EXPERIMENTAL RATIONALE FOR AMINOGLYCOSIDE SINGLE DAILY DOSING

The clinical use of the aminoglycosides is limited by their nephro- an d ototoxicity Animal models contributed to demonstrate the lower toxic ity of aminoglycosides when administered once-daily due to their satur able transport into the renal cortex and the inner ear. Several pharma codynamic features of aminoglycosides favor intermittent dosing regime ns without loss of antibacterial efficacy in animal models of infectio n due to Gram-negative bacilli : first dose-dependant killing followed by all adaptative resistance phase, prolonged post-antibiotic effect. Despite the high clearance of aminoglycosides animals, 8 and 12 hour dosing regimens have been shown equally effective than more frequent r egimens in mice, rats and guinea pig, and once-daily dosing have been shown equally effective than twice or thrice daily dosing in uremic mi ce or in rabbits. However, once-daily dosing can lead to decreased in vivo activity with mono-therapy in neutropenic animals, due to a reduc ed duration of the postantibiotic effect and earlier bacterial regrowt h in comparison with non-neutropenic animals, and for treatment of sev ere enterococcal infection, due to a different mechanism of synergism between beta-lactams and aminoglycoside for this species in comparison with that for Gram negative bacilli.