1 / 80

Clostridium Difficile Associated Diseases

2. . . . CDAD. AAD antibiotic-associated diarrhea. . hospital-acquired diarrhea. . Antibiotic Associated Diarrhea?. Most causes unknown. Several candidates studiedClostridium difficile is the major recognized cause Candida speciesClostridium perfringensStaphylococcus aureusSerendipitous inf

damaris
Download Presentation

Clostridium Difficile Associated Diseases

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. Clostridium Difficile Associated Diseases ???, M.D. PhD Division of Infectious Diseases Infection Prevention and Control Team The First Hospital of China Medical University May 2010

    3. Antibiotic Associated Diarrhea? Most causes unknown. Several candidates studied Clostridium difficile is the major recognized cause Candida species Clostridium perfringens Staphylococcus aureus Serendipitous infection by viruses, Salmonella, etc. Non-infectious changes in colonic fatty acid and carbohydrate metabolism induced by antibiotics

    4. C difficile-causative agent in: 10-25 % of patients with AAD 50-75 % of patients with antibiotic-associated colitis (AAC) 90-100 % of patients with PMC Aslam et al, Lancet Inf. Dis, 2005

    5. Confusing terminology Antibiotic-associated diarrhea(AAD) C. difficile is only one cause Clostridium difficile-associated diarrhea(CDAD) diarrhea + positive stool test Clostridium difficile colitis(CDC) underlying pathologic process Pseudomembranous colitis(PMC) endoscopic demonstration of exudative lesions Toxic megacolon radiologic and surgical diagnosis

    6. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    7. History 1893-first case of PMC -reported as diphtheritic colitis. 1935-“Bacillus difficile” first isolated -Hall & O’Toole 1970s-antibiotic-asociated colitis identified. 1977 - Birmingham General Hospital-C. difficile identified as cause 1978-C. difficile toxins identified in humans. 1979-therapy with metronidazole or vancomycin 2000-increased incidence and virulence

    8. Why are we concerned? Increasing numbers of infections. Potential for severe disease Emergence of hypervirulent strains that may be more transmissible and/or cause more severe disease e.g. ribotype O27. Concerns over possible antibiotic resistance. Increasingly recognized as a major nosocomial pathogen capable of causing outbreaks

    9. Increase in cases More than 50,000 cases reported in England in 2007 Fifty-fold increase since 1990; 20% of cases <65

    10. National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed or Any Diagnosis

    11. C.difficile deaths CDAD cited on 1 in every 250 death certificates in 2005 Further 72% increase in 2006

    12. CDAD Rates and Mortality Increase in Parallel with Patient Age

    13. Acute care hospitals with CDAD outbreaks between 2001 and 2004

    14. Public concern

    15. Official reports

    16. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    17. CDAD Transmission: Carried in GIT of 3% of general population Up to 30% of hospitalized patients become colonized Fecal-Oral Route -sensitive individuals can become infected if they touch items or surfaces that are contaminated with feces and then touch their mouth or mucous membranes. Hands of hospital personnel are important intermediary -can spread the bacteria to other patients or contaminate surfaces with contact.

    18. Exotoxin A (enterotoxin) : MOA unknown/causes outpouring of fluid and a watery diarrhea Exotoxin B (cytotoxin): damages colonic mucosa leading to pseudomembrane formation mechanism is via ADP-ribosylation of Rho (a GTP-BP) this causes depolymerization of actin in the cytoskeleton Pathogenicity of C. difficile

    19. Normal bacterial flora -prevent establishment of C. difficile colonization of the GI tract Antibodies (serum and mucosal?) -prevent CDAD disease if colonization occurs -Antibodies are probably first acquired in infancy Host Protection Against CDAD Occurs at Two Levels

    20. Risk Factors Age >65 years Severe underlying disease Antimicrobial therapy Clindamycin, 3rd G cephalosporins, penicillin, FQs Nasogastric intubation Anti-ulcer medications Proton pump inhibitors Chemotherapy Long hospital stay or long-term care residency

    21. Role of Antibiotics in CDAD Any antibiotic may be associated with CDAD. Disruption of normal intestinal flora -the determining antibiotic event susceptibility window: following an antibiotic there is a variable-length window during which a patient is susceptible. C. difficile resistance to the precipitating antibiotic is thought to be important, but is not always present (e.g. ampicillin).

    22. Time-Course of Antimicrobial Effect on the Normal Gut Flora and CDAD Risk 1. C. difficile resistance to the antibiotic used enables the organism to infect while the antibiotic is being given. 2. Resistant and Susceptible C. difficile can infect after the antibiotic has been stopped and the flora remains disrupted.

    23. Original (Incorrect) Hypothesis for C. difficile Hospital Infection

    24. Rate of CDAD in Patients Colonized and Non-colonized with CD Data from four prospective studies in which rectal swab cultures were obtained weekly from hospitalized patients

    25. Revised Hypothesis for CDAD

    26. Pathogenesis of CDAD

    28. TcdC Variants

    29. Epidemic strains from Quebec/UK/US-carry binary toxin/have tcdC deletion/toxinotype III tested in vitro for toxin A and B,(compared with non-epidemic toxinotype 0 strains). Epidemic C. difficile Strains Produce Increased Toxins A and B in vitro

    30. Epidemic C. difficile Strains Produce Increased Toxins A and B in vitro

    31. States with the epidemic strain of C. difficile confirmed by CDC 11/15/2005 (N=16)

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

    33. Outbreak Strains are NOT New: Comparison of Historic and Epidemic REA “BI” types Historic BI (Bee-Eye) isolates were found from 1983 to 1992, were of BI types BI1 to BI5, contained binary toxin genes, and the 18 bp deletion in the tcdC gene. Historic isolates were NOT resistant to newer fluoroquinolone antibiotics. New epidemic BI isolates (types BI6-BI19) are uniformly resistant to the newer FQs (gatifloxacin, moxifloxacin).

    34. Is Increased Toxin A and B in vitro the Answer to Increased Pathogenicity?

    35. What is the Role of Fluoroquinolone Resistance? Resistance to newer fluoroquinolones (gatifloxacin and moxifloxacin) is the only detectable difference between historic nonepidemic BI group isolates and epidemic current BI group isolates. Fluoroquinolone use has been a risk factor for CDAD in hospitals with outbreaks caused by the epidemic strain of C. difficile.

    36. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    37. Clinical Presentation Asymptomatic colonization Mild disease Non-bloody diarrhea Mild abdominal tenderness Severe disease Pseudomembranous colitis Paralytic ileus Ileitis Toxic megacolon Ulcerative colitis Perforation(peritonitis) Ascites

    38. Clinical presentation: Epidemic Similar to old cases but more severe More toxic megacolon (less diarrhea) Profound leukemoid reactions Severe hypoalbuminemia (PLE) Septic shock Need for colectomy Increased mortality

    40. -Other causes of toxic megacolon are UC, Crohn’s, ischemic colitis, amebiasis, bacterial dysentery, pseudomembranous colitis -cecal perforation is imminent when the transverse diameter reaches 9 cm (normal diameter of cecum is 5 cm, of transverse colon is 4 cm, of descending colon is 3 cm)-Other causes of toxic megacolon are UC, Crohn’s, ischemic colitis, amebiasis, bacterial dysentery, pseudomembranous colitis -cecal perforation is imminent when the transverse diameter reaches 9 cm (normal diameter of cecum is 5 cm, of transverse colon is 4 cm, of descending colon is 3 cm)

    41. Leukocytosis and CDAD – Do Not Miss this Clue to Possible Fulminant Disease Toxin A is a potent neutrophil chemoattractant CDAD found in 16% of patients with WBC>15,000/mm3 25% of patients with WBC>30,000/mm3. Clin Infect Dis 2002;34:1585-92 58% of 60 patients with unexplained WBC >15,000/mm3 had CD toxin in stool. AJM 2003;115:543-6

    42. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    43. Diagnosis of CDAD S/S Endoscopy (pseudomembranous colitis) Culture Cell culture cytotoxin test EIA toxin test PCR toxin gene detection

    45. Pseudomembranous Colitis

    46. Laboratory diagnosis Culture Easy and sensitive but slow High carriage rates in hospitalised patients Non-toxigenic isolates detected as well Not used for initial diagnosis now Toxin detection in faeces Cell culture “Gold standard” but relatively slow Enzyme immunoassays(EIA) Rapid/cheap/specific Need test to include Toxin A and B Variable sensitivity Asymptomatic carriage issue Single negative result does not exclude infection Regardless of method you must take clinical picture into account!

    47. Performance characteristics of diagnostic tests

    48. CDAD Case Definition Stool characteristic Diarrhea (most common) No diarrhea Associated with toxic megacolon or ileitis Documented by radiology = 1 of the following Stool positive for: C. difficile toxin C. difficile determined to be a toxin producer Pseudomembranous colitis by: Endoscopy Histological exam

    49. CDAD vs Antibiotic-Associated Diarrhea

    50. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    51. Treatment of CDAD - General principles Whenever possible withdraw the offending antibiotic Use oral antimicrobials whenever possible Be patient -some improvement seen in first 2 days but mean time until resolution of diarrhea is 2-4 days. Don’t call them nonresponders until 6 days of therapy Treat for 10-14 days Avoid antiperistaltic agents

    52. Muto CA, et al. Infect Control Hosp Epidemiol 2005;26:273-280 Rate of antibiotic resistance in 91 C. difficile isolates from a Pittsburg hospital that experienced a large CDAD outbreak beginning January 2000

    54. Vancomycin Enemas Non-randomized open trial -6/8 patients with ileus responded in 4-17 days -2 patients died, one following colectomy Inf Cont Hosp Epidemiol 1994;15:371-381 Adjunct treatment for severe C. difficile Entry criteria not clearly defined -8/9 cases resolved Apisarnthanarak et al Clin Inf Dis 2002;35:690-96

    55. Patient Management

    56. Relapsed Disease Due to spores that germinate in gut after withdrawal of the antibiotic Happens in 20+ % of patients who initially respond. Increased risk in Age > 65 Increased severity of underlying disease Exposure to additional antibiotics after treatment Low serum IgG response to toxin A Half of relapses are actually re-infections Antibiotic resistance unlikely Most patients will respond to a second course of the same antimicrobial

    57. Treatment of Multiple Relapses No controlled studies, lots of anecdotes and “personal favorite” regimens -tapering courses of vancomycin or metronidazole -vancomycin plus rifampin -yogurt or other Lactobacillus preparations -Saccharomyces boulardii plus antibiotics -Intravenous immune globulin -Cholestyramine with or without antimicrobials

    59. Fecal bacteriotherapy effective: 94-100% success in limited published investigations reduces the risk of resistant bacteria or drug allergy safe: No published adverse effects Low-tech therapy that can be administered easily inexpensive

    60. Treatment Controversies Is metronidazole still effective therapy for CDAD? Have clinically important metronidazole-resistant C. difficile strains been detected? The good news is that new treatment drugs are in clinical trials for the first time in 25 years.

    61. Retrospective Reports of Poor CDAD Responses to Metronidazole Reduced response rates and higher recurrence rates with metronidazole in 207 CDAD patients compared to prospective published studies. Musher DM et al, CID 2005;40:1586-90 Reduced response rates and higher recurrence rates with metronidazole in 438 Quebec patients treated in 2003-2004 than in 688 patients treated from 1991-2002: Epidemic strain identified in Quebec since 2003. Pepin J et al, CID 2005;40:1591-7

    62. Metronidazole Treatment Failure was Not Caused by Metronidazole(MTR) Resistance in One Study 10-year prospective surveillance: 14/632 (2%) episodes of CDAD did not respond to treatment with MTR Susceptibility of 10 isolates from MTR treatment failures compared to 20 isolates from MTR treatment successes:

    63. Treatment of First Recurrence of CDAD with MTD 33% of patients with 1st recurrence had a 2nd Recurrence rate correlates with age and LOS 64% second recurrences occurred within 30 days and the remainder between 31-60 days. Metronidazole was not inferior to vancomycin for treatment of first recurrence of CDAD Treatment of first recurrence with the same or a different agent made no difference in outcome Complications (shock, colectomy, perforation, megacolon, death) developed in 11% with first recurrence, a higher rate than previously observed

    64. Investigational Rx for CDAD

    65. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    66. CDAD prevention and control Antimicrobial stewardship -protocols/consumptionsurveillance/Audit and feedback Surveillance -active surveillance Education -staff and visitors Early diagnosis -timely stool specimens/toxin testing/

    67. CDAD prevention and control Isolation precautions -single rooms or cohorts / designated staff -hand washing facilities/en-suite toilet -dedicated care equipment/door kept closed Hand hygiene-handwashing or alcohol? Personal protective equipment (PPE) Environmental cleaning Use of care equipment

    68. CDAD prevention and control Hand hygiene Personal protective equipment (PPE) Environmental cleaning Use of care equipment

    69. CDAD prevention and control Hand hygiene Personal protective equipment (PPE) Environmental cleaning Use of care equipment

    70. CDAD prevention and control Hand hygiene Personal protective equipment (PPE) Environmental cleaning Use of care equipment

    71. CDAD prevention and control Hand hygiene Personal protective equipment (PPE) Environmental cleaning Use of care equipment

    72. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    73. Community Associated CDAD (CA-CDAD) and Peripartum CDAD Voluntary reporting of 23 CA-CDAD and 10 peripartum CDAD cases from 4 states over 28 months. CA-CDAD rate in Philadelphia was calculated to be a minimum of 7.6 per 100,000 population (no higher than previous community reports). 24% of the patients reported no antibiotic use in the previous 3 months (highly unusual, but not verified). 4 patients (12%) had exposure to another CDAD case. Only 2 isolates were recovered: each had the binary toxin gene and one had the tcdC gene deletion, but neither was toxinotype III (the new “epidemic strain”).

    74. CA-CDAD and Gastric Acid Suppression Community UK GP data base (1994-2004) searched for pts with CA-CDAD and use of gastric acid suppressives CA-CDAD rate increased from 1/100K to 22/100K. PPIs 23% CA-CDAD cases 8% controls (Adj Rate Ratio 2.9 (95% CI 2.4-3.4). H2 antagonists 8% CA-CDAD cases 4% controls (Adj RR 2.0 (95% CI 1.6-2.7). NSAIDS 38% CA-CDAD cases 24% controls (Adj RR 1.3 (95% CI 1.2-1.5). Antibiotics 37% CA-CDAD cases 13% controls (Adj RR 3.9 (95% CI 2.7-3.6).

    75. Stomach Acid-Suppressing Medications and Community-Acquired CDAD, England

    76. Are PPIs a Risk for CDAD in Canada? In 1187, 591 (50%) received abx and PPIs -CDAD rate of 9.3% [RR=2.1(95% CI 1.4-3.4)]. 596 received only abx -CDAD rate of 4.4% CMAJ 2004;171:33-38 Case control study of 94 CDAD patients, PPI use had an Adjusted Odds Ratio=2.6 (95% CI 1.3-5.0) CMAJ 2004;171:33-38 In 7421 admissions, 293 CDAD cases occurred, and PPI use had an Adjusted Hazard Ratio=1.0 (CI 0.8-1.3) CID 2005;41:1254-1260 In a case control study of 237 CDAD patients, PPI use in 47.3% of cases and 46.8% of controls (P=0.92) NEJM 2005;353:2442-9

    77. Role of Chemotherapy Administration in CDAD True incidence remains unknown Of 70 patiens hospitalized with diarrhea after chemotherapy ,1/3 responded to empiric metrinidazole or vancomycin Clostridium difficile can induced in animals with metrotrexate or 5- FU administration. Vancomycin added to the drinking water of the animals was found to be protective.

    78. History and Epidemiology Pathogenesis Clinical pictures Diagnosis Management Prevention and control Future Summary

    79. Summary CDAD-important hospital diarrhea and AAD Emerging epidemic C. difficile isolates are associated with higher CDAD rates and increased mortality. Candidate pathogenicity factors at present are increased toxin A and toxin B production, binary toxin, and FQs resistance, which is the only factor not found in nonepidemic, but FQs are not the only antibiotic risks. Emerging CA-CDAD The role of PPIs, chemotherapy as risk factors for CDAD remains elusive as well.

    80. Summary Treatment of CDAD -metronidazole and vancomycin till the maistay -metronidazole response may be reduced or slowed and recurrence rates increased, but retreatment is effective -vancomycin recommended in severe cases Prevention and control -alcohol gels remove more C. difficile spores than expected but are not as effective as hand washing.

    81. ???? THANK YOU

More Related