Gentamicin and Tobramycin in Neonates: Comparison of a New Extended Dosing Interval Regimen with a Traditional Multiple Daily Dosing Regimen

ABSTRACT

Because of a lack of data supporting traditional dosing regimens for aminoglycosides, especially in extremely low-birth-weight infants, the authors developed revised dosing guidelines. The new guidelines increased doses to 5 mg/kg (over traditional doses of 2.5 mg/kg) and lengthened the dosing interval. When results of the two regimens were compared in 120 infants, 26.8% of infants in the traditional dosing group had subtherapeutic levels at <5 μg/mL, whereas only 1.3% of infants in the new practice dosing group were subtherapeutic. With the new dosing practice, serum levels in 1.3% of infants also exceeded the upper therapeutic range of 12 μg/mL. In conclusion, by increasing the dose of aminoglycosides and extending the dosing intervals, therapeutic levels-as defined by a C_min <2 μg/mL and a C_max of 5 to 12 μg/mL-were obtained significantly more often. In essence the regimen involves once daily dosing for infants <1200 g who are >30 days of age and for infants <1200 g who are >7 days of age. Serum concentrations still need to be monitored where clinically indicated.

KEYWORD

Aminoglycosides - gentamicin - tobramycin - neonates - pharmacokinetics - dosing guidelines

REFERENCES

• 1 Lundergan F S, Glasscock G F, Kim E H, Cohen R S. Once-daily gentamicin dosing in newborn infants.  Pediatrics . 1999;  103 1228-1234
• 2 Nelson J D. Pocket Book of Pediatric Antimicrobial Therapy 1996-1997.  Baltimore: Williams & Wilkins 1997: 16
• 3 Prober C G, Stevenson D K, Benitz W E. The use of antibiotics in neonates weighing less than 1200 grams.  Pediatr Infect Dis J . 1990;  9 111-121
• 4 Murphy J E, Austin M L, Frye R F. Evaluation of gentamicin pharmacokinetics and dosing protocols in 195 neonates.  Am J Health Syst Pharm . 1998;  55 2280-2288
• 5 de Hoog M, Schoemaker R C, Mouton J W, van den Anker N J. Tobramycin population pharmacokinetics in neonates.  Clin Pharmacol Ther . 1997;  62 392-399
• 6 Hayani K C, Hatzopoulos F K, Frank A L. Pharmacokinetics of once-daily dosing of gentamicin in neonates.  J Pediatr . 1997;  131 76-80
• 7 Vervelde M L, Rademaker C M, Krediet T G, Fleer A, van Asten P, van Dijk A. Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen.  Ther Drug Monit . 1999;  21 514-519
• 8 Thureen P J, Reiter P D, Gresores A, Stolpman N M, Kawato K, Hall D M. Once- versus twice-daily gentamicin dosing in neonates ≥34 weeks' gestation: cost-effectiveness analyses.  Pediatrics . 1999;  103 594-598
• 9 Ohler K H, Menke J A, Fuller L. Use of higher dose extended interval aminoglycosides in a neonatal intensive care unit.  Am J Perinatol . 2000;  17 285-290
• 10 Koren G, James A, Perlman M. A simple method for the estimation of glomerular filtration rate by gentamicin pharmacokinetics during routine drug monitoring in the newborn.  Clin Pharmacol Ther . 1985;  38 680-685
• 11 Landers S, Berry P L, Kearns G L, Kaplan S L, Rudolph A J. Gentamicin disposition and effect on development of renal function in the very low birth weight infant.  Dev Pharmacol Ther . 1984;  7 285-302
• 12 Young T E, Mangum B. Neofax. 13th ed. Raleigh, NC: Acorn 2001: 32-53
• 13 Chicella M. Once-daily aminoglycoside dosing in pediatrics: what is its role?.  J Pediatr Pharm Pract . 2000;  5 98-103
• 14 Skopnik H, Wallraf R, Nies B, Troster K, Heimann G. Pharmacokinetics and antibacterial activity of daily gentamicin.  Arch Dis Child . 1992;  67 57-61
• 15 Moore R D, Smith C R, Lietman P S. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia.  Am J Med . 1984;  77 657-662
• 16 Noone P, Parsons T M, Pattison J R, Slack R C, Garfield-Davies D, Hughes K. Experience in monitoring gentamicin therapy during treatment of serious gram-negative sepsis.  Br Med J . 1974;  1 477-481
• 17 Moore R D, Lietman P S, Smith C R. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration.  J Infect Dis . 1987;  155 93-99
• 18 Gal P, Ransom J L, Weaver R L. Gentamicin in neonates: the need for loading doses.  Am J Perinatol . 1990;  7 254-257
• 19 Watterberg K L, Kelly H W, Angelus P, Backstrom C. The need for a loading dose of gentamicin in neonates.  Ther Drug Monit . 1989;  11 16-20
• 20 Semchuk W, Shevchuk Y M, Sankaran K, Wallace S M. Prospective, randomized, controlled evaluation of a gentamicin loading dose in neonates.  Biol Neonate . 1995;  67 13-20
• 21 Chan G LC. Alternative dosing strategy for aminoglycosides: impact on efficacy, nephrotoxicity, and ototoxicity.  DICP . 1989;  23 788-794
• 22 Verpooten G A, Giuliano R A, Verbist L, Eestermans G, De Broe E M. Once-daily dosing decreases renal accumulation of gentamicin and netilmicin.  Clin Pharmacol Ther . 1989;  45 22-27
• 23 Glover M L, Shaffer C L, Rubino C M. A multicenter evaluation of gentamicin therapy in the neonatal intensive care unit.  Pharmacotherapy . 2001;  21 7-10
• 24 Mercado C K, Brodsky N L, Hurt H. Extended interval dosing of gentamicin in preterm infants. Proceedings of the 2001 Pediatric Academic Societies Annual Meeting, Baltimore, April 28-May 1, 2001
• 25 McCormack J P, Jewesson P J. A critical reevaluation of the ``therapeutic range'' of aminoglycosides.  Clin Infect Dis . 1992;  14 320-339
• 26 Powell S H, Thompson W L, Luthe M A. Once-daily versus continuous aminoglycoside dosing: efficacy and toxicity in animal and clinical studies of gentamicin, netilmicin, and tobramycin.  J Infect Dis . 1983;  147 918-932
• 27 Rastogi A, Agarwal G, Pyati S, Lariosa A, Reyes D, Pildes R S. Does gentamicin cause renal toxicity and ototoxicity: ``new'' versus ``traditional''. Proceedings of the 2001 Pediatric Academic Societies Annual Meeting, Baltimore, April 28-May 1, 2001
• 28 Talati A J, Rinehart E, Korones S B. Evaluation of efficacy and safety of extended interval gentamicin dosing in very low birth weight neonates. Proceedings of the 2001 Pediatric Academic Societies Annual Meeting, Baltimore, April 28-May 1, 2001