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Gian Maria Rossolini Dip. Biologia Molecolare Sezione di Microbiologia Università di Siena UO Microbiologia e Virologia Azienda Osp-Univ Senese. Evoluzione dell’antibiotico-resistenza: miti e realtà. Inhibition zones. How do we define resistance?. Broth or agar dilution tests. - PowerPoint PPT Presentation
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Evoluzione dell’antibiotico-resistenza: miti e realtàEvoluzione dell’antibiotico-resistenza: miti e realtà
Gian Maria RossoliniDip. Biologia Molecolare Sezione di MicrobiologiaUniversità di Siena
UO Microbiologia e VirologiaAzienda Osp-Univ Senese
MIC valuesInhibition zones
Broth or agar dilution tests
How do we define resistance?How do we define resistance?
Interpretation of resultsbased on clinical breakpoints
Interpretation of resultsbased on clinical breakpoints
Reference MIC/zone values for interpretation of the results of in vitro
susceptibility testing
Reference MIC/zone values for interpretation of the results of in vitro
susceptibility testing
The clinical breakpointsThe clinical breakpoints
Definition of susceptibility category (S/I/R) referred to clinical use
Definition of susceptibility category (S/I/R) referred to clinical use
Clinical breakpoints are defined by specific committees
Clinical breakpoints are defined by specific committees
Breakpoint committees in EuropeBreakpoint committees in Europe
Committee Country
BSAC United Kingdom
CA-SFM France
CRG The Netherlands
DIN Germany
NWGA Norway
SRGA Sweden
CLSI USA
Enterics / cefotaxime S< / R>BSAC United Kingdom 1 / 1
CA-SFM France 4 / 32CRG The Netherlands 4 / 8DIN Germany 2 / 8CLSI U.S.A. 8 / 32NWGA Norway 1 / 2SRGA Sweden 0.5 / 1
with different opinions...with different opinions...
Kahlmeter et al – JAC 2003
December 2004
The EUCAST MissionThe EUCAST Mission
• to harmonise clinical breakpoints in Europe
• to determine breakpoints for new antimicrobials
• to provide standardised methodology for AST
Setting clinical breakpoints for new drugs in Europe
Co-ordinated process between the Company, EMEA and EUCAST
When a Company applies for registration of a new agent: EUCAST defines the breakpoints EMEA decides on all other aspects
EUCAST breakpoints for new drugs are the only ones included in the SPC (Summary of Product Characteristics)
EUCAST clinical breakpointsEUCAST clinical breakpoints
Freely available on the WEBFreely available on the WEB
Defined by consensusDefined by consensus
Institutional decision body (industry has a consulting role but does not participate in the decisional process)
Institutional decision body (industry has a consulting role but does not participate in the decisional process)
Rationale for decision disclosed (rationale documents available)Rationale for decision disclosed (rationale documents available)
EUCAST vs. CLSI breakpoints:a remarkable diversity
Courtesy by G. Kahlmeter
EUCAST CLSI
S≤ R> S≤ R>
Cefepime 8 8 8 16
Ceftazidime 8 8 8 16
Imipenem 4 8 4 8
Meropenem 2 8 4 8
Pip/Tazo 16 16 64 64
Aztreonam 1 16 8 16
Ciprofloxacin 0.5 1 1 2
Gentamicin 4 4 4 8
Tobramycin 4 4 4 8
Amikacin 8 16 16 32
Colistin 2 2 2 4
EUCAST vs. CLSI breakpoints: Pseudomonas aeruginosa
For S: EUCAST 5/11 lowerFor S: EUCAST 5/11 lower For R: EUCAST 8/11 lowerFor R: EUCAST 8/11 lower
EUCAST vs. CLSI breakpoints: Enterobacteriaceae
(beta-lactams & quinolones)
EUCAST CLSI
S≤ R> S≤ R>
Cefepime 1 8 8 16
Ceftriaxone 1 2 8 32
Ceftazidime 1 8 8 16
Ertapenem 0.5 1 2 4
Imipenem 2 8 4 8
Meropenem 2 8 4 8
Pip/Tazo 8 16 16 64
Levofloxacin 1 2 2 4
Ciprofloxacin 0.5 1 1 2
For S: EUCAST 9/9 lowerFor S: EUCAST 9/9 lower For R: EUCAST 7/9 lowerFor R: EUCAST 7/9 lower
EUCAST CLSI
S≤ R> S≤ R>
Amikacin 8 16 16 32
Gentamicin 2 4 4 8
Tobramycin 2 4 4 8
Cotrimoxazole 2 4 2 2
Colistin 2 2 NA NA
Tigecycline 1 2 NA NA
For S: EUCAST 3/4 lowerFor S: EUCAST 3/4 lower
For R: EUCAST 3/4 lower, 1/4 higherFor R: EUCAST 3/4 lower, 1/4 higher
EUCAST vs. CLSI breakpoints: Enterobacteriaceae
(other agents)
EUCAST vs. CLSI
Will the change from CLSI to EUCAST breakpoint system significantly affect the epidemiology of antibiotic resistance?
EUCAST vs. CLSI
• A comparative analysis of AST results interpreted according to CLSI or EUCAST
• Data source: historical records from clinical microbiology service, Siena University Hospital (year 2008)
Pseudomonas aeruginosaGentamicin (N = 295)
2 4 8 16 32 64
EUCASTCLSI
MIC (mg/L)
EUCAST: RCLSI: I
Pseudomonas aeruginosaAmikacin (N = 296)
2 4 8 16 32 64
EUCASTCLSI
MIC (mg/L)
EUCAST: RCLSI: I
EUCAST: ICLSI: S
Pseudomonas aeruginosaCeftazidime (N = 294)
1 2 4 8 16 32
EUCASTCLSI
MIC (mg/L)
EUCAST: RCLSI: I
Pseudomonas aeruginosaMeropenem (N = 216)
2 4 8 16 32 64
EUCASTCLSI
MIC (mg/L)
EUCAST: ICLSI: S
Pseudomonas aeruginosaPip/Tazo (N = 289)
2 4 8 16 32 64
EUCASTCLSI
MIC (mg/L)
EUCAST: RCLSI: S
Pseudomonas aeruginosaAztreonam (N = 133)
1 2 4 8 16 32
EUCASTCLSI
MIC (mg/L)EUCAST: I
CLSI: S
Pseudomonas aeruginosaCiprofloxacin (N = 295)
0.25 0.5 1 2 4 8
EUCASTCLSI
MIC (mg/L)
EUCAST: RCLSI: I
EUCAST: ICLSI: S
Pseudomonas aeruginosaCLSI vs. EUCAST
% s
usc
epti
bil
ity
Antibiotics
MRSA impact (USA)MRSA impact (USA)
Boucher & Corey Clin Infec Dis 2008
a in hospital deaths
Resistance trends in major pathogens Europe
EARSS annual report, 2007
MRSAMRSA
Cou
ntr
ies
8/30
8/30
14/30 =
8/30
8/30
14/30 =
E. coli R to 3GCE. coli R to 3GC
23/30
1/30
6/30 =
23/30
1/30
6/30 =
2008:
2/31
10/31
19/31 =
2008:
2/31
10/31
19/31 =
2008:
21/30
0/30
9/31 =
2008:
21/30
0/30
9/31 =
Resistance trends in major pathogens Europe
EARSS annual report, 2007
MDR E. coli (R to 3GC,AG,FQ)
MDR E. coli (R to 3GC,AG,FQ)
24/30
0/30
6/30 =
24/30
0/30
6/30 =
Cou
ntr
ies
E. coli R to 3GCE. coli R to 3GC
23/30
1/30
6/30 =
23/30
1/30
6/30 =
The growing challenge of resistant Gram-negatives
• MRSA and VRE rates have leveled off or decreasing in several European countries
• Resistant Gram-negatives are increasing in most European countries
Rossolini & Mantengoli, CMI 2008
Major challenges:
• Enterobacteriaceae ESBL/AmpC, MDR, XDR (ESC/FQ/AG/NEM)
• Pseudomonas aeruginosa and Acinetobacter MDR, XDR (COL-S only)
EARSS databaseYear
% r
esis
tan
t to
3G
C
K. pneumoniaeK. pneumoniae
ESBLs: increasing trends
EARSS database
Year
% r
esis
tan
t to
3G
C E. coliE. coli
ESBLs: increasing trends
%
Spanu et al. - AAC 2002; Luzzaro et al. - JCM 2006; OASIS study, data on file
ESBL-producing Enterobacteriaceae , Italy
Suspect ESBL
2003: Proteus mirabilis (isolates from UTIs and ulcers)
Aztreonam
Ceftazidime
Cefotaxime
Ceftriaxone
Amoxi/Clav
Resistant to 3rd gen. ceph.but ESBL-negative
Ampicillin >128 RAmoxi/Clav 32 RPip/Tazo 4 SCephalotin 32 RCefotaxime 64 RCeftazidime 32 RCefepime 2Ertapenem 0.12 S
Amikacin 2 S Gentamicin 4 SCiprofloxacin >32 RLevofloxacin >32 R
MIC (mg/L)
RS
.
P. mirabilis resistant to
3rd gen. cephalosporins
Luzzaro et al – IJAA 2009
Same clone detected in LTCFs
By clonal expansionBy clonal expansion
Luzzaro et al – IJAA 2009
Clinical features of infections caused by the P. mirabilis CMY-16+
Mean age: 75±15 yrs (76±16 for ESBL+; 57±28 for susceptible strains)
Female/male ratio: 1.1(1.6 for ESBL+; 2.1 for susceptible strains)
Inpatients
LTCFs
HCAss
CA
51%37%
Patients
UTIs
LRTIs
SSSIs
BSIs
80%
Sources
2007-2008:P. mirabilis CMY+ spreading in Italy
2007-2008:P. mirabilis CMY+ spreading in Italy
Clonally related isolates detected in Greece and Poland: an internationally spreading clone
D’Andrea et al – unpublished
>30 cases from BSIs>30 cases from BSIs
Courtesy of Vincent Jarlier, Sept 2009 (modified)
ESBLs/AmpC and carbapenem overuse
Increased # ESBL/AmpC cases Increased Carb-R strains
Cross transmission
of Carb-R strains
Selection of Carb-R strains
Increased carbapenem
use
Production of:- CTX-M-15 ESBL- SHV-11- (OXA-9) (TEM-1)
Production of:- CTX-M-15 ESBL- SHV-11- (OXA-9) (TEM-1)
D’Andrea et al. – 19th ECCMID
2007-2008: emergence of MDR Klebsiella pneumoniae ERT-R from several hospitals …
Ampicillin >16 RAmoxi/Clav >16 RPip/Tazo >64 RCefotaxime >16 RCeftazidime >32 RCefepime >16 RAztreonam >16 RImipenem ≤1Meropenem 2-4Ertapenem >4 R
Amikacin >32 RGentamicin >8 RTobramycin >8 RCiprofloxacin >32 RLevofloxacin >32 RTMP/SXT >2 RTigecycline 1 - 2Colistin <1
MIC (mg/L)
Reduced porin expressionReduced porin expression
No carbapenemase act.No carbapenemase act.
Nationwideclonal spread
(ST37)
Nationwideclonal spread
(ST37)
Ampicillin >16 RAmoxi/Clav >16 RPip/Tazo >64 RCefotaxime >16 RCeftazidime >32 RCefepime >16 RAztreonam >16 RImipenem ≤1 RMeropenem 2-4 RErtapenem >4 RESBL positive
Amikacin >32 RGentamicin >8 RTobramycin >8 RCiprofloxacin >32 RLevofloxacin >32 RTMP/SXT >2 RTigecycline 1 - 2 SColistin <1
MIC (mg/L)
Klebsiella pneumoniae with reduced carbapenem susceptibility due to ESBL prod. + porin loss:
detection and reporting issues
Vitek-2 AES: changes to resistance to all carbapenemsVitek-2 AES: changes to resistance to all carbapenems
KPC-2K. oxytoca
KPC-2K. oxytoca
Yigit et al. AAC 2003
22% of isolates resistant to:- Aminoglycosides- Fluoroquonolones- 3rd 4th gener. Cephems- Carbapenems
Klebsiella pneumoniae
Susceptibility only to:- Colistin- Tigecycline
Due to spread of KPC carbapenemases
Brooklyn, New York …
Landman et al – JAC 2007
KPC-type carbapenemases in Israel: a major problem
Nationwide outbreak
Carbapenem resistance rates in K. pneumoniae from Israel:2006: 11%2007: 22%2008: 19%
EARSS database
KPC-type carbapenemases: a new pandemic?
Two cases, one with Israel connection
Clonally related
7 cases
4 from Greece2 from Israel
Clonally related
Nordmann et al. Lancet ID 2009
Villegas et al. AAC 2007Tsakris et al. JAC 2008
Hawser et al. IJAA 2009Literacka et al. AAC 2009
Intercontinental spread of ST258 KPC+ clone
KPC-type carbapenemases: emerging in Italy
Giani et al - JCM 2009
Florence
Oct 2008: KPC-3 positive K. pneumoniae ST258 isolated from a cIAI (high-level carbapenem resistance)
No epidemiological link with areas of endemicity, but patient cared for by a trainee from Israel
Lecco
May 2009: KPC positive K. pneumoniaePatient transferred from another hospitalLarge outbreak ongoing in that hospital (26 patients colonized or infected), variable carbapenem resistance
Luzzaro et al - unpublishedSantoriello et al - unpublished
Mostly by clonal spread (ST258), but at least two clones and also in Enterobacter
Additional reports
Carbapenem-resistant K. pneumoniae, GreeceCarbapenem-resistant K. pneumoniae, Greece
Production of
VIM-1 MBL
Production of
VIM-1 MBL
Multiple clones
Often susceptible
only to colistin and
tigecycline(XDR)
Vatopoulos et al. - Eurosurveillance 2008Psichogiou et al. – JAC 2008
KPC-type (active-site serine, class A)
OXA-type (active-site serine, class D)
Metallo-β-lactamases (class B)
Carbapenemases of clinical relevance
GM
COL
AK
TOB
FEPIPM
MEMCAZTZP
ATM
CIP
PRLLauretti et al. – AAC 1999
Cornaglia et al. – CID 2000
VERONA1997
VIM-1 MBL-producing index strainVR-143/97 (ser. O11; ST227)
VIM-1 MBL-producing index strainVR-143/97 (ser. O11; ST227)
Acquired MBLs in Pseudomonas aeruginosafirst Italian nationwide survey
VARESE 2.6%
PAVIA 1.3%
CREMONA 0.6%
PERUGIA 1.1%
SASSARI 0.9%
ROME 0.3% AVELLINO 1.4%
NEAPLES 9.2%
FOGGIA 1.2%
GENOA0%
TURIN0%
L’AQUILA0%
2004:Overall prevalence
1.3%
2004:Overall prevalence
1.3%
Rossolini et al. AAC 2008
2008:Overall prevalence
7%
2008:Overall prevalence
7%
Luzzaro et al. - unpublished
•CLSI soon replaced by EUCAST: resistance rates will be affected in some cases
•Resistance in Gram-negatives: now a major problem
•XDR phenotypes not only in Pseudomonas and Acinetobacter but also among enterobacteria
•Multiple resistance mechanisms: not easily deducible from the antibiotype
•Open issues in: lab detection, reporting, infection control and treatment
ConclusionsConclusions