InspiRaTI

on
Consensus Forum

1–3 February 2006

Cairo, Egypt
Practical Issues:

Implementing

principles–I
Peter Ball
University of St Andrews,
Scotland
Calls to action:
24 articles on resistance
(Lancet 1998)
• Window between drug discovery and appearance of resistance
is shortening
• Indiscriminate attempts to sterilize the environment (Levy)
• Community = 85% : 80% = RTI (Huovinen & Cars)
– free return visits for no Rx
– 18 hours F/U for acute otitis media
• “Prudent animal usage… benefits society” (McKellar)
• Must reduce both prescription frequency and duration (Wise
et al.)
• Political: little effect on Rx, none on resistance (Carbon & Bax)
• Behavioural aspects:
– care of the elderly
– paediatric day care
• Accurate surveillance – essential (Livermore et al.)
• “We are running out of time and need to act now” (Krag)

Wise et al. BMJ 1998; 317:609–671

Consensus Group 2002
onwards
Principles of appropriate prescribing:

– TREAT bacterial infection only

– OPTIMIZE diagnosis / severity assessment
– MAXIMIZE bacterial eradication (or load reduction)
– RECOGNIZE (local) resistance prevalence
– UTILIZE PD – effective choice of agent and dose
– INTEGRATE local resistance, efficacy and cost-
effectiveness

Ball et al. Antibiotic therapy of community respiratory tract infections: strategies for optimal
outcomes and minimized resistance emergence. J Antimicrob Chemother 2002; 49:31–40
What are we trying to do?

• Prevent (or reduce prevalence of)

increased bacterial resistance
• By improving the quality of prescribing
– reducing inappropriate prescribing
– optimizing appropriate prescribing
• Targeting RTI and primary / out-patient
clinical care
– via governments, health-care providers,
doctors (societies), patients, media
• Reducing overall costs
– to the health-care system (repeat Rx and
consultations, tests, hospital)
– to patients
 Steps to implementation and
audit plus feedback

CORE CONSENSUS: REGIONAL CONSENSUS:

REVIEW DATABASE ASSESS RELEVANCE OF
Surveillance of resistance PRINCIPLES
and usage
Review existing local
Assess costs and outcomes initiatives
Formulate and illustrate Interface with principles
Principles
Local surveillance data
Publish
Implementation -
Identify and meet regional
methodology and barriers
experts LOCAL
CONSENSUS:
RECRUIT
ADVOCATES
Education campaign
Pilot implementation
Feedback prior to
 Antibiotic usage in South
Africa
5000 Broad penicillins
Cephalosporins
4500 Quinolones
4000 Macrolides
Total units in 000s

Trimethoprims
3500 Med/narrow pen
3000

2500

2000

1500

1000

500

0
1998 1998 2000 2001 2002 2003

Data from IMS 2003

Total antibiotic usage influences
resistance rates:
higher usage = higher resistance
prevalence
100
50
Frequency (%)

80 DDDs/1000
25
60 DDDs/1000

40

20

0
0 100 200 300 400 500 600 700 800 900 1000

Time (weeks)

Austin et al. Proc Natl Acad Sci USA 1999; 96:1152–1156

 Middle East and Africa:
penicillin-resistant S.
pneumoniae
Tunisia Lebanon Turkey
24.0% 11.0% 38.0% 18.0% 26.8%
Israel
16.9% 29.7%
Kuwait
1.6% 45.6%
18.3%
Algeria
11.4% 5.7%

Ghana Saudi Arabia

17.0% 0.0% 39.8% 21.7%
Egypt
29.1% 0.0%
Nigeria
36.0%
Kenya
41.2% 1.8%
South Penicillin-intermediate (MIC 0.12–1 µg/
Africa Penicillin-resistant (MIC ≥ 2 µg/mL)
20.9% Data from various sources and various years
51.0%
Resistance in Africa-Middle
East region
• S. pneumoniae pen I/R
– Cairo pen I/R: 63% El Kholy et al. 2003
– Saudi Arabia: 24% I/R, 1.7% R Rahman et al. 1999
– Saudi Arabia: 40–51% I/R, 6–22% R Shibl et al. 2000; Jacobs 2003
– Turkey (Istanbul): 5–25% I/R, 0–9% R Gür et al.
2002
– Turkey (UNI): 84% I/R, 16% R Inar et al 2004
– South Africa: 24–30% I/R, 46–50% R Liebowitz 2003; Baskett study
– Nigeria: 93% (92% ® to Co-Trim) Habib et al, 2003
– Kenya: 48% I/R (~80% Co-Trim) Revathi 2003

• S. pneumoniae ERY 58-61% (ermB 75%)

Liebowitz 2003; Baskett study
• S. pneumoniae LEVO 16 mg/L (x 1 isolate) Ak
et al. 2002 (Turkey)
Resistance mirrors usage:
individuals, specific populations,
regions, countries
• INDIVIDUALS (Gustafsson et al JAC 2003,52:645-50)
– CF, haematology patients vs 1º care controls:
– CEF / ERY resistance  50-60% ~ 0% in controls
• REGIONAL POPULATIONS (Garcia-Rey et al J Clin Microbiol
2002; 40:159-64)
– Usage mirrors β-lactam/macrolide resistance in Spain
– LA macrolides and oral cephalosporins specially implicated
– Correlation coefficients 0.75-0.85 (p 0.003)
• SPECIFIC POPULATIONS (Fry et al CID 2002; 35:395-402)
– Mass prophylaxis of trachoma in Nepalese children
– After one exposure NP Pn resistance 0%: after two exposures 4.3%
• COUNTRIES – FINLAND (Seppälä et al. NEJM 1997;
337:441–446)
– DDD/1000 macrolides: 2.4 reduced to 1.4 in 1990s
– macro-R gpA strept: 16.5% reducing to 8.6% over the period
Will restriction to appropriate
use (principle compliance)
reduce resistance
Icelandic experience RTI
prevalence?
•
– YES!
• Swedish experience RTI
– YES (but slowly)
• Finnish experience RTI (Seppälä et al, NEJM
1997)
– YES
– DDD/1000 macrolides: 2.4 reduced to 1.4 in 1990s
– macro-R gpA strept: 16.5% down to 8.6% over the
period
• Conversely: RTI (Pihlajamäki et al, 2001)
– Increased use = increased resistance
Pressures on the primary-care
physician
Peer groups / prescribing and pharmacy
advisors
Pharmaceutic
al Patients’
representativ demand
es s
(Industry and
spends 35%
physician
of profits on
aspiration
marketing)
s
Regulatory
Hospital experts, formularies and guidelines
control
mechanisms
Why don’t physicians follow
RTI guidelines?
Barriers to implementation include lack of:
• Awareness / familiarity TOO MUCH INPUT
• Agreement: between guidelines MANY
CONFLICTS
• Time and motivation I AM TOO BUSY
• Credibility (applicability and practicability)
WHICH “EXPERTS”
• Proven outcome benefit BENEFIT TO WHO?
– to patient and PC physician PROVE IT!
Industry spends ≥ 35% of income on promotion
Cabana et al. JAMA 1999; 282:1458
Monnet & Sorenson. Clin Microbiol Infect 2001; 7(s6):27–30
Are practice guidelines useful
in practice?
• Italian physicians (2001 survey) perceived practice
guidelines as:
– externally imposed, cost-containment tools – 76%
– NOT as decision-supporting tools
• Applicability to their practice:
– too rigid for individual patients – 61%
– inflexible for local situations – 59%
• Guidelines are MOST useful if:
– Produced by a team: specialists AND primary care (i.e. the
users!)
• Guidelines more useful (% responding YES) than:
– Personal experience (6%), Journals (10%), conferences (6%)
– Pharmaceutical reps (72%)

Formoso et al. Arch Intern Med 2001; 161:2037–2042

Primary care prescribing
information sources – 1990s
100
90
80
70
60
50
40
30
20
10
0
Medical school
Medical journals
Postgraduate Pharmaceutical National
teaching companies guidelines

UK Spain Italy
Huchon et al. Eur Respir J 1996; 9:1590–1595
Where do patients get
information (Taiwan)?
Who should provide education about antibiotics? (% total
response)
– Physicians 70
– Pharmacists 54.5
– Public health officers 50
– Nurses 35
– Teachers 35
– Mass media 62
45-50% thought antibiotics = anti-inflammatory /
antipyretic agents
92% thought taking less than the full course was more
healthy
Chen et al, J Microbiol Immunol Infect 2005; 38:53-9
Cochrane reviews: methods of
changing practice
• Audit and feedback has the potential to change
practice (12 studies)
• reminders based on audit positive
• frequent feedback reinforcement positive (>> infrequent)
• written versus discussion feedback (no trials)
• Educational outreach visits (18 studies)
• promising but cost-effectiveness not measured
• Use of local key opinion leaders (KOLS) (8 studies)
• 6/7 trials measured (at least) one improvement in outcome (2 s.d.)
• three trials on patient outcomes: one achieved significant impact
• BUT how are KOLS identified?

O’Brien et al 2001 a,b,c

Targeting doctors in US HMOs:
can we influence prescribing / care
patterns?
• Written recommendations
– Breast screening (NC, USA): 83% GPs aware – only 8% complied
– Cholesterol reduction: only 6.6% of those eligible received drug
• BUT with CME:
– Attendees (any session) more likely to change practice
– CVS risk : 40% of attendees prepared to change
– Care of homebound elderly: 63% attendees made home visits (47% NA)
• Impact of peer and patient feedback - MINOR to MODERATE :
– 83% considered change in therapy
– 66% initiated change
• Impact of pharmaceutical detailing – MAJOR effect

Sbarbaro, CID 2001; 33 (s3):S240-4

Patients, doctors, regulators
and industry
• CONFLICTS BETWEEN PRIMARY CARE DOCTORS AND
OTHERS
– Patient demands
– Time demands of familiarization with formularies and guidelines
– OTC delivery by pharmacies (nurse prescribing in UK)
– Advice from Pharmaceutical representatives
– Persuasion / inducements
• REGULATORY AUTHORITIES
– desire appropriate prescribing BUT
– don't pay to support education and working practices
• INDUSTRY: MARKETING BUDGET 35% ≥ R&D + PROFITS
33%
• DOCTORS GET ++ DRUG INFORMATION FROM INDUSTRY
Holmes; Monnet & Sorenson, CMI 2001; 7 (s6);
Huchon et al. Eur Respir J 1996; 9:1590–1595
Resistance is a (marketing)
opportunity!
• To alter prescribing (Consensus perspective):
– Restriction to ‘appropriate’ use
– Preserving current drugs for the future
• To alter prescribing habits (industry perspective):
– ‘Our’ drug rather than ‘their’ drug
– ‘Our’ drug (which is more appropriate) than ‘their’ drug
• Most effective drug:
– Maximum PD effect: choice, dose, duration
• Partnership in initiatives:
– Non-promotional: GlaxoSmithKline, Bayer (guidelines)
– Others
The Iowa experience 1998–2000:
implementing a strategy to
counter resistance
Dept Public Health Task Overall effects on
Force: prescribing
• Statewide surveillance   use of first-line
• Guidelines on agents
appropriate use
  inappropriate
• Repeated press prescribing
conferences
  costs
• Media coverage - TV -
Internet • ?? effects on
• HMOs target top resistance ??
prescribers:
 Notification letters
 Guidelines
 Prescribing algorhythms Bell, Amer J Managed Care 2002, 8:988-94
The Iowa experience 1998–2000:
effects on three healthcare
systems prescribers
• Medicaid:
– 81% reduced their prescribing
– 21% fewer insurance claims
– 20% fewer patients ‘treated’
• John Deere: Effects on resistance
  16% first-line prescribing prevalence
– 10% fewer insurance claims ‘not measured’
• Wellmark:
– 23%  penicillin prescriptions
– 23%  macrolide prescriptions

Bell, Amer J Managed Care 2002, 8:988-94

European Union, North
America and
WHO initiatives
Guidance includes:
– control of resistance in the community
– surveillance of resistance and antibiotic usage
– encouragement of judicious use
– in addition, guidance advises:
• prevention, including vaccination (Pn, influenza), infection
control
• rapid diagnosis (near patient testing)
• audit and (regular) feedback
Details:
– 18 national initiatives: UK, US, Canada, France,
Belgium, Aus, Fin, Swe
– 5 international: WHO, EU, Copenhagen, Toronto,
Washington

But ‘implementation is lacking’

Carbon et al, CMI 2002;8 Suppl 2):92-106
Moving from recommendation to
implementation:
repeated education and feedback
initiatives
INTERVENTIONS: reduce inappropriate use, disease burden & bacterial
colonization
ANTIBIOTIC USE:
• Education using relevant data, interactive teaching with feedback,
AUDIT
– Link use and resistance (and outcomes) VIA SURVEILLANCE
– IMPROVE DIAGNOSIS and severity assessment
– Assess OUTCOMES: mortality, morbidity, complication rates, QoL,
hospitalizations
– Assess COST savings
• Implement (consistent) guidelines (principles) and treatment
algorithms
• Delayed treatment or non-antibiotic therapy
• TARGET (AND CONTROL) HIGH PRESCRIBERS
• EDUCATE CONSUMERS Carbon et al, CMI 2002;8 Suppl 2):109-128
Initiatives in lower-income
countries:
recognized problems
• Inadequate healthcare infrastructure and
cohesion
– NB public services, country clinics and private services
• Lack of resources (money, people, diagnostics,
surveillance)
• Difficulties with training and education
• Poor regulatory controls
• Geographical / political logistics
• Population dynamics and beliefs
Unrecognized problems
Initiatives in low-income
countries:
37 available studies by region and
targetTarget
groupGroups:
Region Communit Prescribers Dispenser Multi- Total
y s target
Asia 4 8 3 6 21 (57%)

Africa 2 4 2 1 9 (24%)
Latina 3 1 1 1 6 (16%)
MENA - - 1 - 1 (3%)
Newly - - - - NONE
Indep
Totals 9 (24%) 13 (35%) 7 (19%) 8 (22%) 37
(100%)

Radyowijati and Haak 2003, Soc Sci Med ; 57: 733-44

Practical Issues:

Implementing

principles–II
Peter Ball
University of St Andrews,
Scotland
Implementation process:
continued education, audit
and feedback
Identify Educate:
prescribers:
Resistance /
Specific targets: outcomes Use of
high prescribers, TARGETS principles in RTI
incentivesPatients: age, disease Assisted
Site: 1o care, clinic, hospital,
diagnosis
pharmacy (OTC), unqualified
personel, others
CHOICES
Audit: Implement:
Confidential or Achievable
public. objectives in
reinforcement, appropriate groups
support (HS and - with incentives (if
 Implementation process:
integrating messages and
targets
Prescribers: Service
providers($$):
Doctors,
pharmacists, NHS, HMOs, AID
nurses, clinics, organisations
quacks and (WHO, Red
others Cross), military,
Current
initiativ
es?
Support
Patients: organisations:
Individual Media (press,
education, radio, TV),
consumer clerics, teachers.
groups, disease Posters,
focus and
Changes in prescribing USA:
1989-2000
Good news and bad news
• Office prescribing
(children) 20
14
15
– Decade 1989-2000:
47% reduction 10 8
4
– McCaig JAMA 2002, 5 2
287:3096
0

Pharyngitis

bronchitis
Colds / ARI

media
Otitis
• Out-patients (children) -5

Ac
– Decade 1989-2000: -10
50% reduction
-15
– Steinmann et al Ann Int Med
2003; 183:525-33 -20

– BUT a 23% → 40% increase -25

in broad spectrum
prescriptions Overall
BS antibiotics

– Cost of proprietary BS was

10-fold higher than generics
in 1997
Are administrative (imposed)
restrictions beneficial?
An example
• Restrictive formulary policy imposed on six
US HMOs
– Limitations on drugs within a class or classes
– Exclusion of certain classes completely
• Overall care costs increased
– The most restrictve policies = greatest cost increase
• Policies driven by cost (acquisition of drug)
– ignore overall benefits,
– have unexpected consequences

Han et al. Amer J Managed Care 1996; 2:253

Unexpected outcomes in
Australia:
initiative to reduce co-
moxiclav usage
• The policy created:
in primary
– unintended changes in prescribing behaviour
care
– higher costs (significant increased hospitalization/investigation)
– a trend towards poorer individual patient outcomes
Before letter
600
Number of patients

After letter
500
400
300
200
100
0
n

ts
gy

gy
l
io

ra

es
lo

lo
at

er

t
io

ho
liz

er
ef

ad

t
ta

th
R

Pa
R
pi

Beilby et al. Clin Infect Dis 2002

os
H
 To reduce misuse/abuse by
doctors:
Message: do not use
antibiotics
Diagnosis
for ………….
Message
Potential
reduction (%)

Otitis media No antibiotic for OME 30

Pharyngitis No antibiotic unless Strep+ 50

Bronchitis No antibiotic unless specific 80

infection or lung disease

Sinusitis No antibiotic unless prolonged

/ severe 50

Common cold No antibiotic 100

CENTERS FOR DISEASE CONTROL

AND PREVENTION
Similar campaign highly effective in HK: Seto, 2003
Patients also need messages

• Antibiotics are under threat

– current ones are less effective than before
– new ones are ‘running out’
• MANY INFECTIONS DO NOT NEED ANTIBIOTICS: COLDS, FLU,
SORE THROATS ETC.
• In this situation: antibiotics do no good, and may cause
– side effects,
– ‘friendly bacteria’ to become resistant
• Your GP should advise you when antibiotics are needed
• He should use antibiotics which
– kill bacteria rapidly and make you better sooner
– are cost-effective
– cause less ‘side effects
– are least likely to cause resistance
• Please do not hoard antibiotics for ‘the next time’
Impact of a public campaign
for more rational use of
antibiotics in Belgium,
Nov
• 2000
Expect to for
antibiotic March
flu: 2001
49% (before) vs. 30% (after)
• Expect antibiotic for sore
throat:
32% (before) vs. 18% (after)
• Less antibiotic to avoid
resistance:
64% (before) vs. 75% (after)
• Antibiotics must be
protected:
13% (before) vs. 25% (after)
• Total antibiotic sales
Beauraind et al, personal communication; http://www.antibiotiques.org
decreased by
Reduced prescribing in AOM:
observation, pain relief, safety-net (delayed)
antibiotic prescription
• Excluding severe illness: Rx pain relief and safety-net antibiotic prescription to
be filled only if symptoms persist

• 20% reduction in antibiotic usage (UK)1

• only 55/178 (31%) parents filled prescription (OHIO /KENTUCKY USA)2

Reducing demand in acute bronchitis

• Explanatory pamphlet: reduced prescription uptake by 15% (p=0.04)3
• Education of both patient AND doctor: reduced Rx 74%  48% (p=0.003)4
• BUT 93% of US parents think antibiotics ‘essential’ for childhood bronchitis5

1. Cates Brit Med J 1999; 318:715-6,

2. Siegel et al, Pediatrics 2003; 112:527-531 ;
3. Macfarlane et al. BMJ 2002; 324:1–6;
4. Gonzales et al. JAMA 1999; 281:1512–1519;
5.Belongia et al Prevent Med 2002, 34:346-352
In lower income countries:
patient factors in Pakistan
• 50% of the population live below the poverty line
– half the population is illiterate
– access to doctors is limited
• Prescriptions from Quacks and Hikmat
• Compliance problems are common and include:
– lapse in dosing, stopping Rx early, hoarding
• Over-the-counter (OTC) sales are available:
– excessive costs and unnecessary side effects
– driving antibiotic resistance
– sub-optimal dosage and inadequate duration

Zafar Ullah Khan 2003

Initiatives in low-income
countries:
37 available studies by region and
targetTarget
groupGroups:
Region Communit Prescribers Dispenser Multi- Total
y s target
Asia 4 8 3 6 21 (57%)

Africa 2 4 2 1 9 (24%)
Latina 3 1 1 1 6 (16%)
MENA - - 1 - 1 (3%)
Newly - - - - NONE
Indep
Totals 9 (24%) 13 (35%) 7 (19%) 8 (22%) 37
(100%)

Radyowijati and Haak 2003, Soc Sci Med ; 57: 733-44

Determinants of antibiotic
prescribing in
low-income countries (overview
Prescribers Dispensers Public
of 37 studies)
Untrained advice / self medication

Marketing influences

Patient/customer demand

Folk beliefs/traditions

Doctors fear of failure

Economic incentives
Many clear
Inadequate drug supply
opportunities
Poor or delayed lab results
for
Lack of knowledge
intervention
0 16
Number of studies reporting

Radyowijati and Haak 2003, Soc Sci Med ; 57: 733-44

Suggested priorities for action

in low-income countries
• Government:
– regulate prescribers (NB private sector)
– INITIATE AND SUPPORT surveillance of use and resistance
– PROMOTE preventative medicine and education of dispensers
• Health Service and Health Care Organisations:
– ASSESS appropriate use,
– PROVIDE principles and guidelines, AUDIT compliance
• Training institutions: SCHEDULE curriculum time and TEACH
appropriate use
• Professional Societies: PROVIDE evidence-based CME
• Pharmaceutical Industry:
– CONTROL promotion, INFORM prescribers/consumers as to prudent use
• Consumer Associations: MAKE APPROPRIATE USE A
CONSUMER ISSUE
Radyowijati and Haak 2003, Soc Sci Med ; 57:
Kenya:
Some key issues driving antibiotic
resistance
National issues:
• no (or inadequate) resistance surveillance
• no antibiotic policies (or no compliance) in most large hospitals
• inadequate infection control protocols
• insufficient qualified personnel for supervision of laboratories
Clinical / laborarory issues:
• antibiotic choices: empirical or based on poor quality specimens /
lab reports
• > 40% of clinicians only send specimens after failure of initial
therapy
• misinterpretation of serology, e.g. Widal reactions (false
epidemics)
– massive abuse of ciprofloxacin and increase in FQ resistance
• misuse of BSPs: for example, 3rd gen Cefs for ARI
• massive burden of HIV-AIDS population

Revathi, 2003
Kenya:
Prevalence of HIV in
hospitalized children
2500 HIV uninfected
HIV infected
Number of children

2000

1500

1000

500

0
1997 1998 1999 2000 2001 2002
Year
 Differences between rural areas
and towns:
Prescriptions and PRSP in
Pharmacies prescribing antibiotics for ALL RTI: ~ 99%
Vietnamese children
Healthcare preferences Urban % Rural %

Pharmacy (cost factor 37 95

dominant)
adequate dose and duration 50 27

Family member 11 80

Private doctor 77 47

Traditional doctor 7 8

Penicillin I/R pneumococi NP 83% 38%

Quagliarello et al J Hlth Popul Nutr 2003; 21:316-24

Improved prescribing in Viet
Nam
(Hai Phong)
• Commune health station study:
AB prescribed
Appropriate dose
• given US$ grant for drugs (and
implementation of education) 100
• Outcome measures: % receiving AB
and % receiving adequate dosage
after retraining and incentives 75
• NB continued evaluation and
supervision
• Chalker, WHO Bulletin 2001; 50
79:313-320

25

Observation period
0 (months)
0 1 6 12 15 18
(Some) barriers to
implementation
of Principles
• Lack of Interest in resistance and relevance of existing guidelines
• Inadequate funding
– Health-care systems
– staffing of health care (clinical AND laboratory)
• Restriction of availability and reimbursement issues (costs to
underprivileged)
• OTC or other non-medical prescribing
• Formulary (DTC) and guideline committees
• Pharmacists fear threats to autonomy / integrity Are these
• Excessive pressures from Industry factors
• Patient (or parent) problems or
– Expectations are they the
– self diagnosis and beliefs about antibiotics keys to
– Cultural and religious issues
potential
answers?
Please consider:
are barriers actually
opportunities?
• Implementation: a message with a benefit
– reduced failures ~ resistance Patients / System
– reduced consultations / return visits Primary Care / System
– reduced acquisition / retreatment costs Pharmacy budget / patients
– reduced hospitalisation costs Government / HMO / Patients
– reduced litigation potential Doctors
• Proven outcome benefit
– more time, patients, income (leisure) Doctors
– less time off work Patients / Society
• Reduced bacterial resistance Future generations
• THERE IS NO DOWNSIDE OR DISADVANTAGE TO
WIDESPREAD IMPLEMENTATION
Please consider:
Where should implementation
commence?
• Areas of high resistance • Which patients, disease
prevalence? groups?
– Best chance of showing a • How can the Core Consensus
difference, or, Group assist with:
– best chance of failure?
– Regional / local consensus?
• Countries with highest
antibiotic consumption? – Societies and Prescriber / Patient
Groupings?
• Countries with active
society structure? – Credibility: to whom will PCPs
listen?
• Countries with existing
initiatives? – What will change their practice?
– Do they work – Implementation, audit, feedback?
• Countries with
authoritarian infra- • Where will the funding come
from?
structure