Update on C diff guidelines - msipc.org · Carey-Ann Burnum and Karen Carroll. Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians and for Clinical Labs

UPDATE ON C DIFF GUIDELINESWHAT IS BEHIND THE CURTAIN?

ANDREW JAMESON, MD, FACP, AAHIVS

ASSISTANT PROFESSOR OF MEDICINE

MICHIGAN STATE UNIVERSITY- COLLEGE OF HUMAN MEDICINE

AGENDA

• EPIDEMIOLOGY

• CRITERIA FOR TESTING

• WHO TO TEST

• TESTING METHOD

• INFECTION CONTROL

• TREATMENT

EPIDEMIOLOGY

• C DIFF IS BAD

• CDC ESTIMATED AT 453,000 INCIDENT CASES IN 2012

• 64.7% HEALTHCARE ASSOCIATED

• 94% HAD RECENT HEALTHCARE EXPOSURE

• NOW THOUGHT TO BE MOST COMMON HAI

• SEVERITY OF CDI INCREASED SINCE NORTH AMERICAN PULSED FIELD TYPE 1 (NAP1 STRAIN) BEGAN

CIRCULATING

• COSTS

• $3427-9960 PER EPISODE

• $1.2-$5.9 BILLION ANNUALLY IN THE US

McDonald L, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children.: 2017 Update by IDSA

and SHEA. Clin Inf Dis, Vol 66, Issue 7, 19 March 2018, Pages e1-e48

EPIDEMIC VS ENDEMIC PERIODS

• MORBIDITY CHANGES DRAMATICALLY

• COLECTOMY RATES GO FROM 0.3%-1.3% TO 1.8%-6.2%

• MORTALITY (ATTRIBUTABLE)

• 4.5%-5.7% DURING ENDEMIC PERIODS

• 6.9%-16.7% DURING EPIDEMIC SETTINGS



INFECTION/COLONIZATION

• FECAL/ORAL VS EXPOSURE TO ENVIRONMENT

• POOLED COLONIZATION RATE FROM 2009-2014

• 8.1% ON HOSPITAL ADMISSION

• RISK WAS PREVIOUS HOSPITAL STAY

• NEITHER ABX USE NOR PREVIOUS C DIFF WERE FOUND TO BE RISK FACTORS FOR COLONIZATION

• INCUBATION PERIOD VARIABLE



(A) SITES POSITIVE ON PATIENTS

(B) GLOVES POSITIVE FROM HEALTHCARE

WORKERS.

(C) GLOVES AFTER CONTACT WITH GROIN,

THE PATIENT HAD SHOWERED 1 H BEFORE

COLLECTION OF THE CULTURE SPECIMEN.

Bobulsky GS, et al. Clostridium difficile. skin contamination in patients

with C. difficile-associated disease. Clin Infect Dis 2008; 46:447–50.

Bobulsky GS, Al-Nassir WN, Riggs MM, Sethi AK, Donskey CJ. Clostridium difficile. skin contamination in patients with C.

difficile-associated disease. Clin Infect Dis 2008; 46:447–50.

Freedberg DE, et al. Receipt of Antibiotics in hospitalized patients and risk for clostridium difficile in subsequent

patients who occupy same bed. Jama Int Med. 2016 Dec 1; 176(12) 1801-1808

CHANGING RECOMMENDATIONS

• 1974- TEDESCO ( >5 LOOSE STOOLS IN 1 DAY)

• 1983- TEASLEY ET ALL (>6 LOOSE STOOLS OVER 36 HOURS)

• 1989- FEKETY AT AL (>4 BOWEL MOVEMENTS PER DAY FOR 3 DAYS)

• 2013- JOHNSON ET AL (>3 LOOSE STOOLS IN 24 HOURS)

• IMPORTANT TO TEST THE RIGHT PATIENT

McDonald L, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children.: 2017 Update by

IDSA and SHEA. Clin Inf Dis, Vol 66, Issue 7, 19 March 2018, Pages e1-e48

POLAGE R, ET AL. NOSOCOMIAL DIARRHEA: EVALUATION AND TREATMENT OF CAUSES OTHER THAN CLOSTRIDIUM DIFFICILE. CLIN INF DIS, VOLUME 55, ISSUE

7, OCT 2012, PAGES 982-989

POLAGE R, ET AL. NOSOCOMIAL DIARRHEA: EVALUATION AND TREATMENT OF CAUSES OTHER THAN CLOSTRIDIUM DIFFICILE. CLIN INF DIS, VOLUME 55, ISSUE

7, OCT 2012, PAGES 982-989

HOW TO TEST



WHAT THE HECK IS A CELL CULTURE CYTOTOXICITY NEUTRALIZATION ASSAY?

• STOOL FILTRATE IS APPLIED TO A LAYER OF CELLS (HUMAN FIBROBLASTS, VERO CELLS)

• 24-48 HOURS INCUBATION

• CELLS ARE OBSERVED FOR CYTOPATHIC EFFECT

• NEUTRALIZATION ASSAY IS PERFORMED TO ENSURE CORRECT CYTOPATHIC EFFECT

• CLOSTRIDIUM SORDELLI OR DIFFICILE ANTI-SERUM

• PREVIOUSLY GOLD STANDARD

• NOW WHEN COMPARED TO TOXIGENIC CULTURE, SENSITIVITY OF 75-85%

Carey-Ann Burnum and Karen Carroll. Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians

and for Clinical Labs. Clin Micro Rev. 2013 Jul; 26(3): 604-630

HOW DO YOU PERFORM TOXIGENIC CULTURE?

• ANAEROBIC CULTURE THAT TAKES 5-7 DAYS

• SELECTIVE MEDIA TO INHIBIT BOWEL MICROBIOTA

• ONCE COLONIES ARE ISOLATED

• GRAM STAIN

• “HORSE BARN” ODOR

• RAPID ANA KIT

• FINALLY ASSESSED TO SEE IF TOXIN CAN BE PRODUCED

• REFERENCE TEST RATHER THAN DIAGNOSTIC TEST

Carey-Ann Burnum and Karen Carroll. Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians

and for Clinical Labs. Clin Micro Rev. 2013 Jul; 26(3): 604-630

TOXIN IMMUNOASSAYS

• LOW SENSITIVITY

• GOOD SPECIFICITY

• VARIABLE POSITIVE PREDICTIVE VALUE

• GOOD NEGATIVE PREDICTIVE VALUE

• CORRELATES WELL WITH CLINICAL DISEASE

Carey-Ann Burnum and Karen Carroll. Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians and

for Clinical Labs. Clin Micro Rev. 2013 Jul; 26(3): 604-630

GDH TESTING

• GLUTAMATE DEHYDROGENASE

• TOXIGENIC AND NONTOXIGENIC C DIFF HAVE IT

• GREAT SCREENING TEST WITH TOXIN/PCR TO DETECT TOXIN GENE

• GREAT SENSITIVITY/GREAT NEGATIVE PREDICTIVE VALUE



NUCLEIC ACID AMPLIFICATION TESTS

• IDENTIFY THE TOXIN A/B TOXIN PRODUCING GENE

• THEORETICALLY THE BEST SCREENING TEST

• VERY HIGH SENSITIVITY

• VERY HIGH NEGATIVE PREDICTIVE VALUE

• NHSN HAS MADE IT LESS TENABLE

• VERY APPEALING IN SURVEILLANCE AND EPIDEMIOLOGY



TESTING RECOMMENDATIONS

McDonald L, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and

Children.: 2017 Update by IDSA and SHEA. Clin Inf Dis, Vol 66, Issue 7, 19 March 2018,

Pages e1-e48

EVIDENCE FOR TESTING RECOMMENDATIONS

• DUBBERKE ER, ET AL. EXTREMELY LARGE STUDY ASSESSING NUMEROUS PLATFORMS AND

NUMEROUS TESTING METHODS

• 9 DIFFERENT METHODS

• 4 DIFFERENCE REFERENCE METHODS

• CYTOTOXICITY CELL ASSAY WITH SYMPTOMS

• CYTOTOXICITY CELL ASSAY WITHOUT SYMPTOMS

• SYMPTOMS ALONG WITH 4 POSITIVE ASSAYS

• 4 ASSAYS POSITIVE

Dubberke ER, et al. Impact of clinical symptoms on interpretation of diagnostic assays for Clostridium difficile infections. J Clin

Microbiol. 2011 Aug; 49(8) 2887-2893

Stool samples

positive by

toxigenic

culture plus

clinically

significant

diarrheaDubberke ER, et al.

Impact of clinical

symptoms on

interpretation of

diagnostic assays for

Clostridium difficile

infections. J Clin

Microbiol. 2011 Aug;

49(8) 2887-2893

Stool samples

positive by

toxigenic culture

only

TOXIGENIC C DIFF PRESENT….. DOES IT MATTER

Planche TD, et al. Difference in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic

validation study of C difficile infection. Lancet Infect Dis. 2013 Nov; 13(11):936-45

2012 STUDY ASSESSING DIFFERENCES IN PATIENT OUTCOMES WITH DISCORDANT TESTING

• ASSESS PATIENT CHARACTERISTICS IN TESTING DISCORDANCE

• TREATING PHYSICIANS WERE NOT AWARE OF TESTING

• 23/56 PATIENTS POSITIVE FOR PCR ALONE DID NOT GET TREATMENT

(OUTCOMES FINE)

• 2 OF THOSE 23 DID GET CLINICALLY EVIDENCT C DIFF 4-6 MONTHS AFTER THE

POSITIVE TEST

• PCR CYCLE TIME SIGNIFICANTLY DIFFERENT

• POSITIVE CYTOTOXIN CELL ASSAY TURNED POSITIVE IN THE PCR AT CYCLE 21 VS CYCLE 25

• MORE GENETIC BURDEN FOR TOXIN PRODUCTION?

Kaltas A, et al. Clinical and Laboratory Characteristics of Clostridium difficile infection in Patient with Discordant

Diagnostic Test Results. Jour Clin Micro. Jan 2012

Date of download: 10/15/2018Copyright © 2015 American Medical

Association. All rights reserved.

From: Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era

JAMA Intern Med. 2015;175(11):1792-1801. doi:10.1001/jamainternmed.2015.4114

Kaplan-Meier Curves of Time to Resolution of Diarrhea by Clostridium difficile Test GroupThe median duration of diarrhea for

patients with at least 1 day was 3 days (interquartile range, 1-6 days) for Tox+/PCR+ (121 of 131), 2 days (interquartile range, 1-4

days) for Tox−/PCR+, and 2 days (interquartile range, 1-3 days) for Tox−/PCR− (927 of 1123) (P < .001). Log-rank P values are

P < .001 for all groups, P = .003 for Tox+/PCR+ vs Tox−/PCR+, (143 of 162) P < .001 for Tox+/PCR+ vs Tox−/PCR−, and P < .001 for

Tox−/PCR+ vs Tox−/PCR−. Tox+/PCR+ indicates C difficile toxin immunoassay positive and polymerase chain reaction positive;

Tox−/PCR+, C difficile toxin immunoassay negative and polymerase chain reaction positive; Tox−/PCR−, C difficile toxin

immunoassay negative and polymerase chain reaction negative.

Figure Legend:

Duration of diarrhea with real C

diff

Duration of diarrhea

no different in Tox -

/PCR + compared to

PCR -

TOXIN ASSAYS DO HOWEVER SEEM TO HAVE CLINICAL RELEVANCE

• LARGE STUDY OUT OF UC DAVIS EVALUATING 7046 PATIENTS

• 925 (13.1%) POSITIVE BY TOXIN

• 6121 (86.9) TESTED NEGATIVE

• DRAMATIC DIFFERENCES IN CLINICAL OUTCOMES

• THAT WAS EXPECTED BUT

• 1/6121 WAS SUBSEQUENTLY DIAGNOSED WITH C DIFF

• ALTHOUGH SOME TOXIN NEGATIVE WERE EMPIRICALLY TREATED

Polage C, et al. Outcomes in patients test for Clostridium difficile toxins. Diagnostic microbiology and infectious disease. 2012

Dec; 74(4): 369-373

OLDER

LONGER LOS

MORE ICU STAYS

INCREASED DEATH

BIOPSY PROVEN CDI

Polage C, et al. Outcomes in patients test for Clostridium difficile toxins.

Diagnostic microbiology and infectious disease. 2012 Dec; 74(4): 369-373

Polage C, et al. Outcomes in patients test for Clostridium difficile toxins. Diagnostic microbiology and infectious disease. 2012

Dec; 74(4): 369-373

BOTTOM LINE?IF YOU ARE GOOD AT RESTRICTING TESTING, PCR IS OKAY.

IF IT’S THE WILD WEST, GO WITH MULTI-STEP ALGORITHM



TESTING KIDS?

NEONATES?

1-2 YEAR OLDS?

>2 YEARS



FINAL THOUGHTS ON TESTING

REPEAT TESTING WITHIN 1 WEEK STILL NOT RECOMMENDED

NO TEST FOR CURE!



INFECTION CONTROL BASICS(ALL STRONG RECOMMENDATIONS, MODERATE-STRONG LEVEL OF EVIDENCE)

• SINGLE ROOMS

• COHORT IF NO PRIVATE ROOMS

• GOWNS AND GLOVES

• ISOLATE AS SOON AS TESTING IS INITIATED



ISOLATION

CONTINUED FOR AT LEAST 48 HOURS AFTER DIARRHEA HAS RESOLVED

PROLONGED PRECAUTIONS DURING EPIDEMIC SETTINGS

MY PERSONAL EXAMPLE



EVIDENCE FOR DURATION OF ISOLATION

Sethi AK, et al. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after

treatment of infection. Infect Control Hosp Epidemiol. 2010 Jan; 31(1):21-7

Stool shedding drops down temporarily

Shedding goes back up,

likely due to spore

reactivation.

• HANDS CULTURED AFTER CONTACT WITH

BODY PARTS

• FRIGHTENING FIGURE

• UNFORTUNATELY FROM STAFF

Sethi AK, et al. Persistence of skin contamination and environmental shedding of Clostridium difficile during and after

treatment of infection. Infect Control Hosp Epidemiol. 2010 Jan; 31(1):21-7

HAND HYGIENE

SOAP/WATER OR HAND SANITIZER IN ROUTINE SITUATIONS

SOAP/WATER DURING EPIDEMICS

SOAP/WATER WITH DIRECT CONTACT



FINAL INFECTION CONTROL THOUGHTS

BATHING IS GOOD!

USE DEDICATED EQUIPMENT

USE OF SPORICIDAL AGENTS (MANUAL VS AUTOMATED)?

MEASURE CLEANING EFFECTIVENESS

McDonald L, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children.:

2017 Update by IDSA and SHEA. Clin Inf Dis, Vol 66, Issue 7, 19 March 2018, Pages e1-e48

ROLE OF RESTRICTING MEDICATIONS

ANTIBIOTIC STEWARDSHIP IS A MUST!

PROTON PUMP INHIBITORS?





HOW DOES DIVERTING LOOP ILEOSTOMY WORK?

• SURGICALLY PULL UP THE TERMINAL ILEUM

• CREATE 2 CONNECTIONS

• ONE FOR ANTEGRADE INSTILLATION

• ONE FOR COLLECTING STOOL

• EASY TO PUT BACK TOGETHER

1ST C DIFF TREATMENT

VANCOMYCIN OR FIDAXOMICIN

EACH FOR 10 DAYS

IF LIMITED ACCESS TO MEDS, OKAY FOR METRONIDAZOLE X 10 DAYS FOR MILD DISEASE ONLY



FIDAXOMICIN VS VANCOMYCIN

• GUIDELINES TREAT VANCOMYCIN AND FIDAXOMICIN EQUALLY FOR INITIAL CURE

• NEW STUDIES?

• FIDAXOMICIN

• PROLONGED POST-ANTIBIOTIC EFFECT

• BACTERICIDAL

• LESS DISRUPTIVE TO MICROBIOTA

• INHIBITS SPORULATION

Al momani L A, Abughanimeh O, Boonpheng B, et al. (June 11, 2018) Fidaxomicin vs Vancomycin for the

Treatment of a First Episode of Clostridium Difficile Infection: A Meta-analysis and Systematic Review.

Cureus 10(6): e2778. DOI 10.7759/cureus.2778

META-ANALYSIS INCLUDED 4 STUDIES

Al momani L A, Abughanimeh O, Boonpheng B, et al. (June 11, 2018) Fidaxomicin vs Vancomycin for the

Treatment of a First Episode of Clostridium Difficile Infection: A Meta-analysis and Systematic Review.

Cureus 10(6): e2778. DOI 10.7759/cureus.2778

Al momani L A, Abughanimeh O, Boonpheng B, et al. (June 11, 2018) Fidaxomicin vs Vancomycin for

the Treatment of a First Episode of Clostridium Difficile Infection: A Meta-analysis and Systematic

Review. Cureus 10(6): e2778. DOI 10.7759/cureus.2778

PENDULUM SHIFT?

• MANUSCRIPT PUBLISHED IN ICHE 2018

• FOR EVERY 100 PATIENTS TREATED WITH VANCOMYCIN, 10 FEWER WOULD

HAVE HAD RECURRENCE IF FIDAXOMICIN WOULD HAVE BEEN USED

• FIDAXOMICIN HAD HIGHEST QALY GAIN BUT AT A COST OF 500,000 PER

QALY

• CONCLUDED THAT VANCOMYCIN STILL REPRESENTED THE BEST FINANCIAL

CHOICE

Lam S, et al. Cost-Effectiveness of three different strategies for the treatment of first recurrent Clostridium difficile infection

diagnosed in a community setting. Infection Control and Hospital Epidemiology. (2018), 39, 924-940

HOW IS RECURRENT C DIFF TREATED DIFFERENTLY

• NUMEROUS RISK FACTORS HAVE BEEN IDENTIFIED TO PUT PATIENTS AT RISK FOR RECURRENT C

DIFF

• 2015 SYSTEMATIC REVIEW/META ANALYSIS IN ICHE

• INCLUDED 33 STUDIES WITH A 20-30% RECURRENCE RATE WITHIN 2 WEEKS

• (A) FOREST PLOT WITH RISK PER EACH

ADDITIONAL YEAR IN AGE

• (B) FOREST PLOT OF ASSOCIATION OF

RECURRENT C DIFF AND AGE >65

Deshpande A, et al. Risk factors for Recurrent Clostridium difficile infection: A systematic review and meta-analysis.

Infect Control Hosp Epidemiol 2015;00(0): 1-9

• (A) ANTIBIOTICS

• (B) FLUOROQUINOLONES

• RISK OF RECURRENT C DIFF AND PPI USE

• RECURRENT C DIFF AND RENAL

INSUFFICIENCY

OPTIONS IF RECURRENCE OCCURS?

• 1ST RECURRENCE WITH TAPERED VANCO

• 1ST RECURRENCE WITH FIDAXOMICIN

• 1ST RECURRENCE WITH VANCOMYCIN (IF METRONIDAZOLE)

• >1 RECURRENCE, TAPER/PULSE

• >1 RECURRENCE, STANDARD VANCOMYCIN PLUS RIFAXIMIN

• >1 RECURRENCE, FMT

WHAT ABOUT BEZLOTOXUMAB?

• HUMAN MONOCLONAL ANTIBODY

• TARGET THE BINDING DOMAIN OF TOXINS A/B

• 2 LARGE DOUBLE BLINDED TRIALS

• BENEFIT NOTED IN NUMEROUS RISK FACTORS

• >65 YEARS

• HISTORY OF CDI

• IMMUNOCOMPROMISE

• SEVERE CDI

Johnson S, Gerding D. Bezlotoxumab. Clin Inf Dis. 18 July

MECHANISM

Johnson S, Gerding D. Bezlotoxumab. Clin Inf Dis. 18 July

• DOUBLE BLIND STUDY

• BIG STUDY

• SIGNIFICANT REDUCTION IN RECURRENT C

DIFF

• DOES IT MAKE FINANCIAL SENSE?

Prabhu V, et al. Thirty-day readmissions in Hospitalized Patients

Who Received Bezlotoxumab with Antibacterial Drug Treatment

for Clostridium difficile Infection. Clin Inf Dis. 2017:65

(1October)

AREAS FOR THE FUTURE

• NUMEROUS GAPS WITH EPIDEMIOLOGY

• WHAT IS THE BEST TEST FOR C DIFF

• WHAT IS THE TRUE GOLD STANDARD FOR REFERENCE TESTING

• HOW TO IDENTIFY THOSE AT HIGHEST RISK FOR RECURRENCE

• WHEN IS OPTIMAL TIMING AND ROUTE OF FMT

• IS THERE A C DIFF BUNDLE?

• BASIC SCIENCE OPPORTUNITIES

THANK YOU!

Documents

Update on C diff guidelines - msipc.org · Carey-Ann Burnum and Karen Carroll. Diagnosis of Clostridium difficile Infection: an Ongoing Conundrum for Clinicians and for Clinical Labs