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Dichiarazione su potenziali conflitti di interesseConsulenze, partecipazione advisory boards, speaker’s
bureau, contratti/contributi di ricerca e di eventi studio: Abbott, Accelerate Diagnostics, Ada, Alifax, Angelini,
Becton Dickinson, Bellco, Merck Sharp & Dohme, Pfizer, Thermofischer Scientific
Dr Bruno ViaggiDipartimento di Anestesia
SOD NeuroAnestesia eRianimazione CTO AOUC
Il paziente settico in Terapia Intensiva: cosa vorrebbe il rianimatore e che risposte può avere dal microbiologo
Presupposti:- Parlare la stessa lingua- Disponibilità a comunicare ed incontrarsi- Flessibilità nell’orario
Contesto:- Strutturato (es. programma AS)- Non strutturato
Esempi:- 3 casi di infezioni gravi- un protocollo per la antimicrobial
stewardship - un concept per la diagnostic stewardship
Il dialogo tra il microbiologo e il clinico
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Caso n.1
uomo 37 aaanamnesi mutapolitrauma a dinamica maggiore (scontro frontale)danno assonale diffuso .. rottura milza(splenectomia) .. ematoma transmurale arco aortico .. emotorace bilaterale .. frattura sterno .. fratture costali multiple bil .. frattura soma D11 .. frattura acetabolo sx .. frattura olecrano sx .. grave shock emorragico
ricovero in ambiente intensivo, stabilizzazione del quadro clinico e trasferimento dopo 98 h ℅ la nostra Rianimazione per proseguo cure (doppio drenaggio toracico)
TR ingresso positivo per KPC
dopo 4 gg deterioramento degli scambi
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
real life …..
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
TigeciclinaGentamicina
Fosfomicina?Ceftazidime/avibactam?
KPC
Discussione intensivista – microbiologo clinico
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Monaco et al Euro Surv 2014
Activity of Fosfomicin and other antibiotics anti-CRE against KPC-K.pneumoniae (EuSCAPE 2013-2014 Italy)
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
-90,0
-45,0
0,0
45,0
90,0
135,0
N=78 KPC-producing K. pneumoniae (45 S, 33 R)
Pe
rce
nt
False resistant False susceptible
Parisio et al – AMCLI 2017
Fosfomycin testing: reference agar dilution vs. other methods
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
MIC = 16 mg/L - S
Saggio ceftazidime-avibactam per microdiluizione
MIC = 2 mg/L - S
Saggio fosfomicina per agar-diluizione
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
1.2
5
real life …..
HI=140TB+++
HI=132TB+++ HI=190
TB++
HI=260TB+
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Caso n.2
uomo 46 aaESA Fischer 4 da rottura ACoAforte fumatore recente terapia con fluorochinolonici per episodio di tracheobronchite
dopo 8 gg paziente francamente settico
terapia empirica PIP/TAZ + Amikacina
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
VIMnon rilevato
OXA non rilevato
CTX-M RILEVATO
KPC non rilevato
NDM non rilevato
IMP non rilevato
SangueKlebsiella pneumoniae(ceppo produttore di ESBL)
bacillo gram negativo
ANTIBIOTICI ceppo MIC
Amikacina S <=4
Cefepime R 4
Ceftazidima R 16
Ciprofloxacina R >2
Colistina S <=0.5
Gentamicina R >4
Imipenem S <=1
Meropenem S <=0.12
Pip/Taz R 32/4
Tigeciclina S 0.5
Trimethoprim/sulfa
R >4/76
Cefotaxima S <=4
Ceftolozane/tazobactam and carbapenem sparing strategy
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Ming Ng T et al. PlosONE 2016
0
10
20
30
40
30-daymortality
LOS after BSIonset
30-dayacquisition ofMDR and IFI
30-dayrelapsed BSI
31
18
73
30
16
25
16
Empiric active PIPTAZ (N=94) Empiric carbapenem (N=57)
Empiric Piperacillin-Tazobactam versus Carbapenems in the Treatment of Bacteraemia Due to ESBL-Producing Enterobacteriaceae
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Adjusted ORs and 95% CI for
cure/improvement at day 14 for empirical (A)
and targeted (B) therapy with BLBLIs vs
carbapenems in different subgroups
365 ptz
601 ptz
Multinational, Preregistered Cohort Study of BL/BLI Combinations for Treatment of Bloodstream Infections Due to ESBL-Producing Enterobacteriaceae
Gutierrez-Gutierrez B et al. AAC 2016
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
E’ possibile fare una terapia carbapenem-sparing?
Discussione intensivista – microbiologo clinico
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Rossolini et al, unpublished results
0,
25,
50,
75,
100,
ESBL E. coli AmpC E. coli ESBL Klebsiella ESBL Proteus AmpC Proteus
TLZ-TZB AMOXI-CLAV PIP-TZB ERT MER
Per
cen
t su
scep
tib
ility
N=366 N=14 N=74 N=41 N=25
Ceftolozane/Tazobactam activity vs ESBL/AmpC-positive Enterobacteriaceae from Italy
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Pannello in Microdiluizione
1 2 3 4 5 6 7 8 9 10 11 12
APIP32
PIT126:4
AZT16
CAZ32
CEP8
MER16
FOS64
AMK32
TOB32
GEN32
CIP8
LEV8
BPIP16
PIT64:4
AZT8
CAZ16
CEP4
MER8
FOS32
AMK16
TOB16
GEN16
CIP4
LEV4
CPIP8
PIT32:4
AZT4
CAZ8
CEP2
MER4
FOS16
AMK8
TOB8
GEN8
CIP2
LEV2
DPIP4
PIT16:4
AZT1
CAZ4
CEP1
MER2
FOS8
AMK4
TOB4
GEN4
CIP1
LEV1
ECAA8:4
PIT8:4
T/S8:152
CAZ2
CTA8:4
MER1
IMP8
COL8
TOB2
GEN2
CIP0.5
LEV0.5
FCAA4:4
PIT4:4
T/S4:76
CAZ1
CTA4:4
MER0.5
IMP4
COL4
TOB1
GEN1
CIP0.25
LEV0.25
GCAA2:4
PIT2:4
T/S2:36
CAZ0.5
CTA2:4
MER0.25
IMP2
COL2
TOB0.5
GEN0.5
CIP0.125
LEV0.125
HCAA1:4
PIT1:4
T/S1:19
CAZ0.25
CTA1:4
MER0.125
IMP1
COL1
TOB0.25
GEN0.25
CIP0.0625
Growth
Control
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
✓ Gradient strips available, but some concerns with accuracy
✓ Commercial broth microdilution panels available
✓ Upcoming but not yet available in the most popular semi-automated systems
Ceftolozane-Tazobactam: susceptibility testing issues
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Caso n.3
uomo 25 aapolitrauma a dinamica maggiore (moto vs auto) .. sulla scena GCS 3FLC temporali e fronto basali dx.. ESA .. fratture multiple massiccio facciale .. frattura rocca petrosa e timpano dx .. ematoma intramurale istmo aortico .. fratture costali multiple bil .. frattura diafisaria femore sx e subamputazionetraumatica coscia sx .. shock emorragico .. stop di flusso a livello del tripodeceliaco
ricovero in ambiente intensivo - cefazolina metronidazolo e gentamicina x 72h e meropenem 2gr x 3 x 5 gg su positività nel BA di PSA multisensibile
Fissatore esterno e VAC
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Polmone (BA)Pseudomonas aeruginosa(ceppo XDR)
ANTIBIOTICI ceppo MIC
Amikacina I 16
Cefepime R >8
Ceftazidima R >32
Ciprofloxacina R 4
Colistina R 4
Gentamicina R 16
Imipenem R >8
Meropenem R >16
Pip/Taz R 64
Cefto/Taz S 2
Ceftolozane/tazobactam and Pseudomonas aeruginosa XDR
Conta, >100 mila CFU/ml
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Quale partner per ceftolozane-tazobactam?
MIC fosfomicina >128 mg/L
Discussione intensivista – microbiologo clinico
fosfomicina?
ANTIBIOTICI ceppo MIC
Amikacina I 16
Cefepime R >8
Ceftazidima R >32
Ciprofloxacina R 4
Colistina R 4
Gentamicina R 16
Imipenem R >8
Meropenem R >16
Pip/Taz R 64
Cefto/Taz S 2
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Aminoglycoside Concentrations Required for Synergy with Carbapenems against Pseudomonas aeruginosa
Yadav R et al Antimicrob Agents Chemother dec 2017
The MBM indicated that aminoglycosides enhanced the
imipenem target site concentration up to 4.27-fold
tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested
aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill
patients.B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Percent susceptibility of all P. aeruginosa isolates (n 1,257) to ceftolozane-
tazobactam (pink bar) compared to that to B-lactams alone (light-blue bars) or in
combination with ciprofloxacin (dark-blue bars) or tobramycin (green bars).
Definitions: CAZ, ceftazidime; C/T, ceftolozane-tazobactam; FEP, cefepime; MEM,
meropenem; TZP, piperacillin-tazobactam.
In Vitro Comparison of Ceftolozane-Tazobactam to traditional Beta-Lactams and Ceftolozane-Tazobactam as an Alternative to Combination Antimicrobial Therapy for Pseudomonas aeruginosa
Goodlet KJ et al Antimicrob Agents Chemother dec 2017
Ceftolozane-tazobactam should be considered for
use in patients at high risk for resistant P.
aeruginosa infection and as an alternative to
empirical combination therapy, especially for
patients unable to tolerate aminoglycosides
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Considerations for effect site PK to estimate drug exposure: C of ATBs in the LUNG
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Antibiotic Dose
Penetration ratio
(ELF-to-total plasma)
Penetration ratio
(ELF-to-unbound plasma)
ceftazidime/avibactam
2 g q8h 31,3% NR
0.5 g q8h 34,9% NR
3 g q8h 32,4% NR
1 g q8h 32% NR
ceftolozane/tazobactam
1 g 8h 48% 59%
0.5 g 8h 44% NR
Rodvold KA et al Curr Opin in Pharmacology 2018
Flow-chart Carbapenem-sparing in area critica nel paziente con c-IAI : Scelta RagionataA
zie
nd
a O
sped
aliero
Un
ivers
ita
ria
Care
ggi
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
B.Viaggi - NeuroIntensive Care Unit - Department of Anesthesiology Careggi University Hospital
Boutal H t al J Antimicrob Chemother 2018;73:909-915
carba5 a multiplex lateral flow immunoassay for the rapid identification of NDM-, KPC-, IMP- and VIM-type and OXA-48-like carbapenemases-producing
Enterobacteriaceae
Overall, this assay reached 100% sensitivity and 95.3%
(retrospectively) to 100% (prospectively) specificity.
Conclusions: Carba5 is efficient, rapid and easy to implement in
the routine workflow of a clinical microbiology laboratory for
confirmation of the five main carbapenemases encountered in
Enterobacteriaceae.