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 and funders providers 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 Specimen sent to laboratory Other NHS Direct Accident Departments (OTC Pharmacy) 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
Specimen referral by location and age for community LRTI: Sputum 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48h 16-40 0.28 0.11 40-49 0.16 0.05 50-59 0.15 0.07 60-69 0.19 0.18 70-79 0.17 0.31 80 0.05 0.27 Lovering, unpublished
Assessment of Biases: Sputum Referral Single Practice 1:35 episodes of GP diagnoses Chest Infection results in sputum referral 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 Bias: Laboratory Database vs UTI Symptoms in UTI Group, i.e. culture >10 5 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 Patient Group TMP n %S P CI Acute UTI 55 81 0.343 0.394 1.38 Laboratory data 5448 76 Lovering & MacGowan, 2003
But significantly underpowered:- If true rate of resistance in laboratory database is 24% Number of isolates required 90% power 80% power +10% 208 152 +5% 801 592-5% 714 542-10% 163 127 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) E.Coli (n=59) Proteus (n=3) Klebsiella (n=4) Other (n=2) Potential pathogen (n=23) H.influenzae (n=13) S.pneumoniae (n=8) M.catarrhalis (n=1) Potential pathogen (n=38) 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)
HAP Programme: ESBL prevalence 2008-09 2009-10 2010-11 non- non- non- ICU ICU ICU ICU ICU ICU Klebsiella spp. Escherichia coli Enterobacter spp. %ESBL 18% 20% 7% 9% 13% 8% % ctx-m 30% 35% 17% 33% 67% 50% %ESBL 16% 13% 17% 16% 13% 9% % ctx-m 81% 71% 85% 53% 85% 73% %ESBL 9% 6% 8% 7% 5% 6% % ctx-m 57% 60% 60% 50% 0% 0%
HAP Programme: S. aureus (226) % non-susceptible P <0.0005
0 10 20 30 40 50 60 Bacteramia Programme: % MRSA over time (BSAC surveillance) 2001 2002 2003 2004 2005 2006 2007 2008 England Wales, Scotland, N. Ireland, Ireland
N of MRSA bacteraemias 60 MRSA bacteraemia in England 12000 50 40 30 20 10 10000 8000 6000 4000 2000 0 2001 2002 2003 2004 2005 2006 2007 2008 % MRSA in S. aureus bacteraemia (BSAC surveillance) Number of MRSA bacteraemias (mandatory reports) 0
% Vancomycin non-susceptibility: enterococci, BSAC bacateraemia surveillance 45 40 35 30 25 20 15 10 5 0 E. faecalis E. faecium 01 02 03 04 05 06 07 08 09 10
BSAC E. coli from bacteraemia (n = 3149; 242-530 p.a.) 30 25 20 Cipro C'taxime Gentamicin 15 10 5 0 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
0 5 10 15 E.coli - ESBL prevalence segmented logistic regression p = 0.15 OR = 0.86 p <0.0005 OR = 1.76 Q3 2005 2001 2002 2003 2004 2005 2006 2007 2008 Observed, mean for year Model BSAC Bacteraemia 2001-2008
Ceph-R mechanisms BSAC % Prevalence E. coli 16 14 12 10 8 6 4 2 0 Other/undefined AmpC non-ctx-m ESBL CTX-M 02 03 04 05 06 07 08 09 10 Livermore et al., JAC 2008; 62 2: ii41-54, updated
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
0.25 0.5 1 2 4 log2(mic) -2-1 0 1 2 Vancomycin MIC creep bacteraemia isolates Original MICs for 271 MRSA 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 2001 2002 2003 2004 2005 2006 2007 Year
0.25 0.5 log2(mic) 1 2-2 -1 0 1 Vancomycin MICs for 271 MRSA - re-test Geometric mean with 95% CI, from interval regression Gradient of fitted line = -0.027 log2 units/year; p = 0.006 2001 2002 2003 2004 2005 2006 2007 Year
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