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

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Presentation on theme: "What’s New for Clostridium difficile and other Infectious Diarrheas 2014 John Lynch MD MPH Harborview Medical Center University of Washington."— Presentation transcript:

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

2

3 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. Airline food linked to illnesses May 20, 2005

4 The outbreak has sparked one lawsuit, filed Thursday, against airline caterer Gate Gourmet Inc., which included the carrots in meals served last August 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. Airline food linked to illnesses May 20, 2005

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, enterotoxigenic E 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 A.HIV/AIDS B.Malaria C.Tuberculosis D.Lower respiratory infections E.MRSA What is # 1?

7 What are the four leading causes of infectious diarrhea in children <2 yrs in developing countries? 1.Rotavirus 2.Cryptosporidium 3.ETEC 4.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 ml 98-99% Diarrhea occurs when reabsorption decreases to around %; 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? Small Bowel Colon Symptoms Nausea, bloating, cramping, gas, weight loss Fever, rectal pain, frequent painful stools Physical signs Dehydration, orthostasis, decreased skin tugor Fever, abdominal pain Diarrhea Large volume, watery Small volume, pasty, and/or blood, mucous Microscopic exam of stool Without inflammatory cells or blood, with/without mucous Inflammatory cells, blood, mucous

11 Agents of diarrhea based on localization within the intestine Small BowelColon Bacteria E. coli (ETEC, EPEC), Staphylococcus aureus, Clostridium perfringens, Bacillus cereus, Vibrio cholera, Salmonella sp. Campylobacter sp., Shigella sp., Salmonella sp., Clostridium difficile, Yersinia sp., STEC (0157:H7), Vibrio parahemolyticus, Plesiomonas shigelloides, Aeromonas hydrophila Viruses Rotavirus Norwalk agent Astroviruses Caliciviruses Cytomegalovirus Adenovirus Parasites Giardia lamblia, Cyclospora cayatenensis, Cryptosporidium parvum, Microsporidium sp., Dientamoeba fragilis, Isospora belli Entamoeba histolytica, Balantidium coli

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. jejuni resistance to FQs is widespread) Antimotility drugs? –Usually not for dysentery, although they are probably safe if antibiotics are being co- administered

13 Recommended treatments Shigella spp. –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 2011 Shiga toxin-producing E. coli (STEC) By July, 2011:By July, 2011: –4000 illnesses –823 pts with hemolytic uremic syndrome (HUS) –50 deaths –71% females Five confirmed travel-associated cases in USA.Five confirmed travel-associated cases in USA. Cause of outbreak:Cause of outbreak: –E. coli serotype O104:H4 –Produces: Shiga toxin 2 AND aggregative adherence factors Source: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 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 Antibiotics alter colonic microflora (dysbiosis) Increased osmotic concentration in colonic lumen Osmotic diarrhea (80%) Impaired carbohydrate fermentation C difficile infection Organism grows and releases toxin Toxin mediated diarrhea and colitis (20%) C difficile colonizes bowel 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% % 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 a)Known as: 027/NAP1/BI epidemic strain b)16-fold increased expression of toxin A and 23-fold expression of toxin B c)Toxin is produced earlier in the course of CDI d)The strain is associated with increased severity of disease, death, and higher recurrence rates e)Uniformly quinolone resistant f)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: Warny et al. Lancet. 2005;366: Stabler et al. J Med Micro. 2008;57:771–5. Akerlund et al. J Clin Microbiol. 2008;46:1530–3.

23 Community-acquired CDAD ~20% of CDI is community associated (20-50/100,000) CDC, 8 EIP surveillance sites, 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? a)Increasing age b)Systemic antibiotic therapy c)Use of proton pump inhibitors d)Female sex e)Presence of comorbid conditions f)Contact with active carriers g)Inflammatory bowel disease

25 C. difficile infection Risk factors for CDI: Which is false? a)Increasing age b)Systemic antibiotic therapy c)Use of proton pump inhibitors d)Female sex e)Presence of comorbid conditions f)Contact with active carriers g)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 Loo NEJM 2011 Main modifiable risk factors

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) 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) 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 AVOID anti-motility drugs No “test of cure” No “test of cure”

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

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) DrugCost for 10 day course Metronidazole$15-$30 Vancomycin pills$1100 Vancomycin (IV given orally)$40-$300 (compounding pharmacy) Fidaxomicin$2700 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? a)Age >65 b)Neonates c)Narcotic medication use d)Immunosuppressive medication use e)Altered mental status f)Fever g)Hypoalbuminemia h)Acute kidney injury or chronic kidney disease i)  10 bowel movements per day j)Leukocytosis

35 C. difficile infection (CDI) Among risk factors for and predictors of SEVERE CDI, which is false? a)Age >65 b)Neonates c)Narcotic medication use d)Immunosuppressive medication use e)Altered mental status f)Fever g)Hypoalbuminemia h)Acute kidney injury or chronic kidney disease i)  10 bowel movements per day j)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 difficile and 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: 2 nd 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 2 nd recurrence Of those with 2 recurrences, 65% have a 3 rd

44 Risks for Relapse based on EMR Hebert ICHE 2013

45 CDI: 3 nd recurrence

46 May soon become preferred treatment for second or even first relapses Konejeti et 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, Fabricius Aquapendente in the 17 th 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

51 Fecal Microbiota Transplantation One systemic review: – 317 patients, 8 countries, 27 case series/reports – Overall cure rate of 92% One long-term follow-up study – 5 US centers (including HMC) – F/U 3-68 months – 74% had resolution of diarrhea in <4 days – 82% had resolution with 5 days, 17% had improvement – 91% had primary cure, 98% secondary cure, 1 death of unk etiology while in hospice care Gough CID 2011 Brandt Am J Gastro 2012

52 Pre-FMT patient data Brandt Am J Gastro 2012

53 FMT: Nuts and Bolts Donors: no abx x 3m, no chemo, no HIV,HBV,HCV, ID, high risk behaviors, illicit drugs, incarceration, endemic diarrhea exposure, IBS, IBD, Giardia, cryptosporidium Pt abx till day -2 or -3, donor stool collected collected and used within 8hrs Dose: 6 tablespoons to entire donation ( cc) depending on institution All via colonoscopy into various parts of colon from terminal ileum to rectum Gough CID 2011

54 Post-FMT patient data Brandt Am J Gastro 2012

55 After FMT 53% of patients stated they would prefer FMT as 1 st treatment option with another recurrence 4 pts did not report improvement in abdominal pain after FMT Fatigue: 42% resolved, 51% improved, took avg of 4 weeks 4 pts w/ recurrence responded to vancomycin or nitazoxanide, 2 had successful 2 nd FMT 2 pts reported improvement in allergic sinusitis and arthritis 4 pts reported new conditions: peripheral neuropathy, Sjogren disease, ITP and RA

56 Fecal microbiota diversity after FMT Clin. Inf. Dis. 58:1515, 2014

57 Fecal transplantation Meta-analysis* of 317 pts (27 case series) –Disease resolution in 92% –Better outcomes with the following: Related donor (including spouse to partner) Administration by enema or colonoscope as opposed to gastroscope or NJ tube Increased volume (e.g. 500 mL and >50g of stool) Donor selection** –Exclude pts with HIV, HCV, IBD, others Gough E. et al. CID 53:994, 2011 Fecal Microbiota Transplantation Workgroup. Clin. Gastro. Hep. 9:1044, 2011

58 Fecal transplantation Clin. Inf. Dis. 58:1515, 2014 Unrelated donors Screened for HIV, etc., etc. No antibiotics for >6 months Avoid allergens (peanuts, shellfish, etc.) for 5 days Stool samples processed and frozen in glycerol (41 g per sample)

59 Fecal transplantation from unrelated donors (colonoscopy or NG tube?) Clin. Inf. Dis. 58:1515, 2014 ColonoscopyNG tube Cure with 1 st Rx8/10 (80%)6/10 (60%) With second Rx10/10 (100%)8/10 (80%) An additional 11 patients were treated by NGT with 10/11 cures Treatment details: no antibiotics for 2 days for all patients Colonoscopy: standard 4 liter PEG solution Administration of 90 cc of thawed inoculum to right colon Given dose of loperamide Nasogastric tube: Given omeprazole (up to 20 mg QD) x 2 days NGT inserted to stomach and position checked by Xray Administration of 90 cc of thawed inoculum to stomach Remove NGT and drink glass of water

60 Stool Substitute Transplant Therapy Two patients infected with hyper-virulent C difficile (ribotype 078) with recurrent disease RePOOPulate = 62 anaerobic bacterial isolates from a 41 yo woman Purified isolates sequenced and underwent drug susceptibility testing 33 isolates representing commensals were used for the substitute 100ml via colonoscopy Petrof Microbiome 2013

61 C difficile Prevention Stop antibiotic therapy if possible Probiotics

62 C difficile and Probiotics Johnston Ann Intern Med 2012: moderate quality evidence from 13 trials suggests there is a large reduction in CDAD and few adverse effects Goldenberg Cochrane Review 2013: 23 RCTs support moderate quality evidence that probiotics are “safe and effective for preventing” C difficile-associated diarrhea

63 “Administration of currently available probiotics is not recommended to prevent primary CDI, as there are limited data to support this approach and there is a potential risk of bloodstream infection (C-III)” Clinical Practice Guidelines for Clostridium difficile Infections in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Inf. Control and Hosp. Epid. 31: 431, C difficile and Probiotics

64 Control Measures Barrier protection: –Gloves –Gowns Alcohol hand-gel products are not sporicidal Hand washing with chlorhexidine gluconate containing soap Patient isolation until diarrhea resolved Cleaning and disinfection of environmental surfaces after pt discharge

65 A Systems Approach to Prevention Bundle at Rhode Island Hospital – Infection control plan based on risk assessment – Monitor hospital-wide morbidity and mortality associated with CDAD – Switch to PCR-based testing – Enhanced environmental cleaning – Standardized CDAD treatment plan /1000 discharges, 52 deaths /1000 discharges, 19 deaths Mermel Jt Comm J Qual Patient Saf 2013


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