The design of a dosing regimen begins with an assessment of the minimal inhibitory concentration (MIC) of the 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 concentration [sometimes referred to as dose-dependent antimicrobials], such as the aminoglycosides and the fluorinated quinolones) or be above the MIC (T>MIC) for most (50%–75%) of the dosing interval (time-dependent antibiotics, such as cell-wall inhibitors [β-lactams, fosfomycin, vancomycin], sulfonamides, 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 several times higher than the calculated concentration-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 increasing the dose and shortening the dosing interval or by choosing a drug with a long half-life.
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) and the pharmacokinetics of that drug in the target species. Appropriate pharmacokinetic parameters on 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 found in the literature. For example, if the MIC of a Pseudomonas aeruginosa isolate for amikacin (a concentration-dependent drug) is 4 mcg/mL, the dose should be selected so that peak plasma drug concentrations achieve 40–48 mcg/mL. Ideally, tissue concentrations should be that high as well. As such, the dose should be adjusted further if the drug does not penetrate the tissue well in the presence of marked inflammatory debris. Cephalexin is a time-dependent drug. If Staphylococcus pseudintermedius cultured from a skin biopsy in a dog has an MIC of 2 mcg/mL, then the dosing regimen should be selected to assure that drug concentrations are >2 mcg/mL for at least 50%–75% (and ideally 100%) of the dosing interval. The half-life of cephalexin is ~3 hr in dogs. Using data reported in the literature for dogs, an oral dosage of cephalexin at 22 mg/kg will achieve a Cmax of 25 mcg/mL. In one half-life, concentrations (mcg/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, three elimination half-lives, or 9 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 of time-dependent drugs, particularly for drugs with a short half-life—for each half-life to be added to the T>MIC, the dose must be doubled. Amoxicillin (with or without clavulanic acid) has been an extremely popular lower-tier drug used for urinary tract and soft-tissue infections. For the latter, at 10 mg/kg, the drug achieves a concentration of ~5 mcg/mL in plasma. At an MIC of 2 mcg/mL, only one half-life can lapse. The half-life of amoxicillin is only 1–1.5 hr, indicating that dosing should occur every 3 hr. As such, amoxicillin may not be an appropriate choice for soft-tissue infections, and if used, it should be dosed at least every 8 hr, if not more often. However, because it is excreted in the urine, it is a good first choice to treat uncomplicated urinary tract infections, as long as urine is retained in the bladder.
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 dosing interval.