Clinical Pharmacology of Gentamicin in the Newborn Infant

Milner, R. D. G.; Ross, Julia; Froud, D. J. R.; Davis, JohnA.

doi:10.1136/adc.47.256.927

Cited by 17 publications

(4 citation statements)

References 5 publications

(12 reference statements)

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“…Although many authors512 believe trough concentrations are most important in predicting toxicity, others suggest that peak values, or both peak and trough values are most useful.1819 Steady state serum concentration or bioavailability (AUC) of gentamicin may be more closely related to the toxic effects of this drug. The volume of distribution of gentamicin is increased in the newborn9 20 and it is possible that intracellular penetration with subsequent slow release may occur in young neonates. How this may influence the toxicity of gentamicin in the neonate is unknown.…”

Section: Discussionmentioning

confidence: 99%

Incidence of potentially toxic concentrations of gentamicin in the neonate.

Mulhall¹,

Louvois²,

Hurley³

1983

Archives of Disease in Childhood

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SUMMARY The incidence of putatively toxic serum concentrations and the factors influencing their occurrence were investigated in a study of 91 neonates receiving parenteral gentamicin twice daily at a dose of mean (SD) 5 5 (O 1) mg/kg/day. Most neonates were preterm and of low birthweight.Serum concentrations, area under-the curve (AUC), and clearance were calculated.Potentially toxic trough concentrations (>2 mg/l) were recorded in 57 of 91 (63%) neonates; 24 of these had trough concentrations greater than 3 mg/I. These babies were of a significantly lower gestational age and were younger than the remainder of the population. Toxic trough concentrations were not accompanied by raised peak serum values. A wide variation in all pharmacokinetic variables was observed. Peak serum concentration was most highly correlated with dose, while trough concentration, AUC, and clearance were more dependent on postnatal age. Clearance of gentamicin decreased significantly with increasing serum urea and creatinine concentrations.Preterm neonates in the first week of life are likely to develop potentially toxic serum concentrations when receiving the currently recommended dose of gentamicin (5-6 mg/kg/day). To prevent accumulation the dosage interval may need to be increased to 18 hours in these babies.Gentamicin is a valuable broad spectrum antibiotic and is extensively used for the treatment of serious sepsis in the newborn. It is ototoxic and nephrotoxic in the adult,1-3 and although toxicity in the neonate is not well documented, it would be reasonable to expect similar or more pronounced effects to those seen in adults. To avoid toxic effects it has been suggested that trough serum gentamicin concentrations should be below 2 mg/l and that peak values should not exceed 12 mg/1.4 5 Peak serum values less than 4 mg/l are considered subtherapeutic.6 Using these criteria, the incidence of putatively toxic and of subtherapeutic serum concentrations of gentamicin were determined in a study of the records of 64 neonates: a further 27 neonates were examined prospectively. Data on physiological and clinical factors that influence serum values and total body clearance of gentamicin were analysed. Materials and methodsStudy population. Ninety one neonates (52 boys and 39 girls) between 1 and 28 days of age were treated. Fifty one of 91 babies began treatment in week 1 of life. Their gestational age and birthweight were mean (SEM) 31 (0-5) weeks (range 25-40 weeks) and 1725 (100) g (range 700-4300 g) respectively. The dose of gentamicin was mean (SD) 5 5 (0. 1) mg/kg/day divided 12 hourly and administered by either the intravenous or intramuscular route.Specimen collection and assay of gentamicin. One hundred and thirty eight blood samples (300 ,ul) were collected by heelprick immediately before (trough value) and one hour after (peak value) gentamicin. One hundred and thirty of 138 specimens were collected more than 48 hours after treatment began, that is at 'steady state'. Gentamicin concentration was determined on the day of recei...

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Section: Discussionmentioning

confidence: 99%

Incidence of potentially toxic concentrations of gentamicin in the neonate.

Mulhall¹,

Louvois²,

Hurley³

1983

Archives of Disease in Childhood

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“…Increased recovery of drug with age and duration of therapy has also been observed for gentamicin (16,20). However, for all ages and time periods studied, netilmicin excretion was greater than that reported for gentamicin.…”

Section: Discussionmentioning

confidence: 72%

“…This has also been reported for gentamicin and other aminoglycosides in infants ( 14,20). The low concentration after the first dose may be the result of rapid distribution of the drug to tissue compartmen ts outside the circulation before equili brium occurs.…”

Section: Discussionmentioning

confidence: 84%

Netilmicin Use in Pediatric Patients

Chindasilpa¹,

Schauf²,

Lr³

et al. 1980

Dev Pharmacol Ther

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40 newborn infants and children were treatcd with netilmicin. With a 2-mg/kg dose, the average peak serum concentration was 4.4 μg/ml. Serum concentrations resulting from the first dose were markedly lower than subsequent doses and therapeutically inadequate. Significant drug accumulation did not occur: peak and trough concentrations on days 2 and 7 were the same in patients with normal renal function. The half-life of netilmicin in infants Jess than I weck old was 3. 8 h, and 3. 0 h in infants older than I weck. Infants Jess than 7 days old require a prolonged dose interval (12 h ) to adequately clear the administered dose. Recovery of netilmicin in urine ranged from 50 to 100% and correlated with age and duration of treatment. Elimination of netilmicin was prolonged in newborn infants with renal failure and requires dosage adjustment. Transient change in creatinine clearance occurred in 2 patients (4.6%,) and ototoxicity was observed in 2 other patients.

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“…A loading dose of 3 mg/kg was used to ensure a satisfactory peak concentration from the start of treatment. 10 The distribution of aminoglycosides, in this case netilmicin, is related to birthweight and postnatal age. The volume of distribution of the drug depends on the extracellular fluid space of the patient,11 with the result that lower peak and smaller peak-trough differences are seen in low birthweight infants who have a larger fractional extracellular volume.…”

Section: Discussionmentioning

confidence: 99%

Clinical pharmacology of netilmicin in the newborn.

Phillips¹,

Milner²

1983

Archives of Disease in Childhood

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SUMMARY The plasma peak, trough, and peak-trough concentrations of netilmicin given to preterm and term infants were measured after different regimens to determine which dosage would provide satisfactory peak and trough concentrations. In infants aged less than 7 days, dosage regimens of 3 0 or 2-5 mg/kg every 12 hours gave satisfactory peak levels (range 592-12O0 Fg/ml) but troughs were above the desirable maximum level of 3 ,ug/ml in more than half the preterm infants. Subsequently a dosage regimen of 3 0 mg/kg immediately followed by 2 0 mg/kg every 12 hours resulted in trough levels that exceeded 3 ,ig/ml in only 2 of 25 preterm determinations and never in term infants, yet gave satisfactory peak levels (range 4 5-7.4 Fg/ml). In preterm infants aged 4 to 7 weeks a dosage of 3 mg/kg every 8 hours gave satisfactory peak and trough evels.Netilmicin is a recent addition to the aminoglycoside range of antibiotics which is claimed to be less nephrotoxic and ototoxic than gentamicin,1 2 is well tolerated clinically,3-8 and is effective against several gentamicin resistant strains of bacteria.9In view of the potential value of the drug in the treatment of newborn infants this study was undertaken to determine which dosage regimens would provide satisfactory peak and trough concentrations of netilmicin in preterm and term infants. The manufacturers recommend the clinician to aim for a peak concentration of less than 12 Fg/ml and a trough concentration of less than 3 t±g/ml. Patients and methodsThe infants studied were those admitted to the Regional Neonatal Intensive Care Unit, Jessop Hospital for Women, Sheffield from September 1981 to March 1982 who required broad spectrum antibiotic therapy for confirmed or suspected infection. At the time the trial began, the policy at the unit advocated the use of a combination of penicillin G and gentamicin and the only change in clinical management was the substitution of netilmicin for gentamicin. Measurements were made on 80 babies, 48 of whom were preterm (<37 weeks' gestation). Netilmicin (paediatric preparation 10 mg/mi, Kirby-Warrick Pharmaceuticals Ltd) was given by slow injection over 3 minutes into a peripheral vein.The dosage in use on the unit for gentamicin was an immediate dose of 3 mg/kg with 2 mg/kg subsequent doses 12 hourly for neonates <7 days of age and 8 hourly for >7 days of age. However, the initial regimen for netilmicin was recommended as 3 mg/kg every 12 hours but in the light of plasma netilmicin results the following regimens were also studied: 2-5 mg/kg every 12 hours, 3 mg/kg immediately followed by 2 mg/kg every 12 hours, and in infants aged 4 weeks or more, 3 mg/kg every 8hours. Blood (100-150 [L) was collected by heel prick into EDTA microtubes after at least four doses of netilmicin had been given to monitor plasma peak and trough levels. Specimens for trough levels were collected immediately before a netilmicin injection, and those for peak levels 30 minutes after the intravenous injection. Blood levels were monitored every 3 days to ensure ag...

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Clinical Pharmacology of Gentamicin in the Newborn Infant

Cited by 17 publications

References 5 publications

Incidence of potentially toxic concentrations of gentamicin in the neonate.

Incidence of potentially toxic concentrations of gentamicin in the neonate.

Netilmicin Use in Pediatric Patients

Clinical pharmacology of netilmicin in the newborn.

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