Antimicrobial Resistance: A Growing Concern for HealthcareSecurity and Resilience

Neil WoodfordHPA – AMRHAI - Colindale

Resistance is entirely natural ...and is ancient

Permafrost samples

Late Pleistocene (30,000 y)

DNA recovered from extinct megafauna

+ resistance genes• tet(M) – tetracyclines• blaTEM – penicillins• vanHAX - glycopeptides

D’Costa et al. Nature 2011

Resistance genes through the millenia

Genes have flowed through ecological niches, ‘without’selective pressure (from us)

from species to species,

eventually reaching an isolate that was subject to susceptibility testing = resistance ‘discovery’

1960s: blaTEM-1 in E. coli

2008: blaNDM in K. pneumoniae

Stokes & Gillings, FEMS Microbiol Rev, 2011

We chose to pick a fight with evolution

“Now, here, you see, it takes all the running you can do, to keep in the same place."

Silver Clin Microbiol Rev 2011; 24:71-109

The resistance mantra:

↑ antibiotic use = ↑ selective pressure = ↑ resistant isolates

Resistant bacteria can be found everywhere ..., but the public health impact varies

Any use of antibiotics will select resistant bacteria

Resistant bacterium in a population

Susceptible bacteria killed by antibiotics;resistant bacterium

has advantage

Resistant bacterium survives to reproduce I have called this principle, by which each

slight variation, if useful, is preserved, “Natural Selection”

Bacteria carry resistance in their DNA

mutations in chromosomal DNA can cause resistance e.g. M. tuberculosis

..., but many bacteria also have extra DNA in rings, known as plasmids e.g. E. coli• plasmids can also carry resistance

Antibiotic classes Genes Mechanism

Aminoglycosidesaac6’-Ib-cr

aadA5Modify drug

β-lactams

blaCTX-M-15

blaOXA-1

blaTEM-1

Destroy drug

Chloramphenicol catB4 Modify drug

Macrolides mph(A) Efflux

Fluoroquinolones aac6’-Ib-cr Modify drug

Sulfonamides sulI By-pass

Trimethoprim dhfrXVII By-pass

Tetracycline tet(A) Efflux

Plasmids help to spread resistance to many antibiotics in neat genetic packages

Woodford, Carattoli et al. AAC

www.biotoon.com

…and they don’t keep resistance plasmids to themselves

Why worry about resistance ?

Schwaber & Carmeli, JAC 2007; 60: 913

Mortality Delayed appropriate Rx

The ‘forensics’ of antibiotic resistance

• Resistance involves- emergence of mutations- spread of resistance genes- spread of resistant strains of bacteria

• Tracking and characterizing- the resistant strains: in hospitals, the community and non-human

reservoirs- their resistance genes

Assessing Public Health risk when the biogeography / ecology of resistance is so complex

Stokes & Gillings, FEMS Microbiol Rev, 2011• 5 UK regions: study contemporaneous

ESBL +ve E. coli from blood, routine diagnostic stool samples, sewage, raw

meat, farm slurry

The resistance ratchet keeps turning

Pathogen Established problems Emerging threatsE. faecium VRE, HLGR, Amp-R Lin-R, Dap-R, Tig-RS. aureus MRSA (ha/ca) Van-R, Lin-R, Dap-RKlebsiella ESBLs Carbapenemases, Col-RAcinetobacter MDR, Carbapenemases Tig-R, Col-RPseudomonas MDR, except Col Carbapenemases, Col-REnterobacter 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

Reasons for the spread of resistance

ESBLs CarbapenemasesSuccessful host strains / clones +++ +++Successful plasmids +++ +++Community reservoirs (human) +++ +

International human travel +++ +++Animal reservoirs +++ +/- (?)Food chain + - (?)

• Multifactorial; highly complex; diverse

• Generalizations are overly simplistic

• Country-to-country variation in relative importance

ESBL+ve isolates, Asia-Pacific 2007; intra-abdominal infection

Hawser et al., AAC 2009; 53: 3280

3rd-gen cephalosporin non-susceptibility, 2010 (Ears-Net)

• In the UK: • c. 30,000 cases E. coli bacteraemia p.a.• c. 6.5 % CTX and/or CAZ resistance = c. 2000-3000 cases p.a

E. coli Carba-I/RK. pneumoniae

CTX-M ESBLs are global

Hawkey and Jones. JAC 2009; 64 (Suppl. 1), i3-i10

Travel-associated ESBL +ve E. coli carriage – NW London study

ESBL Country visited

CTX-M-15 (n=174) * India, Pakistan, Afghanistan, Egypt, Kenya, Kuwait, Thailand

CTX-M-14 (n=7) Egypt, Hong Kong/Japan

CTX-M-2 (n=1) Bolivia

* 28 phylogroup B2; 21 ST131, 8 UK strain A

(Dhanji, et al. JAC)

ESBL +ve E. coli in 18% (182 / 1031) samples =

Foreign travel and CO-UTI with ESBL E. coli, Calgary Region

Laupland et al. J Infect 2008; 57: 441-8

Community-acquired

Healthcare-associated CTX-M-15: India, Europe, Africa

CTX-M-14 (group 9): Asia (esp. China)

Relative risks:Africa 7.7Middle East 18.1India 145Europe 1.1

Resistance in bloodstream E. coliHPA voluntary surveillance

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

Carbapenem non-susceptibility, 2010 (Ears-Net)

3GC-I/R K. pneumoniae

• Negligible resistance in E. coli as judged by surveys• 4 countries reported >5% non-susceptibility in K. pneumoniae

E. coli

How to treat when multi-resistance is the norm ?

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

Metallo-enzyme Producers (IMP, NDM or VIM)

≥90%

Carbapenemase-producing Enterobacteriaceae in the UK (n = 1659)

AMRHAI, Unpublished data

Early cases often imported

Imported & ‘home grown’

The rise of OXA-48-like carbapenemases in Europe

Endemic in Turkey.

Many European cases linked to North Africa, but few prevalence data for this region

Trauma patients transferred to Europe from the Libyan conflict

• Denmark. 45 patients. Many with OXA-48 K. pneumoniae; A. baumannii with OXA-23 & NDM; novel MRSA clone

• Germany. One K. pneumoniae with OXA-48 & CTX-M-15; A. baumannii with OXA-23 & NDM

• Slovenia. First introduction of OXA-48 Klebsiella ex-Libya

• Cohorted to aid containment

• UK: 50 patients. At least 6 with OXA-48 K. pneumoniae & 12 with novel OXA-23 A. baumannii

• Spread throughout the NHS – a strategy that tests resilience and risks national seeding

Livermore IJAA 2012;39:283 & HPA on file; Hammerum et al., IJAA, in press; Kaase et al. ECCMID, London 2012; Pirs et al. Euro Surveill 2011;16, pii:20042.

NDM-1: the global media frenzy ! (Sept’ 2010)

Furore fueled by…

13th August 2009

Although it was an older story…

NDM carbapenemases: global reports, but a clear epicentre

Many cases with travel links / hospitalization in sub-continentSome link to the Balkans …2nd epicentre ?

Most countries have at least 1 case of XDRTB

XDR-TB = MDR-TB (R to INH + RIF) + any FQ +AMIK/CAP/KAN

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Prevalence of HIV drug resistance in ART-naive patients

‘Resistance’ threatens the UK and the NHS every day

Colonized residents or visitors

Non-human reservoirs: animals

and environment

Military and civilian casualties 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)

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

Effective IPC

Outbreaks contained

Can’t underestimate travel in dissemination of resistance

• From areas of high prevalence to low prevalence• myriad examples• importation of MRSA, ESBLs, carbapenemases

• ‘High risk’ patients • targetted for screening and IPC• ...but they need not come from other countries• look closer to home as well; inter-hospital transfers

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