Minutes count: rapid detection/identification and susceptibility - ESCMID
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a r
Minutes count: rapid
i b r
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detection/identification and susceptibility
e
testing in bloodstream infections
I D r
Brigitte Lamy,
M o
Laboratoire de bactériologie, Hôpital l’Archet2, Nice, France
h
Team "microbial virulence and inflammation signaling", INSERM U1065 Université Côte d’Azur
SC u t
Symposium: diagnostic stewardship: making the most out of
a
diagnostic opportunities
E ECCMID 2019, Amsterdam 13-16 April
1
a r
COI Disclosure
i b r
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Curetis: Research grant to Bacteriology department 2018
(polymicrobial BSI diagnosis)
I D o r
C M t h
S a u
E
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Rapid methods and time saved
i b r
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Numerous rapid methods
D
Many data on method performance
I o r
Less data on clinical impact
M
C t h
Scarce data on (actual) time saved in routine use
u
S
with clinical impact
E a Many different designs and comparators
Limited to IVD
a r
Minutes count (1)
i b r
24h delay
e L
D
x2
I r
Lee et al, 2017
o
Fraser et al, 2006
Carbapenems x 2 in 5 yrs…
M
Rhodes et al, 2016
C t
30%
h
Honda et al, J 2018
Goto et al, 2013
S u
Sogaard et al, 2010
Yagama et al, 2018
a
x 2.5 Cattoir et al, 2018
E Earlier information, reduced
selective pressure
Garnier et al, 2019; Idelevich et al, 2018
a r
Minutes count (2)
i b r
e L With ASP
I D r
Sepsis cases
M t h o
SC u
Without ASP Angus et al, 2000, Angus et al, 2001
E a Timbrook et al, CID 2017
a r
Minutes count (3)
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L
Effectiveness
PNA FISH
e
(QALY) Conventional
PNA FISH
I D r
PCR
D: conventional, without ASP
C: conventional, with ASP
o
Conventional
B: rapid, without ASP
M h
A: rapid, with ASP
C t
mArray
S u
MALDI-TOF Several to be evaluated
Costs ($)
a
mArray
E Pliakos et al, Clin microbiol Rev 2018
a r
What strategy ?
i b r
e L 1. Rapid methods
I D r
and revised lab workflowRapid disk
diffusion assay
M o
Unyvero
Icubate
t h
Verigene
C
FilmArray
u
HYPLEX
S
iPlex
a
Accelerate
E
Direct MALDI-
Resist TOF MS
IDtect geneExpert T2bacteria
slidex
a r
How to reduce time to result
i b r
L
Direct AST
e
Rapid phenotypic tests
MALDI-TOF hydrolysis assays Conventional AST
D
Pheno AST
1h
MI o r 24h 48h
h
T2MR To incubation Quickfish
C t
Magicplex Direct MALDI-TOF MS /FilmArray, Xpert, Pheno
u
Septifast
S
Iridica BAC BSI Verigen
a
Sepsitest
E
Icubate, MALDI-TOF early subculture
Conventional ID
Dubourg G et al, Expert Rev Mol Diagn. 2019
a r
Clinical case
i b r
e L
Mr. D., age 72, hospitalized in Medicine
Fever of unknown origin, qSOFA>2
D
No antibiotics before admission
I r
3 BC sets collected
o
Cefotaxime (2g x 3 / day)
M h
No favorable evolution at H24
C t
S a u
1700 bed Institution
E
30 000 BC sets/ year
10 to 40 positive bottles / day
a r
Rapid methods
i b r
e L
I D o r
Rapid disk
diffusion assay
M
Unyvero
h
Icubate
C t
Verigene
u
FilmArray
S
iPlex HYPLEX
a
Accelerate
E
Direct MALDI-
Resist TOF MS
IDtect geneExpert T2bacteria
slidexa r
Rapid ID (scenario 1)
i b r
e L
Direct MALDI-TOF MS from positive BC
"Universal" and evolutive method, large database
Cost-effective, rapid and reliable in-house
D
protocols
MI o r
Bacteria correctly identified
t h
100
100 15 min
C
GNB
preparation
80
80
u
GPB
Reliable ID (%)
S
Yeasts
60
60
a
Klein et al, 2012,
sepsityper
E
Moussaoui et al, CMI,
40
40 2010, Schubert et al,
In-house
2011, Simon et al, 2018
Several accurate protocols available
20
20 Chen et al, JCM, 2013
Buchan et al, JCM, 2012 Different lysis procedures (saponin, TFA,
Jamal DMID 2012,
00 Saffert et al, DMID, 2012 triton)
Tadrs et al, CanJIDMed Faron et al, JCM 2018, Dubourg et al, CMI 2018
Score ≥2 Score
Score ≥1.7
≥1.7 Score
Score≥1.5
≥1.5 Microbiola r
News from future : Rapid AST with MALDI-TOF MS ?
i b r Lyophilized ATB
L
on target
Direct-on-target microdroplet growth assay Inoculum 0.5 McF
e
(DOT-MGA) S R
Incubate for 4h in humidity chambers 0 0.06 0.12 0.25 0.5 1 2
etc.
Growth / no Growth detected by MALDI- ATB 1
I D r
TOF MS (10 min,a r
News from future : Rapid AST with MALDI-TOF MS ?
i b r
e L
Blood culture broth flagged as positie
I D o r
C M t h
S a u
Ea r
Rapid ID with AST (scenario 1)
i b r
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Other rapid RAST, ~8 hours
e RAST from EUCAST, 4-8 hours
I D r
No AST with
MALDI-TOF MS
o
− BKP tables and QC on website, specific for species
M
and incubation time
h
− Validated for
t
Read after 4, 6
C
and/or 8h incubation
E.coli, K.pneumoniae, P.aeruginosa, A. baumannii
S.aureus, S. pneumoniae, E. Faecalis, E. faecium
S a u − Large validation (55 countries)
E
100-150 µL onto
MH agar plates
− The method provides ”S” and ”R”
− ME & VME kept low by introducing an ATU
where interpretation is not allowed
RAST from EUCAST
www.eucast.orga r
RAST from EUCAST
i b r
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Categorical agreement E. coli 0:00
e
Incubation time 4h 4h 6h 6h 8h 8h 21:00
Results calculated on readable zones (%) 18:00
Time to AST report
D
Area of Technical Uncertainty (ATU) 20 18 17 8.8 16 6.9 15:00
I r
Interpreted to S or R 80 82 83 91 84 93
12:00
o
Errors calculated on zones interpreted to S or R (%)
M
9:00
mE 1.1 0.7 1.3 1.5 1.2 1.6
h
6:00
t
ME 2.1 2.1 0.5 0.9 0.5 0.7
C
Errors
VME 0.5 0.3 0.3 0.3 0.4 0.5 3:00
S u
Total errors: 3.7 3.1 2.1 2.7 2.1 2.8 0:00
a
RAST
RAST StandardDD
(n = Standard DD
(n=476)
476) (16-20h)
16-20 h (n =
E
Tested antimicrobial agents: piperacillin-tazobactam, cefotaxime, ceftazidime, N=80
80)
meropenem, ciprofloxacin, amikacin, gentamicin and tobramycin
Courtesy of Gunnar Kahlmeter, Emma Jonasson, Ericka Matuscheka r
Clinical case (scenario 1)
i b r
e L
Mr. C., age 72, hospitalized in Medicine
Fever of unknown origin, qSOFA>2
D
No antibiotics before admission
I r
3 BC sets collected
o
Cefotaxime
M h
No favorable evolution at H24
C t
u
BC collection signal
S
IDH0within 1-4 hours
H 20 H 24
a
RAST results < 8-12 hours
Direct MALDI-TOF MS
E
post signal Rapid & direct AST
What if the strain is
Cefotaxime resistant?a r
Rapid ID with AST
i b r
L
RAST (EUCAST), 4-8 hours
No AST with
e Other rapid RAST, ~8 hours
D
MALDI-TOF MS
MI o rRapid tests PCR (mecA) or PBP2a
~1h
h
betaLacta test
C t
Carbapenemase detection
S u
BC collection signal
a
H0
E
H 20 H 24
Direct MALDI-TOF MS
Rapid tests (resistance detection)
Rapid & direct ASTa r
Fast ID with rapid resistance detection
i b r
L
Direct ID Appro Contact
e
+ direct AST (n=141) priate TTT precaution
(MALDI)
IDD BLT+ direct AST (n=141)
Positive
D
(MALDI)
I
BC
r
Infect dis 2018
o
89.8% ID
M h
89.3% 3GC R detected
-lacta-test # 30 min + ASP
C t
Prospective study, pre, post intervention
u
141 GNB positive BC, 28 (19.9%) 3GC-R
S a
75% non-
E
adapted first
Se= 89.3%, Sp = 100%
line treatment
PPV= 100%; NPV=97.4% Theoretical optimal 28 h
time saved
35 ha r
Rapid ID with rapid resistance detection
i b r
e L control
NDM
D
KPC
I r
Oxa-48 like
M t h o RESIST-3 O.K.N assay (Coris)
SC u
a
20-45 min Sensitivity 100% (n=126)
E Hamprecht et al, PlosOne, 2018a r
Workflow Integration
i b r
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Small modifications in lab workflow ID in less than
ea r
Overall workflow
i b r
e L
The batchwise approach
I D o r
8:00
C M t h
12:00 16:00 20:00 24:00 4:00
S
Batch 1
a u Batch 2 Batch 3 Batch 4 Batch 5 Batch 6
E
- ID
- RAST
± additional testa r
Combined methods
(scenario 2)
8-10h
To incubation
i b r 48 h
From signal to ID To AMST
65 h
L
To incubation
R detec
e
Time to result, routine use
From BC positive signal
D
Median time to escalation/ de-
System Comments Reference
I r
Median time escalation
resistance
to ID (IQR)
detection (IQR)
M o
Pheno (Accelerate) 5.3 10.7
h
MIC (8-12 antibiotics) +++ / +++ Descours et al, EJCMID 2018
2h / 7h (3.4 -7.8) (8.6 – 12.8)
C t
Film Array
u
(bioMérieux) 2.8 (1.4 – 5.1) AMR Gene detection +++ / ± Buss et al, OFID, 2018
S
1h
E a
Unyvero (Curetis) AMR Gene detection Burrack-Lange et al, J Med
13.4 +++ / ± Microbiol, 2018
4.5h +++
ePlex (GenMark) AMR Gene detection
??? +++ / ± Huan et al, JCM, 2019
1.5 h +++a r
Combined methods
(scenario 2) 8-10h
i b r 48 h 65 h
L
SOP = walkaway To incubation From signal to ID To AMST
To incubation
e
To AMST
I D r
Lundgring et al, JCM 2018
7% failure
o
Descours et al, EJJCMID 2018
M
- IDa r
Clinical case
i b r
e L
Mr. C., age 82, hospitalized in Medicine
Fever of unknown origin, qSOFA>2
No antibiotics before admission
I D r
3 BC sets collected
Cefotaxime
o
M h
ID from 3 to 13 hours post signal
C t
AMR detection from 3 to 13 hours post
u
signal
S
Faster but more partial relevant
a
information on resistance
E
What if the patient
had indeed
polymicrobial BSI ?a r
Polymicrobial BSI
i b r
L
Monomictobial (n=336)
15% BSI
e
Survival
30-day Mortality rate x 3 (30.3% et 11.6%)
Polymicrobial (n=112, p100h
signal
25a r
Rapid relevant information, polymicrobial BC
i b r
L
100 Correct ID (all bacteria of the mix)
Direct MALDI-TOF MS Scohy et al, Eur J CMI Dis 2018
80
e
Sepsistyper kit + updated 60
correct ID (%)
version MBT sepsityper 40
(Bruker Daltonics)
D
20
I
Partial
r
Agree No ID 0
No AST 2/2 1/2 0/2
M o
40(33.1) 66(54.5) 15(12.4)
h
Descours et al, Eur J CMI Dis 2018, Buchan et al, Plos Medicine, 2013, Siu et al, Plos one, 2015,
C t
Ledeboer et al, 2015, Altun et al, 2013, JCM; Scohy et al, 2018; Southern et al, 2015; ECCMID
80 66 0 P2361
S u 0 66 30 Resistance detection
Maximum saved timeand(Unyvero,
clinical simulated)
impact
a
(Unyvero,
60 Poster P2361)
E
- 43% 40positive impact
Hours
0 9 4 Au regard
- 35% no impact
20
- 22% negative impact (derepressed
cephalosporinase,
0
ident
ESBL) ATB
Unpublished, P2361 ID Resistancea r
Clinical case
i b r
e L
Mr. C., age 72, hospitalized in Medicine
Fever of unknown origin, qSOFA>2
D
No antibiotics before admission
I r
3 BC sets collected
o
Cefotaxime
C M t h
S u
Performance to be improved
a
Promising reduced TTR mith mArray methods
E
To be evaluateda r
Clinical case
i b r
e L
Mr. C., age 72, hospitalized in ICU
Fever of unknown origin, SOFA>>>2
D
Febrile neutropenia
I r
Antibiotics for 15 days
o
3 BC sets collected
M h
Imipenem - gentamicin
C t
S a u
Ea r
Improve your workflow (2)
i b r
T2 bacteria: E. faecium, E. coli, K. pneumoniae,
L
T2 magnetic resonance (T2MR) nanodiagnostic P. aeruginosa,, S. aureus.
e
No blood incubation T2 candida: 95% species involved in BSI
BC collection
I D r
4h 48 h 65 h
Conventional
o
From signal to ID To AMST
M
T2 system ?
C
Mean time to:
u t h
Candida detection & species identification: 4.4+1.0 h
S
T2 candida: Se >89%, Sp 98%,
a
Bacteria detection/species identification: 5.5+1.4 T2 bacteria: Se 83%, Sp 98%
E
negative results: 6.1+1.5 h
De Angelis et al, 2018
Mean time to appropriate therapy with T2 candida: 6h (1-13h) Clancy et al, CID 2018
Clansy & Nguyen, JAC, 2018
vs 34h (1-92h) Patch et al, 2018a r
Several (complementary) strategies
i b r
e L 1. Rapid methods
I D o r
C M t h
2. Laboratory Workflow
S a u
E
3. Workflow
(outside the lab) Cattoir et al, 2018a r
Where are the minutes to save ??
i b r
H0
e L H14 H18 H40 H60
I D o r
M h
Analytic phase, turn around time
C t
Pre-analytics Post-analytic phase
S a u
E
Here !
Also here ! and here !a r
Pre-analytical times, example 1
i b r
L
Reduced laboratory Reduced
e
service transportation service
30
I D r
20
From collection to
Time to bottle load (h)
20
o
16 bottle load,
M h
12
t
Weekdays
C
10
8
u
Quartile 3
S
4
E a
00
6-7
1-2
2-3
3-4
4-5
5-6
7-8
8-9
10-11
11-12
12-13
13-14
14-15
15-16
16-17
17-18
18-19
19-20
20-21
21-22
22-23
23-00
9-10
Time of the day Montpellier’s hospitala r
Pre-analytical times, example 2
i b r
No 24/7
(discontinuous)
e L Continuous loading
(incubation outside the lab)
I D o r
Proportion of antibiotic change
standard conditions immediate
M
80
h
Time to result (h)
C t
60
Délai de résultat (h)
u
40 Immediate
S a
20 Standard
conditions
E
0
Positive
Flacon positif ID
Identification AMST
ATBgramme
signal
Kerremans et al, J Clin Microbiol 2009 Delay (h)a r
Post-analytical times
i b r
L
Montpellier University hospital
(January 2017)
e
Personal data (submitted)
I D o r ❶visu
BACTERIOLOGIE
M
Vizu signal/ order (n=47)
signal/prescription (n=47) iMessage
17 March 2019 à 16:00
h
❷ visu ident/prescription (n=32)
Vizu ID/ order (n=32)
C t
❶ ❷ ❸ ❸visuATBGR/prescription
Vizu AMST/ order (n=19)
(n=19)
u
hours 0 20 40 60 80 100
E S a
Post-analysis
presc/adm
order/adm
order/adm AMST
Prescription/adm
signal
signal
prescription/adm
order/adm ident
(n=49)
(n=49)
(n=32)
ID (n=32)
ATBGR(n=19)
(n=19)
hours 0 20 40 60 80 100a r
Reducing post-analytical times: promises and hurdles
i b r
L
Identity vigilance &
Confidentiality
e
Expert system knows where is the patient
Expert system does
not cause extra
D
cognitive overload Expert system knows to which physician
I r
the information should be sent
M o
Expert system knows how to
h
contact the right physician
C t
(smartphone)
u
Expert system confirms message reception to the lab
E S a
Expert system knows what to do if the first
recipient does not confirm message receptiona r
Take home message
i b r
More studies with greater
L
Many actions power required
Additive actions to are possible
e
shorten time to result 1. Rapid methods
and time to action 2. Lab workflow
3. Workflow outside the lab Many new systems in
D
development
I r
No Universal
solution
(RAST in 2 h; ID in 45 mn)
M t h o
C
Don’t forget Choices depend on
u
local characteristics
S
post- analytical
a
times
Choices depend on
E
- microbiological situation
Important (monomicrobial/polymicrobial)
role ASP - local ecology
- Clinical situationa r
i b r
Thanks for your attention
L
Acknowledgements
e
Prof Gunnar Kahlmeter
D
Dr Emma Jonasson
I r
Dr Erika Matuschek
o
Dr Caroline Bonnefoy
M
Jordan Lejeune
t h
Prof Alban Lemonnier
C
Dr David Morquin
S u
Prof Raymond Ruimy
a
Mathilde Vannini
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