Abstract
Pharmacokinetic/pharmacodynamic (PKPD) studies of anti-infectives are frequently performed in in vitro infection models where accurate quantification of antibiotic concentrations in bacterial growth media is crucial to establish PK/PD relationships. Here, a sensitive and rapid high-performance liquid chromatography (HPLC) method was developed to quantify tedizolid (TDZ) in the bacterial growth medium Mueller-Hinton broth (MHB). Matrix components were separated by direct protein precipitation with methanol (1:1). The chromatographic separation was carried out in a Dionex Ultimate 3000 HPLC system using an Accucore® C-18 RPMS HPLC column (2.6 µm, 100 × 2.1 mm) using isocratic elution with 25% acetonitrile and 75% of 0.1% formic acid. The lower limit of quantification was 0.03 mg/L when measured at 300 nm. Following relevant European Medicine Agency guidelines, the method was successfully validated for linearity, selectivity, recovery, inter- and intra-day precision, and accuracy and stability. When applied to in vitro PKPD studies, the method successfully quantified a range of TDZ concentration (Cmin, 0.09-Cmax, 0.65 mg/L) in MHB. The analyzed concentrations were in line with the planned PK profiles. The application of the developed method to quantify TDZ in MHB in in vitro PKPD studies is warranted.
Highlights
The growing concern of antibiotic resistance globally necessitates optimal antibiotic and dosing regimen selection
Tedizolid (TDZ, Figure 1) is a second-generation oxazolidinone that is effective against Methicillin-resistant Staphylococcus aureus (MRSA) and many linezolid- and vancomycin-resistant bacteria [1]. It is currently prescribed in patients with acute bacterial skin and skin structure infections, and it exhibited noninferiority in efficacy when compared to linezolid in phase 3 clinical studies [2]
The Mueller-Hinton broth (MHB) matrix provided no interference at the retention time of
Summary
The growing concern of antibiotic resistance globally necessitates optimal antibiotic and dosing regimen selection. Tedizolid (TDZ, Figure 1) is a second-generation oxazolidinone that is effective against Methicillin-resistant Staphylococcus aureus (MRSA) and many linezolid- and vancomycin-resistant bacteria [1] It is currently prescribed in patients with acute bacterial skin and skin structure infections, and it exhibited noninferiority in efficacy when compared to linezolid in phase 3 clinical studies [2]. In vitro pharmacokinetic/pharmacodynamic (PKPD) studies are frequently performed to quantify the concentration–effect relationship of TDZ against various bacteria using a variety of media and experimental settings [3,4,5]. Accurate quantification of the pharmacokinetics (PK), the concentration time profile, is a core component in PKPD studies to affirm the mimicked PK profile and quantify any deviation or/and potential degradation of the antibiotic under study during the course of the experiment [6]
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