presentation - garey, kevin€¦ · grant/research support: ... have any relevant financial...

11/5/2019

1

Activity Description

Target AudienceThis activity will help to empower Doctors of Osteopathy (DOs) at the front-line of patient care with the knowledge and tools needed to detect and diagnose patients presenting with symptoms of C. difficile infection. Participants will build awareness of how to make an accurate and timely diagnosis of CDI through improved communication and evaluation. This activity also reviews the latest guidelines recommendations in the management of CDI as well as allows DOs to recognize when referral to a specialist or acute care setting is needed.

Learning ObjectivesAt the conclusion of the educational activity, the learner should be able to: Utilize communication and evaluation techniques to aid in the early detection of

C. difficile infection Identify and interpret diagnostic tests to help differentiate C. difficile infection from

other gastrointestinal disorders Evaluate current therapeutic options available for the management of C. difficile

infection

11/5/2019

2

Faculty and Disclosure

Dr. Kevin Garey has relevant financial relationships with the following commercial interests:Grant/Research Support: PI on grant to University of Houston from Merck & Co., Inc.

Dr. Garey intends to discuss the following off-label uses: Metronidazole use for CDI

No (other) speakers, authors, planners or content reviewers have any relevant financial relationships to disclose.

Content review confirmed that the content was developed in a fair, balanced manner free from commercial bias. Disclosure of a relationship is not intended to suggest or condone commercial bias in any presentation, but it is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

Kevin W. Garey, PharmD, MS, FASHPChair, Department of Pharmacy Practice and Translational ResearchProfessor of Pharmacy PracticeCollege of PharmacyUniversity of Houston Houston, TX

Side Note: Nomenclature Changes

CLSI AST News Update. 2018;3(1):1-21.

11/5/2019

3

Britton RA, Young VB. Gastroenterology. 2014;146:1547-53.

Antibody response

A History of C. difficile

1893 – pseudo-membranous

colitis first described

1935 - isolated in stool

1978 –C. difficile

responsible for antibiotic-associated

diarrhea

1996-2003 CDC reports rate of CDI increased from 31 cases per 100,000

persons to 61 cases per 100,000

persons

1. Heinlen L, Ballard JD. Am J Med Sci. 2010;340(3):247-252.2. Valiente, E. et al. Clin Microbiol Infect. 2014;20:396-404.

2005 – US continues to report increased CDI

rates

2008-11 – England directs significant

resources to control CDI (and MRSA)

Current – endemicpersistence of

RT 027 in North America and

Europe

11/5/2019

4

C. difficile is the Main Contributor to Gastroenteritis-associated Deaths in the USA

0

10

20

30

40

50

60

1999-2000 2007-2007

Dea

ths

per

100

,000

per

son

sMortality attributed to CDI

Analysis of National Center for Health Statistics (NCHS) multiple-cause-of-death mortality data for the years 1999–2007, a 5-fold increase in mortality attributed to CDI was noted.

Hall AJ, et al. Clin Infect Dis. 2012;55:216-23.

The Impact of Clostridium difficileInfections (CDI)

Source: CDC. Antibiotic Resistance Threats in the United States, 2013. Available: https://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. Lessa CF, et al. N Engl J Med. 2015;372:825-34.

500,000 29,000

Of patients with CDI given metronidazole or oral vancomycin, 25% will experience recurrent CDIUp to 35% of all CDI is diagnosed in the community setting!

11/5/2019

5

How Did We Get Here?

• Let’s review a few key concepts on CDI to get everyone up to speed

–Emergence of ‘hypervirulent’ strains

Hypervirulent C. difficile

McDonald LC, et al. N Engl J Med. 2005;353:2433-41.

11/5/2019

6

Incidence of Hypervirulent Strains of C. difficile, 2005

McDonald LC, et al. N Engl J Med. 2005;353:2433-41.

Pepin, J. et al. CMAJ. 2004;171:466-472

Increasing Mortality and Complications Due to CDI

11/5/2019

7

Who You Calling “Hypervirulent”

PredictorDerivation OR

(95% CI)P Value Validation OR (95% CI) P Value

Hypervirulent ribotype:

027/078 vs non-027/078 (reference)

0.82 (.07–10.0) .874 1.34 (.53–3.16) .516

White blood cell count: Leukocytosis (>12 000 cells/mL) or leukopenia

(<4000 cells/mL) vsnormal (reference)

4.27 (1.14–19.46) .041 2.32 (1.07–5.18) .035

Low albumin level (g/dL)

0.25 (.07–.77) .025 0.47 (.25–.87) .018

Walk ST, et al. Clin Infect Dis. 2012;55:1661-8.

Michigan: Derivation (n=310/34 severe) and validation (n=433/45 severe) of predictors of severe CDI (ICU admission, colectomy, or death). After accounting for disease presentation severity, ribotype did not predict outcome

…And There are More Ribotypes Than Just 027

A lot of ribotypes are associated with CDI

Many ribotypes are virulent, including 027Ribotype

Severe CDI presentation

Severe CDI outcome

027 (n=170) 54.7% 18.9%

014-020 (n=118) 22.9% 4.2%

FP11 (n=70) 31.4% 8.6%

078-126 (n=42) 21.4% 9.5%

001 (n=35) 42.9% 8.6%

FP24 (n=35) 37.1% 22.9%

17 (n=23) 39.1% 17.4%

FP8 (n=19) 36.9% 10.5%

053-163 (n=16) 37.5% 6.25%

FP16 (n=16) 35.3% 11.8%

FP9 (n=16) 25.0% 18.8%

Aitken SL, et al. Infect Control Hosp Epidemiol. 2015;36:1318-23.

11/5/2019

8

You are All Now Expert C. difficile Ribotypes

• 027 is definitely a virulent ribotype

• …..but, there are lots of ribotypes that are equally virulent

• Without a doubt, the ribotype 027 strain has put a large focus on the value of strain typing in C. difficile

• Now, let’s use this technology to understand where C. difficile may be coming from

– (answer: everywhere)

Part 1: Let Me Convince You That We Have a Lot of C. difficile Around Us

(Challenge the Current Paradigm)

11/5/2019

9

C. difficile is Becoming More Common in the Community Setting

0

1

2

3

4

5

6

7

8

No medicalconditions

Infant younger than1 y

Household memberwith active CDI

Od

ds

rati

o High-level healthcareexposure

Low-level healthcareexposure

No exposureP=0.04

P=0.05

Chitnis AS, et al. JAMA Intern Med. 2013;173:1359-67.

CDC: 10 US states identified 984 patients with community-acquired CDI (No previous antibiotics: 36%; No outpatient healthcare exposure: 18%).

How Do Patients Get Infected in the First Place? Where are C. difficile Strains Coming From?

0%10%20%30%40%50%60%70%80%90%

100%

1 2 3 4 5 6 7 8 9 10 11

Per

cen

tag

e o

f is

ola

tes

SNVs used to define two cases as genetically related

No previous case

No known epidemiologiclink

Community contact

Any hospital contact

Direct ward contact

Leeds, England: Whole genome sequencing of 1223 cases of CDI. This allows for a highly discriminatory way to see where C. difficile strains are coming from.

SNV, single-nucleotide variantEyre DW, et al. N Eng J Med. 2013;369:1195-205.

11/5/2019

10

We Hypothesized the Community Environment May Contain a Large Burden of C. difficile

Contamination

Isolate source Number

Environmental

Home 1173

Chain stores 230

Fast-food restaurants 125

Parks 540

Clinical isolates 613

Alam MJ, et al. Open Forum Infect Dis. 2017;4(1):ofx018. DOI: https://doi.org/10.1093/ofid/ofx018

Community Environmental Contamination of Toxigenic C. difficile

**

**

**p<0.001 compared to either chain stores, fast-food restaurants, or other commercial stores


11/5/2019

11

Home Environmental Contamination of Toxigenic C. difficile

**

**p<0.001 comparing shoe soles and doorsteps to cleaning supplies, kitchen and restroom samples


These Results Have Generated Some Public Health Interest!

http://www.menshealth.com/health/disgusting-disease-your-shoes

11/5/2019

12

CDI Update #1: C. difficile is Ubiquitous

So, this new knowledge makes this guy way more important! Why do some patients get colonized with CDI while others do not?

Part 2

Diagnosis

11/5/2019

13

Risk Factors for CDI - Antibiotics

Hensgens MP, et al. J Antimicrob Chemother. 2012:67;742-748.

Can I Use This Information to Help Identify Patients with CDI?

• ANTIBIOTICS!!!

• Antibiotics!!

• Antibiotics!

• ……and other things that disrupt the microbiome• Chemotherapy• Underlying GI diseases (Crohn’s / IBD)• Proton pump inhibitors (synergistic with antibiotics)

• So, how do I diagnose CDI?

11/5/2019

14

• While on therapy

• Immediately following therapy (prolonged shedding)• Up to 50% of patients 6 weeks after completion of

therapy• 10‒20% become long-term carriers• Repeat testing for “cure” and retreatment not

recommended during this period unless accompanied by symptoms

Bagdasarian N, et al. JAMA. 2015;313:398-408.

Who Should Not Be Tested?

• Diarrhea• ≥3 loose bowel movements (BMs)/24 hours • No alternate explanation

• Ileus + leukocytosis

• Colitis on imaging

• Acute abdomen with bowel wall thickening

• Toxic megacolon

• Pseudomembranes on endoscopy

Who Should Be Tested: Symptomatic Patients

11/5/2019

15

• Antibiotic-associated diarrhea• Klebsiella oxytoca• Post-infectious IBS• IBD• Celiac disease• Ischemic colitis• Collagenous colitis• Cytomegalovirus (CMV) colitis • Routine enteric pathogens• Parasitic pathogens

• Right risk factors or exposures (Giardia/Cryptosporidium)

• Carcinoid syndrome / other hypermotility states

Differential Diagnosis

Diagnostic Strategies for CDI

1. Only test unformed stool (or ileus)2. Don’t test asymptomatic patients

(not applicable in our case)

1. Stool culture is the most sensitive diagnostic technique

2. Usually not clinically practical

A B B A A

B A B A A

Test for Toxins A and B1. Cell cytotoxicity2. Enzyme immunoassay (EIA)3. Polymerase chain reaction (nucleic acid amplification test (NAAT))

11/5/2019

16

The PCR Diagnosis is Very Sensitive. May See an Increase in Rate with the Switch from Other Diagnostics

CDC: Increasing use of molecular-based diagnosis to diagnose CDI via presence of toxin genes. Increased rates vs. EIA!!

Gould CV, et al. Clin Infect Dis. 2013;57:1304-7.

0

0.2

0.4

0.6

0.8

California (14 switch vs. 56non-switch)

Colorado (24 switch vs. 161non-switch

Georgia (50 switch vs. 149 non-switch)

Percent increase in CDI rate in switch compared to non-switch hospitals

But PCR Diagnostic Strategies May Detect Patients Colonized with CDI but Not Infected

0

2

4

6

8

10

12

14

16

18

CTA positive(n=435)

CC positive, CTAnegative (n=207)

NAATpositive/CTA

negative (n=311)

All negative(n=5880)

Mo

rtal

ity

(%)

Planche TD, et al. Lancet Infect Dis. 2013;13:936-45.

UK: prospective, multicenter study of suspected CDI patients tested for cytotoxicity assay (CTA), cytotoxigenic culture (CC), or nucleic acid amplification test (NAAT)

Mortality increased significantly in CTA-positive patients (OR 1.61, 95% CI 1.12–2.31)

11/5/2019

17

We Observed the Same Phenomenon in HoustonC. difficile Rates Before and After Use of the New PCR

Diagnostic

0.0

6.7

13.3

20.0

26.7

33.3

40.0

0 9 18 27 36 44 53 62 71 80Time (months)

C d

iff r

ate

per

10,0

00 a

dmits

C diff diagnostic

01

Cytotoxicity assay

BD PCR assay

Koo HL, et al. Infect Control Hosp Epidemiol. 2014;35:667-73.

Can PCR detect colonized patients?• N=101 fecal specimens

collected from hospitalized patients.

• C. difficile in 18 subjects• 5 subjects (28%) with either

definite or probable CDI• 13 patients (72%) with

asymptomatic C. difficile colonization

CDI Laboratory Test Recommendations Based Upon Pre-agreed Institutional Criteria

Clinicians and laboratory personnel agree at the institutional level to not submit stool samples on patients receiving laxatives and to submit stool specimens only from patients with unexplained and

new onset ≥3 unformed stools in 24 h for CDI testing

Stool toxin test as part of a multiple-step

algorithm usually GDH plus toxin test

NAAT alone or stool EIA toxin test as part

of a multiple-step algorithm

No Yes

McDonald LC, et al. Clin Infect Dis. 2018;66(7):e1-e48.

11/5/2019

18

These Recommendations Have Already Spurred on New Research:

Clinical Course of GDH+/EIA+ vs. GDH+/EIA-/PCR+

33.9%

19.2%25.5%

7.2%0%

5%

10%

15%

20%

25%

30%

35%

40%

GDH+/EIA+ GDH+/EIA-/PCR+

Per

cen

t (%

)

Severe/severe complicated CDI CDI recurrence

Retrospective cohort evaluation of 231 patients that tested positive for C. difficile with EIA vs. PCR

‘toxin-positive group’ ‘toxin-negative, PCR-positive group’

Origuen J, et al. Clin Microbiol Infect. 2018;24:414-21.

New Diagnostics are on the Way:Single Molecule Array Technology (SIMOA)

• Able to detect proteins (not genes) to a very low level

– Limits of detection: toxin A: 0.6 and toxin B: 2.9 pg/mL– The optimal clinical thresholds for the toxin A and B:

22.1 and 18.8 pg/mL– Sensitivities: 84.8‒95.5%– Comparator: a high performing EIA toxin test had a

sensitivity of 71.2%.

Banz A, et al. J Clin Microbiol. 2018;56(8): pii:e00452-18. PMID: 29898996.

11/5/2019

19

Part 3: Treatment of CDI

Therapeutic Goals for C. difficile Infection (CDI)

Essential: Correct dysbiosis Kill the organism Adaptive immunity

Optional Safe and convenient Also affects toxins Short vs. long-termbut nice: and spores

AA

A BB

B

Adamu BO, Lawley TD. Curr Opin Microbiol. 2013;16:596-601.

11/5/2019

20

There Has Been an Explosion in Treatment Possibilities for CDI

Current: Probiotics Metronidazole IVIG FMT Vancomycin BezlotoxumabUse narrow-spectrum Fidaxomicin

antibiotics

Future: 2nd-generation FMT Ridinilazole Toxoid vaccinesNon-tox C. difficile M3Ecobiotics

AA

A BB

B

11/5/2019

21

• Don’t treat asymptomatic patients!– Uncertain if colonization treatment has any effect– Treatment may increase colonization/spread!– Prophylaxis not well studied

• Stop other antibiotics– 15‒20% clinical success in mild CDI (alone!)

• Stop proton pump inhibitors (PPIs) and antimotilityagents

• Stop/alter use of binding agents (cholestyramine)– Can bind vancomycin/metronidazole!

Bagdasarian N, et al. JAMA. 2015;313:398-408.

Treatment for CDI: First Steps

More Recently, Metronidazole has Been Shown to be Globally Inferior to Vancomcyin

(Tolevamer Phase III RCT)

0.44

0.045

0.73

0.23

0.81

0.21

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Clinical success Recurrence

Pro

po

rtio

n

Tolevamer

Metronidazole (n=278)

Vancomycin (n=259)

P=0.02

Johnson S, et al. Clin Infect Dis. 2014;59:345-354.

11/5/2019

22

Increased Failure Rate of Metronidazole Also Associated with Increased 30-day Mortality

8.6%

5.9%

15.3%

10.6%

6.9%

19.8%

0%

5%

10%

15%

20%

25%

Any severity Mild-moderate Severe

30-d

ay m

ort

alit

y (%

)

CDI severity

Vancomycin Metronidazole

VA dataset (vancomycin: n=2,068; metronidazole: n=8,069 propensity matched). Patients given vancomycin had a significantly lower risk of 30-day mortality (RR: 0.86, 95% CI: 0.74-0.98). No difference in CDI recurrence regardless of disease severity or choice of antibiotic (16.3-22.8%).

Stevens VW, et al. JAMA Intern Med. 2017;177:546-53.

Summary of Metronidazole vs. Vancomycin Clinical Studies

Study Year Location n Single center Blinded RandomizedMetro dose

Vancodose

Clinical failure Recurrence

metro vanco metro vanco

Teasley, 1983

82-83 MN 101 yes no yes250 mg

QID500 mg

qid2 of 37 (5.4%)

0 of 45 (0%)

2 of 37 (5.4%)

6 of 45 (13%)

Wenisch, 1996

93-95 Austria 62 yes no yes500 mg

TID500 mg tid

2 of 31(6%)

2 of 31 (6%)

5 of 31 (16%)

5 of 31 (16%)

Musher, 2006

02-04USA

(Houston)34 no yes yes

250 mg QID

125 mg qid

6 of 34 (17%)

N/A9 of 28 (32%)

N/A

Zar, 2007 94-02 Chicago 150 Yes yes yes250 mg

QID125 mg

qid13 of 79 (16%)

2 of 71(3%)

9 of 66 (14%)

5 of 69 (7%)

Johnson, 2013

05-07 World 552 no yes yes375 mg

QID125 mg

qid76 of 278

(27%)49 of 259

(19%)48 of 202

(23%)43 of 210

(21%)

11/5/2019

23

There May Have Been MIC Creep With Metronidazole Over the Decades

Author Location Time period IsolatesMetronidazole

MIC50 MIC90 RangeAll strainsHecht et al Various 1983–2004 110 0.125 0.25 0.025–0.5Edlund et al Sweden 1998 50 0.125 0.25 0.125–0.25Betriu et al Spain 2001 55 0.5 1 ≤0.06–1Citron et al USA 2003 18 0.5 1 0.25–1Finegold et al USA (CA) 2003 72 0.5 1 0.25–2

Karlowsky et alCanada

(Manitoba)2007 208 0.5 1 0.25–4

Debast et al Europe 2008 398 0.25 0.5 <0.06-2Reigadas et al Spain 2013 100 0.25 0.5 0.06-1Snydman et al USA 2011-12 925 1 2 <0.06-4BI/027/NAP1 strainsCitron et al USA 2004–2005 NR 2 0.5–2Debast et al Europe 2008 0.5 1 0.5-1Snydman et al USA 2011-12 2 2 <0.06-4

Shah D, et al. Expert Rev Anti Infect Ther. 2010;8:555-64.

Bottom Line: This May Simply be a PK/PD Problem

• Mean concentrations of metronidazole in stool: <0.25‒9.5 g/g

• MIC50: 1 g/mL MIC90: 2 g/mL– May be higher

• A poor response rate to metronidazole should be expected given these numbers!

Bolton RP, Culshaw MA. Gut. 1986;27:1169-72.

11/5/2019

24

Recommendation for Initial Treatment of CDI in Adults

Clinical definitionSupportive clinical

dataRecommended treatment

Initial episode, non-severe

WBC <15,000 cells/mL and serum creatinine <1.5 mg/dL

VAN 125 mg given four times daily for 10 days, orFDX 200 mg given twice daily for 10 daysAlternative if above agents are not available: metronidazole 500 mg three times daily by mouth for 10 days

Initial episode, severe

WBC ≥15,000 cells/mL or a serum creatinine >1.5 mg/dL

VAN 125 mg given four times daily for 10 days, orFDX 200 mg given twice daily for 10 days

Initial episode,fulminant

Hypotension or shock, ileus, megacolon

VAN 500 mg given four times daily by mouth or nasogastric tube. If ileus, consider adding rectal instillation of VAN. Add intravenous metronidazole 500 mg every 8 hrs if ileus present

VAN, vancomycin; FDX, fidaxomicin; SD, standard dose


Explosion in Treatment Possibilities for CDI Minus 1

AA

A BB

B

Current: Probiotics Metronidazole IVIG FMT Vancomycin Monoclonal antibodiesUse narrow-spectrum Fidaxomicin vs. C. difficile toxins

antibiotics

Future: 2nd-generation FMT Ridinilazole Toxoid vaccines Non-tox C. difficile M3Ecobiotics

11/5/2019

25

Fidaxomicin: Equal Efficacy as Vancomycin to Cure Patients and Lessens the Risk of Recurrence

92.1

13.3

77.789.8

24

67.1

0

10

20

30

40

50

60

70

80

90

100

Clinical cure Recurrence Global cure

Res

po

nse

rat

e (%

)

Fidaxomicin Vancomycin

P=0.004

Louie T, et al. N Eng J Med. 2011;364:422.-310.

The second phase III study showed similar results (Crook et al. Lancet ID)

Recurrent CDI is Costly:Healthcare Utilization for Recurrent CDI

*Of disease-attributable readmission, 85% returned to the initial hospital for care

45.3

3.1

42.2

9.4

61.0

0.0

39.0

0.00

10

20

30

40

50

60

70

Outpatient only Emergency departmentonly

Hospitalization* ICU admission

Per

cen

tag

e o

f to

tal

First recurrence (n = 64) Second or later recurrence (n = 18)

Aitken SL, et al. PLoS One. 2014;9(7):e102848.

11/5/2019

26

Increased Healthcare Utilization = Increased Healthcare Costs

0

5

10

15

20

25

30

Without recurrent CDI With Recurrent CDI

Med

ian

LO

S (

in d

ays)

Total LOS CDI-attributable LOS

Cost in US dollars,median (IQR)

Withoutrecurrent CDI

Withrecurrent CDI

CDI pharmacologic treatment $60 (23 – 200) $140 (30 – 260)

CDI-attributable hospitalization $13,168 (7,525 – 24,455) $28,218 (15,049 – 47,030)

Total hospitalization $20,693 (11,287 – 41,386) $45,148 (20, 693 – 82,772)

Shah DN, et al. ICAAC 2014 Poster #K-356, Sat., Sept 6, 2014.

Any Evidence That Fidaxomicin May Reduce These Costs?

6,333

62,112

454,800

196,200

$0

$100,000

$200,000

$300,000

$400,000

$500,000

Vancomycin Fidaxomicin Vancomycin (183 days) Fidaxomicin (87 days)

Patients who received oral vancomycin (n=46) or fidaxomicin (n=49) for the treatment of CDI via a protocol that encouraged fidaxomicin for select patients.

CDI-related re-admissions: fidaxomicin: 20.4%; vancomycin: 41.3%

Drug-acquisition costs Hospital re-admission costs

Gallagher JC, et al. Antimicrob Agents Chemother. 2015;59:7007-10.

11/5/2019

27

Real-world Evidence That Fidaxomicin May Reduce These Costs?

10.6

16.3

21.1

7.7

12.9

16.9

5.4

3.1 3.1

12.5

8.3

11.8

9

5.8

0

5

10

15

20

25

A (n=98) B (n=162) D (n=127) C (n=511) E (n=209) F (n=178) G (n=278)

90-

day

ho

spit

al r

ecu

rren

ce r

ate Before Fidaxo After Fidaxo

First line, all episodes Select episodes onlyFirst line, R-CDI

UK, 2012‒13: Seven hospitals incorporate fidaxomicin into clinical protocols. Letters below indicate individual hospitals

Goldenberg SD, et al. Eur J Clin Microbiol Infect Dis. 2016;35:251-9.

Real-world Evidence That Fidaxomicin May Reduce These Costs?

0

5

10

15

20

25

30

35

A (n=98) B (n=162) D (n=127) C (n=511) E (n=209) F (n=178) G (n=278)

Re-

adm

issi

on

wit

hin

30

day

s o

r p

rim

ary

CD

I

Before Fidaxo After Fidaxo

First line, all episodes Select episodes onlyFirst line, R-CDI

UK, 2012‒13 : Seven hospitals incorporate fidaxomicin into clinical protocols. Letters below indicate individual hospitals. Mortality rates decreased from 18.2% and 17.3% to 3.1% and 3.1% in hospitals A and B, respectively (p<0.05, each)

P<0.05

Goldenberg SD, et al. Eur J Clin Microbiol Infect Dis. 2016;35:251-9.

11/5/2019

28

The EXTEND Trial

*Dosage: Fidaxomicin 200 mg oral tablets, twice daily on days 1-5, then once daily on alternate days on days 7-25; Vancomycin 125 mg oral capsules, four times daily on days 1-10Guery B, et al. Lancet Infect Dis. 2017;18:296-307.

Restore the Microbiome

A BA

BA

AA

AA

AAAB

BB

B B BBEnteric flora

Colonic epithelium Colonic epithelium

Microbiome of non-CDI patients vs. CDI patients

Healthy Microbiome Recurrent CDI Microbiome

Total CFU abundance

Diversity of microbiologic species

Other pathogenic organisms

11/5/2019

29

Recommendation for Recurrence of CDI in Adults

Clinical definitionSupportive clinical data

Recommended treatment

First recurrence

• VAN SD if metronidazole was used for the first episode OR

• Prolonged tapered and pulsed VAN if VAN SD was used for first regimen OR

• FDX SD if VAN was used for the initial episode

Second or subsequent recurrences

• VAN in a tapered or pulsed regimen OR• VAN SD followed by rifaximin 400 mg three times

daily for 20 days OR• FDX SD OR• Fecal microbiota transplantation

VAN, vancomycin; FDX, fidaxomicin; SD, standard dose


FMT for Patients with Recalcitrant CDI

11/5/2019

30

Before stool transplant

After stool transplant

Deaths N/A 2 (unrelated)

# of Recurrence 64

(Range 2‒7)1

Aas J, et al. Clin Infect Dis. 2003;36:580-5.

Recurrent C. difficile Colitis

Case series involving 18 patients treated with donor stool administered via a nasogastric tube

Duodenal Infusion of Donor Feces for Recurrent C. difficile Infection

0

10

20

30

40

50

60

70

80

90

PO vanco + FMT PO vanco PO vanco + lavage

CD

I re

solu

tio

n (

%)

RCT of PO vanco + FMT (n=16), PO vanco alone (n=13), or PO vanco + bowel lavage (n=13). Study stopped prematurely due to superiority of FMT.

Resolution: no diarrhea without relapse after 10 weeks

van Nood E, et al. N Engl J Med. 2013;368:407-15.

11/5/2019

31

Protocol Utilizing a Staggered and Tapered Antibiotic Treatment Regimen for the Treatment of Recurrent CDI that

has Failed to Respond to Standard Antibiotic Therapy

Bakken JS. Clin Infect Dis. 2014;59:858-61.

25 patients with recurrent CDI that were not able to perform FMT. Twenty-one of the 25 patients (84%) remained free of diarrhea during the following 9 months. The 4 patients who relapsed permanently resolved their diarrhea after a conventional 2-week course of oral vancomycin 125 mg 4 times daily followed by a 2-week course of rifaximin 200 mg twice daily. All 4 patients remained symptom-free at 12 months of follow-up.

Explosion in Treatment Possibilities for CDI: Augment Immune Response!

Current: Probiotics Metronidazole IVIG FMT Vancomycin Monoclonal antibodiesUse narrow-spectrum Fidaxomicin vs. C. difficile toxinsantibiotics

Future: 2nd-generation FMT Ridinilazole Toxoid vaccines Non-tox C. difficile M3Ecobiotics

AA

A BB

B

11/5/2019

32

Serum Concentrations of IgG Antibodies Against Toxin A, Toxin B, and Non-toxin Antigens

Kyne L, et al. Lancet. 2001;357:189-93.

Single episodeRecurrent diarrhea

Monoclonal Antibody: Phase II Study

7

25

0

5

10

15

20

25

30

Monoclonal antibodies (n=101) Placebo (n=99)

Rat

e (%

)

Recurrence at 12 weeks

Recurrence at 12weeks

Lowy I, et al. N Engl J Med. 2010;362:197-205.

P<0.001

11/5/2019

33

*p<0.001Wilcox MH, et al. N Engl J Med. 2017;376:305-17.

1716

17

2826

27

0

5

10

15

20

25

30

MODIFY I MODIFY II Pooled Data

Par

tici

pan

ts w

ith

Infe

ctio

n R

ecu

rren

ce

thro

ug

h W

eek

12 (

%)

Bezlotoxumab Placebo

* **

Phase III Studies of Bezlotoxumab: CDI Recurrence

Bezlotoxumab Was Also Shown to Reduce Hospital Re-admissions (European Population)

4.5

23

13.3

26.6

0

5

10

15

20

25

30

CDI-associated All-causeHo

spit

al 3

0-d

re-

adm

issi

on

rat

e (%

)

Re-admission type

Bezlo+SOC (n=265) Placebo + SOC (n=256)

P<0.05

Gerding DN, et al. Abstract 2000. Presented at: ECCMID; April 9-12, 2016; Amsterdam.Wilcox MH, et al. Abstract 1996. Presented at: ECCMID; April 9-12, 2016; Amsterdam.

11/5/2019

34

And Last but Not Least, the Patient Perspective

I Wonder if We are Missing the Most Important Endpoints?

0

10

20

30

40

50

60

Overall SF36 Physical healthlimitations

Social functioning

SF

36 s

core

(av

erag

e)

CDI<1 mo (n=19) CDI 1-12 mo (n=26) CDI > 12 mo (n=21)

Aitken SL, et al. ICAAC 2014 Poster #K-360, Sat, Sept 6, 2014.

11/5/2019

35

The Driver for Decreased Quality of Life (QOL) is Not so Much Physical as a Worry/Anxiety of

Transmissibility or Symptom Persistence

Goddu S, Bozorgui S et al. Presented at ISPOR 18th Annual European Congress, Milan, Italy, Nov. 7-11, 2015.

QOL Goes Down Considerably with Recurrent CDI

0

20

40

60

80

100

CdiffO

verall

CdiffP

hysical

CdiffS

ocial

CdiffM

ental

SF

36Physical

SF

36Mental

Qua

lity

of li

fe

Primary or recurrent C

PrimaryRecurrent

Primary or recurrent CDI

Garey K, et al. J Clin Gastroenterol. 2016;50:631-7.

11/5/2019

36

Patient Perspective

“It was a little over a year ago I was diagnosed and treated with metronidazole, then treated again in April with vancomycin for it as tested positive again, and am 50 years old and otherwise healthy except for hypertension issues. I think I acquired it as a caretaker for my elderly mother (who has since passed away), and having antibiotics for dental issues. I wouldn't wish this illness on my worst enemy, and it's been a life changer for me.”

Final Conclusions

• C. difficile is all around. Diagnosis is made first and foremost by identifying patients at risk

• Prior use of antibiotics

• Know your diagnostics!• PCR diagnosis may identify colonized patients

• Treatment of CDI is evolving• Limit (eliminate) use of metronidazole• Bezlotoxumab is here (and can be used in outpatient

infusion centers)• Complete the triad: Correct dysbiosis

11/5/2019

37

Q and A

presentation - garey, kevin€¦ · grant/research support: ... have any relevant financial...

Documents