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