JAC Advance Access originally published online on May 30, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):413-417; doi:10.1093/jac/dkl185
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European Surveillance of Antimicrobial Consumption (ESAC): outpatient cephalosporin use in Europe
1 Department of General Practice, University of Antwerp Antwerp, Belgium 2 Fund for Scientific Research—Flanders Brussels, Belgium 3 Laboratory of Microbiology, University of Antwerp Antwerp, Belgium 4 Unit of Epidemiology, Scientific Institute of Public Health Brussels, Belgium 5 Laboratory of Microbiology, Leiden University Medical Center Leiden, The Netherlands
*Correspondence address. Laboratory of Microbiology, University of Antwerp, Universiteitsplein 1, 2610 Antwerp, Belgium. Tel: +32-3-820-2751; Fax: +32-3-820-2752; E-mail: samuel.coenen{at}ua.ac.be
Received 23 August 2005; returned 2 November 2005; revised 12 April 2006; accepted 16 April 2006
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Abstract |
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Background: Data on outpatient cephalosporin use in Europe were collected from 25 countries within the ESAC project, funded by DG SANCO of the European Commission, using the WHO ATC/DDD methodology.
Methods: For the period 1997–2003, data on outpatient use of systemic cephalosporins aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Use was analysed in detail, using the new ATC codes J01DB, J01DC, J01DD and J01DE, introduced in the 2005 issue of the WHO ATC index and assigned to the four cephalosporin generations.
Results: Total outpatient cephalosporin use in 2003 varied by a factor of 270 between the country with the highest (6.18 DID in Greece) and lowest (0.02 DID in Denmark) use. First-, second- and third-generation cephalosporins were used most in 6, 16 and 3 countries, respectively. We observed fourth-generation use (mainly cefepime) in ambulatory care in 11 countries. From 1997 to 2003 cephalosporin use decreased in 13 countries, in France by more than 1 DID. A relative increase of second-generation (mainly cefuroxime) or third-generation use (mainly cefpodoxime or cefixime) by more than 10% in 12 countries coincided with an equally large decrease of first-generation use in eight countries (mainly cefadroxil, cefalexin or cefatrizine). In six countries, first-generation use increased, second-generation use decreased or both occurred.
Conclusion: The new ATC codes allow a more detailed description of outpatient cephalosporin use. The variation in antibiotic use in Europe is most extreme for this class of antibiotics, suggesting that in many countries in Europe these antibiotics are prescribed inappropriately.
Keywords: antibiotic use , cephalosporins , drug consumption , pharmacoepidemiology , ambulatory care , Europe
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Introduction |
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In this paper we will describe outpatient use of 40 substances classified as cephalosporins in more detail (Table 1), trends of their use (1997–2003) and seasonal variation. Additional data are available on the ESAC website (www.ua.ac.be/ESAC). As the WHO has included new Anatomic Therapeutic Chemical (ATC) codes in the January 2005 issue of the ATC index,1 cephalosporin use in Europe will be described according to this new classification, subdividing cephalosporins into four generations.
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Methods |
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The methods for collecting use data of systemic antibiotics were described in the introductory paper of this series,2 and elsewhere.3,4 Of the ATC group J01D ‘Other beta-lactam anti-bacterials, including monobactams and carbapenems’ outpatient use of cephalosporins was compared across 25 countries. New ATC codes for first- (J01DB), second- (J01DC), third- (J01DD) and fourth-generation (J01DE) cephalosporins were used to assess use in more detail. In addition, trends in time and seasonal variation were analysed.
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Results |
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For only 11 cephalosporins, the use represented more than 1% of the total cephalosporins use in 2003 in Europe, while no use was recorded for nine substances (Table 1). Figure 1 shows the total cephalosporin use in 2003, as well as the use of first-, second-, third- and fourth-generation cephalosporins according to the new ATC classification, expressed in defined daily doses (DDD) per 1000 inhabitants per day (DID). Cephalosporin use varied by a factor of 270 between the country with the highest (6.18 DID in Greece) and lowest use (0.02 DID in Denmark).
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Outpatient use varied enormously for first- (2.12 DID in Finland versus 0.01 in Denmark), second- (5.73 DID in Greece versus no use in Norway) and third-generation (1.69 DID in France versus no use in Norway) cephalosporins (see also Table 2). In 2003, we observed fourth-generation cephalosporin use in ambulatory care in 11 countries [less than 0.001 DID except for Italy (0.026 DID), Greece and Israel (both 0.002 DID)].
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First-generation cephalosporins still represented more than 50% of the total cephalosporin use in 2003 in Norway, Finland, the UK and Croatia (mainly cefalexin), and in Sweden and Estonia (cefadroxil). The second-generation cephalosporins, however, represented the most used subclass in Iceland, Slovakia, the Netherlands, the Czech Republic, Portugal, Poland, Denmark, Israel, Luxembourg, Belgium, Hungary and Spain (mainly cefuroxime), and in Ireland, Slovenia, Germany and Greece (cefaclor). The third-generation cephalosporins represented about half of the cephalosporin use in 2003 in France (mainly cefpodoxime), Italy and also Austria (mainly cefixime) (Table 2; Figure S1, Online Supplementary data). The fourth-generation cephalosporin used in most countries was cefepime.
Table 2 and Figure S1 also provide the overview of the consumption trends in the participating countries between 1997 and 2003. Thirteen countries showed a decreasing cephalosporin use between the first and the last year of observation. Only in France, however, was there more than 1 DID difference in cephalosporin use (4.65 versus 3.34 DID, respectively). Except for Austria, Germany, Spain, Croatia, Israel and Norway, the proportional use of the different generations of cephalosporins showed more dramatic variations, i.e. absolute differences of 10% or more between 1997 and 2003. Proportional use of first-generation cephalosporins decreased by more than 30% in Greece and Slovakia (mainly cefatrizine and cefalexin, respectively), by more than 20% in France and Luxembourg (mainly cefatrizine), and by more than 10% in Belgium, the Czech Republic and Poland (mainly cefadroxil) and in Slovenia (mainly cefalexin). This decrease was matched by increasing use of second-generation cephalosporins (mainly cefuroxime) in all these countries except for France, where the decrease was compensated by an equally increasing use of third-generation cephalosporins (mainly the oral cefpodoxime). Second- and third-generation cephalosporin use also increased by more than 10% in Ireland and Portugal (mainly cefaclor), and in Italy and Hungary (mainly cefixime), respectively. Proportional use of first-generation cephalosporins increased by more than 10% in Finland, Iceland and the UK (mainly cefalexin) and Sweden (mainly cefadroxil). This increase coincided with an equivalent decrease of second-generation cephalosporin use (mainly cefuroxime). In Denmark and the Netherlands, both countries with a very low use in absolute numbers, proportional use of second-generation cephalosporins decreased by more than 10% (mainly cefuroxime and cefaclor, respectively) as well.
In most countries with higher proportions of first-generation cephalosporin use, this proportion increased even further, whereas in most countries with lower proportions of first-generation use, this proportion decreased further (Figure S1).
Figures S2 and S3 (Online Supplementary data) show the seasonal fluctuation of cephalosporin use in 21 European countries that provided quarterly data. Seasonal fluctuations were observed in most countries, especially for the most commonly consumed generation of cephalosporins (see ESAC website). In Austria, Belgium, Croatia, the Czech Republic, Estonia, Germany, Hungary, Ireland, Italy, Poland, Portugal, Slovakia, Slovenia and Spain the mean of the use in the first and fourth quarter was more than 30% higher than the mean of the use in the second and third quarter (mainly the second-generation cephalosporins cefaclor and cefuroxime, and third-generation cephalosporin cefixime). In Greece and the UK the increase in antibiotic use in winter quarters was 24% and 23%, however, representing 1.38 and 0.17 DID, respectively. In the five remaining northern European countries (Denmark, Finland, Iceland, the Netherlands and Sweden) both the absolute and the relative difference was limited or even absent (ranging from –0.05 to 0.08 DID and from –2.3% to 15.1%, respectively).
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Discussion |
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European outpatient cephalosporin use showed striking variation. In 2003, the highest use was observed in Greece. Most countries used second-generation cephalosporins. This pattern remained stable, except for Slovakia, France and Italy, which shifted to a newer, i.e. higher, generation in the period 1997–2003. Cephalosporin use tended to decrease between 1997 and 2003, especially in France. Compared with 1997, however, the use of the newer (i.e. broad-spectrum) cephalosporins increased to the detriment of the older (narrower-spectrum) ones in most countries. An increase of second- (mainly cefuroxime) or third-generation (mainly cefpodoxime or cefixime) use by more than 10% in 12 countries coincided with an equally large decrease of first-generation use in eight countries (cefadroxil, cefalexin or cefatrizine). In six countries first-generation use increased and/or second-generation use decreased substantially.
The extreme variation observed suggests that in many countries this class of antibiotics is prescribed inappropriately. In France, for example, cephalosporin use has been increasing for treatment of uncomplicated respiratory tract infection with a presumed aetiology, despite no recommendation for cephalosporin use for this indication.5 This high use was due to the markedly high use of oral third-generation cephalosporins, cefpodoxime and cefixime. These achieve a t > MIC of <40% for Streptococcus pneumoniae, resulting in inadequate bacterial killing and selection for resistance.6
Before the introduction of the new WHO ATC classification, cephalosporins had been given one fourth level ATC code (J01DA). At the same time the most widely used system of classification of cephalosporins in daily clinical practice as well as by researchers presenting drug utilization figures was by generations.1,7,8 Although there was no consensus regarding the rationale of such a classification, the WHO Collaborating Centre for Drug Statistics Methodology has adopted it. In the chapter on cephalosporins in the Guidelines for ATC classification and DDD assignment 2005,1 reference is made to the textbook of Mandell et al.9 regarding this classification and the description of the four generations. Nevertheless, the definition of the generations has been criticized, because expanding the family of cephalosporins with new generations was merely driven by pharmaceutical marketing and is not necessarily based on substantial differences in their spectrum or other characteristics.
Although the current classification of cephalosporins might not be ideal, it nevertheless provided ESAC with a tool to describe the use of these 40 substances in Europe in a comprehensive, comparable and more detailed way than before. In conclusion, our results demonstrate extreme variation across Europe, the trends in time and the shift between generations in cephalosporin use, which need further exploration. These ESAC results can be used as a historical reference to gauge future interventions to optimize prescribing, and call for future research to gain a deeper understanding of cephalosporin use.
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Transparency declarations |
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The authors have no interests to declare.
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Supplementary data |
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Figures S1–3 are available as Online Supplementary data at http://jac.oxfordjournals.org.
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Footnotes |
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These authors contributed equally to this work. 
Members are listed in the Acknowledgements section.
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Acknowledgements |
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This ESAC project was granted by DG/SANCO of the European Commission (2001/SID/136). The information contained in this publication does not necessarily reflect the opinion or the position of the European Commission.
The ESAC Project Group members are Helmut Mittermayer, Sigrid Metz (Austria); Herman Goossens (Belgium); Boyka Markova (Bulgaria); Arjana Andra
evi
, Igor Franceti (Croatia); Despo Bagatzouni (Cyprus); Ji
í Vl
ek (Czech Republic); Dominique L. Monnet, Annemette Anker Nielsen (Denmark); Ly Rootslane (Estonia); Pentti Huovinen, Pirkko Paakkari (Finland); Philippe Cavalié, Didier Guillemot (France); Winfried Kern, Helmut Schroeder (Germany); Helen Giamarellou, Anastasia Antoniadou (Greece); Gábor Ternák, Ria Benkö (Hungary); Karl Kristinsson (Iceland); Robert Cunney, Ajay Oza (Ireland); Raul Raz (Israel); Giuseppe Cornaglia (Italy); Sandra Berzina (Latvia); Rolanda Valinteliene (Lithuania); Robert Hemmer, Marcel Bruch (Luxembourg); Michael Borg, Peter Zarb (Malta); Robert Janknegt, Margreet Filius (The Netherlands); Hege Salvesen Blix (Norway); Waleria Hryniewicz, Pawel Grzesiowski (Poland); Luis Caldeira (Portugal); Irina Codita (Romania); Leonid Stratchounski (deceased 7 June 2005), Svetlana Ratchina (Russia); Viliam Foltán, Tomá Tesa (Slovakia); Milan 
i
man (Slovenia); José Campos, Edurne Lazaro, Francisco de Abajo (Spain); Otto Cars, Gunilla Skoog, Sigvard Mölstad (Sweden); Giuliano Masiero (Switzerland); Serhat Ünal (Turkey); Peter Davey (UK).
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References |
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1 World Health Organization. (2005) Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment (WHO, Oslo, Norway).
2
Ferech M, Coenen S, Malhotra-Kumar S, et al. (2006) European Surveillance of Antimicrobial Consumption (ESAC): outpatient antibiotic use in Europe. J Antimicrob Chemother 58:401–7.
3 Vander Stichele R, Elseviers M, Ferech M, et al. (2004) European surveillance of antimicrobial consumption (ESAC): data collection performance and methodological approach. Br J Clin Pharmacol 58:419–28.[CrossRef][Web of Science][Medline]
4 Goossens H, Ferech M, Vander Stichele R, et al. (2005) Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 365:579–87.[Web of Science][Medline]
5 Guillemot D, Maison P, Carbon C, et al. (1999) Trends in antimicrobial drug use in the community—France, 1981–1992. J Infect Dis 177:492–7.
6
Ball P, Baquero F, Cars O, et al. (2002) Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence. J Antimicrob Chemother 49:31–40.
7 American Society of Health-System Pharmacists (ASHP). (2005) American Hospital Formulary Service (AHFS) Drug Information (ASHP, Bethesda).
8 Hardman JG, Gilman A, Limbird LE. (1996) Goodman & Gilman's: The Pharmacological Basis of Therapeutics (McGraw-Hill, New York).
9 Karchmer AW. (2000) Chapter 19 cephalosporins: classification. In Mandell GL, Bennett JE, Dolin R (Eds.). Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases, Vols 1 & 2 (Churchill Livingstone, Philadelphia) pp. 277–8.
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