Defined daily doses of antimicrobials reflect antimicrobial prescriptions in ambulatory care

Dominique L. Monnet1,*, Sigvard Mölstad2,3 and Otto Cars3,4

1 Antimicrobial Resistance Surveillance Unit, National Center for Antimicrobials and Infection Control, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S, Denmark; 2 Unit of Research and Development in Primary Care, Jönköping; 3 Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance (STRAMA), Swedish Institute for Infectious Disease Control, Solna; 4 Department of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden

Received 13 January 2004; returned 23 February 2004; revised 5 March 2004; accepted 9 March 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background: Data on actual antimicrobial prescriptions are rarely made available and the World Health Organization (WHO) recommends using the number of defined daily doses (DDDs) as a measurement unit for inter-country comparisons of antimicrobial use in outpatients. However, because antimicrobials are given for limited periods of time and the DDDs may not represent the doses used in practice, this measurement unit has been blamed for poorly reflecting the number of antimicrobial prescriptions in outpatients.

Methods: For 11 out of 15 European countries, data on national outpatient sales of antimicrobials and on antimicrobial prescriptions to outpatients in 1997 were purchased from the Institute for Medical Statistics (IMS) Health. For two additional countries, i.e. Sweden and Denmark, similar data were obtained from the National Corporation of Swedish Pharmacies and the Danish Medicines Agency, respectively. The relationships between the number of DDDs and the number of prescriptions, on the one hand, and the antimicrobial use density (DDD per 1000 inhabitant-days) and the prescription rate (prescriptions per 1000 inhabitants), on the other hand, were assessed with the two-tailed Spearman coefficient for non-parametric correlations.

Results: The number of DDDs, as defined by the WHO, and the number of prescriptions of antimicrobials to outpatients in European countries in 1997 were strongly correlated. Similarly, the antimicrobial use density and the prescription rate in these countries were strongly correlated. These relationships were found for total systemic antimicrobials and for all major antimicrobial classes.

Conclusion: Our results confirm the relevance of the number of DDDs per 1000 inhabitant-days as a measurement unit to compare outpatient antimicrobial use among countries or regions.

Keywords: antibiotics, utilization, outpatients


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Reports on increasing antimicrobial resistance worldwide, and on major differences in levels and patterns of resistance among European countries have renewed interest in national antimicrobial consumption data. Data on actual drug prescriptions in outpatients are rarely made available because collection of such data is difficult. When available, they are often based on a sample of community physicians chosen to represent the whole country.1,2 Another method to measure national drug consumption data is to use drug sales from pharmaceutical companies, distributors or reimbursement systems. From the number of packages sold, distributed or reimbursed, one calculates the number of grams of drugs, converts it into a number of defined daily doses (DDDs) and finally adjusts for the size of the population.3 Recently, Cars et al. reported on the levels and patterns of antimicrobial use in outpatients in European countries as the number of DDDs per 1000 inhabitant-days.4

The DDDs were originally developed by the Nordic Council on Medicines in close collaboration with WHO. The WHO Collaborating Centre for Drug Statistics and Methodology now has the responsibility of defining and updating the DDDs and the Anatomical Therapeutic Chemical (ATC) classification of drugs through its WHO International Working Group for Drug Statistics Methodology, a group which consists of 12 WHO-appointed experts in clinical pharmacology, drug utilization, drug regulation, drug evaluation, statistics and medicine.5,6 For each drug, the DDD is an international unit and corresponds to the assumed average maintenance dose per day for its main indication of the drug in adults. It is usually expressed in grams. When dosage depends on body weight, the DDD is calculated for an adult of 70 kg.3,6 If the average duration of treatment is known, one can then estimate the number of prescriptions from the number of DDDs.

Unlike drugs for the treatment of chronic diseases, which are usually given throughout life, antimicrobials are given for limited, and sometimes variable, periods of time. Because of this, the number of DDDs might not reflect the number of antimicrobial prescriptions and the number of patients having being treated with antimicrobials.3 Additionally, the DDDs defined by WHO have been criticized because they may not represent the doses used in practice in some countries and that national average daily doses should be preferred to report antimicrobial consumption from individual countries.7 If such national average daily doses were to be used, each country in the world would have to define its own average daily doses, and this for each drug on the market, which seems quite unrealistic considering the difficulties of establishing and updating such a system as demonstrated by 20 years of experience at the WHO Collaborating Centre for Drug Statistics Methodology. Clearly, the only available method to carry out inter-country comparisons of antimicrobial use when prescription data are not available is to measure the number of DDDs from the number of sold packages as recommended by WHO.3,6 The question remains, however, whether the number of DDDs of antimicrobials properly reflects the number of antimicrobial prescriptions.

This study was carried out to assess the relationship between the number of DDDs, as defined by WHO, and the number of prescriptions of antimicrobials in outpatients in European countries, thus assessing the relevance of DDDs for inter-country comparisons of antimicrobial use in outpatients.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Data on national outpatient sales of antibacterials for systemic use (ATC group J01) in 1997 were purchased from the Institute for Medical Statistics (IMS) Health (London, UK) for 11 of the 15 EU Member States. This private company gathers data from different sources including manufacturers, wholesalers and pharmacies. The amount of antibacterial drug in kilograms was converted to a number of DDDs as defined by WHO,8 or for a few antibacterials not given a DDD by WHO, by using the common daily dose in published work. Where such an estimate was not possible, i.e. for less than 0.01% of total, data were excluded from analysis. Data from Sweden and Denmark were obtained directly as a number of DDDs from the National Corporation of Swedish Pharmacies and the Danish Medicines Agency, respectively. In Sweden, all pharmacies belong to the National Corporation of Swedish Pharmacies and report data on all drugs dispensed to this corporation. In Denmark, all pharmacies must report data on all drugs dispensed to the Danish Medicines Agency.

Data on prescriptions of antibacterials for systemic use (ATC group J01) in 1997 were purchased from IMS Health for the same 11 European countries. These data were generated in physicians’ offices from a sample of general practitioners and community-based specialists and extrapolated to a national level. The prescriptions classified as ‘composition unknown’ in this database were excluded from the study, but only represented 0.16% of total prescriptions. For Sweden and Denmark, data on prescriptions of antibacterials were obtained from the same sources as above and included all prescriptions redeemed at community pharmacies.

Information on the total population by 1 January 1997 was obtained from Eurostat,9 and consumption was expressed as a number of DDDs per 1000 inhabitant-days and a number of prescriptions per 1000 inhabitant-year, respectively.

The analysis was carried out using SPSS 10.0 for Windows (SPSS Inc., Chicago, IL, USA). Correlations between the number of DDDs and the number of prescriptions on the one hand, and between incidence density of use (number of DDDs per 1000 inhabitant-days) and prescription rate (number of prescriptions per 1000 inhabitant-year) on the other hand, were assessed with the two-tailed Spearman coefficient for non-parametric correlations.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The results are presented in Table 1. There were very strong correlations, both between the number of DDDs and the number of antimicrobial prescriptions, and between antimicrobial use incidence density and the prescription rate. These correlations were found for total use, as well as for specific classes of antimicrobials.


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Table 1. Correlations between the number of defined daily doses (DDDs) as defined by WHO and the number of prescriptions, and between incidence density of use and prescription rate for total and major classes of antibacterials for systemic use
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This study is, to our knowledge, the first attempt to openly compare antimicrobial use data collected by two different methods and expressed in two different measurement units among several countries. It showed strong correlations between these two ways to express consumption for total and for major classes of antimicrobials.

There are a few limitations to this study due to the quality of available data. IMS Health data on the total number of prescriptions were an extrapolation from the data obtained from a sample of community-based physicians and might not reflect the actual number of prescriptions in these countries. IMS Health data on sales included antimicrobials sold over-the-counter at community pharmacies and antimicrobials sold for parallel export to other countries, but did not include antimicrobials originating from parallel import. Countries with low prices, such as Greece, Spain or Italy, tend to be the source of parallel exports, whereas countries where prices are higher, such as Germany, UK, Denmark, Sweden and the Netherlands, encourage parallel import as a way to promote price competition.10 The extent to which parallel trade influences IMS Health data on antimicrobial sales is unknown and future studies should take this point into account since parallel trade patterns are likely to change in an enlarged European Union. Nevertheless, the strength of the observed correlations in our study suggests that these limitations were minor.

In conclusion, outpatient antimicrobial use expressed as a number of DDD as defined by WHO correctly reflected the number of antimicrobial prescriptions for outpatients at the national level. This study confirms that the number of DDDs per 1000 inhabitant-days is an acceptable measurement unit to express outpatient antimicrobial use and to benchmark countries or regions for their level of antimicrobial consumption. Similar studies should now be carried out to analyse the relationship between the number of DDDs and the number of prescriptions for individual antimicrobials within one class and to assess the DDDs defined by WHO as a means to express hospital antimicrobial use for benchmarking of countries or individual hospitals. These questions should be answered by on-going public health surveillance systems such as the newly implemented European Surveillance of Antimicrobial Consumption (ESAC) project (http://www.ua.ac.be/esac/).


    Footnotes
 
* Corresponding author. Tel: +45-3268-8190; Fax: +45-3268-3231; E-mail: dom{at}ssi.dk Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . McCaig, L. F., Besser, R. E. & Hughes, J. M. (2002). Trends in antimicrobial prescribing rates for children and adolescents. Journal of the American Medical Association 287, 3096–102.[Abstract/Free Full Text]

2 . Mölstad, S., Lundborg, C. S., Karlsson, A. K. et al. (2002). Antibiotic prescription rates vary markedly between 13 European countries. Scandinavian Journal of Infectious Diseases 34, 366–71.[CrossRef][ISI][Medline]

3 . Capellà, D. (1993). Descriptive tools and analysis. WHO Regional Publications, European Series 45, 55–78.[Medline]

4 . Cars, O., Mölstad, S. & Melander, A. (2001). Variation in antibiotic use in the European Union. Lancet 357, 1851–3.[CrossRef][ISI][Medline]

5 . WHO Collaborating Centre for Drug Statistics Methodology. (2003). Anatomic Therapeutic Chemical (ATC) classification index with Defined Daily Doses (DDDs). WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway. [Online.] http://www.whocc.no/atcddd/ (5 January 2004, date last accessed).

6 . WHO Collaborating Centre for Drug Statistics Methodology. (2003). Guidelines for ATC Classification and DDD Assignment. WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway.

7 . Baquero, F., Baquero-Artigao, G., Cantón, R. et al. (2002). Antibiotic consumption and resistance selection in Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 50, Suppl. S2, 27–37.[Abstract/Free Full Text]

8 . WHO Collaborating Centre for Drug Statistics Methodology. (1999). Anatomic Therapeutic Chemical (ATC) Classification Index with Defined Daily Doses (DDDs). WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway.

9 . Eurostat. (2000). Eurostat Yearbook 2000, 5th edn. Eurostat, Luxembourg.

10 . Kanavos, P. (1999). Pharmaceutical Pricing and Reimbursement in Europe—1999 Edition. Scrip Reports, PJB Publications, Richmond, Surrey, UK.