Continued emergence & identificationof multiresistant gram-negatives...

UK perspective

David LivermoreCentre for Infections Colindale, London

E. coli from blood & CSF

0

5

10

15

20

25

90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09

Cipro

3 gen ceph

both

% R

esis

tant

Cephalosporin resistance % Prevalence BSAC surveillance

0

4

8

12

16

20

24

02 03 04 05 06 07

Other/undefinedAmpCnon-CTX-M ESBLCTX-M

0

4

8

12

16

20

24

02 03 04 05 06 07

E. coli Klebsiella

Livermore DM et al., JAC 2008;62 Suppl 2:ii41-54.

PFGE: CTX-M +ve E. coliMost (including A-E) have

CTX-M-15 & OXA-1 +TEM-1, large related plasmids

5 major strains, A-E- All serotype O25- All phylogenetic group B2

Strain A- IS26 between blaCTX-M &

normal promoter; gent SOthers: diverse/small clusters

Woodford et al. 2004 JAC 54, 735

Strain A

Strains B-E

CTX-M-15 ST131 E. coliserotype O25: a global clone

Nicholas-Chanoine et al. JAC 2008, 61, 273Coque et al. EID 2008 14, 195Fox/Woodford JAC 2008 in press

ST131 includes our strains A-E

But O25:H4 ST131 doesn’t always have CTX-M-15

• CiproR, ESBL-ve ST131 in faecal flora of 7% of healthy Paris residents1

• CiproR, ESBL-ve ST131 in UTIs among renal transplant recipients in Galveston Texas2

• ST131 with CTX-M-14 in Canada3

• ST131 with CTX-M-9 in gut of Brown Rat, Germany4

Lefton-Guilbout et al., JCM 2008 46:3900; Johnson et al., AAC 2010, 54:546;Richardson et al., AAC 2010 epub;Guenther et al., JAC 2010, epub

Plasmids encoding CTX-M-15 β-lactamase in E. coli ST131

70 to 150 kb; IncFII; R100 backbone

Multi-resistance; variable transmissibility.

Mosaic structure but shared features in those from Canada, UK, France, Tunis, Banjul, Lebanon

e.g pEK516, (UK strain D) very similar to pC15-1a from Canada

pEK499 (UK strain A) = fusion of pEK516 & pRSB107

Boyd et al. AAC. 2004;48:3758-64Kanj et al CMI 2008;14:501-4. Lavollay et al., AAC. 2006;50:2433-8Woodford et al., AAC 2009; 53:4472

Classes Genes

Aminoglycosidesaac6’-Ib-cr

aadA5

β-LactamsblaCTX-M-15, blaOXA-1

blaTEM-1

Chloramphenicol catB4Macrolides mph(A)

Fluoroquinolones aac6’-Ib-cr

Sulphonamides sulI

Trimethoprim dhfrXVII

Tetracycline tet(A)

pEK499: the CTX-M-encoding plasmid of ST131 strain A

5 separate addiction systems

Woodford et al., AAC 2009; 53:4472

Hospital antibiotic sales (kg)IMS data

0

5000

10000

15000

20000

25000

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

CarbapenemsOxyimino cephsAmox clavPiptazFluoroquinolones

Belfast- nursing home survey, July 2005- May 2006, molecular

• Faeces from 336 residents @ 18 care homes cultured for ESBL +ve, cipro R E. coli

• 136 / 336 +ve (40%)---- 135/136 ST131• 76 x ST131 Strain A – CTX-M-15 coded by IncF11 plasmid pEK499

• 6 x ST131 Strain C – CTX-M-3 coded by IncI1 plasmid pEK204

• 29 ....belonging to 5 PFGE types...... pEK204-like plasmids

• 13 ......IncN plasmids coding CTX-M-3

• 12 .....IncFIA plasmids coding CTX-M-3 (n = 2) or M-15 (n =10)

Rooney et al. JAC. 2009;64:635-41 + Dhanji ICAAC 2009, C2-677

MICs (mg/L) for multi-resistant UK Klebsiella

Example 1 2 3 4Cefotaxime >64 >64 >64 >64Ceftazidime >64 >64 >64 >64PIP/TAZ >64 >64 >64 >64CTX/clav >32 >32 >32 >32CAZ/clav >32 >32 >32 16Cefoxitin >64 >64 >64 >64Ertapenem >16 >16 >16 >16Meropenem 8 16 16 4Imipenem 2 4 8 1

OMP Profile

S R R R R

Woodford et al., Int J Antimicrob Agents 2007; 29: 456.

Acquired carbapenemases

Class A – KPC, SME & NMC/IMI• KPC important; others very rare

Class B -IMP, VIM & NDM metallo β-lactamases• Diverse in sequence; similar in behaviour• Attack all β-lactams except aztreonam

Class D • OXA types: mostly Acinetobacter, but OXA-48 in Turkey

Carbapenemase-mediated resistance in the UK (n = 297)*

ARMRL, Unpublished data

Non-fermenters = 191

Enterobacteriaceae = 106

*excludes A. baumannii with OXA-types

Carbapenemase +ve Enterobacteria sent to ARMRL

NDM-1 >50% patients epidemiological link India

OXA-48 >75% renal unit o/break

VIM/KPC >50% imports from Greece, Cyprus, Israel

Carbapenem R K. pneumoniae from blood, 2008, EARSS

http://www.earss.rivm.nl

VIM-positive K. pneumoniae, Greece, 2001 onwards

• Mostly VIM-2, integron-borne on IncN plasmids

• Plasmid spread; not clone spread

• In 25 or 40 surveillance hospitals

• Most S to carbapenems at CLSI breakpoints

• If MIC >4 mg/L, 54% bacteraemia mortality, vs. 13% if MIC < 4 mg/L, vs. 10.7% among controls

• Extensively, but variably, cross resistant

Vatopoulos Eurosurv 2008, 13 pii 8023

NDM-1 metallo-β-lactamase

First reported Klebsiella & gut E. coli. Patient in Sweden, transferred from India (Yong et al., ICAAC)

2008-9; 29 cases in UK; 25 hospitals

• K. pneumoniae 21; E. coli 7, Enterobacter 5; others 9

• Mostly from urines- 3 from blood

• >11 with prior hospitalisation in India or Pakistan

• >17 with travel to India or Pakistan

• Two cases of likely cross infection in UK hospitals

Mostly resistant to everything except colistin & tigecycline

2008-929 patients, 25 hospitals

21x K. pneumoniae7x E. coli2x C. freundii5x Enterobacter spp.1x M. morganii1x Providencia sp.(5x A. baumannii)

17 of first 29 patients had travel / hospital links with India or Pakistan

Enterobacteriaceae with NDM-1 carbapenemase in the UK

13th August 2009

NDM-producing Enterobacteriaceae in the UK: geom mean MICs (mg/L)

K. pneumoniae

(n = 17)

E. coli

(n = 5)

IPM 57 51IPM + EDTA 0.5 0.5

MEM 28 27ETP >16 >16ATM 51 >64CTX 241 >256CAZ 245 >256CPR >64 >64TZP >64 >64

K. pneumoniae

(n = 17)

E. coli

(n = 5)

Cipro 7 >8GEN 30 >32TOB 31 >32AMK 61 >64MIN 15 18TIG 1.7 0.4COL 1.2 0.7

a) β-lactams b) Non-β-lactams

Reason for overseas admissions: NDM cases

Renal Transplant, Pakistan 4Cerebral infarction 1COPD 1Cosmetic Surgery (tummy tuck) 1Pregnancy 1Bone Marrow transplant 1Dialysis 1Road Traffic Accident & subsequent surgery 1Unwell 1UTI, nephrectomy, Stent 1

Total 13

Spread of NDM-1 fromIndia/Pakistan to the UK

blaNDM-1-positive bacterial clones?

MDR plasmids?

NDM +ve K. pneumoniae in the UK are diverse

100

50

M-16

M-16

M-14

M-18

M-7

M-11

M-25

M-24

M-2

M-15

M-1

M-1

M-8

M-22

M-19

M-23

M-9

M-10

K

P

I

A

D

H

O

N

A

J

B

C

E

M

L

L

F

GCross-infection ?

Cross-infection ?

Mobile patients provide a random sampling of strains

circulating in India & Pakistan

Spread of NDM-carrying resistance element in vivo ?

blaNDM gene is on diverse plasmids

S1 nuclease digest hybridized with blaNDM

Courtesy, Mark Toleman

• Patient 1; NDM +ve K. pneumoniae, M. morganii• Patient 2: NDM +ve E. coli, Enterobacter, Providencia

Increasing plasmid size

KPC by 2009…..

IsraelOutbreak Klebsiella& Diverse E. coli

Clonal Klebsiellaacross USA

Isolated reports: France, Sweden & UK

China- few reports: K. pneumoniae & Serratia

Colombia Disseminated inK. pneumoniae & P. aeruginosa

Greece- clonalspread ofproducer K. pneumoniae

ST258 clone with KPC-3 …spreading worldwideUSA -10 states out of 19 with KPC, Israel.....

imports to Scandinavia & UKR to all except gentamicin, tigecycline & colistin

2003-4:KPC-4 in Enterobacter

1 patient, Scotland….

No overseas link

2007-9:18 K. pneumoniae, KPC-2 / -3

1 Enterobacter sp.

19 patients in 16 hospitals

Includes imports from Greece, Israel & Curacao– others no overseas link…

Enterobacteriaceae with KPC carbapenemases in the UK

KPC K. pneumoniae in the UK

ST258

ST11

KPC-producing K. pneumoniae in the UK: mean MICs (mg/L)

ST258

(n = 10)

ST11

(n = 2)

Unique

(n = 1)Imipenem 45 8 >128Meropenem >32 8 >32Ertapenem >16 >16 >16Aztreonam >64 >64 >64Cefotaxime 128 181 128…+ clav 26 4 32Ceftazidime >256 16 32…+ clav 32 4 32Piptaz >64 >64 >64

KPC K. pneumoniae UK: Geom. mean MICs (mg/L): non β-lactams

ST258

(n = 10)

ST11

(n = 2)

Unique

(n = 1)Ciprofloxacin >8 >8 ≤ 0.125Gentamicin 1.4 4 0.5Tobramycin 30 16 1Amikacin 21 0.7 1Minocycline 17 23 4Tigecycline 1.7 2 1Colistin 0.7 0.5 ≤ 0.5

OXA-48 carbapenemase

Mostly K. pneumoniae, but also E. coli in TurkeyMajor clonal outbreaks in Istanbul

Widely scattered across country

>20 cases in UK: K. pneumoniae

2009 ICAACIndia, Lebanon, Egypt, Argentina…..

Carrer et al., AAC 2008 ;52 :2950-4Glumez et al., IJAA 2008;31:523-6

2007:

1 patient, RTA ex-Turkey

2008-9:

25 K. pneumoniae

17 patients in 7 hospitals

Include: - 1 ‘import’, RTA ex-Morocco- 12-patient outbreak, London

K. pneumoniae with OXA-48 carbapenemase in the UK

Outbreak strain(ST353)

OXA-48-producing K. pneumoniae in the UK

OXA-48-producing K. pneumoniae(London): mean MICs (mg/L)

Outbreak strain

(n = 11)

Other

(n = 4)

IPM 21 50IPM + EDTA 7 9

MEM 9 18ETP 11 10ATM 0.4 64CTX 2.9 >256

CTX + clav 2.4 17CAZ 0.7 120

CAZ + clav 0.5 9.7CPR 5.1 >64TZP >64 >64

Outbreak strain

(n = 11)

Other

(n = 4)

CIP 4.2 7GEN 0.6 8.7TOB 0.9 22AMK 2 6.5MIN 10.3 13.5TIG 1 1.2COL 0.7 0.9

a) β-Lactams b) Non-β-lactams

Interesting times…• E. coli with ESBLs and quinolone resistance

• Endemic.... but maybe declining

• Decline may reflect changed antibiotic use

• Emerging carbapenemases.... NDM, VIM, KPC, OXA

• Many are imported.... vigilance for infection control

• UK NOT an island when it comes to resistance