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Disclosures Genentech: Consultant Infectious diarrhea with a focus on Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 4.20.16

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[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 4/14/2016 1

Infectious diarrhea with a focus

  • n Clostridium difficile

Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 4.20.16

Disclosures

  • Genentech: Consultant

Objectives

  • To recognize patients at risk for CDI
  • To understand management principles for treatment of mild,

severe, and fulminant CDI

  • To have a treatment approach to recurrent and relapsed CDI
  • To have strategies to prevent CDI
  • To generate a differential diagnosis for foodborne illness
  • To develop an approach to evaluating patients with diarrhea

Outline

  • Clostridium difficile infection (CDI)
  • Brief background, epidemiology, diagnosis, infection

control

  • Management—mild, uncomplicated disease
  • Management—moderate-severe disease
  • Management—recurrent/relapsed disease
  • Management—fulminant disease
  • Prevention
  • Non-CDI infectious diarrhea
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[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 4/14/2016 2

CDI Background

  • Anaerobic, spore-forming gram-

positive bacillus

  • Toxins A + B
  • Multiple strains
  • Epidemic strain ID’d 2004
  • 078 strain
  • Fecal-oral spread
  • 12% of all HAIs
  • Carriage of C. difficile
  • < 3% for healthy adults in community
  • 20% in hospitalized pts
  • Up to 50% in LTCF
  • Risk factors:
  • Antibiotics
  • Age
  • Hospitalization
  • Acid-suppression
  • IBD
  • Tube feeds
  • Host immune factors
  • Chemotherapy
  • Female gender
  • Domestic animals? Retail food?

Magill SS et al., NEJM 2014

Epidemiology trends

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6034a7.htm

Epidemic strain Molecular testing era

Diagnostic testing

  • Polymerase chain reaction (PCR)
  • Newest gold standard
  • (culture very difficult, time consuming, research only)
  • Glutamate dehydrogenase Ag (GDH)
  • Sensitive but not specific
  • Tests for presence of bacteria, not toxin
  • Enzyme immunoassay (EIA)
  • Less sensitive but may be a better predictor of
  • utcomes

CDI overdiagnosis

Polange CR et al., JAMA Intern Med. 2015 Nov;175(11):1792-801.

  • 21% +PCR
  • 44% + toxin
  • Toxin-/PCR+
  • ↓bact load
  • ↓abx
  • ↓diarrhea
  • No CDI-

complications

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MANAGEMENT

Treatment scenario #1

  • 63 y/o F recently treated for a UTI with levofloxacin, now having

watery stools 4x/day, fever to 38.3, WBC 16K, Cr 1.7 (baseline 0.5). PCR positive for C. difficile toxin. With what should you treat her? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Metronidazole 500 mg po tid D. Fidaxomicin 200 mg po bid

CDI treatment depends on severity

  • Mild to moderate: Does not meet criteria for severe
  • Diarrhea ≥ 3 stools/24 hours
  • Severe
  • Not well validated
  • IDSA/SHEA guidelines: Severe disease = Peak WBC > 15K or

Cr > 50% above baseline or “advanced age” (65? 75?)

  • Severe, complicated
  • Severe plus hypotension, shock, ileus, and/or megacolon

Zar F A et al. Clin Infect Dis. 2007;45:302-307; Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455 Zar F A et al. Clin Infect Dis. 2007;45:302-307; Leffler DA and Lamont JT. NEJM 2015; 372:1539-1548; Johnson S et al., Clin Infect Dis 2014;59(3):345-54

RCTs metronidazole vs. vancomycin

  • Similar findings for recent study of metronidazole vs vancomycin vs tolevamer
  • Cure not differential with regard to levels of severity
  • Higher recurrence across the board (20%)
  • Only vancomycin is FDA-approved

20 40 60 80 100 120 Cure, all Cure, mild-mod Cure, severe Recurrence MTZ Vanco

p = 0.005 p = 0.02 NS NS

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What about fidaxomicin?

Cure Relapse Strain Epidemic Same Same Non-epidemic Same  Concomitant abx   Prior CDI Same =/

Louie TJ, et al. NEJM 2011;364:422-431; Cornely et al, Lancet Infect Dis 2012;12:281-8 ; Petrella LA, et al. Clin Infect Dis 2012;55(3):351-7; Mullane et al., CID 2011;53(5):440-7; Corneley et al., CID 2012;55:s154-s161.; Bartsch SM et al., CID 2013; 57(4): 555-561; Konijeti GG et al., CID 2014; 58:1507-1514.

  • Bottom line vs. vanco: Similar cure (~88%), lower recurrence (13-

15% vs. 25-27% )

  • Unclear role in multiply recurrent or severe disease
  • Unlikely cost effective under any circumstance

Fidaxomicin Vancomycin Metronidazole $2800 $250-680 $22

Additional considerations

  • Stop unnecessary antibiotics
  • Shorten antibiotic courses
  • Narrow antibiotic spectrum
  • Stop acid-suppressive medications when possible
  • Esp PPI
  • Do not use anti-peristaltic agents until acute symptoms of

CDI improve

Take-home

  • For mild-moderate disease, can choose metronidazole, more

movement towards PO vancomycin in recent years

  • For severe disease, choose vancomycin
  • Higher cure, but same relapse
  • Role of fidaxomicin unclear
  • Consider if high risk of relapse or need CA
  • ? Use in multiply recurrent disease
  • ? Role in severe disease

Treatment scenario #2

  • You are referred a 62 y/o F in clinic who has takes chronic

amoxicillin acid for suppression of cellulitis and has developed her second bout of C. difficile colitis. Her WBC count is 9 and Cr is 0.3. What should you treat her with? A. Metronidazole 500 mg po TID B. Vancomycin 125 mg PO QID C. Vancomycin taper

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Risk for recurrent CDI

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 1st episode 2nd episode 3rd episode No recurrence Recurrence

Johnson S. J Infect 2009;58(6):403-10; Pepin J et al. Clin Infect Dis. 2005 Jun 1;40(11):1591-7

Treatment scenario #3

  • This patient returns one month after you have treated her with a

14-day course of PO metronidazole complaining of ongoing

  • diarrhea. A repeat stool toxin is positive. What do you do?

A. Metronidazole 500 mg po TID x 14 days B. Vancomycin 125 mg PO QID x 14 days C. Vancomycin taper D. Fidaxomicin 200 mg PO BID x 10 days E. Other

Kelly and LaMont, N Engl J Med. 2008;359(18):1932-40.

Vancomycin taper

  • 125 mg po 4x daily x 14 days
  • 125 mg po 2x daily x 7 days
  • 125 mg po 1x daily x 7 days
  • 125 mg po every other day x 8 days (4 doses)
  • 125 mg po every 3 days x 15 days (5 doses)

Stool transplant

  • “Fecal microbiota transplantation” (FMT)
  • First performed in 1958 for pseudomembranous

colitis

  • Colonization resistance
  • Purified stool via NJ tube, scope, enema
  • Most resolve with 1, some (<25%) require ≥ 2
  • Related donors or banked stool
  • Need to screen for transmissible diseases
  • Multiple RCTs have now been done
  • Guidance document available (Bakken et al)

Kassam et al., Arch Intern Med. 2012;172(2):191-3. Gough et al., CID 2011;53(10):994-1002; Bakken JS et al Clin Gastroenterol Hepatol 2011; 9: 1044-49

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Van Nood E, et al. NEJM 2013; 368: 407-15; Cammarota et al, Alim Pharm Ther 2015:41:835; Youngster I et al., CID 2014;58:1515-1522

FMT leads to better cure rates

  • Similar results for

RCT vs vanco taper

  • Good results when

given by NGT as well

Poop pill?

  • Open-label, single group feasibility study of patients with

recurrent or refractory CDI

  • N = 20
  • No SAEs
  • 14/20 (70%; 95% CI, 47%-85%) had sustained (8 wk) resolution

after 1 treatment

  • Nonresponders were re-treated (~7 days later)
  • Overall response: 90% (95% CI, 68%-98%)

Youngster I, et al. JAMA 2014;312(17):1772-8. www.npr.org

FMT adverse events

Common

  • Diarrhea
  • Cramping
  • Belching
  • Nausea
  • Bloating

Rare/serious

  • Procedure-related harms
  • Perforation
  • Aspiration
  • Norovirus
  • Bacteremia
  • IBD flare

Drekonja D et al. Ann Intern Med 2015;162(9):630-8.

Take-home

  • Recurrent CDI is a challenge
  • Treat first episode with same agent, adjust for severity
  • Subsequently, use vanco (taper if multiply recurrent)
  • Primary FMT indications
  • Recurrent or relapsing FMT (usu > 2 episodes)
  • Moderate CDI not responding to Rx
  • More to follow on severe/complicated
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Treatment scenario #4

  • 63 y/o F recently treated for a UTI with levofloxacin, now with

profuse diarrhea, T 38.7, BP 79/50, HR 140, WBC 30K, Cr 3.2, and lactate 3.7. What do you treat her with? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Vancomycin 500 mg PR qid D. Metronidazole 500 mg iv tid E. Fidaxomicin 200 mg po bid F. A+C+D G. B+C+D

Treatment scenario #4

  • 63 y/o F recently treated for a UTI with levofloxacin, now with

profuse diarrhea, T 38.7, BP 79/50, HR 140, WBC 30K, Cr 3.2, and lactate 3.7. What do you treat her with? A. Vancomycin 125 mg po qid B. Vancomycin 500 mg po qid C. Vancomycin 500 mg PR qid D. Metronidazole 500 mg iv tid E. Fidaxomicin 200 mg po bid F. A+C+D G. B+C+D

Surgical options

1. Colectomy with end-ileostomy: 53% death rate: aOR death 0.2 (0.1-0.7) vs. medical rx

‒ WBC > 50K and lactate > 5 very poor prognosis ‒ Selection bias likely

2. Alt: Diverting loop ileostomy + colonic lavage

Lamontagne et al., Ann Surg 2007;245(2):267-72; Neal et al. Ann Surg. 2011 Sep;254(3):423-7; discussion 427-9.

  • 79% had ileostomy

reverted

  • VS historical colectomy

controls, OR for death = 0.24 (0.09-0.63)

  • RCT planned

FMT for severe +/- disease

  • Multiple retrospective studies
  • Both colo and NGT routes
  • Cure: 71-94%
  • Multiple FMTs often needed
  • Mortality in this population remains high

28

Cammarota et al, Aliment Pharmacol Ther 2015; Fischer et al, Aliment Pharmacol Ther 2015; Zainah H et al. Dig Dis Sci 2015; Aroniadis et al. J Clin Gastroenterol 2015

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Take-home for severe, complicated CDI

  • Use high-dose oral +/- rectal vancomycin
  • Use IV metronidazole
  • Consider surgical intervention early
  • Consider diverting loop ileostomy
  • FMT is promising
  • Likely, multiple FMTs may be needed
  • Make sure medical therapy has been optimized
  • Additional therapies (IVIG, other antibiotics) lack data

Treatment scenario #5

  • You are starting your 70 y/o M patient on 4 weeks of

ciprofloxacin for prostatitis. He asks you whether he should take probiotics. How do you counsel him?

  • A. Probiotics will prevent antibiotic-associated diarrhea,

including CDI

  • B. Probiotics will prevent antibiotic-associated diarrhea

but not CDI

  • C. Probiotics are useless

RCT of probiotics for CDI

Diarrhea class Probiotic Placebo OR AAD 159/1470 (11%) 153/1471 (10%) 1.04 (0.83–1.32) CDI 12/1470 (0.9%) 17/1471 (1.2%) 0.70 (0.34–1.48)

Allen SJ et al., Lancet 2013 Oct 12;382(9900):1249-57

  • No benefit for probiotic
  • Very low rates of CDI in this population
  • Majority of patients were receiving

amoxicillin/ampicillin or second-generation cephalosoporins (UK study)

  • Likely underpowered for the CDI outcome

Meta-analysis + PLACIDE trial

Daneman N, Lancet 2013.

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Approaches to prevent CDI

Gerding D N , Johnson S. CID 2010;51:1306-1313

Non-toxigenic C. diff for secondary prevention

  • 173 patients with 1st or 2nd episode of CDI w/i 28 days (phase II)
  • 1-2 days after stopping CDI treatment randomized to non-

toxigenic C diff (NTCD-M3) vs. placebo

Recurrence:

  • OR 0.3; 95% CI, 0.1-0.7
  • Of NTCD-M3 group, 2% for

those colonized vs. 31% if not colonized

Gerding DN et al., JAMA 2015; 313(17):1719-1727 Kyne et al., NEJM 2000;342(6):390-7.; Lowy et al. NEJM 2010 Jan 21;362(3):197-205.

Monoclonal Ab, toxins A + B CDI prevention summary

  • Unclear role for probiotics, unlikely to be a game-changer
  • Non-toxigenic C. diff may be promising
  • Passive immunity is effective but costly
  • There may be a role for vaccine in the future
  • Do not forget good infection control and antimicrobial stewardship

practices!

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[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 4/14/2016 10

Shifting gears

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Foodborne illness

  • Mostly fecal-oral spread
  • FDA and USDA (meat and poultry) oversee food safety in

the United States

  • Most food still reaches shelves without inspection,

though

  • Widespread distribution makes it more difficult to

identify outbreaks

  • FoodNet = lab-based surveillance of common pathogens
  • CDC, USDA, FDA, 10 states (incl CA)
  • PulseNet = network of labs that can do PFGE

Foodborne illness epidemiology

  • 1/6 Americans (48 million) affected annually
  • 128,000 hospitalizations
  • 3000 deaths

http://www.cdc.gov/foodborneburden/2011-foodborne-estimates.html

Pathogen # of illnesses # hospitalizations # deaths Norovirus 5.5 million 14,663 149 Salmonella, nontyphi 1.0 million 19,336

378

  • C. perfringens

965,958 Campylobacter spp. 845,024 8,463 76 Staph aureus 241,148

  • E. coli 0157

2,138 Toxoplasma gondii 4,428

327

Listeria 255

Pathogenesis

  • Preformed toxins
  • Staphylococcus aureus, Bacillus cereus emetic toxin,

and botulism

  • Pathogens that make toxin post-ingestion
  • Vibrio cholerae, Enterotoxigenic Escherichia coli,

Shiga toxin-producing E. coli

  • Direct damage or invasion
  • Cryptosporidium parvum, enteric viruses, Salmonella,

Campylobacter, Shigella, L. monocytogenes

www.uptodate.com

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Foodborne disease by incubation period

  • < 2 hours: Chemical agent
  • 2-7 hours: Preformed toxin (except C. perfringens)
  • Staph aureus, B cereus
  • 8-14 hours: Increased inoculum diseases and C.

perfringens

  • Not necessarily more severe
  • > 14 hours: Most viruses and bacterium

Usual inoculum

Organism Inoculum Shigella 10-100 Giardia 30-100 Cryptosporidium parvum 30-100 Shigatoxin-producing E. coli 10-100 Norovirus 100 Salmonella 103-105 Campylobacter 103-106 Cholera 106 ETEC 108

Question #1

  • 25 attendees of your office holiday party become ill, and you are

suspicious for a foodborne disease

  • Median incubation period = 28h
  • 90% with vomiting
  • 50% with diarrhea
  • 30% with fever
  • Recovery occurred in 12-60 hours

What is the etiology?

A. Norovirus B. Shigella sonnei C. Staphylococcus aureus enterotoxin D.

  • C. perfringens

E.

  • B. cereus
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What is the etiology?

A. Norovirus B. Shigella sonnei

  • Diarrhea predominates

C. Staphylococcus aureus enterotoxin

  • Too long an incubation
  • No fever

D.

  • C. perfringens
  • Too long incubation
  • Vomiting is unusual

E.

  • B. cereus
  • Too long incubation

Kaplan criteria

  • Used to determine if outbreak likely 2/2

Norovirus

  • 99% sp, 68% sn if all criteria met
  • 1. Mean/median illness duration of 12-60 hrs
  • 2. Mean/median incubation period of 24-48 hrs
  • 3. > 50% of people with vomiting
  • 4. No bacterial agent found

Turcios RM et al., Clin Infect Dis. 2006 Apr 1;42(7):964-9

When should you do a work-up of diarrhea?

  • > 24 hours if associated with fever or blood
  • Hospital admission
  • Outbreak settings
  • Even if not useful for rx, can have public health benefit
  • Immunocompromised patients
  • Risky patients: HCW, food handlers, daycare
  • Persistent diarrhea

Guerrant RL et al. Clinical Infectious Diseases ; 2001 ; 32 : 331 -350

Question #2

  • You are called to see a patient from a local nursing home who

has developed diarrhea with fever and mild hypotension.

  • 30% of the residents have similar symptoms, and a non-typhoid

Salmonella has been cultured from the stool of multiple patients.

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Which residents should you treat?

A. Only those with fever B. All cases of diarrhea C. Only those with severe diarrhea D. None

Which residents should you treat?

A. Only those with fever B. All cases of diarrhea C. Only those with severe diarrhea D. None

When to treat non-typhoid Salmonella

  • Young (< 3 mths) or old (>50 years): High rates of

bacteremia

  • Fever or other markers of toxicity
  • Immunosuppression
  • Renal failure/uremia
  • Malignancy
  • Sickle cell
  • IBD
  • Aortic aneurysm or prosthetic device (c/f seeding)

Ceftriaxone for infants, FQ for adults (7-10 dd, 14 dd for IC)

Diarrhea take-home

  • Foodborne illness and diarrhea are common
  • History and exposures are important clues
  • Diagnosis can be narrowed based on syndrome and incubation
  • Kaplan criteria for Norovirus
  • Most respond to supportive rx alone
  • Work-up high risk patients, outbreak settings
  • Treatment is based on the etiology and is often

symptomatic

  • Extraintestinal complications are rare but can occur
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Thank you!

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