A pharmaco-epidemiological study of antibacterial treatments and bacterial diseases in Norwegian aquaculture from 2011 to 2016.

The sales and prescription of antibacterials for use in Norwegian fish-farming according to diagnosis, fish species and production stage from 2011 to 2016 are analysed. The study is based on antibacterial sales data from wholesalers, pharmacies and feed mills and on prescription data obtained from a register of all prescriptions of antibacterials used in farmed fish. The results show that the fish-farming industry uses very small volumes of antibacterials. In 2016, a total of 212 kg were sold; the only antibacterial substances sold were florfenicol and oxolinic acid. The total amount corresponded to 0.16 mg kg-1 fish slaughtered, or to approximately 0.14% of the fish produced that year. The majority of prescriptions were for non-specific bacterial infections; as most common diseases are under control by vaccination. Most prescriptions for salmonid fish were during early production stages. However, due to higher biomasses of fish, the highest quantities of antibacterials were prescribed during the seawater production phase of Atlantic salmon Salmo salar. An increasing proportion of the prescriptions was for other species, including cleaner fish used for salmon lice control; in 2016 most prescriptions were for this fish category. Due to the negligible use of antibacterials in Norwegian aquaculture, in particular for on-growers, the risk of development of antimicrobial resistance and its transmission to humans through consumption of fish is considered negligible.

Use of colistin-containing products within the European Union and European Economic Area (EU/EEA): development of resistance in animals and possible impact on human and animal health.

Since its introduction in the 1950s, colistin has been used mainly as a topical treatment in human medicine owing to its toxicity when given systemically. Sixty years later, colistin is being used as a last-resort drug to treat infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae (e.g., Escherichia coli, Klebsiella pneumoniae), for which mortality can be high. In veterinary medicine, colistin has been used for decades for the treatment and prevention of infectious diseases. Colistin has been administered frequently as a group treatment for animal gastrointestinal infections caused by Gram-negative bacteria within intensive husbandry systems. Given the ever-growing need to retain the efficacy of antimicrobials used to treat MDR infections in humans, the use of colistin in veterinary medicine is being re-evaluated. Despite extensive use in veterinary medicine, there is limited evidence for the development of resistance to colistin and no evidence has been found for the transmission of resistance in bacteria that have been spread from animals to humans. Since surveillance for colistin resistance in animals is limited and the potential for such transmission exists, there is a clear need to reinforce systematic monitoring of bacteria from food-producing animals for resistance to colistin (polymyxins). Furthermore, colistin should only be used for treatment of clinically affected animals and no longer for prophylaxis of diseases, in line with current principles of responsible use of antibiotics.

Variations in the sales and sales patterns of veterinary antimicrobial agents in 25 European countries.

OBJECTIVES: To describe sales and sales patterns of veterinary antimicrobial agents in 25 European Union (EU)/European Economic Area (EEA) countries for 2011. METHODS: Data on the sales of veterinary antimicrobial agents from 25 EU member states and EEA countries for 2011 were collected at package level (name, formulation, strength, pack size, number of packages sold) according to a standardized protocol and template and presented in a harmonized manner. These data were calculated to express amounts sold, in metric tonnes, of active ingredient of each package. A population correction unit (PCU) was applied as a proxy for the animal biomass potentially treated with antimicrobial agents. The indicator used to express sales was milligrams of active substance per PCU. RESULTS: Substantial variations in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents, expressed as mg/PCU, between the countries were observed. The proportion of sales, in mg/PCU, of products applicable for treatment of groups or herds of animals (premixes, oral powders and oral solution) varied considerably between the countries. CONCLUSIONS: Some countries reported much lower sales of veterinary antimicrobial agents than others, when expressed as mg/PCU. Sales patterns varied between countries, particularly with respect to pharmaceutical forms. Further studies are needed to understand the factors that explain the observed differences.

Sales of veterinary antibacterial agents in nine European countries during 2005-09: trends and patterns.

OBJECTIVES: To identify trends and patterns of sales of veterinary antimicrobial agents in nine European countries during 2005-09 in order to document the situation. METHODS: Existing sales data, in tonnes of active ingredients, of veterinary antimicrobial agents by class were collected from nine European countries in a standardized manner for the years 2005-09 (one country for 2006-09). A population correction unit (PCU) is introduced as a proxy for the animal population potentially treated with antimicrobial agents. The sales data are expressed as mg of active substance/PCU. RESULTS: Data coverage was reported to be 98%-100% for the nine countries. Overall, sales of veterinary antimicrobials agents, in mg/PCU, declined during the reporting period in the nine countries. Substantial differences in the sales patterns and in the magnitude of sales of veterinary antimicrobial agents, expressed as mg/PCU, between the nine countries are observed. The major classes sold were penicillins, sulphonamides and tetracyclines. The sales accounted for by the various veterinary antimicrobial agents have changed substantially for most countries. An increase in the sales of third- and fourth-generation cephalosporins and fluoroquinolones were observed for the majority of the countries. CONCLUSIONS: Through re-analysis of existing data by application of a harmonized approach, an overall picture of the trends in the sales of veterinary antimicrobial agents in the nine countries was obtained. Notable differences in trends in sales between the countries were observed. Further studies, preferably including data by animal species, are needed to understand the factors that explain these observations.

Uptake and translocation of metformin, ciprofloxacin and narasin in forage- and crop plants.

Transfer of bioactive organic compounds from soil to plants might represent animal and human health risks. Sewage sludge and manure are potential sources for bioactive compounds such as human- and veterinary drugs. In the present study, uptake of the anti-diabetic compound, metformin, the antibiotic agent ciprofloxacin and the anti-coccidial narasin in carrot (Daucuscarota ssp. sativus cvs. Napoli) and barley (Hordeumvulgare) were investigated. The pharmaceuticals were selected in order to cover various chemical properties, in addition to their presence in relevant environmental matrixes. The root concentration factors (RCF) found in the present study were higher than the corresponding leaf concentration factors (LCF) for the three test pharmaceuticals. The uptake of metformin was higher compared with ciprofloxacin and narasin for all plant compartments analyzed. Metformin was studied more explicitly with regard to uptake and translocation in meadow fescue (Festucapratense), three other carrot cultivars (D.carota ssp. sativus cvs. Amager, Rothild and Nutri Red), wheat cereal (Triticumaestivum) and turnip rape seed (Brassicacampestris). Uptake of metformin in meadow fescue was comparable with uptake in the four carrot cultivars (RCF 2-10, LCF approximately 1.5), uptake in wheat cereals were comparable with barley cereals (seed concentration factors, SCF, 0.02-0.04) while the accumulation in turnip rape seeds was as high as 1.5. All three pharmaceuticals produced negative effects on growth and development of carrots when grown in soil concentration of 6-10 mg kg(-1) dry weight.

Comparison of the sales of veterinary antibacterial agents between 10 European countries.

OBJECTIVES: To compare the sales of veterinary antibacterial agents between 10 European countries. METHODS: Data were compiled from published reports from the 10 countries. We express the usage as amounts sold of veterinary antibacterial agents per country and year, in mg active substances per kg biomass of slaughtered pigs, poultry and cattle plus estimated biomass of (live) dairy cattle for the corresponding year. RESULTS: The usage, as expressed in mg antibacterial drugs sold/kg biomass of slaughtered pigs, poultry and cattle and of (live) dairy cattle, varied from 18 to 188 mg/kg. The relative proportion of the various classes of antibacterial agents sold varied considerably. CONCLUSIONS: The apparent wide variations in the usage of veterinary antimicrobial agents between countries cannot be explained by differences in the animal species demographics alone. Further in-depth analyses are required to identify the factors underlying the observed differences.

Human health consequences of use of antimicrobial agents in aquaculture.

Intensive use of antimicrobial agents in aquaculture provides a selective pressure creating reservoirs of drug-resistant bacteria and transferable resistance genes in fish pathogens and other bacteria in the aquatic environment. From these reservoirs, resistance genes may disseminate by horizontal gene transfer and reach human pathogens, or drug-resistant pathogens from the aquatic environment may reach humans directly. Horizontal gene transfer may occur in the aquaculture environment, in the food chain, or in the human intestinal tract. Among the antimicrobial agents commonly used in aquaculture, several are classified by the World Health Organisation as critically important for use in humans. Occurrence of resistance to these antimicrobial agents in human pathogens severely limits the therapeutic options in human infections. Considering the rapid growth and importance of aquaculture industry in many regions of the world and the widespread, intensive, and often unregulated use of antimicrobial agents in this area of animal production, efforts are needed to prevent development and spread of antimicrobial resistance in aquaculture to reduce the risk to human health.

Prescription of antimicrobial drugs in Norwegian aquaculture with an emphasis on "new" fish species.

The usage of antimicrobial (AM) drugs in farmed fish in Norwegian aquaculture for the period 2000-2005 was investigated by using prescription data. These data were validated against national sales data of AM drugs sold for use in farmed fish and were found to be highly valid. The defined course dose (DCD) was applied as the unit of measurement to correct for the variations in the dosages between different AM drugs. The DCD(kg) was the amount of an AM drug recommended for the treatment of a 1-kg fish. The calculated number of prescribed DCD(kg)s is an estimate of the biomass of farmed fish that can be treated with a certain amount AM drug. In the present study, the number of prescriptions issued (i.e., numbers of initiated treatments), weight of active substance prescribed and biomass treated were applied to describe the usage. An increase, although modest, in the AM drug usage in Norwegian aquaculture was observed from 2002 to 2005. This increase was accounted for by new-farmed fish species (other than Atlantic salmon and rainbow trout), especially Atlantic cod. The increased usage of AM drugs in cod in the study period was significantly positively correlated to the biomass produced; even so from 2001 to 2005 the number of prescriptions for cod relative to the produced biomass declined. The AM drug usage in Atlantic halibut as well as the production varied during the study period. For other species such as turbot, coalfish and wolffish the usage of AM drugs was found to be negligible. "Mono-therapy" with quinolones may present a selective pressure in regard to development of quinolone resistance.

Usage of veterinary therapeutic antimicrobials in Denmark, Norway and Sweden following termination of antimicrobial growth promoter use.

Antimicrobial growth promoters (AGPs) were phased out in Denmark, Norway and Sweden in 1998-1999, 1995 and 1986, respectively. The annual usage of therapeutic antimicrobials in animals in Denmark almost doubled during the period when AGPs were phased out (1988-1999) and in the subsequent 2 years. The increase was mainly due to an increased consumption of therapeutic antimicrobials in weaning pigs. The annual increase in usage of therapeutic antimicrobials and the annual increase in numbers of slaughter-swine produced in Denmark correlates well, except for 1999 when AGP use was discontinued in weaning pigs, and the following year. In Norway, the usage of therapeutic antimicrobials in animals decreased by 39% from 1995 to 2000. During 2001-2003 the annual usage remained at the 2000-level. The annual numbers of slaughter-swine produced in Norway increased gradually by 10% after the AGP discontinuation (from 1995 to 2003). In Sweden, the usage of therapeutic antimicrobials in animals increased by 21% the first 2 years subsequent to the AGP ban (1986-1988), remained then constant until 1994; from 1994 to 2003 this usage declined by 47%. The initial increase was caused by increased use in broilers and in weaning piglets. The amounts used in animals in Sweden in 2003 were half of the amounts used in 1994. The annual numbers of slaughter-swine produced in Sweden declined gradually by 16% in the study period, although fluctuating. In Denmark, Norway and Sweden the number of dairy cattle and beef cattle declined only slightly in the various study periods while numbers of broilers produced increased notably, especially in Norway and Sweden. Following the termination of AGPs the total usage of antimicrobials (AGPs and therapeutic antimicrobials) in animals in Denmark declined 36% (from 1996 to 2003): in Norway this figure was 45% (from 1995 to 2003). In Sweden, the total usage of antimicrobials in animals in 2003 amounted to only one third of the amounts used in 1984 (decreased from 51 to 16 tonnes). Termination of AGPs was only a temporary risk factor for increased usage of therapeutic antimicrobials in food-animals in Sweden and Denmark; however, an exception might be usage in weaning piglets in Denmark. Furthermore, the discontinuation of AGP use has decreased the overall annual usage of antimicrobials in animals in Denmark, Norway and Sweden considerably.

What has happened in norway after the ban of avoparcin? Consumption of antimicrobials by poultry.

When avoparcin was prohibited for use as feed additive in poultry in Norway on 31 May 1995, an increased incidence of Clostridium perfringens-associated necrotic enteritis (NE) and an increase in the use of antibacterial (AB) drug therapy in meat-type poultry was expected. The consumption of AB drugs for use against NE in poultry in the period 1990-2001 was investigated by use of sales statistics at the drug-wholesaler level. Defined daily dose (DDD) per kg live weight poultry was the unit of measurement for drug use (to correct for differences in the dosages). Sales figures of the AB drugs were converted to number of DDDpoultry sold for the numbers of broilers at risk (broilers were 97% of the slaughter poultry). Estimated annual percentages of the broilers treated against NE increased abruptly after the avoparcin ban--but in 1996, this figure declined to the same level as before the ban and has remained at that low level since then. In November 1995, narasin was approved temporarily as an ionophore feed additive (IFA) in broilers. The usage patterns of IFAs in broilers were measured as the weight of feed to which an IFA was added per broiler chicken produced. In 1996-2001, the IFAs used in broilers were predominantly narasin. We note that the temporary increase in NE after the avoparcin ban coincide with the period before narasin became available. The increase in the consumption of AB drugs for the treatment of NE in poultry following the avoparcin ban has been negligible.