Rational therapeutics (Proceedings)

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.

Some drugs are available in several different formulations. One example is ceftiofur which is supplied as the sodium salt, the hydrochloride salt, and as a free acid. Each of these preparations has different pharmacologic properties when administered subcutaneously. The antimicrobial administered as a sodium salt is rapidly absorbed, the hydrochloride is moderately rapidly absorbed, and the free acid is very slowly absorbed. However, therapeutic drug concentrations can be achieved with any of the salts. Penicillin G is also available as a sodium or potassium salt, a procaine salt, and a benzathine salt. When administered as a sodium or potassium salt, the penicillin is so rapidly absorbed and eliminated that it is not routinely used in cattle. The procaine salt is the most frequently used form because it can be administered once or twice every 24 hours. The benzathine salt is also available (usually in combination with the procaine salt) but the plasma concentrations of penicillin G following the administration of the benzathine salt are so low that they are in the sub-therapeutic range for most organisms. Therefore, in my opinion, only rarely is the benzathine salt of penicillin indicated. If one wishes to administer penicillin less frequently, it is possible to administer a larger dose of procaine penicillin to achieve a longer period while the drug is above the MIC. Remember that any change in the dose of the drug from that listed on the label requires a change in the recommended withdrawal time also.

Which is more important; tissue concentration or plasma concentration? Most infections occur in the tissues. Therefore, with the exception of conditions like septicemia, tissue concentration is more important than plasma concentration. Some drugs move into and out of tissues rapidly, making the plasma concentration almost equivalent to tissue concentration. Other drugs concentrate in tissues and accumulate higher concentrations in the tissue than in the plasma. Still other drugs are not taken up by the tissues much at all. In the latter two cases, observing the plasma concentration can lead to an over or under estimation of the drug available at the site of infection. For example, aminoglycosides tend not to concentrate in tissues, ceftiofur tends to reach tissue concentrations similar to plasma concentrations and tulathromycin accumulates in lung tissue at a much higher concentration than in the plasma. Not only does the accumulation of a drug in the tissue increase efficacy in that tissue, but it also reduces the risk of systemic toxicity because plasma concentrations may be kept at a minimum. The properties of some drugs like tetracycline result in their accumulation in the tissues over time. Therefore, after several doses, the concentration in the tissues approaches that in the plasma at peak concentrations, but the tissue concentration remains higher than the plasma concentration between doses.

Does the age of the animal affect the pharmacokinetics of a drug? Definitely, for some drugs, it does. For example, the elimination half-life for oxytetracycline and ceftiofur are significantly longer for calves in the first week of life compared to calves over 6 months of age. Knowing this allows the veterinarian to reduce the dose are dosing interval for very young calves and also helps the veterinarian to avoid toxicity which could occur from aggressive use of antimicrobials in very young calves. Another change that occurs between the first week of life and the sixth week of life is the absorption of trimethoprim after oral administration. Almost no trimethoprim is absorbed after oral administration of the drug to calves 6 weeks of age. Based on available studies, it appears that the use of oral trimethoprim after about 2 weeks of age is unlikely to produce therapeutic concentrations in plasma or tissue.

How long does it take a drug to start to "work"? I guess in most cases one could say that it "starts" immediately. A better question would be, "How long does it take for a drug to reach therapeutic concentrations?" Of course the answer to this question depends on the drug, the route, and the formulation to name a few important variables. To explore the influence of route and formulation, we can look at the various forms of ceftiofur. Ceftiofur Na is the form most rapidly absorbed from an intramuscular or subcutaneous site. It is absorbed so rapidly that the plasma concentration from an intramuscular injection is nearly the same as that from an intravascular injection soon after injection. Therefore, there is no pharmacokinetic justification for intravenous administration. The pharmacokinetic profiles of ceftiofur Na and ceftiofur HCl administered intramuscularly are very similar. However the pharmacokinetic profile of ceftiofur crystalline free acid is quite different compared to the Na salt and the HCl salt. The tables above are from the package inserts of the products (Pfizer Animal Health)

The peak plasma concentration of ceftiofur and its active metabolites administered as a Na salt are quite different than the crystalline free acid (about 14mcg/ml vs 5 mcg/ml) when the label dose of each is administered (2.2 and 3.0 mg/kg, respectively). However, because ceftiofur is a time-dependent antibiotic, and because the MIC of the important respiratory pathogens is much lower than the maximal concentration, the difference is clinically unimportant in most cases. The time to maximum concentration is quite different also (about 1 hour compared to about 20 h) for the Na salt and the crystalline free acid, respectively. But the time to reach therapeutic concentrations for the crystalline free acid is only a few hours, therefore there is usually no need to administer a more rapidly absorbed form as the initial treatment. An exception to this might be as a perioperative antimicrobial.

There is one instance in which the time to reach therapeutic concentration is clinically important. When a drug has a very long elimination half-life and a relatively long dosing interval, the time to reach therapeutic concentration can be clinically important. A good example of this is phenylbutazone. The half-life of phenylbutazone in cattle is greater than 48 hours. If the drug is administered at 48 hour intervals, we can expect it to take 4 to 5 dosing intervals (half-lives) to reach the steady-state. That means it will probably take 3 half-lives to reach therapeutic concentration. That's 6 days. That's too long. In order to shorten the period to therapeutic plasma concentrations, we administer a loading dose. The graph on the left shows the hypothetical plasma concentration curve for a drug administered with a loading dose compared to one administered by maintenance doses only. Therefore, for phenylbutazone the recommended loading dose is 10 to 20 mg/kg with the maintenance dose of 2 to 5 mg/kg daily or 5 to 10 mg/kg every 48 hours. Remember that the extra-label use of phenylbutazone in dairy cattle is prohibited, and its use in beef cattle should be limited and should be accompanied with an extended withdrawal time, as it is currently a high priority of the FDA to avoid tissue residues.

References

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Brown SA, Robb EJ (1995), Plasma disposition of ceftiofur and metabolites after intravenous and intramuscular administration of ceftiofur sodium to calves of various ages, The Bovine Proceedings 27: 206-207

Burrows E, Barto PB, Martin B. Comparative pharmacokinetics of gentamicin, neomycin and oxytetracycline in newborn calves. J Vet Pharmacol Ther 10, 54-63. 1987.

Guard CL, Schwark WS, Friedman DS, Blackshear P, Haluska M (1986), Age-related alterations in trimethoprim-sulfadiazine disposition following oral or parenteral administration in calves, Can J Vet Res 50: 342-346

Luthman J, Jacobsson SO (1986), Distribution of penicillin G serum and tissue cage fluid in cattle, Acta Vet Scand 27: 313-325

in Ziv G, Wanner M, Nicolet J (1982), Distribution of penicillin G, dihydrostreptomycin, oxytetracycline, and chloramphenicol in serum and subcutaneous chamber fluid, J Vet Pharmacol Ther 5: 59-69