Once-a-Day Administration of Amikacin in Neonates: Assessment of Nephrotoxicity and Ototoxicity

Abstract

Neonates, especially preterms, are known to have low glomerular filtration rates (GFR). This may result in elevated trough concentrations during multiple administration of aminoglycosides (AGs), potentially leading to nephro- and ototoxic reactions. The once-daily administration (q.d.) of AGs has been shown to be equally or better tolerated in adults and children than the conventional schedules (twice daily, b.i.d.; thrice daily, t.i.d.), while offering potential pharmacodynamic and nursing advantages. No data, however, are available for neonates. As a consequence, this pilot study was conducted in order to assess the tolerance of the once-a-day administration of amikacin in comparison with the twice daily dose regimen, in relation to the pharmacokinetics of the drug under these two schedules. 22 Male neonates (gestational age ≥ 34 weeks; postnatal age ≤ 2 days) were randomized to receive amikacin (AK) (15 mg/kg/day) q.d. (n = 10) or b.i.d. (n = 12) together with ampicillin (50 mg/kg/12 h). AK plasma levels were measured at days 1,3,5 and 7 of treatment just before the next dose (trough level) and 1 h after completion of infusion (peak level) and after 3 and 6 h only at day 1. Due to the small size of the samples, no difference in efficacy could be assessed and was not the aim per sc. Glomerular dysfunction was assessed by creatinine clearance, and tubular injuries by the urinary excretion of proteins (retinol binding protein, ß2- microglobulin, clara cell protein (PI) and microalbumin), enzymes (Nacetyl- ß-D-glucosaminidase, alkaline phosphatase, alanine aminopeptidase, and y-glutamyltransferase), and total phospholipids (TPL) in urine. Ototoxicity was assessed by brainstem auditory evoked potentials (BAEPs) at days 0, 3 and 9 of therapy. Eight healthy neonates served as controls. All patients showed a normal and similar increase of GFR during the first postnatal days. Proteinuria did not increase, but enzymuria and TPL increased significantly during the treatment in both AK groups without significant difference between groups. BAEPs at day 9 were not significantly different between treated and untreated patients. We conclude from this pilot study that, in the absence of more toxicity, the q.d. administration of AK in neonates of ≥ 34 weeks of gestational age may be recommended over its bid schedule in view of its potential advantages.

Extended-Interval Aminoglycoside Administration for Children: A Meta-analysis

“…The majority of clinical failures occurred in 2 trials, 31,45 ie, 1 trial involving critically ill children in the pediatric intensive care unit of a South African university hospital 45 and 1 trial involving children 1 month to 8 years of age with suspected or proven severe bacterial infections in a university hospital in Zimbabwe. 31 In the other 8 trials 24,26,37,39,40,43,44,46 with pertinent data, clinical failure rates ranged from 0 to 11% in the ODD arms and from 0 to 10% in the MDD arms and there was no major difference in the compared regimens.…”

“…Twenty-four eligible studies [21][22][23][24][25][26][27][28][29][30][31][35][36][37][38][39][40][41][42][43][44][45][46][47] published between 1991 and 2003 were identified (Table 1). Aminoglycosides were used in different clinical settings (neonatal intensive care unit: 6 studies; cystic fibrosis: 3 studies; cancer: 5 studies; urinary tract infections: 4 studies; diverse infectious indications: 5 studies; pediatric intensive care unit: 1 study).…”

“…However, in 5 cases 21,23,27,28,47 slightly higher aminoglycoside dose was used in the MDD arm; and in 1 case 36 a slightly lower dose was used in the MDD arm. Most of the children included in the meta-analysis received short-term aminoglycosides (up to 10 days' duration), although some children in at least 11 trials 22,24,27,29,[36][37][38]42,[44][45][46] were treated for over 10 days.…”

“…The pooled ototoxicity rates for studies that provided auditory testing results 21,23,25,[35][36][37][38][39][40]42,44,46,47 were 2.3% (10 of 436 cases) in the ODD arms and 2.0% (8 of 406 cases) in the MDD arms. The fixedeffects risk ratio was 1.06 (95% CI: 0.51-2.19; P ϭ .92) ( Table 3).…”

Clinical pharmacokinetics of aminoglycosides in the neonate: a review

“…A study on the extended interval between doses is lacking. Langhendries et al [46] suggest administrating amikacin to neonates once daily. These authors compared peak and trough concentrations of amikacin after once-daily and twice-daily dosing.…”