Policy-Relevant Determinants for the Control of Macrolide-Resistant Streptococcus pneumoniae: Do

International Comparisons Help?

Harbarth S, Monnet DL, Pechère JC, Cars O.

BACKGROUND

Evaluating policy-relevant determinants of antibiotic overuse and bacterial resistance is a complex task.

Standardized assessment of these determinants may enable cross-cultural comparisons and allow policy makers to identify and implement those control measures that are the most likely to be successful.

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Total antibiotic use (DDD/1000 pop/day)

403020100

Pen

icil

lin

-no

nsu

scep

tib

le S

. p

neu

mo

nia

e (%

) 60

50

40

30

20

10

0

USA

UK

Sweden

Spain

Portugal

NorwayNetherlands

LuxemburgItaly

Ireland

Iceland

Greece

Germany

France

FinlandDenmark

Canada

BelgiumAustria

AustraliaAlbrich, Monnet & Harbarth, Emerg Infect Dis 2004

TaiwanPenicillin-resistant pneumococci and outpatient AB-use

OBJECTIVES The purpose of this retrospective, ecologic

study was to explore macro-level determinants explaining the large variation in MRSP prevalence in 14 European countries.

Specifically, we attempted to test different hypotheses (e.g., antibiotic usage patterns, population characteristics) linked to low or high MRSP prevalence.

Antibiotic-resistant

pneumococci

Patient factors

Cultural influences

Social determinants

Regulatory practices

Antibiotic overuse and

misuse

Prescriber factors

Harbarth et al, Emerg Infect Dis 2002; 8: 1460-1467

Macro-level determinants influencing AB overuse

METHODS An extensive list of all possible

determinants that might explain variations in MRSP prevalence was established.

Data on MRSP prevalence and explanatory factors were retrieved from electronic databases, reports from multinational and national surveillance systems, and international organizations.

Correlations were assessed with the 2-tailed Spearman coefficient for non-parametric correlations.

• 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 protection against disease?

Less cross-transmission?Lower Proportion of

Macrolide-R S. pneumoniaein Community-Acquired RTIs

More rational use of antibiotics?

RESULTS

0

20

40

60

0 2 4 6 8Consumption of macrolides and lincosamides

in primary health care in 1997 (DDD/1,000 inh.-days)

Ery

thro

myc

in-r

esis

tant

S

. pne

umon

iae

in 1

998

(%)

Sources: Alexander Project, FINRES, STRAMA, DANMAP, and Cars O, et al. Lancet 2001; 357: 1851-3.

Macrolide-Resistant Streptococcus pneumoniae and Macrolide Consumption in EU Member States, 1997-1998

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Independent variable (ATC group) No. EU

countries R P

Macrolides and lincosamides (J01F) 14 0.88 <0.001

Extended spectrum penicillins (J01CA) 14 0.83 <0.001

Cephalosporins and related (J01D) 14 0.75 0.002

Quinolones (J01M) 14 0.55 0.04

Beta-lactamase sensitive penicillins (J01CE) 14 (-) 0.69 0.007

Tetracyclines (J01A) 14 0.12 NS

Beta-lactamase resistant penicillins(J01CF) 14 0.02 NS

Trimethoprim (J01EA) 14 0.07 NS

Macrolide-R S. pneumoniae (%) and Antimicrobial Consumption in Europe

Source for resistance data: Alexander Project.Source for antimicrobial consumption data: Cars O, et al. Lancet 2001; 357: 1851-3.

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Independent variable

No. EU

countries R P

Admit having used antibiotic left-overs during the last 12 months (%)

14 0.84 < 0.001

Admit having used antibiotics without a prescription during the last 12 months (%)

14 0.74 0.002

Source: EUROBAROMETER 2002.

Macrolide-R S. pneumoniae (%): Factors Affecting Compliance with Antibiotic Treatment

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Independent variable No. EU

countries R P

Persons living in households with children (%) 14 0.62 0.02

Nights spent in EU countries with high MRSP rate

(per 1,000 inh.-days)

14

0.55 0.04

Children in preschool services (%)

10

0.56

0.09

Persons in overcrowded households (%) 14 0.46 NS

Sources: Danish National Institute of Social Research, EC Eurostat, and European Travel Commission (ETC) Tourism Statistics.

Macrolide-R S. pneumoniae (%):

Factors That Might Facilitate Cross-Transmission

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Independent variable

No. EU

countriesR P

Infants breastfed at 3 months of age (%) 13 (-) 0.69 0.007

General vaccination coverage of infants 14 (-) 0.58 0.03

Persons with at least 3 hours of leisure physical activity per week (%)

14

(-) 0.59

0.03

Population whose age is >65 years (%) 14 0.47 0.09

Population whose age is <= 4 years (%) 14 (-) 0.31 NS

Incidence of hospital discharges for respiratory diseases 14 0.14 NS

Daily cigarette smokers (%) 14 0.35 NS

Distributed doses of pneumococcal vaccine 14 0.07 NS

Sources: U.S. Bureau of the Census, EC Eurostat, WHO Regional Office for Europe, and Fedson DS. Clin Infect Dis 1998;26:1117-23.

Macrolide-R S. pneumoniae (%):Population Characteristics and Protection against Disease

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Independent variable

No. EU

countries R P

Responsiveness of health care system 14 (-) 0.54 0.05

Health system performance (in DALYs) 14 0.60 0.03

Households that cannot afford to keep home adequately warm (%)

13 0.49 0.09

Persons living below the ”poverty line” (%) 12 0.40 NS

Source: World Health Report 2000.

Macrolide-R S. pneumoniae (%): Economic and Health Care System

Responsiveness of health system is a measure of how the system performs relative to non-health aspects (e.g. choice of provider,client orientation) thus meeting or not meeting the population’s expectations of how it should be treated by providers of care.

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Independent variable

No. EU

countries R P

Power distance 14 0.59 0.03

Uncertainty avoidance 14 0.57 0.03

Masculinity 14 0.55 0.04

Individualism 14 0.04 NS

Long-term orientation 13 (-) 0.32 NS

Source: HOFSTEDE.

Macrolide-R S. pneumoniae (%): Culture Determinants

Power distance is a measure of the interpersonal power or influence between two individuals when one is the subordinate of the other. Uncertainty avoidance is a measure of tolerance to ambiguous situations, which leads some individuals to feel more pressed for action than others. Masculinity is a measure of the implications that differences between the sexes should have for the emotional and social roles of the genders. Individualism is a measure of the relation between the individual and the collectivity that prevails in a society and is reflected in the way people live together.Long-term orientation is based on the long-term aspects of Confucius thinking: persistence and thrift to personal stability, and respect for tradition.

Summary Determinants positively correlated with MRSP prevalence:

Use of macrolides and other antibiotic classes (e.g., cephalosporins) Misuse of antibiotics (low compliance, self-medication with antibiotics) Factors facilitating cross-transmission of MRSP (having children at

home, attendance of daycare, foreign travel)

Determinants negatively correlated with MRSP prevalence: Use of narrow-spectrum penicillins Protection against infectious diseases (breastfeeding, general

vaccination coverage of infants, and physical activity of adults) Responsiveness of the health system

No correlation at the macro-level for several determinants that were presented as hypotheses (e.g., population density, socio-economic status)

Discussion & Conclusions A substantial part of the problem is certainly due to

antimicrobial use! Hypotheses should be tested in future research Problem of multiple statistical testing Further multivariate analyses will be performed Several determinants already appear as candidates for

confirmatory studies at the patient level and potential targets for interventions in countries with high prevalence of MRSP: Increase breastfeeding and immunization coverage Decrease daycare attendance in early life (< 1y) Decrease self-medication and OTC sales Decrease non rational use of macrolides