Evaluation of Extended-Interval Aminoglycoside Dosing (EIAD) in Pediatric Patients

Background: Aminoglycosides (AG) are common antimicrobial agents used for additional gram-negative bacterial coverage in pediatric patients (pts).  Conventional dosing of gentamicin (G) is 2.5mg/kg/dose IV q8h based on IBW. Based on pharmacokinetics (PK) and pharmacodynamics, EIAD optimizes antimicrobial activity (maximizing peak to minimum-inhibitory concentration ratio) while minimizing toxicity. We adopted stratified, age-based EIAD dosing recommendations for pediatric patients >3 months (mo)-<2 years (yr)(Group 1), 2 yr-8 yr (Group 2), and ≥8 yr (Group 3).  We describe the safety and efficacy of this dosing strategy.

Methods: Retrospective review of all EIAD orders of G from 2/1/13-12/31/14 in pediatric pts >3 mo was performed. Inclusion criteria:  pts who received EIAD with 2 serum drug concentrations obtained. Exclusion criteria: neonates <44 weeks corrected gestational age, pregnant women, acute burn injury, estimated creatinine clearance <40mL/min, cystic fibrosis, dialysis, use for gram-positive synergy or mycobacterial infection. Data collected included age, gender, height, weight (wt), concomitant antimicrobials, baseline renal function, initial dosing regimen and serum concentrations.

              

Results: 279 EIAD courses in 136 pts were reviewed; 107 courses in 54 pts were included in the analysis.  The mean age, wt and AG dose are listed in table 1.  Concomitant beta-lactam therapy was administered during all courses of G therapy except 1 course for only 1 patient (concern for UTI). PK parameters were calculated for each course of therapy with associated levels. For the entire study population, mean Ke was 0.3 hr^-1 ± 0.1, t_1/2 2.6 hr ± 1.1, Vd 0.5 L/kg ± 0.1, Cmax 17.1 mcg/mL ± 4.6 and C24hr 0.1 mcg/mL ± 0.2. PK parameters by age group are listed in table 2. Ke was lower for our study population than reported in the literature except for group 1. For all groups, calculated Vd was much larger than reported in the literature. No cases of nephrotoxicity were identified.

Conclusion: EIAD appears of be safe in pediatric pts. An age based approach to dosing per wt seems appropriate. Doses of 9.5 mg/kg/dose for those >3 mo-<2 yr, 8.5 mg/kg/dose for those 2yr- <8yr and 7 mg/kg/dose for those ≥8yr is likely to achieve a Cmax of 15 – 20 mcg/mL with a C24hr of <1 mcg/mL. Future studies evaluating ototoxicity with prolonged use are needed.