Increase and change in pattern of hospital antimicrobial use, Denmark, 1997–2001

Berit Müller-Pebody1, Mark Muscat1,*, Benjamin Pelle1, Bjarke M. Klein2, Christian T. Brandt1 and Dominique L. Monnet1

1 National Center for Antimicrobials and Infection Control and 2 Biostatistics Unit, Statens Serum Institut, Copenhagen, Denmark

Received 29 March 2004; returned 31 May 2004; revised 4 October 2004; accepted 5 October 2004


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives: To analyse the changes and compare antimicrobial consumption in public hospitals in Denmark over the period 1997–2001.

Methods: Data on the number of WHO defined daily doses (DDD) were obtained from the Danish Medicines Agency. Data on the number of bed-days were obtained from the National Board of Health. We calculated antimicrobial consumption in hospitals as the number of DDD per 100 bed-days for all antibacterials for systemic use i.e. group J01 of the Anatomical Therapeutic Chemical (ATC) classification and for classes of this group.

Results: During 1997–2001, antimicrobial use in hospitals in Denmark significantly increased by 18%, from 38.0 to 44.8 DDD per 100 bed-days (P < 0.005). Most of this increase (55%) was attributed to an increase in consumption of commonly used classes of antimicrobials, mainly penicillins with extended spectrum (ATC group J01CA), ß-lactamase-sensitive penicillins (J01CE) and ß-lactamase-resistant penicillins (J01CF). The ‘broad-spectrum’ and newer antimicrobials, i.e. combinations of penicillins with ß-lactamase inhibitor (J01CR), cephalosporins (J01DA), carbapenems (J01DH) and fluoroquinolones (J01MA) contributed to 36% of the increase. Together, these amounted to 16% of total consumption in hospitals in Denmark in 1997, rising to 19% in 2001.

Conclusions: Although antimicrobial consumption in public hospitals in Denmark is low compared with other countries, the steady increase and change in pattern of their use are causes of concern, deserving close monitoring and further investigations.

Keywords: antibiotics, drug utilization, surveillance


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
To reduce the rate of development of bacterial resistance to antimicrobials in Denmark efforts to optimize the use of these drugs have been made since the late 1960s. Collaboration between clinical microbiologists, medical staff, pharmacists and the Statens Serum Institut, as well as educational initiatives for health professionals, have led to the establishment and implementation of Danish national guidelines on the prudent use of antimicrobials.1,2 Additionally, most hospitals in Denmark have developed their own local antibiotic policy and guidelines.3,4 As a general rule, both the national and hospital guidelines recommend the so-called ‘narrow-spectrum’ antimicrobials for most indications. ‘Broad-spectrum’ and the newer antibiotics are reserved for specific patients and indications. Antimicrobial use in Denmark, both in the community and in hospitals, is considered one of the lowest per capita and one of the most narrow-spectrum amongst developed countries.5,6

To monitor the consumption and cost of medicinal products in Denmark, a national register of drug statistics was implemented in the early 1990s by the Danish Medicines Agency (Lægemiddelstyrelsen). On a monthly basis, community pharmacies report data on each prescription redeemed by patients, and hospital pharmacies report data on drugs dispensed to hospital wards.

Although ~90% of antimicrobials are consumed in primary healthcare, there is evidence to suggest that antimicrobial selection pressure is much higher in hospitals.7 This, together with suboptimal infection-control practices, form the main reason for the high prevalence of antimicrobial resistance generally observed in hospitals.8 Therefore, monitoring antimicrobial consumption in hospitals is important in order to establish a relationship with the occurrence of resistance. Monitoring also reveals trends in prescribing practices in a country, and allows comparisons to be made between different hospitals and countries.6,9,10 This study was implemented to analyse antimicrobial consumption in public hospitals in Denmark during 1997–2001.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We analysed retrospective data on antimicrobials dispensed and occupancy data from public hospitals in Denmark for the period 1997–2001.

Hospitals

All public hospitals in Denmark active during the study period were included in the analysis. Three hospitals that closed during this time, two in 1999 and one in 2000, were included. Hospitals that merged for functional or administrative reasons during the study period were treated as single groups for the entire period and their data were retrospectively merged. Psychiatric hospitals, rehabilitation centres as well as a neurological centre were excluded because of their particular patient recruitment. One small hospital did not consistently report antimicrobial data for the entire study period and was excluded. As at 2001, there were 55 hospitals or hospital groups included in the study. Data from inpatient wards as well as day patient wards were included. Data from psychiatric wards, emergency wards and outpatient clinics were excluded.

Antimicrobial data

Information on the antimicrobials used in hospitals in Denmark was obtained from the national register of drug statistics maintained by the Danish Medicines Agency.11 In this study, antimicrobials were defined as ‘antibacterials for systemic use’ and are equivalent to group J01 of the Anatomical Therapeutic Chemical (ATC) classification system from the WHO Collaborating Centre for Drug Statistics Methodology.12 The group comprises the antimicrobial classes as listed in Table 1. For each hospital ward the Danish Medicines Agency provided data on consumption of each antimicrobial class—as a number of defined daily doses (DDD)—using the 2001 version of the ATC/DDD index.12 For each individual antimicrobial, the DDD is defined—by the WHO Collaborating Centre for Drug Statistics Methodology—as the assumed average maintenance dose per day for a drug used for its main indication in an adult.13


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Table 1. Table 1. Consumption of antimicrobials as a total and by ATC group in hospitals in Denmark, 1997 and 2001

 
Hospital occupancy data

As recommended by the WHO, the number of bed-days was chosen as the denominator.13,14 Bed-days denote the number of days each patient occupies a hospital bed. For each hospital such data were obtained from the National Board of Health (Sundhedsstyrelsen).1519

Data and statistical analysis

Data were processed and analysed using Microsoft Excel 2000, and SAS, Version 8.2. Hospital antimicrobial consumption was expressed as a number of DDD per 100 bed-days.13,14 Linear regression was used to determine the significance of the change in antimicrobial use in the observation period.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The total number of DDD of antibacterials for systemic use (ATC group J01) consumed each year in public hospitals in Denmark increased by 13%, from 2.3 million in 1997 to 2.6 million in 2001. Overall, the total number of bed-days in hospitals in Denmark decreased by 4%, from 6.1 million in 1997 to 5.8 million in 2001. Between 1997 and 2001, antimicrobial consumption of antibacterials for systemic use significantly increased by 18%, from 38.0 to 44.8 DDD per 100 bed-days in 2001 (P < 0.005) (Figure 1). The yearly rate of increase was 1.6 DDD per 100 bed-days (95% CI 1.0 to 2.3). Most of this increase (55%) was attributed to an increase in consumption of commonly used classes of antimicrobials, mainly penicillins with extended spectrum (ATC group J01CA), ß-lactamase-sensitive penicillins (J01CE) and ß-lactamase-resistant penicillins (J01CF) (Table 1). There was also an increased consumption of broad-spectrum and newer antimicrobials, i.e. combinations of penicillins with a ß-lactamase inhibitor (J01CR), cephalosporins (J01DA), carbapenems (J01DH) and fluoroquinolones (J01MA), together contributing to 36% of the increase in total consumption. These broad-spectrum and newer antimicrobials amounted to 16% of total consumption in hospitals in Denmark in 1997 and this percentage rose to 19% in 2001. Additionally, the largest percentage change in consumption was for combinations of penicillins, including ß-lactamase inhibitors (J01CR) and fluoroquinolones (J01MA), with increases of 414% and 94%, respectively (Figure 2). These, however, only amounted to 0.4% and 5.6% of the total DDD of antibacterials for systemic use in 2001, respectively. The consumption of lincosamides (J01FF), glycopeptides (J01XA) and imidazoles (J01XD) also increased (Figure 2). In contrast, the consumption of macrolides (J01FA), aminoglycosides (J01GB), polymyxins (J01XB), steroid antibacterials, i.e. fusidic acid (J01XC), nitrofuran derivatives (J01XE) and other antibacterials, i.e. methenamine (J01XX) declined over the study period (Figure 2).



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Figure 1. Total consumption of antibacterials for systemic use (ATC group J01) in hospitals in Denmark, 1997–2001.

 


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Figure 2. Percentage changes in DDD/100-bed-days of antimicrobials by ATC group in hospitals in Denmark, 1997–2001.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
A steady and significant increase in antimicrobial consumption was observed in public hospitals in Denmark during 1997–2001. Preliminary data for 2002 show that this increase continued even after the study period.20 Literature on hospital antimicrobial use from other countries is scarce for comparisons to be made at any one point during the study period. To our knowledge, only the Netherlands has published data on a 10.6% increase in the use of antimicrobials in hospitals, from 47.2 DDD per 100 bed-days in 1997 to 52.2 DDD per 100 bed-days in 2000.21 Extended hospital antimicrobial use data are now available from the European Surveillance of Antimicrobial Consumption (ESAC) project. This shows that antimicrobial consumption is low in Denmark compared with other European countries.22 However, ESAC reports hospital antimicrobial use per 1000 inhabitant-days in the participating countries, and not specifically per population of hospitalized patients exposed to the antimicrobials used, as recommended by WHO and presented in this study.

In Denmark, the observed increase in hospital antimicrobial use, expressed in DDD per 100 bed-days, was due to both an increase in the number of antimicrobial DDD (numerator) and a decrease in the number of hospital bed-days (denominator). This means that whereas the number of hospital bed-days decreased, hospitals in Denmark increased their consumption of antimicrobials. The decrease in the number of bed-days can be explained by the closing of several general and local hospitals. However, the proportion of bed-days originating from acute care referral hospitals, which are believed to admit the sickest patients, decreased slightly from 17.3% in 1997 to 16.7% in 2001, whereas the fraction of bed-days originating from teaching hospitals increased from 70.2% in 1997 to 70.5% in 2001. These minor changes in the structure of the hospital sector are unlikely to explain the observed large increase in antimicrobial use. During the same period, the average length of inpatient hospital stay decreased, from 5.8 days in 1997 to 5.2 days in 2001.15,19 This trend towards earlier discharge of patients led to a slight increase in hospital admissions despite a decreasing number of available hospital beds and could have contributed to the increase in antimicrobial prescribing. Firstly, whenever possible after a few days of parenteral therapy, patients who need antimicrobial treatment are now sent home with oral therapy provided by the hospital pharmacy. Secondly, the number of surgical procedures increased, from 888 117 in 1997 to 1 163 567 in 200123—a 31% increase, which probably required increasingly greater quantities of antimicrobials for surgical prophylaxis. Thirdly, as a result of earlier discharge of the less sick patients, bed-days registered by hospitals may increasingly originate from sicker patients, who more often require antimicrobial treatment.

Finally, several recent articles in the Danish medical literature recommended combination antimicrobial therapy for initial empirical treatment of sepsis.2427 The observed increase in antimicrobial use could therefore be the consequence of the more frequent prescription of combination therapy to treat hospital patients. Unfortunately, antimicrobial-use data are only made available to the Danish Medicines Agency as aggregated data at ward level. Audits of prescription practices at patient level would be needed to verify this hypothesis.

In this study, we also demonstrated a shift from the so-called narrow-spectrum to the broad-spectrum and newer antimicrobials, although these still represented a small percentage of total use in hospitals in Denmark. A likely explanation is that Danish hospital doctors now practice a more defensive kind of medicine. Despite national and local guidelines for antimicrobial therapy,24 hospital doctors might be more prone to prescribe broad-spectrum antimicrobials for empirical treatment of bacterial infections. Additionally, they might increasingly be under pressure to produce speedy recoveries and less likely to step down therapy to narrow-spectrum antimicrobials when this becomes possible on the availability of microbiological results. With rare exceptions, such as ampicillin and sulphonamide resistance in Escherichia coli that lie between 30%–50%, antimicrobial resistance in the microorganisms commonly isolated from clinical samples remains very low in Denmark and showed no significant increase during the study period.18 For example, resistance to cefuroxime, gentamicin and ciprofloxacin in Escherichia coli clinical isolates in Denmark is still <5%.18 Moreover, marketing of broad-spectrum and newer antimicrobials certainly plays a role in the change in pattern of antimicrobial use seen in Denmark.

Our study has a few limitations. Firstly, due to the progressive implementation of the data collection system from 1994 onwards, the original datasets on the number of DDD sometimes contained missing information on the wards' names. In this case, the DDD could only be assigned to the individual hospitals, but not at ward level. An unknown proportion of these DDD might have originated from use by outpatients, emergency or psychiatric patients. Such a bias, however, is believed to be small because these ‘unassigned’ DDD only represented 11%–13% of the total DDD used per year of the study period. Additionally, outpatients, emergency and psychiatric patients only represented a small percentage of patients in the identified wards and are believed to represent the same proportion in non-identified wards.

Secondly, data on antimicrobial use in private hospitals were not available; however, altogether these contribute very little to the hospital service in Denmark as there were only 13 small private hospitals in total representing ~200 beds.28 Thirdly, we included use in paediatric wards but reported this use implementing the DDD that are only defined for adults by the WHO Collaborating Centre for Drug Statistics Methodology. This is, however, the only method to report total antimicrobial use from aggregated pharmacy data when it includes both adult and paediatric use.

In Denmark, hospital antimicrobial-use data represent an extremely useful source of information that is apparently not yet readily available in most other European countries, possibly because of the lack of centralized electronic data on the number of DDD and of reliable data on the number of occupied bed-days. Both the increase in total antimicrobial use and the shift towards broad-spectrum antimicrobials in hospitals in Denmark are causes of concern and deserve close surveillance and additional investigations. These national figures represent a first step towards a better understanding of antimicrobial use in hospitals in Denmark. Future efforts should be directed at analysing changes in individual hospitals and comparing levels and patterns of use between them. As a follow-up to this study, feedback reports are being prepared for each individual hospital to provide detailed information on the changes observed since 1997. These reports will be sent to the hospitals' microbiologists, who in Denmark are responsible for the hospital's antibiotic policy. It is expected that these individual reports will stimulate more detailed studies on local prescribing practices and help to set up interventions to improve antimicrobial prescribing in hospitals in Denmark.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank the Danish Medicines Agency, and especially Karin Hovgaard, for providing antimicrobial data, and the Danish National Board of Health for data on surgical procedures.


    Footnotes
 
* Correspondence address. Antimicrobial Resistance Surveillance Unit, National Center for Antimicrobials and Infection Control, Statens Serum Institut, Artillerivej 5, 2300 Copenhagen S, Denmark. Tel: +45-3268-3191; Fax: +45-3268-3231; Email: mmc{at}ssi.dk


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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2 . Justesen, T., Korsager, B., Kolmos, H. R., et al. (2002). Vejledning i brug af antibiotika. In Lægeforeningens Medicinfortegnelse 2002/2003, 25.udgave, pp. 856–80. Lægeforeningens forlag, Copenhagen, Denmark.

3 . Balslev, U., Benfield, T., Bremmelgaard, A. et al. (2001). Rationel anvedelse af antibiotika, 3. udgave. Klinisk Mikrobiologisk Afdeling 445, H:S Hvidovre Hospital, Hvidovre, Denmark. [Online.] http://www.hosp.dk/HHmikrobiologisk.nsf/ResponseDokumenter/2CF14A32B3507EEDC1256C2A002F242F (8 July 2004, date last accessed).

4 . Generel vejledning i antibiotikaterapi. (2002). Klinisk Mikrobiologisk Afdeling, Århus Universitetshospital,Århus, Denmark. [Online.] http://www.auh.dk/sks/afd/KlinMik/dk/ABvejled/ABVEJ_.AUH.pdf (8 July 2004, date last accessed).

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

6 . Cars, O., Mölstad, S. & Melander, A. (2000). Large variation in antibiotic usages between European countries [abstract]. Clinical Microbiology and Infection 1, Suppl. 6, 216.

7 . Monnet, D. L., Sørensen, T. L. & Johansen, H. L. (2000). Comparison of the level of antimicrobial use in hospitals and in primary health care Denmark [abstract]. Infection Control and Hospital Epidemiology 21, 91.

8 . McGowan, J. E., Jr (1987). Is antimicrobial resistance in hospital microorganisms related to antibiotic use? Bulletin of the New York Academy of Medicine 63, 253–68.[ISI][Medline]

9 . Krcmery, V., Grausova, S., Balin, O. et al. (1999). Decreased consumption of antimicrobial drugs after implementation of a new antibiotic policy in 1990. Journal of Hospital Infection 41, 75–7.[CrossRef][ISI][Medline]

10 . Monnet, D. L. & Sørensen, T. L. (1999). Interpreting the effectiveness of a national antibiotic policy and comparing antimicrobial use between countries. Journal of Hospital Infection 43, 239–48.[CrossRef][ISI][Medline]

11 . Danish Medicines Agency. Forbrug af antibiotika. [Online.] http://www.laegemiddelstyrelsen.dk/1024/visLSArtikel.asp?artikelID=1437 (8 July 2004, date last accessed).

12 . WHO Collaborating Centre for Drug Statistics Methodology. (2001). ATC index with DDDs 2001. WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway.

13 . WHO Collaborating Centre for Drug Statistics Methodology. (2001). Guidelines for ATC classification and DDD assignment. WHO Collaborating Centre for Drug Statistics Methodology, Oslo, Norway.

14 . Capellà, D. (1993). Descriptive tools and analysis. In Drug utilization studies. Methods and uses. (Dukes, M. N. G., Ed.), pp. 55–78. WHO Regional Publications, European Series no. 45, Copenhagen, Denmark.

15 . Sundhedsstyrelsen. (1999). Virksomheden ved sygehus 1997. Munksgaards Forlag, Copenhagen, Denmark.

16 . Sundhedsstyrelsen. (2000). Virksomheden ved sygehus 1998. Schultz Information, Albertslund, Denmark.

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20 . DANMAP 2002. Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. (2003). Danish Veterinary Institute, Copenhagen, Denmark. [Online.] http://www.dfvf.dk/Files/Filer/Zoonosecentret/Publikationer/Danmap/Danmap_2002.pdf (8 July 2004, date last accessed).

21 . Stichting Werkgroep Antibioticabeleid (SWAB). (2003). NETHMAP 2003 – Consumption of antimicrobial agents and antimicrobial resistance among medically important bacteria in the Netherlands. [Online.] http://www.swab.nl/swab/swabfu.nsf/uploads/BBCDA0D2C7969870C1256D210030F9EC/$file/Nethmap2003.pdf (8 July 2004, date last accessed).

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