A Single-Run HPLC-MS Multiplex Assay for Therapeutic Drug Monitoring of Relevant First- and Second-Line Antibiotics in the Treatment of Drug-Resistant Tuberculosis

• मुख्य लेखकों: Niklas Köhler (लेखक), Hande Karaköse (लेखक), Hans-Peter Grobbel (लेखक), Doris Hillemann (लेखक), Sönke Andres (लेखक), Christina König (लेखक), Barbara Kalsdorf (लेखक), Thomas Theo Brehm (लेखक), Laura Böttcher (लेखक), Inna Friesen (लेखक), Harald Hoffmann (लेखक), Dražen Strelec (लेखक), Dagmar Schaub (लेखक), Charles A. Peloquin (लेखक), Stefan Schmiedel (लेखक), Laurent A. Decosterd (लेखक), Eva Choong (लेखक), Sebastian G. Wicha (लेखक), Rob E. Aarnoutse (लेखक), Christoph Lange (लेखक), Patricia M. Sánchez Carballo (लेखक)
• स्वरूप: पुस्तक
• प्रकाशित: MDPI AG, 2023-10-01T00:00:00Z.
• विषय: article
• ऑनलाइन पहुंच: Connect to this object online.
• Notes: 10.3390/pharmaceutics15112543; 1999-4923
• Keywords: TDM; levofloxacin; moxifloxacin; bedaquiline; linezolid; clofazimine; Pharmacy and materia medica; RS1-441
• Source: Pharmaceutics, Vol 15, Iss 11, p 2543 (2023)

The treatment of drug-resistant <i>Mycobacterium tuberculosis</i> relies on complex antibiotic therapy. Inadequate antibiotic exposure can lead to treatment failure, acquired drug resistance, and an increased risk of adverse events. Therapeutic drug monitoring (TDM) can be used to optimize the antibiotic exposure. Therefore, we aimed to develop a single-run multiplex assay using high-performance liquid chromatography-mass spectrometry (HPLC-MS) for TDM of patients with multidrug-resistant, pre-extensively drug-resistant and extensively drug-resistant tuberculosis. A target profile for sufficient performance, based on the intended clinical application, was established and the assay was developed accordingly. Antibiotics were analyzed on a zwitterionic hydrophilic interaction liquid chromatography column and a triple quadrupole mass spectrometer using stable isotope-labeled internal standards. The assay was sufficiently sensitive to monitor drug concentrations over five half-lives for rifampicin, rifabutin, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, terizidone/cycloserine, ethambutol, delamanid, pyrazinamide, meropenem, prothionamide, and para-amino salicylic acid (PAS). Accuracy and precision were sufficient to support clinical decision making (≤±15% in clinical samples and ±20-25% in spiked samples, with 80% of future measured concentrations predicted to fall within ±40% of nominal concentrations). The method was applied in the TDM of two patients with complex drug-resistant tuberculosis. All relevant antibiotics from their regimens could be quantified and high-dose therapy was initiated, followed by microbiological conversion. In conclusion, we developed a multiplex assay that enables TDM of the relevant first- and second-line anti-tuberculosis medicines in a single run and was able to show its applicability in TDM of two drug-resistant tuberculosis patients.