Clostridium difficile: An Emerging Threat L. Clifford McDonald, MD, FACP, FSHEA Division of Healthcare Quality Promotion

Clostridium difficile Anaerobic spore-forming bacillus Clostridium difficile-associated disease (CDAD) Pseudomembranous colitis, toxic megacolon, sepsis, and death Fecal-oral transmission through contaminated environment and hands of healthcare personnel Antimicrobial exposure is major risk factor for disease Acquisition and growth of C. difficile Suppression of normal flora of the colon Clindamycin, penicillins, and cephalosporins Healthy colon Pseudo-membranous colitis

The Historic Impact of CDAD Rates Acute care: 3-25/10,000 patient days Long term care: carriage in 5-7% of patients Boston, 19981 Very low attributable mortality Average of $3,600 excess costs per case Average of 3.6 extra hospital days Kyne L, et al. Clin Infect Dis. 2002;34:346-353.

Annual CDAD Rates, Hospitals with >500 Beds, Intensive Care Unit Surveillance Component, NNIS From Archibald LK, et al. J Infect Dis. 2004;189:1585–158.

National Estimates of US Short-Stay Hospital Discharges with C National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed or Any Diagnosis From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

Rates of US Short-Stay Hospital Discharges with C Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Age From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

Rates of US Short-Stay Hospital Discharges with C Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Region From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

Proportion of US Short-Stay Hospital Discharges with C Proportion of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Hospital Bed Size From McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

Increasing Severity of CDAD Pittsburgh, 20002 Life-threatening disease from 1.6% to 3.2% 2000-2001: 26 colectomies and 18 deaths Quebec, 2004 30-day attributable mortality 6.9% 12-month attributable mortality 16.7% Dallal RM, et al. Ann Surg. 2002;235:363-372. Muto C, et al. Infect Control HospEpid. 2005 Pepin J, et al. CMAJ. 2005

CDAD in long term care Number of patients with CDAD diagnosis transferred to long term care Doubled between 2000 and 2003 2% of all transferred patients Ohio, 2006

Emerging Infections Network (EIN) Surveys, 2004 2 surveys conducted 6 months apart, 531 unique Infectious Disease Clinician respondents with observations over prior 6 months Layton BA, et al. 15th Annual Scientific Meeting of The Society for Healthcare Epidemiology of America (SHEA), April 9-12, 2005; Los Angeles, CA.

Potential Reasons for Increased CDAD Incidence and Severity Changes in underlying host susceptibility Changes in antimicrobial prescribing New strain with increased virulence Changes in infection control practices

Acute Care Hospitals with CDAD Outbreaks* Between 2001-2004 *Detected by increases in the number of positive routine clinical laboratory tests for C. difficile. Data from McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Epidemic (BI/NAP1) Strain From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Nonepidemic (Non-BI/NAP1) Strains From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Resistance of Current (after 2000) BI/NAP1 Isolates to Clindamycin and Fluoroquinolones Compared with Current Non-BI/NAP1 Isolates and Historic (before 2001) BI/NAP1 Isolates No. (%) Intermediate or Resistant to: Current BI/NAP1 Isolates n=24 (%) non- P-Value for vs. Non- Historic n=14 (%) Current vs. Clindamycin 19 (79) 1.0 10 (71) 0.7 Levofloxacin 24 (100) 23 (96) 14 (100) Gatifloxacin 10 (42) <0.001 Moxifloxacin From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Distribution of Levofloxacin Minimum Inhibitory Concentrations in Current (ie, after 2000) BI/NAP1 and Non-BI/NAP1 Isolates From McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

Increased Toxin A Production in vitro Approximately 16 fold increased toxin A production by the epidemic strain In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations. From Warny M, et al. Lancet. 2005;366:1079-1084.

Increased Toxin B Production in vitro In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations. Approximately 23 fold increase in toxin B production From Warny M, et al. Lancet. 2005;366:1079-1084.

States with the Epidemic Strain of C States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=23), Updated 2/9/2007 DC HI PR AK

Lethal hospital bug cases rocket, United Kingdom Potentially lethal cases of C. difficile “rocketed” from 1990s to 2004 Cases had increased from 1,000 in 1990 to over 35,000 in 2003 44,488 cases of C. difficile in > 65 year olds in 2004. BBC News. http://news.bbc.co.uk/2/hi/health/4186834.stm

BI/NAP1 in the Netherlands, 2006 Kuiper EJ et al. Emerg Infect Dis 2006;12(5):827-830.

Challenges Emergence of a new epidemic strain Toxinotype III or “BI” by REA Distinct from “J” strain of 1989-19921 Binary toxin as a possible virulence factor In addition to toxins A and B containing 18 bp deletion in tcdC gene Could lead to increased toxin production (18-fold for toxin A, 23-fold for toxin B) observed by Warny et al.2 Increased resistance to fluoroquinolones Appears responsible for increase in cases May be responsible for increase in disease severity Johnson S, et al. N Engl J Med. 1999;341:1645-1651. Warny M, et al. Lancet. 2005;366:1079-1084.

Recommendations for Hospitals Hospitals should conduct surveillance for CDAD Recently proposed surveillance recommendations1 Early diagnosis and treatment important for reducing severe outcomes and should be emphasized Subset of epidemic isolates tested: metronidazole susceptible Strict infection control: CDC Fact Sheet2 Contact precautions for CDAD patients An environmental cleaning and disinfection strategy Hand-washing with CDAD patients in outbreak Further research needed Role for antimicrobial controls in stemming this epidemic 1McDonald et al. Infect Control Hosp Epidemiol 2007; 28:140-145 2See CDC C. difficile Fact Sheets: http://www.cdc.gov/ncidod/dhqp/.

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (1) Recent reports to the Pennsylvania Department of Health and CDC Young patients without serious underlying disease C. difficile toxin-positive by routine diagnostic testing Responded to CDAD-specific therapy Peripartum Within 4 weeks of delivery Reports from PA, NJ, OH, and NH Community-associated No hospital exposure in prior 3 months Reports from Philadelphia and 4 surrounding counties CDC. MMWR. 2005;54:1201-1205.

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (2) Characteristic, No. (%) Community (N=23) Peripartum (N=10) Total (N=33) Aged < 18 years 11 (48) 0 (0) 11 (33) Female 15 (65) 10 (100) 25 (76) Antimicrobial exposure 9 (90) 24 (73) Bloody diarrhea 6 (26) 2 (20) 8 (24) Hospitalization necessary 4 (40) 10 (24) ER visit necessary 3 (13) 5 (15) Relapse 8 (35) 5 (50) 13 (39) CDC. MMWR. 2005;54:1201-1205.

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (3) Recent onset dates February 26, 2003 – June 28, 2005 Only 1 case in 2003 Transmission to close contacts in 4 cases 8 cases without antimicrobial exposure 5 children; 3 required hospitalization 3 had close contact with diarrheal illness Another 3 cases with < 3 doses of antimicrobials Clindamycin most common exposure (10 cases) Estimated minimum annual incidence of community-associated disease 7.6 cases per 100,000 population 1 case per 5,000 outpatient antimicrobial prescriptions CDC. MMWR. 2005;54:1201-1205.

Comparison of Molecular Characteristics of 2 C Comparison of Molecular Characteristics of 2 C. difficile Isolates with Historical Standard-Type Strains and a Recently Recognized Epidemic Strain, by Selected Characteristics, OH and PA, 2005 Characteristic Standard Strain Epidemic Strain Ohio Strain Pennsylvania Strain Toxinotype PFGE* pattern Binary toxin 18 bp deletion in tcdC < 80% related to NAP1† _ III NAP1 + IX 85% related to NAP1 XIV/XV 64% related to NAP1 *Pulsed-field gel electrophoresis. † North American pulsed-field type 1. McDonald LC, Killgore GE, Thompson A, Owens RC Jr, Kazakova SV, Sambol SP, Johnson S, Gerding DN. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353:2433-2441. CDC. MMWR. 2005;54:1201-1205.

Stomach Acid-Suppressing Medications and Community-Acquired CDAD, England From Dial S, et al. JAMA. 2005;294:2989-2995.

Recommendations for CDAD in Previously Low-Risk Populations Further investigation and surveillance in these populations are warranted Strains responsible for severe CDAD in previously low-risk populations unknown May be other toxin variants and/or hospital epidemic strain Clinicians should consider the diagnosis CDAD in patients without traditional risk factors Patients should seek medical attention Diarrhea lasting longer than 3 days Fever Blood Antimicrobial exposure is not benign Continue to emphasize judicious antimicrobial use