Antimicrobials: from a blessing to a curse

Introduction

There has been extensive use of antimicrobials – both in people and in animals – on a worldwide basis since they were first introduced, and such drugs have made a huge contribution to better human and animal health as well as animal welfare. Unfortunately, these improvements have come at a price, as the widespread use of these drugs in the past decades has led to a dramatic emergence of antimicrobial resistance (AMR), with worst-case scenarios estimating that AMR could contribute to 10 million human deaths annually by 2050 1. This article offers a brief overview of antimicrobial resistance and the path ahead. Whilst the term antimicrobials include antibiotics, antifungals, antivirals and antiprotozoals, resistance problems mainly relate to antibiotics, and in this paper antimicrobial resistance and antibiotic resistance are used synonymously.

The antimicrobial resistance crisis has brought into question every aspect of antibiotic use, especially when employed in food producing animals. The classes of antibiotics used to treat animals are mostly the same as the ones used to treat human bacterial infections, and in many countries this has led to intense scrutiny as to how antibiotics are used in animals, and especially in the livestock sector. Some individuals and groups have gone so far as to blame antibiotic use in food producing animals as the main source for the human AMR burden.

How have countries responded to the threat of AMR?

To combat antimicrobial resistance, many countries have started to monitor bacterial resistance 2 and the quantities of antimicrobials sold for use in farm animals and humans, notably the European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) and European Surveillance of Antimicrobial Consumption Network (ESAC) 3. Similar, although often less detailed, monitoring systems have been developed or are under development in other parts of the world, including countries in North America, Oceania and Asia.

Resistance rates vary greatly between countries, antibiotic classes and bacteria, but they are at levels that give cause for concern almost everywhere. Common bacteria such as E. Coli, Klebsiella, Pseudomonas and Staphylococcus 4 often show high resistance rates against one or several antimicrobial groups, making treatment extremely challenging, especially for the most vulnerable members of society (e.g., young children, the elderly or immunocompromised individuals). In addition, bacteria such as Campylobacter and Salmonella species, which can cause zoonotic diseases that may be transmitted between animals and humans, show alarmingly high levels of resistance (Figure 1). This brings us to the point where more and more common infections are becoming difficult – or sometimes even impossible – to treat. Unfortunately, resistance data for common bacteria that infect dogs and cats are – as yet – not routinely monitored.

The amount of antibiotics sold for use in farm animals has been scrutinised in the European Union for more than a decade now 5. Prudent and responsible use of drugs has been encouraged, with a focus on disease prevention, and there has been a concerted effort made to raise awareness of this important topic amongst everyone involved. This has resulted in the use of antibiotics in farm animals in Europe decreasing overall by 32% in the last 6 years, with some individual countries going even further, demonstrating a reduction in use of over 50% 5. In the USA the use of antibiotics in animals has declined by 28% since 2009 6. What is extremely positive is that all this was possible without major detrimental effects on animal health, welfare or productivity loss.

Some countries have gone further than simply monitoring “sales” data and have started to record data on how antibiotics are used, and have even started benchmarking the quantities of antibiotics employed per farm and veterinarian. New European legislation on veterinary medicines was adopted in 2019 6 which will make it obligatory to monitor all antimicrobial use in animals – including companion animals – from 2029 onwards 7 8. In most cases this information will be collected by collating prescription data from veterinarians. However, while a lot of attention has been paid to antibiotic use and antimicrobial resistance in food producing animals, until now much less notice has been given to companion animals. Why is this?

Antimicrobial resistance and companion animals: an issue?

As companion animals, dogs and cats differ from food producing animals in many aspects. On the one hand they are probably less often treated with antimicrobials than food producing animals. In addition, they do not usually live together in large groups (unlike pigs or poultry), they are less exposed to herd diseases, and they are treated on an individual basis and mostly only for a short period of time. As a result, when looking at the volumes of antibiotics used for companion animals compared to farm animals, it is clear that they take up only a fraction of the total volume 5. However, on the other hand, companion animal numbers have substantially increased over recent years, and more people are starting to see them as a part of the family. Dogs and cats live in much closer contact with their owners, often even sleeping in the same bed, and as a result zoonotic bacteria can spread easily between companion animals and their owners 9; for example, dogs can be a source of human Campylobacter 10 or Staphylococcus infections 11. Therefore the risk for human pathogens to acquire “resistance genes” derived from resistant bacteria that come from companion animals, or for transmission of resistant microorganisms between humans and their pets, is much higher than with food producing animals. Companion animals can share MRSA (methicillin-resistant Staphylococcus aureus) strains that seem to originate from and exchange with a human reservoir 12, and have been found to harbour other resistant species of Staphylococcus 13. Furthermore, this exchange can go two ways, not only from companion animals to owners, but vice versa; owners that work in a health-care facility or who have been hospitalised may transfer bacteria to their pets (Figure 2).

In recent years pet owners have also devoted more efforts to ensuring the welfare of their four-legged friends. More animals are taken to the veterinary clinic more often, not only when they are unwell but for preventative treatments too, and will potentially be given antibiotic treatment. Critically important antimicrobials are also more likely to be prescribed for companion animals compared with other species 14.

For all these reasons, it is essential that companion animals are taken into consideration when talking about antimicrobial resistance.

Antibiotic use and AMR in companion animals: what is the situation?

Unfortunately, data is scarce with respect to antibiotic use and resistance in companion animals. While resistance rates for human bacteria and zoonotic bacteria are officially monitored in many countries and regions of the world, this is not the situation for pets. The same is true when considering the surveillance of antimicrobial use in companion animals, with only very few countries currently systematically recording antimicrobial use in dogs and cats. As a result, it is difficult to obtain a reliable global overview of antimicrobial use and resistance in companion animals.

The few studies that have looked at resistance rates of bacteria isolated from companion animals give different results. Most of these publications are based on diagnostic laboratory analysis, but it should be recognised that reports of resistance coming from these laboratories are mostly “worst-case” scenarios, since they often represent treatment failures. Treatment successes tend to not reach the laboratory at all 9. Some studies show an increasing trend of resistance, whilst others report increased resistance towards particular antibiotic classes, which may be because certain classes of antimicrobial start to be used more than others 15. For example, a 2014 study looking at 14,555 clinical Staphylococcus intermedius isolates from UK dogs and cats identified increasing resistance to important antimicrobials and confirmed the emergence of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in clinical cases 16. A study from Singapore analyzed diagnostic samples collected in a small animal clinic between 2014 and 2016 and isolated 359 bacterial species, of which 186 were zoonotic 17; of the 359 bacteria, 45% were multi-drug resistant and 18% were extended-spectrum beta-lactamase resistant species. Another study, conducted in Belgium, Italy and the Netherlands, collected 303 samples and determined resistance profiles of 282 Escherichia coli isolates, and found the bacteria to be resistant to at least one antibiotic in 27% of the isolates 18.

Looking at reasons why antimicrobials are used in dogs and cats, a European study showed that the most common indications to prescribe antibiotics for dogs are skin conditions (wounds, dermatitis, pyoderma), otitis, urogenital infections, respiratory problems, gastrointestinal and dental diseases 19. For cats the most common indications for antimicrobial use were skin diseases (wounds, abscesses, dermatitis), respiratory complaints, urinary tract disorders and periodontal problems. The situation is similar in other countries, but importantly, studies have shown that antibiotic use can be reduced for several of these indications. For example, antibiotics may not be appropriate for many cats that present with lower urinary tract disease.

Data regarding antibiotic use also show great variations between countries. Denmark, which is one of the countries officially recording antibiotic use in animals, has seen a decline in antimicrobial use in companion animals of around 10% since 2012 20. A study from the Netherlands also identified that antibiotic use for companion animals decreased significantly from 2012 to 2014 21, although large differences in total use were seen between different veterinary clinics, ranging from a 64-fold decrease in 2012 to a 20-fold decrease in 2014. The cross-country study in Belgium, Italy and the Netherlands referred to above 18, found that on average cats and dogs were given antibiotics for 1.8 and 3.3 days respectively over the course of a year. Importantly, this study could not find a correlation between antibiotic use and resistance, and therefore concluded that the most important aspect is the quality of antibiotic use, not the quantity. As of 2030 more data will become available on this because – as mentioned earlier – from January 2029 it will become mandatory for all EU countries to monitor the use of antibiotics in dogs and cats 7.

What can we do to fight AMR in dogs and cats?

The positive news about AMR is that both veterinarians and owners can help combat it. In some countries which have seen a large decrease in antibiotic use, a decline in resistance has also been observed, e.g., there has been a decline in the levels of MRSA in food producing animals in Germany 22, so resistance can be reversed. Some general principles that can help in this fight are as follows:

• Prescribe the right drug for the right bug. Only prescribe antibiotics when a bacterial infection has been proven to be present, or if there is well-grounded clinical suspicion. Whenever needed, and especially after treatment failure, perform sensitivity testing (Figure 3).
• Work with your clients to minimize and stop the need for antimicrobials. Preventative health measures are essential for all animals, including companion animals. Through appropriate vaccination, strict hygiene practices, good feeding and proper housing, many infections can be prevented and hence also the need to treat with antimicrobials. Illness in an animal is not always due to a bacterial infection, and one study has shown that veterinarians and owners sometimes have differing perceptions of where pressure to prescribe antibiotics inappropriately originated. The veterinarians perceived that it was mainly pet owners who pushed for inappropriate antibiotics, whereas pet owners reported they felt it was the professional who overprescribed (Figure 4) 23.
• Use “Critically Important Antibiotics” only as a last resort. These should ideally only be prescribed after sensitivity testing, and critically important antibiotics, such as fluoroquinolones, 3^rd and 4^th generation cephalosporins and colistin, should be used with great caution.
• Avoid off-label use. As far as possible, use antimicrobials that are authorised specifically for the species and condition (e.g., canine uterine infections), and follow the instructions on the leaflet with respect to dosage and treatment duration. Avoid at all costs the use of human antimicrobials not authorised for companion animals, e.g., carbapenems, oxazolidones and glycopeptides; these are vitally important antibiotics that should be used only for public health.
• Follow antibiotic use guidelines. Studies show that national guidelines for antibiotic use can have a positive influence on prescription patterns among companion animal practitioners; countries that employ such guidelines have reported more prudent, responsible use of antimicrobials 24. Recommended prescribing policies are especially useful for common problems such as skin, urinary and ear infections.
• Notify adverse events to the competent authority. Reporting such occurrences allows authorities and manufacturers to monitor the safety and efficacy of their products and, when necessary, to take appropriate corrective measures. As such, veterinarians, pet owners, and the animals themselves benefit from adverse event reporting and subsequent actions taken (e.g., label changes). Note that adverse events include the lack of treatment efficacy.

Are there “good antibiotic use” guidelines for companion animals?

In the context of promoting prudent use of antimicrobials under veterinary supervision, the World Veterinary Association (WVA) and the World Organization for Animal Health (OIE) created a global repository of available guidelines in 2019 for responsible use of antimicrobials in animals 25. More than 130 guidelines, action plans and promotional materials on prudent use of antimicrobials have been identified, and although only a few deal specifically with dogs and cats (Table 1) they can be a useful resource for the veterinary team, alongside materials produced by FECAVA and FVE (Figure 5).

Antimicrobials have been of huge benefit to both human and animal welfare over the past decades, but the rising threat of AMR must make all veterinarians more aware of their prescribing habits. For clinicians in companion animal practice, we should only use antibiotics where they are specifically indicated, and reference to manufacturers’ data sheets is to be recommended in all cases. Careful analysis of a clinical case can help ensure that antimicrobials are prescribed only in appropriate situations, and good communication with the pet owner will help ensure that they are used properly.