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. This is where a large graphic or chart can go. Total outpatient antibiotic use (DDD/1000 pop/day) 403020100 Penicillin-nonsusceptible S. pneumoniae (%) 60 50 40 30 20 10 0 USA UK Sweden Spain Portugal NorwayNetherlands Luxemburg Italy Ireland Iceland Greece Germany France Finland Denmark Canada Belgium Austria Australia Albrich et al, Emerg Infect Dis, March 2004 Taiwan Penicillin-resistant pneumococci and outpatient AB-use

3. 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

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

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

10. This is where a large graphic or chart can go. Independent variable (ATC group) No. EU countries RP Macrolides and lincosamides (J01F)140.88<0.001 Extended spectrum penicillins (J01CA)140.83<0.001 Cephalosporins and related (J01D)140.750.002 Quinolones (J01M)140.550.04 Beta-lactamase sensitive penicillins (J01CE)14 (-) 0.690.007 Tetracyclines (J01A)140.12NS Beta-lactamase resistant penicillins(J01CF)140.02NS Trimethoprim (J01EA)140.07NS 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.

11. This is where a large graphic or chart can go. Independent variable No. EU countriesRP Admit having used antibiotic left-overs during the last 12 months (%) 140.84< 0.001 Admit having used antibiotics without a prescription during the last 12 months (%) 140.740.002 Source: EUROBAROMETER 2002. Macrolide-R S. pneumoniae (%): Factors Affecting Compliance with Antibiotic Treatment

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

13. This is where a large graphic or chart can go. Independent variable No. EU countries RP Persons living in households with children (%)140.620.02 Nights spent in EU countries with high MRSP rate (per 1,000 inh.-days) 14 0.550.04 Children in preschool services (%) 10 0.56 0.09 Persons in overcrowded households (%)140.46NS 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

14. This is where a large graphic or chart can go. Independent variable No. EU countries RP Infants breastfed at 3 months of age (%)13(-) 0.690.007 General vaccination coverage of infants14(-) 0.580.03 Persons with at least 3 hours of physical activity per week (%) 14 (-) 0.59 0.03 Population whose age is >65 years (%)140.470.09 Population whose age is <= 4 years (%)14(-) 0.31NS Incidence of hospital discharges for respiratory diseases140.14NS Daily cigarette smokers (%)140.35NS Distributed doses of pneumococcal vaccine14 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

15. This is where a large graphic or chart can go. Independent variable No. EU countriesRP Responsiveness of health care system14(-) 0.540.05 Health system performance (WHO ranking)140.600.03 Households that cannot afford to keep home adequately warm (%) 130.490.09 Persons living below the ”poverty line” (%) 120.40NS 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.

17. This is where a large graphic or chart can go. Independent variable No. EU countriesRP Uncertainty avoidance140.570.03 Masculinity140.550.04 Power distance140.590.03 Individualism 140.04NS Long-term orientation 13(-) 0.32NS Source: Hofstede GH. Culture's consequences: comparing values, behaviors and organizations across nations. 2nd edition. Thousands Oaks, CA: Sage, 2001. Macrolide-R S. pneumoniae (%): Cultural Determinants 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.

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. Independent variable  tP Macrolides and lincosamides (J01F)0.8406.7960.012 Infants breastfed at 3 months of age (%, Ln tr.)-1.619-13.1000.011 Multiple Linear Regression Models for Prediction of Proportion of Macrolide-R S. pneumoniae (Preliminary Results) R 2 =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