Authors’ response on Perkins et al. (2021) “Dead in the water: comment on “Development of an aquatic exposure assessment model for imidacloprid in sewage treatment plant discharges arising from use of veterinary medicinal products”

In 2020, Anthe et al. published a newly developed model to predict imidacloprid surface water concentrations stemming from sewage treatment plant (STP) effluent as a consequence of the use of veterinary medicinal products containing imidacloprid in the UK (Anthe in Environ Sci Eur (2020) 32:147, https://doi.org/10.1186/s12302-020–00424-4). The modelled data indicate that these veterinary medicinal products make only a very small contribution to the levels of Imidacloprid observed in the UK water monitoring programme.The commentary by Perkins et al. (Perkins in Environ Sci Eur (2021) 33:88, https://doi.org/10.1186/s12302-021-00533-8) questioned the validity and conclusions of the modelling approach. We believe the modelling approach, which considered what we anticipated to be, the major exposure pathways, gives a realistic picture of the chronic emission via STPs to UK rivers.

Novelties of the legislation on veterinary medicinal products

The article is devoted to the analysis of the latest innovations in the legislation on veterinary medicine, namely the regulation of the production, distribution and use of veterinary medicines. The adoption of the new Law of Ukraine “On Veterinary Medicine” is caused by the need to approximate the relevant national legislation with the legislation of the European Union to fulfill Ukraine’s international obligations under the Association Agreement. This law reflects the latest trends in the development of legislation on veterinary medicinal products in the European Union. The article pays attention to the strengthening of state regulation of production and distribution of veterinary medicines, in particular the introduction of licensing of imports, wholesale and retail sales of these medicines in Ukraine, due to the need to combat counterfeiting and veterinary medicinal products of dubious quality. It is also noted that the changes in the procedure of state registration of veterinary medicines provided by this law will on the one hand reduce the administrative burden on business due to the transition to indefinite state registration of veterinary drugs, and on the other hand new requirements for the registration dossier will improve the safety, quality and efficacy of veterinary medicinal products. New requirements for the use of antibiotics are analyzed. Attention is drawn to the fact that along with the regulation of the use of antibiotics in animal husbandry, it is also necessary to regulate in more detail the issues of control of the circulation of active substances (active pharmaceutical ingredients). The article also deals with the mechanism of veterinary pharmacovigilance, which is new for Ukraine. At the same time, it is necessary to study the practical experience of implementing the European model of pharmaco to improve the relevant legislation in Ukraine.

Critical discussion of the current environmental risk assessment (ERA) of veterinary medicinal products (VMPs) in the European Union, considering changes in animal husbandry

Background Veterinary medicinal products (VMPs) administered to livestock might affect the environment. Therefore, an environmental risk assessment (ERA) is conducted during the approval process of VMPs. In the European Union (EU), the ERA, which was established approximately 10 years ago, consists of two phases. In the present review, we examined the first phase. In this phase, VMPs are subjected to a decision-making process comprising 19 questions and several tables with default values published in the “Guideline on environmental impact assessment for veterinary medicinal products in support of the VICH guidelines GL6 and GL38 (European Medicines Agency 2016).” Since a proportion of livestock husbandry systems is currently shifting toward ecological husbandry and free-range production systems, there is a lower risk of VMP consumption in general, but livestock excretions possibly containing VMPs might be directly released into the environment instead of being stored and applied as manure. In the present study, the first phase of the current ERA of VMPs in the EU was critically discussed with respect to the changes in animal husbandry. The large number of default values used in the ERA were checked for topicality. In a three-step approach, firstly trends and changes in animal husbandry in Europe that might be relevant for the ERA were collected, secondly, the interactions between Phase I and animal husbandry were evaluated and thirdly, the default values used in Phase I were verified in order to identify research gaps. Results Several default values used in the current ERA were identified as outdated. Together with the lack of valid data (e.g., on animal husbandry systems or VMP treatments), this may have an impact on the predicted environmental concentration (PEC) as the central decision threshold of the ERA. Conclusions The results of the present study indicate that an update of the ERA of VMPs in the EU is required to consider the changes in animal husbandry. Several aspects related to this issue are critically discussed.

Registration of Novel Parasiticides under the New 2022 EU Regulation

Twenty-one years after Directive 2001/82/EC regulating veterinary medicinal products (VMPs) came into force, a new veterinary regulation will apply from 28 January 2022. Future applicants will have to follow the requirements of Regulation (EU) 2019/6. This regulation defines different products, non-biologicals (equivalent to formerly defined pharmaceuticals), and biological products. Biological VMPs belong either to the new class, non-immunological VMPs or immunologicals, including those known as vaccines. This new regulation also defines novel therapies covering innovative medicinal therapeutic approaches. Antiparasitic products will always be VMPs, and additional requirements for environmental safety and potential risks for the development of resistance are enforced.

Dead in the water: comment on “Development of an aquatic exposure assessment model for imidacloprid in sewage treatment plant discharges arising from use of veterinary medicinal products”

Anthe et al. (Environ Sci Eur 32:147, 2020. 10.1186/s12302-020-00424-4) develop a mathematical model to calculate the contribution of veterinary medicinal products (VMPs) to the levels of imidacloprid observed in the UK water monitoring programme. They find that VMPs make only a very small contribution to measured pollution levels, and that the estimated concentrations do not exceed ecotoxicological thresholds. However, shortcomings in methodology—including the implicit assumption that imidacloprid applied to pets is available for release to the environment for 24 h only and failure to incorporate site-specific sewage effluent data relating to measured levels—raise questions about their conclusions. Adjusting for these and other deficiencies, we find that their model appears consistent with the conclusion that emissions from VMPs may greatly exceed ecotoxicological thresholds and contribute substantially to imidacloprid waterway pollution in the UK. However, the model utilises imidacloprid emissions fractions for animals undergoing the different scenarios (for example, bathing) that are extrapolated from unpublished studies that do not clearly resemble the modelled scenarios, with insufficient evidence provided to support their derivation. As a result, we find that the model presented by Anthe et al. provides no reliable conclusions about the contribution of veterinary medicinal products to the levels of imidacloprid in UK waterways.

Environmental risk assessment of veterinary medicinal products intended for use in aquaculture in Europe: the need for developing a harmonised approach

The current and future expansion of aquaculture production appears to be only manageable by using veterinary medicinal products (VMPs) to prevent and reduce disease outbreaks. However, only a very low number of VMPs are available for use in aquaculture systems. In addition, the environmental risk potentially emanating from the use of these products has gained increased attention in the last years. In this context, the present review represents an in-depth analysis of the current two-tiered (phase I and phase II) approach for the environmental risk assessment (ERA) of VMPs mandatory in the European Union and the European Economic Area (EU/EEA), and its applicability to medicinal products intended for use in aquaculture. The following conclusions are drawn: (i) the current regulatory guidance documents detailing the phase I and II ERA procedure should be updated and harmonised across Member States and simple approach(es) applicable to the assessment of the environmental exposure of VMPs intended for use in aquaculture facilities should be devised; (ii) current and future regulatory guidance documents detailing the phase II ERA procedure for VMPs intended for use in aquaculture should comprise advanced mathematical models suitable for addressing different exposure scenarios relevant across the whole EU/EEA (including scenarios addressing the exposure of VMPs to agricultural soils from fish sludge); and (iii) it is recommended that any updates of relevant ERA guidelines clearly detail the types of studies needed to determine potential adverse effects of VMPs used in aquaculture on non-target organisms. Furthermore, the application of risk mitigation measures tailored to the reduction of the environmental exposure of VMPs on an individual aquaculture farm level should be considered in any future or updated guideline. Finally, it is anticipated that the present analysis of the main drawbacks surrounding the current ERA regulatory framework will help competent authorities to harmonise and facilitate the approval process for VMPs intended for use in aquaculture.

Use of tetracyclines and sulfonamides for the treatment of infectious diseases in animals

The use of antimicrobial medicines in human and veterinary medicine has led to the problem of the development of acquired antimicrobial resistance, which causes a global threat. Were described principles of tetracyclines and sulfonamides use, which are the most common among antimicrobial substances in veterinary medicinal products for the treatment of infectious diseases of food-producing and domestic animals. The aim. To substantiate the clinical relevance of antimicrobial veterinary medicinal products containing tetracyclines and sulfonamides+trimethoprim in veterinary medicine. Materials and methods. Research materials: sales reports of antimicrobial veterinary medicinal products in Ukraine for 2015–2019, EU countries, and the USA. Methods used: written and electronic survey; bibliosemantic, analytical and generalization. Results and discussion. As a result of the annual monitoring for 2015–2019 sales volumes in Ukraine, it was determined that tetracyclines (29.5–37.91 %) and sulfonamides + trimethoprim (12.1–18.7 %) were most often used in the composition of veterinary medicines. The same trend regarding the use of these classes of antimicrobials exists in many countries around the world. Factors determining the clinical relevance of these groups of substances are based on the criteria for their selection. The principle proposed by the EMA for the choice of antimicrobial veterinary medicinal products is based on the following criteria: categories of target animal species; treatment indications; the route of administration; the type of pharmaceutical formulation; the choice of a dosage regimen. Following this principle was substantiated the feasibility of tetracyclines and sulfonamides+trimethoprim use in veterinary medicine. By pharmacokinetic and pharmacodynamic parameters evaluated the rationality of the choice of antimicrobial veterinary medicines. Conclusions. The study revealed clinical efficacy and safety of tetracyclines and sulfonamides+trimethoprim as Veterinary Critically Important Antimicrobial Agents of Category D “Prudence”

A Retrospective Study of the Prevalence of Virulence Factors of Escherichia Coli Causing Postweaning Diarrhoea in Spain.

Background: Postweaning diarrhoea is one of the most prevalent disease which occurs after weaning. The aim of the study reports the prevalence of virulence factors of Escherichia coli from clinical cases of postweaning diarrhoea on Spanish pig farms based on PCR directly from pooling of faeces samples. A total of 328 pig farms with acute cases of postweaning diarrhoea were sampled, between January 2018 and December 2020. These farms were all located in Spain. Animals were selected based on clinical signs (diarrhoea, dehydration, and increased mortality). A total of 984 four- to eight-week-old pigs within the first 24 hours of the acute phase of the disease were sampled and three rectal swabs were collected from three different pigs on each farm.Results: A total of 328 farms with PWD cases were analyzed between 2018 and 2020. The classification was based on the presence or absence of the different Escherichia coli’s virulence factors. Only 1.2% (4 out of 328) of farms were negative for all the Escherichia coli’s virulence genes. Adhesin involved in diffuse adherence was the most prevalent adhesion factor (68.6%) followed by F18 (67.7%) and F4 (53.4%). Conclusions: the present study shows the high prevalence Escherichia coli in postweaning diarrhoea cases. There is a high degree of variability in the Escherichia coli’s virulence factors within country as well as differences between countries. Further Investigation is needed to fight against postweaning diarrhoea since the use of zinc oxide will be withdrawn from veterinary medicinal products on 26 June 2022 [26,27]and the responsible use of antibiotics is being regulated very closely to be used only when is necessary.