Skip to main content
SpringerLink
Log in

Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling

  • short communication
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Objective

Our objective was to determine the population pharmacokinetic parameters of amikacin in pediatric patients to contribute to the future development of a revised optimum dose and population-specific dosing regimens.

Methods

We performed a retrospective chart review in non-critical pediatric patients (aged 1–12 years) who received amikacin for suspected or proven Gram-negative infection at a university hospital. The population pharmacokinetic models were developed using Monolix 4.4. Pharmacokinetic/pharmacodynamic (PK/PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets.

Results

The analysis included 134 amikacin plasma concentrations from 67 patients with a mean ± standard deviation age of 4.1 ± 3.9 years and bodyweight of 15 ± 8.4 kg. The patients received an amikacin total daily dose (TDD) of 23 ± 7.3 mg/kg, which resulted in peak and trough concentrations of 20.65 ± 7.6 and 2.4 ± 1.7 mg/l, respectively. The estimated pharmacokinetic parameters for amikacin were 1.2 l/h and 6.5 l for total body clearance (CL) and the volume of distribution (V), respectively. Dosing simulations showed that the standard dosing regimen (15 mg/kg/day) of amikacin achieved the PK/PD target of peak serum concentration (Cpeak)/minimum inhibitory concentration (MIC) ≥ 8 for an MIC of 2 mg/l; higher doses were required to achieve higher MIC values.

Conclusion

The simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Tally FP, Louie TJ, Weinstein WM, Bartlett JG, Gorbach SL. Amikacin therapy for severe gram-negative sepsis. Emphasis on infections with gentamicin-resistant organisms. Ann Intern Med. 1975;83(4):484–8.

    Article  PubMed  CAS  Google Scholar 

  2. Cho SY, Choi SM, Park SH, Lee DG, Choi JH, Yoo JH. Amikacin therapy for urinary tract infections caused by extended-spectrum beta-lactamase-producing Escherichia coli. Korean J Intern Med. 2016;31(1):156–61.

    Article  PubMed  CAS  Google Scholar 

  3. Han SB, Lee SC, Lee SY, Jeong DC, Kang JH. Aminoglycoside therapy for childhood urinary tract infection due to extended-spectrum beta-lactamase-producing Escherichia coli or Klebsiella pneumoniae. BMC Infect Dis. 2015;13(15):414.

    Article  CAS  Google Scholar 

  4. Bassetti M, Righi E, Esposito S, Petrosillo N, Nicolini L. Drug treatment for multidrug-resistant Acinetobacter baumannii infections. Future Microbiol. 2008;3(6):649–60.

    Article  PubMed  CAS  Google Scholar 

  5. Paul M, Lador A, Grozinsky-Glasberg S, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2014;07(1):CD003344.

    Google Scholar 

  6. Kumana CR, Yuen KY. Parenteral aminoglycoside therapy. Selection, administration and monitoring. Drugs. 1994;47(6):902–13.

    Article  PubMed  CAS  Google Scholar 

  7. Isaksson B, Nilsson L, Maller R, Soren L. Postantibiotic effect of aminoglycosides on gram-negative bacteria evaluated by a new method. J Antimicrob Chemother. 1988;22(1):23–33.

    Article  PubMed  CAS  Google Scholar 

  8. 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(1):93–9.

    Article  PubMed  CAS  Google Scholar 

  9. Beaucaire G, Leroy O, Beuscart C, Karp P, Chidiac C, Caillaux M. Clinical and bacteriological efficacy, and practical aspects of amikacin given once daily for severe infections. J Antimicrob Chemother. 1999;127(Suppl C):91–103.

    Article  Google Scholar 

  10. Moore RD, Smith CR, Lietman PS. The association of aminoglycoside plasma levels with mortality in patients with gram-negative bacteremia. J Infect Dis. 1984;149(3):443–8.

    Article  PubMed  CAS  Google Scholar 

  11. Moore RD, Smith CR, Lietman PS. Association of aminoglycoside plasma levels with therapeutic outcome in gram-negative pneumonia. Am J Med. 1984;77(4):657–62.

    Article  PubMed  CAS  Google Scholar 

  12. Boucher BA, Coffey BC, Kuhl DA, Tolley EA, Fabian TC. Algorithm for assessing renal dysfunction risk in critically ill trauma patients receiving aminoglycosides. Am J Surg. 1990;160(5):473–80.

    Article  PubMed  CAS  Google Scholar 

  13. Garraffo R, Iliadis A, Cano JP, Dellamonica P, Lapalus P. Application of Bayesian estimation for the prediction of an appropriate dosage regimen of amikacin. J Pharm Sci. 1989;78(9):753–7.

    Article  PubMed  CAS  Google Scholar 

  14. Zelenitsky SA, Harding GK, Sun S, Ubhi K, Ariano RE. Treatment and outcome of Pseudomonas aeruginosa bacteraemia: an antibiotic pharmacodynamic analysis. J Antimicrob Chemother. 2003;52(4):668–74.

    Article  PubMed  CAS  Google Scholar 

  15. Begg EJ, Barclay ML, Kirkpatrick CM. The therapeutic monitoring of antimicrobial agents. Br J Clin Pharmacol. 2001;52(Suppl 1):35S–43S.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Kashuba AD, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram-negative bacteria. Antimicrob Agents Chemother. 1999;43(3):623–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Craig WA, Redington J, Ebert SC. Pharmacodynamics of amikacin in vitro and in mouse thigh and lung infections. J Antimicrob Chemother. 1991;27(Supple C):29–40.

    Article  PubMed  CAS  Google Scholar 

  18. Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–55.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Best EJ, Gazarian M, Cohn R, Wilkinson M, Palasanthiran P. Once-daily gentamicin in infants and children: a prospective cohort study evaluating safety and the role of therapeutic drug monitoring in minimizing toxicity. Pediatr Infect Dis J. 2011;30(10):827–32.

    Article  PubMed  Google Scholar 

  20. Contopoulos-Ioannidis DG, Giotis ND, Baliatsa DV, Ioannidis JP. Extended-interval aminoglycoside administration for children: a meta-analysis. Pediatrics. 2004;114(1):e111–8.

    Article  PubMed  Google Scholar 

  21. Freeman CD, Nicolau DP, Belliveau PP, Nightingale CH. Once-daily dosing of aminoglycosides: review and recommendations for clinical practice. J Antimicrob Chemother. 1997;39(6):677–86.

    Article  PubMed  CAS  Google Scholar 

  22. FerriolsLisart R, AlosAlminana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Ph. 1996;53(10):1141–50.

    CAS  Google Scholar 

  23. Smyth AR, Bhatt J, Nevitt SJ. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane Database Syst Rev. 2017;3:CD002009.

    PubMed  Google Scholar 

  24. Lavielle M, Mentre F. Estimation of population pharmacokinetic parameters of saquinavir in HIV patients with the MONOLIX software. J Pharmacokinet Pharmacodyn. 2007;34(2):229–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatr. 1984;104(6):849–54.

    Article  PubMed  CAS  Google Scholar 

  26. Schwartz GJ, Gauthier B. A simple estimate of glomerular filtration rate in adolescent boys. J Pediatr. 1985;106(3):522–6.

    Article  PubMed  CAS  Google Scholar 

  27. Staples A, LeBlond R, Watkins S, Wong C, Brandt J. Validation of the revised Schwartz estimating equation in a predominantly non-CKD population. Pediatr Nephrol. 2010;25(11):2321–6.

    Article  PubMed  Google Scholar 

  28. Tam VH, Ledesma KR, Vo G, Kabbara S, Lim TP, Nikolaou M. Pharmacodynamic modeling of aminoglycosides against Pseudomonas aeruginosa and Acinetobacter baumannii: identifying dosing regimens to suppress resistance development. Antimicrob Agents Chemother. 2008;52(11):3987–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Anderson GD. Developmental pharmacokinetics. Semin Pediatr Neurol. 2010;17(4):208–13.

    Article  PubMed  Google Scholar 

  30. Kopcha RG, Fant WK, Warden GD. Increased dosing requirements for amikacin in burned children. J Antimicrob Chemother. 1991;28(5):747–52.

    Article  PubMed  CAS  Google Scholar 

  31. Sherwin CM, Wead S, Stockmann C, Healy D, Spigarelli MG, Neely A, et al. Amikacin population pharmacokinetics among paediatric burn patients. Burns. 2014;40(2):311–8.

    Article  PubMed  Google Scholar 

  32. Bressolle F, Gouby A, Martinez JM, Joubert P, Saissi G, Guillaud R, et al. Population pharmacokinetics of amikacin in critically ill patients. Antimicrob Agents Chemother. 1996;40(7):1682–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Belfayol L, Talon P, Eveillard M, Alet P, Fauvelle F. Pharmacokinetics of once-daily amikacin in pediatric patients. Clin Microbiol Infect. 1996;2(3):186–91.

    Article  PubMed  CAS  Google Scholar 

  34. Treluyer JM, Merle Y, Tonnelier S, Rey E, Pons G. Nonparametric population pharmacokinetic analysis of amikacin in neonates, infants, and children. Antimicrob Agents Chemother. 2002;46(5):1381–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Yu T, Stockmann C, Healy DP, Olson J, Wead S, Neely AN, et al. Determination of optimal amikacin dosing regimens for pediatric patients with burn wound sepsis. J Burn Care Res. 2015;36(4):e244–52.

    Article  PubMed  Google Scholar 

  36. Burdet C, Pajot O, Couffignal C, Armand-Lefevre L, Foucrier A, Laouenan C, et al. Population pharmacokinetics of single-dose amikacin in critically ill patients with suspected ventilator-associated pneumonia. Eur J Clin Pharmacol. 2015;71(1):75–83.

    Article  PubMed  CAS  Google Scholar 

  37. Delattre IK, Musuamba FT, Nyberg J, Taccone FS, Laterre PF, Verbeeck RK, et al. Population pharmacokinetic modeling and optimal sampling strategy for Bayesian estimation of amikacin exposure in critically ill septic patients. Ther Drug Monit. 2010;32(6):749–56.

    Article  PubMed  CAS  Google Scholar 

  38. Gonzalez LS 3rd, Spencer JP. Aminoglycosides: a practical review. Am Fam Phys. 1998;58(8):1811–20.

    Google Scholar 

  39. Langhendries JP, Battisti O, Bertrand JM, Francois A, Darimont J, Ibrahim S, et al. Once-a-day administration of amikacin in neonates: assessment of nephrotoxicity and ototoxicity. Dev Pharmacol Ther. 1993;20(3–4):220–30.

    Article  PubMed  CAS  Google Scholar 

  40. Prescott WA Jr. A survey of extended-interval aminoglycoside dosing practices in United States adult cystic fibrosis programs. Respir Care. 2014;59(9):1353–9.

    Article  PubMed  Google Scholar 

  41. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ. 1996;312(7027):338–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 8.0, 2018. http://www.eucast.org.

  43. Kato H, Hagihara M, Hirai J, Sakanashi D, Suematsu H, Nishiyama N, et al. Evaluation of amikacin pharmacokinetics and pharmacodynamics for optimal initial dosing regimen. Drugs R D. 2017;17(1):177–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Clinical Pharmacy, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451, Saudi Arabia

    Saeed Alqahtani, Abdullah Alsultan & Wael Mansy

  2. Clinical Pharmacokinetics and Pharmacodynamics Unit, King Saud University Medical City, Riyadh, Saudi Arabia

    Abdullah Alsultan

  3. Pediatric Clinical Pharmacy Services, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia

    Manal Abouelkheir

  4. Drug and Poison Information Center, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia

    Yasmine Elsharawy & Aljawharah Alkoraishi

  5. Drug Information Center, Sultan Bin Abdulaziz Humanitarian City, King Saud University, Riyadh, Saudi Arabia

    Reem Osman

Authors
  1. Saeed Alqahtani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Manal Abouelkheir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abdullah Alsultan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasmine Elsharawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aljawharah Alkoraishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Reem Osman
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wael Mansy
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Saeed Alqahtani.

Ethics declarations

Funding

The authors acknowledge financial support from the College of Pharmacy Research Center and the Deanship of Scientific Research, King Saud University (Riyadh, Saudi Arabia).

Conflict of interest

Saeed Alqahtani, Manal Abouelkheir, Abdullah Alsultan, Yasmine Elsharawy, Aljawharah Alkoraishi, Reem Osman, and Wael Mansy have no conflicts of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alqahtani, S., Abouelkheir, M., Alsultan, A. et al. Optimizing Amikacin Dosage in Pediatrics Based on Population Pharmacokinetic/Pharmacodynamic Modeling. Pediatr Drugs 20, 265–272 (2018). https://doi.org/10.1007/s40272-018-0288-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-018-0288-y

Search

Navigation