ESBL- and carbapenemase-producing microorganisms; state of the art

Laurent POIREL

Medical and Molecular Microbiology Unit Dept of Medicine

University of Fribourg Switzerland

INSERM U914 « Emerging Resistance to Antibiotics »

Associate National Reference Center on Antibiotic Resistance

South-Paris Medical School Hospital Bicêtre

France

Broad-spectrum ß-lactams

AMX : amoxicillin CAZ : ceftazidime AMC : amoxicilline + clav FEP : cefepime TCC : ticarcillie + clav TZP : piperacillin + tazobactam CTX : cefotaxime CS : colistine CF : cefalotine TIC : ticarcillin TM : tobramycin AN : amikacine GM : gentamicin OFX : ofloxacin CIP : ciprofloxacin IPM : imipenem

Escherichia coli: wild-type susceptibility profile

Resistance to ß-lactams in Gram negatives

β-Lactamases

Modification of penicillin-binding proteins Decrease

of permeability

Overexpression of efflux

Pump

ß-lactam

ß-lactam

Penicillins Cephalosporins 1st et 2nd

generation*

ß-lactams/ Inhibitors of

ß-lactamases

Carbapenems

Ambler class

Cephalosporins 3rd generation cefepime**, cefpirome**

Enzyme

A ESBLs

C Overexpressed cephalosporinases/plasmid-mediated

B Metallo-enzymes)

* Cephamycins excluded for ESBLs ** Cefepime, cefpirome excluded for overexpressed cephalosporinase

Cephalosporinases

D Oxacillinases

Hydrolysis activity of broad-spectrum ß-lactamases

EXTENDED-SPECTRUM ß-LACTAMASES

What was the emergence scenario in the 80’s?

• First description in Germany, 1983 • Second description in France, 1984 • Recognized in the USA in 1987

• 3rd generation cephalosporin use • Aminoglycoside use in hospitals • Difficulties in recognition of ESBL producing isolates • - Lack of adequate breakpoints • - No accurate phenotypic methods for detection

• Numerous nosocomial outbreaks

“New epidemiological scenario”

• Increased prevalence of ESBL-producing isolates

• Increased isolates from the community, mainly E. coli

• Higher prevalence in E. coli than in K. pneumoniae

• Increased prevalence in other Enterobacteriaceae

• Accelerated evolution of ESBL in single institutions • Complex population structure • - High clonal variability but coexisting with clonal spread • - Spread of gene capture units (plasmids, In,Tn)

EXTENDED-SPECTRUM ß-LACTAMASES

Inferring ESBLs; synergy with clav is diagnostic

General rule (there are exceptions)

-CAZ > CTX = « classic » ESBL

- CTX > CAZ = CTX-M type

-Be wary of

- hyper-K1 in K. oxytoca -AmpC in Serratia

E. coli isolate producing CTX-M-1

ESBL Detection on a disc diffusion antibiogram

Clavulanic-acid inhibited ESBLs are rising….

0

1

2

3

4

5

6

1997 1998 1999 2000 2001 2002 2003 2004 2005 Ann仔s

%ES

BL

Escherichia coli Klebsiella spp

Hospital Bicetre

Clavulanic-acid inhibited ESBL producers are different…

0

1

2

3

4

5

6

1997 1998 1999 2000 2001 2002 2003 2004 2005 Ann仔s

%ES

BL

Escherichia coli Klebsiella spp

Hospital Bicetre

Clavulanic-acid inhibited ESBL producers are different…

Resistance trends for resistance to 3GC in Europe

I: 1.12 % R: 0.76 %

E. coli K. pneumoniae

2002

2010

2005

2010

I: 1.53 % R: 7.25 %

I: 0.97 % R: 4.13 %

I: 1.43 % R: 17.83%

Explanation: ESBLs !

TOHO-like

Geographical dissemination of blaCTX-M genes

CTX-M-2

Endemicity

CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-9

CTX-M-9, (-14)

CTX-M-8

CTX-M-10

CTX-M-1, 3, 15

CTX-M-2, -5

CTX-M-9, -14, 18, 19, 20, 21

CTX-M-4, -6

CTX-M-3, 15

CTX-M-, 3, 15

CTX-M-2, -5

CTX-M-16, -17

Sporadic reports

CTX-M-9, -13, -14

CTX-M-9, -16

prepared by Teresa Coque, 2001 - 02

TOHO-like

Geographical dissemination of blaCTX-M genes

CTX-M-2

Endemicity

CTX-M-1 CTX-M-2 CTX-M-8 CTX-M-9

CTX-M-9,-14

CTX-M-8

CTX-M-1,10,15,32

CTX-M-1, 3, 15

CTX-M-2, -5

CTX-M-9, -14, 18, 19, 20, 21

CTX-M-4, -6

CTX-M-3, 15

CTX-M-, 3, 15

CTX-M-2, -5

CTX-M-16, -17

Sporadic reports

CTX-M-9, -13, -14

CTX-M-9, -16

CTX-M-3

CTX-M-3

CTX-M-3

CTX-M-15

CTX-M-2

CTX-M-3, 15

CTX-M-14

CTX-M-9,-14

CTX-M-1,10,15

Worldwide prevalence of ESBL producers

K. pneumoniae E. coli USA 5.3% 2.8% Latin America 27.6% 12.0% Northern Europe 5.2% 1.4% Southern/East. Europe 25.7% 6.6% China 37.3% 31.3% Australasia 4.6% 1.6%

Adapted from Badal R et al. Poster presented at 48th Annual ICAAC; Oct 2008

2004

Prev

alen

ce, %

0

45 40

2003 2005 2006 2007

35

30

25

20

15

10

5

Asia/Pacific Latin America Middle East/Africa Europe North America

ESBL-producing Enterobacteriaceae

Prevalence of ESBL-producing isolates among 18,845 E. coli, K. pneumoniae and K. oxytoca isolates (SMART study, 2003-2007)

ESBL evolution; from TEM/SHV penicillinases

TEM/SHV

The novel ESBLs

CTX-Ms: cefotaxime… and ceftazidime hydrolysis

CTX-M-3 CTX-M-15 E. coli

Where are those CTX-M producers ?

• Community-aquired infections • Urinary tract infections • E. coli (+++ ), K. pneumoniae, Salmonella sp Shigella sp, Citrobacter sp, Enterobacter sp, Serratia sp…..

Consequences for hospitals; ESBL producers now in the emergency unit, maternity, urology nephrology, gastro-enterology, internal medicine, pediatrics….

Where do they originate from ?