in elderly patients Currently, the most common inducing agents are fluoroquinolones and cephalosporins Bartlett JG. Ann Intern Med. 2006;145:

33 Metronidazole - Often Standard Treatment for C. difficile Diarrhea During acute colitis adequate fecal levels result (  transit with diarrhea, serum movement across inflamed mucosa), but fall during recovery allowing germination of spores Bolton RP and Culshaw MA, Gut 1986:27:1169 Ings RM et al. Xenobiotica 1975;5:223 Drug resistance has been reported although it does not explain recurrences Johnson S, et al. Clin Infect Dis 2000;31;625 Continuing antibiotics  risk of failure Relapses following treatment commonly occurs (20%-40%) Inexpensive, high relapse rate, drug-drug interactions

34 Oral Vancomycin Treatment of C. difficile Diarrhea and Colitis Only FDA approved form of therapy Dose is mg qid for 10 days May be the drug of choice for life-threatening disease due to hypervirulent strains and more severe cases* Relapse rates are high Concern is promotion of vancomycin-resistance (especially for Enterococcus) Vancomycin (Oral) *Zar FA, et al. Clin Infect Dis 2007;45:302-7

35 Response to Metronidazole Treatment of CDAD Aslam S et al. Lancet Infect Dis. 2005;5:

36 Response to Vancomycin Treatment of CDAD Aslam S et al. Lancet Infect Dis. 2005;5:

37 Hospital-Associated C. difficile Diarrhea and Colitis 10%-30% of healthcare associated diarrhea is caused by C. difficile 50%-75 of cases of antibiotic-associated colitis are caused by the organism 90% of pseudomembranous colitis are caused by C. diff with adherent intestinal plaques composed of neutrophils, fibrin, mucin and cell debris in areas of mucosal destruction

38 Clinical Expressions of C. difficile Diarrhea C. difficile diarrhea consists of passage of unformed stools per day (average 6-10/d) Mean duration of of illness is 19 d Recurrent disease occurs in 20-50% of cases after treatment: re-infection with new organism vs. relapse (50%/50%) Recurrences typically occur 3-21 d after recovery from first bout (mean 6 d) with rate of subsequent recurrence rate of > 50% often over years Bartlett JG. N Engl J Med 2002;346: Wilcox MH & Spencer RC. J Hosp Infect 1992;22:85-92 Johnson S, et al. J Infect Dis 1989;159;340-3

39 Rifaximin Susceptibility of C. difficile Isolates at St. Luke’s 163 consecutive isolates collected MICs by agar dilution: MIC 90 = <0.01µg/mL Two strains (1%) were resistant Jiang Z-D, DuPont HL et al. Anaerobe 2008, June 24-27, 2008, Long Beach, CA

40 Rifaximin Treatment of Recurrent CDAD Garey KW, Jiang ZD, Bellard A, and DuPont HL. J Clin Gastroenterol (in press) Cure rate: 5 of 6 patients (one death unrelated to CDAD)

41 C. difficile rifaximin study: recruitment ongoing Primary outcome: Recurrence of disease within 3-months of antibiotic discontinuation Secondary outcome: Impact of IL-8 polymorphism on recurrence rates CDI patient given conventional therapy (metronidazole or PO vanco) Rifaximin 400 mg TID for 20 days Placebo TID for 20 days IL-8 AA promoterOther IL-8 phenotypeIL-8 AA promoterOther IL-8 phenotype Rifaximin or placebo started on the day after conventional therapy stopped


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