Determinants of efficacy and toxicity of aminoglycosides

Abstract

The relative efficacy of different aminoglycosides or of different dosage schedules of the same aminoglycoside should be quantitated and related to relative toxicity. Quantitative experimental indicators of efficacy should not only include MIC and MBC, but also the postantibiotic effect in vitro and in vivo, the emergence of resistance in in-vitro and in-vivo models, and the relationship between plasma concentration profiles and efficacy. Parameters of clinical efficacy are to be related to pharmacokinetic parameters such as the ratio between the peak serum concentration and the MIC.Toxicity in clinical trials should be assessed by the most sensitive methods available. Experimental and clinical studies have shown cortical uptake to be a sensitive indicator of renal toxicity. As far as ototoxicity is concerned endolymph and perilymph pharmacoldnetics are not dearly related. Chnical ototoxicity should be assessed by sensitive methods, such as high frequency tone audiometry. Finally, risk factors for nephrotoxicity and ototoxicity (e.g., duration of treatment, associated nephrotoxk drugs, dehydration) should be assessed in the evaluation of clinical trials.

Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy

“…Although we have recently shown that a 25 mg/kg loading dose of amikacin is necessary in patients with severe sepsis or septic shock in order to achieve therapeutic peak concentrations [3], aminoglycosides are potentially A c c e p t e d M a n u s c r i p t 5 nephrotoxic and clinical studies have suggested that renal impairment is more prevalent when there is pre-existing kidney dysfunction [12]. We therefore wondered whether optimising peak amikacin concentrations during CRRT with a higher dose regimen would be associated with prolonged high drug concentrations, which can potentially worsen renal function.…”

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

“…Selectivity, rather than potency or affinity, is the most relevant feature that impacts on drug efficacy in vivo (Mattie et al, 1989;Troke et al, 1990;Brook, 1991;Vella and Floridia, 1998;Waldman, 2002). For example, despite its high TrkA binding affinity (K d , 10-100 pM), NGF has a narrow therapeutic window partly because of poor selectivity (e.g., it binds p75 receptors), partly because of pleiotropic activation, and partly because of a short half-life.…”

Efficacy of once- and thrice-daily dosing of aminoglycosides in in-vitro models of infection

“…However, data from in-vitro and experimental in-vivo studies suggest that once-daily dosing of aminoglycoside might be at least as efficacious and potentially less toxic (Frame et al, 1977;Blaser, Stone & Zinner, 1985a;Gerber et al, 1989;Mattie, Craig & Pechere, 1989). Single-daily dosing of aminoglycosides has also been studied clinically (Powell et al, 1983;Hollender et al, 1989).…”