Antibiotic Stewardship Matthew Dryden MD Hampshire Hospitals, Southampton University matthew.dryden@hhft.nhs.uk
Overview The Problem What antibiotic have achieved Antibiotic stewardship Rapid diagnostics Antibiotic strategy New antibiotics
We can not remember a time before antibiotics Antibiotics have saved more lives than any type of drug Antibiotics are different from all other drugs because their action is targeted against the invaders physiology rather than the host Antibiotic stewardship is complementary to infection control
Sir Luke Fildes 1891 The Doctor Tate Gallery, London
What antibiotics have achieved Major reductions in mortality Mortality, Pre- Antibiotic Mortality Postantibiotic Change (%) Community pneumonia 1 ~35 ~10 71 Hospital pneumonia 2 ~60 ~30 50 Endocarditis 3 100 ~25 75 Meningitis / brain infection 4 ~80 ~23 71 Skin / soft tissue infection 5 ~11 ~0.5 95 1 IDSA Position Paper 08 Clin Infect Dis 47 (S3): S249-65; 2IDSA/ACCP/ATS/SCCM Position Paper 10 Clin Infect Dis In Press; 3Kerr AJ. Subacute Bacterial Endocarditis. Springfield IL: Charles C. Thomas, 1955 & Lancet 1935 226:383-4; 4 Lancet 38 231:733-4 & Waring et al. 48 Am J Med 5:402-18; 5 Spellberg et al. 09 Clin Infect Dis 49:383-91 & Madsen 73 Infection 1:76081
Antibiotics a finite resource Diagnostic limitations mean that antibiotics are given to patients who have no infection or a viral infection Antibiotics are life saving in sepsis Empirical treatment is often very broad De-escalation rarely occurs Duration often too long Dryden MS, Cooke J, Davey P JAC. 2009; 64, 885 888
Antibiotic discovery Selective pressure and resistance Antibiotic treatment Public health, Infection prevention, and control
Whatever happens in India, happens in large numbers
Boost Antibiotic discovery Reduce Selective pressure and resistance REDUCE VOLUME of Antibiotic use IMPROVE Public health, Infection prevention, and control
Questionable use of antibiotics Where Antibiotics are used Types of use Questionable use Human use (50%) 20% hospital 80% community 20-50% Unnecessary Agricultural use (50%) 20% Therapeutic 80% Prophylactic growth promotion 40-80% Highly questionable Harrison PF, Lederberg J, eds. Antimicrobial resistance: issues and options. Washington, DC: National Academy Press, 1998
Megraj room, 1st floor, Commonwealth Building, Hammersmith Campus, W12 0NN
MRSA as % S. aureus bacteraemias 2010 vs. 2005 Up >25% Down >25% http://ecdc.europa.eu/en/activities/surveillance/ears-net
Rise and fall of MRSA bacteraemias in the UK The black line shows the number of cases in England (only) reported under the mandatory scheme initiated in 2001, and the grey bars show percent MRSA amongst all S. aureus bacteraemias reported under the Health Protection Agency s voluntary surveillance, covering >90% of hospitals in England, Wales and Northern Ireland 1, first recognition of EMRSA-15 and -16 2, initiation of mandatory surveillance of MRSA bacteraemias 3, beginning of decline of EMRSA-16 4, issue of Department of Health targets for MRSA reduction Livermore DM. Int J Antimicrob Agents 2012;39:283 94
Intercontinental Exchanges of CA-MRSA Clones ST8, ST59, ST80, ST30 DeLeo FR, et al. Lancet 2010; 375: 1557 68 18
E. coli from bloodstream infections: Turning nasty Cephalosporins: 2001/10 Quinolones: 2001/10 http://ecdc.europa.eu/en/activities/surveillance/ears-net
Mortality in ESBL vs. non-esbl Enterobacteriaceae bacteraemia Schwaber & Carmeli JAC 2007 60:913 920
Falling dominoes: Carbapenem-resistant K. pneumoniae, EARS-net 2006 2008 2010 Initially spread of VIM plasmids among K. pneumoniae in Greece From 2008 spread of K. pneumoniae ST258 with KPC enzyme http://ecdc.europa.eu/en/activities/surveillance/ears-net
Pan-resistant Gram negative Klebsiella pneumoniae from ICU patients Susceptibility profile: Carboxy-pen. Ureido-pen. BLICs Cefepime Ceftazidime Cefotaxime Imipenem Meropenem R R R R R R R R Amikacin Gentamicin Tobramycin Netilmicin Tetracycline SXT Chloramph. R R R R R R R Miriagou et al. JAC 2005; 55:810 Production of: VIM-1 MBL SHV-5 ESBL
A precious resource The aim is not to preserve antibiotics The aim to continue to have drugs to treat infection To better target antibiotics for patients who will benefit Volume of AB use= Selection pressure We must reduce the volume of antibiotic use And improve public health & infection control
Strategies to reduce antibiotic overuse 1. Diagnose infection more accurately 2. New antibiotic classes and antimicrobial therapy 3. Antibiotic guidelines and stewardship 4. Infection management and early discharge
Diagnostics Can we target antibiotic use better with rapid diagnostics? Need to give antibiotics to the patients who can benefit, NOT to patients for which there is NO benefit.
Accelerating microbiology Potential to revolutionise stewardship Now. 24 h to pure culture 48 h to susceptibility data Meanwhile the patient is on empirical R x May be inappropriate --- or unnecessarily broad
Accelerating microbiology Potential to revolutionise stewardship & therapy Future. PCR on specimen Recognise key pathogens and a few resistances some systems available Next generation sequencing Comprehensive pathogen and resistance detection.under development Potential to deliver results in 6h benefitting patient and stewardship. but much work still to do
Little et al Lancet 2013
Diagnostics to improve stewardship Procalcitonin trial Royal Hampshire Hospital 99 Medical Admissions Unit (MAU) patients; also 42 ICU patients with 87 procalcitonin tests Procalcitonin results within 90 minutes of request Antibiotics withheld in 52/99 MAU cases and on 42/87 ICU occasions based on low procalcitonin 6 MAU patient died: deaths NOT infection related 5 ICU patients died with infection, all receiving antibiotics Saeed K, Dryden MS, Bourne S, Paget C, Proud A. Journal of Hospital Infection 2011;78(4),289 292;doi:10.1016/j.jhin.2011.03.018
UK Five-Year Antimicrobial Resistance Strategy 2013 to 2018 3 strategic aims: Improve the knowledge and understanding of AMR Conserve and steward the effectiveness of existing treatments Stimulate the development of new antibiotics, diagnostics and novel therapies
7 key areas for future action 1. improving infection prevention and control practices in human and animal health 2. optimising prescribing practice through implementation of antimicrobial stewardship programmes 3. improving professional education, training and public engagement 4. developing new drugs and diagnostic tests
7 key areas for future action 5. better access to and use of surveillance data 6. better identification and prioritisation of AMR 7. strengthened international collaboration
Getting it right
Right drug: in sepsis, early antibiotics are critical Mortality increases with each hour s delay Fraction of total patients 1.0 0.8 0.6 0.4 0.2 0.0 Survivors if antibiotic initiation takes stated period Fraction on adequate antibiotics Time from hypotension onset (h) Adequate antimicrobial therapy should start within 1 hour Kumar et al. Crit Care Med 2006;34:1589-96
Frequency (% patients) Mortality (% patients) Right drug Resistance makes empirical therapy harder Inappropriate Dead 40 20 30 15 20 10 10 5 0 0 1 2 3 No. resistances 0 0 1 2 3
Good stewardship General principles Start smart, then focus Start antibiotics immediately in severe infection Right drug, right dose and right duration Document, review and audit Have stewardship team Ensures compliance, audit and update
Start Smart with empirical antibiotics and within 1h in life-threatening infections Don t start without clinical evidence of infection Use local guidelines to choose appropriate antibiotic - Should reflect likely pathogens & patient risk factors for resistant strains - Consider relevant allergies and interactions Obtain specimens for culture before dosing Document: indication, duration/review time, route & dose - Record on drug chart and in medical notes
Right drug- risk of collateral damage C. difficile risk varies with therapy
Right drug: once microbiology results available typically 48h after specimen / R x initiation Clinical & microbiology review STOP iv/oral switch Move to narrow spectrum agent Continue & re-review after 24h OPAT
Right drug: Why switch to oral? Rationales are clinical and economic More convenient for patient May be possible to discharge patient i.v. sites are portal for super-infection Cost Caveat.. Don t use oral drugs based on microbiology if they lack the clinical indication, e.g. fosfomycin for ascending UTI due to ESBL E. coli
Concentration Right dose Pharmacodynamics vary with drug class C max = Peak C max / MIC T > MIC b-lactams Aminoglycosides AUC / MIC Fluoroquinolones Macrolides Glycopeptides Tetracyclines Oxazolidinones MIC Time
Right dose Ensure efficacy whilst minimising resistance Excessive dose may increase toxicity Depends on drug class Under-dosage may promote selection of resistance Lack of good evaluations Was seen in 200 vs 600 mg linezolid trials Combinations especially with aminoglycosides often increase toxicity without improving outcomes
Right duration Lack of good studies, BUT Excessively long durations associated with More collateral damage to normal flora No improvement in outcomes Excessively short durations associated with Failures Selection of resistance e.g. in tuberculosis
8 Days R x or 15 days in ventilator pneumonia? Kaplan-Meier estimates of patient survival in VAP No increase of mortality or recurrence Longer R X still advised with P. aeruginosa CAVEAT Trial comparing 7 days doripenem (1g tds) vs 10 days imipenem (1 tds) in VAP stopped owing to worse outcomes in doripenem arm.
The Stewardship Team reports to Director of Infection Control & Prevention & to Drugs & therapeutics committee Microbiologist / Infectious Disease physician Antimicrobial / Infectious Disease pharmacist A lead clinician A surgeon Senior member of pharmacy team Senior nurse, ensuring links to infection control
Roles of the stewardship team Review and audit, ensuring Regular review of local guidelines Regular review of stewardship practice Regular review of organisation s antibiotic consumption Overall use, and at ward level Especially of broad spectrum agents Identification and discussion of any non-compliance
Antibiotic Stewardship in Europe European: 170 hospitals in32 countries Hospital has: Drugs & Therapeutics Committee North n=19 (%) West n=55 (%) South n=40 (%) Southeast n=13 (%) Central east n=43 (%) Total n=170 (%) 19 (100) 53 (98) 27 (68) 9 (69) 38 (88) 146 (86) Written formulary 16 (84) 51 (94) 23 (59) 5 (42) 36 (84) 131 (77) Formulary lists restricted antibiotics 7 (39) 36 (71) 21 (78) 7 (78) 32 (82) 103 (61) Written AB policy 15 (79) 39 (72) 18 (46) 3 (25) 22 (54) 97 (57) Antibiotic committee 14 (74) 30 (57) 17 (45) 4 (31) 24 (56) 89 (52) Prescription improvement as a strategic goal No AB committee or AB policy 8 (44) 32 (59) 17 (45) 5 (46) 25 (61) 87 (51) 2 (5) 7 (19) 13 (35) 6 (16) 9 (24) 37 (22) DTC = Drugs and Therapeutics Committee; AB = Antibiotic; SE = Southeast; CE = Central-East Bruce J, et al. J Antimicrob Chemother. 2009;64:853-860.
Challenges and uncertainties It is easier to regulate than to be right How restrictive should guidelines be? Class restriction Cycling, Diversity among appropriate agents Can we use biomarkers to better guide therapy? How can microbiology be accelerated to shorten the period of empirical treatment?
Three models of empirical Rx control Restrictive policy, cycling & diversity Restrictive B & C only for microdirected therapy A A A A A A A A A A A A B B B C C C Cycling A B C A B C A B C Diverse 3 month periods
Restrictive policy or guideline One favoured empirical therapy per setting Simple, easy to audit / enforce Has come apply de facto in the UK for severe infection Piperacillin-tazobactam hugely used; carbapenems reserved; cephalosporins & quinolones restricted owing to fear of C. difficile Concentrates selection pressure on few agents Led to sequential loss of therapies in gonorrhoea Sulphonamides, penicillin, quinolones abandoned in turn Cephalosporin MICs now creeping upwards
Carbapenem Cephalosporin Pip/tazo No Pip/tazo No Cephalosporin No Carbapenem Antibiotic diversity vs. cycling & restriction Prospective cohort study 44 months, one ICU Months 1-10 Patient Specific Months 11-22 Priority / Cycling Months 23-34 Single agents restricted 11-22 23-34 Months 35-44 Mixing Physician choice, based on risk factors Sequential patients allocated to different R x
Positive isolates/100 admissions Different strategies to control resistance One unit, lot of caveats, but mixing & choice seem best 1 Acinetobacter solid, carbapenem R 2 Enterobacteria ESBL 3 P. aeruginosa any R 4 S. aureus methicillin R 5 E. faecalis Physician choice Cycling Restriction Mixing
Restriction vs. cycling vs. diversity Caveat one study, one unit.. Prioritization (cycling) & restriction increased homogeneity - Associated with colonisation by Enterobacteriaceae and gram-negative non-fermenters - Outbreaks of carbapenem-r Acinetobacter during carbapenem prioritization - ESBL-producing Enterobacteriaceae during cephalosporin prioritization Patterns favouring diverse use were less damaging Implies that guidelines should list reasonable R x options but allow choice among them
Assessing the future
Dwindling supply of new antibiotics FDA approvals by 5-year period 20 15 10 5 0 83-87 88-92 93-97 98-02 03-07 08-12
Antibiotics A brief interlude in human history Age of ignorance Age of discovery golden age Age of the antibiotic revolution Age of neglect Age of reality Silver. Clin Microbiol Rev 2011;24:71 109
Comparison of novel Antimicrobials Drug Vancomycin / teicoplanin Quinupristin/ dalfopristin Linezolid Daptomycin Ceftaroline Tigecycline Dalbavancin Advantages Familiarity, long history of use. Poor for CAP Alternative to vancomycin. Hardly used now Positive pharmacoeconomic outcome data are available. Oral dosing removal of catheters, early discharge, evidence of superiority to vancomycin in cssti and pneumonia Potential for less resistance, bactericidal. cssti, bacteraemia Broad spectrum. B-lactam; cssti, CAP Broad spectrum, fixed dosages, cssti, IAI Long acting (weekly dosing), bactericidal, cssti
Surgihoney: in vitro activity
77 year old man Peripheral vascular disease Large ischaemic ulcers Non healing Heavily colonised with coliforms and Pseudomonas aeruginosa.
Who will win? Louis Pasteur: Messieurs, c est les microbes qui auront le dernier mot