|D.L. Monnet1, H.D. Emborg2, S.R. Andersen3, C. Schöller3, T.L. Sørensen1, F. Bager2
1 Dept. of Microbiological Research and Development, Statens Serum Institut, Copenhagen, Denmark
2 Danish Zoonosis Centre, Danish Veterinary Laboratory, Copenhagen, Denmark
3 Danish Veterinary and Food Administration, Søborg, Denmark
Recent data of the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) show that, in Denmark, resistance levels among Salmonella enterica are modest and that resistance in Escherichia coli isolates causing disease in animals should be seen as a resistance reservoir rather than a threat to the public health. Furthermore, trends of resistance in Danish E. coli clinical isolates were consistent with Danish patterns of antimicrobial use. Resistance in Staphylococcus aureus andStreptococcus pneumoniae remains rare. However, the recent emergence of penicillin and erythromycin resistance in S. pneumoniae is of concern. Finally, monitoring of resistance in commensal bacteria from food animals and food, shows the positive impact on resistance of interventions such as the ban of antimicrobial growth promoters in farm animals.
In 1995, in the interest of consumer safety and the health of animals and humans, the Danish ministry of agriculture and fisheries, and the ministry of health, asked the Danish Veterinary Laboratory, the Danish Veterinary and Food Administration, and the Statens Serum Institut to collaborate in surveillance and research on antimicrobial resistance. This request resulted in the development of the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP). The Danish Medicines Agency joined the programme in 1998. The programme focuses mainly on the control of resistance in food animals and the risks of transmission of resistant enteric pathogens and commensal bacteria to humans through food. Data are also reported on resistance in other bacteria, such as Staphylococcus aureus and Escherichia coli, which are responsible for infections in food animals and humans.
This article summarises the most recent results from DANMAP, which have been published in full in English by the Danish Zoonosis Centre as an annual report (1). The report describes DANMAP’s objectives, principles, and methods, which have also been described inEurosurveillance (1-3). Similarly, detailed data on antimicrobial use in humans and food animals have been presented elsewhere (1,4).
Surveillance of resistance in enteric pathogens
A main objective of DANMAP is to follow variations of resistance levels over time. This objective has been difficult to fulfil for enteric pathogens because the isolates included in the programme do not represent unbiased, random samples. For example, increasing recognition of outbreaks of Salmonella enterica serotype Typhimurium definitive phage type (DT)104 – two domestic outbreaks in 1999 (5) – means that this pentaresistant phage type accounts for a disproportionally high percentage of S. Typhimurium isolates from cattle. Nevertheless, an overall assessment of the occurrence of resistance in Salmonella enterica shows that, apart from the bias due to S. Typhimurium DT104, resistance levels are modest. For example, only 11% and 13% of S. Typhimurium other than DT104 isolated from human clinical specimens in 1999 were resistant to ampicillin and tetracycline, respectively. For S. Enteritidis, about 2% were resistant to ampicillin or to tetracycline in 1999.
The same reasons make it difficult to study resistance trends in campylobacter isolates. In 1999, 1% of Campylobacter jejuni isolates from broilers, 13% from broiler meat samples, and 10% from human stool specimens were resistant to tetracycline. Tetracycline resistance was significantly commoner in C. jejuni isolates from imported than from Danish broiler meat from retail outlets. Resistance to erythromycin among C. coli isolates from pigs fell by almost 50% from 1998 to 1999, probably because tylosin’s use as an antimicrobial growth promoter was withdrawn from Danish pig production.
Surveillance of resistance in other bacteria of clinical importance
DANMAP monitors resistance in bacteria identified in specimens submitted for diagnosis from food animals and from humans. In 1999, the programme showed that resistance was generally rare in Staphylococcus aureus and coagulase-negative staphylococci isolates from mastitis in cattle. Conversely, a high level of resistance was detected in Escherichia coliisolated from diseased cattle and pigs, although resistance in commensal E. coli isolated from animals at slaughter is still rare. Thus, resistance in E. coli isolates causing disease in animals should be seen as a resistance reservoir rather than an immediate threat to the public health.
Resistance in E. coli isolates from human clinical specimens was estimated from the results of susceptibility testing from the clinical microbiology laboratories serving four counties throughout Denmark and serving about a third of the Danish population. Since 1995, these laboratories have provided summary reports once a year of the numbers of clinical E. coliisolates from blood (hospital isolates only) and urine (hospital and primary health care isolates) tested for antimicrobial susceptibility, and the numbers of these isolates that were resistant to selected antimicrobials. Although all laboratories were asked to remove duplicate isolates from the same patient within a window of 30 days, only the laboratories serving North Jutland County and Copenhagen Municipality were able to comply with this rule. Susceptibility testing methods also vary between laboratories. Neo-SensitabsÒ tablets (A/S Rosco) are used in the laboratories from Roskilde County and North Jutland County, and were also used in Copenhagen Municipality until June 1999, when they were replaced by disk diffusion (Oxoid). A home-made pre-diffusion disk method was used in Aarhus County laboratory during this period. All laboratories take part in the United Kingdom National External Quality Assessment Schemes (NEQAS).
Some surveillance results for E. coli from 1995 to 1999 are presented in the figure. In 1999, each laboratory reported data on 162 to 585 E. coli isolates from hospital blood specimens, on 2009 to 5228 E. coli isolates from hospital urine samples, and on 2501 to 4107 E. coliisolates from urine specimens from primary health care. Because of differences in susceptibility methods, breakpoints, data handling, and possibly frequencies of sampling, comparisons among counties are difficult. One should also be aware that a substantial proportion of urine specimens from primary health care is submitted to the laboratory because of treatment failure and therefore represent a selected population. Despite these methodological limitations, resistance levels showed little variations between counties. Additionally, the four laboratories generally reported similar resistance trends – for example, to ampicillin – which indicates that the data can be used to estimate the levels and trends of resistance in Danish E. coli clinical isolates. In 1999, resistance to ampicillin was detected in 35% to 45% of E. coli isolated from blood and urine, to sulphonamides in 30% to 40% of E. coli (urine isolates only), to cefuroxime in less than 3% (blood isolates only), and to ciprofloxacin in less than 2%. These resistance levels were consistent with Danish patterns of antimicrobial use. For example, fluoroquinolone use in Denmark amounted only 0.26 DDD (Defined daily dose) per 1,000 inhabitant-days in 1999 (or 1.8% and 4.7% of total use in primary health care and in hospitals, respectively), which is among the lowest usages of fluoroquinolones in the European Union. Sulphonamides are often the drug of choice foruncomplicated urinary tract infections in Denmark.
With the exception of penicillin resistance, less than 5% of S. aureus blood isolates are resistant to antimicrobials; methicillin resistant isolates only represent about 0.5% of S. aureus isolated from blood specimens collected nationwide and registered by the national reference centre for staphylococci. Between 1994 and 1999, the percentage of penicillin resistant or intermediate (MIC ³ 0.125 mg/ml) Streptococcus pneumoniae isolates from blood and cerebrospinal fluid, as reported by the national reference centre for pneumococci, increased from 0.3% to 3.8%. This increase has been paralleled by an increase in erythromycin resistance. There has been no major change in the annual amount of penicillins and macrolides used in Denmark in recent years, but the emergence of penicillin and erythromycin resistance in S. pneumoniae coincided with the introduction of azithromycin and has paralleled its use in primary care. While resistance in S. pneumoniae is still very rare in Denmark, this recent and steady increase is of concern.
Surveillance of resistance in commensal bacteria
Finally, DANMAP monitors resistance in commensal bacteria from food animals and food. A practical approach to the regular monitoring of resistance in commensal bacteria from healthy humans is being investigated. Since the programme was set up there has been a marked decrease in the percentage of Enterococcus faecium isolated from food animals at slaughter with resistance to avoparcin, virginiamycin, avilamycin, and macrolides. With a delay of about one year, these changes in resistance have paralleled similar changes in the consumption of the same antimicrobials used as growth promoters. These results show that interventions on antimicrobial use in farm animals, such as the ban of antimicrobial growth promoters initiated in Denmark in 1995, have an effect on resistance. A decrease in resistance has also been observed in E. faecium from food samples collected at retail outlets. For example, the proportion of E. faecium isolates from beef, broiler and pork meat with erythromycin resistance has fallen by 30% to 40% between 1998 and 1999. Although the pressure due to vancomycin resistant E. faecium (VRE) in the food chain has fallen dramatically, studies by the Danish Veterinary Laboratory using selective methods show that small numbers of VRE are still commonly found in broiler flocks.
Until now the programme has focused mainly on the control of resistance in food animals and the risks of transmission of resistant bacteria to humans through food. A wide range of pathogens from human clinical specimens are tested for resistance in Danish clinical microbiology and reference laboratories, but only data on enteric pathogens, E. coli, staphylococci, and S. pneumoniae are presently made available to DANMAP. Recently, the Statens Serum Institut received additional funding from the Danish Ministry of Health to implement a national system for the surveillance of antimicrobial resistance through a network of clinical microbiology laboratories. This new initiative should result in a better, standardised, system for the collection of susceptibility data on bacteria isolated from human clinical specimens. In the five years since DANMAP was launched, it has provided a basis for controlling antimicrobial resistance, especially in the food chain, and has demonstrated the value of an integrated, practical, and active approach to monitoring and controlling bacterial antimicrobial resistance.
We thank CS Elsberg, J Engberg, P Gerner-Smidt, HB Konradsen, K Mølbak, JK Møller, HC Schønheyder, H Westh, and N Frimodt-Møller for providing resistance data in bacteria isolated from clinical microbiological samples, and K Hovgaard and HL Johansen for providing data on antimicrobial use in humans.
|References1. Anonymous. DANMAP 99 – Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, food and humans in Denmark. Copenhagen: Danish Veterinary Laboratory, 2000. <http://www.svs.dk/dk/Organisation/z/forsider/Danmap%20forsider.htm>
2. Wegener HC, Bager F, Aarestrup FM. Surveillance of antimicrobial resistance in humans, food stuffs and livestock in Denmark. Eurosurveillance1997; 2: 17-9.
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5. Mølbak K, Baggesen DL, Aarestrup FM, Ebbesen JM, Engberg J, Frydendahl K, et al. An outbreak of multidrug-resistant, quinolone-resistant Salmonella enterica serotype typhimurium DT104. N Engl J Med 1999; 341: 1420-5.