Antimicrobial Resistance - Current Threats

Camilla WiuffNovember 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

~ 80% of antimicrobial use in humans was for patients in the community

Overview of AntimicrobialUsage and BacterialResistance in Selected Humanand Animal Pathogens in theUK: 2007 – Joint Report

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, 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

E.coli bacteraemia – Scotland 2009

0

10

20

30

40

50

60

70

ampi

cillin

amox

icillin

co-a

mox

iclav

cefu

roxim

ece

ftria

xone

cefo

taxim

ece

ftazid

ime

gent

amici

ncip

roflo

xacin

mer

open

empi

p/ta

zotri

meth

oprim

CRO/CIP

CRO/GEN

% r

esis

tan

ce

2008

2009

SAPG annual AMR report, due Jan 2011

• 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?

Gram-negative bacteraemia – Trends Scotland

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. coli7.5% of all E. coli bacteraemia50% of isolates resistant to cefuroxime (2. gen)70% of isolates resistant to ceftriaxone/cefotaxime/ceftazidime

(3. gen)

• K. pneumoniae8.8% of all K. pneumoniae bacteraemia45% 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

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