Once daily dosing of aminoglycoside: one step forward

Aminoglycosides continue to be widely used for treating severe infections (EORTC, 1987; Barriere, 1988), despite their limited antibacterial spectrum, their potential for toxicity and the availability of many other potent antibiotics. Rapid bactericidal activity against susceptible Gram-negative bacilli, and synergism with /Mactam compounds, further justifies the continuing popularity of the aminoglycosides. Recent experimental data have suggested that increasing dosage intervals while maintaining the usual daily dose would ensure maximum efficacy and limit the development of nephrotoxicity. However, before endorsing these new schedules, several issues deserve careful consideration. With regard to the pharmacodynamics there is strong support for these new regimens. Various in-vitro and animal models have shown that the higher the concentration of aminoglycoside in these models, the more effective bacterial killing (Flueckiger, Feller & Gerber, 1986; Vogelman & Craig, 1986; Dudley & Zinner, 1991). This concentrationdependent activity favours the concept of increased dosing intervals whereby higher intermittent doses produce higher peak levels and improved bacterial killing. Aminoglycosides also produce significant, concentration dependent, post-antibiotic effects (PAE) against both Gram-positive and Gram-negative organisms (Craig & Vogelman, 1987). In vivo the PAE is able to maintain inhibition of bacterial growth for several hours when concentrations fall below the MIC. In mice with impaired renal function, aminoglycoside pharmacokinetics have been shown to mimic those in man and ensure antimicrobial activity for approximately 24 h owing to the PAE. As a consequence, the efficacy of the once daily dosing of amikacin was virtually identical to that observed after administration of the same daily amount of drug given in two or four divided doses (Craig, Redington & Ebert, 1991). In addition, it is interesting to note that synergistic PAEs have been observed with various combinations of /Mactams and amikacin (Isaksson et al., 1991).