What’s happening now ? Epidemiology of (carbapenem) resistance

Neil WoodfordHPA – AMRHAI - Colindale

The resistance ratchet keeps turning

Pathogen Established problems Emerging threatsE. faecium VRE, HLGR, Amp-R Lin-R, Dap-R, Tig-R

S. aureus MRSA (ha/ca) Van-R, Lin-R, Dap-R

Klebsiella ESBLs Carbapenemases, Col-R

Acinetobacter MDR, Carbapenemases Tig-R, Col-R

Pseudomonas MDR, except Col Carbapenemases, Col-R

Enterobacter AmpC, ESBLs Carba-R, CarbapenemasesE. coli Cip-R, ESBLs Carbapenemases

• 5 of 7 ESKAPEEs are Gram-negative• Increasing reliance on carbapenems• Rising incidence of carbapenem resistance• The resistance issue for the next 5-10 years

E. coli from blood & CSF in the UK- a recent fall in resistance

% R

esis

tant

Hospital antibiotic sales (kg)IMS data

1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 20090

5000

10000

15000

20000

25000CarbapenemsOxyimino cephsAmox clavPiptazFluoroquinolones

• use of pip/taz, co-amoxiclav (& carbapenems)• new selective pressures ..., but what consequences ?

Carbapenem non-susceptibility, 2011 (Ears-Net)

K. pneumoniae• <1.5% non-susceptibility in E. coli as judged by surveys• 3 countries reported >5% non-susceptibility in K. pneumoniae

E. coli

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

...a worsening picture

Canton et al, CMI 2012

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

29.6%

70.8%

Carbapenemase-producing Enterobacteriaceae in the UK (n = 1802)

AMRHAI, Unpublished data

Early cases often imported

Imported & ‘home grown’

Klebsiella spp. 79%; E. coli 12%, Enterobacter spp., 7%; others 2%

AMRHAI, Unpublished data

More labs are isolating ‘CPE’ in the UK

133 labs referred at least one isolate, 2003-2012

Regional distribution of ‘CPE’ referrals, 2003-2012KPC NDM

VIMOXA-48

AMRHAI, Unpublished data

No denominators.

Not mandatory = no tru

e sense of ascertainment.

Need national surveillance.

Why isn’t ‘ST258’ K. pneumoniae a bigger problem in the UK?

13

1

7

2

3

1

4

2

31

0

• The dominant KPC +ve lineage internationally• Several related STs• Endemic in many parts of US, most of Greece• Caused a nationwide outbreak in Israel• Rapid, nationwide spread in Italy

• First detected in UK in 2007

• Ongoing NIHR study (non-NW isolates)• 65/108 tested = ‘ST258 complex’• 42/82 ‘MLST-ed’ isolates are classic ST258• 8/82 are its SLV, ST512• ≥1 isolate in most UK regions, …but over 6 years

• Why not (yet) a major problem in the UK ?

Findlay et al., Unpublished data

2 SNPs

2 SNPs

3 SNPs

3 SNPs

1 SNPs

pKpQIL-D1

pKpQIL-D2

1 SNPs

Highly-related IncFII plasmids are spreading KPC in NW England

Doumith et al., Unpublished data

Non-fermenters with metallo-carbapenemases in the UK (n = 393)

AMRHAI, Unpublished data

Number

P. aeruginosaAcinetobacterPseudomonas spp.

More labs are isolating MBL +ve non-fermenters in the UK

AMRHAI, Unpublished data

98 labs referred at least one isolate, 2000-2012

VIM +ve Pseudomonas, 2003-2012

VNTR analysis of MBL-producing P. aeruginosa

• 6 groups account for 85% (251/297) of MBL- positive isolates

• 25 ‘types’ in remaining 15%

• do widely occurring strains represent true spread or just prevalence ?

• horizontal spread of MBL genes

Wright et al., Unpublished data

ST11190 isolates,

28 labs

ST23558 isolates,

28 labs

ST23335 isolates,

16 labs

ST65431 isolates,

13 labs

ST77321 isolates,

12 labs

ST35716 isolates,

8 labs

Advice on treatment when multi-resistance is the norm

HPR, 2011; 5: issue 24 (17/06/11; Woodford & Livermore)

Metallo-enzyme Producers (IMP, NDM or VIM)

≥90%

Activity of colistin in vitro, carbapenemase +ve vs. -ve

0.125 0.25 0.5 1 2 4 8 16 320

20

40

60

80

+-

0.125 0.25 0.5 1 2 4 8 16 320

20

40

60

80

+-

0.125 0.25 0.5 1 2 4 8 16 320

20

40

60

80

+-

% is

olat

es

AMRHAI, Unpublished data

E. coli 1-2% Col-R

Klebsiella 5-6% Col-R

Enterobacter 5-6% Col-R

MIC, mg/L

Containing multi-resistant bacteria: the critical triangle

Multi-disciplinary approach to limit risk and impact

• microbiology • surveillance • infection prevention and

control• diagnostics • drug development• diagnostic / reference /

R&D / industrial partnerships

Rapid Detection

Effective IPC

Effective treatment

Outbreaks contained

Containing multi-resistant bacteria: the critical triangle

Multi-disciplinary approach to limit risk and impact

• microbiology • surveillance • infection prevention and

control• diagnostics • drug development• diagnostic / reference /

R&D / industrial partnerships

Rapid Detection

Effective IPC

Outbreaks contained

Effective treatment

‘Resistance’ threatens the UK and the NHS every day

Colonized residents or visitors

Non-human reservoirs: animals

and environment

Victims from conflict zones

Hospital treatment ortravel overseas

• Multiple risks to be assessed to minimize damage• Requires the detail to be understood

• Continuous education of NHS staff at all levels

Inter-hospital transfers (UK)

Non-human reservoirs: foodstuffs (domestic or imported)

Multi-pronged attack on resistance

• Better intelligence (improved global surveillance initiatives)• Identify global hot spots / high risk patients• Inform damage limitation strategies...

• Faster and more accurate diagnostics

• Better infection prevention and control (public health)

• More effective therapies (individuals)• Now...rational antibiotic use (right drug, right time, right regimen)• Future...a pipeline of new agents to overcome current problems

Training Opportunities

21st March - Carbapenem resistance: how should we respond? (MIC Centre, Euston)

20th May – “A Crash Course on Carbapenem Resistance”

(Colindale; pilot ½-day course for Greater London)