Clinical Pharmacokinetics

, Volume 48, Issue 2, pp 71–88

Therapeutic Drug Monitoring of Aminoglycosides in Neonates

  • Daniël J. Touw
  • Elsbeth M. Westerman
  • Arwen J. Sprij
Review Article

Abstract

The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to extended-interval dosing. This evolution has also taken place in neonates. Neonates, however, display large interindividual differences in the pharmacokinetics of aminoglycosides due to developmental differences early in life. The volume of distribution of aminoglycosides shows a strong relationship with bodyweight, which tends to be larger (corrected for bodyweight) in more premature infants and those with sepsis. Renal clearance of aminoglycosides increases with gestational age and accelerates immediately after birth. Because of these developmental influences, there is great inter- and intraindividual variability in the volume of distribution and clearance of these drugs, and investigators have established aminoglycoside dosing regimens based on bodyweight and/or gestational age. Widely practised dosing regimens comprise 4–5 mg/kg bodyweight of gentamicin every 24–48 hours as a first dose, followed by dose adjustment based on therapeutic drug monitoring. Although formal toxicity studies are scarce, there is no evidence that aminoglycoside toxicity in neonates differs from that in adults. Monitoring of blood drug concentrations and intelligent reconstruction of individual pharmacokinetic behaviour using a population pharmacokinetic model, optimally chosen blood sampling times and appropriate pharmacokinetic software, help clinicians to quickly optimize aminoglycoside dosing regimens to maximize the clinical effect and minimize the toxicity of these drugs.

References

  1. 1.
    Trijbels-Smeulders M, Gerards LJ, Paskerde Jong PCM, et al. Epidemiology of neonatal group B streptococcal disease in the Netherlands. 1997–98. Pediatr Perinat Epidemiol 2002; 16(4): 334–41CrossRefGoogle Scholar
  2. 2.
    Fanos V, Dall’Agnola A. Antibiotics in neonatal infections. Drugs 1999; 58: 406–27CrossRefGoogle Scholar
  3. 3.
    Mingeot-LeClercq M-P, Glupczynski Y, Tulkens P. Aminoglycosides: activity and resistance. Antimicrob Agents Chemother 1999; 43: 727–37PubMedGoogle Scholar
  4. 4.
    Noone P, Parsons TMC, Pattison JR, et al. Experience in monitoring gentamicin therapy during treatment of serious Gram-negative sepsis. Br Med J 1974; 1:477–81PubMedCrossRefGoogle Scholar
  5. 5.
    Anderson ET, Young LS, Hewitt WL. Simultaneous antibiotic levels in “breakthrough” Gram-negative rod bacteremia. Am J Med 1976; 61: 493–7PubMedCrossRefGoogle Scholar
  6. 6.
    Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in Gram-negative pneumonia. Am J Med 1984; 77: 657–62PubMedCrossRefGoogle Scholar
  7. 7.
    Moore RD, Lietman PS, Smith CR. Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 1987; 155: 93–9PubMedCrossRefGoogle Scholar
  8. 8.
    Lorian V. Antibiotics in laboratory medicine. 4th ed. Baltimore (MD): Williams and Wilkins, 1996Google Scholar
  9. 9.
    Nicolau DP, Freeman CD, Belliveau PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother 1995; 39: 650–5PubMedCrossRefGoogle Scholar
  10. 10.
    Lundergan FS, Glasscock GF, Kim EH, et al. Once-daily gentamicin dosing in newborn infants. Pediatrics 1999; 103: 1228–34PubMedCrossRefGoogle Scholar
  11. 11.
    Stickland MD, Kirkpatrick CMJ, Begg EJ, et al. An extended interval dosing method for gentamicin in neonates. J Antimicrob Chemother 2001; 48: 887–93PubMedCrossRefGoogle Scholar
  12. 12.
    Daikos GL, Lolans VT, Jackson GG. First-exposure adaptive resistance to aminoglycoside antibiotics in vivo with meaning for optimal clinical use. Antimicrob Agents Chemother 1991; 35: 117–23PubMedCrossRefGoogle Scholar
  13. 13.
    Mingeot-LeClercq M-P, Tulkens P. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999; 43: 1003–12PubMedGoogle Scholar
  14. 14.
    Lehly DJ, Braun BI, Tholl DA, et al. Can pharmacokinetic dosing decrease nephrotoxicity associated with aminoglycoside therapy? J Am Soc Nephrol 1994; 8: 81–90Google Scholar
  15. 15.
    Giuliano RA, Verpooten GA, Verbist L, et al. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986; 236: 470–5PubMedGoogle Scholar
  16. 16.
    Rougier F, Ducher M, Maurin M, et al. Aminoglycoside dosages and nephrotoxicity: quantitative relationships. Clin Pharmacokinet 2003; 52: 493–500CrossRefGoogle Scholar
  17. 17.
    Brummett RE, Fox KE. Aminoglycoside-induces hearing loss in humans. Antimicrob Agents Chemother 1989; 33: 797–800PubMedCrossRefGoogle Scholar
  18. 18.
    Scheenstra J, Heijerman HG, Touw DJ, et al. Cochleotoxicity of systemically administered tobramycin in cystic fibrosis patients [abstract]. J Cyst Fibros 2007; 6 Suppl. 1:94Google Scholar
  19. 19.
    Smith PF. Are vestibular hair cells excited to death by aminoglycoside antibiotics? J Vest Res 2000; 10: 1–5Google Scholar
  20. 20.
    Leung JC, Marphis T, Craver RO, et al. Altered NMDA receptor expression in renal toxicity: protection with a receptor antagonist. Kidney Int 2004; 66: 167–76PubMedCrossRefGoogle Scholar
  21. 21.
    Chattopadhyay B. Newborns and gentamicin: how much and how often? J Antomicrob Chemother 2002; 49: 13–6CrossRefGoogle Scholar
  22. 22.
    Dahlgren JG, Anderson ET, Hewitt WL. Gentamicin blood levels: a guide to nephrotoxicity. Antimicrob Agents Chemother 1975; 8: 58–62PubMedCrossRefGoogle Scholar
  23. 23.
    Godman EL, Van Gelder J, Holmes R, et al. Prospective comparative study of variable dosage and variable frequency regimens for administration of gentamicin. Antimicrob Agents Chemother 1975; 8: 434–8CrossRefGoogle Scholar
  24. 24.
    Barclay ML, Kirkpatrick CMJ, Begg EJ. Once daily aminoglycoside therapy: is it less toxic than multiple daily doses and how should it be monitored? Clin Pharmacokinet 1999; 36: 89–98PubMedCrossRefGoogle Scholar
  25. 25.
    Koren G. Therapeutic drug monitoring principles in the neonate. Clin Chem 1997; 43: 222–7PubMedGoogle Scholar
  26. 26.
    Touw DJ, Bos JM. Development of gentamicin population parameters in pediatric patients [abstract]. Ther Drug Monit 1997; 19: 570Google Scholar
  27. 27.
    Stolk LML, Degraeuwe PLJ, Nieman FHM, et al. Population pharmacokinetics and relationship between demographic and clinical variables and pharmacokinetics of gentamicin in neonates. Ther Drug Monit 2002; 24: 527–31PubMedCrossRefGoogle Scholar
  28. 28.
    Allegaert K, Anderson BJ. Interindividual variability of aminoglycoside pharmacokinetics in preterm neonates at birth. Eur J Clin Pharmacol 2006; 62: 1011–2PubMedCrossRefGoogle Scholar
  29. 29.
    Contrepois A, Brion N, Garaud JJ, et al. Renal disposition of gentamicin, dibekacin, tobramycin, netilmicin, and amikacin in humans. Antimicrob Agents Chemother 1985; 27: 520–4PubMedCrossRefGoogle Scholar
  30. 30.
    Besunder JB, Reed MD, Blumer JL. Principles of drug disposition in the neonate: a critical evaluation of the pharmacokinetic-pharmacodynamic interface (part 1). Clin Pharmacokinet 1988; 14: 189–216PubMedCrossRefGoogle Scholar
  31. 31.
    Sum BL, Veltkamp SA, Westerman EM, et al. An extended-interval gentamicin dosing regimen in newborns: a prospective study. Eur J Hosp Pharm Science 2007; 13:98–104Google Scholar
  32. 32.
    Allegaert K, Anderson BJ, Van den Anker J, et al. Renal drug clearance in preterm neonates: relation to prenatal growth. Ther Drug Monit 2007; 29: 284–91PubMedCrossRefGoogle Scholar
  33. 33.
    Van den Anker JN. Pharmacokinetics and renal function in preterm infants. Acta Paediatr 1996; 85: 1393–9PubMedCrossRefGoogle Scholar
  34. 34.
    Veltkamp SA, Westerman EM, Sprij AJ, et al. Gentamicin in preterm neonates: an extended interval dosing schedule. Eur J Hosp Pharm Science 2007; 13:92–7Google Scholar
  35. 35.
    Faura CC, Garcia MR, Horga JF. Changes in gentamicin serum levels and pharmacokinetic parameters in the newborn in the course of treatment with aminoglycoside. Ther Drug Monit 1991; 13: 277–80PubMedCrossRefGoogle Scholar
  36. 36.
    Vervelde ML, Rademaker CMA, Krediet TG, et al. Population pharmacokinetics of gentamicin in preterm neonates: evaluation of a once-daily dosage regimen. Ther Drug Monit 1999; 21: 514–9PubMedCrossRefGoogle Scholar
  37. 37.
    Gal P, Gilman JT. Drug disposition in neonates with patent ductus arteriosus. Ann Pharmacother 1993; 27: 1383–8PubMedGoogle Scholar
  38. 38.
    Williams BS, Ransom JL, Gal P, et al. Gentamicin pharmacokinetics in neonates with patent ductus arteriosus. Crit Care Med 1997; 25: 273–5PubMedCrossRefGoogle Scholar
  39. 39.
    Touw DJ, Proost JH, Stevens R, et al. Gentamicin pharmacokinetics in preterm infants with a patent and a closed ductus arteriosus. Pharm World Sc 2001; 23: 200–4CrossRefGoogle Scholar
  40. 40.
    Allegaert K, Andersen BJ, Cossey V, et al. Limited predictability of amikacin clearance in extreme premature neonates at birth. Br J Clin Pharmacol 2006; 61: 39–48PubMedCrossRefGoogle Scholar
  41. 41.
    Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet 2003; 42: 403–17PubMedCrossRefGoogle Scholar
  42. 42.
    Southgate WM, DiPiro JT, Robertson AF. Pharmacokinetics of gentamicin in neonates on extracorporeal membrane oxygenation. Antimicrob Agents Chemother 1989; 33: 817–9PubMedCrossRefGoogle Scholar
  43. 43.
    Bhatt-Mehta V, Johnson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving extracorporeal membrane oxygenation. Pharmacotherapy 1992; 12: 28–32PubMedGoogle Scholar
  44. 44.
    Dodge WF, Jelliffe RW, Zwischenberger JB, et al. Population pharmacokinetic models: effect of explicit versus assumed constant serum concentration assay error patterns upon parameter values of gentamicin in infants on and off extracorporeal membrane oxygenation. Ther Drug Monit 1994; 16: 552–9PubMedCrossRefGoogle Scholar
  45. 45.
    Paap CM, Nahata MC. Clinical pharmacokinetics of antibacterial drugs in neonates. Clin Pharmacokinet 1990; 19: 280–318PubMedCrossRefGoogle Scholar
  46. 46.
    Dodge WA, Jelliffe RW, Richardson CJ, et al. Gentamicin population pharmacokinetic models for low birth weight infants using a new nonparametric method. Clin Pharmacol Ther 1991; 50: 25–31PubMedCrossRefGoogle Scholar
  47. 47.
    Jensen PD, Edgren BE, Brundage RC. Population pharmacokinetics of gentamicin in neonates using a nonlinear, mixed effects model. Pharmacotherapy 1992; 12: 178–82PubMedGoogle Scholar
  48. 48.
    Rocha MJ, Almeida AM, Afonso E, et al. The kinetic profile of gentamicin in premature neonates. J Pharm Pharmacol 2000; 52: 1091–7PubMedCrossRefGoogle Scholar
  49. 49.
    Lanao JM, Calvo MV, Mesa JA, et al. Pharmacokinetic basis for the use of extended interval dosage regimens of gentamicin in neonates. J Antimicrob Chemother 2004; 54: 193–8PubMedCrossRefGoogle Scholar
  50. 50.
    Garciá B, Barcia E, Pérez F, et al. Population pharmacokinetics of gentamicin in premature neonates. J Antimicrob Chemother 2006; 58: 372–9PubMedCrossRefGoogle Scholar
  51. 51.
    Rocha MJ, Almeida A, Falcao AC. Retrospective evaluation of gentamicin dosage guidelines for premature neonates. Eur J Hosp Pharm Science 2006; 12: 16–8Google Scholar
  52. 52.
    Ariano RE, Sitar DS, Davi M, et al. Bayesian pharmacokinetic analysis of a gentamicin nomogram in neonates: a retrospective study. Curr Ther Res 2003; 64: 178–88CrossRefGoogle Scholar
  53. 53.
    Falcao AC, Santos Buelga D, Méndez ME, et al. Population kinetics of tobramycin in neonates. Ther Drug Monit 2001; 23: 202–8PubMedCrossRefGoogle Scholar
  54. 54.
    De Hoog M, Mouton JW, Schoemaker RC, et al. Extended-interval dosing of tobramycin in neonates: implications for therapeutic drug monitoring. Clin Pharmacol Ther 2002; 71: 349–58PubMedCrossRefGoogle Scholar
  55. 55.
    Tréluyer J-M, Merlé Y, Semlali A, et al. Population pharmacokinetic analysis of netilmicin in neonates and infants with use of a nonparametric method. Clin Pharmacol Ther 2000; 67: 600–9PubMedCrossRefGoogle Scholar
  56. 56.
    Kenyon CF, Knoppert DC, Lee SK, et al. Amikacin pharmacokinetics and suggested dosage modifications for the preterm infant. Antimicrob Agents Chemother 1990; 34: 265–8PubMedCrossRefGoogle Scholar
  57. 57.
    Izquierdo M, Lanao JM, Cervero L, et al. Population pharmacokinetics of gentamicin in premature infants. Ther Drug Monit 1992; 14(3): 177–83PubMedCrossRefGoogle Scholar
  58. 58.
    De Hoog M, Schoemaker RC, Van den Anker JN, et al. NONMEM and NPEM2 population modelling: a comparison using tobramycin data in neonates. Ther Drug Monit 2002; 24: 359–65PubMedCrossRefGoogle Scholar
  59. 59.
    Siegel JD, McCracken GH, Thomas ML, et al. Pharmacokinetic properties of netilmicin in newborn infants. Antimicrob Agents Chemother 1979; 15:246–53PubMedCrossRefGoogle Scholar
  60. 60.
    Faura CC, Feret MA, Horga JF. Monitoring serum levels of gentamicin to develop a new regimen for gentamicin dosage in newborns. Ther Drug Monit 1991; 13: 268–76PubMedCrossRefGoogle Scholar
  61. 61.
    De Hoog M, Schoemaker RC, Mouton JW, et al. Tobramycin population pharmacokinetics in neonates. Clin Pharmacol Ther 1997; 62: 392–9PubMedCrossRefGoogle Scholar
  62. 62.
    Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, et al. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics 2007; 114: 111–8CrossRefGoogle Scholar
  63. 63.
    Gooding N, Elias-Jones A, Shenoy M. Gentamicin dosing in neonatal patients. Pharm World Sc 2001; 23: 179–80CrossRefGoogle Scholar
  64. 64.
    Begg EJ, Barclay ML, Duffull SB. A suggested approach to once-daily aminoglycoside dosing. Br J Clin Pharmac 1995; 39: 605–9CrossRefGoogle Scholar
  65. 65.
    Nesthaas E, Bangstad H-J, Sandvik L, et al. Aminoglycoside extended interval dosing in neonates is safe and effective: a meta-analysis. Arch Dis Child Fetal Neonatal Ed 2005; 90: F294–300CrossRefGoogle Scholar
  66. 66.
    Jelliffe RW, Schumitzky A, Van Guilder M, et al. Individualizing drug dosage regimens: roles of population pharmacokinetic and dynamic models, Bayesian fitting, and adaptive control. Ther Drug Monit 1993; 15: 380–93PubMedCrossRefGoogle Scholar
  67. 67.
    Jelliffe R, Schumitzky A, Van Guilder M. Nonpharmacokinetic clinical factors affecting aminoglycoside therapeutic precision: a simulation study. Drug Invest 1992; 4:20–9CrossRefGoogle Scholar
  68. 68.
    D’Argenio DZ. Optimal sampling times for pharmacokinetic experiments. J Pharmacokinet Biopharm 1981; 9: 739–56PubMedGoogle Scholar
  69. 69.
    Jelliffe RW, Iglesias T, Hurst AK, et al. Individualising gentamicin dosage regimens: a comparative review of selected models, data fitting methods and monitoring strategies. Clin Pharmacokinet 1991; 21: 461–78PubMedCrossRefGoogle Scholar
  70. 70.
    Jelliffe RW. Clinical applications of pharmacokinetics and control theory: planning, monitoring, and adjusting dosages regimens of aminoglycosides, lidocaine, digitoxin and digoxin. In: Maronde R, editor. Selected topics in clinical pharmacology. New York: Springer Verlag, 1986: 26–82CrossRefGoogle Scholar
  71. 71.
    Pons G, Tréluyer J-M, Dimet J, et al. Potential benefit of Bayesian forecasting for therapeutic drug monitoring in neonates. Ther Drug Monit 2002; 24: 9–14PubMedCrossRefGoogle Scholar
  72. 72.
    Touw DJ, van Weissenbruch MM, Lafeber HN. The predictive performance of therapeutic drug monitoring (TDM) of amikacin in neonates using an early single determination of the serum concentration together with a population model [abstract]. Br J Clin Pharm 2000; 50: 487–8Google Scholar
  73. 73.
    Jelliffe RW, Tahani B. A library of serum drug assay error patterns, and some suggestions for improved modeling and simulation of pharmacokinetic behavior. Technical Report no: 92-5. Los Angeles (CA): USC School of Medicine, Laboratory of Applied Pharmacokinetics [online]. Available from URL: http://www.lapk.org/techreports.php [Accessed 2009 Jan 16]Google Scholar
  74. 74.
    Touw DJ, Neef C, Thomson AH, et al. Cost-effectiveness of therapeutic drug monitoring: an update. Eur J Hosp Pharm Sci 2007; 13: 83–91Google Scholar
  75. 75.
    Van Lent-Evers NAEM, Mathot RAA, Geus WP, et al. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: a cost-effectiveness analysis. Ther Drug Monit 1999; 21: 63–73PubMedCrossRefGoogle Scholar
  76. 76.
    El Desoky ES, Sheikh AA, Al Hammadi AY. Aminoglycoside and vancomycin serum concentration monitoring and mortality due to neonatal sepsis in Saudi Arabia. J Clin Pharm Ther 2003; 28: 479–83PubMedCrossRefGoogle Scholar
  77. 77.
    De Hoog M, Van Zanten BA, Hop WC, et al. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr 2003; 142: 41–6PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Daniël J. Touw
    • 1
    • 2
  • Elsbeth M. Westerman
    • 1
    • 2
  • Arwen J. Sprij
    • 1
    • 3
  1. 1.Haga Teaching Hospitalthe Haguethe Netherlands
  2. 2.Central Hospital Pharmacythe Haguethe Netherlands
  3. 3.Juliana Children’s Hospitalthe Haguethe Netherlands
  4. 4.Den Haagthe Netherlands

Personalised recommendations