Vibeke Frøkjær Jensen

Danish Integrated Antimicrobial Resistance Monitoring and Research Program

This program has led to changes in the use of antimicrobial agents in Denmark and other countries.

Changes in the use of antimicrobials and the effects on productivity of swine farms in Denmark

OBJECTIVE To evaluate changes in antimicrobial consumption and productivity by Danish swine farms during 1992 to 2008. SAMPLE POPULATION All Danish swine farms for antimicrobial consumption data and a representative sample of Danish swine herds for productivity data. PROCEDURES Antimicrobial consumption by Danish swine farms from 1992 to 2008 was determined and evaluated in light of policies to regulate antimicrobial consumption, changes in disease patterns, and productivity data. Trend analyses of productivity data were conducted before and after a ban on use of antimicrobial growth promoters (AGPs). Results-Antimicrobial consumption peaked at 100 mg/kg of swine produced in 1992, decreased to 31 mg/kg in 1999, and increased to 49 mg/kg in 2008. Key factors for changes were regulations banning subtherapeutic use of antimicrobials and veterinary profits from the prescription and sale of antimicrobials in 1994 and termination of AGP use by January 2000. Pig production increased from 18.4 to 271 million pigs, and the mean number of pigs per sow per year raised for slaughter increased from 21 in 1992 to 25 in 2007 Average daily gain for weaning (< 35 kg) and finishing (> 35 kg) pigs was higher in 2008 than in 1992, but mortality rates for weaning and finishing pigs were similar in 1992 and 2008. CONCLUSIONS AND CLINICAL RELEVANCE From 1992 to 2008, antimicrobial consumption per kilogram of pig produced in Denmark decreased by > 50%. Furthermore, there was improvement in productivity, suggesting that long-term swine productivity was not negatively impacted by a ban on AGP use.

Genome-Wide Association Study in Dachshund: Identification of a Major Locus Affecting Intervertebral Disc Calcification

Intervertebral disc calcification and herniation commonly affects Dachshund where the predisposition is caused by an early onset degenerative process resulting in disc calcification. A continuous spectrum of disc degeneration is seen within and among dog breeds, suggesting a multifactorial etiology. The number of calcified discs at 2 years of age determined by a radiographic evaluation is a good indicator of the severity of disc degeneration and thus serves as a measure for the risk of developing intervertebral disc herniation. The aim of the study was to identify genetic variants associated with intervertebral disc calcification in Dachshund through a genome-wide association (GWA) study. Based on thorough radiographic examinations, 48 cases with ≥ 6 disc calcifications or surgically treated for disc herniation and 46 controls with 0-1 disc calcifications were identified. GWA using the Illumina CanineHD BeadChip identified a locus on chromosome 12 from 36.8 to 38.6 Mb with 36 markers reaching genome-wide significance (P(genome) = 0.00001-0.026). This study suggests that a major locus on chromosome 12 harbors genetic variations affecting the development of intervertebral disc calcification in Dachshund.

Indications and patterns of therapeutic use of antimicrobial agents in the Danish pig production from 2002 to 2008.

This study describes trends in the use and indications for prescriptions of antimicrobial agents in the Danish pig production in the period between 2002 and 2008 and is the first description of a complete prescription pattern for one animal species in an entire country. Data on all prescription for pigs in Denmark were retrieved from the VetStat database. Antimicrobial use was measured in defined animal daily doses (ADD) for the specific age-group and in ADD(kg) as a measure of amounts used. According to the results of the ADD(kg) data, 26% of all antimicrobials were prescribed for sows, 38% for weaner pigs, and 33% for finisher pigs. In weaner and finisher pigs, gastrointestinal infections accounted for 74-83% and 56-65% of the use, while respiratory infections accounted for 9-17% and 18-24%, respectively. From 2002 to 2008, prescription for respiratory disease increased by 145% for sows/piglets, by 141% for weaning pigs, and by 81% for finisher pig. The most commonly used class of antibiotics was tetracycline for all age-groups, replacing the previously used macrolide/lincosamide group. The use of pleuromutilin increased in 2008 to the level of macrolides. In sow/piglets, the second most used class was penicillins. The switch in choice of antimicrobial classes prescribed seems to be related primarily to changes in the price of the drugs.

Antimicrobial drug consumption in companion animals.

To the Editor: During the last decade, use of antimicrobial drugs for growth promotion and therapeutic treatment in food animals has received much attention. The reservoir of resistant bacteria in food animals implies a potential risk for transfer of resistant bacteria, or resistance genes, from food animals to humans. Subsequent emergence of infections in humans, caused by resistant bacteria originating from the animal reservoir, is of great concern. These unintended consequences of antimicrobial drug use in animals led to termination of antimicrobial growth promoters in food animals in countries in the European Union, including Denmark, where the consumption of antimicrobial drugs by production animals was reduced by 50% from 1994 to 2003 (1). In Denmark, the VetStat program monitors all veterinary use of medicines for animals. VetStat is based on reporting from the pharmacies and from veterinary practitioners and contains detailed information, such as animal species, reason for prescription, and dosage on each prescription. In Denmark, antimicrobial drugs can be obtained only by prescription and only at pharmacies. So far, use of antimicrobial drugs in companion animals has received little attention; monitoring programs have focused on antimicrobial drug consumption in food animals. According to data generated by the VetStat program in 2003, consumption of fluoroquinolones and cephalosporins in companion animals was substantial when compared to consumption in food animals (1). Fluoroquinolones and cephalosporins are antimicrobial drugs ranked by the U.S. Food and Drug Administration as critically important in human medicine, and for which emergence of resistant bacteria is especially undesirable (2). Considering the shared environment of humans and companion animals, transfer of resistant bacteria or mobile resistance determinants from companion animals to humans would be possible, and emergence of resistance to fluoroquinolones and cephalosporins in companion animals should be a matter of concern. Several scientific publications have reported the occurrence of the same resistance genes in companion animals and in humans (3–6) and the possible transfer of bacteria between companion animals and humans (3–9). Companion animal owners and their families are likely in close contact with their animals daily, which provides the opportunity for transfer of bacteria between companion animals and humans. A large proportion of the human population presumably has daily contact with companion animals, not only in Denmark but also in other countries. In Denmark, 20% of families own dogs and 16% own cats (10). In 2002, legal restrictions aimed to reduce the usage of fluoroquinolones in food animals were imposed in Denmark. The total annual consumption of fluoroquinolones in animals (companion and food animals) in Denmark was reduced from 183 kg in 2001 to 53 kg in 2003 (1). Of these 53 kg of fluoroquinolones, almost half (24 kg) was used in companion animals (data based on reporting on use in veterinary practice and sales from pharmacies on prescription). These data document that fluoroquinolones remain widely used for infections in companion animals, even though the emergence of fluoroquinolone resistance in bacteria is especially undesirable and regarded as a human health hazard. A similar situation exists with cephalosporins. The total consumption of cephalosporins in animals (companion and food animals) in Denmark in 2003 was 461 kg, of which more than half (254 kg) was consumed by companion animals (1). Thus, a comparatively small number of companion animals (550,000 dogs and 650,000 cats) (10) consume approximately the same amount of fluoroquinolones and cephalosporins as consumed annually in the much larger population of food animals in Denmark (23 million slaughter pigs, 130 million broiler chickens, and 1.2 million cattle and dairy cows) (10). We do not believe that antimicrobial drugs are more generously prescribed for companion animals in Denmark than in other industrialized countries. Rather, the data presented here reflect the apparent contrast between policies of antimicrobial drug use for food animals and policies for companion animals. The use of these antimicrobial drugs is avoided or restricted in food animals to minimize spread of resistance, while in companion animals prescription continues unimpeded. This situation may create undesirable antimicrobial drug resistance in bacteria, which may subsequently spread to humans from the previously neglected reservoir in companion animals.

Use of register data to assess the association between use of antimicrobials and outbreak of Postweaning Multisystemic Wasting Syndrome (PMWS) in Danish pig herds

In 2001, the first case of Postweaning Multisystemic Wasting Syndrome (PMWS) was reported in the Danish pig population. During subsequent years, the number of affected farms increased exponentially. The aim of this study was to determine how this increase influenced the use of antimicrobials between 2002 and 2004. We used national register data of herd characteristics, antimicrobial usage and disease occurrence. The analysis included data on antimicrobial usage in 3371 pig herds with weaners and 7434 pig herds with finishers, which accounted for 56 and 82% of the national amount of antimicrobials prescribed to weaners (prescribed by 347 practitioners) and finishers (prescribed by 522 practitioners), respectively. The estimation of the effect of PMWS was done by comparing the amount of antimicrobials (measured as Animal Defined Daily Doses (ADDkg) used per pig-day at risk each month in each herd) used in herds before and after an outbreak of PMWS, and by comparing the amount of antimicrobials used in herds experiencing PMWS with the amount of antimicrobials used in herds not experiencing PMWS. The effects were estimated in a three-level (veterinarian/herd/study-month) linear mixed regression model with an autoregressive correlation of order 1 (AR1). We found that after a herd had experienced an outbreak of PMWS, the antimicrobial usage in weaners was increased for a year. During the first 3 months post outbreak the usage increased by 22%, followed by an increase of 7% during the next 4th to 12th month when compared to the pre-outbreak usage. There was a significant variation between herds in this effect. Additionally, in herds experiencing an outbreak of PMWS, the usage of antimicrobials before the outbreak was 37 and 19% higher in herds with weaners and finishers, respectively, compared to herds not experiencing PMWS. Generalisation of the results to the entire Danish pig population indicated that the increase of PMWS infected herds from almost zero to about 20% during a 4-year period resulted in a national increase of 4-5% in antimicrobials usage in weaners. The effect of PMWS on usage of antimicrobials in finishers was unclear.

Monitoring of Antimicrobial Drug Usage in Animals: Methods and Applications

Monitoring antimicrobial drug usage in animals at the national and international levels is important for identification and tracking if and how often quantities are used. This information can be used for many purposes, including raising awareness, comparing use patterns across countries, identifying trends over time, integrating with antimicrobial resistance data, conducting risk assessment, and evaluating the effectiveness of measures to manage antimicrobial usage. The goal of this article is to describe how monitoring systems for antimicrobial drug usage in animals are set up and conducted, using examples from specific countries as well as international efforts. Several key figures and variables are used to describe and evaluate antimicrobial consumption in animals, including the amount in kilograms of active ingredient, standardized units (e.g., number of defined daily dose animals, DDDAs) and number of treatments (e.g., number of used daily doses, UDDA). Data can be collected from a variety of sources including pharmaceutical sales, pharmacy dispensing, veterinary prescriptions, and farm records. In many countries, data analysis and reporting at the national level provide statistics on overall quantities used in animals, in some cases by animal species. Antimicrobial consumption data should be contrasted to the respective animal population, for example, the weight of different categories of livestock and slaughtered animals. Several countries have established antimicrobial usage monitoring systems. Most report overall sales data, but some provide usage data to the levels of animal species and production type. At the international level, several organizations (e.g., European Union, World Organization for Animal Health, World Health Organization) have initiatives to support the development of antimicrobial consumption data collection and reporting. However, these initiatives are ongoing and so far lack harmonization, which will be the biggest challenge for the future.

Regional, seasonal, and temporal variations in the prevalence of antimicrobial-resistant Escherichia coli isolated from pigs at slaughter in Denmark (1997-2005)

The aim of this study was to analyze and discuss regional, seasonal, and temporal trends in the occurrence of antimicrobial-resistant Escherichia coli isolated from pigs at slaughter in Denmark between 1997 and 2005. Data on antimicrobial-resistant E. coli were obtained from the Danish Integrated Antimicrobial Resistance Monitoring and Research Programme database. The Cochran-Armitage trend test was used to detect the presence and evaluate the significance of regional, seasonal, and annual trends in the occurrence of antimicrobial-resistant E. coli for four drugs. Associations between resistance and explanatory variables region, season, and the year of isolate sampling were analyzed using a logistic regression model. The Cochran-Armitage test provided evidence of significant temporal trends for ampicillin-resistant E. coli (an increasing trend, p < 0.0001) and streptomycin-resistant E. coli (a decreasing trend, p < 0.0001). The prevalence of ampicillin-resistant E. coli increased over time for all seasons (p < 0.001) except for winter when no significant variations in prevalence of resistant E. coli were captured over time. On the other hand, a significant decreasing trend in prevalence of streptomycin-resistant E. coli was observed for the spring, summer, and winter months (p < 0.001); however, there were no statistically significant trends for the autumn months (p > 0.05). The prevalence of ampicillin-resistant E. coli was observed to increase over time for the various regions, whereas that for streptomycin-resistant E. coli presented an overall significant decrease over time. The estimated odds ratios from the logistic regression model indicated varying risks for the occurrence of resistance by season and by region. The winter months were associated with an increased risk for the occurrence of resistant E. coli as compared to the other seasons of the year. Our study provides evidence of statistically significant regional, seasonal, and temporal variations for ampicillin- and streptomycin-resistant E. coli isolated from pigs at slaughter in Denmark between 1997 and 2005.

Promoting prudent antimicrobial use in the veterinary field.

ANTIMICROBIAL resistance has been identified by the World Health Organization (WHO) as one of the major threats to human health (WHO 2011). The emergence of resistance respects no borders and the problem must be solved internationally using a ‘One Health’ perspective. This involves the promotion of prudent antimicrobial use in all sectors. Promoting prudent use has been a major concern of international organisations such as the WHO, the World Organisation for Animal Health (OIE) and the European Medicines Agency (EMA) for years. The term ‘prudent’ implies both responsible use and continuing to reduce use, a strategy that may not always be appropriate in the clinical setting. In contrast, ‘responsible’ implies appropriate use whether or not this results in an overall reduction. Both prudent use and responsible use imply veterinary prescription of antimicrobials only when based on proper diagnostic work and selection of agents according to guidelines, and should consider resistance patterns in the target organism, optimum antibiotic and dosage regime, and the risk of resistance selection. Furthermore, prudent use must also take into account the One Health perspective; for example, the potential transmission of resistance to people. Prudent use needs to balance regulatory and therapeutic needs. Legal restrictions can have an impact; for example, limiting the use of antimicrobials that are critically important for the treatment of people. Regulation of antimicrobial use overall is more complex, as veterinarians have to be able to treat sick animals. Therefore, strategies to reduce antimicrobial use must be targeted …