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Antimicrobial resistance; Gram-negatives vs. Gram- positives

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					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
antibioti         Antibiotic not
c                 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
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.    Fluoroquinolone resistant E. coli
pneumoniae




                                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,
    CTX-M, 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
  EARS-Net 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
                                                                            % resistance
                                        am




                                                                  10
                                                                       20
                                                                              30
                                                                                        40
                                                                                             50
                                                                                                  60
                                                                                                       70




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                                                                                                            E.coli bacteraemia – Scotland 2009




                                                                               2009
                                                                                      2008




SAPG annual AMR report, due Jan
           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
                                                        Magiorakos et al.,
PDR: resistant to all antimicrobial categories          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 beta-
    lactamases (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 community-
    acquired 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
                 Mupiroci
                 n
• 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
                               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
       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