a National Institute of Public Health and the Environment, Bilthoven; Public Health Laboratories at b Leeuwarden, c Nijmegen and d Haarlem, The Netherlands
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Abstract |
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Introduction |
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Materials and methods |
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Data on the use of antibiotics in The Netherlands during the period 19941999 were obtained from the Foundation for Pharmaceutical Statistics (The Hague). This database contains the total number of prescriptions and defined daily doses (DDDs) for each drug supplied by 1125 of the 1600 Dutch pharmacies to patients outside hospitals. These data were recalculated to DDD per 1000 persons per day using demographic data from the Central Bureau of Statistics. The data were analysed using Microsoft Excel. Trends in resistance percentage were tested by a Mantel Haenszel 2 or
2 test using SAS software version 8.1 (SAS Institute, Cary, NC, USA).
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Results |
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Penicillins and tetracyclines were the antibiotics most often used in The Netherlands during 19941999. The use of most classes of antibiotics was fairly stable. The average use was 3.4 DDD/1000/day penicillins (Figure 1), 0.066 DDD/1000/day ß-lactams other than penicillins, 2.3 DDD/ 1000/day tetracyclines and 0.71 DDD/1000/day trimethoprim/sulfamethoxazole. In contrast, the use of macrolides doubled from 0.51 DDD/1000/day in 1994 to 1.0 DDD/ 1000/day in 1997 and stayed at 1.07 DDD/1000/day in 1998 and 1999 (Figure 2
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The number of first isolates per year of S. pneumoniae (one per patient) decreased from 4733 in 1994 to 3580 in 1999. The average number of repeat isolates per year was 1789 ± 207. The penicillin resistance of first isolates doubled from 0.70% to 1.5% during the period of investigation (P < 0.0001; Figure 1). The percentage of penicillin resistance in repeat isolates increased significantly from 0.73% to 3.3% (P < 0.0001). Resistance to erythromycin of first isolates increased from 2.5% to 3.8% (P < 0.0001), but levelled off in 19981999 (Figure 2
). The resistance to erythromycin of repeat isolates was slightly higher and increased to 4.3% in 1999 (P = 0.0007). The percentage resistance to co-trimoxazole of first isolates remained stable, 4.2% in 1994 and 4.4% in 1999, but the resistance of repeat isolates rose from 4.6% to 7.1% (P = 0.022) (Figure 3
). The tetracycline resistance of first isolates increased from 4.7% to 6.6% (P = 0.0011), but the resistance of repeat isolates remained stable and was 6.0% in 1999 (Figure 4
).
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Discussion |
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We found that the resistance of pneumococci to erythromycin followed an increase in the use of macrolides with a time lag of 23 years. Such a time-lag has been observed before in a Finnish study describing a relationship between macrolide consumption and erythromycin resistance in Streptococcus pyogenes.8
Penicillin resistance of pneumococci rose from 0.70% in 1994 to 1.5% in 1999 subsequent to the increase in the use of macrolides. Similar observations led Goldstein9 to conclude that increased use of macrolides or co-trimoxazole might enhance the percentage of penicillin-resistant pneumococci. However, only 28% of the penicillin-resistant strains in our survey were also resistant to erythromycin. So the increased use of macrolides alone cannot explain the increase in penicillin resistance.
We found the resistance of repeat isolates (second and subsequent isolates from the same patient) to be higher for all investigated antibiotics except tetracyclines. This may indicate that resistant organisms infect patients preferentially during therapy with antibiotics,10 that patients harbouring resistant pneumococci have prolonged illness, which may give rise to one or more repeat cultures, or that resistant pneumococci are selected in individual patients during therapy, as has been shown for azithromycin resistance in vitro.11
Recently, we found a great difference in the quinolone resistance rate of Escherichia coli of different age categories corresponding to the lower use of quinolones in earlier calendar years and in children, who are less frequently exposed to quinolones owing to the toxicity of these compounds to cartilage formation.6 In the present study, we observed a lower frequency of resistance to tetracycline of pneumococci from children, in whom tetracyclines are contra-indicated.
Denmark is a country similar to The Netherlands with respect to limited use of antibiotics and low resistance. In Denmark, the percentage resistance to penicillin of pneumococci from blood increased from <1% in 1995 to 4% in 1999.2 This percentage was significantly higher than the percentage of penicillin resistance in our survey (P < 0.001). The difference may be explained by the different spectrum of antibiotics used in the two countries. In 1998 the consumption in The Netherlands was 3.5 DDD/1000/day penicillins, 1.1 DDD/1000/day macrolides and 2.3 DDD/1000/ day tetracyclines. In the same year in Denmark the use of penicillins (7.6 DDD/1000/day) and of macrolides (2.2 DDD/1000/day) was much higher, but the use of tetracyclines (1.0 DDD/1000/day) was two-fold lower than in The Netherlands. In Spain, the percentage of penicillin-resistant pneumococci was 10-fold higher than the percentage in Denmark.1 In Spain, 11.8 DDD/1000/day penicillins, 1.9 DDD/1000/day cephalosporins and 3.6 DDD/1000/day macrolides were used, whereas the use of 0.8 DDD/1000/ day tetracyclines was as low as in Denmark.12 So the higher rates of penicillin resistance in Denmark and Spain may be related to the higher use of ß-lactams and macrolides and the lower use of tetracyclines compared with The Netherlands, though other factors such as patient compliance may have played a role.4
The increase in the use of macrolides and the resistance to erythromycin has levelled off in the last 3 years. The rising resistance to penicillin seems not to be related to increased use of ß-lactam antibiotics. Recently, the epidemic spread of a penicillin-resistant strain of S. pneumoniae in a Dutch clinic was described.13
In conclusion, the resistance of pneumococci to penicillin and erythromycin in The Netherlands is low compared with other European countries. The use of macrolides increased during 19941997 and may have enhanced the resistance to erythromycin. Continuous monitoring of antibiotic use and resistance is needed.
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Notes |
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References |
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2 . Anonymous. (2000). DANMAP 99 Consumption of Anti-Microbial Agents and Occurrence of Antimicrobial Resistance in Bacteria From Food Animals, Food and Humans in Denmark. ISSN 16002032.
3 . Hermans, P. W. M., Sluijter, M., Elzenaar, K., van Veen, A., Schonkeren, J. J. M., Nooren, F. M. et al. (1997). Penicillin-resistant Streptococcus pneumoniae in the Netherlands: results of a 1-year molecular epidemiologic survey. Journal of Infectious Diseases 175, 141322.[ISI][Medline]
4 . Pradier, C., Dunais, B., Carsenti Etesse, H. & Dellamonica, P. (1997). Pneumococcal resistance patterns in Europe. European Journal of Clinical Microbiology and Infectious Diseases 16, 6447.[ISI][Medline]
5 . Cristino, J. M. (1999). Correlation between consumption of antimicrobials in humans and development of resistance in bacteria. International Journal of Antimicrobial Agents 12, 199202.[ISI][Medline]
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Goettsch, W., van Pelt, W., Nagelkerke, N., Hendrix, M. G. R., Buiting, A. G. M., Petit, P. L. et al. (2000). Increasing resistance to fluoroquinolones in Escherichia coli from urinary tract infections in The Netherlands. Journal of Antimicrobial Chemotherapy 46, 2238.
7 . Appelman, C. L. M., Van Balen, F. A. M., Van de Lisdonk, E. H., Van Weert, H. C. L. M. & Eizinga, W. H. (1999). NHG-standard Otitis media acuta (eerste herziening). Huisarts en Wetenschap 42, 3626.
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Seppala, H., Klaukka, T., Vuopio-Varkila, J., Muotiala, A., Helenius, H., Lager, K. et al. (1997). The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. Finnish Study Group for Antimicrobial Resistance. New England Journal of Medicine 337, 4416.
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Goldstein, F. W. (1999). Penicillin-resistant Streptococcus pneumoniae: selection by both ß-lactam and non-ß-lactam antibiotics. Journal of Antimicrobial Chemotherapy 44, 1414.
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Austin, D. J., Kristinsson, K. G. & Anderson, R. M. (1999). The relationship between the volume of antimicrobial consumption in human communities and the frequency of resistance. Proceedings of the National Academy of Sciences, USA 96, 11526.
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Nagai, K., Davies, T. A., Dewasse, B. E., Pankuch, G. A., Jacobs, M. R. & Appelbaum, P. C. (2000). In vitro development of resistance to ceftriaxone, cefprozil and azithromycin in Streptococcus pneumoniae. Journal of Antimicrobial Chemotherapy 46, 90915.
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Ruiz Bremón, A., Ruiz-Tovar, M., Pérez Gorricho, B., Díaz de Torres, P. & López Rodríguez, R. (2000). Non-hospital consumption of antibiotics in Spain: 19871997. Journal of Antimicrobial Chemotherapy 45, 395400.
13 . de Galan, B. E., van Tilburg, P. M., Sluijter, M., Mol, S. J., de Groot, R., Hermans, P. W. et al. (1999). Hospital-related outbreak of infection with multidrug-resistant Streptococcus pneumoniae in the Netherlands. Journal of Hospital Infection 42, 18592.[ISI][Medline]
Received 13 October 2000; returned 8 January 2001; revised 5 March 2001; accepted 18 June 2001