Molecular Sepsis Diagnostics

Molecular Sepsis Diagnostics:
Great technology – now what?
EU-US Workshop,
p, September
p
28 2011,, Brussels Belgium
g
Gorm Lisby, MD PhD
Chief Scientific Officer, QuantiBact Inc, Copenhagen, Denmark
&
Chief, Section for Molecular Biology & Serology (on leave)
Dept of Clinical Microbiology, University of Copenhagen
Hvidovre Hospital, Denmark
For more than 100 y
years,, blood culture
alone has been the (inadequate) Gold
standard for routine detection of
non-viral pathogens in the blood
Why is blood culture imperfect?
• Time delay
• Suboptimal sensitivity in clinical sepsis
– Microorganisms are phagocytized
– Microorganisms are only present in infectious focus
– Antimicrobials are present at time of blood culture
• Sepsis is NOT a “blood
blood stream infection”
infection
Why not just treat?
• Even broad-spectrum is often not enough
• Antimicrobial resistance on the rise
– ESBL
– MRSA
– Vancomycin
• Impossible to step down – more resistance
• The pipeline is dry
• No information regarding patient management
The urgency:
A step in the right direction:
Molecular sepsis
p
test vs. blood culture
558 episodes with corresponding BC and SeptiFast
176 episodes with
ith one or both systems
s stems positi
positive
e
Contamination: 22 (4 not in panel)
BC+ : 96
Not in SeptiFast panel: 6
Included: 68
SeptiFast + : 50
S tiF t - : 18
SeptiFast
Contamination: 12
SeptiFast+ : 186
BC+ : 50
Included: 174
Other culture: 67
BC- : 124
Unresolved: 57
Th truth
The
t th
H
How
d
do we d
define
fi “the
“th truth”:
t th”
D we ttrustt all
Do
ll SeptiFast
S tiF t results
lt
(“SeptiFast” friendly truth)
or
Only the culture-confirmed SeptiFast
positives
(“Acceptable truth”)
O kind
One
ki d off truth
t th
“SeptiFast friendly truth”
All positive uncontaminated SeptiFast (174)
OR SeptiFast negative but BC positive (18)
OR BC positive but not in SeptiFast panel (6)
Sensitivity
S
iti it BC:
BC 37%
Sensitivity SeptiFast: 88%
A th ki
Another
kind
d off truth
t th
“Acceptable truth”
Positive
P
iti in
i both
b th systems
t
(50)
OR SeptiFast positive but BC negative but confirmed by
other relevant culture (67)
OR uncontaminated BC positive but SeptiFast negative
(18) OR BC positive but not in SeptiFast panel (6)
Sensitivity BC: 53%
Sensitivity
y SeptiFast:
p
83%
Bacteremia
vs
DNAemia
Bacteremia vs DNAemia
• Normal test persons do not have bacterial DNA in blood
• Post-abdominal
P t bd i l surgery patients
ti t without
ith t suspicion
i i off
infection do not have bacterial DNA in blood
• CoNS DNA equals CoNS in blood culture
• Majority of PCR+/BC- could be confirmed by culture
• Balance between sensitivity and false positives
S what
So,
h t is
i the
th problem?
bl ?
We have a great technology, but………
C t
Cost
Cost of blood culture: $35
Cost of molecular test: $300+
C t
Cost
• Do NOT compare expensive molecular
t t tto cheap
test
h
blood
bl d culture……..
lt
• Compare cheap molecular test to
expensive stay in ICU
C t off Di
Cost
Diagnostics
ti
• Everyone is used to “cheap microbiology”
• Every
E
patient
ti t can gett every test
t t
• In the future, expensive diagnostics will be offered
• Not every
yp
patient can get
g every
y test
Cli i l Utility
Clinical
Utilit
Lehmann et al
Crit Care Med, 2009
99 episodes BC+, 131 episodes PCR+
PCR: 106 days with inadequate ab avoided (ICU: 36 days/100 test)
Diekers et al
BMC Inf Dis, 2009
Adjustment of ab in 5/77 patients
Lehman et al
Crit Care, 2010
13,1% of PCR test enabled earlier adequate ab
2,6% reduction in overall mortality expected
Cost-neutral in ICU ptt with >25% inadequate ab + 15% pos BC
Cli i l Utility
Clinical
Utilit
Prospective clinical outcome studies
are still missing !!
Roadmap to clinical value
of molecular sepsis diagnostics
PCR+
BC+
0.05
PCR%
No infection
PCR+
0.95
0.60
False pos. / comtamination
-no antibiotics
-neg. predictive value low
BC%
PCR%
Suspicion of
systemic infection
0.65
PCR+
BC+
0.40
0.25
0.35
True negative
-neg. predictive value low
PCR%
-earlier adequate ab
-changed clinical management
-mortality , hosp stay, sequelae
I f ti
Infection
0.20
0.75
PCR+
NO CLINICAL VALUE
BC%
0.80
PCR%
Cli i l value
Clinical
l off molecular
l
l sepsis
i test
t t
Can we improve the odds??
Yes, we can…
Treat: Sub-set of blood cultured patients
identified for molecular sepsis diagnostics
PCR+
BC+
Treat
software
False pos. / comtamination
PCR%
-no antibiotics
Positive rate in blood culture: 1.7%
-neg. predictive value low
Patient
0.20
population
No infection
17%
0.60
PCR+
0.80
BC%
PCR%
Patient
population
2514 ptt with
suspicion of
systemic infection
Positive rate in blood culture: 13.1%
64%
0.65
PCR+
BC+
0.40
True negative
-neg. predictive value low
0.25
0.35
Patient
I f ti
Infection
population
19%
0.75
0.20
PCR%
Positive rate in blood culture: 28.8%
PCR+
NO CLINICAL VALUE
BC%
0.80
-earlier adequate ab
-changed clinical management
-mortality , hosp stay, sequelae
PCR%
Conclusion
• Pending prospective clinical outcome analysis,
molecular sepsis diagnostics will find its position
• A sub-set of blood cultured patients that will
benefit the most from molecular sepsis
diagnostics needs to be identified
• Blood culture will still be the cornerstone