Extended-Interval Dosing of Aminoglycosides in Pediatrics: A Narrative Review

Abstract

Aminoglycosides (AGs) are frequently used in pediatric settings, especially for empiric treatment of early-onset neonatal sepsis. Although AGs are used for several decades, the optimum method of administration and their dosing schemes needs more clarification. The risks of ototoxicity and nephrotoxicity, two main toxicities associated with AGs, have been contributed to the peak and trough plasma levels, respectively. One approach to decrease these potential toxicities of AGs is to administer higher doses with a prolonged interval, named extended-interval dosing (EID). Post-antibiotic effect (PAE) and concentration-dependent killing of AGs provide rational basis for the efficacy of EID. PAE refers to the extended bactericidal activity of AGs against many Gram-negative organisms after the drug was removed by metabolism. One concern is that the higher initial peak concentration with EID may be accompanied with more toxicities, especially ototoxicity. It was demonstrated that due to saturation of binding site of AGs in renal and cochlear tissues, transiently higher concentration of AGs does not cause additional nephrotoxicity or ototoxicity. Experience and clinical evidence regarding EID in pediatrics is suboptimal. In this review, we presented the rational and studies focusing on EID in pediatric setting. The overall finding of trials is that in pediatric setting, EID is a safe and effective dosing method. The risk of serum drug concentration outside the therapeutic range is lower in neonates treated with EID, leading to less need of therapeutic drug monitoring (TDM) with EID. Moreover, there are evidences supporting lower chance of bacterial resistance with EID compared with traditional dosing approach.

Development of Gentamicin Resistance During Treatment of Escherichia coli Ventilator-Associated Pneumonia in a Neonate

“…28 The reported duration of postantibiotic effect varies with a range of 1 to 7.5 hours and depends on several factors including organism, peak level obtained, and oxygen levels. [28][29][30][31] It has been suggested that the maximal gentamicin postantibiotic effect depends on reaching gentamicin concentrations 8 to 16 times the MIC for 2 hours. 24 However, it is not known what percentage of neonates obtain these concentrations with the different dosing regimens being used.…”

Clinical and Pharmacological Approaches to Optimize the Dosing Regimen of Antibacterial Drugs in Pediatrics

“…Бактерицидное действие аминогликозидов осуществляется за счет образования ковалентных связей с белками бактериальных рибосом и нарушения их синтеза, а степень их активности зависит от максимальной (пиковой) концентрации в сыворотке Таблица. Механизмы противомикробной активности, связанные с фармакокинетикой и фармакодинамикой антибактериальных препаратов [8,9] [18]. Опасения врачей, связанные с развитием нефрои ототоксичности, серьезно ограничивают применение антибиотиков группы аминогликозидов в терапии тяжелых инфекций, в том числе вызванных полирезистентными возбудителями.…”

Evaluation of Aminoglycosides Consumption in Open Heart Surgery Based on the Defined Daily Dose Index

“…Prescription of their single daily dose results in optimal activity and prevention of drug resistance [9]. The most important side effects of this group of drugs are nephrotoxicity, ototoxicity, and rarely neuromuscular blockade [10,11].…”