Learning Goals. Clostridium difficile. Historical Context. Historical Context 6/27/2012

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1 Learning Goals Clostridium difficile Justin L. Sewell, MD, MPH Assistant Clinical Professor of Medicine University of California San Francisco San Francisco General Hospital Understand the epidemiology, pathophysiology, and clinical presentation of Clostridium difficile infection (CDI) Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission I have no conflicts of interest to report Historical Context Pseudomembranous colitis first described in 1893 Rare in pre-antibiotic era (4 cases per year at Mayo) Usually associated with colonic, gastric, or pelvic surgery Clostridium difficile first isolated from the stool of healthy neonates in 1935 Historical Context In antibiotic era, pseudomembranous colitis became increasingly common Initially thought to be due to S. aureus because successfully treated with vancomycin 1974: study of patients receiving clindamycin found 10% incidence of pseudomembranous colitis, S. aureus not isolated from stool Five years later C. difficile was isolated from 8 of 8 stool specimens recovered during that study Subsequently, C. difficile recognized to be an important opportunistic pathogen Kelly CP. New Engl J Med Hurley BW. Arch Intern Med Kelly CP. New Engl J Med Hurley BW. Arch Intern Med

2 Bacteriology Gram-positive, anaerobic, spore-forming, toxinproducing bacillus transmitted by fecal-oral route Has both vegetative (intracolonic) or spore (extracolonic) forms Spores can remain viable for at least 5 months on hospital floor Hospital room contamination ranges from 3 to 75% after housing a patient with CDI Spores not killed by alcohol-based hand sanitizers and are resistant to heat, acid, and antibiotics Inoculum can be as low as 10 spores Case #1 71 year-old male nursing home resident with nosocomial pneumonia In ICU for 8 days on ventilator New onset of nonbloody diarrhea, abdominal cramping, leukocytosis Status post 10-day course of vancomycin and cefepime Also on a PPI Hurley BW. Arch Intern Med Weber DJ. Am J Infect Control Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Antibiotic-Associated Diarrhea Antibiotic-associated diarrhea occurs in up to 39% of hospitalized patients receiving antibiotics Broad-spectrum antibiotics are most often implicated Costs are more than $1 billion annually in the US 20% of antibiotic-associated diarrhea cases are due to C difficile Surawicz CM. Best Pract Res Clin Gastroenterol Hurley BW. Arch Intern Med

3 C difficile Prevalence Varies by population Healthy asymptomatic adults: 0-3% Normal colonic microflora confers colonization resistance Healthy neonates and infants: 25-80% Lack of established bowel microflora CDAD rare, possibly due to lack of toxin receptor expression in immature gut Hospital inpatients: 20-34% Most are asymptomatic carriers Patients with pseudomembranous colitis: % Changing Epidemiology Rising incidence of infection noted in early 2000s among multiple individual centers Canada: study of Quebec from 1991 to 2003 calculated population-based incidence rates Hurley BW. Arch Intern Med Kelly CP. JAMA Schroeder MS. Am Fam Phys Pepin J. CMAJ Annual incidence per 100, Changing Epidemiology Age <17 Age Age>64 Total Changing Epidemiology Rising incidence of infection noted in early 2000s among multiple individual centers Canada: study of Quebec from 1991 to 2003 calculated population-based incidence rates CDI-related mortality increased three-fold Complicated CDI increased two-fold Pepin J. CMAJ Pepin J. CMAJ

4 Changing Epidemiology United States: National Hospital Discharge Survey data Changing Epidemiology National death certificate analysis McDonald LC. Emerg Infect Dis Figures used with permission per journal policy. Redelings MD. Emerg Infect Dis Figure used with permission per journal policy. BI/NAP1/027 Hypervirulent Strain 1,703 patients from 12 Canadian centers Stool samples yielded 157 C. difficile isolates 132 had tcdc gene deletion and binary toxin genes CDAD severe in 17% compared with 0% lacking these features Near universal resistance to fluoroquinolones Suspicion that single strain responsible for rising incidence and severity of infection Loo VG. New Engl J Med Used with permission, NEJM. 4

5 BI/NAP1/027 Hypervirulent Strain 187 C. difficile isolates collected from eight healthcare facilities in six US states in which outbreaks had occurred from Characterized using restriction-endonuclease analysis (BI), pulsed-field gel electrophoresis (NAP1), and PCR ribotyping (027) Results compared with database of isolates obtained before 2001 BI/NAP1/027 Hypervirulent Strain Hypervirulent strain accounted for 50% of C. difficile isolates from versus 17% of historical control strains 86% of the BI/NAP1 strains were >90% related to one another; remaining 14% were >80% related All binary toxin positive with tcdc deletion Greater antibiotic (mostly fluoroquinolone) resistance Few non-bi/nap1 isolates were more than 80% related None were binary toxin positive and none had tcdc deletion McDonald LC. New Engl J Med McDonald LC. New Engl J Med Community-Acquired CDI Community-Acquired CDI Studies from US and UK suggest that approximately 10 to 50 per 100,000 cases appear to be community acquired Age seems to be important risk factor Incidence per 100, years years >64 years Acid suppression and antibiotic use are also risk factors Possible role for antibiotic therapy in food animals 42% of beef, pork, and turkey samples were C difficile positive in a study in Arizona (both raw and ready-to-eat) Many BI/NAP1/027 positive Dial S. JAMA Kuntz JL. BMC Infect Dis Kutty PK. Emerging Infect Dis Gould LH. Clin Infect Dis

6 Case #1, continued Multiple aspects of the patient s presentation put him at increased risk for CDI 71 y/o man in the hospital Nursing home resident Prolonged hospital stay Status post broad spectrum antibiotics New diarrhea and abdominal discomfort Taking PPI Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Requirements for CD-related disease Positive regulator for toxin release Antagonist of toxin release Toxin release Binary toxin produced by BI/NAP1/027 ( toxin virulence) Exposure to C difficile Altered colonic microflora & impaired colonization resistance Loo VG. New Engl J Med Used with permission, NEJM. Toxin B Toxin A O Connor JR. Gastroenterology Loo VG. New Engl J Med

7 tcdc deletion results in 16 to 23-fold increase in toxin elaboration C difficile life cycle Toxin A titer (µg/ml) strain Control strain Exposure C difficile ingested Most cells killed in stomach, but some survive Spores germinate on exposure to bile acids, migrate to colon hours 24 hours 48 hours 72 hours Kelly CP. New Engl J Med Exposure C difficile ingested Most cells killed in stomach, but some survive Spores germinate on exposure to bile acids, migrate to colon Exposure C difficile ingested Most cells killed in stomach, but some survive Spores germinate on exposure to bile acids, migrate to colon Residence Reside in colon without symptoms until microflora disturbed Reduced colonization resistance leads to multiplication Residence Damage Reside in colon without symptoms until microflora disturbed Reduced colonization resistance leads to multiplication Toxins cause disordered cell signaling, actin filament disassembly, disruption of cellular junctions, cell death Activate inflammatory pathways (NF-κB, MAP kinases, IL-1, IL-8, TNF-α) 7

8 Exposure Residence Damage C difficile ingested Most cells killed in stomach, but some survive Spores germinate on exposure to bile acids, migrate to colon Reside in colon without symptoms until microflora disturbed Reduced colonization resistance leads to multiplication Toxins A&B endocytosed into epithelial cells, causing disordered cell signaling, actin filament disassembly, disruption of cellular junctions, cell death Active inflammatory pathways (NF-κB, MAP kinases, IL-1, IL-8, TNF-α) Immune Response IgM, IgG and IgA produced against toxin A and toxin B High antitoxin IgG is protective against: Initial episode of CDAD Seen in asymptomatic carriers of toxigenic C difficile Recurrent CDAD Symptoms Breakdown in colonic epithelium causes diarrhea and malabsorption Kyne L. Lancet Serum IgG antitoxin A (ELISA units) Immune Response Days after onset of C difficile diarrhea No recurrence Recurrence Kyne L. Lancet Case #1, continued Patient mildly febrile and tachycardic No BM s recorded in past 24 hours Abdomen markedly distended with diffuse moderate tenderness, mild rebound and voluntary guarding 1+ edema bilaterally CBC 16>32<454, creatinine 1.8, albumin 2.2 8

9 Learning Goals Clinical Presentation Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Asymptomatic carriage 0-3% healthy adults 20-34% hospitalized adults 10-16% of inpatients on antibiotics Can be transient Antibiotic treatment can extend carriage Mild moderate disease Loose, watery BM s Fever, leukocytosis Abdominal pain, cramps Absence of direct colonic damage or complications in other organ systems Severe disease Ileus Toxic megacolon Evidence of damage to other organ systems May lack diarrhea and present only with leukocytosis, fever, abdominal pain Kelly CP. JAMA No scoring system has been validated Question #1 Potential Complications Which of the following is not a potential complication of C difficile? A. Ileus B. Toxic megacolon C. Colonic perforation D. Reactive arthritis E. All of the above are potential complications 0% 0% 2% 29% 69% Ileus Toxic megacolon Colonic perforation Dehydration Electrolyte disturbances Hypovolemia Hypoalbuminemia Anasarca Reactive arthritis Post-infectious IBS A. B. C. D. E. Fekety R. Am J Gastroenterol

10 Case #1, continued Next steps Make sure adequately resuscitated Test for C difficile Empiric antibiotic therapy Surgical consultation! Surgery confers 24% survival benefit for moderately ill patients with severe/fulminant colitis Lower time to surgical consultation and time to OR associated with increased survival Usual approach is subtotal colectomy with end ileostomy Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Noblett SE. BMJ Case #2 A 45 year-old woman is seen by her PCP with two weeks of worsening watery diarrhea She completed a 2-week course of levofloxacin for community-acquired pneumonia 4 weeks ago She was seen at urgent care where all initial stool studies were negative, including o&p, bacterial culture, and C difficile testing Could this be a false negative result? Laboratory Diagnosis Assay Sensitivity Specificity Caveats C difficile culture % Reduced Not specific for toxinproducing strains; time consuming Tissue culture cytotoxin assay Gold standard Gold standard Takes hours, requires tissue culture ELISA 63-99% % Produce rapid results; some only detect toxin A PCR % % Studies excluded solid stool Curry S. Clin Lab Med

11 Endoscopic Diagnosis Not required but can be used to make diagnosis rapidly Finding of pseudomembranes essentially pathognomonic Findings may be atypical in IBD patients Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Case #2, continued A second stool which is found to be positive for toxin B by ELISA The patient continues to have 5-7 watery, nonbloody BM s per day and mild abdominal discomfort; her vitals and physical examination are normal, and WBC is 11 Metronidazole or vancomycin? Question #2 In which of the following clinical scenarios has vancomycin been shown in studies to be superior to metronidazole in treating Clostridium difficile diarrhea? A. In patients with >4 bowel movements per day B. In hospitalized patients C. In patients with severe Clostridium difficile diarrhea D. In patients with inflammatory bowel disease E. In patients who are status post bowel surgery 6% 12% 62% 15% 6% A. B. C. D. E. 11

12 Metronidazole & vancomycin Metronidazole & vancomycin Early studies suggested similar efficacy for oral metronidazole and oral vancomycin Post-2001 there was increased evidence of metronidazole failure among patients with severe disease, likely due to BI/NAP1/027 Treatment failure 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Pre-2000 Post-2000 Metro Vanco Recurrence 35% 30% 25% 20% 15% 10% 5% 0% Pre-2000 Post-2000 Metro Vanco Curry S. Clin Lab Med Leffler DA. Gastroenterology Leffler DA. Gastroenterology Metronidazole & vancomycin Treatment Comparative Effectiveness Metronidazole Pros Lower cost (~$200) Historically similar efficacy Cons Low stool concentrations (6-15% excretion in stool day 1 with rapid decrease subsequently) Lower activity against BI/NAP1/027 Not well-tolerated Vancomycin Pros Well-tolerated High stool concentrations throughout therapy (not wellabsorbed) Likely superior for BI/NAP1/027 Superior for severe disease FDA approved Cons Higher cost (~$1,500) VRE risk Systematic review of RCT of antibiotic therapy for C difficile among adults ( ) English-language trials with medications available in the US 11 trials with 1,463 subjects 3 trials: metronidazole versus vancomycin 8 trials: metronidazole OR vancomycin versus other agents or placebo Strength of evidence from studies low No studies showed superiority of any agent for initial cure Drekonja DM. Ann Int Med

13 Metronidazole versus vancomycin Metronidazole versus vancomycin Double blind RCT of 172 hospitalized patients with CDAD ( ) Severity score gave one point for: age>60, T>38.3, albumin<2.5, WBC>15K <2 points = mild disease >2 points = severe disease Cure = resolution of diarrhea by day 6 plus negative ELISA at day 6 and 10 Cure rate 120% 100% 80% 60% 40% 20% 0% P=NS Mild disease P=0.02 Severe disease Metro Vanco Relapse rate 25% 20% 15% 10% 5% 0% P=NS Mild disease P=NS Severe disease Metro Vanco Zar FA. Clin Infect Dis Zar FA. Clin Infect Dis Metronidazole versus vancomycin Concluded that vancomycin is superior to metronidazole for severe CDAD Limitations Severity score not validated Cure required both symptomatic resolution and negative ELISA Largely pre-2001 But it s the best data available! Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Zar FA. Clin Infect Dis

14 Question #3 Your patient has recalcitrant C difficile with active infection despite several different antibiotic courses. Which of the following therapies has been shown to be of benefit in this scenario? A. Combination oral antibiotic therapy B. Combination oral and IV antibiotic therapy C. Probiotics D. IVIG E. Fecal bacteriotherapy ( stool transplant ) 3% 3% 9% 3% 82% A. B. C. D. E. Agent Evidence Recommended? Tigecycline 1 Nitazoxanide 2 Toxin binders 3 Rifaximin 4 IVIG 5 6 case reports 5/6 successful 1/6 died Small RCT s compared with metronidazole and vancomycin nitazoxanide not superior CDAD is toxin mediated Multiple agents with no benefit One small trial and several case series show little benefit May augment immune response, can neutralize toxin A 46 cases reported, 87% cure Trials needed No No Trials needed Trials needed 1 Larson KC. Ann Pharmacother Musher DM. Clin Infect Dis Weiss K. Int J Antimicrob Agents Nelson RL. Cochrane Review Abougergi MS. Dig Dis Sci Fidaxomicin Randomized, double blind, noninferiority RCT of vanco 125 mg po QID versus fidaxomicin 200 mg po BID with intervening placebo x 10 days N=309 (vanco), 289 (fidaxomicin) Inpatients and outpatients May 2006 August 2008 Clinical cure = resolution of symptoms with no further need for treatment second day after antibiotic course Louie TJ. New Engl J Med Used with permission, NEJM. Louie TJ. New Engl J Med

15 Multiple issues with study: 1) Authorship 2) Noninferiority trial 3) ~1/3 received pre-enrollment C difficile treatment 4) Similar risk of relapse with BI/NAP1/027 strain Louie TJ. New Engl J Med Used with permission, NEJM. Probiotics Evidence favors benefit of probiotics in treating CDAD but significant heterogeneity exists in published studies May help prevent antibiotic associated diarrhea May prevent recurrence Better trials may identify role for probiotics Unlikely to be harmful Pillai A. Cochrane Review McFarland LV. Am J Gastroenterol Tung JM. Can J Gastroenterol Fecal Bacteriotherapy Process of instilling a liquid suspension of stool from a healthy donor into the GI tract Goal of restoring normal, healthy flora Can be instilled into either UGI or LGI tract Until recently, literature limited to case reports and small case series Bakken JS. Anaerobe

16 Fecal Bacteriotherapy 2 Recent Studies Treatment Guidelines Infectious Diseases Society of America Study #1 Study #2 Number of subjects Follow-up time 3 months 3 months Courses of antibiotics Days till resolution of symptoms 6 Not reported Treatment success 91% 94% Relapses Not reported 4 Reference Mellow M. ACG 2011; Abstract 10. Mattila E. Gastroenterology Cohen SH. Infect Control Hosp Epidemiol Used with permission from U Chicago Press. Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Acid Suppression and C difficile UK General Practice Research Database Case-control study ,672 cases with 1 st occurrence of CDAD matched with 10 controls Subset of 1,233 community-acquired cases (subset not hospitalized within 1 year) matched with 10 controls PPI and antibiotic use assessed for 2 years prior to index date Dial S. JAMA

17 Acid Suppression and C difficile Rate of C difficile increased more than 20-fold PPI use increased (2-fold), antibiotic use decreased (25%) 3-fold increased risk with PPI use, 2-fold increased risk with H2RA High proportion (>75%) of community cases 1/3 of cases lacked confirmatory laboratory testing Case #3 29 y/o woman with ulcerative colitis, controlled on 6MP and mesalamine Now 4-5 BM/day, nonbloody New, mild, crampy abdominal discomfort with a few weeks of bloating Physical examination reassuring Labs show mild leukocytosis and increased ESR/CRP Dial S. JAMA C difficile & IBD Epidemiology C difficile & IBD Epidemiology Incidence among hospitalized IBD patients has increased 2-3x over the past decade Prevalence among inpatients higher than for non-ibd patients (Nationwide Inpatient Sample ) C. difficile cases per 1,000 admissions All patients GI patients Crohn's Disease Ulcerative colitis Nguyen GC. Inflamm Bowel Dis Nguyen GC. Inflamm Bowel Dis

18 C difficile & IBD Epidemiology C difficile & IBD Ambulatory subjects not well-studied but suggest as many as 20% of suspected IBD flares may be associated with CDI Percent of suspected ambulatory IBD flares associated with C difficile Higher rate of asymptomatic carriage Often seen in absence of antibiotic exposure Further increased risk with colonic disease and immunosuppressant use Can have atypical appearance on endoscopy 5 0 Rolny 1983 Gryboski 1991 Meyer 2004 Ananthakrishnan AN. Gastroenterol Clin N Am Issa M. Clin Gastroenterol Hepatol Nguyen GC. Am J Gastroenterol Case #3, continued Suspicious for CDI, you send a stool sample for C difficile PCR and start the patient empirically on metronidazole However, she comes back 3 days later with BM s per day, now with blood, worse abdominal pain, and fever to 39.1 C difficile & IBD Prognosis Longer and more costly hospitalizations 5-fold increased in-hospital mortality risk 6-fold increased inpatient risk for bowel surgery versus CDI without IBD 2-fold increased risk for colectomy at 1 year for UC Ananthakrishnan AN. Gastroenterol Clin N Am Ananthakrishnan AN. Gut Nguyen GC. Am J Gastroenterol

19 C difficile & IBD Have a high index of suspicion Patients with IPAA can get CD-pouchitis Patients with end ileostomy can get CD-enteritis Consider vancomycin over metronidazole (expert consensus) Consider waiting to start new immunosuppressive agents for apparent disease flares 10x increased risk of adverse outcomes with new IM 17x increased risk of adverse outcomes with 2-3 IM s Consider holding current immunosuppressives until anti-cdi therapy started Call surgical consultation early Case #4 65 y/o woman received ciprofloxacin for an uncomplicated UTI 10 days later she develops diarrhea and is diagnosed with CDI Symptoms resolve with a 10-day course of metronidazole, but diarrhea recurs 2 weeks later, ELISA is positive for C difficile Ben-Horin S. Clin Gastroenterol Hepatol Question #4 Which antibiotic therapy is recommended by the Infectious Disease Society of America for patients with a first relapse of Clostridium difficile diarrhea? A. Metronidazole B. Vancomycin C. Fidaxomicin D. The same antibiotic that was used the first time E. Combination metronidazole and vancomycin 34% 54% 0% 6% 6% Recurrent CDI Recurrent CDI is common (20-30% post- 2000) For non-severe CDI, choice of metronidazole or vancomycin does not affect: Likelihood of complicated first recurrence Likelihood of second recurrence Age >65 is greatest risk: Increased risk of complicated first recurrence (4% increased risk per year of advancing age) 75% increased risk of second recurrence A. B. C. D. E. Pepin J. Clin Infect Dis

20 Second Recurrence and Beyond Vancomycin taper followed by pulsed regimen should be used Keeps vegetative form of C difficile under control while allowing healthy flora to be restored Data are from two large RCT s of probiotics among patients with recurrent CDAD (only placebo subjects) Compared dosing of metronidazole and vancomycin Antibiotic therapy at discretion of clinician N=163 80% 70% 60% 50% 40% 30% 20% 10% 0% Percent with recurrence of C difficile Cohen SH. Infect Control Hosp Epidemiol Cocanour CS. Surg Infect McFarland LV. Am J Gastroenterol McFarland LV. Am J Gastroenterol Taper & pulse example: 125 mg QID x days 125 mg BID x 7 days 125 mg daily x 7 days 125 mg q2-3 days x 2-8 weeks Cohen SH. Infect Control Hosp Epidemiol Used with permission from U Chicago Press. Taper & pulse example: 125 mg QID x days 125 mg BID x 7 days 125 mg daily x 7 days 125 mg q2-3 days x 2-8 weeks 20

21 Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission Question #5 Which of the following methods of reducing nosocomial Clostridium difficile transmission has the strongest supporting evidence? A. Wearing isolation gowns in rooms of infected patients B. Hand washing C. Glove use D. Private rooms and/or cohorting of infected patients E. B and C 5% 10% 3% 8% 74% A. B. C. D. E. Reducing Transmission Toilet Flushing and CDI Toilets in a UK hospital inoculated with fecal suspension containing C difficile grown in the laboratory Toilets flushed air and surfaces sampled for C difficile Lidless versus lidded toilets compared Cohen SH. Infect Control Hosp Epidemiol Used with permission from U Chicago Press. Best EL. J Hosp Infect

22 Toilet Flushing and CDI Lidless toilets aerosolized 12-fold higher CFU s of C difficile compared with lidded, as high as 25 cm above the toilet No C difficile isolated from bathroom surfaces lidded toilet flushes compared with 100% of lidless toilet flushes Switching to lidded toilets could reduce nosocomial transmission of C difficile Summary CDI is increasingly common and severe CDI is associated with significant morbidity and mortality, especially among the elderly Have a high index of suspicion for CDI, especially among hospitalized patients and patients with IBD Choice of antibiotic therapy should be based on guidelines but requires clinical reasoning Simple maneuvers have the potential to reduce nosocomial transmission of C difficile Best EL. J Hosp Infect Learning Goals Understand the epidemiology, pathophysiology, and clinical presentation of CDI Understand the strengths and limitations of testing for CDI Know the roles of metronidazole and vancomycin in treating CDI Review evidence for other agents in treating CDI Know how to manage special clinical scenarios related to CDI Know how to reduce risk for Clostridium difficile transmission justin.sewell@ucsf.edu 22