Design of Dosing Regimens for Animals

Design of a dosing regimen begins with assessment of the minimal inhibitory concentration (MIC) of the antimicrobial agent for a particular pathogen. Antimicrobial efficacy (or pharmacodynamic index) is determined by various criteria and depends on the properties of each antimicrobial. For time-dependent antimicrobials (eg, beta-lactams, carbapenems, chloramphenicol, sulfonamides, tetracyclines, and macrolides), plasma or tissue drug concentrations should remain greater than the MIC for most (50%–75%) of the dosing interval.

In animals that are immunocompromised, or for some bacteriostatic antimicrobials, the time that plasma or tissue drug concentrations remain greater than the MIC may need to approach 90%–100% of the dosing interval, requiring constant-rate infusions or extremely frequent dosing regimens. For infections that are sequestered in protected sites, antimicrobials that are typically time dependent may require high plasma concentrations to create enough of a concentration gradient to enter the site. In those situations, use of the ratios between maximum plasma concentration and the MIC (C_max:MIC ratio) or between the area under the concentration-time curve of the unbound drug from 0 to 24 hours and the MIC (AUC_0-24:MIC ratio) that are more characteristic of concentration-dependent antimicrobials may be necessary.

For concentration-dependent antimicrobials (eg, metronidazole, aminoglycosides, and enrofloxacin), the C_max:MIC ratio during a dosing interval is the variable of interest. In addition, concentration-dependent antimicrobials (eg, lincosamides, glycopeptides, metronidazole, fluoroquinolones, and aminoglycosides) may exhibit a time dependence, where the AUC_0-24:MIC ratio may provide a more accurate characterization of pharmacokinetic (PK) and pharmacodynamic (PD) effects. The optimal C_max:MIC ratio or AUC_0-24:MIC ratio is antimicrobial dependent. For fluoroquinolones, the AUC_0-24:MIC ratio considered minimally effective is 125 for gram-negative organisms and 55 for gram-positive organisms. For amikacin, the AUC_0-24:MIC ratio considered minimally effective is 75. For some bacteria with very high MICs, achieving an optimal PK/PD index may not be feasible, so alternative antimicrobials or combination treatment should be considered in those cases.

To compensate for drug disposition to tissue sites and the effect of host factors on antimicrobials, 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, efficacy is enhanced by increasing the dose and shortening the dosing interval or by choosing a drug with a long half-life.

How a Dosage Regimen is Establ...

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Therapeutic Drug Monitoring, P...

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Therapeutic Drug Monitoring, P...

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In the contemporary 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, the MIC for the pathogen cultured from the patient, or the MIC₉₀ for 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 C_max for concentration-dependent drugs, and C_max and drug elimination half-life for time-dependent drugs. Information supporting the design of dosing regimens often can be found in the literature.

For example, if the MIC₉₀ of an E coli isolate for amikacin (a concentration-dependent drug) in a foal is 4 mcg/mL, a dose should be selected so that peak plasma drug concentrations achieve a minimum 40–48 mcg/mL, equating to a C_max:MIC ratio between 10:1 and 12:1.

Both healthy and septic foals achieved a peak concentration of at least 40.0 mcg/mL when treated with amikacin at 25 mg/kg, IV, every 24 hours.1 Furthermore, because the nephrotoxic effects of amikacin require a minimum (trough) concentration of > 3 mcg/mL, therapeutic drug monitoring (TDM) should be conducted to ensure that both peak and trough concentrations are achieved after repeated dosing of aminoglycosides such as amikacin. TDM of hospitalized foals administered 25 mg/kg of amikacin, IV, every 24 hours revealed that trough concentrations of < 3 mcg/mL may not be achieved in critically ill patients.

In patients with decreased renal clearance, such as in cases of acute kidney injury, the accumulation of aminoglycosides may lead to nephrotoxic effects, even with established dosing regimens. In patients with renal disease, creatinine clearance correlates well with drug clearance for drugs that are eliminated primarily by the kidneys. For this reason, dose adjustments that lengthen the dosing interval (the interval extension method) may be the most appropriate for aminoglycosides, to achieve adequate trough concentrations and maintain an optimal C_max:MIC ratio. With aminoglycoside administration, prolonging subtherapeutic concentrations to reach adequate trough concentrations is not detrimental, because of the long postantimicrobial effect of this class. The interval extension method can be calculated from either the patient's serum creatinine concentration (Cr):

Adjusted interval = Normal interval[1/(Normal serum Cr/Patient's serum Cr)]

or the patient's creatinine clearance:

Adjusted interval = Normal interval[1/(Patient's Cr clearance/Normal Cr clearance)]

Therefore, if a foal has a serum creatinine concentration of 3 mg/dL, and the normal creatinine concentration is 1.5 mg/dL, the interval extension method indicates that a 48-hour dosing interval is most appropriate for this patient. Although typically the elimination half-life of renal-eliminated drugs remains stable until there is a 30%–40% decrease in creatinine clearance, dose adjustment formulas may not be accurate for serum measurements of creatinine > 4 mg/dL. For these reasons, TDM is recommended in patients treated with aminoglycosides that are suspected of having or are known to have acute kidney injury or chronic renal disease, to most accurately determine the need for dose interval adjustment.

Cephalexin is a time-dependent drug. If Staphylococcus pseudintermedius cultured from a skin biopsy in a dog has a MIC of 2 mcg/mL, then a dosing regimen should be selected to ensure that drug concentrations are > 2 mcg/mL for at least 50%–75% (ideally 100%) of the dosing interval. The half-life of cephalexin is ~3 hours in dogs. Data reported in the literature for dogs indicates that a cephalexin dose of 22 mg/kg, PO, will achieve a C_max of 25 mcg/mL. In one half-life, concentrations (in mcg/mL) will decline to 12.5; in the second half-life, to 6.25; in the third, to 3.125; and concentrations will be below target by the fourth half-life, or after 12 hours. Thus, three elimination half-lives, or 9 hours, can elapse before the target MIC is reached, and the next dose should be administered by 12 hours. For time-dependent drugs, shortening the interval is generally more cost-effective than increasing the dose, particularly for drugs with a short half-life (ie, for each half-life to be added to time that drug concentrations remain greater than the MIC, the dose must be doubled).

Amoxicillin (with or without clavulanic acid) has been a popular lower-tier drug in the treatment of urinary tract and soft-tissue infections. For amoxicillin with clavulanic acid, a dose of 13.2 mg/kg, PO, achieves an amoxicillin plasma concentration of 6 mcg/mL. Assuming a MIC of 2 mcg/mL, only two half-lives can lapse before concentrations fall below the MIC. The half-life of amoxicillin with clavulanic acid is only 1–2 hours. Given the short half-life, amoxicillin may not be an appropriate choice for all soft-tissue infections, and if it is used, it may need to be administered at least every 8 hours depending on the MIC. Because it is excreted in the urine, however, it is a good first choice to treat uncomplicated urinary tract infections, as long as urine is retained in the bladder.