Benoit Llopis1,2, Alexandre Bleibtreu3, Dimitri Schlemmer2, Pascal Robidou1, Olivier Paccoud3, Nadine Tissot1,2, Gaëlle Noé1,2, Helga Junot4, Charles-Édouard Luyt5, Christian Funck-Brentano1, Noël Zahr1,2. 1. AP-HP. Sorbonne Université, Pitié-Salpêtrière Hospital, Department of Pharmacology, CIC-1901, Pharmacokinetics and Therapeutic Drug Monitoring Unit, UMR-S 1166, Paris, France. 2. AP-HP. Sorbonne Université, Laboratoire de suivi thérapeutique pharmacologique spécialisé, Paris, France. 3. AP-HP. Sorbonne Université, Pitié-Salpêtrière Hospital, Service de Maladies Infectieuses et Tropicales, Paris, France. 4. AP-HP. Sorbonne Université, Pharmacy Department, Pitié-Salpêtrière Hospital, Paris, France. 5. AP-HP. Sorbonne Université, Service de Médecine Intensive Réanimation, Institut de Cardiologie, Assistance Publique Hôpitaux de Paris (AP-HP), Sorbonne-Université, Hôpital Pitié-Salpêtrière, Paris, France.
Abstract
OBJECTIVES: Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients. METHODS: After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode. RESULTS: Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-200 mg/L for cefiderocol and 0.5-100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both. CONCLUSIONS: A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy.
OBJECTIVES: Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients. METHODS: After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode. RESULTS: Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1-200 mg/L for cefiderocol and 0.5-100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both. CONCLUSIONS: A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy.