a Research Area, Fundación Jiménez Díaz, Madrid; b Medical Department, SmithKline Beecham Pharmaceuticals, C/Valle de la Fuenfria no 3, 3° D. 28034 Madrid; c Microbiology Department, National Centre of Microbiology, Instituto de Salud Carlos III, Majadahonda (Madrid); d Microbiology Department, Ramón y Cajal Hospital, Madrid, Spain
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Abstract |
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Introduction |
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Materials and methods |
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For each study identified, the year-specific prevalence of resistance was obtained. For each year, the rates of resistance from different studies were combined to obtain an overall estimate for that given year. A fixed-effects model with weights equal to the inverse of the variances of the prevalence was used to obtain the combined estimates. The prevalence of resistance was plotted against the consumption of macrolides for each year in the study period. Spearman non-parametric correlation coefficients (r) between the prevalence of resistance and the consumption of macrolides were calculated. Confidence intervals were calculated by the exact method. A multivariate model was performed analysing the bd and od models. SPSS for Windows, release 7.5, was used for statistical analysis.
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Results |
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The total consumption of macrolides showed a good correlation with the erythromycin resistance curve (r = 0.88; P < 0.001). When specific macrolide classes were analysed separately, no association was apparent between consumption of tds macrolides and erythromycin resistance (r = 0.04; P = 0.90). However, there was a strong association between prevalence of resistant strains and consumption of bd macrolides (r = 0.86; P < 0.001), with a 12 year lag between the observed increase in consumption and increase in resistance. The association between consumption of od macrolides and prevalence of resistance was also high (r = 0.87; P < 0.001), but these drugs were introduced after the increase in prevalence of resistant strains in the early 1990s. The results were essentially unchanged when a multivariate model was used to assess the simultaneous correlation of the three classes of macrolides with the prevalence of resistance.
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Discussion |
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From a pharmacodynamic point of view, other factors may have contributed to the selective process. It has been suggested that macrolide agents with low Cmax and long half-life (like bd or od macrolides) are likely to produce a longer selective window, which means longer bacterial exposure to resistance-selective concentrations.32 Long-acting agents optimize selective effects.33 In any case, either directly or indirectly, both bd and od macrolides appear to be the main reason for the increase in erythromycin resistance.
Some reports have shown a monoclonal spread of resistance3 related to macrolide consumption4 while in other reports, resistance was polyclonal,6 including in our country.9 In Spain, as in other European countries, a new efflux phenotype is responsible for the increase in resistance.8,9,12 The high prevalence (>90%) of this resistance phenotype described in Spanish studies8,9,12 may affect the choice of empirical antibiotic therapy in clinical practice.11 This is even more relevant when considering that the prevalence of resistance is higher in younger people8,10 and that a positive relationship has been described between the reduction of macrolide use and the decline of erythromycin resistance prevalence.34 Nevertheless, formal (mathematical) population analysis suggests that the decay in antibiotic resistance after a significant decrease in consumption of particular drugs takes much longer than it does for the resistance to emerge.35
This study has gathered all the reliable evidence available for the last 12 years in Spain, and put it into relation with the global trend in antibiotic use, trying to sketch hypotheses that warrant further investigation. This study shows that the increase in overall macrolide use, caused by bd and od macrolides, has resulted in an increased prevalence of erythromycin-resistant S. pyogenes in Spain. Whether this progressive increase in erythromycin resistance has been due to an increase in total macrolide consumption or can be explained on the basis of pharmacodynamic properties that are specific for the bd and od macrolides, remains unresolved. To answer this question, active intervention studies in close populations are needed, targeting bd and/or od macrolides and then tracking what happens to the level of erythromycin resistance. The relation of antibiotic consumption and prevalence of resistance among Gram-positive cocci stresses the importance of preserving the therapeutic potential of antibiotics by taking into account the ecological consequences of the generalization of their use.4 Population biology studies should be undertaken to explain the theoretical and practical consequences of antibiotic consumption on pathogenic bacteria.36
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Acknowledgments |
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Notes |
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References |
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Received 4 April 2000; returned 5 July 2000; revised 17 July 2000; accepted 16 August 2000