Once-Daily vs. Continuous Aminoglycoside Dosing: Efficacy and Toxicity in Animal and Clinical Studies of Gentamicin, Netilmicin, and Tobramycin

Abstract

The dosing frequency of aminoglycoside antibiotics may alter efficacy and toxicity independent of total daily dose. Once-daily tobramycin dosing was compared with continuous infusion in three models of efficacy. Acute pneumonia due to Pseudomonas aeruginosa in guinea pigs responded better to once-daily dosing, and chronic pneumonia in rats and endocarditis in rabbits responded equally to both regimens. Dogs given gentamicin, tobramycin, or netilmicin once daily, with maximum serum concentrations of greater than 100 mg/liter, had less nephrotoxicity than dogs given continuous infusions. Tobramycin was given once daily or continuously to 52 patients with cystic fibrosis who in 10 days had no change in creatinine clearance or hearing despite maximum serum tobramycin concentrations of 40 mg/liter. Intermittent dosing of aminoglycosides, causing infrequent large maximum serum concentrations, may be less toxic and equally efficacious as frequent dosing.

In-vivo assessment of in-vitro killing patterns of Pseudomonas aeruginosa

“…peak-dependent killing and a PAE, may well indicate an advantage in vivo of high dose, long interval treatment over a low dose, short interval regimen of any antimicrobial agent. This interpretation of the present data is in full agreement with our previous work and with the results of recent investigations by Powell, Thompson & Luthe (1983) who found once daily doses of aminoglycosides to be more effective than more frequent injections.…”

Antibiotic therapy against Pseudomonas aeruginosa in cystic fibrosis: a European consensus

“…An adjustment in dose interval based on the serum tobramycin level has a significant effect on pulmonary function [93]. Due to the subinhibitory MIC effect [101], the bactericidal concentration-dependent killing and adaptive resistance, aminoglycosides might be administered in higher doses less frequently [102]. Indeed, 12 hourly high peak aminoglycoside dosing has been shown to be less toxic and equally efficacious as 8 hourly dosing [103].…”

“…This may lead to high tone deafness and hypokalaemia or hypomagnesaemia [119]. Acute vestibular toxicity may be seen if the drug is given rapidly [102] and a long infusion is preferable. Some studies suggest tobramycin may be less nephrotoxic than gentamicin [119].…”

“…kg -1 . day -1 of tobramycin [102] and netilmicin [120] has been associated with symptoms of dizziness after the antibiotic infusion. However, surprisingly few side-effects have been reported in high dose aminoglycoside therapy [89,121,122].…”

Pharmacokinetic and pharmacodynamic requirements for antibiotic therapy of experimental endocarditis

“…Most of these conclusions regarding the relation between the pharmacodynamics of antibiotics and optimal dosage have been verified in experimental bacterial endocarditis (9,36,39,50,51,55).…”