48-hour dosing of gentamicin in infants born at less than 28 weeks of gestation

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Few data are available on which to base optimized dosing of antimicrobial agents in very low birthweight (VLBW) neonates. These infants are arguably our most vulnerable patients – at high risk for toxicity of drugs as well as poor outcomes if treatment of infection is suboptimal. Thingvoll et al applied results derived from the Monte Carlo simulations of pharmacokinetics of gentamicin distribution and clearance in VLBW infants, and concluded that 48-hour dosing best fit desired peaks and troughs with least measurements-and-manipulations. They then applied and studied this new standard prospectively in 30 VLBW infants given gentamicin beginning on the first day of life. A historical 24-hour dosing group was used for comparison. Data in the 48-hour dosing group showed no gentamicin peak outside a “target” range of 5-14 ug/mL, or trough outside a range of 0.5-2 ug/mL. The study validates the Monte Carlo simulation method, ie, serum concentrations were as expected. What is missing for the 48-hour dosing (and 24-hour dosing in the opinion of some infectious diseases experts) is proof of efficacy and safety. This study is highly underpowered to answer either question. It is noteworthy that breakthrough gram-negative bacillary bloodstream infections, as well as hearing abnormalities were documented in both 48-hour and 24-hour groups in this small study. Acceptance of a prolonged subinhibitory serum gentamicin concentration (approaching 24-hours in the 48-hour dosing group) and reliance on a prolonged post-antibiotic effect as noninferior therapeutically are hypotheses, not proven results.