HDCN Article Review/Hyperlink

Hatala R, Dinh T, Cook DJ

Once daily aminoglycoside dosing in immunocompetent adults: a meta-analysis

Ann Int Med (Apr) 124:717-725 1996

Objective: To compare efficacy and toxicity of once-daily with standard aminoglycoside dosing regimens in immunocompetent infected adults.

Methods: Meta-analysis based on structured MEDLINE search. Randomized controlled trials were included if they compared a once- daily regimen with a standard regimen and examined efficacy, mortality, or toxicity.

Results: 42 studies were reviewed; 13 met the selection criteria and the results were pooled. The other studies were excluded because of non-randomized trial design, non intravenous route of drug administration, non-adult population, lack of documented infection or preponderance of UTIs, prophylactic antibiotic administration, lack of control group, or lack of outcome criteria or adequate data. Bacteriologic cure was not improved by once- daily dosing; however, there was a trend (not significant) for decrased mortality and toxicity (both nephrotoxicity and ototoxicity) with once-daily dosing.

Conclusion: Once-daily dosing may be less toxic than standard dosing regimens. Ease of administration and decreased cost are other advantages.

Comment: This is a well-done meta-analysis to address the issue as to whether once-daily aminoglycoside dosing confers clinical benefits. On a theoretical basis, once-daily dosing should provide higher peak levels, lower trough levels, and thus improved efficacy and decrease toxicity. However, most studies have been unable to demonstrate these putative benefits. Prins et al (Lancet 1993; 341: 335-9) found that once-daily dosing decreased nephrotoxicity; however, this is the only study in the literature that demonstrates this effect. In a study of 243 patients that compared three dosing strategies, we found that pharmacokinetic dosing did not decrease nephrotoxicity (Leehey et al. J Am Soc Nephrol 1993; 4: 81-90). Rather, nephrotoxicity was dependent on duration of therapy and patient risk factors such as the presence of shock, volume depletion, older age, and liver disease. We did not apply once- daily dosing in our study. However, our results as well as other studies in the literature support the concept that nephrotoxicity is primarily due to duration of therapy and patient risk factors and is unlikely to be substantially affected by attention to dosing and drug monitoring. Use of aminoglycosides in certain patient populations, esp. those with liver disease (Moore et al. Am J Med 1986; 80: 1093-7) or obstructive jaundice (Desai and Tseng.
Am J Med 1988; 85: 47-50) should be avoided if at all possible.

A methodologic flaw in most aminoglycoside studies is the definition of nephrotoxicity; in this meta-analysis, it was defined as a 0.5 or greater increment in serum creatinine. Obviously it is better to use changes in creatinine clearance (or percentage increase in serum creatinine value), as this will more accurately reflect the degree of renal impairment. (David J. Leehey, M.D., Loyola University at Chicago)