The 2023 publication undertakes a retrospective, single-center cohort study at the Beatrix Children’s Hospital to evaluate the effectiveness of current dosing guidelines for gentamicin in neonates and children. The study encompasses data collected between January 2019 and July 2022, involving 658 patients, consisting of 335 neonates and 323 children. The investigators measured the first gentamicin concentration used for therapeutic drug monitoring in each patient, with the target trough concentrations set at ≤1 mg/L for neonates and ≤0.5 mg/L for children, while peak concentrations were set at 8–12 mg/L for neonates and 15–20 mg/L for children. Results indicated that trough concentrations were outside the target range in 46.2% of neonates and 9.9% of children, while peak concentrations were exceeded in 46.0% of neonates and 68.7% of children. Notably, higher creatinine concentrations in children were correlated with increased gentamicin trough concentrations. The findings substantiate earlier observational studies, illustrating that approximately half of the cases did not achieve the target concentrations with standard dosing. The once-daily administration of gentamicin is favored over multiple daily doses to enhance effectiveness while minimizing toxicity. In neonates, the literature recommends initial dosing ranges of 3 to 7.5 mg/kg, and for children, 4 to 10 mg/kg, typically given as a single daily dose. The subsequent dosing is then adjusted based on therapeutic drug monitoring (TDM) to ensure optimal outcomes and reduce the risk of adverse effects. The study further explicates the necessity for refined dosing strategies, particularly highlighting the significant pharmacokinetic variability associated with developmental factors in neonates and children. The research underscores the importance of considering additional clinical parameters to enhance target attainment in pediatric patients, such as gestational and postnatal age and renal function markers. The retrospective nature of the study, combined with its extensive cohort, provides a robust evaluation of current practices and calls attention to the need for ongoing assessment and adjustment of dosing regimens in pediatric antimicrobial therapy. [1]
A 2008 review comprehensively examined the data surrounding the use of extended-interval dosing of gentamicin for the treatment of neonatal sepsis. This detailed exploration included both randomized and non-randomized studies from developed and developing countries. The review meticulously assessed the pharmacokinetic profiles of gentamicin when administered in higher doses at prolonged intervals beyond 24 hours. The analysis revealed that such dosing not only conferred a favorable pharmacokinetic profile but also enhanced clinical efficacy while reducing toxicity, all at a potentially lower cost. The authors suggested an optimal dosing regimen tailored for resource-limited settings: for neonates over 2,500 g, a dose of 13.5 mg every 24 hours; for those between 2,000-2,499 g, 10 mg every 24 hours; and for neonates under 2,000 g, 10 mg every 48 hours was recommended. Furthermore, the review highlighted the global importance of neonatal infections, emphasizing that serious bacterial infections are a leading cause of morbidity and mortality among newborns, particularly in developing countries where neonatal deaths predominantly occur. The study stressed the need for simplified treatment regimens in high-mortality settings to improve antibiotic administration and thereby reduce neonatal sepsis case-fatality rates. The findings underscored the practicality of extended-interval dosing in both health facilities and potentially for community-based management, aiming to optimize treatment strategies for neonatal sepsis in challenging environments where traditional dosing regimens may be logistically demanding. [2]
A 2016 retrospective review evaluated the efficacy and safety of Extended-Interval Aminoglycoside Dosing (EIAD) in pediatric patients. The investigation included patients aged over 3 months who received EIAD with at least two serum drug concentration measurements between February 2013 and December 2014. The study excluded neonates under 44 weeks corrected gestational age, pregnant women, and patients with specific conditions such as cystic fibrosis and acute burn injuries. The analysis focused on 107 courses of gentamicin therapy across 54 patients, assessing parameters like age, gender, weight, concomitant antimicrobial use, renal function, initial dosing regimen, and serum concentrations. The 2016 analysis revealed that the EIAD approach was safe, with no cases of nephrotoxicity detected. The pharmacokinetic evaluation indicated that the mean elimination rate constant (Ke) for the study population was 0.3 hour−1 with a half-life of 2.6 hours. The volume of distribution (Vd) was found to be 0.5 L/kg, and peak serum concentration (Cmax) averaged 17.1 mcg/mL. Age-based dosing, utilizing 9.5 mg/kg for those aged >3 months to <2 years, 8.5 mg/kg for ages 2 to <8 years, and 7 mg/kg for patients aged ≥8 years, efficiently achieved the targeted Cmax range of 15-20 mcg/mL with a C24h of <1 mcg/mL. Although the results were promising, the authors noted the need for future studies to assess potential ototoxicity with prolonged use of EIAD in pediatric populations. [3]
A 2009 retrospective medical record review with pharmacokinetic analysis was conducted within two neonatal intensive care units in a pediatric tertiary care system. This investigation aimed to ascertain the pharmacokinetic outcomes of a simplified, weight-based, extended-interval gentamicin dosing protocol in a sequential sample of 644 critically ill neonates under seven days old without renal dysfunction. These neonates were administered gentamicin on their first day of life for suspected sepsis between February 2003 and January 2008. The protocol involved intravenous administration of a mean dose of 3.96 mg/kg of gentamicin every 48 hours for those weighing less than 1250 g and every 24 hours for those weighing 1250 g or more. For neonates concurrently receiving indomethacin, gentamicin was given every 48 hours. The results indicated that the protocol was effective in achieving therapeutic peak plasma concentrations of gentamicin, with a mean gentamicin peak concentration of 9.38 mg/L and a mean trough concentration of 1.00 mg/L. Notably, 361 neonates, representing 56.1% of the sample, reached the defined successful peak plasma concentration range of 7-10 mg/L, while 610 neonates, or 94.7%, had successful trough concentrations of less than 2 mg/L. The apparent volume of distribution was determined to be 0.48 L/kg and the mean half-life was 8.31 hours. These findings suggest that the protocol may minimize the potential for gentamicin toxicity while effectively achieving therapeutic concentrations in most neonates. [4]
A 2016 survey of Canadian Hospital Pharmacists explored the prescribing practices for high-dose, extended-interval aminoglycosides, specifically gentamicin and tobramycin, in pediatric inpatients across Canada. The research utilized a prospective survey methodology distributed in March 2015 to pharmacists from Canadian health care organizations providing pediatric inpatient services. The survey, crafted with expertise in survey methodology, institutional pharmacy practice, pediatrics, and aminoglycosides, encompassed 18 questions regarding demographic characteristics, clinical indications, dosing, monitoring parameters, and pharmacists' prescribing authority. Forty-five out of the 94 potential participants completed the survey, yielding a 48% response rate. The survey revealed that 78% of the respondents indicated the use of high-dose, extended-interval regimens for pediatric patients in their institutions, with variations in dosing dependent on conditions such as cystic fibrosis, urinary tract infections, and febrile neutropenia. The survey results highlighted significant diversity in dosing and monitoring regimens. Median doses reported were 10 mg/kg for cystic fibrosis, 7 mg/kg for urinary tract infections, and 8 mg/kg for febrile neutropenia. Furthermore, 89% of the institutions reported monitoring serum levels, and 77% monitored for nephrotoxicity, underscoring the emphasis on safety. Also illuminated was that 16% of the pharmacists had the authority to independently adjust dosing, and 31% could independently order monitoring parameters. The gathered data reflects an evident variation in practices across Canada, highlighting the absence of standardized guidelines for aminoglycoside therapy in pediatrics. [5]