Ask the Experts: Understanding and Preventing

Provided by ASHP Supported by an educational grant from Merck

Ask the Experts: Understanding and Preventing Clostridioides difficile Infection Recurrence

Presented as a Live Webinar Wednesday, April 1, 2020 1:00 - 2:00 p.m. ET

On-demand Activity Live webinar recording available May 2020

FACULTY Kevin W. Garey, Pharm.D., M.S., FASHP, Activity Chair Professor and Chair Department of Clinical Sciences and Administration University of Houston College of Pharmacy Houston, Texas

Pablo C. Okhuysen, M.D., FACP, FIDSA Professor, Infectious Diseases The University of Texas MD Anderson Cancer Center Clinical Adjunct Professor Baylor College of Medicine Houston, Texas

View faculty bios at www.ashpadvantage.com/preventcdiff/expert

WEBINAR INFORMATION Visit www.ashpadvantage.com/preventcdiff/expert for: • Webinar registration link• Group viewing information and technical

requirements

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http://www.ashpadvantage.com/preventcdiff/expert

http://www.ashpadvantage.com/preventcdiff/expert

http://elearning.ashp.org/my-activities

Kevin W. Garey, Pharm.D., M.S., FASHP, Activity Chair

Professor and Chair

Department of Clinical Sciences and Administration

University of Houston College of Pharmacy

Houston, Texas

Pablo C. Okhuysen, M.D., FACP, FIDSA

Department of Infectious Diseases

Infection Control and Employee Health

University of Texas MD Anderson Cancer Center

Houston, Texas

Provided by ASHPSupported by an educational grant from Merck

Ask The Experts: Understanding and Preventing Clostridioides difficile Infection Recurrence

Disclosure of Relevant Financial Relationships

Kevin W. Garey, Pharm.D., M.S., FASHP, Activity Chair• Merck: Principal investigator

Pablo C. Okhuysen, M.D., FACP, FIDSA• Summit Therapeutics: Principal Investigator• Pfizer‐Consultant• Merck – Consultant• Jaguar Health, Inc. ‐ Consultant• Singulex ‐ Consultant

All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant to this activity.

©2020 American Society of Health-System Pharmacists, Inc. All rights reserved.

2

• Define the mortality and morbidity associatedwith CDI recurrence.

• Develop a CDI treatment plan with thehealthcare team that optimizes prevention of CDIrecurrence.

• Assess novel therapies in development that focuson prevention of CDI recurrence.

Learning Objectives

On average how many patients with Clostridioides difficile infection (CDI) do you provide care to each month?

a. None‐I am not directly involved in patient care

b. 1‐10 patients/month

c. 11‐20 patients/month

d. 21‐30 patients/month

e. More than 30 patients/month


3


If you participated in our previous C. difficile activity, what changes have you made in your practice since then? (Select all that apply)

a. Educate team members on the identification of risk factors that place patients at riskof recurrent CDI

b. Educate team members on the emerging and current treatment options for managingpatients with recurrent CDI

c. Incorporate most current evidence‐based guidelines into practice when treatingpatients with recurrent CDI

d. Collaborate with other healthcare professionals to formulate care plans for treatingpatients with recurrent CDI

e. Collaborate with other healthcare professionals to develop strategies to preventrecurrent CDI in patients

Clostridioides difficile infection (CDI):Understanding and Preventing CDI

Recurrence

Pablo C. Okhuysen, M.D., FACP, FIDSA


4


• Recap major points from Midyear presentation (December9, 2019) on CDI

• Discuss current and future testing options for thediagnosis of CDI

• Review the most common acute and chroniccomplications of CDI

• Describe the impact that recurrent CDI has on quality oflife

• Discuss the role of the microbiome and probiotics on CDI

Outline

• CDI Case: Diarrhea, severe ileus or megacolon with: Positive laboratory test and/or,endoscopic/microscopic evidence of pseudomembrane formation (defined as incidentcase if no symptoms or negative tests within past 8 weeks)

• Severe CDI: Admission to the ICU, colectomy, death within 30 days

• Recurrent CDI (rCDI): Repeated episodes within 2‐8 weeks

• New episode CDI: Repeat infection after 8 weeks

• Health Care Onset CDI (HO‐CDI): Occurring > 72 hr after admission (rates per 10,000)

• Community Onset Health Care Facility Associated (CO‐HCFA) CDI: Onset within 28 daysafter discharge from a health care facility (rates per 100,000). Also includes CO, presenton admission and not discharged from the same facility within 4 weeks

• Community Associated (CA) CDI: No documented overnight stay in a health care facilityin the prior 12 weeks (>90% have some form of contact with health care)

McDonald LC et al. Clin Infect Dis. 2018; 66:987‐94.

Some Definitions


5


• Diarrheal disease‐related deaths have increased in the U.S. from1980 to 2014. In a big part driven by CDI

– Adjusted mortality from CDI increased 19‐fold

• Estimated to cause 500,000 cases per year with 29,000 deaths

• Adds $4.5 billion in excess medical costs

• Has surpassed methicillin‐resistant Staphylococcus aureus (MRSA)as the most common health care‐associated infection

Hansen V et al. JAMA. 2016; 316(20):2149‐51. El Bcheraoui C et al. JAMA. 2018; 319(12):1248‐60.

Epidemiology

Increasing rates of rCDI and Multiple rCDI

• Due to strains that:– Are more resistant to antibiotics– Are hypervirulent– Have a competitive advantage

• 30% of recurrences linked to a previous case,and 25% can be linked asymptomatic carrier

• Risk of death at 180 days is higher in peoplewith recurrent CDI vs. those w/o recurrence– 36% vs. 26%, p<0.001

• Adjusted hazard ratio 1.33 (95% CI 1.12‐1.58)

rCDI: recurrent Clostridioides difficile infection

Ma G. Ann Intern Med. 2017; 167(3):152‐8. Curry AS. Clin Infect Dis. 2013; 57:1094‐102. Olsen MA, et al. Clin Microbiol Infect. 2015;21;164‐70

2001‐2012% Increase

1st Recurrence 42.7

Multiple rCDI 188.8


6


• Overuse of antibiotics, particularly fluoroquinolones

• Aging population with more severe conditions

• Increasing number of immunocompromised patients

• Spread of hypervirulent, drug‐resistant strains

• Spread of strains that have a competitive advantage

What is Driving the Increase in Frequency and Severity of Recurrent CDI?

• Dietary changes that favor microbiome shifts

• Use of ineffective initial therapy

• Implementation of highly sensitive diagnostictests

• Post‐infectious irritable bowel syndrome (IBS)

What is Driving the Increase in Frequency and Severity of Recurrent CDI?


7


• In the upper GI tract– Limited nutrient environment favors spore formation– Primary bile acids (taurocholate) in the upper GI tract signals sporulation through CspC– Not all C. difficile strains respond to primary bile acids as efficiently

• Variation in the CspC receptor, Δ CspC cause less disease in a hamster model

• In the colon C. difficile growth and toxin production are influenced by– Secondary bile acids– Amino acids and their metabolites (Proline, Tryptophan, Indoles)– Carbohydrates– Free fatty acids– Oxygen tension– Integrity of mucus layer

Shrestha R et al. PLoS Pathog. 2019 Apr 3; 15(4):e1007681.Girinathian et al. mSphere. 2017 Feb 15; 2(1).Kochan TJ et al. PLoS Pathog. 2017 Jul 13; 13(7):e1006443. McDonald AK et al. Gastroenterology. 2018 ; 155(5):1495‐507.

A Diverse Microbiome Inhibits C. difficile

SCFA: Short chain fatty acidsAbt MC. Nat Rev Microbiol. 2016; 14(10):609‐20.


8


Microbiome disruption (antibiotic use) and

Exposure to toxigenic C. difficile (Health care, community)

Susceptible (40‐50%)

‐ No or low Antibodies (Ab) to C. difficile toxin A, B

‐ Comorbidities

First and only episode

(60‐95%)

Recurrence (5‐40%)

Additional Risk Factors

(Advanced age, additional antibiotics, ineffective therapy)

Asymptomatic Carrier

Potential for Transmission to

others

Multiple Recurrences

(10‐50%)

No Further Episodes

(50‐90%)

Not Susceptible

(40‐50%)

‐ Ab to C. difficile and,

‐ Low co‐morbidities

Asymptomatic carrier

Low risk of diarrhea

Potential for transmission to others

Johnson and Gerding. Clin Infect Dis 1998;26:1027‐36 | Poutanent and Simor. CMAJ. 2004; 171: 51–58.Johnson S, Gerding DN. Clin Infect Dis. 1998; 26:1027‐36. Poutanent SM, Simor AE. CMAJ. 2004; 171: 51‐8.

• Diarrhea– Three unformed stools over a 24‐hr period) and,– Signs of gastrointestinal infection, such as fever, nausea, vomiting, abdominal

pain, blood or mucus in stools– No recent use of laxatives

• Toxic megacolon, ileus with a recent history of diarrhea• Verify stools are unformed

– Take shape of the container, Bristol ≥ 6

• Testing for C. difficile within 4 hr of stool being passed isrecommended. Sensitivity for toxin detection decreases with time

Who should be tested?


9


Test Sensitivity (%) Specificity (%) Limitations

Pseudomembranes on colonoscopy 50 100 Sedation, preparation, cost

Cell cytotoxicity 77‐86 97‐99 Not readily available

EIA for toxin A 67‐92 93‐99 Versus cytotoxicity assay

EIA for toxin B 60‐89 93‐99 Versus toxigenic culture

EIA for GDH 71‐100 67‐99 Versus stool culture

Toxigenic culture 95‐100 96‐100 Gold standard

NAATs 88‐100 88‐97 Versus toxigenic culture

Two step GDH 56‐90 81‐97 Discrepancies 13‐19%

Three step GDH 83‐100 93‐100 NAAT arbitration

Diagnostic tests for CDI

EIA: enzyme immunoassayGDH: gluatmate dehydrogenaseNAAT: nucleic acid amplification test

• Fibro purulent exudate originating from erupting crypts• Scattered or confluent. Distal > proximal segments• Most often seen with C. difficile but can be due to other infections

– Highly sensitive but not specific

• Multiple mechanisms for colonic mucosa exudates:– Hypoxia– Ischemia– Infection– Inflammation– Endothelial damage

Tang et al. Cleve Clin J Med. 2016;83:361‐6.

Pseudomembranous colitis


10


Exudates seen on colonoscopyChemicals Drugs Infections Inflammatory conditions

Cocaine Cisplatin C. difficile Behcet disease

Glutaraldehyde Cyclosporine C. ramosum Collagenous colitis

Docetaxel Cytomegalovirus Inflammatory bowel disease

5‐Fluorouracil Entamoeba Ischemic colitis

NSAIDs EHEC 0157:H7

Klebsiella oxytoca

Salmonella

Plesiomonas

Staphylococcus

Shigella

Tang et al. Cleve Clin J Med. 2016;83:361‐6.

• Glutamate dehydrogenase immunoassay (EIA)– High sensitivity

• Fecal nucleic acid amplification test (NAAT)– Single C. difficile DNA Assay. For patients in whom CDI is likely

• Some are coupled with detection of ribotype 027

– Gastrointestinal Multiplex Panel. For patients who are at risk for avariety of GI pathogens due to foreign travel, immunosuppressivetherapy, prolonged neutropenia or lymphopenia, etc.

• Toxin A /B by enzyme immunoassay (EIA)– Lower sensitivity than NAAT for C. difficile, high specificity for CDI

toxin production

What test to order?


11


• CDI is considered to be present when:– GDH EIA and toxin EIA are both positive

• For GDH positive, EIA negative some laboratories perform a NAATarbitration

– NAAT and the Toxin EIA tests are both positive

• Given the high sensitivity of NAATs (>95%):– Single stool specimen is sufficient– Repeated testing over 3 days is not necessary– A negative NAT effectively rules out the presence of C. difficileorganisms

How to interpret results?

One or two step testing ‐ IDSA/SHEA guidelines

IDSA: Infectious Diseases Society of AmericaSHEA: Society for Healthcare Epidemiology of America

Clinicians and laboratory agree at institutional level not to submit formed stools or stools from patients on laxatives and to only submit stools from patients with unexplained and new

onset diarrhea

Stool toxin test as part of a multistep algorithm:

‐ GDH and toxin EIA‐ GDH and toxin arbitrated by NAAT

Rather than NAAT alone

NAAT alone or EIA alone as part of multistep algorithm:

‐ GDH and toxin EIA‐ GDH and toxin arbitrated by NAAT

Rather than toxin alone

No Yes


12


• No need for testing at the end of treatment• No need to test before transferring betweeninstitutions, long‐term acute care (LTAC) facilities, etc.

• No need to repeat within 7 days if a NAAT waspreviously negative

• No indication to test stools that are formed• Only test when presenting with symptoms compatiblewith a recurrence. Follow two‐test algorithm

Re‐testing

• Antibiotic‐associated colitis– Impaired carbohydrate metabolism – osmotic diarrhea– Hastened gut motility – functional diarrhea– Decreased metabolism of primary bile acids – secretory diarrhea

• Other diseases may present as CDI– Staphylococcus colitis– Klebsiella oxytoca colitis

• A diagnostic test is adjuvant to clinical judgment– Treat when in doubt

Akanbi O et al. BMJ case reports. 2017. http://dx.doi.org/10.1136/bcr‐2017‐219915

Still concerned about CDI?


13


• Ultrasensitive single molecule detection methods forlow levels of toxin A/B

• C. difficile bacterial quantitation

• Host inflammatory markers (serum, stool)

• Detection of dysbiotic flora in real time (microbiome)

• Bacterial metabolites (tryptophan, complexcarbohydrates, bile acids)

Promising diagnostic modalities

• Quantitative single molecule array (Simoa)• Toxin A (0.45 pg/ml) and toxin B (1.5 pg/ml) cut off 20 pg/ml

– Compared to cytotoxic assays; Sensitivity 100% and Specificity 96‐98%– A follow up study included a group of asymptomatic carriers

• Could not differentiate between asymptomatic carriers at the proposed cutoff

• Paramagnetic microparticle‐based, single molecule counting• Toxin A 0.8 pg/ml, Toxin B 0.3 pg/ml with a cutoff 12 pg/ml

– Compared to cytotoxic assays 97% sensitivity and 100% specificity– A follow up study showed sensitivity 89%, specificity of 91%

• Unclear if useful as a single diagnostic or supportive in a two stepalgorithm

Song L et al. J Clin Micro. 2015;3204‐12. Shah MD, et. al. J Clin Microbiol. 2020; doi:10.1128/JCM.01681. Pollock NR et.al. Clin Infect Dis. 2019;68:78‐86. Sandlund J, et. al. J Clin Microbiol. 2018;56

Ultrasensitive Fecal Toxin A and B Determination


14


• 146 subjects 24 asymptomatic and122 diarrhea.

• Of the diarrhea patients, 79NAAT+/UST+ and 34 NAAT+/UST‐

subjects– Measured serum IgG, IgA + 12 cytokines

and growth factors.– Measured fecal IgA, IgG, calprotectin

• Differentiated asymptomatic carriersfrom patients with CDI

• Differentiated NAAT+/UST+ fromNAAT+/UST‐

*UST: ultrasensitive testingKelly CP, et. al. Clin Infect Dis. 2020;70:1083‐93

Host Immune Markers

Serum Fecal

GCSF, TNFa, IL‐6

Anti‐toxin A IgG Anti‐toxin A IgA, IgG

• Fluid and electrolyte loss• Intussusception, bowel perforation, peritonitis• Bacteremia• Hypotension, shock

– Dehydration– Bacterial translocation or bowel perforation

• Toxic megacolon– Acute dilatation of the colon > 6 cm– Fulminant, surgical indication

• Chronic symptoms– Reactive arthritis, irritable bowel syndrome

CDI complications


15


• Total colectomy indicated for severe and fulminant cases• The increase in CDI has resulted in a parallel increase in colectomies• Results in creation of a colostomy• Loop ileostomy with vancomycin washout and reanastomosis later• A large retrospective review of 98 patients with C. difficile‐associated

disease showed that loop ileostomy was associated with decreasedadjusted mortality (17% vs. 40%; p=0.002)– Total colectomy patients were treated earlier and required more intensive

support

Ferrada et al. J Trauma Acute Care Surg. 2017; 83:36‐40.

Surgical Management

Impact of recurrent CDI on quality of life

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

EQ‐5D

EQ‐5D Indices

CDI Aged Matched Norm

0

10

20

30

40

50

60

70

80

90

100

Mean EQ‐VAS

EQ‐5D VAS

CDI Age Matched Norm

Mea

n EQ‐5D in

dex

Mea

n EQ‐5D VAS P<0.001 P<0.001

Wilcox MH et al. J Antimicrob Chemother. 2017; 72:2647‐56.


16


C. difficile Quality of Life Scores

Garey KW et al. J Clin Gastroenterol. 2016; 50:631‐7.

0

10

20

30

40

50

60

70

80

Overall Physical Social Mental SF36 Physical SF36 Mental

Primary Recurrent

****

**

** **

** P <0.001

Score

• Most CDI studies focus on short‐term follow up• Irritable bowel syndrome is very common (12% of population)

– Persistent or intermittent abdominal discomfort, distention, andchanges in stool patterns

– Infectious enteritis can be a triggering factor for IBS– Dysbiotic microbiome may contribute to symptoms

• IBS following CDI has been reported in 4‐25% of patients– Four studies have been done, retrospective with methodologic flaws– Unknown if fecal microbiota transplantation (FMT) helps in post‐CDI

IBSDayananda P, Wilcox MH. Curr Opin Gastroenterol . 2019, 35:1‐5. Piche T et al. Can J Gastroenterol. 2007; 21:727‐31.

Wadhwa A et al. Aliment Pharmacol Ther. 2016; 44:576‐82. Sethi S et al. J Hosp Infec. 2011; 77:172‐3.Gutierrez RL et al. Gastroenterology. 2015; 149:1408‐14.

Post‐infectious Irritable Bowel Syndrome


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• Definition– Live organisms that confer a beneficial effect on the host

• Multiple potential mechanisms:– Competition for resources/nutrients/co‐factors– Production of antibacterial products (bacteriocin, reuterin)– Production of proteases that degrade toxin A/B– Production of metabolites that modulate sporulation/toxin production (bile

acids)– Production of metabolites that modulate host immune response (indoles,

fatty acids)– Induction of IgA, mucus production, alteration of O2, pH– Improved barrier function

Mills JP et al. Curr Opin Gastroenterol. 2017; 34:3‐10.

Probiotics and CDI

Probiotics to prevent C. difficile infectionSystematic review of 19 studies, n= 6,261

• Controls: 3.9% (115/2984)

• Probiotics: 1.6% (54/3277) P<0.001

• No differences in adverse events

Relative risk lower when started within:

• Two days (0.32, 95% CI, 0.022‐0.048)

• Later (0.70, 95% CI, 0.40 ‐ 1.23) P=0.02

Limitations

• Various preparations, doses, presentations

• L. acidophilus, L. casei, L. bulgaricus

• L. rhamosus GG, L. plantarum.

• B. bifidum, B. lactis,

• S. thermophilus, S. boulardii

• Non‐immunocompromised patients

Shen NT et al. Gastroenterology. 2007. 152: 1889‐900.


18


Probiotics and antibiotic‐associated diarrhea

• Triple‐blind, placebo‐controlled

• N=503 in three dose groups• Lactobacillus acidophilus, L.

paracasei, Bifidobacteriumlactis Bi‐07, and B. lactis BI‐04

• More than 10% either lost tofollow up or withdrew consentin placebo and low‐dosegroups

Ouwehand AC et al. Vaccine. 2013; 32:458‐3.

0

5

10

15

20

25

30

Placebo Low Dose High Dose

**

0123456

Placebo Low Dose High Dose

CDI

AAD %

CDI % * *

* p<0.05, ** p 0.005

• Starting probiotics <24 hours of starting antibiotics andCDI– Lactobacillus acidophilus or Saccharomyces boulardii– Retrospective study, open‐label design– Sicker patients may have been more likely to receiveprobiotics

– Relative risk reduction 2.3 (1.4‐3.7) in the no probiotics group– Did not evaluate the effect of each preparation– Other risk factors included use of H2 blockers

Saltzman T et al. Am J Infect Control. 2020; 48:184‐8.

Probiotics and CDI


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• Numerous studies with heterogeneous patients, designs, and products tested• Two prospective, randomized controlled studies did not show benefit

– Lactobacilli, Bifidobacterium (PLACIDE)– Lactobacillus reuteri

• Effect is likely strain‐specific and host‐dependent• Many unanswered questions

– Pass through vs. colonization?– Which microbiota are permissive for colonization?– If colonizing, is this transient or persistent?

• Considered generally safe, but risk of bacteremia & fungemia inimmunocompromised patients

Allen SJ et al. Lancet. 2013; 382;1249‐57. Gorgieva M et al. J IMAB‐Annu Proc Sci Pap. 2015; 21:895‐900.

Probiotics

• Fermented milk product made from kefir grains• Symbiotic community of yeasts and bacteria

– Lactobacillus spp, propionibacterium, Bifidobacterium, streptococcusthermophilus, leuconostoc, Kluyveromyces, Saccharomyces, Torulaspora,Kazachstania.

• High in lactate, acetate, propionate, pyruvate, diacetate, acetoin,amino acids

• In vitro inhibits C. difficile toxin production• Pros & cons in animal studies• Case reports in humans to prevent recurrent CDI (21 of 25 patients)

Kefir and CDI

Spinler JK et al. Anaerobe. 2016; 40:54‐7. Bakken JS. Clin Infect Dis. 2014; 59:858‐61. Bolla PA et al. J Dairy Res. 2013; 80:96‐102.


20


• Pre‐test probability and two‐step algorithm improves sensitivity andspecificity

• Not all colonic exudates are C. difficile pseudomembranous colitis• Exercise clinical judgment for patients in gray areas (NAAT+/EIA‐)• In addition to medical costs, recurrent CDI has an impact on quality of

life• A subset of patients will develop post‐infectious irritable bowel

syndrome• Effect of probiotics: conflicting data, the debate remains• Large, blinded, placebo‐controlled studies that examine the efficacy of

probiotics and microbial communities are needed

Summary

Current and future therapies focused on CDI recurrence

prevention

Kevin W. Garey, Pharm.D, M.S., FASHP


21


Antibody response

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

Therapeutic Goals for C. difficile Infection (CDI)

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

AA

A BB

B

Essential: Correct dysbiosis Kill the organism Adaptive immunity

Optional but nice:

Safe and convenient Also affects toxins and spores

Short‐ vs. long‐term


22


There Has Been an Explosion in Treatment Possibilities for CDI

AA

A BB

B

Current: ProbioticsFMTUse narrow‐spectrum antibiotics

MetronidazoleVancomycinFidaxomicin

IVIGBezlotoxumab

Future: 2nd‐generation FMTNon‐tox C. difficile M3Ecobiotics

Ridinilazole Toxoid vaccines


23


More Recently, Metronidazole has Been Shown to be Globally Inferior to Vancomycin (Tolevamer Phase III RCT)

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

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

Proportion

Tolevamer

Metronidazole (n=278)

Vancomycin (n=259)

P=0.02

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

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

8.6%5.9%

15.3%

10.6%

6.9%

19.8%

0%

5%

10%

15%

20%

25%

Any severity Mild‐moderate Severe

30‐day m

ortality (%

)

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%).


24


Summary of Metronidazole vs. Vancomycin Clinical Studies

Study Year Location nSingle center

Blinded RandomizedMetro dose

Vanco dose

Clinical failure Recurrence

metro vanco metro vanco

Teasley, 1983

82‐83

MN 101 yes no yes250 mg QID

500 mg qid

2 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 TID

500 mg tid

2 of 31(6%)

2 of 31 (6%)

5 of 31 (16%)

5 of 31 (16%)

Musher, 2006

02‐04

USA (Housto

n)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 QID

125 mg qid

13 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 QID

125 mg qid

76 of 278 (27%)

49 of 259 (19%)

48 of 202 (23%)

43 of 210 (21%)

There May Have Been MIC Creep With Metronidazole Over the Decades

MIC: minimum inhibitory concentrationShah D et al. Expert Rev Anti Infect Ther. 2010;8:555‐64.

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


25


Houston, TX Initial clinical success of 361 CDI patients by receipt of MTZ or non‐MTZ

Gonzales‐Luna AJ et al. IDWeek 2019

78.1%72.7% 70.0%

100.0%

81.8%

0.0%

44.4%

73.6%81.8%

73.7%81.0%

67.9%

58.3%

45.5%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0.25 0.5 1 2 4 8 16

Initial clin

ical success

MIC (mg/L)

Non‐MTZ therapy*

MTZ receipt

49

n=32 n=72 n=22 n=77 n=20 n=38 n=7 n=21 n=11 n=28 n=1 n=12 n=9 n=11

☨ ≥1 dose of MTZ within 48 hr of treatment start

☨

* vancomycin, n = 95; fidaxomicin, n = 7

• 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 beexpected given these numbers!

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

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


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Recommendation for Initial Treatment of CDI in Adults

VAN, vancomycin; FDX, fidaxomicin; SD, standard doseMcDonald LC et al. Clin Infect Dis. 2018; 66(7):e1‐e48.

Clinical definition Supportive clinical data Recommended 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 hr if ileus present

There Has Been an Explosion in Treatment Possibilities for CDI Minus 1

AA

A BB

B



IVIGBezlotoxumab




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

Louie T, et al. N Engl J Med. 2011; 364:422‐31.

92.1

13.3

77.789.8

24

67.1

0

20

40

60

80

100

Clinical cure Recurrence Global cure

Response rate (%)

Fidaxomicin Vancomycin

P=0.004

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

Recurrent CDI is Costly:Healthcare Utilization for Recurrent CDI

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

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

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

Percentage of total

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


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Any Evidence That Fidaxomicin May Reduce These Costs?

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

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 readmission costs

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 1‐10

Guery B et al. Lancet Infect Dis. 2017; 18:296‐307.


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We may have totally missed the reason why fidaxomicin has anti‐recurrence properties

We may have totally missed the reason why fidaxomicin has anti‐recurrence properties


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Vancomycin resistance, anyone?

Shen et al. J Antimicrob Chemother. 2020

Approx 85% of all C. difficile isolates have a vanG gene cluster, usually silent (cryptic).Turned on = vancomycin resistance

Vancomycin resistance, anyone?

Shen et al. J Antimicrob Chemother. 2020

Approx 85% of all C. difficile isolates have a vanG gene cluster, usually silent (cryptic).Turned on = vancomycin resistance


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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

Recommendation for Recurrence of CDI in Adults

VAN, vancomycin; FDX, fidaxomicin; SD, standard doseMcDonald LC, et al. Clin Infect Dis. 2018;66(7):e1‐e48.

Clinical definitionSupportive clinical data

Recommended treatment

First recurrence

• VAN SD if metronidazole was used for the first episodeOR

• Prolonged tapered and pulsed VAN if VAN SD wasused 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 dailyfor 20 days OR

• FDX SD OR

• Fecal microbiota transplantation


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Before stool transplant

After stool transplant

Deaths N/A 2 (unrelated)

# of Recurrence 64

(Range 2‒7)1

Recurrent C. difficile Colitis

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

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

Duodenal Infusion of Donor Feces for Recurrent C. difficile Infection

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

0

20

40

60

80

100

PO vanco + FMT PO vanco PO vanco + lavageCDI resolution (%)

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


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• 25 patients with recurrent CDI thatwere not able to perform FMT.

• Twenty‐one of the 25 patients(84%) remained free of diarrheaduring the following 9 months.

• The 4 patients who relapsedpermanently resolved theirdiarrhea after a conventional 2‐week course of oral vancomycin125 mg 4 times daily followed by a2‐week course of rifaximin 200 mgtwice daily.

• All 4 patients remained symptom‐free at 12 months of follow up.

Protocol Utilizing a Staggered and Tapered Antibiotic 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.

There Has Been an Explosion in Treatment Possibilities for CDI Augment Immune Response!

AA

A BB

B



IVIGMonoclonal antibodies vs. C. difficile toxins




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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

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

7

25

0

5

10

15

20

25

30

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

Rate (%)

Recurrence at 12 weeks

Recurrence at 12 weeks

P<0.001


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17 16 17

2826 27

0

5

10

15

20

25

30

MODIFY I MODIFY II Pooled Data

Participan

ts with In

fection

Recurrence through

Week 12 (%)

Bezlotoxumab Placebo

* **

Phase III Studies of Bezlotoxumab: CDI Recurrence

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

Bezlotoxumab Was Also Shown to Reduce Hospital Readmissions (European Population)

SOC: standard of careGerding 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.

4.5

23

13.3

26.6

0

5

10

15

20

25

30

CDI‐associated All‐cause

Hospital 30‐day read

mission

rate (%)

Readmission type

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

P<0.05


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• It is remarkably hard to find a good new drug forCDI!

Future therapies for CDI

A lot of CDI drug development starts with a search for a Staph drug and then the molecule ends up being non‐soluble

Daley P et al. J Antimicrob Chemother. 2017; 72:3462‐70. Gerding DN et al. Lancet Infect Dis. 2019; 19:265‐74.

83 8185 86

0

10

20

30

40

50

60

70

80

90

Impact 1 Impact 2

Clin

ical cure

Cadazolid Vancomycin

7983.6

18.322.5

0

10

20

30

40

50

60

70

80

90

Surotomycin 250 mgorally BID (n=290)

Vancomycin 125 mgorally QID (n=280)

Rate (%)

Cure Recurrence

Surotomycin Cadazolid

95% CI: (‐7.2‐4.2) 95% CI: (‐10.7‐1.3)


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Top 2 Candidates Currently in Phase III Clinical Trials

Basseres E et al. J Antimicrob Chemother. 2016; 71:1245‐51. Khoruts A et al. J Clin Gastroenterol. 2010; 44:354‐60.

A. Ridinilazole (Antibiotic) B. RBX2660 (Designer FMT)

Ridinilazole will redefine what is meant by narrow‐spectrum antibiotic (targeted spectrum)

Thorpe CM et al. PLoS One. 2018; 13:e0199810.

Ridinilazole Vancomycin


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Ridinilazole: Good phase II results

Vickers RJ et al. Lancet Infect Dis. 2017; 17:735‐44.

0

10

20

30

40

50

60

70

80

90

Clinical cure Recurrence Sustained clinical cure

Ridinilazole (n=31) Vancomycin (n=28)

RBX2660 (Designer FMT)

• Standardized FMT productprepared from well‐screened healthy subjects

• 150 mL suspensionprovides >107 liveorganisms/mL (single dose)


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RBX2660 also good Phase II results:CDI patients with >3 episodes

61

45

6764

0

10

20

30

40

50

60

70

80

Group A (n=41)2 doses RBX2660

Group B (n=44)2 doses placebo

Group C (n=42)1 RBX2660 1 placebo

Group A + C (n=83)

No further CDI e

pisodes (%

)

• A better appreciation of CDI recurrence leads to anew thought process to optimize therapy for CDIpatients– Thanks, Pablo!

• Consider likelihood (and consequences) of CDIrecurrence as part of the treatment algorithm

• Current and future treatments will help minimizelikelihood of CDI recurrence

Treatment Conclusions


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• Educate team members on the identification of risk factors thatplace patients at risk of recurrent CDI

• Educate team members on the emerging and current treatmentoptions for managing patients with recurrent CDI

• Incorporate most current evidence‐based guidelines intopractice when treating patients with recurrent CDI

• Collaborate with other healthcare professionals to formulatecare plans for treating patients with recurrent CDI

• Collaborate with other healthcare professionals to developstrategies to prevent recurrent CDI in patients

Practice Changes

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Ask the Experts: Understanding and Preventing

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