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

1. Policy-Relevant Determinants for the Control of Macrolide-Resistant Streptococcus pneumoniae: Do International Comparisons Help? Harbarth S, Monnet DL, Pechère JC, Cars O.

2. Penicillin-resistant pneumococci and outpatient AB-use 60 Taiwan 50 Spain France 40 USA Greece 30 Portugal Penicillin-nonsusceptible S. pneumoniae (%) This is where a large graphic or chart can go. Ireland 20 Canada Luxemburg Iceland Italy Austria Belgium UK 10 Australia Germany Albrich et al, Emerg Infect Dis, March 2004 Finland Sweden Denmark Netherlands Norway 0 0 10 20 30 40 Total outpatient antibiotic use (DDD/1000 pop/day)

3. Prescriberfactors Patient factors Antibiotic overuse and misuse Antibiotic-resistant pneumococci Cultural influences Social determinants Regulatory practices Macro-level determinants influencing AB overuse Harbarth et al, Emerg Infect Dis 2002; 8: 1460-1467

4. BACKGROUND • Evaluating determinants of antibiotic overuse and bacterial resistance is a complex task. • Standardized assessment of these determinants may • Enable international comparisons • Allow to identify those control measures that are the most likely to be successful

5. OBJECTIVES • To explore determinants explaining the large variation in prevalence of macrolide-resistant S. pneumoniae (MRSP) in 14 European countries • To test different hypotheses (e.g., antibiotic usage patterns, population characteristics) linked to low or high MRSP prevalence

6. Lower use of macrolides(Shorter courses, higher dosages) • Lower use of other antimicrobials • Better compliance • Pre-school facilities • Better living conditions • Socio-economic status • Health care system • Less travel • Climate • Different clones More rational use of antibiotics? Less cross-transmission? Better protection against disease? Different population? • Age distribution • Respiratory diseases • Vaccination • Breast feeding Lower Proportion of Macrolide-R S. pneumoniae in Community-Acquired RTIs

7. METHODS • Design: retrospective, ecologic study • Listing of possible determinants that might explain variations in MRSP prevalence • Data retrieval from electronic databases, reports from surveillance systems and international organizations • Statistics: • 2-tailed Spearman coefficient for non-parametric correlations • Multiple linear regression analysis

8. RESULTS

9. Macrolide-Resistant S. pneumoniae (MRSP) and Macrolide Consumption in 14 EU Member States, 1997-1998 Sources: Alexander Project, FINRES, STRAMA, DANMAP, and Cars O, et al. Lancet 2001; 357: 1851-3.

10. Macrolide-R S. pneumoniae(%) and Antimicrobial Consumption in Europe This is where a large graphic or chart can go. Source for resistance data: Alexander Project. Source for antimicrobial consumption data: Cars O, et al. Lancet 2001; 357: 1851-3.

11. Macrolide-R S. pneumoniae(%): Factors Affecting Compliance with Antibiotic Treatment This is where a large graphic or chart can go. Source: EUROBAROMETER 2002.

12. Patients’ Misuse of Antibiotics Source: Pechère J-C. Clin Infect Dis 2001; 33 (Suppl 3): S170-S173.

13. Macrolide-R S. pneumoniae(%): Factors That Might Facilitate Cross-Transmission This is where a large graphic or chart can go. Sources: Danish National Institute of Social Research, EC Eurostat, and European Travel Commission (ETC) Tourism Statistics.

14. Macrolide-R S. pneumoniae (%): Population Characteristics and Protection against Disease This is where a large graphic or chart can go. Sources: U.S. Bureau of the Census, EC Eurostat, WHO Regional Office for Europe, and Fedson DS. Clin Infect Dis 1998;26:1117-23.

15. Macrolide-R S. pneumoniae(%):Economic and Health Care System This is where a large graphic or chart can go. 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. Source: World Health Report 2000.

17. Macrolide-R S. pneumoniae(%):Cultural Determinants This is where a large graphic or chart can go. 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. Power distance is a measure of the interpersonal power or influence between two individuals when one is the subordinate of the other. 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. Source: Hofstede GH. Culture's consequences: comparing values, behaviors and organizations across nations. 2nd edition. Thousands Oaks, CA: Sage, 2001.

18. Acceptance of alternative medicine • In a survey, German patients (n= 2,111) were likely to accept alternative medicines • 83% had positive attitudes regarding alternative medicine • 42% disliked antibiotics Harbarth et al, Emerg Infect Dis 2002; 8: 1460-1467

19. Multiple Linear Regression Models for Prediction of Proportion of Macrolide-R S. pneumoniae(Preliminary Results) R2=0.959

20. Breastfeeding • A national survey conducted in 1995 among 12,179 babies at French maternity hospitals showed that France was at the lowest level among all EU countries (52%) Harbarth et al, Emerg Infect Dis 2002; 8: 1460-1467

21. Summary • Determinants positively correlated with MRSP: • 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 (attendance of daycare, having children at home)

22. Summary (2) • 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 healthcare system

23. Summary (3) • No correlation for several determinants presented as hypotheses: • population density • socio-economic status • Climate

24. Limitations • Simple correlations -- No proof of causality • Statistical problems • Multiple statistical testing • Missing values for few countries • Potential ecologic bias (use of group-level data) • Hypotheses should be confirmed in future studies with individual patient-level data • Further multivariate analyses will be performed

25. Conclusions • 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 irrational use of macrolides and replace by use of narrow-spectrum penicillins (e.g., amoxicillin) • A substantial part of the problem:antimicrobial overuse for minor viral respiratory diseases!

26. “There is no question but that antibiotics are used in the treatment of virus diseases to a very much greater extent than is warranted by the present state of our knowledge.” B. Moulton, FDA, Antibiotics Annual 1955, p. 719