Adriaan Blommaert

Determinants of between-country differences in ambulatory antibiotic use and antibiotic resistance in Europe: a longitudinal observational study

OBJECTIVES To identify key determinants explaining country-year variations in antibiotic use and resistance. METHODS Ambulatory antibiotic use data [in defined daily doses per 1000 inhabitants per day (DIDs)] for 19 European countries from 1999 to 2007 were collected, along with 181 variables describing countries in terms of their agriculture, culture, demography, disease burden, education, healthcare organization and socioeconomics. After assessing data availability, overlap and relevance, multiple imputation generalized estimating equations were applied with a stepwise selection procedure to select significant determinants of global antibiotic use (expressed in DIDs), relative use of subgroups (amoxicillin and co-amoxiclav) and resistance of Escherichia coli and Streptococcus pneumoniae. RESULTS Relative humidity, healthcare expenditure proportional to gross domestic product, feelings of distrust, proportion of population aged >65 years and availability of treatment guidelines were associated with higher total antibiotic use expressed in DIDs. Restrictions on marketing activities towards prescribers, population density, number of antibiotics, educational attainment and degree of atheism were associated with a lower number of total DIDs used. Relative prescribing of amoxicillin and co-amoxiclav was mainly determined by healthcare system choices [e.g. general practitioner (GP) registration and restricted marketing]. Specific antibiotic use was found to be a significant determinant of resistance for some but not all drug/organism combinations. Incentives to stimulate GP gatekeeping were associated with lower levels of resistance, and life expectancy at age 65+ and atheism were associated with more resistance. CONCLUSIONS Myriad factors influence antibiotic use and resistance at the country level and an important part of these can be modified by policy choices.

The cost-effectiveness of pneumococcal vaccination in healthy adults over 50: An exploration of influential factors for Belgium

BACKGROUND A recent trial demonstrated the 13 valent conjugate pneumococcal vaccine (PCV13) to be effective against invasive and non-invasive pneumococcal disease in healthy adults. PCV13 might therefore be considered as an alternative to the 23 valent polysaccharide vaccine (PPV23). AIM To explore the cost-effectiveness of vaccinating healthy adults over 50, with either PCV13 or PPV23 alone, or with a combined strategy using both PCV13 and PPV23. METHODS A static multi-cohort model was developed simulating the consequences of pneumococcal vaccination in adults over 50 from a health care payers perspective, for different scenarios of duration of vaccine protection and serotype evolution. RESULTS At currently expected prices, PCV13 vaccination of healthy adults over 50 is unlikely to be cost-effective either compared with no vaccination or in combination with PPV23 versus PPV23 only. CONCLUSION Further research is needed on vaccine efficacy of the combination strategy and of risk groups, as well as the duration of vaccine protection. Serotype evolutions under the influence of the childhood PCV program should be closely monitored.

Estimating costs of care for meningitis infections in low- and middle-income countries.

Meningitis infections are often associated with high mortality and risk of sequelae. The costs of treatment and care for meningitis are a great burden on health care systems, particularly in resource-limited settings. The objective of this study is to review data on the costs of care for meningitis in low- and middle-income countries, as well as to show how results could be extrapolated to countries without sound data. We conducted a systematic review of the literature from six databases to identify studies examining the cost of care in low- and middle-income countries for all age groups with suspected, probable, or confirmed meningitis. We extracted data on treatment costs and sequelae by infectious agent and/or pathogen, where possible. Using multiple regression analysis, a relationship between hospital costs and associated determinants was investigated in order to predict costs in countries with missing data. This relationship was used to predict treatment costs for all 144 low- and middle-income countries. The methodology of conducting a systematic review, extrapolating, and setting up a standard database can be used as a tool to inform cost-effectiveness analyses in situations where cost of care data are poor. Both acute and long-term costs of meningitis could be extrapolated to countries without reliable data. Although only bacterial causes of meningitis can be vaccine-preventable, a better understanding of the treatment costs for meningitis is crucial for low- and middle-income countries to assess the cost-effectiveness of proposed interventions in their country. This cost information will be important as inputs in future cost-effectiveness studies, particularly for vaccines.

Patient and prescriber determinants for the choice between amoxicillin and broader-spectrum antibiotics: a nationwide prescription-level analysis

OBJECTIVES Bacterial resistance to antibiotics, driven by antibiotic consumption, imposes a major threat to the effective treatment of bacterial infections. In addition to reducing the amount of antibiotics prescribed, avoiding broad-spectrum antibiotics could extend the lifetime of the current arsenal of antibiotic substances. Therefore, we documented prescriber and patient characteristics associated with the choice between amoxicillin and broader-spectrum alternatives (co-amoxiclav or moxifloxacin) in recent years in Belgium. METHODS Complete reimbursement claims data (2002-09) for antibiotic prescriptions in outpatient care, including patient and prescriber characteristics, were collected for both young children (1-5 years) and the adult population (30-60 years). A backwards selection procedure within generalized estimating equations retained the most relevant determinants. RESULTS The age, gender and social category of the patient were found to be predictive of the extent to which amoxicillin was prescribed instead of the broader-spectrum alternatives, with female patients generally taking a higher proportion of amoxicillin than male patients. The age category of 40-44-year-old prescribers exhibited a preference for broad-spectrum antibiotics compared with both younger and older age groups. Significant interactions between the region and the prescribers qualification (general practitioner or paediatrician) on the choice of antibiotic for children were found. CONCLUSIONS Patient (age, gender and social category) and prescriber characteristics (age, gender, region and qualification) had an influence on whether amoxicillin or the alternative broad-spectrum antibiotics were prescribed. These findings should help policy makers to better target future campaigns to promote prudent prescribing of antibiotics.

Cost-effectiveness of seasonal influenza vaccination in pregnant women, health care workers and persons with underlying illnesses in Belgium.

Risk groups with increased vulnerability for influenza complications such as pregnant women, persons with underlying illnesses as well as persons who come into contact with them, such as health care workers, are currently given priority (along with other classic target groups) to receive seasonal influenza vaccination in Belgium. We aimed to evaluate this policy from a health care payer perspective by cost-effectiveness analysis in the three specific target groups above, while accounting for effects beyond the target group. Increasing the coverage of influenza vaccination is likely to be cost-effective for pregnant women (median €6589 per quality-adjusted life-year (QALY) gained [€4073-€10,249]) and health care workers (median €24,096/QALY gained [€16,442-€36,342]), if this can be achieved without incurring additional administration costs. Assuming an additional physicians consult is charged to administer each additional vaccine dose, the cost-effectiveness of vaccinating pregnant women depends strongly on the extent of its impact on the neonates health. For health care workers, the assumed number of preventable secondary infections has a strong influence on the cost-effectiveness. Vaccinating people with underlying illnesses is likely highly cost-effective above 50 years of age and borderline cost-effective for younger persons, depending on relative life expectancy and vaccine efficacy in this risk group compared to the general population. The case-fatality ratios of the target group, of the secondary affected groups and vaccine efficacy are key sources of uncertainty.

Data mining for longitudinal data under multicollinearity and time dependence using penalized generalized estimating equations

Penalized generalized estimating equations with Elastic Net or L2-Smoothly Clipped Absolute Deviation penalization are proposed to simultaneously select the most important variables and estimate their effects for longitudinal Gaussian data when multicollinearity is present. The method is able to consistently select and estimate the main effects even when strong correlations are present. In addition, the potential pitfall of time-dependent covariates is clarified. Both asymptotic theory and simulation results reveal the effectiveness of penalization as a data mining tool for longitudinal data, especially when a large number of variables is present. The method is illustrated by mining for the main determinants of life expectancy in Europe.

Economic evaluation of pneumococcal vaccines for adults aged over 50 years in Belgium

ABSTRACT Streptococcus pneumoniae causes a high disease burden including pneumonia, meningitis and septicemia. Both a polysaccharide vaccine targeting 23 serotypes (PPV23) and a 13-valent conjugate vaccine (PCV13) are indicated for persons aged over 50 years. We developed and parameterized a static multi-cohort model to estimate the incremental cost-effectiveness and budget-impact of these vaccines at different uptake levels. Using three different vaccine efficacy scenarios regarding non-invasive pneumococcal pneumonia and extensive uni- and multivariate sensitivity analyses, we found a strong preference for PPV23 over PCV13 in all age groups at willingness to pay levels below €300 000 per quality adjusted life year (QALY). PPV23 vaccination would cost on average about €83 000, €60 000 and €52 000 per QALY gained in 50–64, 65–74 and 75–84 year olds, whereas for PCV13 this is about €171 000, €201 000 and €338 000, respectively. Strategies combining PPV23 and PCV13 vaccines were most effective but generally less cost-effective. When assuming a combination of increased duration of PCV13 protection, increased disease burden preventable by PCV13 and a 75% reduction of the PCV13 price, PCV13 could become more attractive in <75 year olds, but would remain less attractive than PPV23 from age 75 years onwards. These observations are independent of the assumption that PPV23 has 0% efficacy against non-invasive pneumococcal pneumonia. Pneumococcal vaccination would be most cost-effective in Belgium, when achieving high uptake with PPV23 in 75–84 year olds, as well as by negotiating a lower market-conform PPV23 price to improve uptake and cost-effectiveness.