Antimicrobial Resistance: A Growing Concern for Healthcare Security and Resilience

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Chad Dorsey
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1 Antimicrobial Resistance: A Growing Concern for Healthcare Security and Resilience Neil Woodford HPA AMRHAI - Colindale

2 Resistance is entirely natural...and is ancient Permafrost samples Late Pleistocene (30,000 y) DNA recovered from extinct megafauna + resistance genes tet(m) tetracyclines bla TEM penicillins vanhax - glycopeptides D Costa et al. Nature 2011

Resistance genes through the millenia Stokes & Gillings, FEMS Microbiol Rev, 2011 Genes have flowed through ecological niches, without selective pressure (from us) from

3 Resistance genes through the millenia Stokes & Gillings, FEMS Microbiol Rev, 2011 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: bla TEM-1 in E. coli 2008: bla NDM in K. pneumoniae

running you can do, to keep in the same place.

4 We chose to pick a fight with evolution Silver Clin Microbiol Rev 2011; 24: Now, here, you see, it takes all the running you can do, to keep in the same place." The resistance mantra: antibiotic use = selective pressure = resistant isolates

5 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

6 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

7 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

8 Plasmids help to spread resistance to many antibiotics in neat genetic packages Antibiotic classes Aminoglycosides Genes aac6 -Ib-cr aada5 Mechanism Modify drug β-lactams bla CTX-M-15 bla OXA-1 Destroy drug bla TEM-1 Chloramphenicol catb4 Modify drug Macrolides mph(a) Efflux Fluoroquinolones aac6 -Ib-cr Modify drug Sulfonamides suli By-pass Trimethoprim dhfr XVII By-pass Tetracycline tet(a) Efflux Woodford, Carattoli et al. AAC

9 and they don t keep resistance plasmids to themselves

10 Why worry about resistance? Schwaber & Carmeli, JAC 2007; 60: 913 Mortality Delayed appropriate Rx

11 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

12 Assessing Public Health risk when the biogeography / ecology of resistance is so complex Stokes & Gillings, FEMS Microbiol Rev, UK regions: study contemporaneous ESBL +ve E. coli from blood, routine diagnostic stool samples, sewage, raw meat, farm slurry

13 The resistance ratchet keeps turning Pathogen Established problems Emerging threats E. 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, Carbapenemases E. 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

14 Reasons for the spread of resistance Multifactorial; highly complex; diverse Generalizations are overly simplistic Country-to-country variation in relative importance ESBLs Carbapenemases Successful host strains / clones Successful plasmids Community reservoirs (human) International human travel Animal reservoirs +++ +/- (?) Food chain + - (?)

15 ESBL+ve isolates, Asia-Pacific 2007; intra-abdominal infection Hawser et al., AAC 2009; 53: 3280

16 3 rd -gen cephalosporin nonsusceptibility, 2010 (Ears-Net) E. coli K. pneumoniae Carba-I/R In the UK: c. 30,000 cases E. coli bacteraemia p.a. c. 6.5 % CTX and/or CAZ resistance = c cases p.a

17 CTX-M ESBLs are global Hawkey and Jones. JAC 2009; 64 (Suppl. 1), i3-i10

18 Travel-associated ESBL +ve E. coli carriage NW London study ESBL +ve E. coli in 18% (182 / 1031) samples = ESBL CTX-M-15 (n=174) * CTX-M-14 (n=7) Country visited India, Pakistan, Afghanistan, Egypt, Kenya, Kuwait, Thailand Egypt, Hong Kong/Japan CTX-M-2 (n=1) Bolivia * 28 phylogroup B2; 21 ST131, 8 UK strain A (Dhanji, et al. JAC)

19 Foreign travel and CO-UTI with ESBL E. coli, Calgary Region Laupland et al. J Infect 2008; 57: Healthcare-associated CTX-M-15: India, Europe, Africa CTX-M-14 (group 9): Asia (esp. China) Community-acquired Relative risks: Africa 7.7 Middle East 18.1 India 145 Europe 1.1

Cipro 3 gen ceph both Percent 15 10 5 0 90

20 Resistance in bloodstream E. coli HPA voluntary surveillance Cipro 3 gen ceph both Percent

21 Hospital antibiotic sales (kg) IMS data Carbapenems Oxyimino cephs Amox clav Piptaz Fluoroquinolones use of pip/taz, co-amoxiclav (& carbapenems) new selective pressures..., but what consequences?

22 Carbapenem non-susceptibility, 2010 (Ears-Net) 3GC-I/R E. coli K. pneumoniae Negligible resistance in E. coli as judged by surveys 4 countries reported >5% non-susceptibility in K. pneumoniae

23 How to treat when multi-resistance is the norm? Metallo-enzyme Producers (IMP, NDM or VIM) 90% HPR, 2011; 5: issue 24 (17/06/11; Woodford & Livermore)

24 Carbapenemase-producing Enterobacteriaceae in the UK (n = 1659) Imported & home grown Early cases often imported AMRHAI, Unpublished data

25 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

26 Trauma patients transferred to Europe from the Libyan conflict 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: 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

27 NDM-1: the global media frenzy! (Sept 2010) Furore fueled by Although it was an older story 13 th August 2009

28 NDM carbapenemases: global reports, but a clear epicentre Many cases with travel links / hospitalization in sub-continent Some link to the Balkans 2 nd epicentre?

29 Most countries have at least 1 case of XDRTB XDR-TB = MDR-TB (R to INH + RIF) + any FQ +AMIK/CAP/KAN

30 Prevalence of HIV drug resistance in ART-naive patients Percentage of tests NRTI PI nnrti any class Year of sample

Resistance threatens the UK and the NHS every day Colonized residents or

Non-human reservoirs: animals and environment Hospital treatment or

casualties from conflict zones Multiple risks to be assessed to minimize

31 Resistance threatens the UK and the NHS every day Colonized residents or visitors Non-human reservoirs: foodstuffs (domestic or imported) Non-human reservoirs: animals and environment Hospital treatment or travel overseas Inter-hospital transfers (UK) Military and civilian casualties from conflict zones Multiple risks to be assessed to minimize damage Requires the detail to be understood Continuous education of NHS staff at all levels

contained Effective IPC microbiology surveillance infection prevention

32 Containing multi-resistant bacteria: the critical triangle Multi-disciplinary approach to limit risk and impact Outbreaks contained Effective IPC microbiology surveillance infection prevention and control diagnostics drug development diagnostic / reference / R&D / industrial partnerships

carbapenemases High risk patients targetted for screening and IPC.

33 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

34 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

Antibiotic resistance a mechanistic overview Neil Woodford

Antibiotic Resistance a Mechanistic verview BSc PhD FRCPath Consultant Clinical Scientist 1 Polymyxin Colistin Daptomycin Mechanisms of antibiotic action Quinolones Mupirocin Nitrofurans Nitroimidazoles