19 doernberg c.diff

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3/15/20171

Clostridium difficile

Sarah Doernberg, MD, MASAssistant Professor, University of California, San FranciscoMedical Director, Adult Antimicrobial Stewardship

Disclosures: Consultant for Actelion, prior research studies with Cerexa, Merck, Cubist

Objectives

To recognize patients at risk for C. difficile infection (CDI)

To understand diagnostic testing 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 understand concepts in emerging therapies for CDI

Outline

Brief background and epidemiology

Diagnosis

Management—mild, uncomplicated disease

Management—moderate-severe disease

Management—recurrent/relapsed disease

Management—fulminant disease

Prevention


3/15/20172

One of CDC’s 3 “Urgent Threats”

https://www.cdc.gov/drugresistance/biggest_threats.html

500,000

3.8 billion

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, inpatients

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

Epidemic strain

Molecular testing era

Epidemiology snapshot

453,000 estimated cases in the USA in year 2011

• 147 cases/100,000 people

66% healthcare-associated

• 24% hospital-onset

Female > male (rate ratio = 1.26 [1.25 to 1.27])

White > non-white (RR = 1.7 [1.6 to 2.0])

↑65 > ↓65 (RR = 8.7 [8.2 to 9.3])

13% recurred (21% if HAI)

3% died within 30 days (9% if HAI)

$$ millions in excess costs estimated

Lessa FC, et al. N Engl J Med 2015; 372(9):825-34.


3/15/20173

Duration, number, and intensity of antibiotics affect risk for CDI

9Stevens V, et al. Clin Infect Dis 2011; 53: 42-48.

Antibiotic use affects the population risk

Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33

Spread of CDI in the hospital

Asymptomatic carriersSymptomatic cases

25-33%

30%

Walker AS et al. PLoS Med. 2012 Feb;9(2):e1001172.; Kamboj M et al. Infect Control Hosp Epidemiol. 2016 Jan; 37(1): 8–15; Curry SR et al. Clin Infect Dis. 2013 Oct 15; 57(8): 1094–1102; McDonald LC, Clin Infect Dis. 2013 Oct;57(8):1103-5

Endogenous carriage

?

Diagnostic testing

Glutamate dehydrogenase Ag (GDH)• Bacterial detection• Sensitive but not specific

Polymerase chain reaction (PCR): • Toxin-producing gene• ↑Sensitivity

Enzyme immunoassay (EIA)• Protein detection• ↓Sensitivity• ↑Specificity for disease


3/15/20174

CDI overdiagnosis

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

• 21% +PCR• Of these, 44% + toxin• Toxin-/PCR+

• ↓bacterial load• ↓abx• ↓diarrhea• No CDI-

complications

What is wrong with this picture?

63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics for this and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax.

On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization.

Overdiagnosis case

63 year old F s/p spinal fusion c/b hardware infection. She received a 6 week course of antibiotics and is admitted for redo spinal fusion. She has been constipated and has daily orders for senna, colace and miralax.

On HD# 8, she develops 2 loose stools and tests positive for C. difficile. She is afebrile with a normal WBC and is started on PO metronidazole. She has no further episodes of loose stools during the remainder of hospitalization.

MANAGEMENT


3/15/20175

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

0

20

40

60

80

100

120

Cure, all Cure, mild-mod Cure, severe Recurrence

MTZ

Vanco

p = 0.005 p = 0.02 NSNS

New evidence to support vancomycin

Stevens VW et al. JAMA Intern Med. 2017 Feb 6. doi: 10.1001/jamainternmed.2016.9045.

• aRR death vanco vs metronidazole, any severity• Any severity: 0.86;

95% CI, 0.74 to 0.98;• Severe CDI: 0.79; 95%

CI, 0.65 to 0.97• NNT to prevent 1 death,

severe CDI: 25


3/15/20176

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

Fidaxomicin Vancomycin Metronidazole

$2800 $250-680 $22

Real-world fidaxomicin experience

UK Trust Hospitals analyzed pre-and post-information s/p introduction of fidaxomicin

Each hospital had a different approach to rxwith fidaxomicin(e.g. all patients vs. selected populations)

Goldenberg SD et al. Euro J Clin Microbiol and Infect Dis 2016; 35L 251-9.

• A and B: Fidaxomicin used first-line for all• C, E, F, G: Selected episodes• D: Recurrences only

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


3/15/20177

Treatment scenario #2: You are seeing a 62 y/o F who has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcalosteomyelitis 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

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 every other day x 8 days (4 doses)

125 mg po every 3 days x 15 days (5 doses)


3/15/20178

↓↓↓Fecal diversity with rCDI

FMT basics

Colonization resistance

Related donors or banked stool

• Need to screen for transmissible diseases

Multiple RCTs have now been done

Guidance document available (Bakken et al)

Chang JY et al. JID 2008; 197: 435-8; 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

Fecal diversity ↑and abxR ↓post FMT

Millan B et al. Clin Infect Dis 2016;62:1479-1486

FMT trial trends

6 published

• 3 vs. abx management

• 3 vs. FMT refinements

Over time, ↓efficacy in RCTs

↑response to comparator abx

Might matter whether active recurrence vs. prior recurrence?

Might need multiple FMTs

Vanco taper might be better than we thought?

Commercially-prepared FMT in development

Johnson S and Gerding DN. Clin Infect Dis (2016) 64 (3): 272-274; van Nood E et al. N Engl J Med 2013; 368:407-415; Orenstein R et al. Clin Infect Dis (2015) 62 (5): 596-602.

The latest on FMT

Hota SS et al. Clin Infect Dis (2016) 64 (3): 265-271

• Multiple previous trials supported FMT…

• But comparator group not standard of care

• Phase 2/3 open-label RCT• Stopped early for futility• FMT by enema• Recurrence: 9/16 (56%) FMT

vs. 5/12 (42%) taper group• 95% CI for ∆ CDI with FMT =

-2.8% to +47.3%


3/15/20179

Kelly CR et al. Ann Int Med 2016; Van Nood E, et al. NEJM 2013; 368: 407-15; Cammarota et al, Alim Pharm Ther2015:41:835; Youngster I et al., CID 2014;58:1515-1522

FMT may be a tool in the arsenal

• RCT of rCDItreated with autologous vs donor FMT

• ≥ 3 episodes• Via colonoscopy• Note regional

differences• 1 donor had a 9.1

KG wt gain

Poop pill for recurrent CDI?

Phase 1 study: Open-label, single group feasibility study

• 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%)

But, phase 2 study interim analysis: 44% (26/59) recurrences SER-109 vs. 53% (16/30) control patients

Recent study of purified Firmicutes from healthy donors was safe and resulted in increased diversity

Youngster I, et al. JAMA 2014;312(17):1772-8. www.npr.org; Khanna S et al. JID 2016doi: 10.1093/infdis/jiv766; http://ir.serestherapeutics.com/phoenix.zhtml?c=254006&p=irol-newsArticle&ID=2190006

FMT adverse events

CommonDiarrhea

Cramping

Belching

Nausea

Bloating

Rare/seriousProcedure-related harms

• Perforation

• Aspiration

Norovirus

Bacteremia

IBD flare

Unknown long-term effects

• Weight changes

• Chronic disease exacerbation

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

Primary FMT indications

• Recurrent or relapsing FMT (usu > 2 episodes)

• Moderate CDI not responding to Rx

• More to follow on severe/complicated


3/15/201710

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

Total colectomy with end ileostomy

Retrospective cohort pts in ICU for CDI

• N = 161 (38 surgery, 123 medical rx)

Indications: Shock (40%), megacolon (29%), no response to med rx (26%), perforation (5%)

aOR death 0.2 (0.1-0.7) colectomy vs. medical rx

• WBC > 50K and lactate > 5 conferred very poor prognosis

• More beneficial in age ≥ 65, immunocompetent, WBC ≥ 20, lactate 2.2-4.9

• 53% died (58% medical rx, 34% surgical)

• Selection bias likely

Lamontagne et al., Ann Surg 2007;245(2):267-72.

Diverting loop ileostomy + colonic lavage

3/42 (7%) converted to total colectomy (2 for abd compartment sx)

79% had ileostomy reverted

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

• 19% died w/i 30 days

• 14% more died afterwards, all deemed due to underlying illness

RCT recruiting (projected end date 2018)

Neal et al. Ann Surg. 2011 Sep;254(3):423-7; discussion 427-9.

FMT for severe disease

Study Population Intervention Outcome

Cammarota et al, Aliment PharmacolTher 2015

Subgroup of RCT w/ recurrent CDI, N = 7 w/pseudomembranesSingle-center

RCT FMT via colovs vancoInitial 2 pts 1 FMT via colo; remainder FMT q3 days prn

Mortality: 29% (1 FMT)Cure: 71% (≥ 2 FMT)

Fischer et al, Aliment Pharmacol Ther2015

Cohort, N = 29Severe (10) +/-complicated (19)Single-center

FMT via colo ~qwkwith intermittent vanco

Mortality: 7% (both severe/comp)Success: 93% (≥ 2 FMT in 55%)

Zainah H et al. Dig Dis Sci 2015

Cohort, N = 14 with severe, refractory CDI (43% in ICU)Single-center

FMT via NGT, rptat 48-72hr if not response

Mortality: None d/tCDI (29% at 100 dd2/2 underlying dz)Success: 79% (≥ 2 FMT in 21%)

Aroniadis et al. J Clin Gastroenterol2015

Multicenter cohortN = 1776% severe/complicated

FMT mostly via colo

Success: 94% (≥ 2 FMT in 6%)


3/15/201711

IVIG in severe disease

No RCTs

Retrospective review of 14 patients who received IVIG at one institution

• 6 refractory

• 6 recurrent

• 2 severe IS failing to respond to therapy

Dose 150 to 400 mg/kg x 1-2

9 (64%) responded fully

• Of these, 3 (33%) had subsequent recurrences

McPherson et al., Dis Colon Rectum 2006;49:640-5.

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


3/15/201712

Meta-analysis + PLACIDE trial

Daneman N, Lancet 2013.

Approaches to prevent CDI

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

Infection control

Gloves + gowns for duration of diarrhea

Wash with soap and water

Private rooms

• Dedicated commode

Bleach cleaning

Antimicrobial stewardship

Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455

Identification and isolation of carriers

Longtin Y et al. JAMA Intern Med. 2016;176(6):796-804.


3/15/201713

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

Secondary prophylaxis?1. Retrospective cohort at two hospitals in Quebec

2. Retrospective cohort St. Louis

Carignan A et al. Am J Gastroenterol. 2016 Dec;111(12):1834-1840. Van Hise NW et al. CID 2016; 63 (5): 651-3

Adult w/ CDIRx’d non-CDI abx within 90 d

(in or outpt)

Recurrence w/i 6 mo

aHR 0.59 (0.43-0.80)

aHR 1st CDI 0.91 (0.57-1.45)

aHR recurrence 0.47 (0.32-0.69)

Adult w/ CDIRx’d non-CDI abx within 90 d

(inpt)

Recurrence w/i 4 weeks

OR 0.12 (0.04-0.4) No multivariate analysis

Host protection

Kyne et al., NEJM 2000;342(6):390-7. Lowy et al. NEJM 2010 Jan 21;362(3):197-205.

Actoxumab Bezlotoxumab

Monoclonal Abs for secondary preventionMODIFY I and II trials

Wilcox MH et al. N Engl J Med 2017; 376:305-317

• NNT = 10• No clear subgroup

benefited• Cost may be an

issue• Δ sustained cure

Bezlotux vs. SOC: 9.7% (4.8-14.5)


3/15/201714

C diff vaccine? CDI prevention summary

Remember infection control basics

Role of isolation of carriers evolving

Unclear role for probiotics, unlikely to be a game-changer

Non-toxigenic C. diff is 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!

CDI strategies: Bringing it all together

Martin J and Wilcox M. Curr Opin Infect Dis. 2016 Dec;29(6):546-554.

Mechanisms for emerging CDI treatment

Kociolek, L. K. & Gerding, D. N. (2016) Nat. Rev. Gastroenterol. Hepatol. doi:10.1038/nrgastro.2015.220


3/15/201715

CDI take-home

Metronidazole (or vancomycin) for mild-moderate disease

Vancomycin for severe disease

Fidaxomicin may be appropriate for those at high risk for relapse and/or those requiring CA

• But, might not be cost effective

Fulminant disease: PO/PR vancomycin and IV metronidazole

• Consider surgery

• Maybe FMT

1st recurrencesame agent (or fidaxomicin)

2nd and beyondvancomycin pulse and taper

FMT may be the best option for recurrent CDI

Prevention is important

THANK YOU!

19 doernberg c.diff

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