Clostridium difficile infection Sarah Doernberg, MD, MAS Associate - - 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, Basilea Pharmaceutica 1 | [footer text

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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, Basilea Pharmaceutica
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Outline

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

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One of CDC’s 5 “Urgent Threats”

https://www.cdc.gov/drugresistance/pdf/threats-report/clostridioides-difficile-508.pdf, accessed 1/21/20

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.

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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)

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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+toxinPCR
  • PCR+toxin

PCR only if limited to high pretest probability

MANAGEMENT

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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

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, complicated

“fulminant”

  • Severe + hypotension,

shock, ileus, and/or megacolon Mild to moderate

  • Does not meet criteria for

severe

  • Diarrhea ≥ 3 stools/24

hours

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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)

McDonald LC et al. CID, 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, mild- mod Cure, severe Recurrence MTZ Vanco

p = 0.005 p = 0.02 NS NS

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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.

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

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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
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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

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
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First recurrence, non-fulminant CDI

  • If MTZ used initiallyVAN 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)

McDonald LC et al. CID, 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% standard VAN VAN taper

Recurrence

P = 0.01

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

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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)

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

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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.

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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]”

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

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

  • 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

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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% FMT FDX VAN 8wk clinical cure

rCDI (~4 episodes) N = 64 FMT

p = 0.002 p = 0.13

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Does FMT ↓ risk of subsequent BSI and death?

N = 290 pts at 1 center undergoing FMT vs. abx for rCDI Propensity-score matched group: 57 pairs

BSI: 2/57 (4%) vs 15/57 (26%)

  • Difference: 23% (95%CI: 10-35)
  • Overall cohort: 5% vs. 22%
  • FMT gp: less ill, younger, ↓CVCs

Ianiro G et al. Ann Intern Med. 2019;171(10):695-702. DOI: 10.7326/M18-3635

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

  • 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
  • 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)

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
  • MTZStandard VAN course
  • VANVAN taper or FDX
  • Subsequently:
  • VAN taper
  • VAN course + rifaximin chaser
  • FDX
  • FMT (try above options first)
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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. 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)
  • IleusVAN 500 mg in 100 cc saline PR QID (weak, low)
  • MTZ IV (strong, moderate)
  • Recent retrospective article called into question
  • Surgical options:
  • Subtotal colectomy (strong, moderate)
  • Alt: Diverting loop ileostomy with colonic lavage (weak, low)

McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085; Wang Y et al. CID, ciz1115, https://doi.org/10.1093/cid/ciz1115

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Total colectomy with end ileostomy

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

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

  • Multiple observational studies have shown similar

mortality compared to colectomy

  • Becoming more common, now ~1/4 of surgeries for fCDI

Neal et al. Ann Surg. 2011 Sep;254(3):423-7; discussion 427-9; Ferrada P et al. J Trauma Acute Care Surg. 2017 Jul;83(1):36-40; Hall BR et al. Am J Surg. 2019 Jan;217(1):34-39. doi: 10.1016/j.amjsurg.2018.09.023; Juo YY et al. JAMA Surg. 2019 Jul 3. doi: 10.1001/jamasurg.2019.2141

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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

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
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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
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Infection control basics

  • Gloves + gowns for duration of diarrhea + 48 h
  • Universal gloving?
  • Wash with soap and water
  • Private rooms
  • Dedicated commode
  • 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

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.

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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

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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.

Ribaxamase

PO β-lactamasedegrade excess antibiotics in GI tract

CRO for LRTI N = 413

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

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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 2 prevention: MODIFY I and II

  • 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

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C diff vaccine? CDI prevention summary

  • Remember infection control and antibiotic stewardship 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
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CDI take-home

  • VAN or FDX preferred for non-fulminant disease
  • Fulminant disease: PO/PR vancomycin and IV metronidazole
  • Consider surgery
  • Maybe FMT
  • 1st recurrencestratify by initial Rx
  • VANVAN 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!