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, AmpC)
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 (spread
readily 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
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% resistance
E.coli bacteraemia – Scotland 2009
70
60
50
40
2008
30
2009
20
10
0
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 3rd 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 age 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
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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