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Antibiotic Stewardship Matthew Dryden MD Hampshire Hospitals, Southampton University [email protected]
Antibiotic Stewardship Matthew Dryden MD
Hampshire Hospitals, Southampton University
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
Mortality, Pre-
Antibiotic
Mortality Post-
antibiotic
Change (%)
Community pneumonia1 ~35 ~10 71
Hospital pneumonia2 ~60 ~30 50
Endocarditis3 100 ~25 75
Meningitis / brain infection4 ~80 ~23 71
Skin / soft tissue infection5 ~11 ~0.5 95
Major reductions in mortality
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
Public health, Infection prevention, and control
Selective pressure and resistance
Antibiotic treatment
Whatever happens in India, happens in large numbers
Boost Antibiotic discovery
IMPROVE Public health, Infection prevention, and control
Reduce Selective pressure and resistance
REDUCE
VOLUME of Antibiotic use
Harrison PF, Lederberg J, eds. Antimicrobial resistance: issues and options.
Washington, DC: National Academy Press, 1998
Where Antibiotics are used Types of use Questionable use
Human use (50%) 20% hospital
80% community
Agricultural use (50%) 20% Therapeutic
80% Prophylactic
growth promotion
20-50% Unnecessary
40-80% Highly
questionable
Questionable use of antibiotics
• 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
ST8, ST59, ST80, ST30
Intercontinental Exchanges of CA-MRSA Clones
DeLeo FR, et al. Lancet 2010; 375: 1557–68
18
E. coli from bloodstream infections:
Turning nasty
http://ecdc.europa.eu/en/activities/surveillance/EARS-Net
Cephalosporins: 2001/10 Quinolones: 2001/10
Mortality in ESBL vs. non-ESBL
Enterobacteriaceae bacteraemia
Schwaber & Carmeli JAC 2007 60:913–920
Falling dominoes: Carbapenem-resistant K.
pneumoniae, EARS-net
http://ecdc.europa.eu/en/activities/surveillance/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
Carboxy-pen. R Ureido-pen. R BLICs R Cefepime R Ceftazidime R Cefotaxime R Imipenem R Meropenem R
Amikacin R Gentamicin R Tobramycin R Netilmicin R Tetracycline R SXT R Chloramph. R
Klebsiella pneumoniae from ICU patients
Susceptibility profile:
Production of: VIM-1 MBL SHV-5 ESBL
Pan-resistant Gram negative
Miriagou et al. – JAC 2005; 55:810
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 Rx
May be inappropriate --- or unnecessarily broad
Accelerating microbiology Potential to revolutionise stewardship & therapy
Future….
Potential to deliver results in 6h benefitting patient and stewardship…. but much work still to do
PCR on specimen Recognise key pathogens and a few resistances … some systems available
Next generation sequencing Comprehensive pathogen and resistance detection ….under development
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
Adequate antimicrobial therapy should start within 1 hour
Kumar et al. Crit Care Med 2006;34:1589-96
0.0
0.2
0.4
0.6
0.8
1.0 Fraction of total patients
Time from hypotension onset (h)
Survivors – if antibiotic initiation takes stated period
Fraction on adequate antibiotics
Mortality increases with each hour’s delay
Right drug… Resistance makes empirical therapy harder
Inappropriate
No. resistances
Freq
ue
ncy
(%
pat
ien
ts)
0 1 2 3 0
10
20
30
40
Dead
Mo
rtal
ity
(% p
atie
nts
)
0 1 2 3 0
5
10
15
20
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 / Rx 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
Right dose Pharmacodynamics vary with drug class
Concentr
ation
Time
Cmax = Peak
MIC
T > MIC
b-lactams
Cmax / MIC
Aminoglycosides
AUC / MIC
Fluoroquinolones
Macrolides Glycopeptides
Tetracyclines
Oxazolidinones
.
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 Rx or 15 days in ventilator pneumonia? Kaplan-Meier estimates of patient survival in VAP
No increase of mortality or recurrence Longer RX 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
Bruce J, et al. J Antimicrob Chemother. 2009;64:853-860.
European: 170 hospitals in32 countries
Hospital has: North
n=19 (%) West
n=55 (%) South
n=40 (%) Southeast n=13 (%)
Central east n=43
(%)
Total n=170 (%)
Drugs & Therapeutics Committee
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
8 (44) 32 (59) 17 (45) 5 (46) 25 (61) 87 (51)
No AB committee or AB policy
2 (5) 7 (19) 13 (35) 6 (16) 9 (24) 37 (22)
DTC = Drugs and Therapeutics Committee; AB = Antibiotic; SE = Southeast; CE = Central-East
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 micro-directed therapy
Cycling
Diverse
A B C A B C A B C
A A A B B B C C C
A A A A A A A A A
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…
Antibiotic diversity vs. cycling & restriction Prospective cohort study 44 months, one ICU
11-22 23-34
Cephalo
sporin
Pip
/tazo
No P
ip/t
azo
No C
ephalo
sporin
Months 1-10 Patient Specific
Months 11-22 Priority / Cycling
Months 23-34 Single agents
restricted
Months 35-44 Mixing
Sequential patients
allocated to different Rx
Physician choice, based
on risk factors
No
Car
bap
enem
Car
bap
enem
Different strategies to control resistance
One unit, lot of caveats, but mixing & choice seem best
Physician choice
Cycling Restriction Mixing
1 Acinetobacter – solid, carbapenem R 2 Enterobacteria – ESBL 3 P. aeruginosa – any R 4 S. aureus – methicillin R 5 E. faecalis
Posi
tive
iso
late
s/1
00
ad
mis
sio
ns
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 Rx options but allow choice among them
Assessing the future
Dwindling supply of new antibiotics FDA approvals by 5-year period
0
5
10
15
20
83-87 88-92 93-97 98-02 03-07 08-12
Silver. Clin Microbiol Rev 2011;24:71–109
Age of
reality
Age of
ignorance
Age of discovery
“golden age”
Age of
neglect
Age of the
antibiotic revolution
Antibiotics… A brief interlude in human history
Comparison of novel Antimicrobials
Drug Advantages
Vancomycin / teicoplanin Familiarity, long history of use. Poor for CAP
Quinupristin/
dalfopristin
Alternative to vancomycin. Hardly used now
Linezolid Positive pharmacoeconomic outcome data are
available. Oral dosingremoval of catheters, early
discharge, evidence of superiority to vancomycin in
cSSTI and pneumonia
Daptomycin Potential for less resistance, bactericidal. cSSTI,
bacteraemia
Ceftaroline Broad spectrum. B-lactam; cSSTI, CAP
Tigecycline Broad spectrum, fixed dosages, cSSTI, IAI
Dalbavancin 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”
