Pharmacokinetic and pharmacodynamic optimisation of intravenous tobramycin dosing among children with cystic fibrosis

  • Catherine M. T. Sherwin
  • Jeffery T. Zobell
  • Chris Stockmann
  • Bradley E. McCrory
  • Millie Wisdom
  • David C. Young
  • Jared Olson
  • Krow Ampofo
  • Michael G. Spigarelli
Original Paper


This study aimed to characterize the pharmacokinetics of tobramycin administered one, two, or three times daily and to develop an optimal dosing scheme for children with cystic fibrosis. Therapeutic drug monitoring data were obtained from children hospitalized at three academic medical centres from 2006 to 2012. Population pharmacokinetic models were constructed using NONMEM 7.2. Model-based simulations were performed in Matlab R2012b to identify optimal dosing regimens using pharmacodynamic targets. The pharmacokinetic analysis involved 257 patients with a median age of 8.1 years (range 0.1–18.8). Clearance was estimated as 5.59 L/h and the volume of distribution was 18.90 L. Mean (±SD) maximum serum concentrations were highest among patients dosed once per day (24.1 ± 8.9 μg/mL) and were lower among patients dosed two and three times per day (11.2 ± 1.4 and 8.1 ± 2.4 μg/mL, respectively). Simulations revealed that once daily dosing was the only effective regimen for a Pseudomonas aeruginosa MIC of 1.5 μg/mL and none of the tested regimens reliably achieved the pharmacodynamic target for MICs ≥2 μg/mL. Once daily dosing resulted in higher maximum serum concentrations when compared to multiple-daily dosing. In simulations, once daily dosing was the only regimen to achieve the pharmacodynamic target for all subjects with MICs <2 μg/mL.


Pseudomonas aeruginosa Aminoglycosides Pharmacometrics NONMEM 



The authors would like to thank Stephen B. Duffull, M Pharm (Clin), Ph.D, MPS University of Otago, New Zealand and Barbara Chatfield, M.D. Intermountain Cystic Fibrosis Paediatric Centre, UT, USA for their contributions to this study.


  1. 1.
    O’Sullivan BP, Freedman SD (2009) Cystic fibrosis. Lancet 373(9678):1891–1904. doi: 10.1016/S0140-6736(09)60327-5 PubMedCrossRefGoogle Scholar
  2. 2.
    Oppenheimer EH, Esterly JR (1975) Pathology of cystic fibrosis review of the literature and comparison with 146 autopsied cases. Perspect Pediatr Pathol 2:241–278PubMedGoogle Scholar
  3. 3.
    Zuckerman JB, Kotloff RM (1998) Lung transplantation for cystic fibrosis. Clin Chest Med 19(3):535–554PubMedCrossRefGoogle Scholar
  4. 4.
    Cystic Fibrosis Foundation (2007) Cystic Fibrosis Foundation patient registry: 2006 annual data report to the center directors. Cystic Fibrosis Foundation, BethesdaGoogle Scholar
  5. 5.
    Flume PA (2009) Pulmonary complications of cystic fibrosis. Respir Care 54(5):618–627PubMedCrossRefGoogle Scholar
  6. 6.
    Ramsey BW (1996) Management of pulmonary disease in patients with cystic fibrosis. N Engl J Med 335(3):179–188. doi: 10.1056/NEJM199607183350307 PubMedCrossRefGoogle Scholar
  7. 7.
    Young DC, Zobell JT, Stockmann C, Waters CD, Ampofo K, Sherwin CM, Spigarelli MG (2013) Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides. Pediatr Pulmonol. doi: 10.1002/ppul.22813 Google Scholar
  8. 8.
    Coulthard KP, Peckham DG, Conway SP, Smith CA, Bell J, Turnidge J (2007) Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis—caution with trough concentrations. J Cyst Fibros 6(2):125–130. doi: 10.1016/j.jcf.2006.05.015 PubMedCrossRefGoogle Scholar
  9. 9.
    Begg EJ, Barclay ML, Kirkpatrick CJ (1999) The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol 47(1):23–30PubMedCrossRefGoogle Scholar
  10. 10.
    Al-Aloul M, Miller H, Alapati S, Stockton PA, Ledson MJ, Walshaw MJ (2005) Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr Pulmonol 39(1):15–20. doi: 10.1002/ppul.20138 PubMedCrossRefGoogle Scholar
  11. 11.
    Kapusnik JE, Hackbarth CJ, Chambers HF, Carpenter T, Sande MA (1988) Single, large, daily dosing versus intermittent dosing of tobramycin for treating experimental pseudomonas pneumonia. J Infect Dis 158(1):7–12PubMedCrossRefGoogle Scholar
  12. 12.
    Vogelman BS, Craig WA (1985) Postantibiotic effects. J Antimicrob Chemother 15(Suppl A):37–46PubMedCrossRefGoogle Scholar
  13. 13.
    Chambers HF (2010) Chemotherapy of microbial diseases: aminoglycosides. In: Brunton LL, Chabner BA, Knollman BC (eds) Goodman and Gilman’s the pharmacological basis of therapeutics, 12th edn. The McGraw-Hill Companies Inc, New YorkGoogle Scholar
  14. 14.
    Barza M, Ioannidis JP, Cappelleri JC, Lau J (1996) Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 312(7027):338–345PubMedCrossRefGoogle Scholar
  15. 15.
    Smyth A, Tan KH, Hyman-Taylor P, Mulheran M, Lewis S, Stableforth D, Prof Knox A (2005) Once versus three-times daily regimens of tobramycin treatment for pulmonary exacerbations of cystic fibrosis—the TOPIC study: a randomised controlled trial. Lancet 365(9459):573–578. doi: 10.1016/S0140-6736(05)17906-9 PubMedGoogle Scholar
  16. 16.
    Flume PA, Mogayzel PJ Jr, Robinson KA, Goss CH, Rosenblatt RL, Kuhn RJ, Marshall BC (2009) Cystic fibrosis pulmonary guidelines: treatment of pulmonary exacerbations. Am J Respir Crit Care Med 180(9):802–808. doi: 10.1164/rccm.200812-1845PP PubMedCrossRefGoogle Scholar
  17. 17.
    Smyth AR, Bhatt J (2012) Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev 2:CD002009. doi:  10.1002/14651858.CD002009.pub4
  18. 18.
    Young DC, Zobell JT, Stockmann C et al (2013) Optimization of anti-pseudomonal antibiotics for cystic fibrosis pulmonary exacerbations: V. Aminoglycosides. Pediatr Pulmonol 48(11):1047–1061PubMedCrossRefGoogle Scholar
  19. 19.
    Jolley ME, Stroupe SD, Wang CH, Panas HN, Keegan CL, Schmidt RL, Schwenzer KS (1981) Fluorescence polarization immunoassay. I. Monitoring aminoglycoside antibiotics in serum and plasma. Clin Chem 27(7):1190–1197PubMedGoogle Scholar
  20. 20.
    Ette EI, Williams PJ (2004) Population pharmacokinetics I: background, concepts, and models. Ann Pharmacother 38(10):1702–1706. doi: 10.1345/aph.1D374 PubMedCrossRefGoogle Scholar
  21. 21.
    Ludden TM, Beal SL, Sheiner LB (1994) Comparison of the Akaike information criterion, the Schwarz criterion and the F test as guides to model selection. J Pharmacokinet Biopharm 22(5):431–445PubMedCrossRefGoogle Scholar
  22. 22.
    Ette EI (1997) Stability and performance of a population pharmacokinetic model. J Clin Pharmacol 37(6):486–495PubMedCrossRefGoogle Scholar
  23. 23.
    Burgess DS (2005) Use of pharmacokinetics and pharmacodynamics to optimize antimicrobial treatment of Pseudomonas aeruginosa infections. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 40(Suppl 2):S99–S104. doi: 10.1086/426189 CrossRefGoogle Scholar
  24. 24.
    Lacy MK, Nicolau DP, Nightingale CH, Quintiliani R (1998) The pharmacodynamics of aminoglycosides. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 27(1):23–27CrossRefGoogle Scholar
  25. 25.
    Moore RD, Lietman PS, Smith CR (1987) Clinical response to aminoglycoside therapy: importance of the ratio of peak concentration to minimal inhibitory concentration. J Infect Dis 155(1):93–99PubMedCrossRefGoogle Scholar
  26. 26.
    Vogelman B, Gudmundsson S, Leggett J, Turnidge J, Ebert S, Craig WA (1988) Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. J Infect Dis 158(4):831–847PubMedCrossRefGoogle Scholar
  27. 27.
    Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr (1999) Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother 43(3):623–629PubMedCentralPubMedGoogle Scholar
  28. 28.
    Mouton JW, Jacobs N, Tiddens H, Horrevorts AM (2005) Pharmacodynamics of tobramycin in patients with cystic fibrosis. Diagn Microbiol Infect Dis 52(2):123–127. doi: 10.1016/j.diagmicrobio.2005.02.011 PubMedCrossRefGoogle Scholar
  29. 29.
    Burkhardt O, Lehmann C, Madabushi R, Kumar V, Derendorf H, Welte T (2006) Once-daily tobramycin in cystic fibrosis: better for clinical outcome than thrice-daily tobramycin but more resistance development? J Antimicrob Chemother 58(4):822–829. doi: 10.1093/jac/dkl328 PubMedCrossRefGoogle Scholar
  30. 30.
    Guglielmo BJ, Quan LA, Stulbarg MS (1996) Pharmacokinetics of once-daily versus thrice daily tobramycin in cystic fibrosis patients. J Antimicrob Chemother 37(5):1040–1042PubMedCrossRefGoogle Scholar
  31. 31.
    Vic P, Ategbo S, Turck D, Husson MO, Launay V, Loeuille GA, Sardet A, Deschildre A, Druon D, Arrouet-Lagande C (1998) Efficacy, tolerance, and pharmacokinetics of once daily tobramycin for pseudomonas exacerbations in cystic fibrosis. Arch Dis Child 78(6):536–539PubMedCrossRefGoogle Scholar
  32. 32.
    Touw DJ, Knox AJ, Smyth A (2007) Population pharmacokinetics of tobramycin administered thrice daily and once daily in children and adults with cystic fibrosis. J Cyst Fibros 6(5):327–333. doi: 10.1016/j.jcf.2006.12.007 PubMedCrossRefGoogle Scholar
  33. 33.
    Cooney GF, Lum BL, Tomaselli M, Fiel SB (1994) Absolute bioavailability and absorption characteristics of aerosolized tobramycin in adults with cystic fibrosis. J Clin Pharmacol 34(3):255–259PubMedCrossRefGoogle Scholar
  34. 34.
    Levy J, Smith AL, Koup JR, Williams-Warren J, Ramsey B (1984) Disposition of tobramycin in patients with cystic fibrosis: a prospective controlled study. J Pediatr 105(1):117–124PubMedCrossRefGoogle Scholar
  35. 35.
    Town DJ, Vinks AA, Jacobs F, Heijerman HG, Bakker W (1996) Creatinine clearance as predictor of tobramycin elimination in adult patients with cystic fibrosis. Ther Drug Monit 18(5):562–569PubMedCrossRefGoogle Scholar
  36. 36.
    Turnidge J (2003) Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin N Am 17(3):503–528CrossRefGoogle Scholar
  37. 37.
    den Hollander JG, Fuursted K, Verbrugh HA, Mouton JW (1998) Duration and clinical relevance of postantibiotic effect in relation to the dosing interval. Antimicrob Agents Chemother 42(4):749–754Google Scholar
  38. 38.
    Craig WA, Redington J, Ebert SC (1991) Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. J Antimicrob Chemother 27(Suppl C):29–40PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Catherine M. T. Sherwin
    • 1
  • Jeffery T. Zobell
    • 3
    • 4
  • Chris Stockmann
    • 1
    • 2
  • Bradley E. McCrory
    • 5
  • Millie Wisdom
    • 6
  • David C. Young
    • 7
    • 8
  • Jared Olson
    • 1
    • 3
  • Krow Ampofo
    • 1
  • Michael G. Spigarelli
    • 1
    • 2
  1. 1.Department of PaediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  2. 2.Department of Pharmacology and ToxicologyUniversity of Utah College of PharmacySalt Lake CityUSA
  3. 3.Pharmacy, Intermountain Primary Children’s HospitalSalt Lake CityUSA
  4. 4.Intermountain Cystic Fibrosis Paediatric CentreSalt Lake CityUSA
  5. 5.Pharmacy, Cincinnati Children’s Hospital Medical CentreCincinnatiUSA
  6. 6.Phoenix Children’s HospitalPhoenixUSA
  7. 7.Intermountain Cystic Fibrosis Adult CentreSalt Lake CityUSA
  8. 8.Department of PharmacotherapyUniversity of Utah College of PharmacySalt Lake CityUSA

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