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An extended interval dosing method for gentamicin in neonates
M D Stickland1, C M Kirkpatrick, E J Begg
1Department of Paediatrics, Neonatal Intensive Care Unit, Christchurch Womens Hospital, Christchurch, New Zealand.
Insights
Standard gentamicin dosing in neonates often fails to achieve therapeutic levels, risking toxicity. An extended interval dosing strategy significantly improves gentamicin
Area of Science:
- Neonatal pharmacology
- Pediatric infectious diseases
- Clinical pharmacokinetics
Background:
- Traditional gentamicin dosing regimens (every 8-24 hours) in neonates frequently result in suboptimal peak concentrations (Cmax) and elevated trough concentrations (Cmin).
- This suboptimal pharmacokinetic profile can lead to both treatment failure due to sub-therapeutic levels and increased risk of toxicity.
Purpose of the Study:
- To evaluate the efficacy of an extended interval gentamicin dosing strategy in neonates.
- To determine if this new dosing method can achieve ideal concentration-time profiles for improved efficacy and reduced toxicity.
Main Methods:
- Prospective audit of 53 neonates receiving traditional gentamicin dosing (2.5 mg/kg every 8-24 h).
- Development of an extended interval dosing method (24, 36, 48 h) via simulation for infants weighing 0.75-5 kg.
- Prospective audit of 51 neonates receiving the extended interval dosing method.
Main Results:
- Traditional dosing resulted in sub-therapeutic Cmax in 62% and elevated Cmin in 15% after the first dose.
- Extended interval dosing achieved a mean Cmax of 13.1 mg/L and a mean Cmin of 0.7 mg/L after the first dose.
- 78% of neonates on extended interval dosing achieved Cmax >10 mg/L, with acceptable 24-hour exposure (AUC0-24 = 93 mg*h/L).
Conclusions:
- Extended interval gentamicin dosing is a superior strategy for neonates.
- This method optimizes gentamicin's concentration-dependent killing effect while minimizing toxicity.
- The developed dosing method demonstrates good predictive ability for achieving therapeutic gentamicin levels in neonates.
Abstract:
Traditional gentamicin dosing every 8-24 h depending on age and weight in neonates does not provide the ideal concentration-time profile to both optimize the concentration-dependent killing by aminoglycosides and minimize toxicity. Fifty-three neonates were audited prospectively while receiving gentamicin 2.5 mg/kg every 8-24 h, aiming for peak concentrations (Cmax) of 6-10 mg/L and trough concentrations (Cmin) <2 mg/L. After the first dose, the mean (+/- s.d.) Cmax was 5.5 +/- 0.7 mg/L with sub-therapeutic concentrations (<6 mg/L) in 62% of patients, while the mean Cmin was >2 mg/L in 15% of the neonates. After the third dose the Cmax was 7.5 +/- 1.5 mg/L, with 17% <6 mg/L, whereas the mean Cmin was 2.2 +/- 1.1 mg/L with 49% of values >2 mg/L. An extended interval dosing method (24, 36 and 48 h) for infant weights of 0.75-5 kg was developed by simulation, and audited prospectively in 51 neonates. Prospective analysis of the extended interval dosing method showed a mean Cmax after the first dose of 13.1 +/- 3.6 mg/L, while the mean Cmin was 0.7 +/- 0.6 mg/L. Seventy-eight per cent had Cmax of >10 mg/L after the first dose. The mean area under the concentration versus time curve AUC0-24 was 93 mg*h/L (target = 100 mg*h/L). The extended interval dosing achieved higher Cmax values while ensuring that overall exposure per 24 h was acceptable. Prospective testing of the method demonstrated good predictive ability.