Clostridium difficile Sarah Doernberg, MD, MAS Assistant professor - - PDF document

2/7/2018 1

Clostridium difficile

Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 2.19,2018

Outline

• Brief background and epidemiology
• Diagnosis
• Management—mild, uncomplicated disease
• Management—moderate-severe disease
• Management—recurrent/relapsed disease
• Management—fulminant disease
• Prevention

2/7/2018 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

2/7/2018 3

Epidemiology trends, inpatients

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

Epidemic strain Molecular testing era

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

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

2/7/2018 4

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 ?

2/7/2018 5

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

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

2/7/2018 6

Case

• 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.

2/7/2018 7

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

2/7/2018 8

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

2/7/2018 9

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: 0.86; (0.74

to 0.98)

• Severe: 0.79 (0.65 to

0.97)

• NNT to prevent 1 death,

severe CDI: 25

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

2/7/2018 10

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

UCSF guidelines

http://idmp.ucsf.edu/news/updated-ucsfmcvasfzsfgh-guidelines-c-difficile-infection

Clinical definition Criteria Treatment Initial, mild‐mod, Outpatient Not meeting criteria for severe Metronidazole 500 mg po q8h x 10‐14 days If no response @ 5 days, switch to vancomycin 125 mg po q6h x 10‐14 days Initial, mild‐mod, Inpatient Not meeting criteria for severe Vancomycin 125 mg po q6h x 10‐ 14 days If unable to obtain upon discharge, okay to complete the course with metronidazole 500 mg po q8h Initial, severe WBC ≥ 15 OR Cr ≥ 1.5x baseline without hypotension, shock, ileus, and/or megacolon Vancomycin 125 mg po q6h x 10‐ 14 days

2/7/2018 11

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

2/7/2018 12

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

2/7/2018 13

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)

2/7/2018 14

↓↓↓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

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.

2/7/2018 15

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%

FMT meta-analysis

• Overall response:
• Multiple infusions: 92% (89-94%)
• Single infusion: 84% (79-89%)
• Just RCTs:
• Multiple: 91% (88-94%)
• Single: 77% (56-93%)

Quarashi MN et al. Aliment Pharmacol Ther. 2017 Sep;46(5):479-493. doi: 10.1111/apt.14201. Epub 2017 Jul 14.

2/7/2018 16

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 leads to better cure rates

• 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

• Good results for RCT
• f FMT via NGT vs

colo (N = 20)

FMT for abx resistance?

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

2/7/2018 17

FMT via pill?

• Unblinded noninferiority (15%) multicenter RCT of 117 adults with ≥

3 episodes of CDI

• Stratified by age (65) and immunosuppressed status (15%)
• Median duration of rCDI rx prior to transplant: 2.3-2.4 mths
• Absence of rCDI @ 12 weeks: 51/53 (96%) in capsule group

versus 50/52 (96%) colonoscopy group (per-protocol)

• Difference: 0% (95% CI, -6.1% to infinity)
• Pts with recurrence were retreated with same modality
• Sensitivity analyses including LTFU as recurrences still met

noninferiority

• Both groups had increased microbial diversity post-transplant

Kao D et al. JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077

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.

2/7/2018 18

FMT durability

• Single-center retrospective f/u of all patients receiving FMT
• 137/191 (72%) response rate (additional 26 deceased and

15 without contact information)

• 2/26 (7.7%) of deceased died of rCDI
• Median time to f/u: 22 months (range, 3-51)
• Most (97%) got PO vancomycin, 53 (39%) also

fidaxomicin

• 24/137 (18%) had rCDI post-FMT
• 61/137 (45%) got additional antibiotics
• 43/113 (38%) w/o rCDI vs. 18/24 (75%) w/ rCDI (p < 0.01)

2/7/2018 Mamo Y et al. Clin Infect Dis. 2017 Dec 19. doi: 10.1093/cid/cix1097. [Epub ahead of print]

UCSF guidelines

Clinical definition Criteria Treatment 1st recurrence Except special populations below Same as for initial therapy, stratified by illness severity 1st recurrence, special population Hematologic cancer with neutropenia expected > 30 days Recent bone-marrow transplant or treatment for GVHD Solid-organ transplant < 3 mths Otherwise not an FMT candidate Fidaxomicin 200 mg po q12h x 10 days (be sure to check insurance coverage before prescribing for outpatients; if insurance does not cover can try the MERCK pt assistance program at

• www. merckhelps.com)

≥ 2nd recurrence Vancomycin tapered and/or pulsed PLUS Evaluate for FMT Consult ID, GI

http://idmp.ucsf.edu/news/updated-ucsfmcvasfzsfgh-guidelines-c-difficile-infection

2/7/2018 19

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
• Possibly severe/complicated

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

2/7/2018 20

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.

2/7/2018 21

Multicenter loop ileostomy study

• 10 centers, 98 patients
• 21% LI patients ; trend towards lower

APACHE, less vasopressor use, later surgery

• Overall mortality 32% (unadjusted, 34% TC vs

24% LI, p = 0.4)

• Mortality adjusted for confounders, LI 17% vs

TC 40%; p = 0.002

• Less blood loss for the LI group
• LI group did worse if reoperation needed

Ferrada P et al. J Trauma Acute Care Surg. 2017 Jul;83(1):36-40

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%)

2/7/2018 22

FMT for severe disease

• Single center retrospective cohort analysis of 111 patients
• FMT group treated with vanco 2-4 days pre- & 4 days post-FMT
• Clinician discretion whether to offer FMT
• 66 (59%) underwent FMT; 45 (41%) did not (incl 26 due to

clinical improvement on medical rx and 13 due to instability)

• 3 month mortality: 12.1% (8/66) in the transplant group vs

42.2% (19/45) in the antibiotic group (OR 0.19 [95% CI, .073–.49])

‒ Multivariable analysis: FMT OR, 0.13 (95% CI, .04–.44) ‒ However, risk of confounding by indication high ‒ No control for systemic antibiotic receipt

2/7/2018 Hocquart M et al. Clin Infect Dis. 2017 Aug 24. doi: 10.1093/cid/cix762. [Epub ahead of print]

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 but need more data, multiple FMTs

may be needed

• Make sure medical therapy has been optimized
• Additional therapies (IVIG, other antibiotics) lack data

2/7/2018 23

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

2/7/2018 24

Meta-analysis

• Very rigorous
• NNT: 43 (95% CI,

36−58)

• Remained significant

even when missing data was excluded

• Studies limiting people

to initiation within first 1-2 days on abx had stronger effect size

• Limits UK study (Allen)

Shen NT et al. Gastroenterology. 2017 Jun;152(8):1889-1900.

Approaches to prevent CDI

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

2/7/2018 25

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.

2/7/2018 26

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

2/7/2018 27

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

• ∆ sustained

cure Bezlotux

• vs. SOC: 9.7%

(4.8-14.5)

2/7/2018 28

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!

2/7/2018 29

CDI take-home

• Vancomycin preferred, metronidazole okay 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!

2/7/2018 30