Antimicrobial Resistance Current Threats Camilla Wiuff November 2010
Antimicrobial resistance - a threat to public health and patient safety • Infections with resistant organisms are associated with increased morbidity and mortality • Extended stays in hospitals • Reduced treatment options • Untreatable infections • Increased healthcare costs
Evolution of antibiotic resistance is a consequence of selective pressure
Selection for resistance antibiotic Antibiotic not effective
Antibiotic Use Overview of Antimicrobial Usage and Bacterial Resistance in Selected Human and Animal Pathogens in the UK: 2007 – Joint Report ~ 80% of antimicrobial use in humans was for patients in the community
Use of antibiotics in Scotland 1994 -2009 in primary care SAPG – Report on Antimicrobial Use and Resistance – draft (publication January 2011)
Qualitative measures of antimicrobial prescribing in hospitals – ESAC Point Prevalence Survey 2009 SAPG – Report on Antimicrobial Use and Resistance – draft (publication January 2011)
The association between antimicrobial use and resistance is complex and difficult to measure • Time delay (>1 -2 years) between use and the development of resistance • Co-selection by other antibiotics (due to linked resistance genes) • Co-selection by metal-ions, disinfectants, other agents/chemicals • Selection of non-specific resistance mechanisms (e. g. efflux pumps, outer membrane porins) • Spread of highly resistant (and fit) clones and plasmids
Association between use and resistance at country level (ESAC and EARSS data) Penicillin non-susceptible S. pneumoniae Fluoroquinolone resistant E. coli Sande-Bruinsma, EID, 14, Nov, 2008
Gram-negatives • Penicillinase indentified in the laboratory, 1940 Penicillin entered clinical use • Penicillinase quickly spread in clinical isolates Broad-spectrum antibiotics became available in 1950 -60’s • Beta-lactamases with increasing spectrum 1950 -1970 Cephalosporins became available in the 1970’s • Extended spectrum beta-lactamases, ESBLs, 1980 -1990 (TEM, SHV, CTXM, OXA, Amp. C) Carbapenems became available 1985 • 1996 (2003 EU) carbapenemases (KPC, VIM, OXA, NDM-1) • 2009 - carbapenem-non-susceptible Enterobacteriaceae (CSNEs) – “UNTREATABLE”!
Emerging carbapenem resistance in Gram-negatives • Significantly limits treatment options for life-threatening infections • No new drugs are under development for gram-negative infections • Resistance mechanisms (carbapenemases) are mobile (spreadily via plasmids) • Co-resistance to other agents is common • Surveillance, prudent antimicrobial prescribing and infection control are necessary to limit the spread of carbapenemases
Surveillance of Gram-negatives in Scotland • The national surveillance is focussed on bacteraemia • Clinically important infection (high morbidity and mortality) • All symptomatic patients are sampled and tested • Resistance data are comparable with European EARSNet data from 27 countries • Resistance in bacteraemia isolates is likely to reflect earlier resistance problems in other infections (UTI, GTI, RTI)
Cases of bacteraemia and ESBLs in Scotland
E. coli bacteraemia – Scotland 2009 SAPG annual AMR report, due Jan 2011
Gram-negative bacteraemia – Trends Scotland • Large increase in reporting of bacteraemia to HPS (2008 -2009) • Resistance to all clinically important antibiotics (aminopenicillins, cephalosporins, fluoroquinolones, aminoglycosides) • No change in %ESBL (~7 -8 %) • Stabilisation in resistance proportions in 2009 • Significant decrease in (%) resistance to 3 rd gen. cephalosporins in E. coli • No carbapenem resistant bacteraemia reported in 2009 (but 10 isolates of other types) • Are we starting to see an effect of antimicrobial stewardship programmes?
Multi-drug resistance MDR: resistant to at least 1 antibiotic in 3 antimicrobial categories XDR: resistant to all but 2 antimicrobial categories PDR: resistant to all antimicrobial categories Magiorakos et al. , ECDC, draft definitions, 2010
ESBL production among cephalosporin resistant bacteraemia isolates • E. coli 7. 5% of all E. coli bacteraemia 50% of isolates resistant to cefuroxime (2. gen) 70% of isolates resistant to ceftriaxone/cefotaxime/ceftazidime (3. gen) • K. pneumoniae 8. 8% of all K. pneumoniae bacteraemia 45% of isolates resistant to cefuroxime (2. gen) 65% of isolates resistant to ceftriaxone/cefotaxime/ceftazidime (3. gen)
Carbapenemases in Scotland in 2009 Isolates characterised by ARMRL, Colindale: • 4 isolates of Pseudomonas aeruginosa (VIM) • 2 Klebsiella pneumoniae (KPC) • 3 Enterobacter (VIM, KPC) • 1 Citrobacter freundii (NDM) • 4. 7% (9/192) of Pseudomonas aeruginosa bacteraemia isolates were resistant to meropenem
Epidemiology of KPC carbapenemases • Klebsiella pneumoniae clones of KPC carbapenemases circulating in USA, Israel and Greece • Sporadic isolations of KPC in South America, Europe, UK • Further spread in China, Colombia, Puerto Rico • KPC have been reported in E. coli, Salmonella cubana, Enterobacter, Proteus mirabilis, Citrobacter freundii, Serratia marcescens, P. aeruginosa, Acinetobacter baumannii
NDM-1 carbapenemases in the UK • Carbapenemase-producers were sporadic in the UK in 2003 -2007 • Isolations of carbapenemase-producers increased in the UK 2008 -2009 • First NDM-1 isolated in 2008 in the UK • In 2009, NDM-1 became the predominant carbapenemase in Enterobacteriaceae (44%) in the UK • 37 isolates of NDM-1 were referred from 25 UK laboratories in 2008 -2009 (urines (15), blood (3), burns/wound (4), sputum (2). CL (1), throat (1), unknown (3)) • Average of UK patients: 60 years (range 1 -87) (India: 36 years) • 17 out of 29 patients with NDM-1 had been in India/Pakistan within the past year (14 had been in hospitals during their travels) • Most UK carbapenemase-producers concurrently carry additional betalactamases (CTXM-15, CMY-4), fluoroquinolone and gentamicin resistance mechanisms
Carbapenemases Is there a link to medical tourism? Kumarasamy, Lancet Infection, Aug 2010 Clones and plasmids are transported between continents in the human gut flora – most dissemination is undetected!
Carbapenemases – UK and India • UK: Non-clonal isolates (NDM-1 on chromosome, variable plasmids, conjugates easily) • Chennai (South India) : Non-clonal isolates (NDM-1 on plasmids, variation of plasmids, conjugates easily) • Haryana (North India): Clonal isolates – outbreak? • There were no genetic links between isolates from India and the UK (possibly due to too few isolates investigated) • UK is the first Western country to report widespread occurrence of NDM-1 • Most patients in Haryana and Chennai were from communityacquired infections in younger people (mean=36 yrs) • Non-prescription use of carbapenems in India is of major concern
Surveillance of carbapenemases in Scotland • Susceptibility testing in diagnostic laboratories • Sensitive, reliable and standardised testing methodology is key – automated VITEK systems are part of the Scottish strategy for obtaining high quality data on emerging carbapenem resistance • Further investigations by ARMRL, Colindale to determine resistance mechanism and subtype • HPS AMR-alert system that prompts laboratories to unusual susceptibility results (in specific drug-bug combinations) – weekly • Annual report on resistance in bacteraemia isolates • Development of national surveillance of resistance in UTI (proportional system)
Resistance in Gram-positives • Less of a concern in Scotland at the moment • Newer antibiotics with activity against Gram-positives are available (linezolid, daptomycin, tigecycline) • Except for MRSA, resistance rates are generally low among Gram-positive in Scotland • Gram-positive exhibit a remarkable ability to develop antibiotic resistance through a range of mutational events and gene transfers, followed by spread of successful resistant clones
Glycopeptide resistance • Glycopeptides: vancomycin and teicoplanin • Used for life-threatening Gram-positive infections – last resort drugs • Vancomycin Resistant Enterococci (VRE) reported in 1987 -1988 in UK (high-level resistance, later low-level resistance reported) • Vancomycin resistance in Enterococcus faecium (VRE) in Scotland - 17% in 2008, 28% in 2009 • In 2008, Ireland, Greece and the UK reported >25% VRE (and increasing trends) • Enterococci are a common cause of bacteraemia • Glycopeptide resistance transfer via plasmids to more pathogenic bacteria such as MRSA – is a concern
Mupirocin • Mupirocin (pseudomonic acid A) is a topical antibiotic • Used to treat skin and soft tissue infections • Used to eradicate staphylococcal nasal carriage in patients pre-operatively • Used to eradicate MRSA in healthcare facilities • High-level resistance leads to treatment failure • It is a concern that the implementation of the national MRSA screening programme will lead to increased mupirocin resistance
Summary • Evolution and spread of antibiotic resistance is a consequence of how antibiotics are used and mis-used in humans, animals and the environment. • Large efforts are going into improving the quality of antimicrobial prescribing and limiting the spread of resistance in NHS Scotland – activities are coordinated by SAPG • A reduced number of prescriptions was seen in primary care in Scotland in 2009 compared to 2008 (co-amoxiclav, cephalosporins and fluoroquinolones) • Resistance rates in Gram-negative bacteraemia stabilised in 2009, and cephalosporin resistance decreased. • Carbapenem (and multidrug) resistance in Gram-negatives (in particular Enterobacteriaceae) is a worldwide threat to public health • Increasing glycopeptide resistance in Enterococci (e. g. VRE) and increasing mupirocin resistance in S. aureus is causing concern • Improved quality of antimicrobial prescribing and standardised susceptibility testing are key to monitoring and limiting emerging resistance problems
The HPS-ISD AMR Team • • • Anne Eastaway Camilla Wiuff William Malcolm Julie Wilson Tracey Cromwell Marion Bennie A-Lan Banks David Henderson Ernest Amaziro HPS, ISD, NSS IM&T departments
"Don't forget to take a handful of our complimentary antibiotics on your way out“ New Yorker Jan 12, 98
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