Sustainable prescribing – 1 / Veterinary drugs and environmental challenges

Introduction

In the last few years there has been a growing awareness of the effects that drugs used in domestic pets may be having on the environment and in the generation of resistance to their effects. This is the first in a series of three articles that will outline the implications of this environmental contamination and development of resistance. The second article will look at how these drugs can be better monitored and managed in practice, and the final article will suggest what steps need to be taken in the future to safeguard the efficacy of these drugs whilst also protecting the environment.

How big is the problem?

Traces of veterinary drugs used for animal therapeutics have been identified in many places. As these are biologically active compounds designed to interact with biochemical pathways, the implications of such contamination could be significant. For example:

• Organisms such as invertebrates may be exposed to these drugs, resulting in a reduction in their number which can then cause a loss of biodiversity and damage to environmental health.
• Antimicrobial contamination can promote resistance by exposing microorganisms to subtherapeutic drug concentrations. This resistance may spread across populations and eventually re-enter human and veterinary species.

Environmental contamination with human pharmaceuticals is emerging as a concern globally; one large study of rivers around the world showed that these contaminants pose a threat to ecosystems or human health in over a quarter of the 258 rivers studied (1). Until recently, the risk of environmental contamination from pharmaceuticals used in pets was considered negligible (2). However, a growing body of research is challenging this assumption. Studies from the UK have linked widespread freshwater pollution with the pesticides fipronil and imidacloprid to their use in topical pet parasiticides, with multiple pathways to waterways identified, including down-the-drain passage from households with treated pets, and directly from dogs swimming outdoors (3-5) (Figure 1). Concerns regarding environmental exposure are not limited to waterways, as a high prevalence of these parasiticides has been found in fur lining bird nests (Figure 2), and their presence has also been demonstrated in the households of treated pets (6).

Environmental contamination can also occur indirectly through the release of antimicrobial-resistant organisms to the environment. Studies have shown that feces from hospitalized companion animals – and their hospital environment – have relatively high levels of Escherichia coli that show resistance to several important antibiotics including potentiated amoxicillin, fluoroquinolones and third generation cephalosporins. One study found that 11 out of 97 UK bathing waters contained antibiotic-resistant E. coli, and that surfers had a higher colonization risk than non-surfers (Figure 3) (9). The same study estimated that in one year in the UK over 2.5 million water sports sessions occur that result in the ingestion of at least one antibiotic-resistant E. coli. Growing evidence therefore suggests that environmental contamination can play a significant role in the development and spread of antimicrobial resistance.

While most pharmaceuticals have low acute toxicity, their biologically active design may exert chronic effects at low doses, and environmental contamination with pharmaceuticals poses risks to non-target organisms and ecosystems. For example, chronic exposure to some human steroid drugs (e.g., estrogen) has been linked to sexual disruption in wild fish populations (12). Antibiotic pollution in aquatic environments can reduce overall microbial diversity, disrupt carbon cycling and leading to increased frequencies of toxic bacterial species, such as Cyanobacteria, and eutrophication (the process whereby a water body becomes overly enriched with nutrients, leading to excess growth of simple plant life such as algae) in freshwater environments (13). Parasiticides are particularly concerning, because they are intended to kill invertebrates at very low concentrations, and will often persist in the environment. Some, such as fipronil and isoxazolines, are classified as per- and polyfluoroalkyl substances (PFAS) due to the presence of fluorinated methyl groups in their chemical structure. PFAS chemicals, commonly known as “forever chemicals”, have the capacity to accumulate in water, soil and biological organisms, raising concerns about their potential to harm human health (14). Fipronil and imidacloprid have received the most attention among small animal parasiticides regarding environmental residues and risk; their extensive monitoring by environmental surveys and the wealth of ecotoxicological research on them largely stems from their historical agricultural use before stricter regulations were implemented. Both compounds are highly toxic to a wide range of aquatic and terrestrial invertebrates which play a crucial role in many ecosystem functions, such as decomposition and nutrient cycling, as well as serving as food for a wide range of species. Fipronil and imidacloprid can also be toxic to vertebrate species (particularly birds and fish), and can exert sublethal effects, such as reduced growth and reproductive success (Figure 2) (15). Due to the assumption of negligible environmental exposure in the existing international regulatory framework, little research has been done on emissions pathways and ecotoxicity of most other veterinary drugs intended for use in companion animals.

There is also concern surrounding potential health risks to veterinary professionals and pet owners from repeated chronic exposure to topically applied parasiticides. Chronic exposure to pesticides is associated with a range of diseases, including neurodegenerative conditions such as Parkinson’s disease and cancer, and even low levels of exposure may adversely impact children’s early development (16). Fipronil and imidacloprid residues have been demonstrated on the hands of in-contact people for at least 28 days after application (6), but no research has investigated the potential health impacts of this exposure or exposure to other topically applied parasiticides, such as fluralaner, moxidectin or selamectin.

Most of the attention has been paid to the veterinary use of antibiotics and parasiticides and their effect on the environment and levels of resistance. However, other drugs may also pose a threat; for example, anti-neoplastic chemotherapy drugs are often excreted in an animal’s urine and feces. This risks occupational exposure in the hospital environment, and when animals go home after treatment, their natural environment is likely to be exposed to these agents, even with careful disposal of feces. Whilst most anti-neoplastic agents are used in human health, the role of veterinary species in this dispersion is recognized; for example, transference of platinum by workers outside areas where antineoplastic drugs were handled was observed in veterinary and human oncology centers (17).

Environmental risks from veterinary drugs

The presence of antimicrobial-resistant organisms in the environment, as well as in the clinical setting, has been promoted by widespread antimicrobial use in both human and animal healthcare. The population attributable fraction (the contribution of any particular risk factor [e.g., environmental contamination] to a disease [e.g., multi-drug-resistant infection] can be used to determine the risk to health from a particular source. The relative risk from environmental sources has not been calculated, although mechanisms exist by which low concentrations of antimicrobials in the environment may contribute to antimicrobial resistance.

Resistant pathogens may arise from de novo mutation or via the acquisition of genetic material from other bacteria, including non-pathogenic commensals (horizontal gene transfer). Furthermore, exposure to a sub-inhibitory level of antibiotic can induce adaptive resistance in bacteria (10), and the mechanism involved in this resistance may reflect modulation in gene expression following environmental change (11). Bacteria should revert to a non-resistant phenotype upon removal of the inducing signal, as there is a fitness cost to maintaining these resistance mechanisms (10), but a gradual increase in minimum inhibitory concentrations over time may be consequent to increased adaptive resistance, highlighting the dangers of environmental contamination.

Resistance risks for veterinary drugs

Any exposure to antimicrobials favors the survival of resistant organisms and imposes a selection pressure that encourages resistance genes to spread within the microbial population. Resistant bacteria and resistance genes circulate in the ecosystem, posing a persistent threat to animal and human health. Increased antimicrobial resistance will lead to reduced efficacy of antimicrobial treatment, increased treatment failure and greater severity of infection (18). Fewer therapeutic options will increase the likelihood of adverse treatment effects and increase patient morbidity and mortality. Some 60% of all human pathogens and up to 75% of emerging diseases that affect humans are zoonotic (19), and antimicrobial use in animals can lead to the development of resistance in zoonotic pathogens. Indeed, many different multi-drug-resistant bacteria have been documented in companion animals, and their transfer to people has been recorded (20).

In contrast to antibiotic resistance, parasiticide resistance in small animals remains infrequently reported, and there are several potential reasons for this. Resistance may be slow to develop in small animal parasites due to the existence of large wildlife refugia populations for many such organisms (21), significantly different husbandry (e.g., individual rather than herd settings) and historically lower overall intensity of parasiticide administration. Where parasiticide resistance does occur in small animals, it may be undetected, particularly for endoparasites, as these can be asymptomatic in pets and for which little routine monitoring is performed (22). For fleas, treatment failure is often attributed to operational factors – such as improper application or failure to follow label directions – yet without sufficient research to definitively confirm or rule out resistance, true resistance may go undetected. Routine surveillance for pet parasiticide resistance is virtually non-existent worldwide, and field studies on dogs and cats are extremely limited (22).

Evidence of endoparasiticide resistance in small animals is, however, slowly emerging. Multiple-drug resistant hookworm (Ancylostyma caninum) isolates have been described in racing greyhounds, and fenbendazole resistance in A. caninum is now widely distributed in the US dog population (23). Similarly, resistance to pyrantel and benzimidazole in A. caninum is now widespread across Australia (24). Resistance to praziquantel in the tapeworm Dipylidium caninum has also been described in the US, and the first case of suspected resistance was recently reported in Europe (25).

The development of ectoparasiticide resistance is also of concern; resistance to multiple acaricides, including fipronil, has been reported in ticks affecting dogs in several countries in recent years, including Brazil, the USA and Thailand (Figure 4). Resistance is present in fleas to many older parasiticides, including carbamates, organophosphates, pyrethroids, pyrethrins and organochlorines (21), but resistance to more modern ectoparasiticides has also been reported, with fipronil resistance demonstrated in both field and laboratory strains (21). Reports of widespread lack of efficacy for fipronil reflect growing concern around this (26, 27), but a lack of routine surveillance means that the true extent of resistance in flea populations to modern ectoparasiticides is poorly understood. Improved surveillance is necessary to assess and mitigate emerging resistance in pet parasiticides.

Summary

Veterinary drugs, particularly antibiotics and parasiticides, contribute to environmental contamination and resistance development, posing risks to ecosystems as well as human and animal health. While awareness is increasing, significant knowledge gaps remain, particularly regarding pollution pathways and resistance mechanisms. Addressing these issues requires improved environmental and resistance monitoring, responsible prescribing practices, and continued research to protect both drug efficacy and environmental integrity.

References

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