Once-daily dosing decreases renal accumulation of gentamicin and netilmicin

Abstract

The pathogenesis of aminoglycoside nephrotoxicity is intimately related to the extent of drug accumulated in the renal cortex. In the framework of searching for preventive measures of aminoglycoside-induced nephrotoxicity, we investigated the influence of dosage regimen on the renal cortical accumulation of gentamicin and netilmicin in humans. Patients with a tumor partly involving one kidney, with normal renal function, and scheduled for nephrectomy received one dose of either gentamicin (4.5 mg/kg) or netilmicin (5 mg/kg) as a single short-term infusion or as 24-hour continuous infusion. Treatment started 24 hours before surgery. Serum aminoglycoside pharmacokinetics were examined during treatment and renal cortical tissue was sampled at the moment of operation for drug determination. The short-term infusion schedule yielded cortical concentrations of 103.2 +/- 36.3 and 137.4 +/- 34.6 micrograms/gm for gentamicin and netilmicin, respectively. Tissue levels after continuous infusion were 158.1 +/- 52.9 and 178.5 +/- 21.8 micrograms/gm for gentamicin and netilmicin, respectively. For each aminoglycoside, a single short-term infusion resulted in significantly lower renal drug levels than did a continuous infusion of the same dose. From the nephrotoxicity point of view, these data support the administration of gentamicin and netilmicin as once-daily injections. This also supports the appropriateness of further studies to determine clinical efficacy of once-a-day dosing for aminoglycosides.

Plasma Peak and Trough Gentamicin Concentrations in Hospitalized Horses Receiving Intravenously Administered Gentamicin

“…Therefore, effects of higher doses on renal function cannot be determined from this study. Low 22 hour values are expected with once‐daily administration, because typically >10 half‐lives of gentamicin will elapse during the intertreatment interval 30, 31. However, there is no consensus of how low troughs should be.…”

Pharmacokinetics and renal toxicity of three once-a-day doses of amikacin in cows

“…However, histological damage cannot be ruled out. Aminoglycoside uptake into renal tubule cells and the inner ear appears to be saturated at relatively low serum levels, suggesting that higher peaks do not necessarily result in a greater risk of toxicity ( Giuliano et al, 1986a;Giuliano et al, 1986b;Verpooten et al, 1989;De Broe et al, 1991). Duration of exposure to a given aminoglycoside agent appears to be a more important determinant of toxicity.…”

Ventilator-Associated Pneumonia: Diagnosis, Treatment, and Prevention

“…Early eradication minimizes the opportunity for a population of organisms to develop resistance. Peak concentrations for aminoglycosides 10-fold greater than MIC appear to inhibit the emergence of resistant organisms (178,207). When choosing fluoroquinolones, resistant organisms are less likely to be seen when the 24-h areaunder-the-curve/MIC levels are Ͼ100 for gram-negative bacteria and Ͼ40 for gram-positive bacteria (177,179,194).…”