High prevalence of macrolide resistance: not in every country! [Comment on: Halpern et al. J Antimicrob Chemother 2005; 55: 748–57]

Dominique L. Monnet1,*, Christian T. Brandt1, Margit S. Kaltoft2, Line Bagger-Skjøt1, Thomas L. Sørensen1,{dagger}, Hans-Ulrik K. Nielsen1 and Niels Frimodt-Møller1

1 National Center for Antimicrobials and Infection Control, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen S; 2 Streptococcus Unit, Statens Serum Institut, Copenhagen, Denmark


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

Keywords: antimicrobial resistance surveillance , macrolides , Streptococcus pneumoniae , antibiotic usage

Sir,

We would like to comment on the article entitled ‘Meta-analysis of bacterial resistance to macrolides’ by Halpern et al.1 The idea of a meta-analysis of published studies on resistance is interesting. However, it does not add much to our knowledge on the prevalence of macrolide resistance. Pooling the results of randomized studies is a method to assess treatment efficacy. However, it does not make sense to use it for resistance, since the reported prevalences in different studies depend almost solely on local factors and the results could be misleading for readers and prescribers in many countries with low prevalence of resistance.

The first problem with this meta-analysis is publication bias. We disagree with the authors on their view that: ‘Given the nature of this topic, it is likely that there would be equal interest in reports of low or high levels of resistance’. Countries with low resistance rarely feel the need—or are even able—to publish their results in peer-reviewed journals, but rather quickly report at national level. In Denmark and Sweden, this is done within 6 months of the end of a calendar year, e.g. data for 2003 were published in June 2004.2,3 However, most peer-reviewed publications take somewhat longer, thus delaying report to prescribers. As mentioned by Halpern et al., the meta-analysis only confirms results that were already available from multinational surveillance studies such as PROTEKT. Moreover, the view of resistance it offers is already out of date since more recent data are available from multinational surveillance projects, e.g. the European Commission-funded European Antimicrobial Resistance Surveillance system (EARSS; http://www.earss.rivm.nl) or PROTEKT, national reports, e.g. DANMAP2 and SWEDRES,3 or abstracts at international conferences. The meta-analysis included very few studies from some regions of the world, raising the possibility that the exclusion criteria used were too stringent. For example, there are many data from Canada, a country with relatively low, but increasing, macrolide resistance. It is unclear why countrywide data on isolates tested centrally by the Canadian Bacterial Diseases Network4 were excluded. The reasons for exclusion may be that they only covered a short time period and were not stratified by age and condition. However, the meta-analysis failed to report results stratified on these criteria. As it is the norm when performing meta-analyses, e.g. to assess treatment efficacy, Halpern et al. should have contacted the authors of published surveillance studies for more detailed and updated resistance data. For other regions in the world, reliable resistance data simply do not exist and the money invested in the meta-analysis may have been better used for performing studies in those regions where data are crucially missing, i.e. Africa, many parts of Asia, and Central and South America.

Because of the relatively small number of studies included in the meta-analysis, results could not be presented for each year and each country. Consequently, the meta-analysis only reported on pooled results for 1997–2003, whereas EARSS, as well as national sources,2,3 show that macrolide resistance varied during this period. Moreover, by reporting an average 32% erythromycin-resistant Streptococcus pneumoniae for Europe, the meta-analysis gives a biased view of macrolide resistance on this continent. EARSS data show that, in many European countries, resistance to macrolides is still below 10%. In 2004, erythromycin resistance in S. pneumoniae isolates from sterile body sites was only 3.7% in Denmark. However, it showed an increase from 0.5% in 1994 to a maximum of 5.2% in 2003 (Figure 1). Despite the low prevalence, this 10-fold increase prompted us to remind prescribers about the few indications for use of macrolides in a country with low penicillin resistance.5 In Denmark, macrolide resistance data are systematically presented in parallel with macrolide consumption.2,5 The methods for this surveillance are described in the DANMAP report.2 In 2000, a pause in the increase of azithromycin consumption seemed to have halted the increase in macrolide resistance (Figure 1). However, this may now be counterbalanced by an increase in roxithromycin consumption, which is probably due to the availability of generic roxithromycin on the Danish market.



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Figure 1. Community consumption of macrolides and erythromycin-resistant S. pneumoniae from blood and spinal fluid, Denmark, 1994–2004. Lines, community consumption of macrolides [defined daily doses (DDD)/1000 inhabitant-days]: filled squares, total macrolide consumption; open diamonds, erythromycin consumption; open triangles, roxithromycin consumption; open circles, clarithromycin consumption; open squares, azithromycin consumption. Bars, erythromycin-resistant S. pneumoniae from blood and spinal fluid (%). Isolates with an MIC ≥ 1 mg/L were considered resistant to erythromycin.

 
For most European countries, data on antimicrobial consumption are now available from the European Surveillance of Antimicrobial Consumption (ESAC) system (http://www.ua.ac.be/esac). Differences in macrolide consumption are the most likely causes for the observed differences in macrolide resistance among countries.6 In 2005, it does not make sense to report consumption and resistance by continent. Moreover, there is now a consensus in Europe that both should be reported not only by country, but also by region for community microorganisms, or by hospital for nosocomial microorganisms. Rather than providing new information, the meta-analysis by Halpern et al. underscores the importance and need for ongoing surveillance of the local antimicrobial resistance combined with surveillance of antimicrobial consumption.

Footnotes

{dagger} Present address. Clinical Unit for Health Promotion, H:S Bispebjerg Hospital, Copenhagen, Denmark Back

References

1. Halpern MT, Schmier JK, Snyder LM et al. Meta-analysis of bacterial resistance to macrolides. J Antimicrob Chemother 2005; 55: 748–57.[Abstract/Free Full Text]

2. DANMAP 2003. Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. ISSN 1600–2032. http://www.dfvf.dk/Files/Filer/Zoonosecentret/Publikationer/Danmap/Danmap_2003.pdf (30 April 2005, date last accessed).

3. SWEDRES 2003. A report on Swedish antibiotic utilisation and resistance in human medicine. STRAMA, Stockholm, Sweden, 2004. http://soapimg.icecube.snowfall.se/strama/SWEDRES_2003_3_juni_2004.pdf (1 May 2005, date last accessed).

4. Low DE, de Azavedo J, Weiss K et al. Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae in Canada during 2000. Antimicrob Agents Chemother 2002; 46: 1295–301.[Abstract/Free Full Text]

5. Frimodt-Møller N, Monnet DL, Sørensen TL et al. Increased resistance to macrolide antibiotics. EPI-NEWS 2001, week 4. http://www.ssi.dk/sw2863.asp (1 May 2005, date last accessed).

6. Goossens H, Ferech M, Vander Stichele R et al. Outpatient antibiotic use in Europe and association with resistance: a cross-national database study. Lancet 2005; 365: 579–87.[CrossRef][ISI][Medline]