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

This is where a large graphic or chart can go. Total outpatient antibiotic use (DDD/1000 pop/day) Penicillin-nonsusceptible S. pneumoniae (%) 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

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: Macro-level determinants influencing AB overuse

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

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

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?

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

RESULTS

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

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) Quinolones (J01M) Beta-lactamase sensitive penicillins (J01CE)14 (-) 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:

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 (%) < Admit having used antibiotics without a prescription during the last 12 months (%) Source: EUROBAROMETER Macrolide-R S. pneumoniae (%): Factors Affecting Compliance with Antibiotic Treatment

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

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

This is where a large graphic or chart can go. Independent variable No. EU countries RP Infants breastfed at 3 months of age (%)13(-) General vaccination coverage of infants14(-) Persons with at least 3 hours of physical activity per week (%) 14 (-) Population whose age is >65 years (%) 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 vaccine NS Sources: U.S. Bureau of the Census, EC Eurostat, WHO Regional Office for Europe, and Fedson DS. Clin Infect Dis 1998;26: Macrolide-R S. pneumoniae (%) : Population Characteristics and Protection against Disease

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

This is where a large graphic or chart can go. Independent variable No. EU countriesRP Uncertainty avoidance Masculinity Power distance Individualism NS 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, 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.

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:

Independent variable  tP Macrolides and lincosamides (J01F) Infants breastfed at 3 months of age (%, Ln tr.) Multiple Linear Regression Models for Prediction of Proportion of Macrolide-R S. pneumoniae (Preliminary Results) R 2 =0.959

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:

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)

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

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

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

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!

“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