Transcript Slide 1

Minimal TAT, Maximum Impact on
Infection Control for C. difficile
Ellen Jo Baron, Ph.D., D(ABMM)
Director of Medical Affairs, Cepheid
Professor Emerita, Pathology, Stanford University
E.J. Baron’s Conflicts of Interest
• 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)
Inter-relatedness of Healthcare Associated
Pathogens
Which is often treated with
clindamycin
Which selects for
VRSA (or VISA)
Clostridium
difficile
MRSA
Which may lead to
Which can donate
the vanA resistance
gene
Which is treated with
oral vancomycin
VRE
Which selects for
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Clostridium difficile
• 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
Healthcare-Associated Infections (HAI)
U.S. Numbers and Cost/yr
>$32 million
240,000
1,000,000
Surg Site
CLABSI
VAP
CAUTI
CDI
450,000
900,000
800,000
700,000
600,000
52,500
500,000
400,000
92,000
300,000
200,000
100,000
290,000
0
Number
$$
multiply
x 100
The newest HAI
http://www.cdc.gov/VitalSigns/pdf/2012-03-vitalsigns.pdf
Current statistics
from CDC
• 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
Pharmacotherapy 2011;31(6):546–551
Wide spectrum of CDI
Rapidly increasing
numbers
1 recurrence 10-25% pts
Risk of 2nd recurrence ~65%
Average 10-20% of all
stools tested = Positive
Emergence of an epidemic strain
BI/NAP-1/027
Toxinotype III
• 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 toxin
Produces larger #s of spores, leading to larger inocula
and easier transmission
SHEA/IDSA Infect Control and
Prevention Guidelines
 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
Toxigenic culture is gold standard
• Grow the organism
• Test isolates for toxin
Plate direct or
plate from
broth
enrichment
Anaerobic
incubation
Cycloserine-cefoxitin-fructose
agar with taurocholate
<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
Stool supernatant
Normal, negative
or toxin + antitoxin =
neutralized (no effect)
<1% of U.S. labs doing
this test and it takes at
least 2 days
Positive - CPE
Rapid
antigen
detection
CDI
assays
Enzyme
immunoassays
and
LFAs
for toxins
A&B or GDH
Vidas
>50% of U.S.
labs still using
this test type !!
C. difficile Test Result Sensitivities vs Comparator
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%
96%
74%
48%
TechLab GDH
95%
90%
55%
88%
BD GeneOhm PCR
92%
89%
EIA assays
Remel Xpect
Wampole Tox A & B
LM Sloan et al, JCM, 2008 Jun;46(6):1996-2001
Eastwood 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 Toxin
Guerrero 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 method
Robert F. Luo, Niaz Banaei (Stanford UMC) J. Clin. Microbiol. 2010. 48:3738-
<1% repeat
tests gave +
result <7
days
293 patients (24% of all pts)
406 repeat tests (ave. 1.5/pt)
PCR Sens 87.2%; Spec 98.6%
Result following
the first test with
a negative result
7 new TP’s at ≥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
Ribotype
Xpert
P value
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.
Assume 1000 patients are tested, 10% prevalence
Test
Method
Ave.
Cost/
Test
Sens
No. of +
Patients
Missed
not in
Isolation
Spec
Pts in
isolation
with CDI
Patients in
isolation
without CDI
GDH/
EIA
$18 55%
45
94%
55
54
NAAT
$35 95%
5
96%
95
36
Photo by Dr.
Curtis Donskey
(Case Western)
Environmental Control Issues
(027/BI)
(Am J Infect Control 2009;37:15-9.)
 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-
Non-027 Binary+
027 Binary+
A+B+ BinaryNon-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. Vanco
30
%
recur- 25
rence
20
Fidaxo
Vanco
15
10
For pts. with
027 strain,
recurrence
rates were
higher with
Fidaxomicin
than Vanco.
5
0
027
Non-027
Louie et al. 2011. Fidaxomicin versus Vancomycin for Clostridium difficile
Infection. NEJM 364:422-31.
Fecal transplant for CDI relapses or
patients non-responsive to antibiotics
% cured
Poopsickle
• Vanco
• V+bowel lavage
• V+BL+FMT
 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
MRSA surveillance: some data
about one approach
How will preventing MRSA infections
reduce costs?
• 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
14,000
12,000
$$$
10,000
Days in
hospital
8,000
6,000
4,000
2,000
0
MRSA MSSA
10
9
8
7
6
5
4
3
2
1
0
MRSA
MSSA
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 isolation
for detecting and controlling methicillin-resistant Staphylococcus
aureus in critical care: an interventional cohort study
Harbarth et al. 2006. Crit. Care Med.10:128.
93h TAT
Colonized
Infected
22h TAT
Pre-emptive
Isolation
(or <1 h TAT)
Broth enriched culture results (48 hrs)
Sensitivity ~same as PCR. Wolk et al.
MrsaSel
MS- Broth
enriched
CA
orfX
PCR
“PCR is the improved
gold standard..”
JCM 2009. 47: 3933-
VA Hospital systems
s
at
n
20
19
21
1
12
23
11
4
10
15
22
6
9
18
17
7
16
8
20
21
5
8
3
Veterans Affairs Initiative to Prevent MethicillinResistant Staphylococcus aureus Infections
Jain et al. 2011. NEJM 364:1419-
59% decrease
in MRSA HAIs
• 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
457 patients accounted for 3339 patient days of isolation
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