Assessment of a Therapeutic Drug Monitoring Strategy of Once Daily Dosing of Gentamicin/Tobramycin in Paediatric Patients

Abstract

Background: There is limited evidence to support the use of once daily dosing (ODD) of aminoglycosides in paediatric patients, in contrast to the adult population. In July 2014, ODD was implemented for all eligible paediatric patients at the Hospital for Sick Children. Objectives: To evaluate the ability of a once daily intravenous (IV) dose of 9 mg/kg gentamicin or tobramycin to achieve a target maximal concentration (Cmax) of 16-25 mg/L, refine optimal sampling times, assess efficacy and safety in paediatric patients and compliance to the hospital’s therapeutic drug monitoring (TDM) guideline. Methods: Pharmacokinetic parameters were calculated from serum gentamicin or tobramycin levels drawn 3 and 6 hours after the aminoglycoside infusion and summarized using descriptive statistics. Monte-Carlo simulations based on calculated pharmacokinetic parameters were used to assess optimal dosing regimens. Results: One hundred and forty children with 149 aminoglycoside courses were included. Mean pharmacokinetic parameters were: volume of distribution of 0.46±0.22 L/kg, clearance of 0.17±0.07 L/h/kg and half-life of 1.89±0.44 h. Approximately half of the courses achieved Cmax target with the initial dose. Monte-Carlo simulations showed highest Cmax target attainment with 9 mg/kg/dose IV once daily. Approximately half of the empiric courses that did not reach Cmax target stepped down to oral antibiotics. Majority (77%) of patients defervesced at the end of the course. No nephrotoxicity was identified. Almost all courses (99%) used an initial dosing of 9 mg/kg as per formulary guideline. Approximately 65% of all courses followed formulary guidelines in drawing levels for aminoglycosides, while only 34% of courses for post-operative surgical patients had levels drawn on or after post-operative day 2 as per formulary guidelines. Conclusion: An initial dose of 9 mg/kg/dose gentamicin or tobramycin IV once daily is appropriate in achieving a Cmax of 16-25 mg/L and appears to be efficacious and safe in paediatric patients. Majority of courses complied with the TDM guideline for dosing of aminoglycosides, while compliance for timing of drawing levels is lower. Future steps include analyzing additional efficacy and safety data for empiric and prophylactic courses without 3 and 6 hour levels to further assess the feasibility of minimizing levels in these patients.