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Infectious Diarrhea

Infectious Diarrhea. ID Fellows Course July 2, 2010 Frederick S. Buckner, MD. Global mortality from selected infectious diseases. *WHO 2002. Intestinal Fluid Balance:. Site L In / L Out Efficiency Jejunum 9-10/4-5 50% Ileum 4-5/3-4 80% Colon 1.5/1.4 95%

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Infectious Diarrhea

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  1. Infectious Diarrhea ID Fellows Course July 2, 2010 Frederick S. Buckner, MD

  2. Global mortality from selected infectious diseases *WHO 2002

  3. Intestinal Fluid Balance: SiteL In / L OutEfficiency Jejunum 9-10/4-5 50% Ileum 4-5/3-4 80% Colon 1.5/1.4 95% Stool 100-200 ml 98-99% Diarrhea occurs when reabsorption decreases to around 95-96%; minor changes result in major fluid losses

  4. FIC-NIH

  5. Pathogenic mechanisms • Toxins: • Preformed: Staphylococcus aureus, Clostridium perfringens, Bacillus cereus • Formed in the intestine by ingested bacteria: • Stimulate intestinal secretion: Vibrio cholerae, enterotoxigenic E. coli • Cytotoxins: Clostridium difficile, Shigella, enterohemorrhagic E. coli • Invasion: Shigella, Salmonella, Campylobacter, Yersinia • Disruption of enterocytes leading to decreased absorption: Giardia, Cryptosporidium

  6. Is the pathology in the small bowel or colon?

  7. Agents of diarrhea based on localization within the intestine

  8. Important agents of infectious diarrhea

  9. www.staceysstuff.com/ images/diarrhea.jpg

  10. Case 1 • A 72 y/o man with Alzheimer’s disease is sent to the Emergency Room from his nursing home for evaluation of lethargy and fever. He has been incontinent of stool for 2-3 days and his attendants have started using diapers on him. The patient has a history of recurrent UTIs. Exam: T102°, BP 100/60, HR 120, RR24. Abd: moderate tenderness. Rectal: no masses, heme +

  11. Clostridium difficile Anaerobic spore forming bacillus

  12. Coloured transmission electron micrograph of Clostridium difficle forming an endospore (red) Dr Kari Lounatmaa/Science Photo Library

  13. Clostridium difficile colitis Normal colon Pseudomembranous colitis

  14. Overview • Epidemiology of C. difficile infections • Emergence of more virulent strains • Pathogenesis • Clinical spectrum • Diagnostic tests • Management • Fulminant cases • Recurrences • New treatments • Infection control

  15. Frequency of CDAD. Mortality from CDAD.

  16. Annual Incidence (per 100,000 Population) of C. difficile Infection in Sherbrooke, Quebec, 1991–2003 Kelly C, LaMont J. N Engl J Med 2008;359:1932-1940

  17. University of WashingtonC. difficile cases 2008-2010 Health Care + Community acquired Health Care acquired *2008: includes pts with + results after 48 hours **After 2008: Includes pts with + results after 72 hours

  18. C. difficile-associated disease:what’s changing? • Geographic spread of “epidemic” strains • Appearance of strains with increased virulence (?) • Spread of disease into “low risk” populations • Emergence of fluoroquinolones as a major risk factor for CDAD • Increasing failure rate with metronidazole therapy

  19. Recent reports

  20. Fulminant CDAD(Pittsburgh Hospital) 1989-992000 • CDAD rate 6.8 11.6 (rate/1,000 admissions) • Fulminant cases 1.6% 3.2% • Colectomies* 2.7/year 17/year *Recent surgery, immunosupression, and prior CDAD were common predisposing conditions Dallal RM, et al. Ann Surg 2002;235:363

  21. Epidemic strain • Emerged 2000-2003 • NAP1/027, REA Group BI / Toxinotype III • Previously an uncommon strain • First recognized in the 1980’s • Increased toxin production: • Toxin A: 16X • Toxin B: 23X • Binary toxin: unknown significance • Uniformly quinolone resistant in vitro Recent review on B1/NAP1/027 strain: Gastroenterology 136:1913, 2009

  22. States that have had > 1 hospital that has reported CDI caused by the B1/NAP1/027 epidemic strain as of October, 2008 (red).

  23. Clostridium difficileReservoirs (asymptomatic carriage) • 15-70% of healthy neonates (C. diff was discovered in 1933 during a study of the intestinal biota of newborns) • 3-8% of healthy adults • 7-14% of elderly hospital patients • Up to 18% of pregnant women have vaginal colonization

  24. Pathogenesis Asymptomatic C. difficile colonization Antimicrobial C. difficile exposure C. difficile-associated diarrhea Hospitalization Modified from: Johnson S,Gerding DN. Clin Infect Dis. 1998;26:1027-1036

  25. 50 40 30 20 10 0 0 1 2 3 4 Clostridium difficile acquisition is correlated to duration of hospitalization Percentage of patients who acquired c. difficile >4 <1 3-4 1-2 2-3 Length of hospital stay (wks) Johnson and Gerding J Infect Dis 1998; 26:1027

  26. Clostridium difficile diarrhea is toxin-mediated • Large clostridial toxins (LCTs): Large (>250 kDa), single-unit proteins which glycosylate small GTP-binding proteins (Rho, Ras) involved in cell cytoskeleton organization • Toxin A ‘enterotoxin’ • Toxin B ‘cytotoxin’ • Both toxins are pathogenic* *Lyras D et al. Nature 458:1176, 2009

  27. Normal Cytotoxic Effect

  28. Histopathology of CDAD Normal colon brush border Necrotic colon brush border (CDAD)

  29. Clinical Spectrum ofClostridium difficile Infections Syndrome Frequency • Asymptomatic colonization +++++++++ • Diarrhea (+ PMC) ++ • Pseudomembranous colitis + • Severe ileus/ Fulminant colitis <+

  30. Antimicrobial agents that may induce CDAD • Antineoplastic agents have also been associated with CDAD: • Doxorubicin, cisplatin, cyclophosphamide, methotrexate, chlorambucil

  31. Clostridium difficileRisk Factors • Additional risk factors in hospitalized pts. • Advanced age • Severity of underlying illness • Disruption of normal intestinal motility: enemas, stool softeners, pro-motility agents • PPIs (although spores are acid resistant. May be a marker of co-morbidity). • Adverse prognostic factors • Peak WBC > 20,000 (RR 4.8) • Peak creatinine > 2 (RR 3.1)

  32. Clostridium difficileClinical • Usually occurs after 5-10d of antibiotic Rx, but range from 1-70+ days • Diarrhea may range up to “cholera-like” • Fever: 30-50% • Mean peripheral WBC 15-16,000; 25% may have WBC > 35,000 • May present w/ toxic megacolon or acute abdomen without diarrhea, particularly in patients on opiates, anti-motility agents, or post GI-surgery • Case fatality rate ~2-3%

  33. Antibiotic associated diarrhea DDX Only 10-20% of AAD is due to C. difficile

  34. C. difficile disease diagnosis

  35. Toxic megacolon

  36. Pseudomembranous colitis “Accordion Sign”

  37. The d-zone, vol 37, 2008 http://uw.prnrx.org/therapyTopics.asp

  38. C. difficile testing at UWMC + HMCOrder: “Stool for C.difficile testing.” #1 Formed stool samples will be rejected #2 PCR for Toxin B gene* + C. difficile disease *Sensitivity: 98.8%, Specificity: 90.8%

  39. Previous C. difficile testing at UWMC + HMC #1 • C. difficile antigen assay (EIA) • Very sensitive (97%), not specific for disease • >95% negative predictive value + - #2 - • Combo-tox (A/B) testing (EIA) • >95% specificity #3 PCR for Toxin B gene + + - C. difficile disease Negative for C. difficile

  40. CDAD:Appropriate Testing • Only re-test after negative PCR if pre-test suspicion is VERY high • No need to order stool tests in triplicate! • No need to test for cure… pt comes out of precautions if diarrhea is gone and 7 days of treatment under his / her belt!

  41. CDAD:Treatment Basics • STOP the offending abx (if possible) • START anti-C.diff therapy as soon as you start to rule out CDAD (unless pt looks clinically great, in which case you could consider waiting for testing to come back). • AVOID anti-motility drugs.

  42. Clostridium difficileTreatment (circa 2005)

  43. Response Rates to Vancomycin and Metronidazole Therapy, According to the Severity of C. difficile Infection ≥ 2 points = Severe 1 point: Age > 60 Temp >101 F Albumin < 2.5 mg/dL WBC >15K 2 points: PMC at colonoscopy ICU patient Kelly C, LaMont J. N Engl J Med 2008;359:1932-1940

  44. Request imaging (Abd CT) and obtain surgery consult if evidence for toxic megacolon Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010

  45. Clostridium difficileTreatment: Special Situations • When to operate?? • Strong indications: • Megacolon • Prolonged and (?) irreversible ileus • Perforation • Mortality rates (in reported series) of cases requiring surgery range from 30 to > 50%. Are we waiting too long??

  46. Equivalent response rates of low dose and high-dose vancomycin Lefler DA and Lamont JT. Gastroenterology 136:1899, 2009

  47. CDAD:Treatment Pearls • Switch from metro to PO vanco if pt deteriorates, or if no improvement in first 3 days of therapy. • No role for IV vanco. • In SEVERE, COMPLICATED disease, you may combine IV metro with PO vanco (PR if ileus). • No tapering for first episode.

  48. Recurrent C. difficile Diarrhea • Occurs 6-25% • Retreat first-time recurrences with the same regimen used to treat the initial episode (usually MTZ) • Risk of subsequent episode in patients who already have had a recurrence: 45% • Antibiotic resistance not a factor in relapse

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