One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates

Abstract

Gentamicin is widely used in the treatment of suspected or proven neonatal sepsis. Animal studies and systematic reviews from trials in older children and adults suggest that a one dose per day regimen is superior to a multiple doses per day regimen. Pharmacokinetic studies and retrospective audits in neonatal population also favour once a day administration of gentamicin. However, there is no consensus regarding the dose interval regimen in the neonatal population. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching MEDLINE (March 2005), EMBASE 1980 - 2004, Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2005) and CINAHL (December 1982 - March 2005). Abstracts of the Society for Pediatric Research were hand searched from 1980 to 2004 inclusive. No language restrictions were applied. All randomised or quasi randomised controlled trials comparing one dose per day ( 'once a day') compared to multiple doses per day ( 'multiple doses a day') of gentamicin to newborn infants < 28 days of life. Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. Data were sought regarding effects on clinical efficacy, pharmacokinetic efficacy, ototoxicity and nephrotoxicity of the two regimens. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data, the typical relative risk (RR), typical risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using weighted mean difference (WMD). Twenty four studies were initially identified. Thirteen were excluded and eleven studies (N = 574) included. All studies compared the effectiveness and safety of 'once a day' versus 'multiple doses a day' regimen of gentamicin in newborn infants. Only one study enrolled infants less than 32 weeks gestation. All except one trial used intravenous infusion. One trial used gentamicin as a bolus dose over one minute. Two trials used intramuscular gentamicin in some of their study infants. For the primary outcome of 'clearance of sepsis', all infants in both 'once a day' as well as 'multiple doses a day' regimen showed adequate clearance of sepsis [Typical RD 0.00 (95% CI - 0.19, 0.19); 3 trials; N = 36]. For the other primary outcome measures relating to gentamicin pharmacokinetics, 'once a day dosing' of gentamicin was superior. 'Once a day' gentamicin regimen is associated with less failures to attain peak level of at least 5 microg/ml [Typical RR 0.22 (95% CI 0.11, 0.47); Typical RD -0.13 (95% CI -0.19, -0.08); 9 trials; N = 422]; less failures to achieve trough levels of < 2 microg/ml [Typical RR 0.38 (95% CI 0.27, 0.55); Typical RD -0.22 (95% CI -0.29, -0.15); 11 trials N = 503]; higher peak levels [WMD 2.58 (95% CI 2.26, 2.89); 10 trials; N = 440] and lower trough levels [WMD -0.57 (95% CI -0.69, -0.44); 10 trials; N = 440] compared to 'multiple doses a day' regimen. Ototoxicity and nephrotoxicity were not noted with either of the treatment regimens. Significant heterogeneity was noted for some of the outcomes measured. Hence the results need to be interpreted with caution. Possible reasons for heterogeneity are different gestational ages of study infants and the timing of collection of blood samples in relation to a particular dose and the day of therapy on which the samples were collected. There is insufficient evidence from the currently available RCTs to conclude whether 'once a day' or 'multiple doses a day' regimen of gentamicin is superior in treating proven neonatal sepsis. However data suggests that pharmacokinetic properties of 'once a day' gentamicin regimen are superior to 'multiple doses a day' regimen in that it achieves higher peak levels while avoiding toxic trough levels. There is no change in nephrotoxicity or auditory toxicity. Based on this assessment of pharmacokinetics, 'once a day regimen' may be superior in treating neonatal sepsis in neonates more than 32 weeks gestation.