Once Daily Dosing of IV Gentamicin, Tobramycin Safe and Effective in Children

SAN DIEGO, CA—A daily dose of intravenous gentamicin or tobramycin 9mg/kg achieved a safe and effective target C_max range of 16–25mg/L in a pediatric population, a pharmacokinetic (PK) validation study presented at IDWeek 2015 concluded.

The potential benefits of once daily dosing of aminoglycosides based on PK and pharmacodynamic properties include a concentration-dependent effect, a post-antibiotic effect, and decreased risk of adaptive resistance, nephrotoxicity, and ototoxicity, noted Erin Chung, HonBSc, BScPhm, RPh, of The Hospital for Sick Children, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada, and colleagues.

In July 2014, based on a dose-validation study in critically ill patients, the hospital implemented once daily dosing of aminoglycosides for all inpatients. This observational cohort study retrospectively assessed 147 children aged 2 months to 18 years who received 153 courses of gentamicin or tobramycin, with PK parameters calculated using serum levels drawn 3 and 6 hours post-dose. The majority of patients (63.4%) were admitted to surgical units.

Of the aminoglycoside courses, 71% were indicated for empiric use, 24% for microbiologically documented infections, and 5% for prophylaxis.

The mean population PK parameters were volume of distribution, 0.51±0.28L/kg; clearance, 2.83±1.33mL/min/kg; and half-life, 2.13±0.65hrs.

A total of 44.3% of all courses reached target therapeutic C_max range with the first dose of therapy. Mean C_max of gentamicin and tobramycin was 18.65±7.78mg/L. “Of those courses that did not reach C_max target range, half of the extrapolated C_max were accepted due to either: 1) C_max being within 2mg/L away from target range, 2) patients clinically well without documented infection or 3) course duration ended within the next 24 hours,” they reported.

“Monte Carlo simulations demonstrated a minimal increase in proportion of simulated patients achieving target C_max range with a dose increase from 9mg/kg to 10mg/kg (33.5% vs. 33.7%, respectively),” they reported, with 93% of patients having defervesced by end of treatment.

Median change from baseline for white blood cell count was -16.46% (interquartile range (IQR): -37.32 to 9.41); serum creatinine, 5.84% (IQR: -10.96 to 19.18); blood urea nitrogen, 2.27% (IQR: -28.57 to 73.03); and urine output, -13.37% (IQR: -42.02 to 24.51).

“There was significant variability in renal function,” Chung reported. “In patients who had elevated serum creatinine and BUN levels, [the] majority were receiving concomitant nephrotoxic drugs.” However, once daily dosing of aminoglycosides did not seem to be associated with significant changes in renal markers. The majority of courses were shorter than 14 days.

No ototoxic effects were identified in the 1 patient who had audiometry testing. The majority of patients were admitted under surgery, which may limit the study findings’ generalizability, they noted.

Based on these results, the hospital’s therapeutic drug monitoring guidelines will be revised “to address patients who may need 2-point sampling for pharmacokinetic parameters calculation” as well as those “who may only require 1-point sampling to ensure adequate drug clearance,” the investigators concluded.