Hatala R, Dinh T, Cook DJ
Once daily aminoglycoside dosing in immunocompetent adults: a
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
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
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.
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)