Modern approach to Clostridium Difficile Infection Pseudomembranous Colitis: Principles for diagnosis and treatment Aggelos Stefos Internist, Infectious diseases Specialist Department of Medicine and Research Laboratory of Internal Medicine University of Thessaly, Medical School
There is no conflict of interest related to this presentation
Pseudomembranous colitis Clostridium difficile E. coli Campylobacter Salmonella Klebsiella oxytoca CMV IBD Ischemia NSAIDS Glutaraldehyde exposure Berdichevski T. Endoscopy 2010 Surawicz CM. Digestion 1999
1935 Discovered as a bacillus difficult to be cultured «bacillus difficilis» 1960s Occasional case reports in infected wounds 1978 Clostridium difficile C. difficile was identified as a cause of pseudomembranous colitis Gorbach SL. NEJM. 1999
Clostridium difficile: Microbiology Spore-forming, anaerobic, grampositive bacillus Toxin producing A & B Inflammatory diarrhea, colonic mucosal injury Leading cause of healthcare-associated infectious diarrhea in the US Rivals MRSA as the most common organism to cause health-care associated infections in the US McDonald LC, et al. Emerg Infect Dis 2006
CDC. Fact Sheet 2010 Clostridium difficile: Microbiology Colonizer in 2-3% of healthy adults 70% of infants Toxin release responsible for mucosal inflammation and damage Fecal-oral route Difficult to eradicate due to spore formation heat-resistant spores that can persist in the environment for several months to years
1. Ingestion of spores transmitted from other patients via the hands of healthcare personnel and environment Pathophysiology 3. Altered lower intestine flora (due to antimicrobial use) allows proliferation of C. difficile in colon 4. Toxin A & B Production leads to colon damage +/- pseudomembrane 2. Germination into growing (vegetative) form Sunenshine et al. Cleve Clin J Med 2006
Immune Response Patients who are colonized on admission are less likely to develop symptomatic infection Asymptomatic carriers had greater increases in serum IgG antitoxin A than those with diarrhea Higher levels of serum IgM and IgG antitoxin A in those with one episode, vs. multiple episodes Kyne L et al. NEJM 2000 Kelly CP. Eur J Gastroenterol Hepatol 1996
Risk Factors Exposure to antimicrobials (2-3 months) Exposure to healthcare facilities Older age >65years Underlying illness PPI GI surgery that affects microbiota Chemotherapy Denève C, et al. Int J Antimicrob Agents. 2009
Endoscopic diagnosis High clinical suspicion for C. difficile with negative laboratory assay(s) Prompt C. difficile diagnosis needed before laboratory results can be obtained Failure of C. difficile infection to respond to antibiotic therapy Atypical presentation with ileus or minimal diarrhea Tedesco FJ. Gastroenterology 1979
Glutamate Dehydrogenase (GDH) Enzyme Immunoassay (EIA) for toxins A and B Cell Culture Neutralization Assay (CCCNA) Toxigenic Culture (Culture and CCNA) Laboratory Diagnosis Stool Culture Molecular assays (PCR)
Test Advantage Disadvantage Testing Toxins Enzyme immuno-assay (EIA) CDI: Testing Detects toxin A or both A & B Rapid (same day) Less sensitive 63-94% Tissue culture cytotoxicity assay Provides specific and sensitive results for C. diff 67-100% -Detect toxin B -Technical expertise -Expensive -24-48 hours Organism ID Glutamate Dehydrogenase Rapid, sensitive, may prove useful as a triage or screening tool Not specific, toxin testing required to verify diagnosis PCR Rapid, sensitive, detects presence of toxin gene Expensive Special equipment Stool culture Most sensitive test available when performed appropriately False-positive results if isolate is not tested for toxin labor-intensive; requires 48 96 hours
Best Strategy for C. difficile Testing Testing should be performed only on diarrheal stool Testing asymptomatic patients is not indicated Testing for cure is not recommended IDSA Guidelines. Infect Control Hosp Epidemiol 2010
Best Strategy for C. difficile Testing For clinical use: two-step testing uses initially EIA detection of GDH for screening followed by EIA for toxin or PCR for toxin gene confirmation Gold standard are: stool culture followed by toxigenic culture assay and cell culture cytotoxicity assay Toxin is very unstable, degrades at room temperature, and undetectable within 2 hours (false negative results) IDSA Guidelines. Infect Control Hosp Epidemiol 2010
Repeat Testing Conclusion: Repeat tests appears rarely useful. Luo and Banaei, et al. J Clin Microbiol 2010
Best Strategy Possible false negative result GDH EIA EIA Toxin + = Repeat test if you suspect miscollection Pos. CDI of stools Positive Neg.= Neg. CDI EIA Toxin Negative Proceed to endoscopy 10% of positive samples are not detected Molecular Assay Treat the patient upon clinical suspicion Neg.=Neg. CDI Pos.=Pos. CDI Surawicz CM, et al. American College of Gastroenterology Guidelines. Am J Gastroenterol 2013
TREATMENT OF CDI
Treatment Stop or narrow antibiotics Replacement of fluid and electrolytes Metronidazole Vancomycin Fidaxomycin Alternatives Rifaximin Fecal Microbiota Translpantation Surgical management
Metronidazole Not FDA approved for CDI Mechanism: disrupts protein synthesis resulting in cell death in anaerobic bacteria Dose: 500 mg PO Q8h, 500 mg IV Q6-8h Pharmacokinetics: rapidly absorbed Concentration in colon minimal Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009
Metronidazole Use: effective for mild disease Adverse effects Metallic taste, nausea, disulfiram reaction Neurotoxicity, primarily manifested as paraesthesias Paraesthesias are more common with prolonged exposure Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009
FDA approved for CDI Vancomycin Mechanism: inhibits the growth of C.Difficile (bacteroistatic) Dose: 125mg PO Q6h; 500 mg PR IV administration does not treat CDI Oral capsules (expensive) IV product used orally (in hospital administration) Retention enema Cohen SH et al. IDSA Guidelines 2010 Dubberke ER et al. AJT 2009
Fidaxomicin FDA approved for CDI in May 2011 Inhibition of bacterial DNA dependent RNA polymerase resulting in inhibition of protein synthesis in susceptible organisms and cell death (bactericidal) Narrow -spectrum antibiotic, mainly directed against Clostridium difficile Prolonged post antibiotic effect Less effect on normal colonic flora In vitro inhibition of Clostridium difficile sporulation and toxin production Tannock GW, et al. Microbiology 2010 Babakhani et al J Antimicrob Chemother. 2013 Babakhani et al Clin Infect Dis. 2012 Βabakhani F, et al. Antimicrob Agents Chemother 2011
Patients who acquired VRE (%) Low risk of acquisition of vancomycin-resistant enterococci (VRE) 40 30 Comparative effects of fidaxomicin and vancomycin on acquisition of VRE p<0.001 31% 20 10 0 7% 8/114 41/133 Fidaxomicin Vancomycin Nerandzic MN, et al. Clin Infect Dis 2012
Mean log 10 CFU per gram of faeces Activity against Bacteroides fragilis Colonic levels of B. fragilis before (Day 0) and after treatment (Day 10) p=0.56 (NS) p=0.03 8 7 6 7.0 7.3 7.4 Fidaxomicin 200 mg bid (n=12) 5 4 3.6 Vancomycin 125 mg qid (n=8) 3 2 1 0 Day 0 Day 10 Day 0 Day 10 Louie TJ, et al. Antimicrob Agents Chemother 2009
Fidaxomicin Non-inferior to oral vancomycin Lower rate of recurrence of non-nap1 strain Minimal drug interactions Adverse events: nausea, vomiting, constipation (mild) 200 mg PO BID x 10 days Shue et al. Antimicrob Agents Chemother 2008 Louie TJ et al. NEJM 2011
Classifying Disease Severity Clinical Definition Supportive Clinical Data Initial episode, mild or moderate Initial episode, severe Initial episode, severe, complicated WBC < 15,000 cells/mcl OR Scr < 1.5 x above baseline WBC > 15,000 cells/mcl OR Scr > 1.5 x above baseline Hypotension or shock, ileus, megacolon Cohen SH et al. IDSA Guidelines 2010
Fidaxomicin vs Vancomycin Louie TJ et al. N Engl J Med 2011
CID 2013
Theory: Restoration of fecal flora and colonization resistance Data: 1958 to 2000: 9 reports (68 patients); cure rate ~90%. 2003: 18 patients; fecal filtrate (stool transplant); 1 of 16 survivors had a single subsequent recurrence; pre-treated with vancomycin and omeprazole; instilled through nasogastric tube. Test donor: enteric pathogens, C. difficile, ova and parasites, HAV, HBV, HCV, HIV, RPR
Identify patients at risk of recurrence Consider treatment with fidaxomicin from the first episode Debast SB et al. ESCMID Guidelines. CMI 2014
Debast SB et al. ESCMID Guidelines. CMI 2014
Diverted loop ileostomy Alternative surgical management in fulminant colitis 42 patients Prevention of colectomy in 93% Mortality 19% vs 50% Administration of Vanco from ileostomy Neal MD et al. Ann Surg 2011
PREVENTION STRATEGIES
Reduce Risk of CDI Acquisition: Reduce use of high risk antimicrobials Antimicrobial Stewardship Reduce unnecessary antimicrobial use Effective in outbreak and non-outbreak settings 1. Valiquette L. Clin Infect Dis. 2007;45:S112-121; with permission. 2. Fowler S. J Antimicrob Chemother. 2007;59:990-995.
Contact Precautions http://www.medscape.org/viewarticle/558476
Supplemental Prevention Strategies: Rationale for Soap and Water: Lack of efficacy of alcoholbased handrub against C. difficile Oughton et al. Infect Control Hosp Epidemiol 2009;30:939-44.