SUMMARY

DANMAP 2000 is the fifth report from the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme. It reports trends in resistance among zoonotic bacteria and non-zoonotic pathogenic bacteria from food animals and humans and indicator bacteria from food animals. The report also describes trends in use of antimicrobial agents.

The DANMAP monitoring also includes resistance in bacteria from foods, however, due to technical difficulties results for isolates collected in 2000 were not available for this year’s report.

Consumption of antimicrobials

It is often a subject of discussion what proportions of the total amounts of antimicrobials are used in humans, in comparison with animals. We have previously reported the consumption in humans in Defined Daily Doses (DDD) per 1,000 population per day. While using DDD as unit of measurement permits comparison of the use of antimicrobials of unequal potency it makes it very difficult to compare consumption in humans with usage in animals.

Therefore, DANMAP 2000 also provides data on human consumption as amount of active compound, i.e. kg. (Figure 1). Looking at the figure it is clear that of the total usage of antimicrobials in Denmark, far the largest quantity is used in food animals. In 1997, the last year with unrestricted use of antimicrobial growth promoters, the quantity used in humans amounted to about 25% of the total usage in animals.

Figure 1. Trend in usage of antimicrobials for growth promotion (AGP) in food animals and therapy in food animals and humans, Denmark

In animals, the use of antimicrobial growth promoters the use of oral compounds (tetracylines, macrolides and aminoglycosides), mainly in pigs. Reports from practising veterinarians suggest that the initial problems in some herds with diarrhoea in weaned pigs following the discontinuation of antimicrobial growth promoters have been superseded by problems with Lawsonia intracellularis infections. There are, however, also indications that there has been increasing overuse of antimicrobials in recent months. Initiatives are presently underway to attempt to solve this problem.

The use of fluoroquinolones in food animals increased marginally from 1999 to 2000 but remains at much lower levels than in 1998 (see text box below right).

Trend in usage of fluoroquinolones Fluoroquinolones were approved for use in animals in Denmark in 1993. However, prior to granting marketing permission, there had been some sales on the basis of temporary permits. The products have been marketed as formulations for injection, as premixes for use in pigs and as liquid formulations for use mainly in poultry and to a lesser extent in calves. The guidelines for prudent use of antibiotics formulated by the Danish Veterinary Laboratory in consultation with veterinarians and other experts, recognise that on the basis of resistance patterns, fluoroquinolones should not be first-choice agents for treatment of infections in Danish farm animals. In late 1998 the Danish Veterinary and Food Administration issued a recommendation to all veterinarians to restrain their prescription of fluoroquinolones. Early 1999, a major pharmaceutical company withdrew a widely used premix for pigs. The company's move was motivated by a concern about development of resistance and by a wish to safeguard the future use of fluoroquinolones in food animals. The Veterinary and Food Administration is considering legislation to further restrict the use of fluoroquinolones to situations where susceptibility testing shows they are necessary. The effect of these initiatives is shown on Figure 3. The usage declined from just over 400 kg active compound in 1998 to under 150 kg in 1999. In addition to the premix withdrawn by the company, the decline also affected the oral formulation for poultry and the injectables. This indicates that the recommendations about prudent use of fluoroquinolones may have had an effect on usage. The decreasing use in pigs has been accompanied in a decline in quinolones resistance among E. coli O149 isolated from diarrhoea in young pigs. There was an increase in fluoroquinolone usage in 2000 compared with 1999, but the total in the usage is still significantly lower than before the intervention. Some of the oral formulations for poultry may have been used in calves. The decline in fluoroquinolone usage has not been associated with an increase in the usage of cephalosporins, another group of potent broad-spectrum antimicrobials. Kg compound Figure 3. Trend in usage of fluoroquinolones in food animals, Denmark

The use of fluoroquinolones in humans exceeds the use in animals, but has also shown a decline in recent years. The consumption of glycopeptides (hospital use only), while still low, has increased from 25 kg in 1997 to 37 kg in 2000. The reason for the increase is not known; however, it may be associated with an increased incidence of infection with methicillin resistant Staphylococcus aureus in humans.

Resistance in zoonotic bacteria

For Salmonella, comparison of resistance is complicated because of the presence and spread of resistant clones in some reservoirs and not in others. For example, while the overall prevalence of Salmo-nella Typhimurium is low in cattle, a high proportion of the isolates available for testing is penta-resistant S. Typhimurium DT104. Similarly, a high prevalence of resistance to quinolones (nalidixic acid) in Salmonella Enteritidis is caused by the spread of a particular resistant clone. In general, however, resistance levels in Salmonella are relatively low, in particular quinolone resistance. Among S. Typhimurium from pigs there was an increase in tetracycline resistance not explained by an increase in the proportion of DT104.

Tetracycline resistance also increased in domestically acquired human infections. These increases may both be associated with the increase in usage of tetracycline in pigs. There is good agreement between resistance levels in Salmonella from food animal reservoirs and in Salmonella isolates from domestically acquired human cases of salmonellosis, even though resistant bacteria in imported foods also are known to contribute to resistance in humans.

Among Campylobacter, we found for C. coli in pigs, that resistance to macrolides declined following the stop for use of macrolide growth promoters. There was, however, an increase in resistance to macrolides from 1999 to 2000, coinciding with the increased use of macrolides for treatment of pigs. C. coli accounts for only about 5% of human cases of campylobacteriosis while Campylobacter jejuni is responsible for over 90%. In 2000 we have found decreasing quinolone resistance among C. coli from pigs. In contrast, it increased in C. jejuni from broilers and from cattle. Among isolates from humans this increase has occurred continuously since 1997. The high level of quinolone resistance in C. jejuni from domestically acquired cases of campylobacteriosis and a level of tetracycline resistance not seen in isolates from food animal reservoirs is an indication that there are reservoirs of Campylobacter infection not included in the DANMAP programme, probably imported poultry. The presence of quinolone resistance in about 25% of Campylobacter isolates is worrying because of the possible adverse implications for human health.

Resistance in indicator bacteria

We collect faecal samples from animals at slaughter to isolate Escherichia coli and enterococci ( E. faecium and E. faecalis) for susceptibility testing. The samples are collected so that the results provide a measure of antimicrobial resistance in the general population of food animals and of the exposure of the food chain to resistant bacteria. We have not yet collected community samples of enterococci from humans; however, a programme for collection of such isolates is planned for implementation in the second half of 2001.

For enterococci the trends in resistance reflect rather closely changes in antimicrobial usage. The discontinued use of antimicrobial growth promoters is reflected in decreasing resistance to the antimicrobials in question. However, the complexity of the association between usage and occurrence of resistance is illustrated by our finding in 2000 that streptogramin resistance in E. faecium from pigs increased, even though streptogramins were not used. Detailed analyses indicated that the likely explanation was due to dissemination in the pig population of a particular multi-resistant E. faecium clone, which was resistant to streptogramins. The routes of spread have not been determined. The decline in macrolide resistance has also levelled out from 1999 to 2000. Part of the explanation is the spread of the resistant clone responsible for the increase in streptogramin resistance, but the increased use of macrolides for treatment may also have played a role.

Among indicator E. coli resistance to a number of antimicrobials has declined in recent years. For isolates from pigs this is interesting, because it means the increased use of tetracycline, in young pigs is not yet reflected in increased levels of resistance among E. coli in the older age groups that are sampled at slaughter. The likely explanation is the succession of types that takes place in the gut of an animal, as it grows older, so that resistant serotypes are replaced by non-resistant. This may also indicate that tetracycline resistance genes have not yet spread within the bacterial populations to a noticeable extent.

Resistance in non-zoonotic pathogens These bacteria all originate from diagnostic submissions. For E. coli from cattle (serotype F5) resistance levels have been rather stable the last 5 years. For isolates from poultry (serotypes O2 and O78) the trend has been more variable due to the relatively small number of isolates. Among isolates from pigs (serotype O149) it is interesting to see that in contrast to indicator E. coli from pigs at slaughter resistance to tetracycline has increased in 2000. The level of tetracycline resistance in 1999, however, was quite low compared with previous years. Nevertheless the trend coincides well with the increased usage of tetracyclines that has taken place in this age group.

We have also observed a decline in quinolone resistance in E. coli from pigs, which coincides with the decline in fluoroquinolone use in pigs. There is very limited use of gentamicin in Danish food animals. In spite of this, 12% of E. coli from young calves are resistant to gentamicin.

In Streptococcus pneumoniae from humans we have previously expressed concern about increasing levels of resistance to erythromycin and to penicillin. The increase in erythromycin resistance continued in 2000, although there was a small decline in penicillin resistance. Resistance among other isolates from diagnostic submissions from humans has for most part been stable over the last 5 years. We are concerned, however, about the development in incidence of infection with methicillin resistant Staphylococcus aureus (MRSA). In 1996 there were 34 cases, compared with 97 in 2000. Twenty to 30% of the cases were from primary care. It is not yet clear whether the increase is related to an increase in the number of imported cases or whether they are acquired domestically. Preliminary results indicate that a substantial number of the hospital cases corresponded to outbreaks.

Conclusions

In the 5 years DANMAP has been running it has made several important contributions to our understanding of antimicrobial resistance. For example, have found that even though changes can happen quickly, they can also take a long time to manifest themselves. Therefore, effects of intervention, for example discontinuation of use, introduction of a new antimicrobial or increasing use of an existing one may take several years to affect the resistance prevalence and should be evaluated over a long period of time. We have also experienced just how important co-selection can be in affecting trends in occurrence of particular resistance phenotypes. This is seen from the continuing occurrence of, for example, chloramphenicol resistance in isolates from cattle, even though chloramphenicol has not been used in food animals for more than 20 years and from the different rates of decline in glycopeptide resistance in E. faecium from broilers and pigs, respectively.

As seen from this and previous DANMAP reports imported food and infections acquired abroad certainly play a role in the overall picture. While the role of imported foods is relatively modest in Denmark, where most food is produced domestically, this would not be the case for countries that import most of their food.

An area that deserves a dedicated research effort is the interaction between clonal spread of resistant bacterial strains and use of antimicrobials. The relative importance of these two factors should be quantified.

Links

To read the full 56 page pdf report:

DANMAP 2000 - Consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from food animals, foods and humans in Denmark. ... CLICK HERE