FIS 2013

Resistance Surveillance:

The UK Landscape

Alasdair MacGowan Chair BSAC Working Party on Antimicrobial Resistance Surveillance

A statement of the obvious

“Good quality surveillance data on resistant

micro-organisms are essential to underpin

effective interventions to counter the

problems of resistance and developing

guidelines on prescribing antimicrobial drugs.

Such data should be epidemiologically and

clinically relevant.”

Copenhagen Recommendations

European Union, 1998

Problems with antimicrobial surveillance in the last 20 years

routine passive surveillance was biased by disease state,

age, uneven methodologies in and outside labs. However,

large data sets are captured.

sentinel focused surveillance using central laboratory

overcomes some problems by use of standard within lab

methods but not requesting bias and is costly

poor dissemination of data – public/private providers

and funders

Based on Livermore, MacGowan, Wale, 1998; BMJ 317, 614-5

Epidemiologically relevant data?

Passive Surveillance

Collection of antimicrobial resistance data in the community

i.e. UK/Ireland – depends on healthcare system

Patient presents with infection

Primary

Care Doctor Primary Care Nurse Other NHS Direct

Accident Departments

(OTC Pharmacy) Specimen sent to laboratory

Bacteria isolated, identified and susceptibility tests

performed using routine methods

Confirmed and repeated

by central laboratory

using “gold standard

methods”

Results entered into

Laboratory Information

Management System

(LIMS)

Resistance Data Base

Pitfalls with passive surveillance

Data skewed because patients who fail initial empirial

therapy more likely to be tested

Age bias in LIMS towards the elderly and young

Location of patient (Admission Unit vs Primary Care)

Isolates from different disease states included in

database disproportionately:- i.e. Acute Sinusitis vs

UTI, exacerbation COPD vs CAP

Specimens may be sent for non-infective reasons

Proportion of patients

Age Band

In community

In hospital <48h

16-40 0.28 0.11 40-49 0.16 0.05 50-59 0.15 0.07 60-69 0.19 0.18 70-79 0.17 0.31

80 0.05 0.27

Lovering, unpublished

Specimen referral by location and age for community LRTI:

Sputum

Ampicillin resistance in H.influenzae rate

Laboratory database (passive surveillance)

0.20

Unselected patients with LRTI who received an antibiotic (n=20)

0.11

MacGowan et al, 1998

Assessment of Biases: Sputum Referral

Single Practice

1:35 episodes of GP diagnoses “Chest Infection”

results in sputum referral

Patient Group TMP

n %S P CI

Acute UTI

55

81

0.343

0.394 – 1.38 Laboratory data

5448

76

Lovering & MacGowan, 2003

Assessment of Bias: Laboratory Database vs UTI

Symptoms in UTI Group, i.e. culture >105 pathogen

Pain on urination 0.85

Increased frequency 0.87

Blood in urine 0.25

Increased urgency 0.65

Urination at night 0.56

Abdominal pain 0.56

Back pain 0.38

Smelly urine 0.44

Number of isolates required

90% power

80% power

+10% 208 152 +5% 801 592 -5% 714 542 -10% 163 127

But significantly underpowered:-

If true rate of resistance in laboratory database is 24%

Patients recruited over 2-3 years : 55

Problem with sentile surveillance in Primary Care

Acute Infection Group

UTI (n=165) Cough (n=197) Throat (n=249)

Urine sample (n=150) Sputum sample (n=99) Throat swab (n=243)

Potential pathogen

(n=67)

Potential pathogen

(n=23)

Potential pathogen

(n=38)

E.Coli (n=59)

Proteus (n=3)

Klebsiella (n=4)

Other (n=2)

H.influenzae (n=13)

S.pneumoniae (n=8)

M.catarrhalis (n=1)

Group A n=79

Group C n=11

Group G n=6

BSAC antimicrobial resistance surveillance contribution:

Overcomes previous perceived problems:

continuous since 1999

based on uniform within laboratory methodology

target at relevant resistances by use of a core

testing set

allow cross validation with other resistance data

bases

data is widely available

Does not overcome:

bias related to passive surveillance in the

community

partly answers concerns about how

representative sampling is (increase from 25 to 40

collecting labs)

BSAC Surveillance Programme : Outputs

Trends in CAP: S.pneumoniae, H.influenzae

Trends in HAP: S.aureus, ESBL producers

Trends in Bacteraemia: MRSA, ESBL, carbapenemase producers

CAP Programme: S. pneumoniae (420) % non-susceptible

Both Programmes: Penicillin non-susceptible S.pneumoniae

- Great Britain data

Year Respiratory programme

Bacteraemia programme

1999-00 7.2% 2000-01 7.2% 6.8% 2001-02 4.4% 7.1% 2002-03 6.1% 8.0% 2003-04 5.7% 3.0% 2004-05 5.3% 2.0% 2005-06 4.3% 4.2% 2006-07 4.9% 4.3% 2007-08 4.7% 2.2% 2008-09 5.3% 3.7% 2009-10 7.5% 4.3% 2010-11 5.8% 3.6% 2011-12 10.9% 8.3%

% Penicillin non-susceptibility in pneumococci:

BSAC bacteraemia surveillance

CAP Programme: H. influenzae (516) % non-susceptible

HAP Programme: E. coli (274)

2008-09 2009-10 2010-11

non-

ICU ICU

non-

ICU ICU

non-

ICU ICU

Klebsiella spp.

%ESBL 18% 20% 7% 9% 13% 8%

% ctx-M 30% 35% 17% 33% 67% 50%

Escherichia

coli

%ESBL 16% 13% 17% 16% 13% 9%

% ctx-M 81% 71% 85% 53% 85% 73%

Enterobacter

spp.

%ESBL 9% 6% 8% 7% 5% 6%

% ctx-M 57% 60% 60% 50% 0% 0%

HAP Programme: ESBL prevalence

HAP Programme: S. aureus (226) % non-susceptible

P <0.0005

01

02

03

04

05

06

0

Iso

late

s, %

2001 2002 2003 2004 2005 2006 2007 2008

England Wales, Scotland, N. Ireland, Ireland

% MRSA over time (BSAC surveillance)

Bacteramia Programme:

0

2000

4000

6000

8000

10000

12000

N o

f M

RS

A b

acte

rae

mia

s0

10

20

30

40

50

60

MR

SA

, %

of is

ola

tes

2001 2002 2003 2004 2005 2006 2007 2008

% MRSA in S. aureus bacteraemia (BSAC surveillance)

Number of MRSA bacteraemias (mandatory reports)

MRSA bacteraemia in England

0

5

10

15

20

25

30

35

40

45

01 02 03 04 05 06 07 08 09 10

E. faecalis

E. faecium

% Vancomycin non-susceptibility: enterococci, BSAC bacateraemia

surveillance

0

5

10

15

20

25

30

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010

Cipro

C'taxime

Gentamicin

BSAC E. coli from bacteraemia (n = 3149; 242-530 p.a.)

E.coli - ESBL prevalence

segmented logistic regression

BSAC Bacteraemia 2001-2008

05

10

15

ES

BL p

roducers

, %

of is

ola

tes

2001 2002 2003 2004 2005 2006 2007 2008

Observed, mean for year Model

Q3 2005

p <0.0005

OR = 1.76

p = 0.15

OR = 0.86

0

2

4

6

8

10

12

14

16

02 03 04 05 06 07 08 09 10

Other/undefined

AmpC

non-CTX-M ESBL

CTX-M

Livermore et al., JAC 2008; 62 2: ii41-54, updated

Ceph-R mechanisms BSAC % Prevalence E. coli

Carbapenemase-producing Enterobacteria: BSAC bacteraemia

2003-4 2 Enterobacter, KPC-4. ?Same patient

2009 1 Klebsiella, NDM

2009 1 Enterobacter, IMP

2010 1 Enterobacter, VIM

2010 1 Enterobacter, IMI

2010 1 Klebsiella, VIM

Carbapenem resistant GNBs:

Referrals to National Reference Laboratory

IMP VIM KPC OXA-48 NDM IMI KPC-VIM

2003 1 1 1

2004 3

2005

2006 3 1

2007 1 1

2008 1 2 5 9 5

2009 9 4 13 15 32

2010 9 26 229 29 44 2

Data access 28.4.2011 www.hpa.org.uk

Geometric mean with 95% CI, conventional calculation

Vancomycin fitted line = 0.074 log2 units/year; p = 0.002

Teicoplanin fitted line = -0.069 log2 units/year; p = 0.003

-2-1

01

2

log

2(M

IC)

0.2

50

.51

24

MIC

, m

g/L

2001 2002 2003 2004 2005 2006 2007Year

Original MICs for 271 MRSA

Vancomycin MIC creep – bacteraemia isolates

Geometric mean with 95% CI, from interval regressionGradient of fitted line = -0.027 log2 units/year; p = 0.006

-2-1

01

log

2(M

IC)

0.2

50

.51

2

MIC

, m

g/L

2001 2002 2003 2004 2005 2006 2007Year

Vancomycin MICs for 271 MRSA - re-test

Conclusions:

What the BSAC Resistance Surveillance Programme has shown:

Long term non-public sector surveillance of antimicrobial resistance is possible

In CAP:

- decline in penicillin non-susceptible S.pneumoniae with recent increase, with

shift in serotype – vaccine types down

- significant increase in resistance to aminopenicillin H.influenzae

In HAP

- short term results so far

- most resistance stable, ESBL producers, few carbapenem resistant Klebsiella

- P.aeruginosa resistance higher in ICU especially carbapenem and

piperacillin/tazobactam

- S.aureus resitance not higher in ICU with drop in MRSA (MecA, ciprofloxacin,

erythromycin resistance)

…/cont’d

Conclusions cont’d

Bacteraemia

- decline in MRSA

- rise then plateauing and fall of CTXM

- carbapenemase beginning to register

- Not much happening with P.aeruginosa

- vancomycin MIC shift in MRSA is not a problem.

Thanks to:

Dr Ian Morressy, formerly of Quotient

Professor David Livermore

Dr Rosy Reynolds

Also:

- Collecting laboratories

- Central laboratories

- Website provider (MRS)

- Working Party Members

- Commercial Sponsors

- BSAC