Antimicrobial Stewardship in Companion Animal Practice

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Bacteriology Refresher

Bacteria: single-celled microbes; often function as multicellular aggregates (biofilms)
Five morphological groups: cocci (spherical) and bacilli (rods) most common
Exist as single cells, in pairs, chains or clusters
Gram positive: thick cell wall
Gram negative: comparatively thin cell wall which includes a lipid membrane containing lipopolysaccharides (LPS, endotoxin) and lipoproteins
Also aerobic versus anaerobic growth; obligate or facultative

Antibacterials Refresher

Must remember the distinction between theoretical in vitro assertions and in vivo behaviour/effects in real clinical patients with different diseases and sites of infection

Broad- vs. narrow-spectrum classification according to the range of bacteria they are meant to be effective against. Commonly used but no clear and logical definitions for these terms. 

Bactericidal vs. bacteriostatic:

  • Bactericidal antibiotics kill bacteria directly
  • Bacteriostatic antibiotics stop bacteria from growing
  • May be much more relevant under strict laboratory conditions; more arbitrary and inconsistent in clinical situations

Time- vs. concentration-dependent:

Time-dependent:

  • Key pharmacodynamic parameter = time that plasma concentration remains above the minimum inhibitory concentration (MIC) during the dosing interval
  • MIC = lowest concentration of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
  • Higher concentration does not result in greater antibacterial activity
  • Key element is how long the concentration remains above the MIC at the site of infection rather than how high the concentration reaches
  • Dosing interval is critical; missing doses can compromise efficacy
  • Examples include penicillins, cephalosporins and carbapenems

Concentration-dependent:

  • Key pharmacodynamic parameter = ratio between peak plasma drug concentration and the MIC of the antibiotic in question
  • I.e. antibacterial activity is related to how high the concentration reaches at the site of infection rather than how long it remains above the MIC during the dosing interval.
  • Examples include the fluoroquinolones and the aminoglycosides.

Beta-lactam Antibacterials

Most widely used antibiotics in dogs and cats?

Amoxicillin-clavulanate:

Amoxicillin ‘potentiated’ by addition of potassium clavulanate
British Small Animal Veterinary Association’s Formulary (8th edn.):

  • Amoxicillin active against certain Gram-positive and Gram-negative aerobic organisms and many obligate anaerobes but not against those that produce beta-lactamases (e.g. E. coli, Staph aureus)
  • Clavulanate increases spectrum of action and restores efficacy against amoxicillin-resistant bacteria that produce beta-lactamases
  • More difficult Gram-negative organisms (e.g. Pseudomonas, Klebsiella) usually resistant 

Cephalosporins:

  • First-generation (e.g. cefalexin (cephalexin)) active predominantly against Gram-positive bacteria
  • Successive generations (e.g. cefuroxime is second generation) have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms)

Fluoroquinolones:

British Small Animal Veterinary Association’s Formulary (8th edn.):

“Ideally fluoroquinolone use should be reserved for infections where culture and sensitivity testing predicts a clinical response and where first- and second-line antimicrobials would not be effective”.

Active against Mycoplasma and many Gram-positive and Gram-negative organisms, but relatively ineffective against obligate anaerobes

Metronidazole:

Treatment of anaerobic infections, giardiasis and other protozoal infections

Antimicrobial Stewardship

Derived from this review article:

Guardabassi L, Prescott JF. Antimicrobial Stewardship in Small Animal Veterinary Practice: From Theory to Practice. Vet Clin N Am – Sm Anim Prac 2015. 45(2):361–376.

Nature of the problem:

“Antimicrobial resistance [or AMR] is one of the greatest challenges currently facing small animal veterinary medicine. During the past decade, various multidrug-resistant bacteria (MDR) have emerged and spread among dogs and cats on a worldwide basis. The major current MDR organisms of concern are methicillin-resistant Staphylococcus pseudointermedius (MRSP) and Escherichia coli producing extended-spectrum β-lactamase (ESBL). However, these bacteria are just the tip of the iceberg because multidrug resistance has diffused in other common bacterial pathogens encountered in general practice, such as Pseudomonas aeruginosa and enterococci. Additional MDR bacteria that are more likely to be isolated from animals presenting to referral centers include methicillin-resistant Staphylococcus aureus (MRSA), carbapenemase-producing E coli and Klebsiella pneumoniae, and MDR Acinetobacter baumannii.

All these MDR bacteria are frequently resistant to all conventional antimicrobials licensed for animal use and therefore pose a serious threat to animal health by increasing the risk of therapeutic failure and the recourse to euthanasia. MRSP/MRSA and MDR gram-negatives are important hospital-associated pathogens that can be transmitted from patient to patient through contact with personnel, with healthy animal carriers, and with contaminated environmental surfaces. Significant public health concerns exist because of the possible risk of animal-to-human transmission and in part also because of the increasing use in small animals of critically important antimicrobials authorized for human use only, such as carbapenems.

From the owner’s perspective, infections caused by MDR bacteria contribute to increased veterinary expenditures because of additional and more expensive antimicrobial treatments, longer hospitalization, more visits, and more diagnostic tests. Moreover, the negative consequences of MDR infections in household pets include emotional and social effects on the owners and their families. Hospitals and clinics affected by outbreaks of MDR bacterial infections also can be impacted economically by the loss of revenue due to loss of reputation and decreased case load, decontamination procedures, closure, and coverage of patient bills. This situation is worsened by the slow development of new antimicrobial drugs observed over the past decades. The few truly new agents are reserved for human use in hospitals and it is unlikely that these drugs will be authorized for veterinary use in the years to come. Thus, it is of paramount importance to preserve the efficacy of the veterinary antimicrobial products available today.”

Antimicrobial stewardship programs (ASPs) are a cornerstone of the response to the AMR crisis in human medicine; still largely underdeveloped in veterinary medicine.

“the aim of this article is to indicate the necessary steps that should be taken to establish ASPs in small animal veterinary practice, taking into consideration the many and remarkable differences between the human and the veterinary sector, and indeed the remarkable differences within veterinary medicine. Although the article highlights the structural and economic constraints that make implementation of ASPs used in human health care facilities difficult in small animal practice, it provides suggestions and approaches to overcome such constraints and to move toward practical implementation of effective veterinary-specific ASPs in small animal hospitals and clinics. We emphasize the multidimensional and the “mind-set” nature of “good stewardship practice” (GSP), as well the importance of an entire team-based commitment similar to that required for implementation of infection control practices.”

Antimicrobial paradox in small animal practice:

“One of the most effective strategies to manage AMR in human hospitals is to reduce the overall consumption of antimicrobial agents and rationalize the use of the most valuable drugs (eg, carbapenems, fourth-generation cephalosporins, glycopeptides), which are generally reserved for empirical treatment of life-threatening infections or infections that cannot be treated otherwise on the basis of susceptibility data. This strategy is almost completely flipped in small animal practice, where the listed drugs are not authorized and the most powerful veterinary antimicrobials, namely β-lactamase–resistant penicillins, cephalosporins, and fluoroquinolones, are widely used as empiric first-line agents in primary care, including treatment of mild or self-limiting infections….

…High consumption of these drugs provides a strong selective pressure in favor of MDR bacteria resistant to extended-spectrum β-lactams and fluoroquinolones” but the authors acknowledge that “they are indispensable drugs for management of common bacterial infections in small animals, including complicated skin and urinary tract infections and various life-threatening conditions”.

What is antimicrobial stewardship?

“The term “antimicrobial stewardship” is used to describe the multifaceted and dynamic approaches required to sustain the clinical efficacy of antimicrobials by optimizing drug use, choice, dosing, duration, and route of administration, while minimizing the emergence of resistance and other adverse effects. The word stewardship implies the obligation to preserve something of enormous value for future generations, and resonates in a way that “prudent use” or “judicious use” does not. GSP is the active, dynamic process of continuous improvement in antimicrobial use, and is an ethic with many steps of different sizes by everyone involved in antimicrobial use. Stewardship thus links, for example, front-line veterinary practitioners with laboratory diagnosticians, owners, drug regulators, and pharmaceutical companies.”

Examples of elements encompassed by the term antimicrobial stewardship that affect the emergence and spread of resistance include practice guidelines, dosage considerations and clinical microbiology data.
Also “A 5R approach to stewardship: Acceptance of responsibility for resistance as a potential effect of antimicrobial use, and for reduction, replacement, refinement, and review of antimicrobial use on an ongoing basis.”

In human medicine antibiotic stewardship is very much something that is attended to at the individual hospital level. In veterinary medicine it tends to be more about national and international surveillance and guidelines and potentially “legal (regulatory) interventions imposed by national authorities to restrict or ban specific drugs, to limit profit derived from antimicrobial dispensation, and taxes or penalties to prevent antimicrobial overuse”. While the authors support this “broad, multifaceted, approach to sustaining the efficacy of antibiotics for the long term” they also “recognize the need for establishing hospital-based ASPs in small animal practice.”

Establishing an antibiotic stewardship programme:

“No guidelines are available for development of ASPs in small animal clinics”
Article presents information and guidelines from non-veterinary specific resources

Role of microbiology laboratory:

“Liaison with a microbiologist at the diagnostic laboratory, which in contrast to human hospitals is normally placed outside the clinic environment, is an essential aspect for implementation of ASPs in small animal veterinary practice. The microbiology laboratory is not only supposed to provide timely and accurate species identification and antimicrobial susceptibility testing. Its role and responsibilities go beyond correct specimen testing and reporting of results, and include attention to the preanalytical...and postanalytical...components of testing. Selective reporting of susceptibility profiles can be used to discourage unnecessary use of broad-spectrum agents that are not licensed for veterinary use...Indiscriminate reporting of positive culture and susceptibility data on likely contaminants or nonpathogenic commensals should be avoided, because this practice may lead to inappropriate antimicrobial use. Last, but not least, the microbiology laboratory should generate annual reports summarizing the trends of AMR at the clinic level or at least at the regional level.”

Antimicrobial stewardship strategies:

“Various strategies have been shown to improve appropriateness of antimicrobial use and cure rates, decrease failure rates, and reduce health care–related costs in human hospitals”.
Article provides an overview of the most successful strategies used in human hospitals with focus on their implementation in small animal veterinary practice. Including:

Educational approaches:

“outstanding example of a readily and freely accessible Web-based and app-linked resource aimed to support companion animal veterinarians to develop practice policies for antimicrobial stewardship is the PROTECT site of the British Small Animal Veterinary Association”
[http://www.bsava.com/Resources/PROTECT.aspx]

PROTECT = Practice policy, Reduce prophylaxis, Other options, Types of bacteria and drugs, Employ narrow spectrum, Culture and sensitivity, and Treat effectively.

Federation of European Companion Animal Veterinary Associations has released several posters addressing responsible use of antimicrobials, appropriate antimicrobial therapy, and hygiene and infection control in veterinary practice.
[http://www.fecava.org/content/guidelines-policies]

Development and implementation of guidelines:

“General (generic) guidelines providing statements of principles of prudent antimicrobial use have been developed in recent years by most national veterinary organizations…Although important from a conceptual standpoint, their clinical guidance and impact is likely limited. Standard texts have included investigator recommendations on first-choice, second-choice, and last-resort antimicrobial agents… More recently, evidence-based clinical antimicrobial use guidelines have been developed using approaches similar to those for human guidelines. These have typically involved national or international expert panels reviewing and assessing the quality and strength of published literature to produce recommendations for diagnosis and management of specific conditions….The impact of national practice guidelines is likely higher than for international guidelines, because they take into account local factors regarding legislation, drug market availability, and prevalence of resistance.

Many veterinary specialty organizations also have developed guidelines, ranging from generic prudent use guidelines to practice-specific or disease-specific guidelines…Veterinary practice guidelines are negatively affected by numerous knowledge gaps regarding dose-effect relationships between antimicrobial use and resistance, antimicrobial consumption, resistance prevalence, drug-to-drug superiority, and optimal duration of treatment. However, although there are limitations, national guidelines are an essential milestone for development of [local antimicrobial policies] and more complex [antimicrobial stewardship programs] at the clinic level”.

Generic guidelines provided in paper (with references):

  1. Antimicrobials should be used only when there is evidence or at least a well-founded clinical suspicion of bacterial infection
  2. Antimicrobials should not be used for treatment of self-limiting infections
  3. Antimicrobial, pathogen, infection site, and patient factors should be considered when choosing an appropriate treatment
  4. Cytology should be used as a point-of-care test to guide antimicrobial choice for relevant disease conditions (eg, otitis and urinary tract infections)
  5. Antimicrobial susceptibility testing should be performed if:
    • There is suspicion of a complicated or life-threatening infection
    • The patient does not respond to initial treatment
    • The patient has a recurring or refractory infection
    • The patient is immunosuppressed
    • There is a need to monitor the outcome of therapy (eg, long treatment period)
    • The patient is at risk of infection with multidrug-resistant bacteria
  6. As narrow a spectrum therapy as possible should be used
  7. Topical therapy should be preferred over systemic therapy for treatment of superficial skin infections
  8. Antimicrobials should be used for as short a time as possible
  9. Extra-label use should be avoided when on-label options are reasonable
  10. Use of critically important antimicrobials not authorized for veterinary use should at least be restricted to rare and severe patient conditions (eg, diagnosed, life-threatening bacterial infections that cannot be treated by any other available antimicrobials, provided that treatment has a realistic chance of eliminating infection)
  11. Antimicrobial therapy should never be used as a substitute for good infection control, and good medical and surgical practices
  12. Perioperative prophylaxis should be used only when indicated, and follow standard guidelines
  13. Clients should be educated to ensure compliance

“Although there has been a marked increase in available guidelines, there has been little assessment of their impact on practice.”

“The effort spent on introducing guidelines, on educating health care providers, and in monitoring the response to guidelines is often slight compared with the effort of development, but critical to success. Compliance with guidelines may be poor because of inadequate communication, differences in opinion regarding recommended treatments, and resentment of measures to prescribe individual decisions….Thus, it is crucial that national and local veterinary professional and regulatory organizations allocate sufficient time and resources to promote guidelines and facilitate compliance.”

Other antimicrobial stewardship strategies mentioned:

  • Prescription approval
  • Post-prescription review
  • Computer-based decision support

Article also covers:

  • Measuring the outcomes of antimicrobial stewardship programs
  • Potential barriers to their implementation

Key points:

  • “There is increasing recognition of the critical role for antimicrobial stewardship and infection control in preventing the spread of multidrug-resistant bacteria in small animals.
  • Establishment of antimicrobial stewardship programs requires (1) coordination ideally by an infectious disease specialist or at least by a clinician with strong interest in and good knowledge of antimicrobial resistance and therapy, (2) commitment by the clinical staff, and (3) collaboration with the microbiology laboratory.
  • Even in the absence of specialist help, by accessing the increasingly available resources, veterinary clinics should at least develop, implement, and periodically update local antimicrobial policies indicating first-choice, restricted, and reserve drugs.
  • Educational approaches, clinical guidelines, preprescription approval, postprescription review, and computer-based decision support are the most effective strategies to accomplish best practices in antimicrobial stewardship.
  • The main barriers to implementation of antimicrobial stewardship programs comprise (1) economic sustainability; (2) lack of formally trained infectious disease specialists; (3) limited use of culture and antimicrobial susceptibility testing; (4) scientific knowledge gaps for assessment of resistance, development of evidence-based guidelines, and optimization of antimicrobial therapy; and (5) absence of standardized methods for evaluating the outcomes of antimicrobial stewardship programs.”

In 2015 ACVIM published a “Consensus Statement on Therapeutic Antimicrobial Use in Animals and Antimicrobial Resistance” in the Journal of Veterinary Internal Medicine.
[http://onlinelibrary.wiley.com/doi/10.1111/jvim.12562/epdf]

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