What is the Evidence for Once-Daily Aminoglycoside Therapy?

Abstract

Aminoglycosides are important antibacterial agents for the treatment of serious infection. Evidence suggests that high peak plasma concentrations must be achieved early in the course of treatment if these agents are to be effective, but prolonged high concentrations may cause ototoxicity and nephrotoxicity. Peak plasma concentrations of 6 to 10 mg/L and trough concentrations of less than 2 mg/L for gentamicin and tobramycin have been traditional goals of therapy. Extensive recent evidence from in vitro, animal and human studies suggests that these target concentrations need revision. Aminoglycosides display concentration-dependent bacterial killing, have a long postantibiotic effect, and induce adaptive resistance in Gram-negative bacteria. All of these factors support the use of larger doses of aminoglycosides that are given less frequently than conventional therapy. Studies in vitro support this approach, showing greater activity when aminoglycosides are given less frequently. Animal studies comparing different dosage intervals have shown varying results, with only a slight bias favouring the longer dosage interval. However, the short elimination half-lives for the drugs in animals limit the applicability of these models to humans. Importantly, there is convincing evidence in animal studies that nephrotoxicity and ototoxicity are both reduced when the same total daily dose is administered in less frequent doses. There have been at least 29 clinical trials comparing once-daily administration of aminoglycosides with conventional administration 2 to 4 times daily. In general, efficacy has not been shown to be different between regimens, although one trial showed an advantage for once-daily administration compared with administration 3 times daily. A small number of trials have shown less nephrotoxicity and ototoxicity with once-daily administration, leading several authors to suggest that there is sufficient evidence to warrant a change to once-daily administration of aminoglycosides. However, once-daily administration has not been well studied in the paediatric population, or in patients with renal failure or endocarditis, and cannot be recommended in these patients as yet. The choice of a 24-hour dosage interval is somewhat arbitrary, and the optimal interval may not necessarily be 24 hours. No studies have included dosage adjustment based on pharmacokinetic modelling methods, and the effect of this on treatment outcome needs to be assessed. The best method of administering aminoglycosides once daily is yet to be determined.

Aminoglycoside-Induced Nephrotoxicity

“…It is now widely accepted that once-daily dosing is considered as effective and probably less nephrotoxic than traditional dosing. [25][26][27][28][29][30] The rate of nephrotoxicity associated with extended interval dosing is estimated at 0% to 5% versus 17% with traditional dosing. 10,[31][32][33] The use of extended interval dosing is based on 4 central concepts.…”

A suggested approach to once‐daily aminoglycoside dosing.

“…i) Patient selection ii) Starting dose iii) Monitoring iv) Dose 4.25 mg kg-day-l for gentamicin (n = 2) and 4.4 mg kg-day-' for tobramycin (n = 4) [4]. Unfortunately, pharmacokinetic individualisation, the currently accepted optimal method of aminoglycoside dosing, was not used in these trials.…”

Comparison of Tobramycin Nephrotoxicity in Young Adult and Aged Female Rats

“…Recently, there has been increased interest in simplifying therapy and in reducing toxicity of aminoglycosides by using once daily dosing instead of conventional two or three times daily dosing. From animal studies we know that nephrotoxicity (as well as ototoxicity) is reduced when the same daily dose is administered in less frequent doses (Barclay et al 1994). This is related to the amount of drug that accumulates in the renal cortex as a result of saturation of the transport system, by which most aminoglycosides, but not tobramycin, are excreted.…”