Antimicrobial therapy: regimen selection (Proceedings)

Recently, the use of antimicrobials in food animals has been scrutinized by the general public (see report on CBS, http://www.cbsnews.com/video/watch/?id=6191894n), by federal legislators (see AVMA issues brief at http://www.avma.org/advocacy/federal/legislative/issue_briefs/preservation_antibiotics_2009.asp), and by public health organizations (see Infectious Diseases Society of American statements at http://www.idsociety.org/Content.aspx?id=6252). Some of these concerns relate to the use of antimicrobials as growth promotants, while some relate to the use of antimicrobials in food animals in general. Regardless of the focus of the scrutiny, it is not likely to go away anytime soon. Food animal producers and veterinarians must get the message out about how they use antimicrobials appropriately, and they must also provide their own scrutiny to abolish imprudent practices.

Traditionally, we have assumed that if a bacterial pathogen is "susceptible" to an antimicrobial, we just use the dose on the bottle or in a formulary, and the infection will be eliminated. The increasing incidence of "resistant" pathogens, i.e., pathogens requiring high concentrations of antimicrobials such that they become untreatable, has focused attention on identifying ways to reduce the selection for resistant organisms. In addition, we are beginning to recognize more and more frequently that the ecology of bacteria is very complicated and that the use of an antimicrobial in one animal can affect the non-targeted bacteria in that particular animal as well as in any other species of animal (including humans) that come into contact (direct or indirect) with the treated animal. This understanding compels us to use antimicrobials only when needed and only in a manner which is most likely to result in therapeutic success – in other words, balance the benefits and risks of therapy.

The American Veterinary Medical Association has published and disseminated a set of principles which can be used to help guide decision-making about antimicrobial therapy. Those principles are listed below:

      - Preventive strategies, such as appropriate husbandry and hygiene, routine health monitoring, and immunization, should be emphasized.

      - Other therapeutic options should be considered prior to antimicrobial therapy.

      - Judicious use of antimicrobials, when under the direction of a veterinarian, should meet all requirements of a veterinarian-client-patient relationship.

      - Prescription, Veterinary Feed Directive, and extralabel use of antimicrobials must meet all the requirements of a veterinarian-client-patient relationship.

      - Extralabel antimicrobial therapy must be prescribed only in accordance with the Animal Medicinal Drug Use Clarification Act amendments to the Food, Drug, and Cosmetic Act and its regulations.

      - Veterinarians should work with those responsible for the care of animals to use antimicrobials judiciously regardless of the distribution system through which the antimicrobial was obtained.

      - Regimens for therapeutic antimicrobial use should be optimized using current pharmacological information and principles.

      - Antimicrobials considered important in treating refractory infections in human or veterinary medicine should be used in animals only after careful review and reasonable justification. Consider using other antimicrobials for initial therapy.

      - Use narrow spectrum antimicrobials whenever appropriate.

      - Utilize culture and susceptibility results to aid in the selection of antimicrobials when clinically relevant.

      - Therapeutic antimicrobial use should be confined to appropriate clinical indications. Inappropriate uses such as for uncomplicated viral infections should be avoided.

      - Therapeutic exposure to antimicrobials should be minimized by treating only for as long as needed for the desired clinical response.

      - Limit therapeutic antimicrobial treatment to ill or at risk animals, treating the fewest animals indicated.

      - Minimize environmental contamination with antimicrobials whenever possible.

      - Accurate records of treatment and outcome should be used to evaluate therapeutic regimens.

While these principles do not specifically address regimen design, they will help when deciding which drug to select, and when NOT to use antimicrobials. In order to develop a complete regimen, which includes dose, frequency, duration, route of administration, as well as withdrawal time in the case of food animals, the following list of questions will need to be addressed.

1. Is an antimicrobial necessary?

Or is this condition viral in origin, self-limiting in nature, or are other interventions necessary before antimicrobial therapy will be successful?

2. What concentration of antimicrobial inhibits the growth of the pathogen, usually determined in vitro?

Antimicrobial susceptibility testing is addressed in another presentation by this author in these proceedings. The purpose of AST is to make a prediction of clinical efficacy based on standardized in vitro testing of the inhibitory concentrations of antimicrobial drugs.

3. What is the best presentation of the antimicrobial to the organism to maximize bacterial inhibition or growth (pharmacodynamics)?

A review of the literature reveals the following recommendations for assisting in regimen design for various antimicrobial groups. These recommendations are based on retrospective studies in human medicine, prospective studies in laboratory animals, and in vitro studies, where the indices are calculated based on therapeutic success at differing doses or frequencies. These are generalizations only, and the literature continues to expand with specification of indices for different pathogen-drug combinations.

4. What is the concentration (and time-course of concentration) of the antimicrobial in the animal species being treated (pharmacokinetics)?

Pharmacokinetics is the mathematical description of how drugs move through the body. This description includes rates of drug moving into, through, and out of the body. When reviewing pharmacokinetic data, it is important to recognize that often mean data are presented, and these mean data are usually determined in healthy young animals. The following are common terms and parameters used in pharmacokinetics:

Cmax: Peak serum/plasma concentration observed in experimental animals

T½: Elimination half-life (time for serum concentration to decrease by 50%)

T½a: Absorption half-life (time for 50% of drug to be absorbed)

Elimination rate constant (kel): Proportion of drug eliminated per unit time (used to calculate half-life = 0.693/kel)

Tmax: Time at which Cmax occurs

AUC: Area under the curve; calculated from the graph of time-concentration data

AUC0-24: Area under the curve for a 24-hour period – see below for the importance of this parameter

It is important to understand these parameters to be able to interpret data in the literature, on drug labels, or in other sources of information (such as the Veterinary Antimicrobial Decision Support System, www.vads.org).

5. Is there any published evidence that the regimen works?

A discussion of how to evaluate drug information is presented by this author in another section of these proceedings ("How to Evaluate Drug Information"), but briefly, evidence-based medicine suggests the explicit use of the following steps in decision-making about drugs:

      1. Ask a clinically relevant and answerable question about the patient or patients. One commonly used approach is PICO, which refers to asking a question with the elements of patient, intervention, comparison, and outcome. An example of a PICO question encountered in food animal practice might be:

           a) What antimicrobial regimen (I) is most likely (C) to result in minimal weight loss (O) in lambs (P) on pasture in Oregon?

      2. Locate the best evidence to answer the question.

           a) Searching for published evidence has become easier with the advent of the internet. Published papers are increasingly available on-line for little or no cost, particularly with membership in professional associations. Many research libraries at universities will assist practitioners in locating sources. In addition, the Evidence Based Veterinary Medical Association is working to make the search for evidence easier and more straight-forward for practitioners.

           b) Hierarchy typically places evidence in the following order: (1) randomized controlled trials and certain kinds of systematic reviews, (2) cohort and ecological studies, (3) case-control studies, (4) case series, and finally (5) expert opinion, bench research or pathophysiologic rationale.

      3. Critically appraise the evidence for validity, impact and applicability.

      4. Integrate the appraisal with clinical expertise and the patient's and client's unique biology, values, and circumstances.

The best evidence of efficacy of a particular regimen is well-designed studies, which may be found on drug labels, published in the literature as randomized controlled trials, or performed in a clinical setting. Drug labels can be found on company websites, or data generated for the label can be found in Freedom of Information (FOI) Summaries available on the Food and Drug Administration Center for Veterinary Medicine website. The FOI summary includes a synopsis of the studies performed to demonstrate safety and efficacy in order to get label approval. FOIs are listed at http://www.fda.gov/cvm/FOI/efoi.html. The importance of a well-designed study cannot be overemphasized, as poorly designed, poorly randomized, poorly controlled studies do not reveal information of enough quality on which to make a therapeutic decision. There are a number of clinical trials reported in the literature on sheep and goats treated with antimicrobials, but each study must be scrutinized as to the study design, the regimen used, the form of disease (applicability to your animal setting), the population of animals, and so on, before the results can be applied to your patient or group of patients.

In the absence of, or in combination with, results from clinical trials, knowledge of pharmacokinetics, pharmacodynamics, and susceptibility data can be put together to come up with an antimicrobial regimen that is likely to lead to therapeutic success. This knowledge can also lead to the conclusion that a particular regimen is unlikely to lead to clinical success and should therefore be avoided, whether it's a drug, a dose, or a frequency of administration.

6. Are there legal ramifications to a particular drug regimen?

If the drug regimen that has been designed is on an approved drug label, the choice to use that regimen is easy. If the regimen is not on an approved label, in food producing animals, there are restrictions on certain extralabel uses (see section in this proceedings on "Drug Regulations for the Bovine Practitioner" for more details), including a group of drugs that may never be used in an extralabel manner in food animals. As regulatory and legislative scrutiny of antimicrobial use increases, there may be further restrictions on antimicrobial use, so the astute veterinarian will stay abreast of these changes in order to protect their clients interests and in order to continue to produce the safest food supply in the world.

References available on request