Small Ruminant Antimicrobial Decision-Making: Regimen Design
ACVIM 2008
Virginia R. Fajt, DVM, PhD, DACVCP
College Station, TX, USA

Introduction

Traditionally, we have assumed that if a bacterial pathogen is "susceptible" to an antimicrobial, we just pick a dose and regimen, 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 the antimicrobials we do 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. Risk-benefit analysis is performed every day by veterinarians who used any pharmaceutical in an animal, and the following proceedings will help in making those decisions.

Prudent Use of Antimicrobials

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.1

 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.

Questions to Ask

When designing antimicrobial regimens, answers to the following questions will guide your selection of drug as well as design of the regimen:

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 (see author's manuscript in these proceedings on "Small Ruminant Antimicrobial Decision-Making: Interpreting Susceptibility Results" for more information)?

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

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

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

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 encountering pharmacokinetic data, it is important to recognize that often mean data are presented, and these mean data are usually determined in healthy young animals.

Important Terminology

Understanding the meaning of pharmacokinetic terminology will assure that you interpret drug labels, published papers, and drug monographs and technical reports correctly. The following are common terms and parameters used in pharmacokinetics:

 Cmax: Peak serum/plasma concentration observed in experimental animals

 T1/2β: Elimination half-life (time for serum concentration to decrease by 50%)

 T1/2α: 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

Published Pharmacokinetic Data in Small Ruminants

Pharmacokinetic data on sheep and goats are available on a number of drugs. PK data on drugs commonly used in the U.S. include:

 In goats and sheep: amikacin, ampicillin, amoxicillin, ceftiofur, florfenicol, oxytetracycline, sulfadimethoxine, sulfamethazine, trimethoprim, and tylosin

 In goats only: doxycycline, erythromycin, gentamicin, and sulfamethazine

 In sheep only: dicloxacillin, doxycycline, lincomycin, minocycline, penicillin, neomycin, spectinomycin, and tilmicosin

There are also published data on several fluoroquinolones in sheep and goats, but these drugs are currently prohibited in sheep and goats in the U.S.

Pharmacodynamics

A review of numerous sources in the literature reveals the following recommendations for assisting in regimen design for various antimicrobial groups. These recommendations are based on retrospective studies mainly 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 clarification of indices for different pathogen-drug combinations.

Drug Group / Parameter / Values Recommended

 Beta-lactams (penicillins, cephalosporins)

 T>MICT>MIC close to 100% for serious gram-negative infections, in neutropenic animals

 T>MIC 30-70% for gram-positive infection

 Macrolides such as erythromycin

 T>MIC

 Macrolides such as tilmicosin

 Unknown/unreported

 Macrolides such as azithromycin

 Debate over T>MIC vs. AUC:MIC

 Tetracyclines such as oxytetracycline

 Not well studied, assumed to be T>MIC

 Target unknown

 Fluoroquinolones AUC: MIC, often reported as AUC0-24

 Average target of 125 Aminoglycosides Cmax:MIC

 Target of 8-10XSulfonamides

 Assumed to be T>MIC due to their bacteriostatic nature but not well-established

 Target unknown

Susceptibility

Qualitative and quantitative measures of the concentration of drug required to inhibit bacterial growth are the goal of susceptibility testing. A more in-depth discussion is presented by this author elsewhere in these proceedings.

Clinical Data

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 Approvals

Sources of information on drugs that are approved in sheep and goats include drug labels (many of which can be found on company websites) as well as the 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.

Antimicrobials currently approved in goats and sheep in the United States include (example labeled dose provided; not all labels have the same dose so reading the label is important):

 Ceftiofur (Naxcel, injectable) for respiratory disease (Mannheimia haemolytica and Pasteurella multocida) in goats and sheep

 0.5 to 1.0 mg/lb IM for 3 days

 Additional treatments may be given on days 4 and 5 for animals which do not show satisfactory response

 Neomycin (oral, various products) for colibacillosis (E. coli) in goats and sheep

 One product: 10 mg/lb/day in divided doses, maximum 14 days

 Chlortetracycline (in feed) for growth promotion (20-50 g/ton), abortion control (Campylobacter) in sheep

 One product: Breeding sheep: 80 mg/head/day

 Oxytetracycline (for use in water) for enteritis (E. coli) and pneumonia (P. multocida) in sheep

 10 mg/lb daily for 7 to 14 days

 Penicillin (injectable, various products) for pneumonia (P. multocida) in sheep

 One product: 3000 units/lb/day not to exceed 7 days

 Tilmicosin (Micotil, injectable) for respiratory disease (M. haemolytica) in sheep

 10 mg/kg once

Published Randomized Controlled Trials

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-House Randomized Trials

Producers with large operations may be capable of making their own comparisons of antimicrobials and regimens, as long as reasonable case definitions can be made (e.g., a case of pneumonia might be defined as an animal with fever, depression, and dyspnea, or whatever characteristics you might use to clinically diagnose). Randomization between treatment groups is relatively easy to perform with commercial spreadsheet software, and definitions of therapeutic success (or perhaps just survival) can be compared between treatment groups.

References

1.  Andes D, WA Craig. 2002, Animal model pharmacokinetics and pharmacodynamics: a critical review, International Journal of Antimicrobial Agents, 19:261-267.

2.  Cockcroft P, M Holmes. 2003, Handbook of Evidence-Based Veterinary Medicine. Oxford: Blackwell Publishing. American Veterinary Medical Association, http://www.avma.org/issues/policy/jtua.asp, accessed January 30, 2008.

3.  Food and Drug Administration Center for Veterinary Medicine, FDA Approved Drug Products, http://dil.vetmed.vt.edu, accessed January 30, 2008.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Virginia Fajt, DVM, PhD, DACVCP
Texas A&M University
College Station, TX


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