Clostridium difficile Disclosures: Consultant for Actelion, prior - - PDF document

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 1

Clostridium difficile

Sarah Doernberg, MD, MAS Assistant Professor, University of California, San Francisco Medical 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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 2

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.

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 3

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

9 Stevens 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 carriers Symptomatic 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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 4

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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 5 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

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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 6

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 rx with 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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 7 Treatment scenario #2: You are seeing a 62 y/o F who has takes chronic amoxicillin/clavulanic acid for suppression of Enterococcal

• steomyelitis 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 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)

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 8

↓↓↓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%

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 9

Kelly CR et al. Ann Int Med 2016; 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 may be a tool in the arsenal

• RCT of rCDI

treated 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

Common

• Diarrhea
• Cramping
• Belching
• Nausea
• Bloating

Rare/serious

• Procedure-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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 10

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 Pharmacol Ther 2015

Subgroup of RCT w/ recurrent CDI, N = 7 w/ pseudomembranes Single-center RCT FMT via colo vs vanco Initial 2 pts 1 FMT via colo; remainder FMT q3 days prn Mortality: 29% (1 FMT) Cure: 71% (≥ 2 FMT)

Fischer et al, Aliment Pharmacol Ther 2015

Cohort, N = 29 Severe (10) +/- complicated (19) Single-center FMT via colo ~qwk with 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, rpt at 48-72hr if not response Mortality: None d/t CDI (29% at 100 dd 2/2 underlying dz) Success: 79% (≥ 2 FMT in 21%)

Aroniadis et al. J Clin Gastroenterol 2015

Multicenter cohort N = 17 76% severe/complicated FMT mostly via colo Success: 94% (≥ 2 FMT in 6%)

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 11

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

• n 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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 12

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.

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 13

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/ CDI

Rx’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/ CDI

Rx’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 prevention MODIFY 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)

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 14

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

[ADD PRESENTATION TITLE: INSERT TAB > HEADER & FOOTER > NOTES AND HANDOUTS] 3/15/2017 15

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 recurrencesame agent (or fidaxomicin)
• 2nd and beyondvancomycin pulse and taper
• FMT may be the best option for recurrent CDI
• Prevention is important

THANK YOU!