Skip to main content
SpringerLink
Log in

Optimization of β-Lactam Dosing Regimens in Neonatal Infections: Continuous and Extended Administration versus Intermittent Administration

  • Original Research Article
  • Published:
Clinical Pharmacokinetics Aims and scope Submit manuscript

Abstract

Background and Objective

In neonates, β-Lactam antibiotics are almost exclusively administered by intermittent infusion. However, continuous or prolonged infusion may be more beneficial because of the time-dependent antibacterial activity. In this pharmacokinetic/pharmacodynamic simulation study, we aimed to compare treatment with continuous, extended and intermittent infusion of β-lactam antibiotics for neonates with infectious diseases.

Methods

We selected population pharmacokinetic models of penicillin G, amoxicillin, flucloxacillin, cefotaxime, ceftazidime and meropenem, and performed a Monte Carlo simulation with 30,000 neonates. Four different dosing regimens were simulated: intermittent infusion in 30 min, prolonged infusion in 4 h, continuous infusion, and continuous infusion with a loading dose. The primary endpoint was 90% probability of target attainment (PTA) for 100% ƒT>MIC during the first 48 h of treatment.

Results

For all antibiotics except cefotaxime, continuous infusion with a loading dose resulted in a higher PTA compared with other dosing regimens. Sufficient exposure (PTA >90%) using continuous infusion with a loading dose was reached for amoxicillin (90.3%), penicillin G (PTA 98.4%), flucloxacillin (PTA 94.3%), cefotaxime (PTA 100%), and ceftazidime (PTA 100%). Independent of dosing regimen, higher meropenem (PTA for continuous infusion with a loading dose of 85.5%) doses might be needed to treat severe infections in neonates. Ceftazidime and cefotaxime dose might be unnecessarily high, as even with dose reductions, a PTA > 90% was retained.

Conclusions

Continuous infusion after a loading dose leads to a higher PTA compared with continuous, intermittent or prolonged infusion, and therefore has the potential to improve treatment with β-lactam antibiotics in neonates.

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

Similar content being viewed by others

References

  1. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736-88.

  2. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemother. 2012;56(6):2795–805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Drusano GL. Antimicrobial pharmacodynamics: critical interactions of “bug and drug.” Nat Rev Microbiol. 2004;2(4):289–300.

    Article  CAS  PubMed  Google Scholar 

  4. Guilhaumou R, Benaboud S, Bennis Y, Dahyot-Fizelier C, Dailly E, Gandia P, et al. Optimization of the treatment with beta-lactam antibiotics in critically ill patients-guidelines from the French Society of Pharmacology and Therapeutics (Société Française de Pharmacologie et Thérapeutique-SFPT) and the French Society of Anaesthesia and Intensive Care Medicine (Société Française d’Anesthésie et Réanimation-SFAR). Crit Care. 2019;23(1):104.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Vardakas KZ, Voulgaris GL, Maliaros A, Samonis G, Falagas ME. Prolonged versus short-term intravenous infusion of antipseudomonal β-lactams for patients with sepsis: a systematic review and meta-analysis of randomised trials. Lancet Infect Dis. 2018;18(1):108–20.

    Article  CAS  PubMed  Google Scholar 

  6. Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, et al. Continuous versus intermittent β-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med. 2016;194(6):681–91.

    Article  CAS  PubMed  Google Scholar 

  7. Zembles TN, Schortemeyer R, Kuhn EM, Bushee G, Thompson NE, Mitchell ML. Extended infusion of beta-lactams is associated with improved outcomes in pediatric patients. J Pediatr Pharmacol Ther. 2021;26(2):187–93.

    PubMed  PubMed Central  Google Scholar 

  8. Knoderer CA, Karmire LC, Andricopulos KL, Nichols KR. Extended infusion of piperacillin/tazobactam in children. J Pediatr Pharmacol Ther. 2017;22(3):212–7.

    PubMed  PubMed Central  Google Scholar 

  9. Shabaan AE, Nour I, Elsayed Eldegla H, Nasef N, Shouman B, Abdel-Hady H. Conventional versus prolonged infusion of meropenem in neonates with gram-negative late-onset sepsis: a randomized controlled trial. Pediatr Infect Dis J. 2017;36(4):358–63.

    Article  PubMed  Google Scholar 

  10. Visser GH, Eilers PH, Elferink-Stinkens PM, Merkus HM, Wit JM. New Dutch reference curves for birthweight by gestational age. Early Hum Dev. 2009;85(12):737–44.

    Article  PubMed  Google Scholar 

  11. Kanji S, Hayes M, Ling A, Shamseer L, Chant C, Edwards DJ, et al. Reporting guidelines for clinical pharmacokinetic studies: the ClinPK Statement. Clin Pharmacokinet. 2015;54(7):783–95.

    Article  PubMed  Google Scholar 

  12. McNamara PJ, Alcorn J. Protein binding predictions in infants. AAPS PharmSci. 2002;4(1):E4.

    Article  PubMed  Google Scholar 

  13. Herngren L, Ehrnebo M, Broberger U. Pharmacokinetics of free and total flucloxacillin in newborn infants. Eur J Clin Pharmacol. 1987;32(4):403–9.

    Article  CAS  PubMed  Google Scholar 

  14. Lam YW, Duroux MH, Gambertoglio JG, Barriere SL, Guglielmo BJ. Effect of protein binding on serum bactericidal activities of ceftazidime and cefoperazone in healthy volunteers. Antimicrob Agents Chemother. 1988;32(3):298–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Liebchen U, Dorn C, Kees M, Schiesser S, Hitzenbichler F, Kees F, et al. Comment on “Meropenem, Cefepime, and Piperacillin Protein Binding in Patient Samples.” Ther Drug Monit. 2020;42(6):909–10.

    Article  PubMed  Google Scholar 

  16. Quinn EL. Protein binding of semisynthetic penicillins. Postgrad Med J. 1964;40 Suppl:Suppl:23–30.

    Article  Google Scholar 

  17. Carlier M, Noë M, De Waele JJ, Stove V, Verstraete AG, Lipman J, et al. Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. J Antimicrob Chemother. 2013;68(11):2600–8.

    Article  CAS  PubMed  Google Scholar 

  18. Kinderformularium. https://www.kinderformularium.nl/. Accessed 1 Feb 2022.

  19. European Committee on Antimicrobial Susceptibility Testing. Clinical breakpoints - breakpoints and guidance [cited 1/2/2022]. https://www.eucast.org/clinical_breakpoints/. Accessed 1 Feb 2022.

  20. Committee for Medicinal Products for Human Use (CHMP). Guideline on the use of pharmacokinetics and pharmacodynamics in the development of antimicrobial medicinal products. 2016. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-use-pharmacokinetics-pharmacodynamics-development-antimicrobial-medicinal-products_en.pdf. Accessed 8 Aug 2022.

  21. Berry AV, Kuti JL. Pharmacodynamic thresholds for beta-lactam antibiotics: a story of mouse versus man. Front Pharmacol. 2022;13: 833189.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Leroux S, Roué JM, Gouyon JB, Biran V, Zheng H, Zhao W, et al. A population and developmental pharmacokinetic analysis to evaluate and optimize cefotaxime dosing regimen in neonates and young infants. Antimicrob Agents Chemother. 2016;60(11):6626–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li X, Qi H, Jin F, Yao BF, Wu YE, Qi YJ, et al. Population pharmacokinetics-pharmacodynamics of ceftazidime in neonates and young infants: Dosing optimization for neonatal sepsis. Eur J Pharm Sci. 2021;163: 105868.

    Article  CAS  PubMed  Google Scholar 

  24. Padari H, Metsvaht T, Germovsek E, Barker CI, Kipper K, Herodes K, et al. Pharmacokinetics of Penicillin G in Preterm and Term Neonates. Antimicrob Agents Chemother. 2018;62(5):e02238-17.

  25. Pullen J, de Rozario L, Stolk LM, Degraeuwe PL, van Tiel FH, Zimmermann LJ. Population pharmacokinetics and dosing of flucloxacillin in preterm and term neonates. Ther Drug Monit. 2006;28(3):351–8.

    Article  CAS  PubMed  Google Scholar 

  26. Tang BH, Wu YE, Kou C, Qi YJ, Qi H, Xu HY, et al. Population Pharmacokinetics and Dosing Optimization of Amoxicillin in Neonates and Young Infants. Antimicrob Agents Chemother. 2019 Feb;63(2):e02336-18.

  27. van den Anker JN, Pokorna P, Kinzig-Schippers M, Martinkova J, de Groot R, Drusano GL, et al. Meropenem pharmacokinetics in the newborn. Antimicrob Agents Chemother. 2009;53(9):3871–9.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to treatment and mortality during mandated emergency care for sepsis. N Engl J Med. 2017;376(23):2235–44.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Rhodes NJ, MacVane SH, Kuti JL, Scheetz MH. Impact of loading doses on the time to adequate predicted beta-lactam concentrations in prolonged and continuous infusion dosing schemes. Clin Infect Dis. 2014;59(6):905–7.

    Article  PubMed  Google Scholar 

  30. Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA. Continuous beta-lactam infusion in critically ill patients: the clinical evidence. Ann Intensive Care. 2012;2(1):37.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wu CC, Su YC, Wu KS, Wu TH, Yang CS. Loading dose and efficacy of continuous or extended infusion of beta-lactams compared with intermittent administration in patients with critical illnesses: a subgroup meta-analysis and meta-regression analysis. J Clin Pharm Ther. 2021;46(2):424–32.

    Article  CAS  PubMed  Google Scholar 

  32. Morales Junior R, Pereira GO, Tiguman GMB, Juodinis VD, Telles JP, de Souza DC, et al. Beta-lactams therapeutic monitoring in septic children-what target are we aiming for? A Scoping Review Front Pediatr. 2022;10: 777854.

    Article  PubMed  Google Scholar 

  33. Tsafaras GP, Ntontsi P, Xanthou G. Advantages and Limitations of the Neonatal Immune System. Front Pediatr. 2020;8:5.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Jager NGL, van Hest RM, Lipman J, Roberts JA, Cotta MO. Antibiotic exposure at the site of infection: principles and assessment of tissue penetration. Expert Rev Clin Pharmacol. 2019;12(7):623–34.

    Article  CAS  PubMed  Google Scholar 

  35. Roberts JA, Kirkpatrick CM, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Meropenem dosing in critically ill patients with sepsis and without renal dysfunction: intermittent bolus versus continuous administration? Monte Carlo dosing simulations and subcutaneous tissue distribution. J Antimicrob Chemother. 2009;64(1):142–50.

    Article  CAS  PubMed  Google Scholar 

  36. Roberts JA, Roberts MS, Robertson TA, Dalley AJ, Lipman J. Piperacillin penetration into tissue of critically ill patients with sepsis—Bolus versus continuous administration? Criti Care Med. 2009;37(3):926–33.

    Article  Google Scholar 

  37. Layios N, Visée C, Mistretta V, Denooz R, Maes N, Descy J, et al. Modelled target attainment after temocillin treatment in severe pneumonia: systemic and epithelial lining fluid pharmacokinetics of continuous versus intermittent infusions. Antimicrob Agents Chemother. 2022;66(3): e0205221.

    Article  CAS  PubMed  Google Scholar 

  38. Hartman SJF, Brüggemann RJ, Orriëns L, Dia N, Schreuder MF, de Wildt SN. Pharmacokinetics and target attainment of antibiotics in critically ill children: a systematic review of current literature. Clin Pharmacokinet. 2020;59(2):173–205.

    Article  PubMed  Google Scholar 

  39. Raza MA, Yao B-F, Shi H-Y, Xu H-Y, Hao G-X, Van Den Anker J, et al. Optimal dose of meropenem for the treatment of neonatal sepsis: dosing guideline variations and clinical practice deviations. Br J Clin Pharmacol. 2022;88(7):3483–9.

    Article  PubMed  Google Scholar 

  40. Shaffer CL, Davey AM, Ransom JL, Brown YL, Gal P. Ampicillin-induced neurotoxicity in very-low-birth-weight neonates. Ann Pharmacother. 1998;32(4):482–4.

    Article  CAS  PubMed  Google Scholar 

  41. van Donge T, Fuchs A, Leroux S, Pfister M, Rodieux F, Atkinson A, et al. Amoxicillin dosing regimens for the treatment of neonatal sepsis: balancing efficacy and neurotoxicity. Neonatology. 2020;117(5):619–27.

    Article  PubMed  Google Scholar 

  42. Imani S, Buscher H, Marriott D, Gentili S, Sandaradura I. Too much of a good thing: a retrospective study of β-lactam concentration-toxicity relationships. J Antimicrob Chemother. 2017;72(10):2891–7.

    Article  CAS  PubMed  Google Scholar 

  43. Ortgies T, Rullmann M, Ziegelhöfer D, Bläser A, Thome UH. The role of early-onset-sepsis in the neurodevelopment of very low birth weight infants. BMC Pediatr. 2021;21(1):289.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Imburgia TA, Kussin ML. A Review of Extended and Continuous Infusion Beta-Lactams in Pediatric Patients. J Pediatr Pharmacol Ther. 2022;27(3):214–27.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank Dr V. Bekker (Department of Pediatrics, Willem Alexander Children's Hospital, Leiden University Medical Center ,Leiden, The Netherlands) and Professor Dr L.G. Visser (Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands) for their comments on this manuscript.

Author information

Authors and Affiliations

  1. The Hague Hospital Pharmacy, The Hague, The Netherlands

    Emiel Leegwater

  2. Department of Hospital Pharmacy, Haga Teaching Hospital, The Hague, The Netherlands

    Emiel Leegwater & Bert N. Storm

  3. Department of Infectious Diseases, Leiden University Medical Centre, Leiden University, Leiden, The Netherlands

    Emiel Leegwater

  4. Juliana Children’s Hospital, Haga Teaching Hospital, The Hague, The Netherlands

    Leo Wewerinke, Anne M. de Grauw, Mirjam van Veen & Matthijs D. Kruizinga

  5. Department of Paediatrics, Willem Alexander Children’s Hospital, Leiden University Medical Center, Leiden, The Netherlands

    Matthijs D. Kruizinga

Authors
  1. Emiel Leegwater
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Leo Wewerinke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Anne M. de Grauw
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mirjam van Veen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bert N. Storm
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Matthijs D. Kruizinga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emiel Leegwater.

Ethics declarations

Author Contribution

Not applicable.

Funding

The authors carried out this study without any internal or external financial support.

Conflicts of Interest

Emiel Leegwater, Leo Wewerinke, Anne M. de Grauw, Mirjam van Veen, Bert N. Storm, and Matthijs D. Kruizinga have no conflicts of interest to declare.

Ethics Approval

Not applicable.

Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code Availability

The code generated during the current study are available from the corresponding author upon reasonable request.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 2013 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Leegwater, E., Wewerinke, L., de Grauw, A.M. et al. Optimization of β-Lactam Dosing Regimens in Neonatal Infections: Continuous and Extended Administration versus Intermittent Administration. Clin Pharmacokinet 62, 715–724 (2023). https://doi.org/10.1007/s40262-023-01230-w

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40262-023-01230-w

Search

Navigation