Simplified Dosing of Gentamicin for Treatment of Sepsis in Bangladeshi Neonates

Abstract

Extended-interval dosing of gentamicin has several advantages over conventional multiple-daily dosing for the treatment of sepsis. The study was conducted to evaluate the pharmacokinetics of gentamicin for the treatment of neonatal sepsis in predetermined doses at 24-or 48-hour intervals, according to weight category, and to develop a simplified protocol for use in peripheral healthcare settings in developing countries. This prospective observational study was conducted among 59 neonates admitted to the Special Care Nursery at Dhaka Shishu Hospital, Bangladesh, with suspected sepsis and treated with antibiotics, including gentamicin. Intravenous dosing of gentamicin according to weight category was: 10 mg every 48 hours if the infant weighed <2,000 g (n=23), 10 mg every 24 hours if the infant weighed 2,000-2,249 g (n=12), or 13.5 mg every 24 hours if the infant weighed 2,500-3,000 g (n=24). Peak and trough concentrations of gentamicin and the presence of signs of nephrotoxicity and ototoxicity were determined. The mean±standard deviation peak concentration of gentamicin was 12.3±3.7 µg/mL in infants weighing <2,000 g, 9.6±3.1 µg/mL in infants 2,000-2,249 g, and 10.0±3.4 µg/mL in infants 2,500-3,000 g. Initial peak concentration of gentamicin was >12 µg/mL in 28.8% and initial trough concentration was >2 µg/mL in 6.8% of the subjects. No signs of nephrotoxicity or ototoxicity were detected. Favourable pharmacokinetic parameters found with the simplified dosing regimen suggest that it is safe for the treatment of neonatal sepsis.

Clinical Pharmacokinetics of Penicillins, Cephalosporins and Aminoglycosides in the Neonate: A Review

“…Most of the studies on the pharmacokinetics of penicillins, cephalosporins and aminoglycosides are classical pharmacokinetic studies where several blood samples were taken from each patient. Nevertheless, few studies of population pharmacokinetics have been provided for benzylpenicillin [ 11 ], for amoxicillin [ 16 , 18 , 21 ], flucloxacillin [ 22 ], for gentamicin [ 75 , 76 , 77 , 78 , 79 , 107 ], for netilmicin [ 104 ] and for amikacin [ 100 , 101 ]. The results of the population pharmacokinetic studies are consistent with those of the classical pharmacokinetic investigations.…”

“…Increasing the gentamicin dose to 4–5 µg/mL once-daily, the peak and trough concentration of gentamicin ranged between 5 and 12 µg/mL. Increasing the gentamicin dose to 5 µg/mL and extending the interval between doses to 36–48 h the gentamicin peak and trough concentrations ranged between <12 and <2 µg/mL, respectively [ 75 , 76 , 77 , 78 , 79 ]. This consideration also applies to tobramycin and netilmicin.…”

“…Gestational age and postnatal age have an important effect on Cl and consequently on t 1/2 of penicillins [ 10 , 14 , 15 , 18 , 20 , 22 , 23 , 29 ], cephalosporins [ 33 , 38 , 42 , 43 , 45 , 57 , 60 , 63 ] and aminoglycosides [ 78 , 79 , 85 , 86 , 107 ]. Thus, gestational and postnatal ages are factors generating interindividual variability in the pharmacokinetics of penicillins, cephalosporins and aminoglycosides.…”

“…Later, it appeared that once-daily gentamicin dosing of 4–5 mg/kg yields higher peak and lower trough gentamicin concentration than twice-daily dosing [for review see Rao et al [ 71 ] and Miron [ 72 ]. Recently, administering 5 mg/kg gentamicin and extending the dose interval to 36-48 h has been recommended [ 73 , 74 , 75 , 76 , 77 , 78 ]. Extending the dose interval to 48 h and increasing the gentamicin dose to 5 mg/kg causes an increase in peak concentration as compared with the dose of 2.5 mg/kg every 12 h [ 74 , 75 , 76 , 77 , 78 ].…”

“…Recently, administering 5 mg/kg gentamicin and extending the dose interval to 36-48 h has been recommended [ 73 , 74 , 75 , 76 , 77 , 78 ]. Extending the dose interval to 48 h and increasing the gentamicin dose to 5 mg/kg causes an increase in peak concentration as compared with the dose of 2.5 mg/kg every 12 h [ 74 , 75 , 76 , 77 , 78 ]. Begg et al [ 77 ] observed that the optimal interval between doses is 48 h, 36 h, and 24 h for neonates whose body weight is <1 kg, 1–2.49 kg and ≥2.5 kg, respectively.…”