The current status of multiple- drug-resistant bacteria … current status of...

The current status of multiple-

drug-resistant bacteria in Europe

Departamento de

Microbiología II

Universidad

Complutense. Madrid

Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

Dr. Rafael Cantón

24th Annual meeting of Japanese Society for Clinical Microbiolgy

Yokohama, Japan. 2nd and 3rd, February, 2013

http://www.ucm.es/info/farmacia/Farma3.htm

Current status of MDR in Europe

Co-resistance and multi-drug-resistance definition

- microbiological interpretation (genetic capitalisms)

- clinical interpretation

Review microorganisms with propensity to acquire resistance

mechanisms either by mutational events or acquisition of

resistance genes (ESKAPE organisms)

- increasing prevalence of resistance in EU

- emergence of new resistance mechanism in EU

Objectives

Multi-drug- resistance: the microbiological view

Cross resistance (class resistance)

- a R mechanisms affecting antimicrobials from the same family

Multi-resistance (co-resistance)

- different R mechanisms afecting diffent families of antimicrobials

Pleiotropic resistance

- a single R mechanisms affecting antibiotics from different families

E. coli ciprofloxacinR (tooisomerase mutations)

S. aureus meticillinR (PBP2a production)

P. aeruginosa with efflux resistance mechanisms

S. pneumoniae with ribosomal alterations

Multi-drug-resistant P. aeruginosa , A. baumannii

SARM, muti-resistant S. pneumoniae

β-lactamases:

- blaKPC-2, blaVIM-19,

- blaCMY-2, blaCTX-M-15,

- blaSHV, blaTEM

Aminoglycoside modified enzymes

- aacA6;

- aadA

Other resistant genes

- sulI (sulphonamydes)

- dfrA1 (trimetoprim)

Antibiotic MIC (mg/L) Interpretation*

Ampicillin >16 R

Amox/clav >256/2 R

Pip/taz >256/4 R

Cefoxitin >256 R

Cefotaxime >32 R

Ceftazidime >256 R

Cefepime 128 R

Aztreonam >256 R

Imipenem 32 R

Meropenem 16 R

Ertapenem 64 R

Ciprofloxacin >32 R

Gentamicin 64 R

Amikacin 16 R

Trimethoprim >256 R

Tetracycline >256 R

Tigecycline 2 R

Colistin 16 R

*EUCAST

Klebsiella pneumoniae from a urinary tract

infection in a hospitalized patient in Greece

Genetic capitalism

Different antimicrobials might select the same resistant bacteria

A single antimicrobial might select different resistant bacteria

Multi-drug-resistance: the microbiological view

… the model of the blaCTX-M-9 and blaCTX-M-2 ESBL genes

Cantón & Coque. Curent Opin Microbiol 2006; 9:466-75

Valverde et al. Antimicrob Agents Chemother 2006; 50:799-802

Novais et al. Antimicrob Agents Chemother 2006; 50:2741-50

Tn21-like, associated with disemmination and manteinace of blaCTX-M

ANTIBIOTIC AND BIOCIDE RESISTANCE

Variable region, integration of

cassettes of resistance

ANTIBIOTIC RESISTANCE

Insertion sequence, mobilization and

expression of resistance genes

ANTIBIOTICSRESISTANCE


0

10

20

30

40

50

60

70

80

90

100

CTX-M-9 CTX-M-14 CTX-M-10 other CTX-M-

type

SHV-type TEM-type

% o

f R

str

ain

s

AMK GEN TOB KAN STR SUL

TMP TET CMP NAL CIP

Morosini, García-Castillo, Coque, Valverde, Novais, Loza,

Baquero, Cantón. Antimicrob Agent Chemother 2006; 2006; 50:2695-9.

Co-resistance in ESBL producing organisms


Canton & Ruiz-Garbajosa Curr Opin Pharmacol 2011; 11:477-85

Multi-drug-resistance: the consequences

Epidemic & endemic

A

Fixation of resistant genes and resistant

bacteria in bacterial populations Allodemic

A

Mutation

Selection

A = antibiotic pressure

Lateral transfer

Spread

Well-adapted clones

Multi-drug-resistance: the consequences

ESBL - Hospital Universitario Ramón y Cajal (1988-2000)

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5

10

15

20

25

30

88 89 90 91 92 93 94 95 96 97 98 99 0

Year

No

. o

f p

ati

en

ts

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15

20

25

30

88 89 90 91 92 93 94 95 96 97 98 99 0

Year

No

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ts/c

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e

Baquero, Cantón, Coque. Lancet Infect Dis 2002; 2:591-2

Emergence and dissemination of resistant bacteria

Magiorakos et al. Clin Microbiol Infect 2012; 18:268-81

Term Definition Comment

Multi-drug

resistant

(MDR)

Non-susceptibility to at least

one agent in three or more

antimicrobial categories*

R to multiple antimicrobial agents (≥3), classes or subclasses.

Includes XDR and PDR. Definition based on in-vitro

susceptibility data with the aim to alert clinicians when treating

patients and infection control

Extremely

drug resistant

(XDR)

Non-susceptibility to at least

one agent in all but two or

fewer antimicrobial categories*

R to all, or almost all, approved antimicrobial agents.

Pan-drug

resistance

(PDR)

Non-susceptibility to all agents

in all antimicrobial categories *

Organisms resistant to:

- almost all commercially available antimicrobials

- all antimicrobials routinely tested

- to all antimicrobial available for empirical treatment.

*therapeutic categories (i.e. aminoglycosides, fluoroquinolones, cephalosporins, carbapenems, …)

Multi-drug-resistance: the clinical view

Pseudomonas

aeruginosa

Magiorakos et al.

Clin Microbiol Infect 2012; 18:268-81

CLSI (NCCLS) EUCAST

CLINICAL BREAKPOINTS

EPIDEMIOLOGYCAL

CUT-OFF

CLINICAL BREAKPOINTS

Susceptibility interpretation criteria

http://www.eucast.org/

http://www.clsi.org/

ECOFF

S R CLSI

S R EUCAST

Current status of MDR in Europe

Co-resistance and multi-drug-resistance definition

- microbiological interpretation (genetic capitalisms)

- clinical interpretation

Review microorganisms with propensity to acquire resistance

mechanisms either by mutational events or acquisition of

resistance genes (ESKAPE organisms)

- increasing prevalence of resistance in EU

- emergence of new resistance mechanism in EU

Objectives

Enterococcus faecium

Staphylococcus aureus

Klebsiella pneumoniae

Acinetobacter baumannii

Pseudomonas aeruginosa

Enterobacter spp.

Rice. J Infect Dis 2008; 197:1079-81

Boucher et al. Clin Infect nfect Dis 2009; 48:1-12

Rice. J Hosp Epidemiol 2010; 31 (Suppl 1):S7-10

Sandiumenge and Rello. Curr Opin Pulm Med 2012; 18:187-93

Multi-drug- resistance: the relevant bugs

Traditionally not considered as a pathogen

Increasing relevance in nosocomial infections (bacteremia, catheter..)

Epidemiological change in the last years …

- increasing prevalence of:

- E. faecium with respect to E. faecalis

- E. faecium ampR and ampR + vancoR

- clonal dispersión (CC17) of E. faecium ampR vancoR

- emergence of new variants of vancomycin resistance genes

- emergence of new resistance mechanisms

Enterococcus spp.

Witte et al. Int J Med Microbiol 2008; 298:365-77

Top et al. FEMS Immunol Med Microbiol. 2008; 52:297-308

Werner et al. Euro Surveill. 2008; 13(47). pii:19046

Arias & Murray. Nat Rev Microbiol 2012; 10:266-78

Enterococcus spp.: bacteremia

0

10

20

30

40

50

60

70

80

90

100

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

E. faecalis E. faecium Ampi-R-E. faecium

Anual cases (Hospital Ramón y Cajal)

P. Ruiz-Garbajosa et al. Servicio de Microbiología

Hospital Ramón y Cajal. Madrid. Spain

Enterococcus faecalis (2010) Enterococcus faecium (2010)

http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/Pages/Database.aspx

Enterococcus spp.: ampicillin resistance

Invasive isolates (EARS-net)

Enterococcus spp.: vancomycin resistance

Glycopeptyde resistance phenotypes

Regional differences and within species¡

Cercenado E. EIMC 2011; 29 (Supl 5): 59-65

Invasive isolates (EARS-net)

Enterococcus faecalis (2010) Enterococcus faecium (2010)

http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/Pages/Database.aspx

Enterococcus spp.: vancomycin resistance

E. faecium: population estructure

Willems et al.Emerg Infect Dis 2005; 11:821-8; Leavis et al. Curr Opin Microbiol 2006; 9:454-60

Willems et al. FEMS Microbiol Rev 2011; 35:872-900; Willems et al. MBio 2012; 3:e00151-12

Population snapshot based on all unique STs of the entire

E. faecium MLST database and visualized using eBURST

Previously designated as CC17

Enterococcus spp.: emerging resistance

High level-R: PBP5 hyperproduction (E. faecium)

Low level R: β-lactamase production

- constitutive expresion

- sporadic in E. faecalis and E. faecium

- describe in EEUU, Canada, Argentina, Libano, India, …

Penicillin resistance

*Sarti M, et al. J Clin Microbiol 2012; 50:169-72

Description in 2010 in Italy*

- 8 E. faecium, different PFGE of CC17

- chromosomic operon blaZ-blaI-blaR1

- detection of β-lactamase with high

inocullum and preincubation with

methicillin

Control (-)

E. faecium

bla(+) with

and withouf

methicillin

- 16 patients (Jan-2007 – Oct-2008)

- 17 E. faecium and 5. E. faecalis with MICs of linezolid 8-16 mg/L

- different pulsotypes

- 12 isolates with cross resistence with vancomycin

- G2576T mutation (absence of cfr gen)

Enterococcus spp.: emerging resistance

Staphylococcus aureus: paradigm of resistance

Year Antibiotic affected Mechanism of resistance

1940 Penicillin -lactamase

1960 Methicillin PBP2a (mecA) Tetracyclin efflux Chloramphenicol CAT enzyem Macrolides 23s RNA methilase Aminoglycosides ribosomal modification enzymatic modification

1970 Co-thrimoxazole alternative pathways Rifampicin RNA polymerase modification

1980 Quinolones parC, gyrA mutations Efflux Mupirocin target modification

1990 Vancomycin thick cell wall

2000 Linezolid mutaciones 23sRNA y proteínas mutaciones proteínas ribosomales metilación 23sRNA (gen cfr) Vancomycin vanA Daptomycin membrane potential modification Tigecycline eflujx

2010 Methicillin mecC

Adquisition of resistance

mechanisms in MRSA*

(multi-resistance)

Emergence and dispersion

of new clones (CA-MRSA)

Emergence of new

resistance mechanism

- glucopeptide

- linezolid

*MRSA: methicillin resistant S. aureus

Invasive isolates

(EARS-net Project, ECDC)

2010

2001

http://ecdc.europa.eu/en/activities/surveillance/EARS-Net/database/Pages/database.aspx

MRSA in Europe: an endemic situation

Porcentaje de Staphylococcus aureus resistente a meticilina en infección nosocomial

EPINE 1999-2012

2219 18

25 25

29

40

36 37

45

41

4542

44

48 4851

43 43 43,1

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

.

0

10

20

30

40

50

60Tasa de resistencia (%)

Nosocomial infection in Spain (EPINE study)

Angel Asensio (personal comunication)

Percentage of methicillin resistant S. aureus

MRSA in Europe

Co-resistances

Linezolid resistance

Vancomycin MIC creep

New patterns, new clones, …

MRSA in France: an endemic situation

Co-resistances

Patrice Nordmann, 2011

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10

20

30

40

50

60

70

80

90

100

% o

f re

sis

tan

t is

ola

tes

Eritromicina Gentamicina Cotrimoxazol Linezolid

1994 1996 2002 2006

Cuevas et al. Enferm Infec Microbiol Clin 2008; 26: 269-77

MRSA in Spain: an endemic situation

Co-resistances

four different clones (one of them was predominat)

linezolid MIC: 16-32 mg/L

variable susceptibility to other agents:

- 100% S to vancomycin, teicoplanina, daptomycin, and tygecyclin

- 20% R to co-thrimoxazol

- >85% R to ciprofloxacin, gentamicin, erithromycin

- 100% R to clindamycin

Presence of cfr gen in the chromosome

¡Now present in CNS and enterococci! Morales et al. Clin Infect Dis 2010; 50:821-5

MRSA and glicopeptide susceptibility

VISA/GISA (decrease susceptibility to vancomycin and teicoplanin):

- Intermediate homo-resistance

- all cells display similar MIC (vancomycin: 4-8-16 mg/L)

- accurate detection in the laboratory (microdilution, Etest)

- Hetero-resistance

- not all the cells display similar MIC (vancomycin: 1-4 mg/L)

- slow growth and with decreased susceptibility

- selection during the treatment

- difficult detection in the laboratory (phenotypic instability)

Resistance mechanisms associated with

thick cell wall

Glycopeptide hetero-resistance in staphylococci

MIC (mg/L) ≤ 1 1,5 2 4- 8 ≥16

SUSCEPTIBLE RESISTANT

hVISA VISA VRSA

Increased tolerance to glycopeptides

Slightly increment of daptomycin MICs but in

the susceptible range

Increment of therapeutic failure

Well documented in MRSA but less studied

in MSSA and CNS

EUCAST criteria:

MRSA in Spain: vancomycin MIC creep (Spain)

Cuevas et al. EIMC 2008; 26: 269-77

Multicentric studies VIRA study: MRSA

MIC

Year >1 mg/L

2001 6,5%

2004 20,8%

2006 30,9%

2008 16,9%

Picazo et al. EIMC 2006; 24:617-28

Picazo et al. DMID 2009; 64: 448-51

The mortality associated with bacteremia

due to MRSA was significantly higher

when and inadequate antibiotic was used

or when vancomycin MICs > 1 µg/ml

Soriano et al. Clin Infect Dis 2008; 46:193-200

Microbiology challenges in S. aureus

Methicillin resistant Staphylococcus aureus (MRSA)

Few clones has been responsible for the dissemination

of MRSA worldwide in the hospital setting

Occasionally integration of mecA gene within methicillin-

susceptible S. aureus

Emergence of specific clones in the community:

- associated with virulence traits (i.e. USA300 PVL +)

- amplification in the animal environment and latter

invasion of human setting (i.e. ST398)

Muti-resistance pattern

MRSA: new challenges?

MRSA in Denmark – pigs and farm workers

SARM: - 20% in pig farm workers

- 40% in pig samples from slaughter house

Association with ST398 (still infrequent in man)

- origin from SASM from pigs

- polymorphisms of SSCmec (more than one integration)

- associated with avoparcin discontinuation, tetracycline use

- ST398 also in Germany, Belgium, Spain, Italy …

- PVL (-) in MRSA from pigs, occasionally (+) in humans

humanos

Wulf & Voss. Clin Microbiol Infect 2008; 46:62-8

Otter & French. Lancet Infect Dis. 2010;10:227-39

van Loo et al. Emerg Infect Dis. 2007; 13:1834-9

New mec variants

SCCmec type XI,

- mecC (mecA LGA251)

Initially susceptible to non β-lactam antibiotics

Clonal complexes: CC130, CC1943, CC705, CC425 (bovine)

Detection in:

- UK, Denmark, Ireland, Germany (rural environment)

Zoonotic reservoir with transmission to humans

Problems in the detection in the laboratory

Shore AC, et al; AAC 2011; 55:3765

García-Alvarez L, et al; Lancet Infect. Dis. 2011; 11:595

Cuny C, et al. PLoS ONE 2011; 6:e24360

Stegger M, et al. Clin Microbiol Infect 2012; 18:395

Petersen et al. Clin Microbiol Infect. 2013;19:E16-22


Greece, 4 MRSA isolates with

increased values of ceftaroline

(4 mg/L)

- Reduced afinity for PBP2a

- Mutations in non-PBP domine

and transpepetidase

Jones et al. J Antimicrob Chemother 2011 66 (Suppl 3=:iii69-80

CMI (mg/L)

Nº

de a

isla

do

s







Enterobacter spp.

Rice. J Infect Dis 2008; 197:1079-81





ESBLs

Carbapenemasases

Enzymes able to hydrolyzed 3rd / 4rd gen. cephalosporins and

monobactams but not cephamycins or carbapenems

Inhibited by clavulanic acid (sulbactam y tazobactam)

Genetic determinants generally associated with plasmids

Associated co-resistance (aminoglyclosides, quinolones, …)

Health public concern

- high prevalence in E. coli in the community (≈8%)

- variable prevalence in K. pneumoniae (5-50%) (higher in hospitals)

- scarce prevalence in P. aeruginosa

Easy detection in the laboratory

Therapeutic options

- carbapenems

- β-lactams + β-lactamase inhbitors

- tygecycline, colistin

- fosfomycin, nitrofurantoin, ….

Extended spectum β-lactamases

ESBL producing Enterobacteriaceae in Europe

Resistance to 3rd gen cephalosporins (invasive isolates, 2010)

http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/database/Pages/map_reports.aspx

Escherichia coli Klebsiella pneumoniae

Hawser SP, Bouchillon SK, Hoban DJ, Badal RE, Cantón R,

Baquero F. Antimicrob Agents Chemother 2010; 54:3043-6

%

Intraabdominal infection (SMART study 2008)

ESBL – Klebsiella pneumoniae in Europe

Hoban et al. Diagnostic Microbiology Infectr Dis 2012; 74:62-7

%

Urinary tract isolates (SMART study 2009-2010)

CTX-M 65.5%

SHV 31.0%

TEM 1.7%

ESBL producing Enterobacteriaceae in Europe

Hawkey et al. JAC 2009; 64

World wide dissemination of CTX-M-15 enzymes

ESBL producing Enterobacteriaceae worlwide

Enzymes able to hydrolyzed carbapenems and with some

exceptions all β-lactams

Different families (KPC, MBL, OXA)

Genetic determinants generally associated with plasmids

Associated co-resistance (aminoglyclosides, quinolones, …)

Health public concern

- high prevalence in K. pneumoniae

- variable prevalence in different countries

- scarce prevalence in P. aeruginosa

Easy difficult detection in the laboratory

Few therapeutic options

- carbapenems (?)

- tygecycline, colistin

- fosfomycin, nitrofurantoin, ….

Acquired carbapenemases

Carbapenemase producing Enterobacteriaceae

Carbapenem resistance (invasive isolates, 2010)

http://www.ecdc.europa.eu/en/activities/surveillance/EARS-Net/database/Pages/map_reports.aspx

Escherichia coli Klebsiella pneumoniae

Simplified general classification, expression and organisms

MOLECULAR

CLASS ENZYMES

INHIBITION

(in vitro)

CARBAPENEM

RESISTANCE

(expression)

AZTREONAM MICROORGANISMS

A (Ser)

KPC

GES/IBC

Others

CLAV Heterogeneous R

Enterobacterias

(K. pneumoniae)

P. aeruginosa

B (Zn++)

METALO

VIM

IMP

NDM

EDTA

Heterogeneous

S P. aeruginosa

Enterobacteriaceae

D (Ser) OXA CLAV Low S A. baumannii

Enterobacteriaceae

Acquired carbapenemases

Microbiology challenges in ESKAPE infections

Endemic

Interregional spread

Regional spread

Independent hospital outbreaks

Single hospital outbreaks

Sporadic occurrence

Not reported / no data

KPC

VIM

NDM

OXA-48

Other countries:

Israel

Luxembourg

Spread of carbapenemases in Europe (update Feb-2012)

Canton et al. Clin Microbiol Infect 2012 (in press)

Modified from Nordmann et al. Emerging Infect Dis 2011; 17:1791-8

World wide dissemination of KPC-Enterobacteriaceae

?

Dissemination of KPC-Enterobacteriaceae in Europe

Modified from Nordmann et al. Emerging Infect Dis 2011; 17:1791-8

Cross border dissemination from initially endemic areas? Magiorakos et al. Risk assesment on the spread of carbapenemase

producing Enterobacteriaceae. ECDC. 2011

Cantón et al. Clin Microbiol Infect 2012; 18:413-31

? USA

Israel

?

Woodford N, et al. FEMS Microbiol Rev 2011;35 :736-55

Microbiology challenges in ESKAPE infections

K. pneumoniae population structure (eBurst analysis)

KPC

Rolain et al. Clin Microbiol Infect 2010;16:1699-701

Struelens et al. Eurosurveillance 2010; 15 18 nov

NDM-1


OXA-48 First identified in K. pneumoniae in Istanbul (Turkey) in 2003

Extensively reported as a source of K. pneumoniae nosocomial outbreaks

Well disseminated in the Mediterranean area and in western EU countries

(cross-border dissemination)

Nordmann et al. Emerging Infect Dis 2011; 17:1791- 8


Clonal and polyclonal

spread

Difficult detection unless in

isolates:

- coproducing an ESBL

- with porin deficiency

Carbapenemase producing Enterobacteriaceae in Europe

Acelerated increased in some countries: Belgium, France, …


Glupczynski et al. Int J Antimicrob Agents 2012; 39:168-72

Mainly in E.cloacae and

in K. pneumoniae

coproducing ESBLs

- CTX-M-9, -15

- SHV-11, SHV-76

OXA-48 producing Enterobacteriaceae in Europe

Current situation of carbapenemase producing

Enterobacteriaceae at the Ramón y Cajal University Hospital

Endemic

Interregional spread

Regional spread

Independent hospital outbreaks

Single hospital outbreaks

Sporadic occurrence

Not reported / no data

KPC

VIM

NDM

OXA-48

Other countries:

Israel

Luxembourg

Non-endemic country

- 608.810 habitants (10% of the population in Madrid)

- 1058 beds with 6 ICU (including 4 surgical ICU)

- reference hospital of Barajas airport in Madrid

Complex epidemiology


0

2

4

6

8

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12

14

16

MBL KPC OXA-48

Epidemiology situation at Hospital Ramón y Cajal, Madrid (Spain)

New cases per month

Data from Servicio de Micirobiología. Hospital Ramón y Cajal. May 2005- August 2012

KPC

VIM

OXA-48


Epidemiology situation at Hospital Ramón y Cajal, Madrid (Spain)

Clonal and polyclonal endemic situation of VIM-1 producers

since 2005 associated with IncI1, IncN and IncHI2 plasmids

- different species, mainly K. pneumoniae and E. cloacae

- dominance of ST39-K. pneumoniae, but also ST1, ST253, ST463, ST502

- presence of ST131 E. coli coproducing VIM-1 and CTX-M-15

Tato et al. Clin Infect Dis 2007; 45:1171-8; Gijón et al. J Clin Microbiol 2012; 50:1558-63

Ongoing polyclonal outbreak of KPC producers:

- KPC-3-K. pneumoniae clones different of the high-risk clone ST258

- different KPC-2 Enterobacteriaceae (K. pneumoniae, E. coli, and E. cloacae)

Curiao et al. J Antimicrob Chemother 2010; 65:1608-14. Ruiz-Garbajosa et al. (unpublished)

Recent out-burst of OXA-48 producing K. pneumoniae and

E. cloacae epidemics






Enterobacter spp.

Rice. J Infect Dis 2008; 197:1079-81





Increasing prevalence of MDR (ESKAPE) organisms in Europe

- co-selection proceses

- complex epidemiology (allodemia)

Emergence of new resistance mechanisms in Europe both in

Gram-positive and -negative organisms

- zoonotic origin (i.e. mecC variants in S. aureus)

- cross border transfer (i.e. carbapenemase-Enterobacteriaceae)

Dispersion of multi-drug resistance clones (high-risk clones)

within Europe

Concluding remarks

Multi-drug resistant organisms in Europe

Fernando Baquero

Rafael Cantón

Teresa M. Coque

Tania Curiao

Juan Carlos Galán

Desirèe Gijón

María Isabel Morosini

Ana Moreno

Patricia Ruiz Garbajosa

Marta Tato

Arancha Valverde

Comunidad de Madrid: CAM 2000-0049

Fondo de Investigaciones Sanitarias:

FIS PI 2043-2002; FIS 01/412

FIS 040162; REIPI C03/14, CIBER-ESP

Ministerio de Ciencia y Tecnología

SAF 2003-09285

European Commission

LSHM-CT-2003-503335; -CT-2008-223031

Fundación para la Investigación Biomédica

de Hospital Ramón y Cajal (FIBIO)

Fundación de Ciencias Microbianas (FCM)

Antonio Oliver,

Luisa Peixe, Angela Novais

Patrice Nordmann / Laurent Poirel

Johan Pitout

Ackwoledgements

RESISTANCE IN GRAM-NEGATIVE ORGANISMS:

STUDYING INTERVENTION STRATEGIES

The current status of multiple-

drug-resistant bacteria in Europe

Departamento de

Microbiología II

Universidad

Complutense. Madrid

Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

Dr. Rafael Cantón

24th Annual meeting of Japanese Society for Clinical Microbiolgy

Yokohama, Japan. 2nd and 3rd, February, 2013

http://www.ucm.es/info/farmacia/Farma3.htm

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