Is Extended-Interval Aminoglycoside Dosing Safe in Pediatric Patients?

Investigators adopted stratified, age-based extended-interval aminoglycoside dosing recommendations
Investigators adopted stratified, age-based extended-interval aminoglycoside dosing recommendations

NEW ORLEANS, LA—Extended-interval aminoglycoside dosing “appears of be safe in pediatric patients,” a retrospective study presented at IDWeek has found.

“An age-based approach to dosing per weight seems appropriate,” reported Allison H. Bartlett, MD, MS, Pediatrics, Baylor College of Medicine, Houston, TX, and colleagues.

The antimicrobial aminoglycoside agents are commonly used for additional gram-negative bacterial coverage in pediatric patients, with conventional dosing of gentamicin 2.5mg/kg/dose IV every 8 hours based on ideal body weight.

However, based on pharmacokinetics and pharmacodynamics, extended-interval aminoglycoside dosing can optimize antimicrobial activity, maximizing peak to minimum-inhibitory concentration ratio, while minimizing toxicity.

The investigators adopted stratified, age-based extended-interval aminoglycoside dosing recommendations for pediatric patients >3 months to <2 years (group 1); 2–<8 years (group 2), and ≥8 years (group 3) to determine safety and efficacy of this strategy.

A retrospective review was conducted of all extended-interval aminoglycoside dosing orders of gentamicin from February 1, 2013, to December 31, 2014, in pediatric patients >3 months. Included were those who had received extended-interval aminoglycoside dosing with 2 recorded serum drug concentrations. Excluded were neonates younger than 44 weeks by corrected gestational age; pregnant women; those with acute burn injury, estimated creatinine clearance <40mL/min, or cystic fibrosis; those on dialysis; and those for whom the agents were used for gram-positive synergy or mycobacterial infection.

Data collected included age, gender, height, weight, concomitant antimicrobials, baseline renal function, initial dosing regimen, and serum concentrations.

They reviewed 279 extended-interval aminoglycoside dosing courses in 136 patients and included 107 courses in 54 patients in the analysis. Mean age in groups 1 (n=24), 2 (n=17), and 3 (n=66), was 0.8 years, 5.2 years, and 14.5 years, respectively; weight was 7.4kg, 19.8kg, and 56.9kg, and aminoglycosides dose was 10mg/kg, 9.5mg/kg, and 7.3mg/kg.

Concomitant beta-lactam therapy was administered during all courses of gentamicin therapy except for 1 course in 1 patient, due to a concern for urinary tract infection.

Pharmacokinetic parameters were calculated for each course of therapy with associated levels. For the entire study population, mean Ke was 0.3hr-1 ± 0.1, t1/2 was 2.6hr ± 1.1, Vd was 0.5L/kg ± 0.1, Cmax was 17.1mcg/mL ± 4.6, and C24hr was 0.1mcg/mL ± 0.2.

“Ke was lower for our study population than reported in the literature except for group 1,” Dr Bartlett noted. “For all groups, calculated Vd was much larger than reported in the literature. No cases of nephrotoxicity were identified.”

They suggest that doses of 9.5mg/kg/dose for those in group 1, 8.5mg/kg/dose for group 2, and 7mg/kg/dose for group 3 are likely to achieve a Cmax of 15–20mcg/mL with a C24hr of <1mcg/mL. This strategy will allow for optimal aminoglycoside pharmacokinetic parameters by maximizing concentration-dependent kinetics and using post-antibiotic effect while minimizing toxicity, explained Dr. Bartlett.

“Larger studies evaluating clinical outcomes and adverse effects with long-term extended-interval aminoglycoside dosing use including audiology testing are needed” she concluded.

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