Clinical pharmacology of gentamicin in neonates: regimen, toxicology and pharmacokinetics

Abstract

Gentamicin is an aminoglycoside antibiotic. It kills bacteria by inhibiting protein synthesis and to some extent by lysing the cell envelope. Gentamicin is frequently the first choice drug because of its reliability, but also because of the long experience with its use. In combination with β-lactam antibiotics it is recommended for the treatment of sepsis or pneumonia and is active against P. aeruginosa, Enterobacter, Klebsiella and Serratia. However, gentamicin is ototoxic and nephrotoxic. The human mitochondrial genetic variant m.1555A > G has been reported to be an important cause of non-syndromic hereditary hearing dysfunction and may cause permanent hearing loss. Even short courses of gentamicin therapy in healty newborn infants can lead to abnormalities of auditory function. It is active against very resistant bacteria at peak concentrations (> 10 mg/l) that are high enough to be potentially toxic. For safe therapeutic efficacy, peak plasma concentrations of gentamicin should range from 4 to 10 mg/l; but trough concentrations, immediately before a new drug administration, must be lower that 2 mg/L to avoid toxic effects. Pharmacokinetic parameters vary considerably in infants. Half-life ranges from 5.4 to 10.0 hours, clearance 0.50 to 1.71 ml/h/kg and distribution volume from 0.4 to 0.7 l/kg. Preterm infants have a longer half-life than full-term infants. Thus, it is mandatory to monitor gentamicin serum concentrations whenever infants are treated for 48 hours or more.

Transdermal delivery of gentamicin using dissolving microneedle arrays for potential treatment of neonatal sepsis

“…In addition, GEN pharmacokinetics is affected by renal function and neonates present reduced glomerular filtration rate. Therefore, it is expected that neonates have lower renal clearance of GEN compared to older infants and adults [59] , [60] , [61] , [62] . Considering this, the estimated patch sizes could probably be reduced significantly.…”

Control of Klebsiella pneumoniae Infection in Mice by Using Dissolving Microarray Patches Containing Gentamicin

“…GEN is a potent aminoglycoside antibiotic with bactericidal activity against Gram-negative bacteria and is widely utilized due to its efficacy and low cost (4). Similar to other aminoglycosides, GEN has a narrow therapeutic index and has the potential for ototoxicity and nephrotoxicity (5, 6). GEN is excreted in the kidneys primarily by glomerular filtration and has a short plasma elimination half-life in healthy individuals presenting with normal renal function (7).…”

Evaluation of Dosing Guidelines for Gentamicin in Neonates and Children

“…These variabilities in pharmacokinetics are due to changes in body composition and organ maturation and development, especially in children younger than 2 years of age [8]. In healthy neonates, the half-life can decrease by more than 50% over the first 7 to 10 days after birth [9]. Due to this pharmacokinetic variability in neonates and children, in combination with a narrow therapeutic window, appropriate dosing of gentamicin in these populations is challenging and therapeutic drug monitoring (TDM) is recommended, to individualize the dosage and achieve target concentrations in each patient [10,11].…”