Conflicts of Interest Disclosure Daniel Leffler, MD, MS I disclose the following financial relationships with commercial entities that produce health carerelated products or services relevant to the content I am planning, developing, or presenting: Company Relationship Content Area Prometheus Labs Consultant Celiac Testing BETH ISRAEL DEACONESS MEDICAL CENTER HARVARD MEDICAL SCHOOL Clostridium difficile Not Just a Hospital Problem Anymore Daniel Leffler, MD, MS Assistant Professor of Medicine Harvard Medical School Objectives Changing epidemiology of Clostridium difficile Infection (CDI) Diagnosis and management of acute CDI Recurrent CDI New treatment approaches C. difficile Diarrhea: Pathogenesis ANTIBIOTICS Abnormal colonic microflora C. difficile eposure & colonization Effective anti-toin response Toin production Asymptomatic carriage Diarrhea & colitis Inadequate immune response Kelly & LaMont N Engl J Med 2008 The C. difficile Carrier State Nosocomial C. difficile infection & asymptomatic carriage are common Type Prevalence Possible Mechanism Infants 50-60 % Lack of toin receptors Hospitalized/ Long Term Care Healthy adults < 3% 30 % High titer serum antitoin Barrier function of microflora Hospital patients (Acute medical ward) LOS > 2 days Receiving antibiotic 271 enrolled Colonized by C. difficile 84 (31%) Hospital-acquired 47 (17%) Colonized at Admission 37 (14%) CDI case 28 (10%) Carrier 19 (7%) CDI case 19 (7%) Carrier 18 (7%) Kyne et al N Engl J Med 2000;342:390 1
Carriers vs. Colitis Infection should lead to production of antibodies directed at toins High levels of antitoin antibodies are protective against colitis Individuals vary greatly antitoin antibody production Vaccination in animals very protective Serum IgG anti-toin A levels are high in asymptomatic carriers of C. difficile toin A IgG anti-t 2.5 2.5 Carriers 2.0 2.0 1.5 1.5 1.0 1.0 P=0.06 P=0.002 P=0.001 P=0.005 0.5 0.5 Admission Admission Cases Colonization Colonization 3 days days after after Colonization Colonization Discharge Discharge Non-colonized Kyne et al N Engl J Med 2000;342:390 Rates of CDI Tripled in US Hospitals between 2000 and 2005 0,000 population Discharges per 100 120 100 80 60 40 20 0 Any diagnosis Primary diagnosis ~2 McDonald LC, et al. Emerg Infect Dis. 2006;12:409-415, and unpublished CDC data. ~3 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year C. difficile-related Mortality is Rapidly Increasing 25 20 15 10 5 0 5.7 Age adjusted death rate per million 73 7.3 82 8.2 416% increase from 1999 to 2004 In 2004 CDI-related deaths: 4 higher than MRSA infection 6 higher than all other intestinal infections combined 12.2 16.1 23.7 1999 2000 2001 2002 2003 2004 Redelings et al. Emerg Infect Dis. 2007;13:1417-1419. Increasing Mortality is Due to Increasing Incidence and New high Virulence Strains Major High Virulence Cdiff Strain is BI/NAP1/027 Mutated tcd gene : increased toins Epression of fbinary toin Resistant to multiple antibiotics (esp. floroquinolones) Increased severity of disease/death Associated with hospital outbreaks CDI outbreak in Estrie (Quebec) 400% increase 2002 to 2003 > 80% NAP1 strain Total >64 yr 18-64 yr <17 yr Pepin et al. Can Med Assoc J 2004; 171:466-72. 2
C diff in Quebec Epidemic :Probability of Survival:Age >65 States with Hypervirulent C. difficile BI/NAP1/027 Confirmed Confirmed by CDC (N=16) by CDC November, October, 2008 2005 DC 23.0% 30-day mortality rate in patients with CDAD vs 7.0% in controls 29.8% 60-day mortality rate in patients with CDAD vs 11.4% in controls No ecess mortality was seen in those aged <65 years and in those without comorbidity CDAD increased length of stay by 6.7 days during a first admission AK HI PR 16 40 States confirmed by CDC Adapted from Pépin J, et al. Can Med Assoc J. 2005:173. Epub October 25; with permission. http://www.cdc.gov/ncidod/dhqp/id_cdiff_data.html. Community Acquired CDI Previously rare 20 fold increase in the past 15 years 10-30% of CDI is now community acquired ~50% of cases of community acquired CDI require hospitalization Community Acquired CDI 60 50 40 30 20 10 0 1997 1998 1999 2002 2003 2004 Cases of CA-CDI per 100,000 Person years Dial et al. JAMA 2005, Dial CMAJ 2008, Knutty et al. Emerg Infect Dis 2010, Naggie et al. Infection 2010 Dial CMAJ 2008 Risk Factors for CDI High Risk Antibiotics 4-20 fold increased risk Low Risk Antibiotics 2-8 fold increased risk Inflammatory Bowel Disease Proton pump inhibitors 2 fold increased risk H2 Antagonists 1.5 fold increased risk Advanced age Peripartum Comorbidities (cancer, renal failure, CHF ) Antimicrobials Predisposing to CDI Very Commonly Related Clindamycin Ampicillin Amoicillin Cephalosporins Fluoroquinolones Less Commonly Related Other penicillins Sulfonamides Trimethoprim Cotrimoazole Macrolides Uncommonly Related Aminoglycosides Bacitracin Teicoplanin Rifampin Chloramphenicol Tetracyclines Carbapenems Daptomycin Tigecycline Bouza E, et al. Med Clin North Am. 2006;90:1141-1163. Loo VG, et al. N Engl J Med. 2005;353:2442-2449. 3
Community Acquired CDI 25-40% with no clear antibiotic eposure 25-50% with no clear healthcare visits 25% with no underlying comorbidity Younger Low mortality rate (~1%) High relapse rate (~40%) Likely underdiagnosed MMWR Dec 2005, Kuijper, CMAJ 2008 CDI Diagnosis Clinical diagnosis: Diarrhea +/- abdominal discomfort, nausea Current or recent antibiotic use Fever Leukocytosis Stool test t for C. difficileil toin The most commonly used tests (Toin EIA) are rapid (2-4 hours) but have low sensitivity (~75%; 66% - 90%) Tissue culture cytotoicity test more sensitive (>90%) but take 24 hours and more epensive Colonoscopy & biopsy rarely required Rectum and sigmoid colon usually but not always involved Kelly et al. Sleisenger & Fordtran s GI & Liver Disease. W B Saunders Co., Philadelphia. 2006, 2393-412. Initial Treatment Options for CDI Conservative 250 mg QID or 500 mg TID 125 mg QID Fekety R. Am J Gastroenterol. 1997;92:739-750. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. D/C all antimicrobials & observe May be administered PO or IV Resistance rare Historical first-line agent Effective only enterally (oral or rectal) Reserved for severe disease, those failing to respond to metronidazole, or cases in which metronidazole is contraindicated Initial Treatment Options for CDI Historical response (96%) and relapse rates (20%) comparable between metronidazole and vancomycin 1 Efficacy of metronidazole for severe disease called into question 2-4 Recent prospective trials report vancomycin to be superior to metronidazole in severe CDI 5-7 1. Aslam S, et al. Lancet Infect Dis. 2005;5:549-557. 2. Fernandez A, et al. J Clin Gastroenterol. 2004;38:414-418. 3. Gerding DN. Clin Infect Dis. 2005;40:1598-1600. 4. Musher DM, et al. Clin Infect Dis. 2005;40:1586-1590. 5. Lahue BJ, Davidson DM. The 17th ECCMID Meeting, March 31 to April 4, 2007; Munich, Germany. Abstract 1732_215. 6. Zar FA, et al. Clin Infect Dis 2007;45:302-307. 7. Louie T, et al. The 47th Annual ICAAC Meeting, Sept. 17-20, 2007; Chicago, IL. Abstract k-425-a. Clostridium difficile-associated Diarrhea: Response to Treatment in Controlled Trials Year of publication 2005 2005 2004 2001 1996 1994 1983 1982 0 10 20 30 40 50 60 % treated subjects 20% Recurrence 13% Failure Failure Recur Aslam S, et al. Lancet Infect Dis. 2005;5:549-557. Year of publication 2005 1996 1994 Failure 1992 Recur 1989 1989 1986 1985 1984 1983 1981 1980 0 10 20 30 40 50 60 % treated subjects 19% Recurrence 4% Failure Treatment of First Episode of CDI Mild CDI Discontinue offending antibacterial agent Request stool testing Monitor course of disease Moderate or persisting CDI (or patients who must continue antibacterial therapy) As for mild plus: Oral metronidazole 500 mg TID for 10 14 days or 250 mg QID for 10 14 days Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. Poutanen SM, Simor AE. Can Med Assoc J. 2004;171:51-58. 4
Recurrent C. difficile diarrhea Common (~20% of treated patients) Mechanisms of recurrence: NOT due to resistance to metronidazole or vancomycin or vancomycin therapy perpetuate loss of colonization resistance Either: Relapse - Persisting infection Re-infection - New inoculum different strain in ~50% of recurrent CDAD cases Recurrent C. difficile diarrhea (contd) Risk factors: Age > 65 years Continued antibiotic use Increased co morbidities Prior recurrent CDAD ~ 20% risk after first CDAD episode ~ 40% risk after first recurrence > 60% risk after 2 or more recurrences Lack of protective immunity Wilco et al. J Hosp Infect. 1998;38:93-100. Hu et al. Gastroenterology, 2009, Kyne et al. Lancet 2001;357:189-93 Treatment options for recurrent CDI pulsed / taper Vanco followed by rifaamin + rifampin + cholestyramine Probiotic therapy Saccharomyces boulardii Lactobacillus Fecal restoration enema Non-toigenic C. difficile Passive immunotherapy with IVIG Management of recurrent C. difficile diarrhea Supportive only if mild diarrhea First relapse: A second 14 day course of metronidazole or vancomycin Second relapse: Prolonged tapering & pulse dosed vancomycin +/- probiotic Third relapse: Follow vancomycin therapy with RIFAXIMIN 200mg tid for 14 days R Week 1 125 mg qid Week 2 125 mg bid Week 3 125 mg daily Week 4 125 mg qod Week 5-6 125 mg q3d Kyne & Kelly. Gut. 2001;49:152-3. Tedesco et al. Am J Gastroenterol 1985;80:867-868. Saccharomyces boulardii: Non-pathogenic Yeast (McFarland, 1994) or 2 weeks S. boulardii (1 gm qid) or placebo 4 weeks Recurrence reduced by 50% Antibiotics + S. boulardii 24.6% Placebo + Antibiotics 64.7% Other Options for Management of Multiple C. difficile Relapses IVIG 400 mg/kg/week X 2 Cholestyramine 4g qid Fecal transplant Other antibiotics including nitazoanide, tigecycline Avoid treating: Patients with minimal symptoms and positive stool test (progression to carrier state is common) Patients with symptoms but negative stool test (likely post infectious IBS) 5
Serum IgG anti-toin A (Optical Den nsity units) Intravenous immunoglobulin therapy for recurrent C. difficile diarrhea 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0.0 P = 0.03 P = 0.01 Adult Pediatric Pre-IVIG Post-IVIG Healthy controls Children with recurrent C. difficile diarrhea Rifaamin chaser for recurrent C diff Eight women with 4-8 recurrences 10-14 days of vanco with good control Followed by 14 days of rifaamin 400mg bid Eventual cure in all 8 with long-term follow-up Johnson et al. Clin Inf Dis 2007: vol 44 Leung DY, Kelly CP et al J Pediatr 1993 Stool Transplant for Recurrent C.difficile Rationale: Normal flora, especially Bacteroides spp, inhibit C.difficile Stool donor: Healthy relative or family member who is stool pathogen free Stool suspension via enema or colonoscopy Success in open trials : cure in 60/67 pts Mimics of recurrent C diff Post-infectious IBS The post-infectious carrier state Klebsiella oytoca infection Celiac disease triggered by infection IBD following bacterial infection Am J Gastro 2000 Risk Factors for PI-IBS Hospitalized pts with infectious enteritis (n=75) None had prior IBS PI-IBS at 3 months in 22 (29%) Assessment of PI-IBS IBS vs Non IBS pts: Aniety Depression Somatization Neuroticism Gwee et al.lancet 1996;347:150 Klebsiella oytoca and Antibioticassociated Hemorrhagic Colitis Gram negative toigenic bacteria Bloody diarrhea after penicillin Stools negative for C. difficile Colonoscopy: right sided hemorrhagic colitis, no PMs, spares rectum Remits without r (d/c inciting antibiotic) NEJM : Dec 2006, p.2418 6
Markers of Severe CDI: Early recognition is critical Initiate therapy as soon as diagnosis is suspected Severe diarrhea Ileus or toic megacolon >10 bowel movements/day Colonic thickening on CT Marked leukocytosis scan >15,000 associated with Ascites on CT scan severe CDI Pseudomembranes on >25,000 associated with endoscopy increased fatality Severe abdominal Rising (50% increase) distension, pain serum creatinine Hemodynamic instability Low serum albumin (<2.5) Organ failure Pépin J, et al. Can Med J Assoc. 2004;171:466-472. Bartlett JG, Gerding DN. Clin Infect Dis. 2008;46 (Suppl):S12-S18. Management of Severe, Complicated CDI Severe CDI patients who fail to respond promptly to therapy or are clinically unstable generally receive combination therapy: Absence of ileus Oral vancomycin 500 mg QID with IV metronidazole 500 750 mg IV every 8 hours High-dose vancomycin lacking sound data but concern for insufficient drug delivery to bowel Presence of ileus Traditional treatment with oral or IV agents may be insufficient 500 750 mg IV every 8 hours with vancomycin administered via nasogastric tube or rectal instillation Fekety R, et al. Am J Med. 1989;86:15-19. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16:459-477. Colonic distension and small bowel ileus in fulminant Clostridium difficile colitis Severe, complicated CDI may present as an acute abdomen and/or mimic acute colonic pseudo- obstruction Little or no diarrhea May occur post-op & while taking narcotic analgesia Sigmoidoscopic appearance of severe CDI with PMC Immediate bedside diagnosis in severe, complicated CDI Guides surgical management Perforation rare - death usually results from SIDS Kelly & LaMont. Gastrointestinal Pharmacotherapy, W. B. Saunders 1993;199-212. Management of Severe, Complicated CDI Early surgical consultation Reassess frequently Monitor factors that predict negative outcomes 1-3 Marked leukocytosis (>20,000 per μl) Serum lactate > 5 mmol/l Rising serum creatinine (> 1.5 baseline) Subtotal colectomy High perioperative mortality 25% to >75% Management of Severe, Complicated CDI Potential role of intravenous immunoglobulin G (IVIG) 1-6 Antitoin A IgG predicts clinical outcome of CDI Serum antibodies to toins A and B are prevalent in healthy ypopulationsp Recent studies in severe disease 5,6 Well-tolerated in small numbers of patients Conflicting data regarding outcome improvement (mortality and need for colectomy) Often administered when surgery is considered imminent 1. Lamontagne F, et al. Ann Surg. 2007;245:267-272. 2. Pépin J, et al. Can Med J Assoc. 2004;171:466-472. 3. Miller MA. Clin Infect Dis. 2007;45:S122-S128. 1. Salcedo J, et al. Gut 1997;41:366-370. 2. Beales ILP. Gut. 2002;51:456. 3. Kyne L, et al. N Engl J Med. 2000;342:390-397. 4. Kyne L, et al. Lancet. 2001;357:189-193. 5. McPherson S, et al. Dis Colon Rectum. 2006;49:640-645. 6. Juang P, et al. Am J Infect Control 2007;35:131-137. 7
is more effective than metronidazole in treating severe CDI Prospective, RCT in 150 subjects 125 mg QID 10d vs 250 mg QID 10d Stratified for disease severity 2 points = SEVERE 1 point: Age: > 60 years Temp: > 101 F [38.3 C] Albumin: < 2.5 mg/dl WBC > 15,000 cells/mm 3 2 points: PMC at colonoscopy ICU patient Response 100% 90% 80% 70% 60% 50% 98% P=0.4 90% Mild / Moderate 97% P=0.02 Severe 76% Zar et al. Clin Infect Dis 2007;45:302-7 Epected Responses to R of acute C diff with Metro or Vanco Agent Cure Rate* Relapse Rate Time to Resolution 94-95% 5-16% 2.4-3.2 days 94-100% 15-16% 2.6-3.1 days *Successful treatment of the initial episode of C. difficile-associated disease. N.B. No resistance in C diff to metro or vanco so far!! Johnson SJ, Gerding DN. Clostridium difficile. In: Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 2002. Recent increase in reported treatment failures for metronidazole in CDAD Pseudomembranous colitis Accordion Sign Treatment failure 25% 20% 18% 15% 13% 10% 5% 3% 4% 3% 3% 0% Pre 2000 Post 2000 Combined 50% 40% 30% 20% 10% 0% Recurrence 7% Pre 2000 29% 18% 20% 20%18% Post 2000 Combined Aslam S, et al. Lancet Inf Dis. 2005;5:549-557. Management of Fulminant Colitis Oral Therapy: 500 qid IV Therapy: 500 q6h? IVIG Surgery for Perforation or Megacolon Sub-total Colectomy and Ileostomy Overall Mortality : 35 % Alternate Routes of Delivery Adjunctive treatment (anecdotal, no controlled trials) Intracolonic instillation 1 500 mg IV vancomycin in 100 ml normal saline via Foley catheter Clamp for 60 minutes Repeat every 6 hours Insertion of long tube into small intestine 2 Colonic decompression followed by guidewire positioning of a fenestrated tube and perfusion with a vancomycin solution 3 1. Olson MM, et al. Infect Control Hosp Epidemiol. 1994;15:371-381. 2. Silva J Jr. West J Med. 1989;151:644-648. 3. Shetler K, et al. Surg Endosc. 2001;15:653-659. 8
C. difficile infection prevention & control CDI: >70% nosocomial >85% iatrogenic Emerging therapy and management Judicious antibiotic use Hand hygiene with soap and water NOT alcohol based solutions Isolation and barrier precautions for patients with CDI Universal precautions? Probiotics in high risk patients Toin binders (e.g. Tolevamer) Vaccination for C. difficile A non-antibiotic treatment Lower recurrence rates May be useful in many forms of CDI Mild Severe Recurrent May be usful as prophylais (primary or secondary) Low efficacy in active CDI May need to be paired with antibiotic therapy to eploit potential for reducing recurrences High molecular weight soluble polymer Binds C. difficile toins A & B Key Points Clostridium difficile incidence is rising Severity and relapse rate are rising Community acquired infection is much more common and patients may not have traditional risk factors (antibiotics, hospitalization) No antibiotic resistance reported so far Confirm active C. difficile infection especially in presumed recurrence Non-antibiotic treatment emerging 9