STATENS SERUM INSTITUT Antimicrobial Resistance and Usage Patterns in Europe: Focus on Dutch-Belgian Differences and Complementarity & Lessons for the Future Dominique L. Monnet Antimicrobial Resistance Surveillance Unit, Dept. of Antimicrobial Resistance & Hospital Hygiene, Statens Serum Institut, Copenhagen, Denmark
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STATENS SERUM INSTITUT
Antimicrobial Resistanceand Usage Patterns in Europe:Focus on Dutch-Belgian Differences and
Complementarity & Lessons for the Future
Dominique L. Monnet
Antimicrobial Resistance Surveillance Unit, Dept. of Antimicrobial Resistance & Hospital Hygiene,
Statens Serum Institut, Copenhagen, Denmark
STATENS SERUM INSTITUT
MRSA in Europe, 1990-1991
Source: Voss A, et al. Eur J Clin Microbiol Infect Dis 1994;13:50-55.
< 1%1-2%5.5%
20-29%30-35%
STATENS SERUM INSTITUT
Source: EARSS. Available from: URL: http://www.earss.rivm.nl/
< 3% 3-9%
10-29%> 30%
Methicillin-Resistant Staphylococcusaureus (MRSA) from Blood, 2001
STATENS SERUM INSTITUT
Ticarcillin-Resistant Pseudomonasaeruginosa in Europe (ICU NIs only), 1992
Source: EPIC Study (Régnier B. Pathol Biol 1996;44:113-23).
no data 0% 15-25% 50-65% 80%
STATENS SERUM INSTITUTThe World According to… Human BacterialPathogens and Their Habitat
H
S. pneumoniae
H. influenzae
Pseudomonas aeruginosaAcinetobacter baumannii
S. aureus
le MONDe de la Résistance Intrinsèque et Acquise aux ANtibiotiques ;-).
Food
An
imal
sH
uman
sH
uman
s
Salm.
Camp.
E. coli
E. coli
MRSA
S. aureus
STATENS SERUM INSTITUT
< 3% 3-9%
10-29%> 30%
Source: EARSS. Available from: URL: http://www.earss.rivm.nl/ (Accessed: 31/7/2002)
Penicillin-Non Susceptible Streptococcuspneumoniae (PNSP) from Sterile Sites
20022001
STATENS SERUM INSTITUT
< 3% 3-9%
10-29%> 30%
Erythromycin-Resistant Streptococcus pneumoniae from Sterile Body Sites
2002
Source: EARSS. Available from: URL: http://www.earss.rivm.nl/ (Accessed: 31/7/2002)
2001
STATENS SERUM INSTITUTErythromycin-Resistant Streptococcuspneumoniae from Community-Acquired
Respiratrory Tract Infections, 1998
Sources: Alexander Project, FINRES, STRAMA and DANMAP.
no data 0-5% 5.1-10% 10.1-30% >30%
STATENS SERUM INSTITUT
• Lower use of macrolides (less exposed, shorter duration)• Lower use of other antimicrobials• Better compliance (dose, intervals)
• Vaccination• Breast feeding
• Age (extremes)• Respiratory and other diseases
• Pre-school facilities• Long-term care?• Better living conditions• Socio-economic status• Climate?• Less travel• Different clones
Different population?Better protectionagainst disease?
Less cross- transmission?Lower Percentage of
Erythromycin-R S. pneumoniaein Community-Acquired RTIs
More rational utilization of antimicrobials?
STATENS SERUM INSTITUT
Source: Cars O, et al. Lancet 2001; 357: 1851-3.
STATENS SERUM INSTITUT
Is It Relevant to Examine OverallAntibiotic Consumption? (1)
! Overall antibiotic consumption (no. DDD) is relatedto no. antibiotic prescriptions and no. personsexposed to antibiotics
! It only accounts for some aspects of antibioticmisuse, e.g. prescribed when not indicated, durationtoo long, but cannot account for errors in dosing orlow compliance
! Nevertheless, if the antibiotic course prescribed isnot completed, then it is probably used at anotheroccasion
STATENS SERUM INSTITUT
Is It Relevant to Examine OverallAntibiotic Consumption? (2)
! Antibiotics have an effect not only on the patientswho are treated but also an effect on other patientsand the environment
! Relationship between antibiotic use and resistanceis an ecological problem!
! There is room for improvement considering theextent of variations both in the amount and thepattern of use among European countries
STATENS SERUM INSTITUT
0
20
40
60
0 2 4 6 8C o nsu m ption of m acrolides an d lin cosam id es
in p rim ary h ealth care in 1997 (D D D /1,000 in h .-d ays)
Eryth
romycin-resistant
S. pneumoniae in 1998 (%)
Sources: Alexander Project, FINRES, STRAMA, DANMAP, and Cars O, et al. Lancet 2001; 357: 1851-3.
Erythromycin-Resistant Streptococcuspneumoniae and Macrolide Consumptionin EU Member States, 1997-1998
Source for resistance data: Kahlmeter G, et al. ECO.SENS.Source for antimicrobial consumption data: Cars O, et al. Lancet 2001; 357: 1851-3.
%Nalidixic Acid-Resistant E. coli (Logodds transf.)
and Antimicrobial Consumption in Europe
STATENS SERUM INSTITUT
GP or specialist
Patient
Pharmacist
Over-the-counterdispensation of antimicrobials
Prescription ofantimicrobials
Infection /Microorganism
Pathways of Antimicrobial Usein Primary Health Care
STATENS SERUM INSTITUT
GP or specialist
Patient
Pharmacist
Over-the-counterdispensation of antimicrobials
Prescription ofantimicrobials
Infection /Microorganism
Pathways of Antimicrobial Usein Primary Health Care (1)
STATENS SERUM INSTITUT
Different Susceptibility to/ProtectionAgainst Infectious Diseases or Incidence ofCommunity-Acquired Infectious Diseases?
! Demography! Incidence of certain diseases, e.g. diabetes, cancer! Living conditions: overcrowding, day care, hygiene! Protecting factors: breastfeeding, vaccinations
! Incidence of community-acquired infections:bacterial RTIs, influenza-like illness
! Prevalence of resistance among community-acquired bacteria
STATENS SERUM INSTITUT
323 Pop. cannot afford to keep home adequately warm(%)
111217 Pop.below ”poverty line” (%)9310 Pop. in overcrowded homes (%)
868997 Urban population (%, WHO)
151417 Pop. > 65 year old (%)
666 Pop. 0-4 year old (%)
1
464
15.7
Netherlands
37 Pop. without at least one of bath, toilet or hot water (%)
125336 Pop. density (inhab./km2)
5.310.2 Population (million inhab.)
Denmark Belgium
Source: U.S. Bureau of the Census, WHO HFA database & EC Eurostat.
Characteristics of the Populationof 3 EU Member States, 1996-1999 (1)
STATENS SERUM INSTITUT
No repororadic/LoRegional0
10
20
30
40
50
DDD
/1,0
00 in
h.-d
ays
Influenza-Like Illness Activity and OverallConsumption of Systemic Antibacterials (ATC J01)in Primary Health Care, EU Member States, 1997
Influenza-Like Illness Activity, 1997Source: FluNet. Available from:
http://oms2.b3e.jussieu.fr/flunet/activity.html
No activity Sporadic Regional // No report / Local Widespread
50
40 30
20 10
0C
onsu
mpt
ion
of a
ntib
acte
rials
fo
r sys
tem
ic u
se A
TC J
01 (D
DD
per
1,0
00 in
h-da
ys)
STATENS SERUM INSTITUT
Overall Consumption of Systemic Antibacterials(ATC J01) in Primary Health Care andBreastfeeding, EU Member States, 1985-1997
Breastfeeding & Respiratory Illness During Childhood
Wilson AC, et al. BMJ 1998;316:21-25.
0
10
20
30
40
50
0 20 40 60 80 100
Infants breastfed at 3 m onths(% , 1985-1997, U K : at 4 m ths)
Source: Touw-Otten FWMM & Staehr Johansen K. Family Pract. 1992;9:255-262.
Prescription of Antimicrobialsand Bacteriological Testing forAcute Tonsillitis, 1989-1990
STATENS SERUM INSTITUT
Patient
Pharmacist
Over-the-counterdispensation of antimicrobials
Prescription ofantimicrobials
Infection /Microorganism
Pathways of Antimicrobial Usein Primary Health Care (2)
GP or specialist
STATENS SERUM INSTITUT
! Cultural differences: perceived severity of illness! Social issues: pressure to be back at work/day care! Economical issues: income vs. price! Education and information: information campaigns! Health care system and regulation: cost of GP
consultation, price of antimicrobials after reimbursement,direct access to specialists(?)
! Promotion: direct-to-consumer advertising
Factors that Influence Prescription (1):Related to the Patient
STATENS SERUM INSTITUT
Factors that Influence Prescription (2):Related to the GP or the Specialist
! Cultural differences: willingness to help! Education and information: information campaigns,
guidelines, drug compendia, registered indications for aspecific antibiotic, promotional material provided byrepresentatives
! Health care system and regulation: type of healthcaresystem, rostering of patients, GP remuneration, workinghours, point-of-care diagnostic tests, economical incentives,fear of litigation
! Pharmaceutical industry and promotion: competitionamong pharmaceutical companies, intensity of promotionalactivity to GPs/specialists
STATENS SERUM INSTITUT
Source: Deschepper R, et al. Pat. Educ. Counsel. 2002;48:161-169.
Attitude Towards Upper Respiratory TractInfections, by Region and Religion
2544886717
Use of antibiotics during the past 5 years - none/low (%)
0440050 - strong believer (%)251163330
Belief in antibiotics - sceptic (%)
0
0
88
Protestant,
NL (n=8)
44
56
0
Non- churchg., FL (n=9)
0083 Fear of complications (%)
0
33
Catholic,
NL (n=3)
050 - high/very high (%)
750 Healing power of body (%)
Non- churchg., NL (n=4)
Catholic,
FL (n=6)
STATENS SERUM INSTITUT
Majority protestant Majority catholics0
10
20
30
40
50
DD
D/1
,000
inh.
-day
s
What About Cultural Differencesin the European Union?
WELL…, INSTEAD OFALWAYS POINTING AT
CULTURAL DIFFERENCES TOEXCUSE OUR LACK OF ACTION
OR PREVIOUS MISTAKES, MAY BE…WE COULD LEARN FROM (OTHER)DIFFERENCES AMONG COUNTRIES
OR REGIONS AND IDENTIFY AREAS FOR IMPROVEMENT!
P=0.001
Con
sum
ptio
n of
ant
ibac
teria
ls
for s
yste
mic
use
ATC
J01
(DD
D p
er 1
,000
inh-
days
)
50
40
30
20
10
0
Majority Majorityprotestants catholics
STATENS SERUM INSTITUT
Source: Coenen S, et al. Lancet 2001;358:1272; Thiadens HA, et al. Lancet 2001;358:1272-3; Audit Project Odense, 2001 report.
Antimicrobial Prescribing Attitudesof GPs Can Be Modified ThroughPeer-Review/Education!
! Netherlands: peer-review groups (incl. collaboratingpharmacist), mandatory clinical audits every 2 or 4 weeks(pharmacist reviews prescriptions)
! Belgium: no such peer-review groups! Denmark: Audit Project Odense (APO), voluntary audits
and reviews, originally for Danish counties, now expandingin other European countries
STATENS SERUM INSTITUT
Source: Beauraind I, et al. Personal communication. http://www.antibiotiques.org/
! Expect antibiotic for ’flu’: 49% resp. (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 decreased
by approx. 10%
Impact of a Public Campaign for a More RationalUse of Antibiotics in Belgium, 11/2000-03/2001
STATENS SERUM INSTITUT
Dimensions 30x21x7 cm 30x21x5 cm 17x11x2.5 cm Weight 3.1 kg 1.8 kg 380 g Main classif. by company by disease+alph. by disease Financing pharm. industry pharm. industry med. assoc. Guidelines no no yes (27 pages)
Characteristics of Spanish vs. Danish Compendia
STATENS SERUM INSTITUT
NoNo
YesYes
Capitation/Fee
48
Netherlands
Max./yearMax./year
No50 – 100%
Partially15 – 25%
Patient pays for: - consultations - antibiotics
YesYesNo Referral to specialistsYesYesNo Rostering of patients
Salary/FeeFeeFee Remuneration GPs
5664153 GP/100,000 inh.
Sweden Denmark Belgium
Source: Hendrickx E, et al. 41st ICAAC, Chicago (IL), 16-19/12/2001, #401.
Characteristics of Primary HealthCare Systems in Four EU MemberStates, 1997
STATENS SERUM INSTITUT
Salary/capitation Fee-for-service0
10
20
30
40
50
DD
D/1
,000
inh.
-day
s
Rostering No rostering0
10
20
30
40
50
DD
D/1
,000
inh.
-day
s
Overall Consumption of Systemic Antibacterials(ATC J01) in Primary Health Care, Fee-for-Serviceand Rostering of Patients by GPs, EU, 1997
Sources: Cars O, et al. Lancet 2001; 357: 1851-3, and ”Highlights on Health”, WHO/EURO.
Monthly Tetracycline Prescription Rate andTetracycline Resistance in S. aureus BloodIsolates, Denmark, 01/1994-12/1999
0
1
2
3
4
5
1994
1995
1996
1997
1998
1999
0
2
4
6
8 Change in subsidization: from 50 to 0% (01/1996)
Te
trac
yclin
e U
se (
# pr
escr
iptio
ns p
er 1
,000
inha
bita
nts)
Te
trac
yclin
e -R
S. a
ureu
s B
lood
Isol
ates
(%, 5
-mon
th m
ovin
g av
erag
e)
STATENS SERUM INSTITUT
0
2
4
6
0 0.5 1 1.5
A verage cost of 1 D D D of oral tetracycline after reim bursem ent
(P P P U S $, 1998)
Consumption of tetracyc
lines
for sys
temic use A
TC J01A
(DDD per 1,000 in
h-days
, 1997)
0
1
2
3
4
5
0 2 4 6
A verage cost of 1 D D D of oral fluoroquinolone after reim bursem ent
(P P P U S $, 1998)
Consu
mptio
n of flu
oroquinolones
for sy
stemic use ATC J01M
A (DDD per 1,000
inh-day
s, 1
997)
Sources: Sources: Cars O, et al. Lancet 2001; 357: 1851-3, and EudraMat, April 1998.
Cost After Reimbursement and Consumption ofTetracyclines and Fluoroquinolones in PrimaryHealth Care, EU Member States, 1997
[ ]
[ ]
[ ][ ]
STATENS SERUM INSTITUT
0
2
4
6
8
0 10 20 30 40 50
O ral fluoroquinolone product nam es (N o., incl. brands and generics, 1998)
Ex-factory price
of 1 D
DD of oral
fluoroquinolone (P
PP U
S$, 199
8)
Source: EudraMat, April 1998.
Ex-Factory Price and Number of Brands ofTetracyclines and Fluoroquinolones on Market,EU Member States, 1998
0
1
2
3
4
0 20 40 60 80
O ral tetracycline product nam es (N o., incl. brands and generics, 1998)
Ex-factory price of 1 D
DD of oral
tetracyc
line (PPP US$, 1998)
STATENS SERUM INSTITUT
0
2
4
6
0 20 40 60 80
O ral tetracycline product nam es (N o., incl. brands and generics, 1998)
Consu
mptio
n of tetrac
yclin
esfor sy
stemic use ATC J01A
(DDD per 1,000
inh-day
s, 1
997)
0
1
2
3
4
5
0 10 20 30 40 50
O ral fluoroquinolone product nam es (N o., incl. brands and generics)
Consumption of fluoro
quinolones
for sys
temic use A
TC J01MA
(DDD per 1,000 in
h-days
, 1997)
Sources: Sources: Cars O, et al. Lancet 2001; 357: 1851-3, and EudraMat, April 1998.
Overall Consumption of Fluoroquinolones (ATCJ01MA) in Primary Health Care, Companies andBrands of Antibiotics, EU Member States, 1997
( )
R2=0.36 P=0.05
( )
( )
( )
NS
( )
STATENS SERUM INSTITUT
0
10
20
30
40
50
0 40 80 120
C om panies m arketing antibiotics(N o.)
Consumption of antibacterials
for sys
temic use A
TCJ01
(DDD per 1,000 in
h-days
)
0
10
20
30
40
50
0 100 200 300
O ral antibiotic product nam es(N o., incl. brands and generics)
Consumption of antibacterials
for sys
temic use A
TCJ01
(DDD per 1,000 in
h-days
)
( )
( )
( )
R2=0.52 P=0.008
( )
R2=0.42 P=0.01
Sources: Sources: Cars O, et al. Lancet 2001; 357: 1851-3, and EudraMat, April 1998.
Overall Consumption of Systemic Antibacterials(ATC J01) in Primary Health Care, Companies andBrands of Antibiotics, EU Member States, 1997
STATENS SERUM INSTITUT
GP or specialist
Patient
Pharmacist
Over-the-counterdispensation of antimicrobials
Prescription ofantimicrobials
Infection /Microorganism
Pathways of Antimicrobial Usein Primary Health Care (3)
STATENS SERUM INSTITUT
Over-The-Counter (OTC) Dispensation of Antimicrobials in Europe! Anecdotal evidence from colleagues…! Spain: 42% of 1,000 households reported having
antimicrobial packages at home. Only 2/3 of thesepackages were the result of a physician’s prescriptionOrero A, et al. Med Clin (Barc) 1997; 109: 782-785.
! Greece: 69% and 86% of pharmacists offeredantibiotics when presented with a high-fever and alow-fever rhinosinusitis scenario, respectivelyContopoulos-Ioannidis DG, et al. Clin Infect Dis 2001; 33: 76-82.
! EC-funded project ”Self-medication with Antibiotics”started on 1st October, 2002
STATENS SERUM INSTITUT
0
5
10
15
20
E I
FIN
A
UK
S
DK
IRL
Consumption of medicines
without prescription
(% in
terviewed, 1996)
0
10
20
30
40
50
0 5 10 15 20 25
C onsum ption of m edicinesw ithout prescription (% int., 1996)
Consumption of antibacterials
for sys
temic use A
TC J01
(DDD per 1,000 in
h-days
, 1997)
Sources: Eurobarometer 44.3, European Commission; Cars O, et al. Lancet 2001; 357: 1851-3.
Overall Consumption of Systemic Antibacterials(ATC J01) in Primary Health Care and Consumptionof Medicines Without Prescription, EU, 1996-1997
R2=0.37 P=0.02
STATENS SERUM INSTITUT
0
5
1 0
1 5
2 0
2 5
0 5 ,0 0 0 1 0 ,0 0 0 1 5 ,0 0 0 2 0 ,0 0 0N o. inhabitants per public pharm acy
(1997)
Consumption of medicines
without prescription (% pop., 1996)
0
0.1
0.2
0.3
0.4
0.5
0 5,000 10,000 15,000 20,000
N o. inhabitants per public pharm acy(1997)
Annual revenues fro
m sales
of pharm
aceuticals per public
pharm
acy (M
illion PPP US$, 1997)
Sources: Eurobarometer 44.3, European Commission in Key Data on Health 2000, Eurostat;and GIRP and IMS Health.
Consumption of Medicines Without Prescription, No.Inhabitants per Pharmacy, and Annual Revenues fromSales of Pharmaceuticals per Pharmacy, EU, 1996-1997
R2=0.59 P=0.001
STATENS SERUM INSTITUT
Conclusions! Food for thought…! A ”substantial” part of the observed differences in
resistance are certainly due to different levels andpatterns antimicrobial use
! Better understand determinants of antimicrobial use inEurope and generate hypotheses for interventions
! Study the possible adverse effects of restrictive andconservative antimicrobial use!
! Some missing data should soon be provided byEuropean collaborative projects, e.g. ESAC (primaryhealth care and hospitals), ARPAC (mainly hospitals),SAR (self-medication with antibiotics)