Balancing Antibacterial Efficacy and Reduction in Renal Function to Optimise Initial Gentamicin Dosing in Paediatric...

This study aimed to determine the optimal starting dose of gentamicin in paediatric oncology patients. A population pharmacokinetic model describing drug exposure, a semi-mechanistic model describing bacterial killing and an E_max model describing renal cortex accumulation were linked in a utility function using NONMEM®. The optimal gentamicin starting dose was estimated in patients aged from 0.1 to 18.2 years, by balancing the probability of efficacy on day 1 against relative renal function reduction on day 7 with continued dosing. Using achievement of a gentamicin area under the concentration time curve to bacterial minimum inhibitor concentration (MIC) ratio of ≥ 100 and maximum concentration to MIC ratio of ≥ 10 as the efficacy endpoints, a starting dose of 7.1, 9.5, 10.8 and 14.6 mg/kg/q24h was optimal at a MIC of 0.5, 1, 2 and 4 mg/L respectively, with ≥ 75% probability of obtainment. Using achievement of a 2-log₁₀ bacterial count reduction at 24-h post-dose as the efficacy endpoint, a starting dose of 12.8 mg/kg/q24h was optimal, with 85.6% probability of obtainment. Under these different dosing scenarios, relative reduction in renal function ranged on average from 6.9 to 14.5% on day 7. The current recommended starting dose of gentamicin of 7.5 mg/kg/q24h may not be sufficient to achieve efficacy on day 1 if bacterial MIC is > 0.5 mg/L. A higher initial dose (up to 14.6 mg/kg/q24h), in less sensitive microorganisms, would likely cause only a relatively small reduction in renal function at day 7. Close monitoring is crucial if high doses are given, especially for longer than 7 days.