Antimicrobial Resistance: A Growing Concern for Healthcare Security and Resilience Neil Woodford HPA 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 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 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
We chose to pick a fight with evolution Silver Clin Microbiol Rev 2011; 24:71-109 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
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
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
and they don t keep resistance plasmids to themselves www.biotoon.com
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 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
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 + - (?)
ESBL+ve isolates, Asia-Pacific 2007; intra-abdominal infection Hawser et al., AAC 2009; 53: 3280
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. 2000-3000 cases p.a
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 +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)
Foreign travel and CO-UTI with ESBL E. coli, Calgary Region Laupland et al. J Infect 2008; 57: 441-8 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
Resistance in bloodstream E. coli HPA voluntary surveillance 25 20 Cipro 3 gen ceph both Percent 15 10 5 0 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Hospital antibiotic sales (kg) IMS data 25000 20000 15000 10000 Carbapenems Oxyimino cephs Amox clav Piptaz Fluoroquinolones 5000 0 199819992000200120022003200420052006200720082009 use of pip/taz, co-amoxiclav (& carbapenems) new selective pressures..., but what consequences?
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
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)
Carbapenemase-producing Enterobacteriaceae in the UK (n = 1659) Imported & home grown Early cases often imported AMRHAI, Unpublished data
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 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. 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
NDM-1: the global media frenzy! (Sept 2010) Furore fueled by Although it was an older story 13 th August 2009
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?
Most countries have at least 1 case of XDRTB XDR-TB = MDR-TB (R to INH + RIF) + any FQ +AMIK/CAP/KAN
Prevalence of HIV drug resistance in ART-naive patients Percentage of tests 14 12 10 8 6 4 2 NRTI PI nnrti any class 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 Year of sample
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
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
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