Disclosures Consultant: Genentech Clostridium difficile infection - - PDF document

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Clostridium difficile infection

Sarah Doernberg, MD, MAS Associate Professor, Division of Infectious Diseases Medical Director of Adult Antimicrobial Stewardship

Disclosures

§ Consultant: Genentech

Outline

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Brief background and epidemiology

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Diagnosis

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Management—mild, uncomplicated disease

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Management—moderate-severe disease

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Management—recurrent/relapsed disease

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Management—fulminant disease

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Prevention

Some controversy

Clostridium versus Clostridioides difficile

“In summary, both names, Clostridium difficile and Clostridioides difficile, may be currently used. With time the community of microbiologists dealing with

• C. difficile will likely reach

an agreement upon use of a single name.”

Oren A and Rupnik M. https://doi.org/10.1016/j.anaerobe.2018.07.005

2 | [footer text here] One of CDC’s 3 “Urgent Threats”

500,000 3.8 billion

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

CDI background

Biology

• Anaerobic GPR
• Spore-forming
• Toxins A+B+/-binary
• Multiple strains
• Fecal-oral spread

Epidemiology

• 15% of HAIs, #2 cause
• Carriage is common
• < 3% healthy adults
• 20% hospitalized pts
• up to 50% in LTCF

Risk factors:

• Antibiotics
• Age
• Hospital exposure
• Acid-suppression
• IBD
• Tube feeds
• Immune status
• Female gender
• Domestic animals?
• Retail food?
• Trehalose?

Magill SS et al., N Engl J Med. 2018 Nov 1;379(18):1732-1744. doi: 10.1056/NEJMoa1801550.

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

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

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Antibiotic use affects the population risk

Brown K et al. JAMA Intern Med. 2015 Apr;175(4):626-33 Freedberg DE et al. JAMA Intern Med. 2016 Dec 1;176(12):1801-1808

• Risk for CDI if prior room occupant got antibiotics = HR 1.22 (1.02-1.45)

Spread of CDI in the hospital

Asymptomatic carriers Symptomatic cases 25-33% 30% Endogenous carriage 20% Other (environmental contamination, etc)

Diagnostic testing

Glutamate dehydrogenase Ag (GDH)

• Bacterial detection
• Sn but not Sp

Enzyme immunoassay (EIA)

• Protein detection
• ↓Sensitivity
• ↑Specificity

Polymerase chain reaction (PCR):

• Toxin-producing gene
• ↑Sensitivity
• ↓Specificity

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

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New testing guidance

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Guidance on appropriate testing No tests if on laxatives Test only if new onset ≥ 3 stools/24 hours Multistep algorithm preferred over PCR alone

• GDH+toxinàPCR
• PCR+toxin

PCR only if limited to high pretest probability

UCSF CDI testing algorithm (for now)

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 11K, Cr 1.0. Other vitals stable. 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

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CDI Rx no longer depends on severity!

Zar F A et al. Clin Infect Dis. 2007;45:302-307; McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

Severe

• Not well validated
• IDSA/SHEA: WBC > 15K
• r Cr ≥ 1.5
• Severe, complicatedà

“fulminant”

• Severe + hypotension,

shock, ileus, and/or megacolon Mild to moderate

• Does not meet criteria for

severe

• Diarrhea ≥ 3 stools/24

hours

Initial uncomplicated CDI, severe or non-severe

§ VAN 125 mg po QID x 10 days (up to 14) (strong, high) § FDX 200 mg PO twice daily x 10 days (strong, high)

• Favor in patients at high risk for recurrence

§ If above agents are unavailable, can consider metronidazole x

10-14 days (weak, high)

M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085 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 study of MTZ vs VAN vs tolevamer
• Cure not differential with regard to levels of severity

20 40 60 80 100 120 Cure, all Cure, m ild- mod Cure, severe Recurren ce MT Z Vanco

p = 0.005 p = 0.02 NS NS

New evidence to support vancomycin

• aRR death VAN vs MT:Z
• 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

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

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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. VAN: Similar cure (~88%), lower

recurrence (13-15% vs. 25-27% )

• Unclear role in multiply recurrent or severe disease

FDX VAN MTZ $2800 $250-680 $22

Real-world fidaxomicin experience

§ UK Trust Hospitals pre-post

analysis s/p introduction of fidaxomicin

§ Each hospital had a different

approach

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

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

Additional considerations

§ Stop unnecessary antibiotics § Shorten antibiotic courses § Narrow antibiotic spectrum § Stop acid-suppressive medications when possible

(though low quality evidence)

§ No anti-peristaltic agents until acute sxs improve

Take-home

§ For initial treatment of non-fulminant CDI, VAN 125 mg

po QID x 10-14 days for most patients

§ Role of fidaxomicin unclear

• Consider if ↑ risk of relapse or need CA

7 | [footer text here] 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 first episode was treated with VAN x 10 days. Her WBC count is 9 and Cr is 0.3. With what should you treat her?

• A. MTZ 500 mg po TID x 10 days
• B. VAN 125 mg PO QID x 10 days
• C. VAN taper
• D. FDX 200 mg po BID x 10 days

First recurrence, non-fulminant CDI

§ If MTZ used initiallyàVAN 125 mg po QID x 10 days

(weak, low)

§ If VAN used initially, two options:

• 1. VAN taper (weak, low)
• 2. FDX 200 mg po BID x 10 days (weak, mod)

M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085

Evidence to support VAN taper

§ PBO groups from 2

RCTs of probiotics

• (n = 163)

§ 29 got VAN tapers of

varying stripes

• Mean 21.5 +/- 10

days

§ Small #, uncontrolled

N = 10, 71% N = 29, 31% 0% 10% 20% 30% 40% 50% 60% 70% 80% stand ard VA N VA N tap er

Recurrence P = 0.01

McFarland LV et al. Am J Gastroenterol. 2002 Jul;97(7):1769-75 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)

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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 recurr ence Rec urrence

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 10-day course of PO FDX complaining of ongoing diarrhea. A repeat stool toxin is

• positive. What do you do?
• A. VAN followed by rifaximin
• B. VAN taper
• C. FDX 200 mg PO BID x 10 days
• D. Fecal microbiota transplantation
• E. Any of the above

Incidence of mrCDI has increased 188%

Risk factors:

• Age
• Female gender
• Nursing home
• Antibiotic use
• PPI use
• Steroid use
• CKD

Ma GK et al. Ann Intern Med. 2017;167(3):152-158.

Second/subsequent recurrence

§ VAN taper/pulse (weak, low) § VAN 125 mg po QID x 10 days followed by rifaximin 400 mg

po TID x 20 days (weak, low)

§ FDX 200 mg PO BID x 10 days (weak, low) § FMT (strong, mod)

• “appropriate antibiotic treatments for at least 2

recurrences… should be tried prior to offering [FMT]”

M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085

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A word on rifaximin chaser

§ Double-blinded single-center RCT of pts with CDI

• Rifaximin 400 mg po TID x 20 days after standard 10-14 dd

course VAN or metronidazole versus placebo

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Recurrence:17/35 (49%) placebo vs. 5/33 (21%) rifaximin (p = 0.02)

Garey KW et al. J Antimicrob Chemother. 2011 Dec;66(12):2850-5. doi: 10.1093/jac/dkr377

FMT

• ↓Diversity w/ rCDI
• Colonization resistance
• Related donors vs.

banked stool

• R/o transmissible dz
• Colo vs. pill RCT:
• 12-week cure:
• Pill: 96%
• Colo: 96%
• Diff: 0% (-6.1% to ∞)
• Multiple RCTs
• Overall response:
• Multiple: 92% (89-94)
• Single: 84% (79-89)

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; Hota SS et al. Clin Infect Dis (2016) 64 (3): 265-271; Quarashi MN et al. Aliment Pharmacol Ther. 2017 Sep;46(5):479-493. doi: 10.1111/apt.14201. Epub 2017 Jul 14. Kao D et al. JAMA. 2017;318(20):1985-1993. doi:10.1001/jama.2017.17077

Fidaxomicin fared worse than FMT for rCDI

Hvas CL et al. Gastroenterology 2018; https://doi.org/10.1053/j.gastro.2018.12.019

0% 20% 40% 60% 80% 100% FM T FDX VAN 8wk clinical cure

rCDI (~4 episodes) N = 64 VAN x 10 FMT FDX x 10

p = 0.002 p = 0.13

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.

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FMT durability

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Single-center retrospective f/u of all patients receiving FMT

• 137/191 (72%) response rate
• 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

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24/137 (18%) had rCDI post-FMT

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61/137 (45%) got additional antibiotics

• 43/113 (38%) w/o rCDI vs. 18/24 (75%) w/ rCDI (p < 0.01)

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

Take-home

§ rCDI is a challenge § First recurrence: Stratify by initial rx

• MTZàStandard VAN course
• VANàVAN taper or FDX

§ Subsequently:

• VAN taper
• VAN course + rifaximin chaser
• FDX
• FMT (try above options first)

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. With what do you treat her?

• A. VAN 125 mg po qid
• B. VAN 500 mg po qid
• C. VAN 500 mg PR qid
• D. MTZ 500 mg iv tid
• E. FDX 200 mg po bid
• F. A+C+D
• G. B+C+D

Fulminant CDI

§ Paucity of data for medical approaches, expert opinion

• VAN 500 mg po QID (strong, moderate)
• IleusàVAN 500 mg in 100 cc saline PR QID (weak, low)
• MTZ IV (strong, moderate)

§ Surgical options:

• Subtotal colectomy (strong, moderate)
• Alt: Diverting loop ileostomy with colonic lavage (weak, low)

M cD onald LC et al. C ID , cix1085, https://doi.org/10.1093/cid/cix1085

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Total colectomy with end ileostomy

N = 161 pts admitted to the ICU for CDI 38 (24%)àcolectomy

Mortality aOR 0.2 (0.1-0.7) Most benefit: age ≥ 65, immunocompetent, WBC≥20, lactate 2.2-4.9 53% died

• 58% medical RX
• 34% surgical
• Selection bias likely

Indications: Shock (40%), megacolon (29%), failed med rx (26%), perforation (5%)

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 ongoing (NCT02347280)

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

Multicenter loop ileostomy study

N = 98 pts at 10 centers undergoing surgery for CDI 21% loop ileostomy

Mortality adjusted for confounders, LI 17% vs TC 40%; p = 0.002

• ↓blood loss for LI group
• LI group did worse if

reoperation needed 32% died

• 34% TC
• 24% surgical
• p = 0.4

Trend towards lower APACHE, less vasopressor use, later surgery

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

Take-home for severe, complicated CDI

§ Use high-dose oral +/- rectal VAN § Use IV MTZ § 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

12 | [footer text here] 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

Probiotics for CDI

RCT

• 0.9% vs. 1.2%
• OR CDI: 1.0 (0.8-1.3)

Meta-analysis

• 0.42 (0.30 0.50)
• Studies limiting to

initiation w/i 48h on abx had stronger effect size

• Limits UK study
• IDSA guidelines =

insufficient

Shen NT et al. Gastroenterology. 2017 Jun;152(8):1889-1900; McDonald LC CID 2018;

• Lancet. 2013 Oct 12;382(9900):1249-57. doi: 10.1016/S0140-6736(13)61218-0.

Approaches to prevent CDI

• 1. ↓hospitalizations
• C. diff acquisition
• 2. Infection control

Antibiotics

• 3. ABX stewardship
• 4. Restore microbiota
• 5. Passive immunity

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

• 6. Rx w/ microbiota-sparing agents

Infection control basics

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Gloves + gowns for duration of diarrhea + 48 h

• Universal gloving?

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Wash with soap and water

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Private rooms

• Dedicated commode

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Bleach cleaning

• All versus known CDI

§

+/- UV light

Cohen et al., Infection Control and Hospital Epidemiology, 2010; 31: 431-455 Caroff DA et al. CID 2017 McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

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Antimicrobial stewardship

MDRO incidence rate w/ ASP: 0.49 (0.35-0.68) CDI incidence rate w/ ASP: 0.68 (0.53-0.88)

Baur D et al. Lancet Infect Dis. 2017 Sep;17(9):990-1001. doi: 10.1016/S1473-3099(17)30325-0.

Identification and isolation of carriers

IDSA: “insufficient data”

Longtin Y et al. JAMA Intern Med. 2016;176(6):796-804 McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085.

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

Antibiotic prophylaxis?

§ Two poorly/uncontrolled retrospective studies suggest possible

benefit for secondary prophylaxis with VAN in patients receiving systemic antibiotics

• aHR 0.59 (0.43-0.80)
• OR 0.12 (0.04-0.4) –uncontrolled

§ Recent more rigorous observational study:

• aOR 1.06 (0.60-1.81)
• Possible decrease in those with only 1 prior episode

§

FDX for ppx in neutropenic pts on FQ did not meet 1º endpoint but:

• Confirmed CDI: 4.3 vs 10.7% (95%CI for diff, 2.2% to 10.6%)

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

• Epidemiol. 2019 Jun;40(6):662-667. doi: 10.1017; Mullane KM et al. Clin Infect Dis. 2019 Jan 7;68(2):196-203. doi: 10.1093/cid/ciy484.

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Ribaxamase

PO β-lactamaseàdegrade excess antibiotics in GI tract

CRO for LRTI N = 413 PBO Ribaxamase 72h beyond CRO

Kokai-Kun JF et al. Lancet Infect Dis. 2019 May;19(5):487-496. doi: 10.1016/S1473-3099(18)30731-X. Epub 2019 Mar 15.

One-sided p = 0.05

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

• NNT = 10
• No clear subgroup

benefited

• Cost may be an issue
• Δ sustained cure

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

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

C diff vaccine?

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CDI prevention summary

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Remember infection control and antibiotic stewardship basics!

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Role of isolation of carriers evolving

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

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Non-toxigenic C. diff is promising

§

Passive immunity is effective but costly

§

There may be a role for vaccine in the future

CDI take-home

§ VAN or FDX preferred for non-fulminant disease § Fulminant disease: PO/PR vancomycin and IV metronidazole

• Consider surgery
• Maybe FMT

§ 1st recurrenceàstratify by initial Rx

• VANàVAN taper or FDX (standard VAN course if initial rx w/ metronidazole)

§ Subsequently:

• VAN taper
• VAN course + rifaximin chaser
• FDX
• FMT (try above options first)

§ Prevention is important

THANK YOU!