Ellen Jo Baron, Ph.D., D(ABMM)Director of Medical Affairs, Cepheid

Professor Emerita, Pathology, Stanford University

Minimal TAT, Maximum Impact on Infection Control for C. difficile

• Employee of Cepheid

• Consultant for: Merck, OpGen, NanoMR, MorphDesign, MicroPhage

• Stock holdings: Cepheid, ImmunoSciences, PolyRemedy

• Other renumeration: Royalties for contributions to Infectious Diseases Alert newsletter, Palo Alto VAMC, and from various IVD industry consulting companies

• Founder & board member of NGO: Diagnostic Microbiology Development Program (www.DMDP.org)

E.J. Baron’s Conflicts of Interest

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Inter-relatedness of Healthcare Associated Pathogens

Which is often treated withclindamycin Which selects for

Which selects for

Which can donate the vanA resistance

gene

Which may lead to

Clostridium difficile

VRE

MRSAWhich is treated with

oral vancomycin

VRSA (or VISA)

• Sporeforming anaerobic Gr+ rod• Colonizes > 50% of newborns

asymptomatically; even toxigenic strains

• Acquisition of a new, toxigenic strain after antibiotic treatment leads to disease

• Spores stable in environment; not destroyed by alcohol

Clostridium difficile

U.S. Numbers and Cost/yr

The newest HAI

>$32 million

Healthcare-Associated Infections (HAI)

http://www.cdc.gov/VitalSigns/pdf/2012-03-vitalsigns.pdf

• 3 times more CDI hospitalizations in last 10 years• Half of infections in patients >65 yrs but 90% of deaths• 75% of infections first show in nursing home patients or

those seen in clinic recently• Half of patients have CDI at time of admission • Based on 2008 U.S. APIC survey:

Average cost $32.1 million Average extra hospital days = 40,200 Mortality= 14,000 patients/year

Current statistics from CDC

Pharmacotherapy 2011;31(6):546–551

Rapidly increasing numbers

Average 10-20% of all stools tested =

Positive

Wide spectrum of CDI

1 recurrence 10-25% ptsRisk of 2nd recurrence ~65%

• Associated with hospital outbreaks of severe disease• Associated with severe morbidity (toxic mega-colon,

sepsis-like syndrome)• High case-fatality rate• Fluoroquinolone resistant• Produces >20x more toxin B (due to a deletion in TcdC

toxin production regulatory gene) & a binary toxinbinary toxin• Produces larger #s of spores, leading to larger inocula

and easier transmission

Toxinotype III

Emergence of an epidemic strain BI/NAP-1/027

Hand hygiene; gloves & gowns Switch to soap & water from gels Private room, contact precautions,

private commode – duration of diarrhea Remove environmental sources Chlorine cleaning agents Reduce non-essential antibiotics Antibiotic stewardship program

SHEA/IDSA Infect Control and Prevention Guidelines

Toxigenic culture is gold standard Toxigenic culture is gold standard

Cycloserine-cefoxitin-fructose agar with taurocholate

• Grow the organism • Test isolates for toxin

Plate direct or plate from

broth enrichment

Anaerobic incubation

<1% of U.S. labs doing this test and it takes at

least 4 days

Previous gold standard (2+ day TAT)Detection of Cytotoxin B direct from stool in cell culture Previous gold standard (2+ day TAT)Detection of Cytotoxin B direct from stool in cell culture

Normal, negative or toxin + antitoxin = neutralized (no effect)

Positive - CPE

Stool supernatant

<1% of U.S. labs doing this test and it takes at

least 2 days

Rapid antigen detection CDI assays Enzyme immunoassays and LFAs for toxins A&B or GDH

Enzyme immunoassays and LFAs for toxins A&B or GDH

>50% of U.S. labs still using this test type !!

Vidas

C. difficile Test Result Sensitivities vs Comparator

EIA assays Cell culture Cytotoxin

Toxigenic Culture

Meridian Premier Toxins A & B EIA

92% 48%

Meridian Immunocard Toxins A & B

78% 48-67%

TechLab Toxins A & B 91% 74% Remel Xpect 96% 48%Wampole Tox A & B 95% 55%TechLab GDH 90% 88%BD GeneOhm PCR 92% 89%

LM Sloan et al, JCM, 2008 Jun;46(6):1996-2001Eastwood et al. J. Clin. Microbiol. 2009. 47:3211-17.L Alcalá et al, JCM, 2008 Nov;46(11):3833-3835

Clinical and Infection Control Implications of C. difficile Infection With Negative Enzyme Immunoassay for ToxinGuerrero et al. 2011. CID 53:287-. (Cleveland VAMC)

• 132 PCR+ patients (unformed stools)• 43 (32%) EIA negative for toxin A or B (would have been missed if only EIA used for testing or determining whom to treat)

• No difference in presentations: (9 pts had severe CDI and one patient died of fulminant CDI)

• All patients had equal shedding of spores onto body and environment (same ribotype)

• Of 150 strains typed, 50% were 027 (significantly higher in EIA+ than EIA- patients)

Repeat test NOT needed for the diagnosis of CDI if PCR is the methodRobert F. Luo, Niaz Banaei (Stanford UMC) J. Clin. Microbiol. 2010. 48:3738-

Result following the first test with a negative result

293 patients (24% of all pts)406 repeat tests (ave. 1.5/pt)PCR Sens 87.2%; Spec 98.6%

7 new TP’s at ≥7 days

<1% repeat tests gave +

result <7 days

Evaluation of the Cepheid Xpert Clostridium difficile Epi assay for diagnosis of Clostridium difficile infection and typing of the NAP1 strain at a cancer hospital Babady et al. 2010. J Clin Microbiol 48:4519

• 126 patients; 60 had 027. Compared to patients with non 027 strains, they were more likely to:‒Die by day 90 after diagnosis‒Be older and/or residents of a LTCF‒Be treated for a longer duration of time‒Have therapy switched from metro to vanco

• Age, ICU admission, Charlson score, and infection with 027 were significant predictors of mortality

(hazard ratio 2.77)

In revision

EIA only GDH + EIA GDH + Xpert

Xpert C. diff

Sensitivity 58.3% 55.6% 86.1% 94.4% Specificity 94.7% 98.3% 97.8% 96.3%

PPV 68.9% 87.0% 95.8% 84.0%

NPV 91.9% 91.7% 97.2% 98.8%

C. diff PCR vs GDH in Clinical Trials for 027 vs Non-027 Isolates

Sensitivity P value

Ribotype Xpert GDH EIA

027 (11) 90.9% 90.9% 1.0

Non-027 (36) 91.7% 72.2% 0.001

Tenover, et al. 2010. JCM Vol. 48.

Detection of C. difficile Infection (CDI): Impact of Test Method on Infection Control Tenover FC et al. J. Molecular Diag. 2011; 13:573-82.

TestMethod

Ave. Cost/ Test

Sens

No. of + Patients Missed not in

Isolation

SpecPts in

isolation with CDI

Patients in isolation

without CDI

GDH/EIA $18 55% 45 94% 55 54

NAAT $35 95% 5 96% 95 36

Assume 1000 patients are tested, 10% prevalence

Photo by Dr. Curtis Donskey (Case Western)

Environmental Control Issues

(Am J Infect Control 2009;37:15-9.)(027/BI)

105 non-isolation rooms surveyed by culture 16% contaminated with toxin-producing C. difficile Outside of patient rooms:

9 of 29 (31%) physician work areas positive 1 of 10 (10%) nurse work areas 9 of 43 (21%) piece of portable equipment 50% of strains typed were epidemic NAP1 strain

Patient Death vs Binary Toxin Bacci et al. 2011. EID; 17:976-

027 Binary+

Non-027 Binary+

A+B+ Binary-

Non-typed

Relative risk of death in 30 days = 28% (RR 1.6-1.8) vs 17% death from CDI with non-binary toxin producing strain

Recurrence Rates for Fidaxomicin vs. VancoRecurrence Rates for Fidaxomicin vs. Vanco

Louie et al. 2011. Fidaxomicin versus Vancomycin for Clostridium difficile Infection. NEJM 364:422-31.

For pts. with 027 strain, recurrence rates were higher with Fidaxomicin than Vanco.

% recur-rence

Fecal transplant for CDI relapses orpatients non-responsive to antibiotics

Bakken et al. 2011. Treating Clostridium difficile Infection With Fecal Microbiota Transplantation. Clin. Gastroent. Hepatol. 9:1044–1049

van Nood et al. 2013. Duodenal infusion of donor feces for recurrent Clostridium difficile. NEJM. 368:407-15

% cured•Vanco•V+bowel lavage•V+BL+FMT

Poopsickle

MRSA surveillance: some data about one approach

• Patients are more ill with MRSA infections; more interventions, more resources• 18,650 deaths in U.S.A. each year• They cost more than infections with MSSA• MRSA infections = longer length of stay

$$$$$$ Days in hospitalDays in hospital

How will preventing MRSA infections reduce costs?

MRSA Cost data (Duke Univ. Med. Ctr.)

2009 vol 4 pg:e8305 -e8305

Patients with MRSA infections were 30 x more likely to be readmitted and 7 times more likely to die within 90 days.

Patients with MRSA infections cost $61,681 more than patients without infections and $38,000 more than with infections due to MSSA.

Therefore: prevention of one MRSA infection will save the hospital >$61,000.

Evaluation of rapid screening and pre-emptive contact isolationfor detecting and controlling methicillin-resistant Staphylococcusaureus in critical care: an interventional cohort studyHarbarth et al. 2006. Crit. Care Med.10:128.

93h TAT 22h TATPre-emptive

Isolation(or <1 h TAT)

Infected

Colonized

Broth enriched culture results (48 hrs) Sensitivity ~same as PCR. Wolk et al.

CA

MS- Broth enriched

orfX PCR

MrsaSel

“PCR is the improved gold standard..”

JCM 2009. 47: 3933-

VA Hospital systems1 Lucey Chrom Agar -> GeneXpert

2 Lucey Undecided3 Starr Undecided

4 Syed IDI-MRSA

5 Syed Chrome Agar

6 Braden Undecided VA Durham in process of renting Gx7 Jones Unknown Multiple mtgs set8 Jones Unknown

9 Vickery/Lucero IDI-MRSA Interest in Gx10 LaFave Chrome Agar -> ??

11 LaFave

15 Lucero16 Vickery/Moore17 Moore

18 Litavis/Moore

19 Moreno/Bell20 Bell21 Moreno

22 Litavis

23 Francis/Lucero

2121

2222

2323

2020

2020

1818

2121 88

881717

161677

66

111212

151599

111144

5533

1616

1919

1010

59% decrease in MRSA HAIs

Veterans Affairs Initiative to Prevent Methicillin-Resistant Staphylococcus aureus Infections

Jain et al. 2011. NEJM 364:1419-• 61% decrease in C. diff

in non-ICUs• 73% decrease in VRE

infections in non-ICUs

Massachusetts General Hospital adopts automated system for MRSA surveillance

A Randomized Controlled Trial Comparing Passive and Active Screening with Culture and Polymerase Chain Reaction. Shenoy et al. 2013, CID Sr. Author Dr. David Hooper

>2000 tests per day !

Patients removed from isolation if MRSA negative by active surveillance

• Nasal swabs cultured for 48 hours on BD Chromagar• Colonies confirmed by Gram stain and tube coagulase;

– culture took 5 days to complete– PCR took <1 day to complete

• 457 patient included in the analysis– Completion of the protocol: 10% in non-intervention arm ( standard

of care with no active enrollment)– Completion of protocol: 73% in intervention arm (i.e., all 3 cultures

and PCR tests were collected)• Results

– 66 patients in intervention arm were positive for MRSA in at least one culture; 60 were positive on the first culture, 3 on second, and 3 on third

– Discontinuation of contact precautions was 4 times more likely in the intervention (active surveillance) arm

Cost Saving Through Discontinuation of Contact Precautions

Screening Method

Decrease in Contact Precaution Days

Cost savings

Passive screening with cultures

104 $86,950

Active surveillance with cultures

418 $349,472

Active surveillance with PCR

1,841 $1,539,180

457 patients accounted for 3339 patient days of isolation