Meta-analysis of bacterial resistance to macrolides—providing generalizable results: authors' response

Michael T. Halpern1,*, Jordana K. Schmier1, Carl Asche2, Phillip W. Sarocco3 and Lionel A. Mandell4

1 Exponent, Inc., Alexandria, VA, USA; 2 Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA; 3 Aventis US Pharma, Bridgewater, NJ, USA; 4 McMaster University School of Medicine, Hamilton, Ontario, Canada


* Corresponding author. Tel: +1-571-227-7210; Fax: +1-571-227-7299; E-mail: mhalpern{at}exponent.com

Keywords: antibiotic resistance , meta-analysis , respiratory tract infections , Streptococcus

Sir,

Thank you for the letter from Monnet et al.1 regarding our manuscript, ‘Meta-analysis of bacterial resistance to macrolides’.2These investigators raise a number of important points. First is the issue of local factors affecting bacterial resistance. Clearly, local factors can affect resistance, although we do not believe it has been documented, as Monnet et al. state, that levels of resistance ‘depend almost solely on local factors’. With the ever increasing rates of travel and global interactions, spread of resistance between different locales will probably continue to be an important issue. For example, a study by other researchers at Monnet's institute in Denmark reported that foreign travel was a risk factor for quinolone-resistant Campylobacter jejuni infections.3 A recent report also indicated that bacteria collected from international travellers to the same geographic region may not share the same DNA restriction patterns.4 Regardless, our meta-analysis would have been incomplete if we had not explored the potential heterogeneity of the included studies. All of the included studies involved similar criteria in assessing resistance: isolates of Streptococcus pneumoniae and/or Streptococcus pyogenes obtained from community or outpatient settings in 1997–2003 with specified MIC levels. Further, statistical analyses were performed (using the Q-statistic) to evaluate potential heterogeneity between studies. Thus, despite the potential effects of local factors, we were able to identify a statistically homogenous group of studies for pooling in the meta-analysis.

Monnet et al. also question the exclusion of a number of surveillance studies. As discussed in our paper, reports from a number of broad surveillance studies (e.g. PROTEKT) were excluded from this meta-analysis as they did not provide resistance information separately for each macrolide (i.e. they presented pooled results across different macrolides) and/or they did not provide resistance information for patients with only the selected disease conditions (e.g. lower respiratory tract infections). Both of these study characteristics (resistance information for individual macrolides and from patients with selected infectious diseases) were important in enhancing the specificity of the included resistance data and the pooled results. We did attempt to contact authors regarding unpublished work and for additional information when data in an abstract or article were unclear. A number of the resistance studies mentioned by Monnet et al. did not appear in MEDLINE or EMBASE and/or did not meet the meta-analysis inclusion criteria. For example, the DANMAP 2003 study5 presents resistance data for all macrolides combined and does not specify the infectious condition or conditions of individuals from whom isolates were collected. Thus, the studies mentioned by Monnet et al. would have been specifically excluded from the meta-analysis.

Monnet et al. comment that the meta-analysis results are out of date as soon as they are published, with national surveillance reports and meeting abstracts presenting more recent information. This is a clear limitation to any meta-analysis, that it can provide results that are only as current as the data available when it was performed. Further, data that are publicly unavailable are difficult to consider. However, this concern ignores the principal reason for performing a meta-analysis: to pool data across multiple studies in order to assess specific outcomes more accurately and with greater statistical power. Individual studies and meeting abstracts do present more current resistance data, but these reports are limited in their sample size, scope and generalizability. The comments by Monnet et al. that erythromycin resistance is much lower in Denmark illustrate this point; while the resistance figure quoted provides one data point, its relevance to overall erythromycin resistance is uncertain. By combining resistance data across multiple studies in a systematic manner, we were able to evaluate resistance more broadly, without the limitations of any individual study (which, as Monnet et al. point out, may be influenced by local factors).

We are puzzled by the comment from Monnet et al. that the money spent on the meta-analysis would have been better spent collecting resistance data from regions where such data are missing. We are unaware of criteria being used to assess the best global expenditures of research monies. While there are many worthy uses of research funds, we believe that this meta-analysis is an important contribution to the literature, providing broadly generalizable data regarding macrolide resistance in community and outpatient settings. To our knowledge, such an analysis has not been previously performed.

We agree with the conclusion by Monnet et al. that our meta-analysis ‘underscores the importance and need for ongoing surveillance of the local antimicrobial resistance combined with surveillance of antimicrobial consumption’. Collection of local data will continue to be crucial in evaluating trends in bacterial resistance. However, local data provide only isolated pictures of bacterial resistance. In this era with global interactions being increasingly common, combining data in a consistent and robust manner, with the appropriate methods of a meta-analysis, provides broader and more generalizable information for the development of national and multi-national health policy.

References

1. Monnet DL, Brandt CT, Kaltoft MS et al. High prevalence of macrolide resistance: not in every country! [Comment on: Halpern et al. J Antimicrob Chemother 2005; 55: 748–57]. J Antimicrob Chemother 2005; 56: 433–4.[Free Full Text]

2. 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]

3. Engberg J, Neimann J, Nielsen EM et al. Quinolone-resistant Campylobacter infections: risk factors and clinical consequences. Emerg Infect Dis 2004; 10: 1056–63.[ISI][Medline]

4. Kubota K, Barrett TJ, Ackers ML et al. Analysis of Salmonella enterica serotype Typhi pulsed-field gel electrophoresis patterns associated with international travel. J Clin Microbiol 2005; 43: 1205–9.[Abstract/Free Full Text]

5. DANMAP 2003. Use of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. Søborg, Denmark: Danish Zoonoses Centre, July 2004. http://www.dfvf.dk/Files/Filer/Zoonosecentret/Publikationer/Danmap/Danmap_2003.pdf (27 June 2005, date last accessed).





This Article
Extract
Full Text (PDF)
All Versions of this Article:
56/2/434    most recent
dki247v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Halpern, M. T.
Articles by Mandell, L. A.
PubMed
PubMed Citation
Articles by Halpern, M. T.
Articles by Mandell, L. A.