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Controversias en PROA y en la

lucha contra las IRAS y las

resistencias

Resistencia a los

antibióticos en España:

¿qué es lo que nos debe

preocupar más?

Departamento de

Microbiología II

Universidad

Complutense. Madrid

Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

Dr. Rafael Cantón

1 de diciembre de 2017

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

Agradecimientos

http://www.eucast.org/

▪ Elevado consumo de antimicrobianos

▪ Altas tasas de resistencia y tendencia

a su mayor aumento

▪ ¿Resistencias ocultas?

▪ Resistencia a nuevos antibióticos

▪Herramientas poco adecuadas en el

estudio de sensibilidad

Resistencias: ¿qué nos debe preocupar?

Laxminarayan et al. Science 2016; 10.1126/science.aaf9286

Países con mayor consumo de antimicrobianos, 2014

(datos de IMS Health MIDAS)



▪ Elevado consumo de antimicrobianos (2016) en la comunicad en

comparación con otros países con aumento en los últimos años (2012-16)

ECDC. Summary of the latest data on antibiotic consumption in the EU. ESAC-Net surveillance data. Nov 2017

Consumption of

antibiotics for

systemic use in the

community, EU/EEA

countries, 2016

(expressed as DDD/

1000 inhabitants/day)



Consumption of

antibiotics for

systemic use in the

community by

antibiotic group,

EU/EEA countries,

2016 (at ATC group

level 3, expressed

as DDD/1.000

inhabitants/day)

(b) Spain provided reimbursement data (i.e. not

including consumption without a prescription

or other non-reimbursed courses)


▪ Ausencia de datos de consumo de antimicrobianos agregados en los

hospitales españoles en informes del ECDC


Consumption of

antibiotics for

systemic use in

the hospital

sector, EU/EEA

countries, 2016

(expressed as

DDD/1000

inhabitants/day)

Point prevalence survey of healthcare associated infections and antimicrobial use

in European acute care hospitals. 2011-12. Stockholm: ECDC; 2013

Carbapenem use in EU (2011-12)


Tigecycline/colistin use in EU (2011-12)

Sales of colistin for use in food producing animals in 2014 (in mg/PCU), including the 5 and 1 mg/PCU levels

Updated advice on the use of colistin products in animals within the European Union: development

of resistance and possible impact on human and animal health EMA/CVMP/CHMP/231573/2016

PCU: population correction unit,

1 PCU: 1 kg animal




a su mayor aumento






GLOBAL PRIORITY LIST OF ANTIBIOTIC-RESISTANT BACTERIA TO GUIDE RESEARCH, DISCOVERY, AND DEVELOPMENT OF NEW ANTIBIOTICS

Tacconelli and Magrini, 25 Feb 2017

▪ Previous pathogen list issued by the

CDC1 and the Public Health Agency

of Canada2

▪ Guided by pharma companies

according to perceived/unmet

medical need, pressure of

investors, market size, scientific

discovery potential, and availability

of specific technologies

▪ Issued to guide prioritization of

funding and incentives, aling R&D

priorities and coordination in the

fight against antimicrobial resistant

bacteria1CDC, Antibiotic Resistance Threats in the United States, 2013; Disponible en:

http://www.cdc.gov/drugresistance/threat-report-2013/.2Garner MJ. et al. An Assessment of Antimicrobial Resistant Disease Threats in

Canada. PLoS ONE 2015; 10(4): e0125155. Doi:10.1371/journal.pone.0125155.

Disponible en: http://www.who.int/medicines/publications/WHO-PPL-

Short_Summary_25Feb-ET_NM_WHO.pdf?ua=1

3rd generation cephalosporin resistance in Europe

(invasive isolates, EARS-net 2016)

Escherichia coli Klebsiella pneumoniae

ECDC. Antimicrobial resistance surveillance in Europe 2016. Annual Report of the European

Antimicrobial Resistance Surveillance Network (EARS-Net). Stockholm: ECDC; 2017

22.3%

3rd gen. cephalosporin resistance in Spain

(invasive isolates, EARS-net)

15,0%

E. coli

K. pneumoniae

Gráficos extraídos de: ECDC. Surveillance Atlas of Infectious Disease. 2016. Disponible en: http://atlas.ecdc.europa.eu/public/index.aspx

http://atlas.ecdc.europa.eu/public/index.aspx

0

2

4

6

8

10

12

14

16

18

20

2000 2002 2004 2006 2008 2010 2012 2014 2016

% a

isla

do

s

Años

E. coli K.neumoniae

SMART Spain (2002 – 2015)

Evolution of E. coli and K. pneumoniae ESBL producers*

Actualizado de Cantón et al. Rev Esp Quimiother 2011; 24:223-32

0

10

20

30

40

50

60

70

80

90

100

AUG P/T CTX CAZ CPE IMP ETP AK CIP

non-ESBL 2002-2010

non ESBL 2011-2015

ESBL 2002-2010

ESBL 2011-2015

% of susceptible E. coli isolates with and without ESBLs

Updated information from Cantón et al. Rev Esp Quimiother 2011; 24:223-32

SMART España (2002 – 2015)

SMART España (2002 – 2015)

0

10

20

30

40

50

60

70

80

90

100

AUG P/T CTX CAZ CPE IMP ETP AK CIP

non-ESBL 2002-2010

non-ESBL 2011-2015

ESBL 2002-2015

ESBL 2011-2015

Actualizado de Cantón et al. Rev Esp Quimiother 2011; 24:223-32

¿Carbapenemases?

% of susceptible K. pnuemoniae isolates with and without ESBLs

Enterobacterias productoras de carbapenemasas (EPCs)

▪Carbapenemasas: Grupo heterogéneo de enzimas que

hidrolizan carbapenems y, en general, otros β-lactámicos

▪ Clase A KPC, …

▪ Clase B VIM, IMP, NDM, …

▪ Clase D OXA-48

Diferente epidemiología

Expresión variable (detección compleja)

Limitaciones terapéuticas

Manejo del paciente colonizado

Escherichia coli Klebsiella pneumoniae

Carbapenem resistance in Europe

(invasive isolates, EARS-net 2016)



Carbapenem resistance in Spain

(invasive isolates, EARS-net)

3.8%

0.1%E. coli

K. pneumoniae

Gráficos extraídos de: ECDC. Surveillance Atlas of Infectious Disease. 2016. Disponible en: http://atlas.ecdc.europa.eu/public/index.aspx


▪ 2003 Detection of sporadic cases in Barcelona (VIM)Tórtola et al. AAC 2005; 49:3492-4

▪ 2005-09 Outbreaks in different hospitals in Madrid area (VIM and

KPC) with no associated travel history Tato et al. CID 2007; 45:1171-8; Curiao et al. JAC 2010; 65:1608-14

Sánchez-Romero et al. AAC 2012; 56:420-7

▪ 2009 Demonstration of a very low prevalence (mainly VIM) in a

national multicenter study (VIM)Miró et al. EJCMID 2013; 32:253-9

▪ 2010 Detection of imported cases: sporadic cases (NDM) and

important hospital outbreaks (OXA-48) Struelens et al. Euro Surveill 2010; 15:pii:19716; Sole et al. AAC 2011; 55:4402-4

▪ 2011-13 Extrahospitalary cases with no previous sanitary contact Gijón et al. JCM 2012; 50:1558-63

Local outbreaks and dispersion in different areas (OXA-48)Paño-Pardo JAC 2013; 68:89-96; Oteo et al. JAC 2013; 68:317-21

Oteo et al . AAC 2013 ; 57:6344-7

▪ 2017Increase of complexity

Carbapenemase producing Enterobacteriaceae – Spain

Carbapenemase producing Enterobacteriaceae – Europe

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

Cantón et al. Clin

Microbiol Infect 2012;

18:413-31

February, 2012

March, 2013

Glasner et al. Euro

Surveillance

2013 ; 18(28) doi:pii: 20525

CPE: enzyme distribution in Europe: 2015

Albiger et al. Carbapenemase-producing Enterobacteriaceae in Europe: assessment

by national experts from 38 countries, May 2015 (EUSCAPE Project)

KPC

OXA-48 NDM

VIM

Anual evolution of E. coli with carbapenemases

Towards an endemic

situation similar to

that of CTX-M ESBLs?

Hospital No. of

specimens

CPE

(%)

Carbapenemase type

KPC NDM VIM OXA-48 Other

MBL

CHUAC 3088 60 (1.9) 0 0 0 60 0

HCB 1593 28 (1.7) 0 1 0 27 0

HURS 814 15 (1.8) 10 0 0 4 1

HULP 3700 38 (1.0) 0 0 7 31 0

HURyC 2631 48 (1.8) 3 1 2 42 0

Total 11826 189 (1.6) 13 2 9 164 1

169 K. pneumoniae; 9 E. coli; 6 E. cloacae; 4 S. marcescens; 3 K. oxytoca; 1 E. aerogenes

García-Castillo et al. SEIMC 2017. Málaga. Abstract 901

Prevalence of CPE in urine specimens

(iCREST study*, Spain)

*octubre 2016 – enero 2017

Carbapenem and colistin resistance in K. pneumoniae

in Europe (invasive isolates, EARS-net 2016)

ECDC. Summary of the latest data on antibiotic resistance in the EU.

EARS-Net surveillance data November 2017

Colistin resistance in CPE

Chromosomal colistin resistance epidemics

Poirel et al. Clin Microbiol Rev. 2017; 30:557-96

▪ 21 hospitals across Italy. November 2013 to April 2014, EuSCAPE

▪ Consecutive non-replicatecarbapenem non-susceptible Enterobacteriaceae

clinical isolates (n=191)

- 93% (n=178) KPC producers

- 82% (n=146) trimethoprim-sulfamethoxazole-R+I

- 43% (n=76) colistin-R

- 16% (n=29) gentamicin-R+I

- 6% (n=11) tigecyclin-R+I

Multidrug resistant K. pneumoniae

▪ KPC-producing K pneumoniae isolates

increasingly spreading in Spain, mainly

due to the non-ST258 high-risk clones:

- ST11/KPC-2

- ST101/KPC-2 (highly R, hypervirulent)

- ST512/KPC-3 (colistin-R due to a 11 bp

deletion in mgrB gene)

▪ Similar clones than those spreading in

Italy

mcr-1 worldwide

Marston et al. JAMA 2016; 316:1193-1204

Eurosurveillance , 31 March 2016

Euro Surveill. 2017 Aug 3;22(31)

Eurosurveillance; 28 April 2016

mcr-1 gene can be also present in

colistin-susceptible E. coli isolates

mcr-1-(+) isolates

Colistin MIC distribution (EUCAST database)

Antimicrobial resistance in P. aeruginosa(invasive isolates, EARS-net, 2016)

Ceftazidime

Carbapenems



% of invasive isolates with combined resistance to ≥3 antimicrobials* in 2016 (*piper/tazob, ceftazidime, fluoroquinolones, aminoglycosides and/or carbapenems)

Antimicrobial resistance in P. aeruginosa(invasive isolates, EARS-net, 2016)



0

2

4

6

8

10

12

14

16

2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

% of isolates

Antimicrobial resistance in P. aeruginosa(invasive isolates, Spain EARS-net)

% of invasive isolates with combined resistance* to ≥3 antimicrobials (*piper/tazob, ceftazidime, fluoroquinolones, aminoglycosides and/or carbapenems)




a su mayor aumento






0

2

4

6

8

10

12

14

16

18

1983-1987 1988-1992 1993-1997 1998-2002 2003-2007 2008-2012 2013-2017

nu

mb

er

of

ne

w a

nti

mic

roib

ials

Years

Update information from Spielberg, et al. Clin Infect Dis. 2004;3 1: 1279-86

Ceftobiprole (2013)

Telavancina (2014)

Dalbavancina (2015)

Tedizolid (2015)

Oritavancina (2015)

Ceftolozano-tazobactam (2015)

Ceftazidima-avibactam (2016)

Delafloxacina (2017)

Meropenem-vaborbactam (2017)

Nuevos antibacterianos aprobados (FDA y/o EMA)

Ceftaroline (2010)

Fidaxomicin (2012)

En proceso de autorización:

Plazomicina, eravaciclina, imipenem-relebactam, cefepime-tazobactam, aztreonam-avibactam,

cefidericol, fosfomicina (ZTI-01)…

Antibacterials recently approved (FDA or EMA)

Antibacterial drug Approved for Other indications

Ceftaroline CABP, ABSSSI (incl. MRSA)

Fidaxomicin CDI

Telavancin NP due to S. aureus (limited to MRSA in EU) ABSSSI

Dalbavacin ABSSSI CABP, osteomyelitis

Oritavancin ABSSSI due to Gram-(+)s including MRSA

Tedizolid ABSSSI NP

Ceftobiprol HABP (not VABP), CABP

Ceftolozane-tazobactam cUTI (incl. acute pyelonephritis), cIAI

(+ metronidazole)

HABP, VABP

Ceftazidime-avibactam cUTI (incl. acute pyelonephritis), cIAI

(+metronidazole), HABP incl. VABP, multi-R

Delafloxacin cUTI (incl. acute pyelonephritis) ABSSSI

Meropenem-vaborbactam cUTI (incl. acute pyelonephritis) cIAI, HABP, VABP, …

ABSSSI: acute bacterial skin and soft tissue infections; cIAI: complicated intraabdominal infecions; CDI: C. difficile

infection, cUTI: complicated urinary tract infections; CABP: community acquired bacterial pneumonia; HABP: hospital

acquired bacterial pneumonia; NP: nosocomia pneumonia; VABP: ventilator associated bacterial pneumonia


Emergence of ceftolozane-tazobactam (TZC) resistance in P. aeruginosa

▪ In-vitro selection of TZC resistance requires multiple mutations leading

to over expression and structural modifications of AmpC

Cabot et al. AAC 2014; 58:3091-9

▪ In-vivo emergence of TZC resistance in TZC treated patients

MacVane et al. AAC 2017; 61: e01183-17; Fraile-Ribot et al, AAC 2017; 61(9). pii: e01117-17Fraile-Ribot et al. JAC 2017; Nov 14 [Epub ahead of print]

AmpC-high (new mutations/

deletion) + OprD low

CAZ: 16-32 mg/L

IMP: 16 mg/L

TZC: 32->32 mg/L

OXA-14 / OXA-53, OprD-low

CAZ: >64 mg/L

IMP: 16 mg/L

TZC: 32 mg/L

WT

CAZ: 2 mg/L

IMP: 1 mg/L

TZC: 0.5 mg/L

AmpC-high +

OprD-low

CAZ: 16-32 mg/L

IMP: 16 mg/L

TZC: 2 mg/L

OXA-2 / OXA-10

CAZ: 2 mg/L

IMP: 2 mg/L

TZC: 4 mg/L


Emergence of ceftolozane-tazobactam resistance in P. aeruginosa

▪ From isolates with previous hyperproduction of AmpC (ceftazidme

resistance) and porin OprD deficiency (carbapenem resistance)

▪ From isolates with classical acquired β-lactamases (OXA-2 / OXA-10)

widely present in P. aeruginosa

▪ Affecting high-risk clones (i.e. ST175)

▪ In all cases causes resistance to cefazidime-avibactam but might

decrease imipenem and piper.-tazobactam MICs (not in OXA-variants)

Cabot et al. AAC 2014; 58:3091-9; MacVane et al. AAC 2017; 61: e01183-17; Fraile-Ribot et al, AAC 2017; 61(9). pii: e01117-17; Fraile-Ribot et al. JAC 2017; Nov 14 [Epub ahead of print]

2015; 59:5324-30

▪ MIC increase from 2-4 mg/L

to 32->256 mg/L in isolates

from three patients (8%, 3/37)

• Patients with resistant isolates

were treated during 15 days

(range 10-19 days)

▪ Mutations in the bla sequence

after ceftazidime-avibactam

exposure



Emergence of ceftazidime-avibactam resistance in Enteobacteriaceae

▪ Overexpression of extended-spectrum AmpC (ESAC) in E. cloacaeLahiri et al. JAC 2014; 69:2942-6

▪ KPC-K. pneumoniae with multiple resistance mechanisms:

- KPC-3 overexpression plus porin deficiency (OmpK35/OmpK36),

and SHV-12 and enhance efflux activity (AcrAB)Nelson et al. AAC 2017; 61:e00989-17; Humphries et al. AAC 2017; 61:e00537-17

- Doble or triple blaKPC-3 mutationsShields et al, AAAC 2017; 61: e02097-16; Haidar et al. AAC 2017;e02534-16

Lahiri et al. AAC 2017; 61:e00079-17

- blaKPC-2 mutationsCompain et al. AAC 2017; 61:e00451-17

▪ Increase hydrolitic activity of bla CTX-M-14 variantsBoth et al.J Antmicrob Chemother 2017; 72: 2483–8

▪ Restoration of carbapenem susceptibility, expression as an ESBL



a su mayor aumento






J Clin Microbiol 2017; 55:344-5

Tendency to report R as S (VME)


S I R EA CA VME ME mE

BMD 65

(90.3)

1

(1.4)

6

(8.3)

- - - - -

Etest 64

(88.9)

2

(1.4)

6

(8.3)

57/72

(79.2)

69/72

(95.8)

0

(0.0)

0

(0.0)

3/72

(4.2)

Disk 63

(87.5)

3

(4.2)

6

(8.3)

- 68/72

(75.7)

0

(0.0)

0

(0.0)

4/72

(5.5)

CLSI criteria: S≤ 4/4 mg/L; I: 8/4 mg/L; R≥16/4 mg/L

EA: essential agreement; CA: categorical agreement

VME: very major errors; ME: major errors; mE: minor errors

▪ Essential and categorical agreement between BMD and Etest or

disk diffusion susceptibility testing methods for ceftolozane-

tazobactam with 72 carbapenem-resistant P. aeruginosa

Shields et al. J Clin Microbiol 2017; 22 Nov [Epub ahead of print]


Ceftolozano – tazobactam

sensible

Pseudomonas aeruginosa

Ceftolozano – tazobactam

Resistentes

Dra. MI. Morosni


S I R EA CA VME ME mE

BMD 61

(81.4)

-

-

13

(18.6)

- - - - -

Etest 63

(85.1)

-

-

11

(14.9)

66/74

(89.2)

72/74

(97.3)

2/13

(15.4)

0

(0.0)

-

Disk 43

(81.1)

14

(18.9)

- 56/74

(75.7)

0

(0.0)

18/59

(30.5)

-

CLSI criteria: S≤ 8/4 mg/L; R≥16/4 mg/L

EA: essential agreement; CA: categorical agreement

VME: very major errors; ME: major errors; mE: minor errors

▪ Essential and categorical agreement between BMD and Etest or

disk diffusion susceptibility testing methods for ceftazidime-

avibactam with 74 carbapenemase-producing Enterobacteriaceae

Shields et al. J Clin Microbiol 2017; 22 Nov [Epub ahead of print]



a su mayor aumento






Controversias en PROA y en la

lucha contra las IRAS y las

resistencias

Resistencia a los

antibióticos en España:

¿qué es lo que nos debe

preocupar más?

Departamento de

Microbiología II

Universidad

Complutense. Madrid

Hospital Universitario Ramón y CajalSERVICIO DE MICROBIOLOGÍA Y PARASITOLOGÍA

Dr. Rafael Cantón

1 de diciembre de 2017

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

Dr. Rafael Cantón Volver a la Página Inicial · Departamento de Microbiología II Universidad...

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