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Cl Clostridium m difficile difficulties

Sarah Doernberg, MD, MAS Assistant professor and Medical Director of Antimicrobial Stewardship Division of Infectious Diseases, UCSF 3.14.2018

Disclosures

§ Grant/funding from: Antibacterial Research Leadership Group (NIH), Infectious Diseases Society of America § Consultant: Actelion, Genentech

Outline

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

New guidelines hot off the press!

3/14/18

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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

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

8 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%

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 20% Other (environmental contamination, etc)

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

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New testing guidance

§Develop institutional 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

§If institution limits testing to high pretest probability testing, PCR alone okay

3/14/18 McDonald LC et al. CID, cix1085, https://doi.org/10.1093/cid/cix1085

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

Uncomplicated CDI treatment no longer 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 ≥ 1.5

• Severe, complicatedàNow “fulminant”

‒ Severe plus hypotension, shock, ileus, and/or megacolon

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

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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 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

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

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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 (though low quality evidence)

• Esp PPI

§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

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. What should you treat her with?

• A. Metronidazole 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 metronidazole used initiallyàVAN 125 mg po QID x 10 days (weak, low) §If VAN used initially, two options:

• VAN taper (weak, low)
• 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

§Treatment outcomes from pts in placebo group with rCDI of 2 RCTs of probiotics (n = 163) §29 got VAN tapers of varying stripes

• Mean 21.5 +/- 10 days
• 31% recurrence compared to 71% of the 10 pts

given standard VAN courses (p = 0.01)

• Also lower recurrences for VAN pulses

§Small numbers, uncontrolled study

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)

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

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

• ffering [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

↓↓↓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

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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 Δ 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.

FMT via pill?

§ Unblinded noninferiority (15%) multicenter RCT of 117 adults with ≥ 3 episodes of CDI treated with FMT via colo versus pill

• 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

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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.

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)

3/14/18 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

• MetronidazoleàStandard 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. 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

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Fulminant CDI

§Paucity of data for medical approaches, expert

• pinion
• VAN 500 mg po QID (strong, moderate)
• IleusàVAN 500 mg in 100 cc saline PR QID

(weak, low)

• Metronidazole IV (strong, moderate)

§Surgical options:

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

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

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.

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

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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%)

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

3/14/18 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 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

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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

Meta-analysis

§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)

§IDSA guidelines = insufficient data

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

Approaches to prevent CDI

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

Infection control

§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 §Antimicrobial stewardship (possibly PPI stewardship)

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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Identification and isolation of carriers

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.

IDSA: “insufficient data”

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

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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)

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 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

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THANK YOU!