What’s New for Clostridium difficile and other Infectious Diarrheas 2014

1. What’s New for Clostridium difficile and other Infectious Diarrheas 2014 John Lynch MD MPH Harborview Medical Center University of Washington

2. http://bit.ly/1wb7KOz

3. Airline food linked to illnesses May 20, 2005 HONOLULU, Hawaii (AP) -- Contaminated carrots served on several flights out of Honolulu likely caused 45 people to suffer food poisoning across 22 states, Japan, Australia and American Samoa, a state epidemiologist said Thursday.

4. Airline food linked to illnesses May 20, 2005 The outbreak has sparked one lawsuit, filed Thursday, against airline caterer Gate Gourmet Inc., which included the carrots in meals served last August 22-24. The company, based in Virginia and Switzerland, was sent a warning letter by the federal FDA on April 21 citing violations found in a February inspection of its Honolulu facility -- such as a "pink slimy substance" dripping onto the conveyor of the pot washing machine, live cockroaches and flies, and mold growing on the windows of a refrigerator. Gate Gourmet provides meals for Northwest, Delta, United, Hawaiian and Aloha airlines.

5. Pathogenic Mechanisms of Diarrhea • Toxins: • Preformed: S aureus, C perfringens, B cereus • Formed in the intestine by ingested bacteria: • Stimulate intestinal secretion: V cholerae, enterotoxigenicE coli • Cytotoxins: C difficile, Shigella, enterohemorrhagic E coli • Invasion: Shigella, Salmonella, Campylobacter, Yersinia • Disruption of enterocytes leading to decreased absoprtion: Giardia, Cryptosporidium Fred Buckner MD

6. Diarrhea is # 2 highest ID mortality with 2.16 M deaths/year What is # 1? • HIV/AIDS • Malaria • Tuberculosis • Lower respiratory infections • MRSA

7. What are the four leading causes of infectious diarrhea in children <2 yrs in developing countries? • Rotavirus • Cryptosporidium • ETEC • Shigella Global Enteric Multicenter Study (GEMS). Lancet 382:209, 2013

8. 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

9. Case 1 • 36 y/o man has crampy abdominal pain, bloody diarrhea x 1 day, and fever (102). He just returned from a 1 month trip to India and Thailand. • What is this syndrome? • Dysentery • What else do you want to know about the patient? • HIV status? • Other medications? Antibiotics? Immunosuppressives? • Sexual contacts? (Could this be proctitis?) • Foods? (e.g. shellfish are risk for vibrios) • Other travelers with similar illness?

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

11. Agents of diarrhea based on localization within the intestine

12. Case 1: (Scenario A) Pt is otherwise healthy and taking no medications. Stool studies are sent. • Do you want to give empiric treatment? • What antibiotics? • Azithromycin 500 mg PO QD x 3 days (Note: C. jejuniresistance to FQs is widespread) • Antimotility drugs? • Usually not for dysentery, although they are probably safe if antibiotics are being co-administered

13. Recommended treatments • Shigellaspp. • Cipro (or other FQ) 750 mg PO QD x 3 days • Campylobacter jejuni • Azithromycin 500 mg PO QD x 3 days • Salmonella (non-typhoidal) • Mild disease: none* • Possible bacteremia: • Levo (or other FQ) 500 QD • 7 days if immune competent • 14 days if immune suppressed • Aeromonas, non-cholera vibrios, Yersina: treat as for Shigella *Onwuezobe et al. Cochrane Database Syst. Rev. 2012

14. Case 1: Scenario B Instead of India, the patient just returned from Germany (June, 2011) • He has dysentery symptoms but afebrile • What are you concerned about? • STEC (shiga-toxic producing E. coli) • Including non-O157 serotypes (e.g., O104) • How do you treat? • Supportive. No antibiotics!

15. Germany outbreak, May 2011Shiga toxin-producing E. coli (STEC) • By July, 2011: • 4000 illnesses • 823 pts with hemolytic uremic syndrome (HUS) • 50 deaths • 71% females • Five confirmed travel-associated cases in USA. • Cause of outbreak: • E. coli serotype O104:H4 • Produces: Shiga toxin 2 AND aggregative adherence factors • Source:

16. Case 1: Scenario C • Traveler to India with dysentery; stool O&P shows: Entamoeba histolytica/Entamoeba dispar trophozoites have a single nucleus, which have a centrally placed karyosome and uniformly distributed peripheral chromatin.    E. histolytica/E. dispar trophozoites usually measure 15 to 20 µm (range 10 to 60 µm), tending to be more elongated in diarrheal stool. Erythrophagocytosis (ingestion of red blood cells by the parasite) is the only morphologic characteristic that can be used to differentiate E. histolytica from the nonpathogenic E. dispar.  However, erthrophagocytosis is not typically observed on stained smears of E. histolytica. Treatment: MTZ 750 mg TID x 5-10 days, followed by a luminal amebicide Paromomycin 500 mg TID x 10 d Iodoquinol 650 mg TID x 20 d

17. Drug side effects • Metronidazole: • Nausea/vomiting • Metallic taste • Peripheral neuropathy • Seizures • Black Box warning: Carcinogenic • Pregnancy: category B • Paromomycin (oral): non-absorbed aminoglycoside • Nausea/diarrhea • Iodoquinol: • Optic neuritis • Peripheral neuropathy

18. Case 2 65 y/o man with DM, COPD is hospitalized with CAP and dehydration. He is treated with ceftriaxone and azithromycin. On HD #5 he is ready for discharge except he has a new fever of 102 F, abdominal cramping, and watery diarrhea. Labs: WBC 21,000 (from 11,000), Cr 1.7 (from 1.4)

19. Antibiotic-associated Diarrhea DDx Osmotic Diarrhea C difficile infection Antibiotics alter colonic microflora (dysbiosis) Impaired carbohydrate fermentation C difficile colonizes bowel Increased osmotic concentration in colonic lumen Organism grows and releases toxin Osmotic diarrhea (80%) Toxin mediated diarrhea and colitis (20%) adapted from UpToDate 2007

20. Biology of C difficile • Obligate anaerobic, Gram-positive, spore-forming rod • Difficult to isolate due to slow growth compared to other clostridia(1), resistant to high temps and 70% ethanol • Vegetative (replicating) and spore (dormant, transmissible) phases 1. Hall and O’Toole

21. Biology of C difficile • Toxin A and Toxin B • TcdA is an enterotoxin, historically assoc with virulence • TcdB is a cytotoxin assoc with outbreaks of severe disease • Binary toxin in 6% - 12.5% of strains, disrupts cell cytoskeleton • Surface proteins for adherence to epithelial cells stimulate inflammation, upregulated by ampicillin and clindamycin 1. Hall and O’Toole

22. C. difficile hypervirulent strain • Known as: 027/NAP1/BI epidemic strain • 16-fold increased expression of toxin A and 23-fold expression of toxin B • Toxin is produced earlier in the course of CDI • The strain is associated with increased severity of disease, death, and higher recurrence rates • Uniformly quinolone resistant • UW/Harborview perform reflex testing to identify 027/NAP1/BI strains* *How is this information being clinically used? Maybe go straight to Vanco instead of metronidazole? McDonald et al. N Engl J Med. 2005;353:2433-41. Warny et al.Lancet. 2005;366:1079-84. Stabler et al. J Med Micro. 2008;57:771–5. Akerlund et al. J ClinMicrobiol. 2008;46:1530–3.

23. Community-acquired CDAD • ~20% of CDI is community associated (20-50/100,000) • CDC, 8 EIP surveillance sites, 2009-2011 • 984 patients with community-associated CDI • 35.9% did not receive antibiotics* • 18% had no outpatient healthcare exposure • 40.7% had low-level outpatient healthcare exposure • No healthcare exposure: higher exposure to infants under 1 year and household members with CDI • Trend towards more PPI use among those w/o abx exposure Chitnis JAMA Internal Med 2013

24. C. difficile infection Risk factors for CDI: Which is false? • Increasing age • Systemic antibiotic therapy • Use of proton pump inhibitors • Female sex • Presence of comorbid conditions • Contact with active carriers • Inflammatory bowel disease

25. C. difficile infection Risk factors for CDI: Which is false? • Increasing age • Systemic antibiotic therapy • Use of proton pump inhibitors • Female sex • Presence of comorbid conditions • Contact with active carriers • Inflammatory bowel disease

26. Risk Factors for CDAD • Infection • Older age: increases 2% every year after 18yo • Antibiotic use • PPI use • More often NAP1 strains • Colonization • Hospitalization • Chemotherapy • PPI/H2-blockers • Antibiotic exposure • Acquisition of C difficile Main modifiable risk factors Loo NEJM 2011

27. C difficile Testing • Enzyme immunoassay • rapid, low cost, simple • Sensitivity 60%-80% • PCR for toxin B gene • Sensitivity 98.8% • Specificity 90.8% • When hospitals switch to PCR, 2-fold increase in rates and case load Belmares SHEA 2011 Meeting

28. 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 • No “test of cure”

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

30. C difficile Treatment- Drugs • Metronidazole • Vancomycin • Fidaxomicin • Nitazoxanide • Since 2000, failure rates increased from 2.5% to >18%, and >60% after multiple recurrences

31. Fidaxomicin • Fidaxomicin: Narrow spectrum macrocyclic antibiotic. Small study showed lower rate of early recurrence with fidaxomicin compared to vancomycin. • 15% vs. 25% recurrence rates (Advantage only for “non-epidemic”strains) NEJM 364:422, 2011

32. Crook CID 2012

33. 54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly.Imaging:

34. C. difficile infection (CDI) Among risk factors for and predictors of SEVERE CDI, which is false? • Age >65 • Neonates • Narcotic medication use • Immunosuppressive medication use • Altered mental status • Fever • Hypoalbuminemia • Acute kidney injury or chronic kidney disease • 10 bowel movements per day • Leukocytosis

35. C. difficile infection (CDI) Among risk factors for and predictors of SEVERE CDI, which is false? • Age >65 • Neonates • Narcotic medication use • Immunosuppressive medication use • Altered mental status • Fever • Hypoalbuminemia • Acute kidney injury or chronic kidney disease • 10 bowel movements per day • Leukocytosis

36. 54 year old man with DM in the hospital for tx of pneumonia x 5 days, now with diarrhea, WBC 26K, lactate of 4, hypotensive and has a tender belly.Options?

37. Indications for Operative Management Neal Ann Surgery 2011

38. Surgery • Surgical intervention in up to 20% of cases (?) • Post-operative mortality 35% to 80% • Traditional: subtotal colectomy with resection based on visual exam + end ileostomy • New approach? Markelov Am Surg 2011

39. Colon sparing surgery

40. Clostridium difficileand Surgery • 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??

41. Case 4 Pt with C. diff recurence following 14 day course of MTZ 500 PO TID. What next? • About 1/3 of patients have recurrence within 60 days

42. CDI: 2nd recurrence • Tapering doses of Vanco (varying regimens) • 125 mg PO QID x 2 wk • 125 mg PO BID x 1 wk • 125 mg PO QD x 1 wk • 125 mg PO every 2 days x 4 doses • 125 mg PO every 3 days x 5 doses OR • 125 mg PO QID x 10 d followed by • 125 mg PO Q-3 days x 10 doses NEJM 359:1932, 2008 CID 58:1507, 2014

43. C difficile and Recurrence • Most patients respond to therapy • 15% to 30% recur • Of those who recur 40% have a 2nd recurrence • Of those with 2 recurrences, 65% have a 3rd

44. Risks for Relapse based on EMR Hebert ICHE 2013

45. CDI: 3nd recurrence

46. CDI: 3nd recurrence May soon become preferred treatment for second or even first relapses • Konejetiet al, Cost-effectiveness of competing strategies for management • of recurrent Clostridium difficile infection: a decision analysis. Clin. Infect. Dis. 58:1507, 2014

47. Suggested Indications Recurrent or relapsing CDI defined as: at least 3 episodes of mild to moderate CDI and failure of 6 to 8 weeks of vancomycin with or without an alternative antibiotic (such as rifaximin or nitazoxanide) Fecal Microbiota Transplantation Workgroup

48. Fecal Microbiota Transplantation • Transfaunation, FabriciusAquapendente in the 17th Century • 1958, Eiseman treated 4 patients with pseudomembranous colitis

49. Fecal Microbiota Transplantation • Fecal retention enemas common till 1989 • NG tube in 1991 • Colonoscopy in 2000 • Self-administered enemas in 2010 • ~325 reported cases worldwide, ¾ by colonoscopy or retention enema

50. Van Nood NEJM 2013