Liquid Chromatography-Tandem Mass Spectrometry to Monitor Unbound and Total Ceftriaxone in Serum of Critically Ill Patients

Sjoerd Meenks*, Jos le Noble, Norbert Foudraine, Frank de Vries, Paddy Janssen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Ceftriaxone is recommended for empiric antimicrobial therapy in patients with sepsis. Therapeutic drug monitoring (TDM) guided dose optimisation could elucidate pharmacokinetic variabilities, improving treatment efficacy. However, detailed data on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) for unbound ceftriaxone quantification in serum are scarce.

OBJECTIVE: The authors aimed to develop a reliable UPLC-MS/MS method for serum ceftriaxone quantification and exhibit its application potential in routine hospital settings.

METHODS: In this observational, single centre study, UPLC-MS/MS method validation included specificity, carry-over, linearity, repeatability, intermediate precision, accuracy, limit of quantification, and plasma protein binding. Unbound and total ceftriaxone were quantified in the serum of 5 critically ill patients. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment calculations were performed for both unbound and total ceftriaxone. The PK/PD target for unbound ceftriaxone in serum was set at 4 times the non-species related minimum inhibitory concentration breakpoint of 1 mg/L for at least 60% of the dosing interval.

RESULTS: The UPLC-MS/MS method revealed acceptable limits for clinical samples, with coefficients of variation < 15.0% for concentrations between 0.2 - 400.0 mg/L. Ceftriaxone eluted at 1.94 min and ceftazidime, as internal standard, eluted at 1.42 min. Patients demonstrated a median unbound ceftriaxone fraction of 29.1% (IQR: 15.2 - 52.2). Day 1 of ceftriaxone treatment presented a median PK/PD target attainment of 100.0% (IQR: 81.1 - 100.0) for unbound ceftriaxone in serum, while for calculations based on total concentrations, this figure was 23.9 % (IQR: 10.5 - 80.6).

CONCLUSION: The described UPLC-MS/MS method enables reliable and rapid ceftriaxone quantification in the serum of critically ill patients. Method feasibility was exhibited for TDM purposes in routine clinical practice.

Original languageEnglish
Pages (from-to)341-349
Number of pages9
JournalCurrent Clinical Pharmacology
Volume16
Issue number4
Early online date27 Dec 2020
DOIs
Publication statusPublished - 2021

Keywords

  • Ceftriaxone
  • unbound
  • monitoring
  • mass spectrometry
  • critically ill
  • albumin
  • INTENSIVE-CARE-UNIT
  • BETA-LACTAM ANTIBIOTICS
  • PROTEIN-BINDING
  • CLINICAL PHARMACODYNAMICS
  • PHARMACOKINETICS
  • CEFEPIME
  • PROBABILITY
  • CEFTAZIDIME
  • MEROPENEM
  • INFUSION

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