Introduction

Effective antimicrobial therapy requires that concentrations of antimicrobial agents reach the environment of the organism (i.e., foci of infection) at levels that reduce bacterial numbers. Many host and drug factors influence the penetration of antibiotics into the site of concern. The concentration of drug reached depends on rate and extent of drug absorption, volume of distribution, plasma and tissue protein binding, bio-transformation, rate of excretion, and transfer of drug through membranes, and a multitude of other obstacles. The rate of transport of an antimicrobial across membrane barriers, and between compartments is a function of the concentrations of drug in those compartments and the drug's ability to permeate tissues.

Pharmacodynamic determinants of effective antimicrobial therapy include:

1.  The ability of the drug to enter the local environment of infection;

2.  The intrinsic antimicrobial activity of the drug against the infecting respiratory pathogen;

3.  The bactericidal activity of the drug;

4.  The stability of drug activity in the presence of common bacterial resistance mechanisms;

5.  And the absence of major organ toxicity.

Antimicrobial regimens should be formulated rationally for each patient and not simply following recipes. Specific protocols for different patients will not necessarily be identical and protocols for an individual should be dynamic. Factors that help veterinarians formulate rational antimicrobial treatment include the identity or suspected identity of the organism(s) involved, the antimicrobial susceptibility of the organism(s), the host's response to the infection and medication selected, other treatment(s), etc.

It is important to realize that more than one regimen may be appropriate. Even if the same principles are followed, different regimens can be rationally developed and clinical outcome may be identical. If an infection exists at the time treatment is begun, the drug(s) is used therapeutically and therapeutic principles should be followed. If an infection does not exist when treatment is begun, the drug(s) is used prophylactically and prophylactic principles should be followed. A principled approach to rational selection of a regimen does not guarantee absolute success, but it does allow the drugs chosen to have a more likely chance of success.

Therapeutic principles include assessment of the host's response to infectious agents, documentation of infection, determination of antimicrobial susceptibility in vitro, and use of an appropriate dosage regimen. In addition, the user should monitor results of treatment, investigate the causes of adverse reactions and attend to those adverse reactions, and restrict concurrent use of drugs.

Assessment of the host's response to infection is clinically subjective because diagnostic methods for clinical use are not currently available. Influence of inflammatory mediators on immune function, location of the infection, inoculum, organism involved, general condition of the patient, ancillary treatment to be used should be considered. Because professional clinical judgment is necessary for this assessment, and condition of the patient will change during treatment, dogmatic statements that incorporate these factors are not applicable to all patients. It is important to recognize the patient's own role in recovery and to not expect antimicrobial drugs to do something that they are not capable of doing.

Appropriate attempts should be made to document infection. Vegetative growth of bacteria is prerequisite for antimicrobial drugs to be indicated as a component of treatment. Most infectious conditions are accompanied by presence of vegetative microbes; some are caused by microbial byproducts while the causative agent is in a remote site or present in small numbers. Documentation of infection should be viewed as neither impossible nor unnecessary. If one were to follow a principled approach to rational therapeutics, the purpose of that documentation would be clarified and procedures to acquire needed information would become nearly routine. Initial and presumptive evidence is found in clinical signs when the patient is presented. Representative samples of material can usually be obtained for microscopic examination. Based on morphologic characteristics of the microbe(s), the type of inflammatory response, and clinical signs, a preliminary or working etiologic diagnosis can be proposed. Within a few minutes of obtaining that sample, microscopic evaluation can be completed and an appropriate antimicrobial drug can then be rationally selected for initial treatment. A sample of the material collected should be properly submitted for confirmatory identification and antimicrobial susceptibility in vitro if indicated. Results of those procedures will not be available when emergency treatment must be initiated. Those results are still useful for such things as 1) confirmation of initial choice of medication; 2) provision of alternative medication if initial choice was not successful; 3) provision of data-base for future reference. Antimicrobial susceptibility of some microbes is predictable (obligate anaerobes, most streptococcal species); for other microbes (especially gram-negative enteric aerobes) susceptibility is not predictable. For members of the latter group antimicrobial susceptibility in vitro should be determined. Results of those procedures are better for detecting drugs which are least desirable or that should be avoided than they are for selecting the best drug to use. Interpretation of those results is the responsibility of the attending veterinarian and should be done with discernment and wisdom about the drugs as well as about the patient.

When an antimicrobial drug is selected, it should be administered according to a regimen that will present the drug to the microbe for an adequate duration at concentrations that will inflict a harmful effect on the microbe. Therapeutic response will, therefore, be inherently linked to the organism and its susceptibility as well as to the dosage regimen used. The injury caused by some antimicrobial drugs can persist after harmful concentrations of the drug have subsided (post-antibiotic effect). Theoretically, it is desirable to obtain concentrations of the drug at the site of infection, that are lethal (bactericidal) to the microbe, in preference to concentrations that produce an inhibitory effect (bacteriostatic) on the microbe. Although true in theory, this is seldom true clinically as has been shown by studies with other species. The host's response must be relied upon for its importance to the clinical outcome.

The patient's response to the treatment must be monitored. How else would one know if the patient is responding or if the medication was appropriate? Such monitoring may be simple clinical observation of behavior or other grossly visible signs (ex., change in character of nasal discharge), or by another physiologic or morphologic response measurable clinically (ex., body temperature, white blood cell count, radiographic changes). Adverse reactions or side effects of the medication may be manifested and monitored by the same methods described above. Those adverse reactions should receive an appropriate response.

Incidence of adversity increases as the number of drugs concurrently administered increases. For that reason, concurrent use of multiple drugs should be limited to instances when that approach is clearly indicated. Few fixed-drug combinations are truly superior to single-drug protocols. Concurrent administration of multiple drugs may be indicated when 1) synergy is truly of clinical benefit; 2) bacterial resistance can be avoided; 3) antimicrobial spectrum can be extended to include multiple species of concern in life-threatening conditions or mixed-microbial infections. Multiple-drug regimens should not be used to try to compensate for diagnostic inaccuracy; they are not rational substitutes.

Ancillary or supportive measures instituted with primary care can also be of benefit to antimicrobial efficacy. Correction of cardiovascular shock will improve flow of blood to sites of administration and of infection; correction of acid-base imbalances may improve activity of several drugs that are susceptible to subtle changes of pH or oxygen tension; physical cleaning or debridement of a wound can greatly reduce the inoculum size and improve the microenvironment for activity of the drug.

Characteristic of Antimicrobial Classes

The relationship of the time profile to clinical efficacy is dependent on the class of compound. Data from animal models and human studies have shown that the clinical outcome of gram–negative bacteremia in granulocytopenic subjects and nosocomial pneumonia treated with beta-lactam antibiotics is significantly improved when the serum drug levels of these classes of antibiotics remains above the MIC of the pathogen for the whole dosing interval rather than for only a fraction of the dosing interval. These drugs are generally classified as time-dependent antimicrobials. This information favors constant infusion or frequent intermittent administration of beta-lactam antibiotics.

Aminoglycosides differ markedly from beta lactams in that their killing rate of bacilli is more rapid, and they tend to induce a prolonged post-antibiotic effect. Therefore, it is less important for aminoglycosides to maintain serum concentrations above the MIC during the entire dosing interval. The best predictors of a favorable clinical outcome after treatment with aminoglycosides are high peak concentrations (C_MAX) achieved in serum and high peak serum concentration to MIC ratio. Therefore, aminoglycosides need not be given in a frequent dosing schedule to maintain serum levels above the MIC. Twice or once daily aminoglycoside administration provides an adequate pharmacokinetic profile and, theoretically, reduces toxicity and the need for therapeutic monitoring.

Knowing the pharmacokinetic/pharmacodynamic relationship of the various classes of compounds, along with information regarding whether or not a compound may be effective against intracellular pathogens is of great value. Table 1 provides a generalization of the pertinent kinetic-dynamic information pertaining to the major classes of antimicrobial compounds.

Table 1. A generalization of the pertinent kinetic-dynamic information pertaining to the major classes of antimicrobial compounds. PAE, post-antibiotic effect.

The post-antibiotic drug effect (PAE) is an antimicrobial effect beyond the time that a drug is measurable. This activity is both drug and pathogen specific. Post-antibiotic activity is generally associated with compounds that interfere with either protein synthesis or nucleotide function (RNA or DNA) synthesis.

Although many drugs may not necessarily be solely bacteriostatic or bactericidal, they are classified within this table based upon their general tendency of action. In general, time above MIC is the critical pharmacokinetic parameter for bacteriostatic compounds while the activity of bactericidal compounds tends to be concentration/dependent.

In Vitro Tests

Culture and MIC determination are still the hallmarks of antimicrobial drug and dosage selection. The limitations of in vitro tests are numerous. Break points (sensitive, intermediate, resistant) are commonly based on clinical studies in other species. Improving the relevancy of this information is based on the correlation of the zones of inhibition to the MIC. This technique is highly dependent on laboratory conditions. MIC information provided by laboratories that follow the National Committee for Laboratory Standards guidelines provides greater confidence in dosing to control equine pathogens. However, realize that the multiple obstructions to efficacy are not included in the determination of these values, including the patient's individual responses to drugs.

Selection of the Appropriate Drug and Dosage

Initial selection of an antimicrobial drug can be effectively based on clinical information and cytology. At this time the dose comes into question and most often is selected on the known characteristics of resistance in the likely pathogens and the drug's pharmacokinetics (see Table 2).

Table 2. Suggested initial dosage regimens for antimicrobial drugs in horses.

References

1.  Brumbaugh GW. Antimicrobial therapy for the emergency equine patient. Proceedings 36th Annual Convention Am Assoc of Equine Practit. 1990:247-254.

2.  Bertone JJ, Antibiotics in equine respiratory disease. Veterinary Clinics of North America Equine Practice. 1997;13(3)501-517.