Sherwood L. Gorbach, MD Professor of Public Health, Medicine, and Microbiology Tufts University School of Medicine

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1 Sherwood L. Gorbach, MD Professor of Public Health, Medicine, and Microbiology Tufts University School of Medicine Chief Scientific Officer, Optimer Pharmaceuticals, Inc. Conflicts: Chief Scientific Officer, Optimer Phamaceuticals, Inc. Consultant, Cempra Pharmaceuticals, Inc.

2 Clostridium difficile infection 15 25% of antibiotic associated diarrhea Surpasses MRSA as the most common nosocomial infection Recent trends are increased disease severity and increased acquisition outside a healthcare setting Both asymptomatic carriage and C. difficile associated diarrhea and colitis High rate of recurrence Chronic relapsing disease in a minority of patients Significant morbidity and mortality The elderly are particularly susceptible to infection, recurrence, complications, and mortality

3 Pathogenesis Ingestion of spores Germination Proliferation Toxin production Sunenshine RH, McDonald LC. Cleve Clin J Med. 2006;73:187

4 C. difficile toxins Toxin A (TcdA, 308 kda), an enterotoxin Toxin B (TcdB, 260 kda), a cytotoxin Both toxins act as glycosyltransferases and modify small GTPases within the host cell that are involved in actin polymerization and cytoskeleton structure Both toxins play a role in the clinical disease, although toxigenic A B + strains are emerging Binary toxin, mostly in 027/NAP1/BI strains unknown role

5 Genes associated with more severe disease The TcdC gene codes for a negative regulator of TcdA and TcdB transcription and is mutated in more toxigenic strains Some strains also carry a gene encoding a binary toxin (CDT) that contributes to severity of symptoms CDT = Clostridum difficile transferase Binds to lipolysis stimulated lipoprotein receptor Internalized Actin ADP ribosylation enzymatic activity Papatheodorou 2011, Proc Natl Aca Sci USA 108:16422

6 Clinical features Mild, self limiting to severe and fatal Profuse watery diarrhea Pseudomembranous colitis Complications: Dehydration Electrolyte disturbances Ileus Toxic megacolon Fulminant pancolitis Bowel perforation Hypotension Renal Failure Sepsis Need for colectomy Death Severity indicators pseudomembranes Increase in serum creatinine >1.5mg/dL WBC >15,000/µL Fever >38.5 C Advanced age

7 Risk factors for infection Age 65 years (immunosenescence, comorbidities) Duration of hospitalization (exposure) Exposure to antimicrobial agents (number, duration, class) Cancer chemotherapy (antibacterial and immunsuppressive effects) Gastrointestinal surgery Tube feeding Acid suppressing medications (proton pump inhibitors and histamine 2 receptor antagonists)

8 Antibiotics and other drugs associated with increased risk High risk 2nd & 3rd generation cephalosporins Clindamycin Fluoroquinolones, especially moxifloxacin and levotiracetam Intermediate risk Ampicillin, amoxicillin/clavulanate, piperacillin/tazobactam, ticarcillin/clavulanate Trimethoprim/sulfamethoxazole Macrolides Low risk Aminoglycosides Vancomycin Metronidazole Chemotherapeutic agents Methotrexate, doxorubicin, cyclophosphamide, 5 fluorouracil, and others

9 Adaptive and innate immune responses influence C. difficiie infection susceptibility, severity, and course Circulating antibodies to toxins A and B (IgG, IgM, IgA) Innate immune response Acute local inflammatory response contributes to pathophysiology Neutrophil infiltration Tissue injury Immunosenescence with age Susceptibility of immunocompromised (congenital, medications, organ and HSC transplants) Efficacy of passive and active immunotherapy against C. difficile toxins Passive: IV immunoglobulins, bovine immune whey, human monoclonal antibodies Active: Vaccines

10 Increasing incidence National Estimates of US Short Stay Hospital Discharges With C. difficile as First Listed or Any Diagnosis, National Inpatient Sample Number of hospital discharges Any listed diagnosis Primary diagnosis SOURCE: Elixhauser A, Jhung MA. Clostridium difficile associated disease in U.S. hospitals, HCUP Statistical Brief #50. April Agency for Healthcare Research and Quality, Rockville, MD and unpublished data us.ahrq.gov/reports/statbriefs/sb50.pdf.

11 CDI surpasses MRSA Hospital onset, healthcare facility associated CDI and healthcare associated MRSA 10 hospitals in the Duke Infection Control Outreach Network (VA, NC, SC, GA) Median 263 beds ( ) Miller BA et al. Infect Control Hosp Epidem 2011;32:

12 Where is CDI acquired? Electronic data from 88 hospitals 10,170 CDI cases identified 50.4% hospital onset 17.4% community onset, healthcare associated 9.0% community onset, indeterminate healthcare association 23.2% community onset, non healthcare associated Incidence density of healthcare onset: 6.3 per 10,000 patient days Prevalence of community onset: 24.1 per 10,000 admissions Independent risk factors for healthcare onset and community onset CDI Older age Admission to a smaller hospital Zilberberg MD et al. Presented at: ICAAC. 2009;Abstract K 1906

13 Increasing recurrence After metronidazole treatment After vancomycin treatment Pépin J et al. Clin Infect Dis. 2005;40: Quebec, Canada

14 Recurrence After resolution of symptoms and completing treatment, disease recurs in ~20 30% of patients The rate increases to 40 60% after a second recurrence Risk factors Inadequate immune response / immunosuppressive drugs Continuation of other antibiotics Persistent disruption of the normal flora Gastric acid suppressants Advanced age Comorbidities Prolonged hospital stays

15 Recurrence Risk Factors Study Odds Ratio LL UL Z value P value Continued use of antibiotics Kyne et al Nair et al McFarland et al Anti ulcer medication Kyne et al Tal et al Moshkowitz et al Meta analysis Garey et al 2008 J Hosp Infect 70:298 Protective Risk Factor Older age Pepin et al Nair et al McFarland et al

16 Increasing severity Strains and epidemics Epidemic strain, NAP1/BI/027 (toxinotype III) First epidemic in Pittsburg University Hospital 2000/2001 Canada, since 2002 Europe, since 2005, beginning in England and the Netherlands Some clonal isolates of NAP1/027 produce 16 times more toxin A and 23 times more toxin B tcdc 18 bp deletion Produces binary toxin Frequently resistant to fluoroquinolones and

17 CDI-Related Death (%) n=1,008 11/ /2005 Canada NS NAP1/BI/027 Non-NAP1 NS NS P=0.02 P=0.07 Age (years) P= NS NAP1/BI/027 infection was associated with fold increased death rate Miller M et al. Clin Infect Dis 2010;50:194

18 DC AK HI PR States with 1 hospital that had reported CDI due to BI/NAP1/027 strain as of Oct 2008 O Conner et al, Gastroent 2009;136:

19 2005 CNISP survey % of typed isolates The Quebec epidemic began in late 2002 and peaked in March 2004 at 845 cases in 40,852 discharges, or 20.7 cases per 1,000 discharges. O Conner et al, Gastroent 2009;136: Gilca et al, Infect Control Hosp Epidemiol 2010;31:939 47

20 Most frequent PCR ribotypes of toxigenic isolates ( 5%) Ribotype Number (%) of isolates REA correlate? 014/020 61/389 (16%) Y /389 (10%) J /389 (8%) BK /389 (6%) /389 (5%) DH 027* 19/389 (5%)* BI* /389 (5%) G Genotype: CDT+ (binary toxin) 90/389 (23%) A B+ toxigenic 13/389 (3%) Bauer et al. Lancet 2011

21 Emerging virulent strains Type 078 (TcdA+, TcdB+, CDT+, TcdCΔ38bp) Emergent in Italy, Ireland, and other European countries Found in food animals and retail meat Severe, often bloody, diarrhea Hypovolaemia,hypoalbuminaemia, fever, leukocytosis And/or pseudomembranous colitis Type 017 (TcdA, TcdB+, CDT, TcdC wt ) Outbreaks in Canada (2000), Netherlands (2001), Ireland (2007), Argentina (2009) A dominant strain in Japan, South Korea, and China Emergent in Poland, Czech, Hungary, and Turkey High mortality (4 20%)

22 Recent epidemic in the Niagara Region, Ontario, Canada Report as of Thu., Oct. 20, 2011 at 10 a.m. St. Catharines General Total number of cases since the outbreak declared 72 Confirmed cases currently in patients at the site 5 Hospital associated cases currently in hospital 3 Community acquired/other cases currently in hospital 2 Deaths related to outbreak 27 (37.5%) C. difficile outbreak was declared St. Catharines General May 28, 2011 Greater Niagara General and Welland sites June 23, Welland outbreak was declared over on Aug. 5, 2011 (4 deaths) Niagara Falls outbreak was declared over on Sep. 6, 2011 (5 deaths) 36 deaths at the 3 sites (accessed 20 Oct 2011)

23 Morbidity and Mortality Dehydration and gastrointestinal hemorrhage Death rate attributable to CDI Up to 6.9% in outbreaks Up to 15% in frail elderly individuals All cause mortality also increased after CDI Need for Intensive Care Unit in 2 3% Emergency bowel surgery and colectomy in 1% Incidence of CDI has surpassed MRSA as a complication of health care

24 Increasing mortality Age Adjusted Death Rate 1 for Enterocolitis Due to C. difficile, by Race and Sex (US, ) Rate Male Female White Black Entire US population Year

25 Mortality Pooled mortality attributable to CDI in studies before and after 2000 # of studies Total P value # of patients Total attributable deaths Percent 5.99% 3.64% 8.03% <0.001 Karas et al 2010, J Infection 61:1 8; from 27 studies reporting deaths within 30 (12), 60 (1), 90 (2) days of diagnosis, or undisclosed (12) minimum associated mortality of CDI up to 90 days after diagnosis

26 Age in years Number of Cases Cases per 1000 admissions 30 day attributable mortality rate < % % % % % % > % N=1719 episodes of nosocomial C difficile associated diarrhea N=1703 patients with nosocomial C difficile associated diarrhea Loo, V. G. et al. N Engl J Med 2005;353: Similar results were obtained by Karas et al. J Infection 2010;61:1 8

27 Recent concerns C. difficile infection is affecting otherwise healthy adults peripartum women children individuals with no recent history of hospital admission individuals with no recent antibiotic use Asymptomatic carriage and spread of disease Food sources of pathogenic C. difficile

28 Interim recommendations for surveillance of C. difficile infection Admission Discharge 48 h < 4 weeks 4 12 weeks > 12 weeks * HO HCFA CO HCFA Indeterminate CA CDI Time HO: Hospital (Healthcare) Onset CO HA: Community Onset Healthcare associated CA: Community Associated * Depending upon whether patient was discharged within previous 4 weeks, CO HA vs. CA CDAD Surveillance Working Group. Infect Control Hosp Epidemiol 2007; 28:

29 Emerging Infections Programs 8 sites provide surveillance in selected counties of 9.3 million people with estimated CDI burden of 8,370. Oregon Minnesota New York California Colorado Tennessee Connecticut Maryland Georgia Source: Cliff McDonald of the CDC, 2010

30 Outlook Timely diagnosis, severity and risk assessment, and choice of appropriate treatment to improve outcomes Better surveillance, including standardized testing and typing, to respond to outbreaks Antibiotic stewardship Novel therapeutics ready when resistant strains arise