Clinical Spectrum of Disease. Clinical Features. Risk Factors. Risk of CDAD According to Antibiotic Class. Fluoroquinolones as Risk Factor for CDAD

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1 Clinical Features Range from mild diarrhea to severe colitis and death Common clinical symptoms include Watery diarrhea Fever Loss of appetite Nausea Abdominal pain/tenderness Less common ileus CDC Fact Sheet. August 24 (updated 7/22/25). Clinical Spectrum of Disease Asymptomatic colonization Mild to severe diarrhea (CDAD) More severe disease and increased mortality in multiple recent reports Pseudomembranous colitis Toxic megacolon Perforation of the colon Septic shock Death may occur (rarely) CDC Fact Sheet. August 24 (updated 7/22/5). Risk Factors Two most important risk factors Prior antimicrobial use Length of stay in a healthcare setting or long-term care facility Other risk factors Advancing age Serious underlying illness Gastrointestinal surgery or manipulation Bignardi GE. J Hosp Infect. 1998;4:1-15. Pépin J, et al. Clin Infect Dis. 25:41: Gaynes R, et al. Clin Infect Dis. 24;38: CDC Fact Sheet. August 24 (updated 7/22/5). Odds Ratio Risk of CDAD According to Antibiotic Class Cephalosporins Fluoroquinolones Clindamycin Macrolides Loo VG, et al. N Engl J Med. 25;353: Fluoroquinolones as Risk Factor for CDAD Retrospective cohort study during an epidemic in Quebec 293 incident cases of CDAD 5.5% of patients were 8 years old 63.5% received fluoroquinolones 21.8% died within 3 days of diagnosis Fluoroquinolones identified as most important risk factor for CDAD during large epidemic (adjusted hazard ratio = 3.44) Pépin J, et al. Clin Infect Dis. 25;41: CDAD and Gastric Acid Suppression Proton pump inhibitors (PPIs) may play a role in development of CDAD although conflicting data exist to date 1-4 Additional studies are required to delineate the mechanism whereby PPIs might increase the risk of CDAD? Gastric acid suppression; gastric acid plays an uncertain role in protection against a spore-forming bacteria that requires only a small inoculum to cause disease? Antibiotic effect of PPIs 1. Dial S, et al. JAMA. 25;294: Yearsley KA, et al. Aliment Pharmacol Ther. 26;24: Lowe DO, et al. Clin Infect Dis. 26;43: Dial S, et al. Can Med Assoc J. 26;175:

2 Severe CDAD in Previously Low-Risk Populations Four States, 25 Recent reports in Northeastern states Young patients otherwise healthy Peripartum women Community-associated Other cases with atypical epidemiology Transmission to close contacts Some without prior antimicrobial and/or hospital exposure Further studies needed to confirm these findings, but clinicians should consider C. difficile testing in patients with diarrhea and without the usual risk factors Diagnosis of CDAD Clinical suspicion Commonly used laboratory tests Toxin testing Antigen detection assays Stool cultures (rarely) Diagnostic imaging Colonoscopy Abdominal computed tomography (CT) scan Chernak E, et al. MMWR Weekly. December 2, 25;54: Principles of Diagnostic Testing Collection of 1 or 2 specimens is sufficient 1 Do not retest after positive result Current laboratory testing Immunoassays have reduced sensitivity (65% to 85%) compared with cytotoxin assay 2 Many tests do not detect toxin A, B + strains Clinical suspicion overrides negative results Monitor clinical response not repeat testing Test of cure assays discouraged 1. Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: Poutanen SM, et al. Can Med Assoc J. 24;171: Diagnostic Tools Advantages and Disadvantages Test Advantage(s) Disadvantage(s) Toxin testing Enzyme immunoassay Tissue culture Same-day test; detects toxin A, or A and B More sensitive than enzyme immunoassay Less sensitive than tissue culture cytotoxicity assay Detects toxins A and B; is costly; requires hours for a final result Antigen detection Rapid tests (<1 hour) Must be combined with toxin testing to verify diagnosis; may prove useful as screening tool Stool culture Most sensitive test available when performed appropriately * Due to presence of nontoxigenic strains. CDC Fact Sheet. August 24 (updated 7/22/5). Most often associated with falsepositive results*; labor-intensive; requires hours for results National Hospital Discharge Survey Estimates of short-stay hospital discharges with C. difficile listed as primary or any diagnosis Clostridium difficile: Changing Epidemiology From McDonald LC, et al. Emerg Infect Dis. 26;12:49-415; with permission.

3 Fulminant C. difficile-associated Disease (CDAD) in Pittsburgh Outbreaks: CDAD in Quebec by Age From Dallal RM, et al. Ann Surg. 22;3: ; with permission. From Pépin J, et al. Can Med Assoc J. 24;171: ; with permission. Explanations for the Changing Epidemiology Possibly caused by changes in 1 Antimicrobial use Other drug prescribing practices Infection control practices Emergence of a new strain of C. difficile 1 Increased virulence Antimicrobial resistance Aging of the hospital inpatient population 2 1. McDonald LC. Infect Control Hosp Epidemiol. 25;26: US Department of Health and Human Services. healthworkforce/reports/changedemo/aging.htm. Accessed December 21, 25. Emergence of an Epidemic Strain of C. difficile in the United States, 2-23 Outbreaks occurred in 6 states Epidemic strain was predominant (REA group BI and PFGE type NAP1) Previously uncommon strain with putative virulence factors has become epidemic Development of greater fluoroquinolone resistance may have provided selective advantage that promoted widespread dissemination McDonald LC, et al. N Engl J Med. 25;353: States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA Labs (N=27) Updated April 3, 27 AK HI PR DC 27 States confirmed by CDC and/or Hines VA C difficile Research Lab Epidemic Strain Appears to produce greater quantities of toxins A and B 1,2 Has a tcdc gene deletion 2 Is highly resistant to fluoroquinolones 3,4 Binary toxin genes are present Various methods of classification 2,5 Toxinotype III BI (restriction endonuclease analysis [REA]) NAP1 (pulsed-field gel electrophoresis [PFGE]) Ribotype 27 (polymerase chain reaction [PCR]) Pulsovar A (PFGE, Quebec) 1. CDC Fact Sheet. July Warny M, et al. Lancet. 25;366: McDonald LC, et al. 42nd Annual Meeting of IDSA; 24. Abstract LB McDonald LC, et al. N Engl J Med. 25;353: Hubert B, et al. Clin Infect Dis. 27;44:

4 In Vitro Production of Toxins in Epidemic Strain Possible Virulence Factors: Epidemic Strain Hypothesis From Warny M, et al. Lancet. 25;366:79-84; with permission. Adapted from McDonald LC, et al. N Engl J Med. 25;353: ; with permission. Fluoroquinolone Resistance in Epidemic Strains and Controls Epidemiology of CDAD in Quebec Risk for Death and Severe CDAD According to Presence or Absence of Binary Toxin Genes and Partial tcdc Deletion in the Infecting C. difficile Strain Agent Current BI/NAP1 Isolates (n=24) Current Non- Epidemic Isolates (n=24) P-Value* Historic BI/NAP1 Isolates (n=14) P-Value Gatifloxacin 24 (%) (42%) <.1 <.1 Moxifloxacin 24 (%) (42%) <.1 <.1 Percentage OR 1.7 OR 2.1 * P-value for the comparison between BI/NAP1 and non-bi/nap1 isolates. P-value for the comparison between current and historic BI/NAP1 isolates. 2 CDAD deaths Severe CDAD Absent Present Adapted from McDonald LC, et al. N Engl J Med. 25;353: ; with permission. Hubert B, et al. Clin Infect Dis. 27;44: Treatment of CDAD Initial treatment options Metronidazole* Vancomycin Adjunctive therapies Rifampin* Probiotics* Immunoglobulin (IVIG)* Fecal transplantation *Not FDA-approved for the treatment of CDAD. Initial Treatment Options Metronidazole Vancomycin Oral administration preferred 5 mg PO TID for 14 days Historical first-line agent Effective in enteral (oral or rectal) form only 125 mg PO QID for 14 days Typically reserved for severe disease PO=orally; QID=four times a day; TID=three times daily. 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:

5 Historical Response to Initial Treatment Agent Response Rate* Relapse Rate Time to Resolution Metronidazole 94-95% 5-16% days Vancomycin 94 - % 15-16% days Recent Observational Reports of Response of C. difficile-associated Infection to Metronidazole Therapy 1 Reference Response Rate Relapse Rate Fernandez A, et al. J Clin Gastroenterol. 24;38: /99 (62%) *Successful treatment of the initial episode of C. difficile-associated disease. Johnson SJ, Gerding DN. Clostridium difficile. In: Antimicrobial Therapy & Vaccines. 2nd edition. Yu V, et al., eds. New York: Apple Trees Productions; 22. Musher DM, et al. Clin Infect Dis. 25;4: Pépin J, et al. Clin Infect Dis. 25;4: /27 (78%) 47/161 (29%) 323/435 (74%) 9/323 (34%) Markers of Severe Disease Marked leukocytosis Colonic thickening on CT scan Ascites on CT scan Pseudomembranes on endoscopy Hemodynamic instability Severe abdominal distension, pain Oral Vancomycin vs Metronidazole in Severe CDAD Prospective, randomized, double-blind, placebocontrolled trial Vancomycin 125 mg PO QID x days vs Metronidazole 25 mg PO QID x days Patients stratified by disease severity Severe disease defined as admission to an ICU, presence of pseudomembranes on endoscopy, or 2 of the following Age > 6 years Temperature > 1 F Albumin level < 2.5 mg/dl White blood cell count > 15, cell/mm 3 Zar FA, et al. Clin Infect Dis. 27;45:August 1 [Epub ahead of print]. Oral Vancomycin vs Metronidazole in Severe CDAD 172 patients enrolled and 15 completed the trial Percent of Patients Mild CDAD (n=81) 9 98 Metronidazole Vancomcyin P = NS 2 Success Failure Zar FA, et al. Clin Infect Dis. 27;45:August 1 [Epub ahead of print]. Percent of Patients Severe CDAD (n=69) Metronidazole Vancomcyin P =.2 3 Success Failure Multiple Recurrent CDAD Rates of recurrent CDAD 2% after first episode 45% after first recurrence 65% after 2 or more recurrences Antibiotic resistance after treatment not reported Repeated, prolonged courses of metronidazole not recommended Several empirical approaches have been advocated but most have no controlled data McFarland LV, et al. Am J Gastroenterol. 22:97:

6 Multiple Recurrent CDAD: Vancomycin Taper Regimen Oral Vancomycin Taper 125 mg QID x 7 days 125 mg BID x 7 days 125 mg daily x 7 days 125 mg every other day x 7 days 125 mg every 3 days x 7 days Kyne L, Kelly CP. Gut. 21;49: Infection Control Preventive Measures Infection Control Measure 1. Malamou-Ladas H, et al. J Clin Pathol. 1988;6: McFarland LV, et al. N Engl J Med. 1989;32: Bettin K, et al. Infect Control Hosp Epidemiol. 1994; 15: Bender BS, et al. Lancet. 1986;ii: Nolan NPM, et al. Gut. 1987;28: Olson M, et al. Infect Control Hosp Epidemiol. 1994; 15: Struelens MJ, et al. Am J Med. 1991;91:138S-144S. Intervention Efficacy Barrier precautions Gloves 1 Proven Hand-washing 2,3 Probable Private room/isolation 4-6 Probable Environmental cleansing Rooms 7-9 Possible Commodes Untested Single-use rectal thermometers Proven Endoscope disinfection 11,12 Probable Other Antibiotic restriction 13,14 Proven Metronidazole for asymptomatic carriers 4,15 Ineffective Adapted from Gerding DN, et al. Infect Control Hosp Epidemiol. 1995;16: ; with permission. 8. Kaatz GW, et al. Am J Epidemiol. 1998;127: Delmee M, et al. Eur J Clin Microbiol. 1987;6: Brooks SE, et al. Infect Control Hosp Epidemiol. 1992;13: Hughes CE, et al. Gastrointest Endosc. 1986;32: Rutala WA, et al. Infect Control Hosp Epidemiol. 1993;14: Pear S, et al. Ann Intern Med. 1994;12: Brown E, et al. Infect Control Hosp Epidemiol. 199;11; Johnson S, et al. Ann Intern Med. 1992;117: Summary Incidence is increasing Epidemic strain has been identified Optimal method of treating complicated C. difficile-associated disease is unknown Standard regimens may not be useful for severe or multiple recurrent disease Control measures prevent transmission.3.5 p q Y Chromosome Gitschier, J., Science, 1993 (261) p. 679 Testis Determining Factor (TDF) Gadgetry (MAC- locus) Channel Flipping (FLP) Catching and Throwing (BLZ-1) Self-confidence (BLZ-2) (note: unlinked to ability) Ability to remember and tell jokes (GOT-1) Sports Page (BUD-E) Addiction to death & destruction movies (MOV-E) Air Guitar (RIF) Ability to identify aircraft (DC) Pre-adolescent fascination with Arachnid and Reptilia (MOM-4U) Spitting (P2E) Sitting on the john reading (SIT) Inability to express emotion over the phone (ME-2) Selective hearing loss (HUH?) Total lack of recall for dates (OOPS)