Minutes count: rapid detection/identification and susceptibility - ESCMID

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Minutes count: rapid detection/identification and susceptibility - ESCMID
a r
           Minutes count: rapid
                                                                       i b r
                    L
 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
Minutes count: rapid detection/identification and susceptibility - ESCMID
a r
COI Disclosure

                                                       i b r
           e  L
 Curetis: Research grant to Bacteriology department 2018
       (polymicrobial BSI diagnosis)

      I D       o r
   C M      t h
  S     a u
E
Minutes count: rapid detection/identification and susceptibility - ESCMID
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Rapid methods and time saved

                                                      i b r
           e  L
 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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
Minutes count: rapid detection/identification and susceptibility - ESCMID
a r
  Minutes count (3)

                                                                                i b r
                 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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
Minutes count: rapid detection/identification and susceptibility - ESCMID
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
                            slidex
a 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     Microbiol
a 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
E
a r
   Rapid ID with AST (scenario 1)

                                                                   i b r
                 L
                          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.org
a r
    RAST from EUCAST

                                                                                                       i b r
                   L
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 Matuschek
a 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 AST
a 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 h
a 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, 2018
a r
   Workflow Integration

                                                                   i b r
                     L
   Small modifications in lab workflow                                                    ID in less than

                  e
a 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 test
a 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
-   ID
a 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

                                                                                                                              25
a 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                             Resistance
a 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 evaluated
a 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
E
a 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, 2018
a 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, 2018
a 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 hospital
a 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    100
a 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 reception
a 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 situation
a 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

   E                                                37
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