Abstract
Objectives
Novel treatment options for some carbapenem-resistant Gram-negative pathogens have been identified by the World Health Organization as being of the highest priority. Ceftolozane–tazobactam is a novel cephalosporin–beta-lactamase inhibitor combination antibiotic with potent bactericidal activity against the most difficult-to-treat multi-drug resistant and extensively drug resistant Gram-negative pathogens. This study aimed to develop and validate a liquid chromatography – tandem mass spectrometry method for the simultaneous quantification of ceftolozane and tazobactam in plasma (total and unbound), renal replacement therapy effluent (RRTE), cerebrospinal fluid (CSF) and urine.
Methods
Analytes were separated using mixed-mode chromatography with an intrinsically base-deactivated C18 column and a gradient mobile phase consisting of 0.1% formic acid, 10 mM ammonium formate and acetonitrile. The analytes and internal standards were detected using rapid ionisation switching between positive and negative modes with simultaneous selected reaction monitoring.
Results
A quadratic calibration was obtained for plasma (total and unbound), RRTE and CSF over the concentration range of 1–200 mg/L for ceftolozane and 0.5–100 mg/L for tazobactam, and for urine the concentration range of 10–2,000 mg/L for ceftolozane and 5–1,000 mg/L for tazobactam. For both ceftolozane and tazobactam, validation testing for matrix effects, precision and accuracy, specificity and stability were all within the acceptance criteria of ±15%.
Conclusions
This methodology was successfully applied to one pilot pharmacokinetic study in infected critically ill patients, including patients receiving renal replacement therapy, and one case study of a patient with ventriculitis, where all patients received ceftolozane–tazobactam.
Funding source: Merck Sharp and Dohme
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Research funding: This study was funded in part by an investigator-initiated grant from MSD. SLP is a recipient of a National Health and Medical Research Council-funded Fellowship (APP1142757), JAR is a recipient of a National Health and Medical Research Council-funded Centre for Research Excellence Research Excellence (APP1044941), Project Grant (1062040) and Fellowship (APP1048652).
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Author contributions: SLP: method design, data analysis, interpretation of results and writing of manuscript; SP: method design, data analysis, writing of manuscript; FS: study protocol design and writing of manuscript; JL: study protocol design and writing of manuscript; JAR: study protocol design and interpretation of results and writing of manuscript; SCW: method design, data interpretation and writing of manuscript.
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Competing interests: JAR has provided consultancy and has received grant funding from MSD. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Ethical approval: The study was performed in accordance with the ethical standards, with ethical approval obtained for the use of drug-free human blood from the Royal Brisbane and Women’s Hospital Human Research Ethics Committee HREC/16/QRBW/211and HREC/17/QRBW/117.
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