The relationship between trends in macrolide use and resistance to macrolides of common respiratory pathogens
Milan
i
mana,*,
Marko Pokorna,
Katja Semeb,
Andreja Ora
emc and
Metka Paragic
a Department of Infectious Diseases, University Medical Centre Ljubljana, Japljeva 2, SI-1525 Ljubljana;
b Institute of Microbiology, Zalo
ka 4, SI-1525 Ljubljana;
c Institute of Public Health of Slovenia, Trubarjeva 2, Ljubljana, Slovenia
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Abstract
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The correlation between increased macrolide consumption and the resistance of Streptococcus pyogenes, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis to macrolides in Slovenia from 1994 to 1999 was evaluated. The outpatient consumption of macrolides increased from 1.89 to 3.84 defined daily doses (DDD)/1000 inhabitants/day during the observation period. This increase in macrolide consumption was paralleled by a steady increase in macrolide resistance in S. pyogenes (from 0 to 7.4%, r = 0.90, P = 0.014) and upper respiratory S. pneumoniae isolates (from 0 to 9%, r = 0.82, P = 0.044). In other pathogens studied, no significant increase was detected.
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Introduction
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In the 1980s macrolides accounted for 1015% of the world oral antibiotic market and their market share rose to 18% in the 1990s.1,2 Analysis of macrolide prescribing and resistance patterns indicates a correlation between increasing macrolide resistance of Streptococcus pyogenes and Streptococcus pneumoniae and increased use of macrolides.36 In Slovenia, an increase in the use of macrolides has already led to an increase in macrolide resistance of common respiratory pathogens.7,8 In the present study the observation period has been extended for 2 years and an effort was made to evaluate trends in macrolide use and macrolide resistance over a 6 year period.
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Materials and methods
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The data on the use of antibiotics were obtained from the Institute of Public Health of Slovenia. Slovenia is a small central European country with nearly two million inhabitants. Antimicrobial agents can be obtained only by prescription. Throat swabs were obtained from outpatients and inpatients (on admission) with acute respiratory tract infections treated at the Department of Infectious Diseases, University Medical Centre Ljubljana. All isolates of S. pyogenes, S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis collected between January and December in 1999 were analysed. Additionally, all invasive isolates of S. pneumoniae and H. influenzae isolated from blood, CSF and pleural fluid in all Slovenian hospitals in 1999 were included in the study. Duplicate isolates from the same patient were excluded. Susceptibility tests of invasive bacterial isolates were performed at the Institute of Public Health. Upper respiratory isolates were tested at the Institute of Microbiology. The methods were described previously.7
The results of susceptibility testing performed in 1999 were compared with those from the period 19941998, which were obtained in a similar manner. The relationship between resistance rates to macrolides and macrolide consumption was assessed by linear regression analysis. For calculation, Microsoft Excel 97 was used.
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Results and discussion
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The results are shown in the Table
. From 1994 to 1999 macrolide consumption in Slovenia increased from 1.89 to 3.84 defined daily doses (DDD)/1000 inhabitants/day. The increase was due mainly to an increase in consumption of long-acting macrolides (3.23 DDD/1000 inhabitants/day in 1999). This increase in macrolide consumption was paralleled by an almost linear increase in macrolide resistance of S. pyogenes from 0% in 1994 to 7.4% in 1999 (r = 0.90, P = 0.014). A similar increase in macrolide resistance was observed in upper respiratory S. pneumoniae isolates (from 0 to 9%, r = 0.82, P = 0.044). There was no significant increase in macrolide resistance in invasive S. pneumoniae, or invasive and upper respiratory H. influenzae isolates during a 6 year period. Interestingly, in 1999 the first macrolide-resistant isolate of M. catarrhalis was observed.
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Table. Outpatient prescribing of macrolides and resistance to macrolides (erythromycin and azithromycin in S. pyogenes, S. pneumoniae, H. influenzae and M.catarrhalis in Slolvenia, 19941999
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A similar increase in macrolide resistance in S. pyogenes has been observed in Finland, Spain and Italy, although macrolide resistance was already present at the start of the observation period in these countries.46 In Finland the increase was erythromycin associated whereas in Italy and Spain the association was with the new long-acting macrolides.46 In Slovenia, azithromycin was the first registered long-acting macrolide. It has been used since 1988 and consumption has grown steadily. The correlation between total outpatient macrolide consumption and resistance to macrolides in S. pneumoniae shows that in countries with low total usage of macrolides, like Sweden, Denmark and Norway (0.82.0 DDD/1000 inhabitants/day) the prevalence of resistance in S. pneumoniae is low (<10%) whereas in Spain and France, where macrolide consumption is high (>3.6 DDD/1000 inhabitants/day) the resistance was 33 and 46% in 1997.2,3,9 In spite of similar total outpatient macrolide consumption in Spain and Slovenia, macrolide resistance rates in S. pneumoniae and S. pyogenes in Spain are much higher (32.6% compared with 9% for S. pneumoniae and 1426.4% compared with 7.4% for S. pyogenes).2,9,10 The current lower resistance prevalence in Slovenia is probably due to low consumption of macrolides at the beginning of the 1990s, when the consumption of macrolides was 0.89 DDD/1000 inhabitants/day (in 1991) and no macrolide resistance was observed in S. pneumoniae and S. pyogenes. In Spain the consumption of macrolides was 3.63 DDD/1000 inhabitants/day in 1997, increasing from 1.25 DDD/1000 inhabitants/day in 1987.2 In contrast, in France macrolide resistance in S. pyogenes is relatively low (510%), despite high macrolide consumption.10 Obviously, there is no uniform relationship between macrolide consumption and macrolide resistance in S. pyogenes and S. pneumoniae. Correlation between increased total macrolide use and resistance to macrolides in H. influenzae and M. catarrhalis was not observed in our study.
In conclusion, a two-fold increase in macrolide consumption in a 6 year period in Slovenia was associated with a nearly linear increase in macrolide resistance in S. pyogenes and upper respiratory S. pneumoniae isolates. Since a further increase in macrolide resistance in these pathogens is likely, close monitoring is necessary.
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Notes
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* Corresponding author. Tel: +386-1-23-10-558; Fax: +386-1-23-02-781; E-mail: milan.cizman{at}mf.uni-lj.si 
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References
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Received 14 August 2000;
returned 15 October 2000; revised 12 December 2000;
accepted 19 December 2000