Rational therapeutics (Proceedings)


Rational therapeutics (Proceedings)

Nov 01, 2009

Administering pharmaceutical agents is one of the most frequent and most important activities of the bovine veterinarian. Often we use drugs without really knowing or even considering whether we are using them in the most rational manner given the clinical circumstances we are facing. In this paper, I would like to review some pharmacologic principles that will help us make more rational therapeutic decisions. Rather than trying to thoroughly address any particular aspect of pharmacology and therapeutics from start to finish, I will attempt to answer some practical, clinically important questions concerning therapeutics in cattle. Because antimicrobial drugs are the most frequently administered type of drug in bovine practice, I will concentrate on this class of drugs.

Which is more effective, a long acting formulation which produces a lower concentration for a longer period of time or a shorter acting product that produces a higher peak concentration? And the answer to this question is "that depends." Below in figure 1, we see the hypothetical plasma concentration curve of two drugs, A and B. In this figure, the peak concentration of both drugs is above the MIC. To determine which pharmacokinetic profile would be the most favorable, we need to know what type of antibody we are discussing. Antibiotics can be divided into two main categories based on their mechanisms of action; time-dependent antimicrobials and concentration dependent antimicrobials. The effectiveness of time-dependent antimicrobials depends on the time above the MIC. Examples of time-dependent antimicrobials include beta-lactam's (penicillins, cephalosporins), macrolides (erythromycin,tilmicosin,tulathromycin), florfenicol and tetracyclines. The effectiveness of concentration-dependent antimicrobials depends on the peak concentration. Examples of concentration dependent antimicrobials include aminoglycosides (gentamicin) and fluoroquinolones (enrofloxacin, marbofloxacin). For time-dependent antimicrobials the pharmacokinetic profile of drug B in the figure is preferred. For concentration dependent antimicrobials, the pharmacokinetic profile of drug A is preferred. For the aminoglycosides, there is another advantage of utilizing a dose regime that yields a pharmacokinetic profile like drug A. While the efficacy of the aminoglycosides is related to the peak concentration, the toxicity is related to the trough concentration. Therefore, not only are aminoglycosides more effective when administered in large doses to produce high serum concentrations for short periods, but the toxicity is reduced by allowing the trough concentration to drop as low as possible. A long acting preparation of an aminoglycosides which maintained a rather steady concentration of drug above the MIC would be less effective and more toxic.

Does this mean that long acting formulations are always best when administering time-dependent antimicrobials? The answer is "usually", but the concentration must be above the MIC. As you can see from the figure below, the MIC can be determined for each bacterial isolates. The duration of effective antimicrobial concentration depends on the pharmacologic properties of the antimicrobial as well as the MIC of the organism. In the example the drug is florfenicol and the organisms are pathogens of swine.. The MIC 90 for some of the organisms is quite different than for the others. Therefore, in order to keep the drug concentration above the MIC for S suis and B bronchoseptica, florfenicol would need to be administered every 24 hours, but for the other 3 organisms, administering the drug every 48 hours would be sufficient.