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

3. 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.

4. This is where a large graphic or chart can go. Total 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, Monnet & Harbarth, Emerg Infect Dis 2004 Taiwan Penicillin-resistant pneumococci and outpatient AB-use

5. 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.

6. 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

7. 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.

8. 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. pneumoniae in Community-Acquired RTIs More rational use of antibiotics?

9. RESULTS

10. 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

11. 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.

12. 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

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

14. 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

15. 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 leisure 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

16. 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 (in DALYs)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 Power distance140.590.03 Uncertainty avoidance140.570.03 Masculinity14 0.550.04 Individualism14 0.04NS Long-term orientation13 (-) 0.32NS 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.

18. 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

19. 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)

20. 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