What’s New for Clostridium difficile and

other Infectious Diarrheas 2014

John Lynch MD MPHHarborview Medical Center

University of Washington

http://bit.ly/1wb7KOz

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 illnessesMay 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.

Airline food linked to illnessesMay 20, 2005

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

Diarrhea is # 2 highest ID mortality with 2.16 M deaths/year

A. HIV/AIDSB. MalariaC. TuberculosisD. Lower respiratory infectionsE. MRSA

What is # 1?

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

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%

Stool 100-200 ml 98-99%

Diarrhea occurs when reabsorption decreases to around 95-96%; minor changes result in major fluid losses

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?

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

Agents of diarrhea based on localization within the intestine

Small Bowel Colon

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 RotavirusNorwalk agentAstrovirusesCaliciviruses

CytomegalovirusAdenovirus

Parasites Giardia lamblia, Cyclospora cayatenensis, Cryptosporidium parvum, Microsporidium sp., Dientamoeba fragilis, Isospora belli

Entamoeba histolytica,Balantidium coli

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

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

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!

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:

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 dIodoquinol 650 mg TID x 20 d

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

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)

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

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

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

C. difficile hypervirulent straina) Known as: 027/NAP1/BI epidemic strain b) 16-fold increased expression of toxin A and 23-fold

expression of toxin Bc) Toxin is produced earlier in the course of CDId) The strain is associated with increased severity of disease,

death, and higher recurrence ratese) Uniformly quinolone resistantf) UW/Harborview perform reflex testing to identify

027/NAP1/BI strains*

*How is this information being clinically used? Maybego 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 Clin Microbiol. 2008;46:1530–3.

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

C. difficile infectionRisk 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

C. difficile infectionRisk 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

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

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

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”

Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010

Request imaging (Abd CT) and obtain surgery consult if evidence for toxic megacolon

C difficile Treatment- Drugs

• Metronidazole• Vancomycin• Fidaxomicin• Nitazoxanide• Since 2000, failure rates increased from 2.5%

to >18%, and >60% after multiple recurrences

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)

Drug Cost for 10 day course

Metronidazole $15-$30

Vancomycin pills $1100

Vancomycin (IV given orally) $40-$300 (compounding pharmacy)

Fidaxomicin $2700

NEJM 364:422, 2011

Crook CID 2012

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:

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

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

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?

Indications for Operative Management

Neal Ann Surgery 2011

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

Colon sparing surgery

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??

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

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

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

Risks for Relapse based on EMR

Hebert ICHE 2013

CDI: 3nd recurrence

CDI: 3nd recurrence

May soon become preferred treatment for second or even first relapses

Konejeti et al, Cost-effectiveness of competing strategies for managementof recurrent Clostridium difficile infection: a decision analysis. Clin. Infect. Dis. 58:1507, 2014

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

Fecal Microbiota Transplantation

• Transfaunation, Fabricius Aquapendente in the 17th Century

• 1958, Eiseman treated 4 patients with pseudomembranous colitis

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

Van Nood NEJM 2013

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

Pre-FMT patient data

Brandt Am J Gastro 2012

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 (300-700cc) depending on institution

• All via colonoscopy into various parts of colon from terminal ileum to rectum

Gough CID 2011

Post-FMT patient data

Brandt Am J Gastro 2012

After FMT

• 53% of patients stated they would prefer FMT as 1st 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 2nd FMT• 2 pts reported improvement in allergic sinusitis and

arthritis• 4 pts reported new conditions: peripheral neuropathy,

Sjogren disease, ITP and RA

Fecal microbiota diversity after FMT

Clin. Inf. Dis. 58:1515, 2014

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, 2011Fecal Microbiota Transplantation Workgroup. Clin. Gastro. Hep. 9:1044, 2011

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)

Fecal transplantation from unrelated donors(colonoscopy or NG tube?)

Clin. Inf. Dis. 58:1515, 2014

Colonoscopy NG tube

Cure with 1st Rx 8/10 (80%) 6/10 (60%)

With second Rx 10/10 (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

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 colonoscopyPetrof Microbiome 2013

C difficile Prevention

• Stop antibiotic therapy if possible• Probiotics

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

“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, 2010.

C difficile and Probiotics

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

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

• 2006- 12/1000 discharges, 52 deaths • 2012- 3.6/1000 discharges, 19 deaths

Mermel Jt Comm J Qual Patient Saf 2013