Optimization of Aminoglycoside Therapy

Abstract

Aminoglycosides are experiencing a resurgence in use because of the spread of multiresistant Gram-negative pathogens. Use of these agents is attended by the occurrence of nephrotoxicity. Aminoglycoside optimization of dose can be defined as the dose having the highest likelihood of a good outcome and the lowest likelihood of toxicity. We have defined the metric Δ as the difference between the likelihoods of good outcome and toxicity, with higher values being better. We developed a method for explicitly evaluating Δ for different daily doses of drug and different schedules of administration. In the empirical therapy setting, when aminoglycosides are administered every 12 h, treatment of infections caused by microbes with MIC values greater than 1 mg/liter cannot attain a high enough likelihood of a good outcome without engendering an unacceptable toxicity likelihood. Daily administration, by decrementing the likelihood of toxicity, allows higher doses to be employed with more acceptable probabilities of toxicity. Obtaining patient-specific information (concentration-time data) allows better identification of the patient's specific pharmacokinetic parameters and dispersion. As these become better identified, optimal doses become rapidly identified so that optimal outcomes are attained. Optimization of therapy for aminoglycosides requires understanding the relationship between exposure and response as well as that between exposure and toxicity. Furthermore, daily administration is much preferred, and stopping therapy as quickly as possible (a week or less may be optimal) will contribute to the ability to optimize therapy.