Stability - Neonatal Intensive Care Drug Manual

Evidence
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Efficacy
Extended interval dosing for gentamicin in neonates provides a superior pharmacokinetic profile compared to multiple doses a day dosing. However, there is insufficient evidence to conclude whether a 'once a day' or a 'multiple doses a day' regimen of gentamicin is clinically superior in treating proven neonatal sepsis. (17, 18) (Rao SC 2016, Nestaas E 2005)
Current dosing recommendations are based on 4 prospective observational studies using extended-interval dosing interval with a single drug concentration at 22 hours after the first dose.(2-5) Three of them were consecutive Canadian studies. First of the studies evaluated the extended interval dosing (EID) regimen in neonates ≤28-week gestation. The dosing interval was based on a 22 h level after the first dose of 5mg⁄kg. All neonates, except one, achieved therapeutic peak and trough levels. Based on the 22 h level, dosing interval was 36 h in 61% of neonates and 48 h in 39% of neonates. In their second prospective, observational study, similar findings were noted in 104 neonates ≤7 days of life, gestational age 23 weeks to full term. Appropriate peak and trough concentrations were attained in all neonates. A third prospective observational study by the group assessed extended-interval dosing of gentamicin in neonates >7 days old and found appropriate peak and trough concentrations in all neonates.(2-4) Fourth observational study by Matinkova et al, in which 4 mg/kg/dose was given at various intervals based on gestational age groups (<34 weeks-48 hourly; 34-38 weeks – 36 hourly; >38 weeks – 24 hourly). The initial dose of gentamicin 4mg/kg during the first week of life was high enough to reach bactericidal Cmax within 6–10mg/L. However, Cmax <6 mg/L occurred in 13% of neonates. The inter-dose interval modified according to the recommendation resulted in Ctrough values within the target range of 0.5–2.0mg/L in all but 2 neonates.(5)
Patients who have early (l-hr post-infusion) peak plasma aminoglycoside levels that are >5 ug/mL for gentamicin and tobramycin and >20 ug/ml for amikacin are less likely to die from gram-negative bacteraemia. Moore et al reported a 2.4% mortality rate in adults who achieved 1-hour post-infusion gentamicin or tobramycin peak concentrations above 5 μg/mL. Mortality rate increased to 20.9% for patients failing to achieve peak concentrations above 5 μg/mL within 24–48 hours of starting therapy. (19, 20)
Therapeutic hypothermia (TH): Gentamicin clearance is decreased in neonates receiving hypothermia treatment. Modified gentamicin dosing regimens are required to avoid potential toxicity related to higher concentrations.(13)
ECMO: During ECMO, gentamicin has an increased volume of distribution (Vd), and decreased clearance (Cl), leading to a prolonged elimination half-life. The renal dysfunction, which is a common multifactorial condition during ECMO, can be considered as the main determinant of the prolonged elimination half-life of gentamicin. Given the concentration dependent antimicrobial activity of aminoglycosides, it is recommended to perform therapeutic drug monitoring (TDM) to ensure adequate antimicrobial exposure. (14)
Cyclo-oxygenase inhibitors: Renal drug clearance of aminoglycosides is lower in infants on cyclo-oxygenase inhibitors. (6-8)
Safety
Ototoxicity: There is no clear association between peak or trough levels and ototoxicity in neonates. (21-23) The chance of gentamicin ototoxicity is reported to be greater in those who receive the drug for a longer duration.(21)
Nephrotoxicity: Nephrotoxicity does not seem to be related to peak or trough levels and more related to drug concentration and longer duration.(24) Among neonates with PDA and receiving gentamicin, non-steroid anti-inflammatory drugs (ibuprofen, indomethacin) therapy increases the risk of acute kidney injury.(25)
MT-RNR1 genotype: MT-RNR1 gene mutation is one of the common causes of hereditary hearing loss, particularly in Asian population. In individuals who carry mutations in MT-RNR1 gene, a single dose of gentamicin can result in hearing loss.(26, 27)
Intraventricular antibiotics: In infants with meningitis and ventriculitis, intraventricular antibiotics in combination resulted in a three‐fold increase in mortality compared to standard treatment with intravenous antibiotics alone and should be avoided.(28)
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