ONCE DAILY GENTAMICIN DOSING IN NEONATES

Abstract

Aminoglycosides in combination with beta-lactam antibiotics are the cornerstone in the therapy of proved or suspected neonatal septicemia.1 Traditional published dosing schedules of aminoglycosides according to postnatal age as well as body weight recommend dosing intervals of gentamicin in neonates from 12 to 24 h.2 The therapeutic range of gentamicin is small. Because the bactericidal activity and the toxicity of gentamicin are dependent on plasma concentrations, drug monitoring is necessary. Peak serum concentrations >4 μg/ml are recommended for antibacterial efficacy, and higher peak values improve the post-antibiotic effect (a period of suppression of bacterial growth after cessation of exposure to aminoglycoside concentrations above the minimal inhibitory concentration).3, 4 However, trough serum concentrations >2 μg/ml are a risk factor for nephrotoxicity and ototoxicity.3 It has therefore been suggested that the administration of one large dose once daily could maximize the rate of bacterial killing and the post-antibiotic effect preventing regrowth of bacteria during the period of low antibiotic concentrations in serum; moreover the daily single dose regimen might be a less toxic.3, 5-7 Although the efficacy and safety of once daily administration of assessed aminoglycosides have been well-determined in different clinical setting in adults, data are scarce in newborns.8-10 This study was conducted to assess the tolerance and efficacy of once daily administration of gentamicin in comparison with a twice daily dose regimen in neonates. Patients and methods. A prospective, randomized clinical study was conducted from April to July of 1994 and from April to June of 1995 at the Neonatal Service, Hospital "12 de Octubre" (Level III), Madrid, Spain. All neonates weighing ≥1200 g with early suspected bacterial infection, who were born in our hospital and who were treated with gentamicin and ampicillin, were studied. Informed consent was obtained from parents before their infants were included in the study. Exclusion criteria were known renal impairment (serum creatinine >1.2 mg/dl), severe neonatal asphyxia and blood samples not available. Neonates were randomized to treatment with gentamicin 5 mg/kg either once daily (the study group), or in twice divided doses (the control group). According to the gestational age the patients were classified as premature (<37 weeks) or full term (≥37 weeks). Clinical efficacy was determined in both groups by clinical evaluation by customary evaluations. The gentamicin (5 mg/kg/day, in 1 or 2 doses) in 5% dextrose solution was administered intravenously during 60 min with a syringe pump in a concentration of 1 mg/ml. All patients received ampicillin concomitantly. Laboratory tests. The pharmacokinetic profiles of gentamicin and creatinine in serum were determined on the fourth day of treatment. Blood samples were obtained just before the administration of a dose to measure the trough and 2 h after starting the infusion to measure the peak. Serum concentration of gentamicin was measured with a fluorescence polarization immunoassay (FLx System, Abbott Laboratories, Chicago, IL), immediately after sample collection. The interday coefficient of variation of gentamicin concentration was 6.5% at 1 μg/ml, 3.5% at 4 μg/ml and 4.7% at 8 μg/ml. The lower limit of detection was 0.2 μg/ml. Dose and/or dosage interval were adjusted to keep peak concentrations between 6 and 12 μg/ml and trough values below 2 μg/ml. Individual pharmacokinetic indices (clearance, half-life, volume of distribution) were calculated by Pharmacokinetic System (PKS, Abbott Laboratories) assuming a one-compartment open linear model with zero order intravenous infusion and first order elimination and using a nonlinear least square method. We modified the PKS initial parameters and we used the Schwarz formula11 to calculate creatinine clearance. First morning urine was sampled within the 2 first days and on the seventh day of treatment. We determined the N-acetyl-D-glucosaminidase:creatinine ratio in a Hitachi 705 (Boeringher Mannheim S.A.), as a sensitive indicator of gentamicin-induced nephrotoxicity. Statistical analysis. Student's t test was applied (mean ± SD) to analyze continuous variables and chi square for categoric variables. Tests were two-tailed and P < 0.05 was considered significant. Results. Eighty patients were randomized, but only 65 completed the study, 33 in the study group (20 premature and 13 full term) and 32 in the control group (17 premature and 15 full term). The common characteristics of population in the two groups were comparable with respect to gestational age, birth weight, serum creatinine, duration of treatment and clinical or bacteriologic sepsis (Table 1).TABLE 1: Characteristics of the population* The peak concentrations were significantly higher (P < 0.001) in the study group (mean ± SD of 9.5 μg/ml ± 1.7, range of 5.1 - 12.1) than in the control group (mean of 6.4 μg/ml ± 1.6, range of 4 - 11.3). Results were similar when full term and preterm patients were analyzed separately. The full term patients in the study group had a mean peak concentration of 9.2 μg/ml ± 1.5 (range of 6.9 - 11.9), while the full term patients in the control group had a mean peak concentration of 5.7 μg/ml ± 1.3 (range of 4 - 8.4), P < 0.001. For the preterm patients mean values were as follows: study group 9.7 μg/ml ± 1.8 (range of 5.1 - 12.1) and control group 7.1 μg/ml ± 1.7 (range of 4 - 11.3), P < 0.001. There was one premature patient in the study group who presented a high peak just over the desired upper therapeutic limit. The trough concentrations were significantly lower (P = 0.002) in the study group (mean of 1.4 μg/ml ± 0.7; range, 0.4 to 3) than in the control group (mean of 2.2 μg/ml ± 1; range, 0.4 to 4.8). With respect to the gestational age, that significant difference was maintained in the premature group but not in the term group. In the study group the mean trough concentration in full term was 1.1 μg/ml ± 0.4 (range, 0.6 to 1.9) vs. 1.5 μg/ml ± 0.6 (range, 0.4 to 2.1) in the control group (no significant difference). In the study group of preterm patients the mean trough concentration was of 1.6 μg/ml ± 0.8 (range, 0.4 to 3) vs. 2.7 μg/ml ± 0.9 (range, 1 to 4.8) in the control group (P = 0.001). Dosages were adjusted in 12 patients (18.5%): 4 in the study group (all premature); and 8 in the control group (6 premature and 2 full term). Pharmacokinetic indices of the 65 patients included in the study are shown in Table 2.TABLE 2: Pharmacokinetic analyses There was no difference in clinical outcome between the two groups. N-Acetyl-beta-D-glucosaminidase urinary excretion increased during gentamicin therapy in both treatment groups without significant difference between them, although the concentrations were higher in the control group (from 64 ± 65 units/g on the first day to 103 ± 150 units/g on the seventh day of treatment) than in the study group (from 45 ± 38 units/g on the first day to 68 ± 32 units/g on the seventh day of treatment). Discussion. Newborns are known to have low glomerular filtration rates that might result in higher trough and increased volume of distribution resulting in lower peak therapeutic serum concentrations during repeated administration of aminoglycosides. These findings are more prominent in premature than in full term infants.5-7 In our study once daily administration of gentamicin resulted in better therapeutic serum concentrations with similar or fewer renal side effects than twice daily dosage in term and preterm neonates. Once daily dosing led to higher peak serum concentrations. This might result in better bactericidal activity and prolongation of postantibiotic effect.3, 5-7 No subtherapeutic peaks were found in preterm and full term neonates with once daily dosing and adjustment of dosage was required in only one premature patient who had a peak of 12.1 mg/dl. With once daily dosing trough serum concentrations were significantly lower, as has been described by other authors.8-10 All advantages were more evident in the group of premature neonates. Improved renal tolerance for aminoglycosides in neonates, especially in the premature infants, should be an aim of treatment. Some premature infants in both groups and some term infants of the control group developed potentially toxic trough serum concentrations requiring dosage adjustment. Probably the dosage of gentamicin in premature infants should be lower than the current dosing recommendations2 and it has been used in other studies.8-10 As recorded in other studies9-10 there are significant differences in the elimination half-life (t1/2) and the elimination constant (Ke) of gentamicin between premature and full term neonates. There was no difference in clinical outcome and this new schedule had more nursing advantages because of less time expended giving medication. The safety profile was similar in both group as demonstrated by similar increases in enzymuria. In fact there was a tendency to higher values in the control group, probably because of the significantly higher trough serum concentrations. In this study once daily dosing of gentamicin was safe in full term and premature neonates. This schedule has practical advantages and may improve the pharmacodynamic profile of the antibiotic as described in other studies.8-10 Concepción de Alba Romero, M.D., Ph.D. Elvira Gómez Castillo, M.D. Cecilia Manzanares Secades, Pharm.D. Jesús Rodriguez López, M.D. Luisa Arreaza López, Pharm.D. Pilar Saenz Valiente, Pharm.D, Ph.D. Neonatology Department and Biochemistry Service; Hospital 12 de Octubre; Madrid, Spain