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Guidelines for Clinical Use of Antimicrobial Agents


The rational therapeutic management of infection is based on selection of an appropriate antimicrobial agent and course of treatment that will inhibit or destroy the specific pathogens without compromising the animal's response. The pathogen should be inhibited swiftly, or ideally killed, so that the host can begin recovery without relapse and emergence of microbial resistance is avoided. The risk of drug-induced toxicity may also be reduced. This may require doses that are higher or administration that is more frequent as pathogens develop resistance.

Successful antimicrobial therapy begins with the decision to treat. The need to avoid indiscriminant treatment with antimicrobials is increasingly important. Veterinarians should avoid giving medication unless the evidence of infection justifies treatment. For some tissues, the presence of bacteria does not necessarily indicate infection. Normal flora must distinguished from pathogenic microbes. The extent of growth may be used to confirm the presence of infection; for example, the presence of bacteria in urine collected by cystocentesis is not considered an infection unless >100,000 colony forming units are present. Presence of infection alone does not justify treatment with antimicrobials. Some cutaneous abscesses can be better managed by local treatment than by antimicrobial therapy.

Successful treatment of infection (ie, resolution of clinical signs) does not avoid the advent of resistance. In healthy, immunocompetent animals, adequate reduction of pathogen inoculum might be sufficient for the host to overcome residual microbial growth, whereas in the patient at risk, this residual growth may emerge as a resistant population after an initial response.

Once a decision is made to treat an infection, 4 key principles should be followed to ensure that concentrations sufficient to assure microbial death occur at the site of infection: 1) The pathogen(s) should be identified and characterized, including antimicrobial susceptibility, so that the drug matches the organism as closely as possible, narrowing the spectrum of drug used. 2) Among the “susceptible” drugs, one that is more likely to penetrate the infected tissue, considering the host and microbial responses to infection, should be chosen. Often, this requires selecting a drug that is lipid soluble. 3) The dosing regimen must be individualized to assure that the drug reaches the site at effective concentrations without harming the patient. Even if a microbe is historically considered “susceptible,” the amount of drug required to effectively inhibit its growth is likely to be greater now than it was when the drug was originally approved. The dose rate (mg/kg), frequency, and route of administration must be chosen based on what is needed to inhibit the microbe and what is achieved in the patient, ie, based on integration of pharmacodynamics and pharmacokinetics. Identifying the most appropriate duration can be problematic. Short-term therapy at high doses and short intervals should be sufficient to kill the infecting microbe, negating the need for longer duration therapy at lower concentrations or shorter intervals that might facilitate resistance. However, for slower growing organisms or nonhealing tissues, longer durations might be prudent. The longterm use of antimicrobials for infections associated with an underlying cause is particularly problematic. Resistance is more likely in these patients, particularly if dosing regimens are (inadvertently) designed for promotion rather than avoidance of resistance. 4) Specific and appropriate supportive or adjunctive therapy that enhances the animal's ability to overcome the infection and associated disease conditions cannot be overemphasized.

Ideally, a dosing regimen is based on the minimal inhibitory concentration (MIC) or even the minimal antibiotic concentration (MAC) of an antibacterial agent for a particular pathogen. Depending on the antimicrobial, plasma or tissue drug concentrations should either markedly exceed the MIC by 10- to 12-fold (for dose- or concentration-dependent antimicrobials, such as the aminoglycosides and the fluorinated quinolones) or be above the MIC for most (50–75%) of the dosing interval (time-dependent antibiotics, such as β-lactams and most “bacteriostatic” drugs). To compensate for drug disposition to tissue sites and the effect of host factors on antibiotics, dosages for most drugs should result in plasma drug concentrations that are several times higher than the calculated dose-dependent or time dependent MIC in the infected tissues or fluids. For dose-dependent drugs, efficacy is enhanced by increasing the dose; for time-dependent drugs, therapeutic efficacy is enhanced by shortening the dosing interval.

In today's infectious disease environment, appropriate design of a dosing regimen should depend not on labeled doses, but rather on access to information regarding the current pharmacodynamics of the infecting microbe (ie, MIC from the pathogen cultured from the patient, or the MIC90 of a sample population of the pathogen collected from the target animal). This information must be integrated with the pharmacokinetics of the drug measured in a sample population of the species of interest. Appropriate pharmacokinetic parameters upon which the dosing regimen should be designed include maximum plasma concentration or Cmax for concentration-dependent drugs and Cmax and drug elimination half-life for time-dependent drugs. Supportive information for design of dosing regimens often can be acquired from the literature. For example, if the MIC of a Pseudomonas aeruginosa isolate for amikacin is 4 μg/mL, the does should be designed so that peak plasma drug concentrations achieve 40–48 μg/mL. The dose should be adjusted further if the infection is in a tissue not well penetrated by aminoglycosides or in the presence of marked inflammatory debris. Cephalexin is a time-dependent drug. If Staphylococcus intermedius cultured from a skin biopsy in a dog has an MIC of 2 μg/mL, then the dosing regimen should be designed to assure that drug concentrations are above 2 μg/mL for at least 50% (and ideally 75%) of the dosing interval. This may be difficult, because cephalexin's half-life is only 1.5 hr. Using data reported in the literature for dogs, an oral dose of 22 mg/kg of cephalexin will achieve a Cmax of 25 μg/mL. In one half-life, concentrations (μg/mL) will decline to 12.5; in the second, to 6.25, in the third to 3.125, with concentrations below target by the fourth half-life, or 6 hr. Thus, 3 elimination half-lives, or 4.5 hr can elapse before the target MIC is reached and the next dose should occur by 9 hr. Shortening the interval is generally more cost effective than increasing the dose, particularly for drugs with a short half-life—for each 2 half-lives to be added to the dosing interval, the dose must be doubled.

The integration of pharmacokinetics and pharmacodynamics can also be accomplished based on package insert information of more recently approved drugs. For example, for concentration-dependent drugs, the Cmax should be at least 10 × the MIC90 of the target microorganism for that drug. For time-dependent drugs, plasma drug concentrations should be above the MIC90 of the infecting microbe for ≥50% of the doing interval.

Requirements for Successful Antimicrobial Therapy

Successful chemotherapy usually requires a specific diagnosis, even though a reasonable preliminary diagnosis is often all that is possible, at least initially.

Treatment should be aimed at a specific pathogen whenever feasible. However, polymicrobial infections are common. The ideal is a conclusive microbiologic diagnosis, but frequently this must be presumptive (at least initially), and treatment must be based on experience. Rational deduction may be necessary under field conditions. Empirical antimicrobial therapy, that is, the ability to predict the infecting microbe based on site of infection and the drugs to which that microbe are susceptible, without the support of culture and susceptibility data, is increasingly problematic. Older data upon which empirical therapy is based often failed to discriminate between infecting pathogens and normal flora, making it difficult to predict the actual cause of infection. More importantly, microbial resistance has eliminated many drugs that originally were considered effective against the infecting pathogen.

The use of cytology should not be overlooked. Examination of a direct smear stained with Wright's or Gram's stain may help to establish the types of pathogens involved (gram-positive or gram-negative rods or cocci).

Isolation and characterization of the causative pathogen, susceptibility testing, and determination of the MIC provide a sound foundation from which to select the antimicrobial drug, as well as the dosage regimen. However, under field conditions, it is often difficult to attain laboratory support for antimicrobial therapy. Package insert data or recent literature may be helpful for designing a dosing regimen under these conditions.

Ideally, the selection of an appropriate drug and dosing regimen will be based on the minimum inhibitory concentration (MIC) of the drug toward an isolate of the infecting organism that has been cultured from the patient. However, some organisms are too slow-growing for MIC determination, limiting reports to S (susceptible), I (intermediate), or R (resistant) designation. The validity of susceptibility data is only as good as the sample itself. Care should be taken to assure that the sample reflects the infected tissue and that proper cleansing accompanies sample collection. Differences in testing among laboratories can markedly impact interpretation. Ideally, testing will be performed by a laboratory that follows guidelines and interpretive criteria promulgated by the Clinical Laboratory Standards Institute.

Data from even appropriately collected samples tested under ideal conditions remain subject to limitations. Testing cannot take into account the impact of distribution to the site of infection, host factors such as inflammation, or microbial factors, including the size of the inoculum. These and other factors may indicate a need to modify the dosing regimen to assure adequate concentrations at the site of infection. Positive factors not evident during testing include the impact of subinhibitory concentrations (post-antibiotic effects), which may provide persistent antimicrobial effects and facilitate host removal of bacteria. Persistent effects have been demonstrated for penicillins, cephalosporins, macrolides, tetracyclines, aminoglycosides, and several other antibacterial agents. Susceptibility testing also does not take into account the impact of the time course of drug concentrations on antimicrobial efficacy.

Among the factors to be considered are the causative microorganism(s), results of sensitivity tests, pathogenicity of organisms, pathologic lesions, acuteness of infection, pharmacokinetics of the drug(s) indicated, expense, potential drug toxicity, organic dysfunctions (especially kidney and liver function), and possible interactions with drugs administered concurrently.

The integration of pharmacokinetics and pharmacodynamics should facilitate the selection of both drug and dosing regimen. Concentration-dependent drugs should be compared based on the ratio of Cmax of each drug and the MIC or MIC90 of the infecting (or assumed infecting) organism. For time-dependent drugs, comparisons are made in the time that elapses as plasma drug concentrations decline from the Cmax to the MIC of the infecting organisms.

The dosage selected should result in adequate therapeutic concentrations at the site(s) of infection for sufficient time without causing side effects or toxicity. For concentration-dependent drugs, higher dosages that assure the peak drug concentration is 10–12 times the MIC of the infecting organism are more likely to enhance therapeutic success than are shorter intervals. For β-lactam and other time-dependent drugs, therapeutic success appears to be greater if the concentration remains above the MIC for about 50% to 75% of the dosing interval, and efficacy is likely to be improved more by decreasing the interval than by increasing the dose. The advocated dosage schedules should be carefully followed for at least 7 days (although response should be apparent in 3–4 days for most infections), or longer if needed, to ensure elimination of the pathogen and to prevent relapse, reinfection, or development of antimicrobial resistance.

Supportive treatment, optimal nutrition, and general nursing care are often critical for successful management of infectious disease. Ancillary treatment might include the use of anti-inflammatory agents, antidiarrheal preparations, expectorants, bronchodilators, inotropic agents, urinary acidifiers and alkalinizers, immunopotentiators, and fluid and electrolyte replacement. Attention should be given to caloric and nutrient intake, especially of protein and vitamins. These nutrients play a cardinal role in immune responsiveness.

Combination Therapy

Treatment with antimicrobial combinations may be necessary in certain cases. The administration of 2 or more agents may be beneficial in the following situations: 1) to treat mixed bacterial infections in which the organisms are not susceptible to a common agent, 2) to achieve synergistic antimicrobial activity against particularly resistant strains (eg, Pseudomonas aeruginosa), 3) to overcome bacterial tolerance, 4) to prevent the emergence of drug resistance, 5) to minimize toxicity, or 6) to prevent inactivation of an antibiotic by enzymes produced by other bacteria that are present.

Additive or synergistic effects are seen when antibacterial agents are used in combination, but antagonism may also emerge, sometimes with serious consequences. Generally, bacteriostatic agents act in an additive fashion with one another, whereas bactericidal agents are often synergistic when combined. However, the effects of several bactericidal antibiotics are substantially impaired by simultaneous use of drugs that impair microbial growth or “bacteriostatic” drugs (eg, most ribosomal inhibitors). This is a general guideline only; many exceptions are known, and confounding factors also play a role. Classification of antimicrobials as bactericidal or bacteriostatic can also be misleading because “bactericidal” drugs can be rendered bacteriostatic if sufficient drug concentrations are not achieved at the site of infection. However, in general, the following common antimicrobials at MIC concentrations are likely to be bactericidal: penicillins, cephalosporins, aminoglycosides, trimethoprim/sulfonamides, nitrofurans, metronidazole, and quinolones. The following antimicrobials at usual concentrations are generally bacteriostatic: tetracyclines, chloramphenicol, macrolides, lincosamides, spectinomycin, and the sulfonamides.

Ideally, antimicrobial selection should be based on mechanisms of action that are different and on spectra of activity that are complementary. β-Lactams are often selected because their action is unique and not only complements other drugs but also facilitates movement of other drugs through the damaged cell wall into the microbe. Examples of combination therapy for mixed infections include the use of clindamycin, metronidazole, or the semisynthetic penicillins for their anaerobic coverage in combination with aminoglycosides for their gram-negative efficacy. Synergism against certain bacterial pathogens frequently can be achieved with combinations of penicillins or cephalosporins and aminoglycosides. The combined use of trimethoprim with selected sulfonamides or clavulanic acid with other β-lactams are other examples of synergistic effects.

Preventing the development of resistance with combination antimicrobial therapy is best exemplified by the use of carbenicillin or amikacin together with gentamicin or tobramycin for the treatment of Pseudomonas infections.

Bacterial enzymatic inactivation of β-lactam antibiotics, such as the penicillins and cephalosporins, can be decreased by concurrent administration of a β-lactamase inhibitor, such as clavulanic acid or sulbactam.

Mechanisms of Action

Antimicrobial agents affect susceptible organisms in various ways, and bacteria sometimes protect themselves from these destructive effects by a variety of means. The major mechanisms of action of antimicrobial agents, with examples of each type, are as follows (also see Antibacterial Agents): 1) inhibition of cell wall synthesis: penicillins, cephalosporins and cephamycins, vancomycin, bacitracin, cycloserine; 2) impairment of cell membrane function: polymyxin B, colistin, tyrocidin, amphotericin, nystatin; 3) inhibition of protein synthesis: tetracyclines, aminoglycosides, spectinomycin, chloramphenicol, macrolides, lincosamides; 4) inhibition of DNA synthesis and replication: novobiocin, quinolones, griseofulvin; 5) inhibition of DNA-dependent RNA polymerase: rifamycins; 6) inhibition of folinic acid and consequently DNA synthesis: sulfonamides, trimethoprim.

Reasons for Failure of Antibacterial Therapy

Possible reasons for failure of antibacterial therapy include the following: 1) The diagnosis was incorrect, eg, viral and not bacterial infection. 2) The organisms were not susceptible to the action of the antibiotic that was selected, or they were in static phase and therefore refractory (“persisters”). 3) Although originally susceptible, the bacteria developed resistance. 4) The antibiotic(s) was insufficient for multiple pathogens. 5) A combination of incompatible antibiotics was administered. 6) Superinfection by a resistant opportunistic pathogen occurred. 7) Reinfection by the original or by other pathogenic bacteria occurred. 8) Drainage was inadequate in surgical infections, or a foreign body was present. 9) Perfusion and penetration to the site of infection were impaired because of inflammation, cellular debris, tissue destruction, abscessation, etc. 10) The organism is intracellular in location and able to avoid detrimental effects by phagocytic cells. 11) Defense mechanisms (specific and nonspecific) of the animal were compromised by disease, malnutrition, or concurrent therapy. 12) Detrimental changes, such as hypoxia, acidosis, or accumulation of tissue debris, developed in infected tissue, which reduced the effectiveness of the antibiotic or sulfonamide. 13) An inappropriate route of administration was selected or an incorrect dosage regimen was followed because the pharmacokinetic characteristics of the antimicrobial drug were not appreciated. 14) Expired or substandard products were used. 15) The selected agent had to be withdrawn because of adverse effects. 16) Interaction of the selected antimicrobial agent(s) with other concurrently administered drugs occurred, which diminished the antimicrobial effect or altered the pharmacokinetics of the agent(s). 17) The prescribed dosage regimen was not reliably followed (lack of owner compliance). 18) Supportive therapy was inadequate. 19) Nutritional deficits were not corrected. 20) Nursing care was substandard, and the stress associated with the disease process was not reduced. 21) Predisposing management factors were not corrected.

Resistance of Microorganisms to Antibacterial Agents

The emergence of bacteria resistant to antimicrobial agents within an animal population or during therapy is of great concern. Resistance requires that a previously successful therapeutic approach be discarded, and a suitable alternative antimicrobial drug must be sought. In addition, there frequently is concern from an epidemiologic and public health point of view.

There are differences in use of the term “antibiotic resistance.” Natural resistance implies an intrinsic property in an organism that confers resistance, whereas acquired resistance suggests that an organism has obtained, by one mechanism or another, the means to survive exposure to an antimicrobial agent. Chromosomal, extrachromosomal, and transpositional resistance are terms used when the genetic determinants are on chromosomes, plasmids, or transposons, respectively. Phenotypic resistance, due to differences in physical and functional characteristics, is best exemplified by the bacterial-wall-defective variants (such as L-forms, spheroblasts, and protoplasts) and by the impermeability of the cell walls of some gram-negative bacteria due to very narrow conduits or porins. Microbiologic resistance implies an increase in the usual MIC range to levels that are too high to be reached at standard therapeutic dose rates. Clinical resistance, for which there may be many causes, is a general term used to describe unexpected lack of response to treatment in a clinical case.

Causes of conditional resistance include the physiologic state of the organism, antagonism or inactivation by a second agent, inactivation of the drug by enzymes produced by other bacteria at the site of infection, antagonism of the effect of the antimicrobial agent due to tissue debris or a foreign body, and inhibition of antibacterial action because of a low pH or hypoxia.

Resistance may also be classified in terms of the mechanisms of acquisition. Examples include selection of resistant clones, chromosomal mutation, phage transduction, and R-factor acquisition by conjugation.

The biochemical basis for microbial resistance to antibacterial agents permits a further approach to distinguishing various forms of resistance. Examples include the synthesis of destructive enzymes, altered receptor site or enzyme specificity, alternate metabolic pathways, modified carrier systems, and various barriers to penetration.

The means by which bacteria can protect themselves against antimicrobials include the following: 1) increased production of inactivating enzymes, which may be constitutive or inducible, eg, penicillins, cephalosporins, aminoglycosides, chloramphenicol; 2) defective production of autolytic enzymes (“tolerance”), eg, penicillins and cephalosporins; 3) alteration of the specific configuration of target sites, eg, oxacillin, cloxacillin, macrolides, lincomycin, streptomycin; 4) decreased enzyme affinity, eg, trimethoprim; 5) induction of membrane transport systems to remove the antibacterial, eg, tetracyclines; 6) inhibition or changes in membrane transport systems to prevent entry of the antibacterial, eg, aminoglycosides; 7) utilization of alternative metabolic pathways, eg, sulfonamides, trimethoprim; 8) increased synthesis of a key metabolic intermediate, eg, para-aminobenzoic acid in sulfonamide resistance; and 9) development of impermeable cell walls with extremely narrow porins, eg, Pseudomonas aeruginosa in response to many antibiotics.

In each of these cases, a modification of protein synthesis and enzyme activity is necessary to confer resistance; thus, this adaptation is genetically determined.

Bacteria have several types of genetic structures that may confer resistance—chromosomes, mobile elements (including plasmids), and transposons. Integrons are gene-capturing systems found in plasmids, chromosomes, and transposons. Through integrons, gene cassettes imparting resistance to multiple drugs can be either incorporated in chromosomal or plasmid DNA and subsequently expressed or further disseminated.

Chromosomal resistance to antibacterial agents depends on a mutation in the bacterial genes that leads to resistance to particular antimicrobial agents. In this case, the antibacterial drugs act only as selective agents that allow the resistant mutants to emerge either by a single step or sequential mutations. Their genesis is independent of the presence of the agent. Mutated bacteria are often metabolically deranged and are at a selective growth disadvantage; they usually disappear with time in the absence of the antimicrobial agent.

Plasmid-mediated resistance (R-factor or acquired resistance) is far more complex. Plasmids are not essential for survival but do carry genetic determinants that confer both antibiotic resistance and virulence on bacteria. The number of copies of plasmids carrying the gene for resistance varies. Within a plasmid, the number of genes that confer resistance also can vary. Plasmids may contain 20–500 genes that can carry resistance to a number of different antibacterial agents (3–6 is common; up to 9 have been recorded) and specific virulence factors. Many specific plasmids have been isolated, characterized, and identified. The 3 possible mechanisms by which plasmids may migrate from one bacterium to another are transformation, transduction, and conjugation. In transformation, naked DNA seems to pass from the donor to the recipient through the growth medium. This process appears to be confined to a limited range of bacteria. In transduction, the transfer is mediated by a bacteriophage that makes use of its specialized molecular equipment adapted for inserting DNA into recipient bacteria. Normally, it is phage DNA that is transferred; in certain cases, however, some DNA from the episome in the bacterial cell replaces the proper phage nucleic acid sequence. Phage-mediated transduction occurs in some gram-positive (especially Staphylococcus aureus) as well as gram-negative species. In conjugation, the DNA passes from the donor cell to the recipient via a bridge formed during direct cell-to-cell contact. This is the most sophisticated form of transmission because, for transfer to occur at all, the donor must have the necessary surface appendage (sex pilus) to form the bridge. This pilus is coded for by a resistance transfer factor on the plasmid and is called a conjugative sequence (vs a nonconjugative plasmid without a resistance transfer factor).

General facets of conjugation make it an important process for gene transfer under natural conditions. Many types of bacteria can act as recipients, and resistance can pass freely from organisms normally saprophytic in the gut of animals to pathogenic bacteria. Transfer among Pasteurella and Pseudomonas spp seems to be less efficient. In general, transfer occurs more frequently between gram-negative bacteria and only rarely between gram-positive organisms. Conjugation allows the passage of a number of distinct genes at one time. Thus, resistance to several antibiotics, all mediated by different biochemical means, may be acquired in a single step. The great efficiency of the conjugation process makes the probability of gene transfer to a super-infecting pathogen high.

Genetic sequences capable of coding for resistance can migrate from a plasmid to a chromosome and then back to the plasmid. These sequences are then transpositional and are known as transposons. A number of transposons responsible for the transfer of R-factor resistance also have been isolated, characterized, and identified.

The clinical relevance of plasmid-mediated resistance principally concerns the following: 1) intestinal infections, in which the reservoir of R-factors may be carried by saprophytic flora in the gut; 2) the use of low levels of antibiotics (as in animal feeds) or improper dosing regimens, which may lead to a high incidence of R-factors in a given population; and 3) the indiscriminate use of antibiotics, which may eliminate the effectiveness of many antimicrobial agents in the future.

The following guidelines will help to minimize the emergence of bacterial resistance: 1) A broad-spectrum antibacterial agent should not be used if a narrow-spectrum agent is also active against the causative organism(s). 2) Information regarding endemic infections and susceptibility patterns should be obtained and considered when choosing an antibiotic. 3) Appropriate dosing regimens should be used with the intent to kill all infecting microbes. 4) When a combination regimen is used to prevent the development of resistant strains, individual agents should be used at full dosage. 5) Antibacterials for topical application should be selected from those against which development of resistance is uncommon. 6) For prophylaxis, an antibacterial agent that prevents colonization of a specific organism or eradicates it shortly after it has become established should be used. 7) To the extent that it is consistent with reasonable practice, every effort should be made to use antibiotics only when the medical indications are clear and to avoid overuse of newer agents when already available agents are effective.

Role of Veterinarians in Antimicrobial Resistance

Two major aspects of antimicrobial use concern veterinarians—the likelihood of causing a pathogenic organism to become resistant to current antimicrobial therapy and the likelihood of commensal organisms (generally GI) becoming resistant to future antimicrobial therapy. The former largely can be prevented by assuring that adequate concentrations of the appropriate drug reach the targeted site. Although the latter concern has been less problematic in small animals, the risk of transfer of resistant commensal organisms to humans has increased in the last decade, and the focus has shifted to include antibiotics in food production and companion animals. However, these risks are difficult to quantitate. The use of antibiotics in food animals, including use as growth promotants, contributes to the transfer of resistance genes among bacteria and ultimately from food animals to humans, where the organisms become pathogenic. Additionally, contamination of food with resistant pathogenic bacteria during the processing of food is a concern. Carcasses may be contaminated at slaughter and processing, and subsequent improper handling or cooking of the product may lead to infection in people. The development of resistant pathogenic bacteria in poultry treated with fluoroquinolones has been documented. Infection of the human population is of particular concern because the bacterial resistance created in the animal following veterinary use of a drug or drug class may result in resistance to human drugs of the same class. Whereas the organism developing resistance might be nonpathogenic, transfer of the resistance gene to other bacteria in the human intestinal tract may result in a pathogenic organism becoming resistant and ultimately in therapeutic failure in the human patient.

When selecting drug therapies for food animals, veterinarians must be aware of the potential for resistance. Use of antibacterial drugs should be in the context of a valid veterinarian-client-patient relationship. Selection should be based on all information available (clinical signs, experience, laboratory data, physical examination findings, culture and sensitivity data). Pathogens should be identified, and drugs with the narrowest spectrum of activity with known effectiveness against the pathogen should be used. Client education is important in preventing unnecessary use of antibacterial agents (such as using “leftover” antibacterial drugs to treat a new occurrence of disease). In addition to judicious use, veterinarians should be proactive in the education of their clients, including proper withdrawal guidelines of any prescribed drugs, and should administer drugs in the proper classes, at proper doses, and through appropriate routes. (Also see Antimicrobial Feed Additives.)

Last full review/revision March 2012 by Dawn Merton Boothe, DVM, PhD, DACVIM, DACVCP

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