Current practice is to administer the total daily dose as a single injection, which is associated with less toxicity and equal efficacy as multiple-dose regimens. This diminished toxicity is probably due to a threshold effect from accumulation of drug in the inner ear or in the kidney. Despite the higher peak concentration, a once-daily dosing regimen provides a longer period when concentrations fall below the threshold for toxicity than does a multiple-dose regimen (12 hours vs. less than 3 hours total in Figure 45-3), accounting for its lower toxicity. Aminoglycoside bactericidal activity, on the other hand, is related directly to the peak concentration achieved because of concentration-dependent killing and a concentration-dependent postantibiotic effect.
Once-daily regimens are safer with equal efficacy, cost less, and are administered more easily. Exceptions include use in pregnancy, neonatal and pediatric infections, and low-dose combination therapy of bacterial endocarditis. Once-daily dosing also should be avoided in patients with creatinine clearances of <20-25 mL/min, where dosing every 48 hours is more appropriate.
Whether once-daily or multiple-daily dosing is used, the dose must be adjusted for patients with creatinine clearances of <80-100 mL/min, and plasma concentrations must be monitored. Nomo-grams may be helpful in selecting initial doses, but variability in aminoglycoside clearance among patients is too large for these to be relied on for more than a few days. If a patient likely will be treated with an aminoglycoside for more than 3-4 days, then plasma concentrations should be monitored.
For twice- or thrice-daily dosing regimens, both peak (30 minutes after dosing) and trough (immediately before the next dose) plasma concentrations are determined. The peak concentration documents that the dose produces therapeutic concentrations, while the trough concentration is used to avoid toxicity. With once-daily regimens, the trough concentration is either measured directly or estimated using various nomograms; a trough concentration >2 mg/mL predicts toxicity.
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