JAC Advance Access originally published online on May 30, 2006
Journal of Antimicrobial Chemotherapy 2006 58(2):423-427; doi:10.1093/jac/dkl183
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European Surveillance of Antimicrobial Consumption (ESAC): outpatient quinolone use in Europe
1 Laboratory of Microbiology, University of Antwerp Antwerp, Belgium 2 Department of General Practice, University of Antwerp Antwerp, Belgium 3 Fund for Scientific Research—Flanders Brussels, 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: +32-3820-2752; E-mail: matus.ferech{at}ua.ac.be
Received 22 December 2005; returned 17 February 2006; revised 12 April 2006; accepted 16 April 2006
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Abstract |
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Background: Data on outpatient quinolone 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 quinolones aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2004) per 1000 inhabitants per day (DID). Because a new DDD for levofloxacin was published in the ATC 2004 index (0.5 g instead of 0.25 g) all data were recalculated accordingly. Quinolone use was analysed in detail, using a classification into three generations based on their pharmacokinetic and in vitro potency profiles, which determines the area of clinical use.
Results: Total outpatient quinolone use in 2003 varied by a factor of 12 between the country with the highest (3.10 DID in Portugal) and lowest (0.25 DID in Denmark) quinolone use. The second-generation quinolones represented more than 50% of the quinolone use (mainly ciprofloxacin) except for Croatia, where the first-generation was used most (mainly norfloxacin). In 22 countries, the use of second and/or third-generation quinolones increased at the expense of the use of first-generation quinolones. The new so-called respiratory quinolones (levofloxacin and moxifloxacin) represented more than 10% of quinolone use in 12 countries, with extreme seasonal variation in all these countries except for one.
Conclusion: There has been a substantial change in the use pattern of quinolones between 1997 and 2003, since the introduction of quinolones that are effective for the treatment of respiratory tract infections. These quinolones are not the first-line antibiotics for this indication and therefore quinolone use should in general still be limited and not show substantial seasonal variation.
Keywords: antibiotic use , quinolones , drug consumption , pharmacoepidemiology , ambulatory care, Europe
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Introduction |
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This article reviews the geographical variation and temporal trends of quinolone use in 25 European countries between 1997 and 2003. In-depth analysis of quinolone use was performed according to a classification based on their pharmacokinetic and in vitro potency profiles, which determines the area of clinical use. Additional data are available on the ESAC website (www.ua.ac.be/ESAC).
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Methods |
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The methods for collecting use data of systemic antibiotics were described in the introductory article of this series,1 and elsewhere.2,3 For the period 1997–2003, use data of systemic antibiotics for ambulatory care aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD) per 1000 inhabitants per day (DID). According to the ATC/DDD classification (WHO, version 2004),4 the quinolones are divided into two groups, J01MA called ‘Fluoroquinolones’ and J01MB referred to as ‘Other quinolones’. However, for the comparison of outpatient quinolone use, we have adapted the classification of quinolones into three generations introduced by Ball,5 based on their chemical structure and antimicrobial activity (Table 1). As the WHO Collaborating Centre for Drug Statistics Methodology has changed the DDD value for levofloxacin in the ATC 2004 index (0.5 g instead of 0.25 g), all presented data have been adjusted accordingly.4
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Results |
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For only six of 23 unique ATC codes for quinolones, the use represented more than 1% of the total quinolone use in 2003 in Europe, while no use was recorded for five quinolones (Table 1). Figure 1 shows the total quinolone use as well as the use of the three quinolone generations in 2003 for 25 European countries. Quinolone use varied by a factor of 12 between the country with the highest (3.1 DID in Portugal) and lowest (0.25 DID in Denmark) use. The use varied even more for the first-generation (1.3 DID in Croatia and the UK versus no use in Norway and Iceland), second-generation (2.3 DID in Portugal versus 0.17 in Croatia) and third-generation (0.72 DID in Belgium versus no use in eight countries) quinolones (see Table 2). Figure 1 also illustrates the effect of the DDD change of levofloxacin in 2004 (from 0.25 to 0.5 g) on the European picture of quinolone use by means of the whiskers in the chart. Italy and Belgium, the highest levofloxacin users in 2003 were most affected by this change.
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First-generation quinolones (mostly represented by norfloxacin) still represented 85% of the total quinolone use in Croatia, more than 40% in the Czech Republic, Sweden, France and Slovenia and more than 10% in all but six countries (Denmark, Iceland, Israel, Ireland, Norway and the UK) in 2003. Both pipemidic acid and nalidixic acid were used in seven countries, ranging from 0.001 in Germany to 0.25 DID in Italy and from 0.00002 in Italy to 0.04 DID in Ireland, respectively. Among the other representatives of the first-generation, cinoxacin was used mainly in Italy (1.7% of total quinolone use), flumequine in France (1.3%), oxolinic acid in the Czech Republic, Poland and Slovakia (<0.05%), piromidic acid in Italy and rosoxacin in Portugal (both <0.001%).
Second-generation quinolones were by far the most widely used in Europe and exceeded 50% (median 63%) of total quinolone use in all countries except Croatia. Ciprofloxacin itself accounted for 41% of total quinolone use in 25 countries and was the most used in 18 of them. Its use varied from 0.14 DID in Israel to 1.74 DID in Portugal. Ofloxacin was the most used quinolone in two countries (Israel and Slovakia), while its purified S-enantiomer, levofloxacin, was most used in Italy.
Among the third-generation quinolones, which have been just recently introduced in Europe, only gatifloxacin and moxifloxacin have been prescribed in Europe and their use was recorded in all but six countries in 2003 (the Czech Republic, Estonia, Iceland, the Netherlands, Norway and Slovakia). Moxifloxacin represented 99.5% of the third-generation quinolones in 2003, whereas gatifloxacin use was only recorded in Germany. Third-generation quinolones are prescribed most frequently in high antibiotic consuming countries,2 as well as in Austria and Germany.
Table 2 and Figure S1 (Online Supplementary data) provide the overview of the consumption trends in the participating countries between 1997 and 2003. Between the first and the last year of observation, quinolone use was increasing in 20 countries, especially in Luxembourg (1.15 DID) and Belgium (0.98 DID). Only Slovenia, the UK and the Netherlands showed a decreasing trend of quinolone use, particularly due to declining use of the first-generation quinolones.1
The proportional use of the different quinolone generations showed more dramatic variations, i.e. absolute differences of 10% or more between 1997 and 2003, in more than half of the countries. The proportional use of first-generation quinolones decreased by more than 20% in six and by more than 10% in another seven countries. This decrease was mainly the result of a decrease in norfloxacin use, except in Poland, Slovenia, Spain, France and Luxembourg where it also resulted from decreasing use of pipemidic acid and for Finland where from 2000 onwards cinoxacin was no longer used. This decrease was matched by a similar increase either in third-generation quinolones in Austria, Belgium and Spain, or second-generation quinolones in the Czech Republic, Finland, Greece, Ireland, the Netherlands, Poland, Slovenia and Sweden. In France and Luxembourg, the use of both second- and third-generation quinolones increased. On the other hand, the use of third-generation quinolones increased in Germany at the expense of the second-generation quinolones.
Figures S2 and S3 (Online Supplementary data) show the seasonal fluctuation of quinolone use in 21 European countries that provided quarterly data. In all countries but Germany, the mean of the quinolone use in the first and fourth quarter did not exceed by more than 20% the mean of the use in the second and third quarter. The high seasonal fluctuation in Germany is determined by the relatively frequent use of third-generation quinolones, whose use increased in winter quarters by 84%. Similar seasonal fluctuations of third-generation quinolones were observed in most countries and ranged from 60% in Portugal to 118% in Austria, among six countries using more than 0.1 DID of these quinolones. However, second-generation quinolones also showed an increase in use in winter months, and this increase was higher than 20% in the Czech Republic (mainly ofloxacin), Poland (mainly ciprofloxacin) and Italy (mainly levofloxacin). Finally, the seasonal fluctuation of first-generation use varied from –6% in Denmark (summer use was higher than winter for another five countries) to 14% in Estonia (mainly due to norfloxacin).
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Discussion |
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This study describes a striking variation of outpatient quinolone (ATC J01M) use in Europe, suggesting inappropriate prescribing in many countries.
We propose a classification based on Ball's5 description of their pharmacokinetic and in vitro potency profiles. The quinolone in vitro potency profiles have shifted these agents used predominantly for the treatment of urinary tract infections in the 1960s–70s (our first-generation quinolones), to a more systemic use in the 1980s–90s (our second-generation quinolones), and, in the current millennium, to the treatment of respiratory tract infections (our third-generation quinolones). Several compounds have not yet received an ATC code, and are therefore not included in Table 1 (e.g. sitafloxacin, tosufloxacin and garenoxacin). Other classifications have been proposed.4,6 Andersson and MacGowan6 added a fourth group with quinolones widely used against a broad range of tissue-based infections (including temafloxacin, clinafloxacin and trovafloxacin). However, moxifloxacin and garenoxacin (both third-generation quinolones based on our classification) are as active as trovafloxacin against anaerobes and their clinical indication may expand beyond the respiratory tract. In the classification of Andersson and MacGowan, levofloxacin is included in both the second (widely used against tissue-based and urinary infections) and fourth (main use in respiratory tract infections) group. We included levofloxacin in the second-generation because it is the S-enantiomer of ofloxacin.7 This illustrates the complexity of quinolone classification.
During the 1990s, the use of second-generation quinolones was increasing steadily at the expense of the first-generation in most countries. This trend has accelerated more recently, especially in the countries with the highest quinolone use in Europe, through the introduction of the newer so-called ‘respiratory’ agents, levofloxacin as well as moxifloxacin. The pattern of quinolone use, however, is determined by the DDD value given to a certain agent, which is well demonstrated by analysing the quinolone use pattern in 2003, applying two DDD values for levofloxacin. The WHO Collaboration Centre decided to increase the DDD of levofloxacin from 0.25 to 0.5 g in 2004 due to its increased use for the treatment of respiratory tract infections, for which higher doses are prescribed than for urinary tract infections. This adjustment of DDD resulted in a less pronounced increase in consumption expressed in DID in countries with higher consumption of levofloxacin, such as Italy and Belgium. DDD changes of an agent over time create a serious problem for analysing trends of use, because we noticed that some data providers are not able to adjust their use data retrospectively or were not reporting the DDD value they used for levofloxacin.
We were surprised to observe seasonal variation, with winter peaks presumably for the treatment of respiratory tract infections, of so-called ‘urinary’ quinolones with wide activity against Gram-negatives but marginal activity against Gram-positives.2 We suggest that a low seasonal fluctuation of the earlier quinolones, such as ciprofloxacin and ofloxacin, is a good marker of restrained use. Conversely, the new, so-called ‘respiratory’ quinolones (levofloxacin and moxifloxacin), which already represented more than 10% of quinolone use in 12 countries in 2003, showed extreme seasonal variation in all these countries except for one.
In conclusion, although quinolones do not represent the first-line therapy for most adult respiratory tract infections in Europe,8,9 in ESAC we observed a substantial change in the prescribing pattern of these agents. Excessive use of quinolones is associated with development of resistance, requires more resources and exposes patients to the additional risk of side effects. Individual countries should define their own range of acceptable use considering the limited indications of quinolones and their demographical and epidemiological characteristics.
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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 supported by a grant from 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 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.
2 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]
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 World Health Organization. (2004) Collaborating Centre for Drug Statistics Methodology. ATC Index with DDDs (WHO, Oslo, Norway).
5
Ball P. (2000) Quinolone generations: natural history or natural selection? J Antimicrob Chemother 46:Suppl T1, 17–24.
6 Andersson MI and MacGowan AP. (2003) Development of the quinolones. J Antimicrob Chemother 51:Suppl 1, S1–11.
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Okano T, Maegawa H, Inui K, et al. (1990) Interaction of ofloxacin with organic cation transport system in rat renal brush-border membranes. J Pharmacol Exp Ther 255:1033–7.
8 ERS Task Force Report. (1998) Guidelines for management of adult community-acquired lower respiratory tract infections. European Respiratory Society. Eur Respir J 11:986–91.[CrossRef][Web of Science][Medline]
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