Pharmacokinetics of Once‐Daily Amikacin in Healthy Foals and Therapeutic Drug Monitoring in Hospitalized Equine Neonates

Abstract

The objectives of this study were to investigate the pharmacokinetics of once-daily amikacin in healthy neonates, to determine amikacin concentrations in hospitalized foals, and to determine the minimum inhibitory concentrations (MICs) of amikacin against gram-negative isolates from blood cultures in septic foals. Median half-life, clearance, and volume of distribution of amikacin in healthy 2-to 3-day-old foals after administration of an intravenous bolus of amikacin (25 mg/kg) were 5.07 hours (4.86-5.45 hours), 1.82 mL/min/kg (1.35-1.97 mL/min/kg), and 0.785 L/kg (0.638-0.862 L/kg), respectively. Statistically significant (P Ͻ.05) decreases in area under the curve (14% decrease), mean residence time (19% decrease), and C 24h plasma amikacin concentrations (29% decrease) occurred between days 2-3 and 10-11. Plasma amikacin concentrations in healthy foals at 0.5 hours (C 0.5h ) were significantly higher (P ϭ .02) than those of hospitalized foals. Sepsis, prematurity, and hypoxemia did not alter amikacin concentrations. The MIC at which 90% of all gram-negative isolates from equine neonatal blood cultures were inhibited by amikacin was 4 g/mL, suggesting that amikacin C 0.5h of 40 g/mL should be targeted to achieve a maximum serum concentration to MIC ratio of 10:1. The proportion of foals with C 0.5h Ն40 g/mL was significantly higher (P Ͻ.0001) in hospitalized foals receiving a dose of amikacin at 25 mg/kg (22/24 or 92%) than in foals receiving a dose at 21 mg/kg (9/25 or 36%), whereas no difference was found in the proportion of foals with C 24h concentrations Ն3 g/mL between the 2 groups. An initial dose at 25 mg/kg is recommended for once-daily amikacin in equine neonates.

Pharmacokinetics of amikacin in plasma and selected body fluids of healthy horses after a single intravenous dose

“…After comparison of pharmacokinetic parameters of amikacin found in our study with those found in foals after i.v. administration of amikacin once a day at high doses (21 and 25 mg/kg bwt) (Bucki et al 2004;Magdesian et al 2004); the mean peak plasma concentration extrapolated at time zero (C0) was similar with the one reported by Magdesian et al (2004). The zero-time plasma drug concentration intercept of the elimination phase was significantly higher than those reported for foals; indicating higher concentrations of amikacin after the distribution phase.…”

“…The clearance and renal elimination of aminoglycosides (amikacin or gentamicin) in foals was shown to increase with age. Lower values for MRT, t1/2a, t1/2b and AUC were reported in older foals (Cummings et al 1985;Golenz et al 1994;Bucki et al 2004;Magdesian et al 2004). The volume of distribution of amikacin also decreased in foals as they aged (Bucki et al 2004).…”

“…The MIC of amikacin for the most common Gram-negative microorganisms that affect horses is reported to be Յ4 mg/ml (Adamson et al 1985;Orsini et al 1985). The MIC90 of amikacin for Gramnegative bacteria isolated from blood cultures in foals (Bucki et al 2004) and in a variety of samples from equine patients (Jacks et al 2003) was reported to be Յ4 mg/ml. Based on those reports, the peak concentration obtained after a single dose of amikacin should reach values above 40 mg/ml to enhance the efficacy against Gram-negative bacteria and reduce the toxicity of the antibiotic in foals and mature horses.…”

“…However, the recognition that aminoglycosides are concentration-dependent antibiotics whose prolonged post antibiotic effect (PAE) depends on high concentrations led to the recommendation that the same total daily dose administered once a day is anticipated to be simultaneously more effective and less nephrotoxic than the more frequently administered lower doses (Bartal et al 2003;Contopoulos-Ioannidis et al 2004;Nagai and Takano 2004). Amikacin administered once daily at 21 or 25 mg/kg bwt (Bucki et al 2004;Magdesian et al 2004) reduced the potential for aminoglycosideinduced nephrotoxicity in neonates and provided serum concentrations >10x the MIC90 for most Gram-negative pathogens previously isolated from neonatal blood cultures (Bucki et al 2004). These studies provided the basis for dosing recommendations in foals.…”

Neonatal Diarrhea and Septicemia in an American Miniature Horse

“…In this case, at the time the foal was treated, dosing three times per day was deemed most legally defensible, and with the supplementation of fluid therapy so as to protect the foal's kidneys, safe and efficacious. The current recommendation for dosing of amikacin is 25 mg/kg administered once daily [9]. No corticosteroids were given for treatment of possible NI because of lack of symptoms and the contraindication of suspected septicemia.…”