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Optimisation of fluconazole therapy for the treatment of invasive candidiasis in preterm infants
  1. Aline G J Engbers1,2,
  2. Robert B Flint2,3,
  3. Swantje Voeller1,4,
  4. Irwin Reiss2,
  5. Kian D Liem5,
  6. Jan-Willem C Alffenaar6,
  7. Dick Tibboel2,
  8. Sinno Simons2,
  9. Catherijne A J Knibbe1,7,
  10. Roger J Brüggemann8,9
  1. 1 Division of Systems Biomedicine and Pharmacology, LACDR, Leiden, The Netherlands
  2. 2 Department of Paediatrics, Division of Neonatology, Erasmus MC Sophia Children's Hospital, Rotterdam, The Netherlands
  3. 3 Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
  4. 4 Division of Biotherapeutics, LACDR, Leiden, The Netherlands
  5. 5 Department of Neonatology, Radboudumc, Nijmegen, The Netherlands
  6. 6 Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, Groningen, The Netherlands
  7. 7 Clinical Pharmacy, Saint Anthony Hospital, Nieuwegein, The Netherlands
  8. 8 Department of Pharmacy, Radboudumc, Nijmegen, The Netherlands
  9. 9 Radboudumc Center for Infectious Diseases and Center of Expertise in Mycology Radboudumc/CWZ, Radboud University Medical Center, Nijmegen, The Netherlands
  1. Correspondence to Professor Catherijne A J Knibbe, Clinical Pharmacy, Saint Anthony Hospital, Nieuwegein 3430 EM, The Netherlands; c.knibbe{at}


Introduction Fluconazole is an important antifungal in the prevention and treatment of invasive Candida infections in neonates, even though its use in preterm infants is still off-label. Here, we performed a population pharmacokinetic study on fluconazole in preterm neonates in order to optimise dosing through the identified predictive patient characteristics.

Methods Fluconazole concentrations obtained from preterm infants from two studies were pooled and analysed using NONMEM V.7.3. The developed model was used to evaluate current dosing practice. A therapeutic dosing strategy aiming to reach a minimum target exposure of 400 and 200 mg×hour/L per 24 hours for fluconazole-susceptible C. albicans meningitis and other systemic infections, respectively, was developed.

Results In 41 preterm neonates with median (range) gestational age 25.3 (24.0–35.1) weeks and median postnatal age (PNA) at treatment initiation 1.4 (0.2–32.5) days, 146 plasma samples were collected. A one-compartment model described the data best, with an estimated clearance of 0.0147 L/hour for a typical infant of 0.87 kg with a serum creatinine concentration of 60 µmol/L and volume of distribution of 0.844 L. Clearance was found to increase with 16% per 100 g increase in actual body weight, and to decrease with 12% per 10 µmol/L increase in creatinine concentration once PNA was above 1 week. Dose adjustments based on serum creatinine and daily dosing are required for therapeutic target attainment.

Conclusion In preterm neonates, fluconazole clearance is best predicted by actual body weight and serum creatinine concentration. Therefore, fluconazole dosing should not only be based on body weight but also on creatinine concentration to achieve optimal exposure in all infants.

Ethics statement The Erasmus MC ethics review board approved the protocol of the DINO Study (MEC-2014-067) and the Radboud UMC ethics review board waived the need for informed consent for cohort 2 (CMO-2021-8302). Written informed consent from parents/legal guardians was obtained prior to study initiation.

  • intensive care units
  • neonatal
  • neonatology
  • paediatrics
  • pharmacology
  • infectious disease medicine

Data availability statement

The data cannot be made available due to privacy of the participants.

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Data availability statement

The data cannot be made available due to privacy of the participants.

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  • Contributors RJB, RBF and SS conceived the presented idea. IR, KDL, J-WCA, DT and SS collected the data. AGJE, SV, CAJK and RJB analysed the data. AGJE, CAJK and RJB wrote the manuscript with input from all authors. AGJE is the guarantor.

  • Funding The DINO Study was funded by ZonMw (grant number: 80-83600-98-10190).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.