Antimicrobial resistance

Antimicrobial resistance and the role of companion animal veterinary practice

Background

In response to the rising threat to both human and animal health from multidrug-resistant (MDR) infections [1], there is an urgent need to adopt measures to preserve the efficacy of available antimicrobials (AM). Antimicrobial resistance (AMR) is already a public health crisis in human medicine, but in veterinary medicine therapeutic failure owing to AMR is uncommon, so some veterinary practitioners may not fully embrace the severity of the situation [2]. 

Since antimicrobial use (AMU) is recognised as a key driver of AMR [3] any steps that can reduce unnecessary or inappropriate AMU should lower the selection pressure for resistant bacterial strains. 

The vast majority of AMU in animals occurs on farms promoting development of AMR and creating an important potential reservoir of resistance genes [4]. A 35% decrease in overall sales was documented in Europe from 2011 to 2018, reflecting positive efforts in agriculture to reduce unnecessary AMU [5]. In companion animals, the overall AMU is substantially lower compared to production animals and the sales of antimicrobial tablets (a surrogate measure of AMU in companion animals) accounted for 1.1% of the total sales in 2018 although the proportion was higher (<10.3%) in some countries [5]. However, companion animals are increasingly being recognised as an important contributor to the development of AMR [6]. Owing to their close living proximity with humans there is considerable scope for interspecies bacterial transfer.

Much of the work to mitigate the companion animal contribution to AMR focuses on AM prescribing practices. Responsible and rational prescription of AM is the cornerstone to what is known as ‘antimicrobial stewardship programmes’.’ Essentially this is the prescription of the right type of AM, at the correct dose, at the right time. 

Owing to the immediate transmission risk via the food chain, some AMU in food animals is restricted at a National level. However, in companion animals AMU is stewarded by guidelines with few legislative measures in place. Whilst there are many AMU guidelines in existence for companion animals, there is considerable variation between them and there is not one go-to authority as yet. In the UK, RCVS Knowledge is currently leading a National AM stewardship scheme.

AM stewardship 

Allerton et al [5] identified 15 antimicrobial stewardship guidelines (ASG) on rational antimicrobial use for cats and dogs from 11 of 40 countries investigated, highlighting a substantial gap in National recommendations for small-animal antimicrobial stewardship across Europe. None of the included guidelines were initiated by governmental initiatives, further emphasising that small animals constitute a blind spot in the national AMU political agenda.

Key AMG recommendations include 

  • stopping AMU for common, self-limiting indications.
  • use of non- AM therapies- to address prescription pressure from owners.
  • Identification of the pathogen through culture and cytology to guide treatment decisions and ensure optimal drug choice, rather than empirical broad-spectrum prescription.

This third point is universally recommended by all ASGs, but infrequently implemented in practice owing to cost constraints. Private practice makes it difficult to convert recommendation into action. 

  • Use of narrow spectrum AM over broad spectrum is highly recommended however, other factors may influence this choice- drug familiarity, practice purchasing policies.
  • Topical AM should be selected over systemic in appropriate cases such as surface skin disease. Skin disease is one of the most common presenting conditions in small animal practice, hence topical AMU would have significant impact on exposure of GI bacteria to AM and reducing AMR. 

Systemic AM therapy for skin disease has reduced from 92% to 25% in recent times [7, 8]. The four-year gap between the data collection for these studies coincides with the launch of the first edition of national stewardship guidelines in the UK.

  • Certain AM should be reserved exclusively for human use, including carbapenems, linezolid and vancomycin. Some countries legal prohibit veterinary prescription of these drugs. 

WHO and EMA have a published list of highest priority critically important antimicrobials (HPCIAs) including fluoroquinolones, macrolides and third generation and above cephalosporins. Imminent legislation will condition their prescription on culture and sensitivity testing. 

  • Dose and duration of treatment should adhere to the data sheet or summary of product characteristics.

Shorter treatment duration recommendations are spilling over from human medicine. 2019 guidelines on treatment of uncomplicated urinary tract infection favour a shorter 3-5 day course of AM compared to 7-14 days in the original 2011 version [9]. This approach is not, as yet, supported by clinical trial evidence.

This lack of clinical data is a common issue. Guidelines are often set according to key opinion leaders and following human medicine principles. Evaluation of guidelines remains problematic but beyond the scope of this article.

This evidence suggests that whilst there are positive moves to embrace antimicrobial stewardship programs, there is still a long way to go. It is difficult to measure the impact of guidelines and other measures to reduce unnecessary AMU, although some studies have tried to employ an intervention and measure its impact [10, 11].

Worryingly, cefovecin, a third-generation cephalosporin considered a HPCIA is the most commonly prescribed AM in cats in UK (2017) [7]. In a study conducted in 2016, 25% of dogs and 21% of cats attending first opinion veterinary practice in UK received AM. Of these AM, 60% in dogs and 81% in cats were classified as CIAs, with 6% and 34% being HPCIAs [12].

Uncomplicated urinary tract infections

In dogs, an empirical choice of amoxicillin is a reasonable first choice of treatment in most geographic areas. High concentrations are achieved in urine, negating potentiation with clavulanic acid. Trimethoprim-sulphonamides are another first line option but may have increased possibility of side effects. The current recommended therapy term is 3-5 days, with suggestion that the shorter end of this interval may be optimal, although veterinary research to support this is limited [9].

Canine pyoderma

Canine pyoderma is one of the main presentations leading to AM prescriptions in small animal practice [13]. Canine pyoderma offers unique opportunities in terms of exercising good AM stewardship; the skin being immediately accessible for cytology, culture and topical therapy. Pyoderma is always a secondary sign in canine skin disease, so the underlying cause should be sought, rather than embarking on long courses of AM therapy that will ultimate prove unsuccessful.

With the continuing emergence over the past 20 years of methicillin resistant Staphylococcus aureus and Staphylococcus pseudointermedius and other multi drug resistant zoonoses [14], we must focus on how traditional recommendations be adapted to contain this public health threat. Whilst methicillin is no longer available for clinical use it serves as a marker for broad resistance to all beta lactams.

Topical AM therapy has always been advised for surface skin infections, combined with systemic therapy for superficial and deep pyodermas [15]. Options include many different formulations such as shampoos, creams, gels and ointments. The efficacy of shampoos containing 2-3% chlorhexidine +/- benzoyl peroxide is supported by good evidence [16]. In addition localised infections can be additionally treated with gels or ointments containing fusidic acid. While concern has been expressed over resistance to topical AM, to date there is no evidence substantiating this [15].

Systemic therapy of canine pyoderma should constitute ‘as little as possible but as much as necessary’ approach. The efficacy hinges on bacterial susceptibility and correct drug administration. In countries with a low prevalence of MRS, empirical therapy is considered acceptable in most superficial cases. However, in countries with high prevalence of MRs this approach may not be reliable or cost effective. Bacterial culture and sensitivity testing in essential in all cases of deep pyoderma or in other cases with a history of MRS or where empirical therapy has failed [17].

Many AM used for pyoderma are listed by WHO as CIA or HPCIA. Treatment recommendations have now been detailed [18], including first and second tier drugs, depending on the likelihood that they will be effective against staphylococci and their spectrum of activity against Gram negative pathogens. First tier drugs, such as clindamycin, first generation cephalosporins, amoxicillin-clavulanate or potentiated sulphonamides may be chosen empirically in areas with a low prevalence of MRS. Clindamycin, an antimicrobial agent with good efficacy against most staphylococci, can be considered as a responsible treatment choice due to its relatively narrow spectrum of activity. Treatment with second tier agents, such as fluoroquinolones, should always be based on bacterial culture and sensitivity results.

Duration of treatment for pyoderma remains conflicting. Traditionally treatment for 3 weeks (or one week beyond clinical resolution) for superficial pyoderma and 4-8 weeks (or 2 weeks beyond clinical cure) for deep pyoderma was accepted [19]. The practice of continuing AM therapy once clinical resolution has been achieved has been widely questioned; however, in the absence of this approach, closer case supervision and follow up may be needed by the clinician. 

Treatment of MRS pyoderma is beyond the scope of this article. Details can be found in Consensus Guidelines on MRA infections [20].

The role of companion animal veterinary practice in AMR is becoming a more and more closely scrutinised. Guidelines do exist for AM therapy in various common clinical presentations, although much implementation remains down to the individual clinician. AMR is becoming a public health crisis in human medicine and the veterinary industry need to take its role seriously in helping to preserve the efficacy of HPCIAs.

1. Cassini, A., et al., Attributable deaths and disability-adjusted life-years caused by infections with antibiotic-resistant bacteria in the EU and the European Economic Area in 2015: a population-level modelling analysis. Lancet Infect Dis, 2019. 19(1): p. 56-66.

2. Lloyd, D.H. and S.W. Page, Antimicrobial Stewardship in Veterinary Medicine. Microbiol Spectr, 2018. 6(3).

3. Klein, E.Y., et al., Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci U S A, 2018. 115(15): p. E3463-e3470.

4. Woolhouse, M., et al., Antimicrobial resistance in humans, livestock and the wider environment. Philos Trans R Soc Lond B Biol Sci, 2015. 370(1670): p. 20140083.

5. Allerton, F., et al., Overview and Evaluation of Existing Guidelines for Rational Antimicrobial Use in Small-Animal Veterinary Practice in Europe. Antibiotics (Basel), 2021. 10(4).

6. Rantala, M., et al., Antimicrobial resistance in Staphylococcus spp., Escherichia coli and Enterococcus spp. in dogs given antibiotics for chronic dermatological disorders, compared with non-treated control dogs. Acta Vet Scand, 2004. 45(1-2): p. 37-45.

7. Singleton, D.A., et al., Patterns of antimicrobial agent prescription in a sentinel population of canine and feline veterinary practices in the United Kingdom. Vet J, 2017. 224: p. 18-24.

8. Summers, J.F., A. Hendricks, and D.C. Brodbelt, Prescribing practices of primary-care veterinary practitioners in dogs diagnosed with bacterial pyoderma. BMC Vet Res, 2014. 10: p. 240.

9. Weese, J.S., et al., International Society for Companion Animal Infectious Diseases (ISCAID) guidelines for the diagnosis and management of bacterial urinary tract infections in dogs and cats. Vet J, 2019. 247: p. 8-25.

10. Singleton, D.A., et al., A randomised controlled trial to reduce highest priority critically important antimicrobial prescription in companion animals. Nat Commun, 2021. 12(1): p. 1593.

11. Hopman, N.E.M., et al., Implementation and evaluation of an antimicrobial stewardship programme in companion animal clinics: A stepped-wedge design intervention study. PLoS One, 2019. 14(11): p. e0225124.

12. Buckland, E.L., et al., Characterisation of antimicrobial usage in cats and dogs attending UK primary care companion animal veterinary practices. Vet Rec, 2016. 179(19): p. 489.

13. Hughes, L.A., et al., Cross-sectional survey of antimicrobial prescribing patterns in UK small animal veterinary practice. Prev Vet Med, 2012. 104(3-4): p. 309-16.

14. Beever, L., et al., Increasing antimicrobial resistance in clinical isolates of Staphylococcus intermedius group bacteria and emergence of MRSP in the UK. Vet Rec, 2015. 176(7): p. 172.

15. Loeffler, A. and D.H. Lloyd, What has changed in canine pyoderma? A narrative review. Vet J, 2018. 235: p. 73-82.

16. Mueller, R.S., et al., Treatment of demodicosis in dogs: 2011 clinical practice guidelines. Vet Dermatol, 2012. 23(2): p. 86-96, e20-1.

17. Hillier, A., et al., Guidelines for the diagnosis and antimicrobial therapy of canine superficial bacterial folliculitis (Antimicrobial Guidelines Working Group of the International Society for Companion Animal Infectious Diseases). Vet Dermatol, 2014. 25(3): p. 163-e43.

18. Beco, L., et al., Suggested guidelines for using systemic antimicrobials in bacterial skin infections: part 2– antimicrobial choice, treatment regimens and compliance. Vet Rec, 2013. 172(6): p. 156-60.

19. Ihrke, P.J., An overview of bacterial skin disease in the dog. Br Vet J, 1987. 143(2): p. 112-8.

20. Morris, D.O., et al., Recommendations for approaches to meticillin-resistant staphylococcal infections of small animals: diagnosis, therapeutic considerations and preventative measures.: Clinical Consensus Guidelines of the World Association for Veterinary Dermatology. Vet Dermatol, 2017. 28(3): p. 304-e69.

Written on July 14, 2022

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