EXPLORATION OF ONCE-DAILY DOSING OF AMINOGLYCOSIDES THROUGH BAYESIAN SIMULATION

Study Objectives. To simulate peak and trough concentrations, using Ba yesian forecasting, achieved with a variety of once-daily dosing (ODD) regimens; to evaluate dosing regimens required to produce target peak and trough concentrations; to compare the peak-to-MIC (minimum inhibi tory concentration) ratios and time above MIC for various dosing regim ens and MICs; to stratify the information based on renal function esti mates; and to use the results from these simulations to make recommend ations regarding optimum ODD of aminoglycosides. Design. Simulation of ODD using a Bayesian technique and existing patient data. Setting. A tertiary referral, community teaching hospital. Patients. One hundred consecutive adults from the author's data base, with a wide variety of infections and underlying illnesses, who met strict inclusion criteri a. Interventions. Two methods of dosing, weight-based (4-7 mg/kg) and target concentration-based (peak 10, 15, or 20 mu g/ml, trough less th an or equal to 0.3 mu g/ml), were evaluated. Each patient had a known dosing-sampling history, stable renal function, and at least two measu red serum concentrations, and were being treated with either gentamici n or tobramycin. Measurements and Main Results. A wide range of peak a nd trough serum concentrations are achieved when dosages are chosen ba sed on patient weight. Even with large dosages, some patients had very low peak-to-MIC ratios and time above the MIC, and vice versa. Variat ions in MIC had a much greater effect on dosing target values than did variations in dosage. A large degree of variability was also noted in doses and dosing intervals when using a target serum concentration ap proach. For both methods, an inverse relationship existed between calc ulated creatinine clearance and time above MIC, although there was lit tle change over the range of 60-119 ml/minute. Conclusions. Bayesian s imulation showed that weight-based ODD of aminoglycosides did not prod uce clinically acceptable serum concentrations or target values in man y patients. Young and elderly patients, and any patient with a creatin ine clearance below 60 or above 119 ml/minute, are especially likely n ot to achieve an optimum serum concentration profile. Aminoglycoside O DD should be individualized by evaluating the peak-to-MIC ratio, time above MIC, and patient response.