Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study.

Abstract

INTRODUCTION:

Individualised treatment through therapeutic drug monitoring (TDM) may improve tuberculosis (TB) treatment outcomes but is not routinely implemented. Prospective clinical studies of drug exposure and minimum inhibitory concentrations (MICs) in multidrug-resistant TB (MDR-TB) are scarce. This translational study aims to characterise the area under the concentration-time curve of individual MDR-TB drugs, divided by the MIC for Mycobacterium tuberculosis isolates, to explore associations with markers of treatment progress and to develop useful strategies for clinical implementation of TDM in MDR-TB.

METHODS AND ANALYSIS:

Adult patients with pulmonary MDR-TB treated in Xiamen, China, are included. Plasma samples for measure of drug exposure are obtained at 0, 1, 2, 4, 6, 8 and 10 hours after drug intake at week 2 and at 0, 4 and 6 hours during weeks 4 and 8. Sputum samples for evaluating time to culture positivity and MIC determination are collected at days 0, 2 and 7 and at weeks 2, 4, 8 and 12 after treatment initiation. Disease severity are assessed with a clinical scoring tool (TBscore II) and quality of life evaluated using EQ-5D-5L. Drug concentrations of pyrazinamide, ethambutol, levofloxacin, moxifloxacin, cycloserine, prothionamide and para-aminosalicylate are measured by liquid chromatography tandem-mass spectrometry and the levels of amikacin measured by immunoassay. Dried blood spot on filter paper, to facilitate blood sampling for analysis of drug concentrations, is also evaluated. The MICs of the drugs listed above are determined using custom-made broth microdilution plates and MYCOTB plates with Middlebrook 7H9 media. MIC determination of pyrazinamide is performed in BACTEC MGIT 960.

ETHICS AND DISSEMINATION:

This study has been approved by the ethical review boards of Karolinska Institutet, Sweden and Fudan University, China. Informed written consent is given by participants. The study results will be submitted to a peer-reviewed journal.

TRIAL REGISTRATION NUMBER:

NCT02816931; Pre-results.

• Authors: Lina Davies Forsman, Katarina Niward, Yi Hu, Rongrong Zheng, Xubin Zheng, Ran Ke, Weiping Cai, Chao Hong, Yang Li, Yazhou Gao, Jim Werngren, Jakob Paues, Johanna Kuhlin, Ulrika S H Simonsson, Erik Eliasson, Jan-Willem Alffenaar, Mikael Mansjö, Sven Hoffner, Biao Xu, Thomas Schön, Judith Bruchfeld
• Journal: BMJ open (BMJ Open) Vol. 8 Issue 9 Pg. e023899 (Oct 04 2018) ISSN: 2044-6055 [Electronic] England
• PMID: 30287613 (Publication Type: Clinical Trial Protocol, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Antitubercular Agents

Topics

• Adult
• Female
• Humans
• Male
• Antitubercular Agents (administration & dosage, classification, pharmacokinetics)
• China (epidemiology)
• Cohort Studies
• Drug Monitoring (methods)
• Microbial Sensitivity Tests (methods)
• Mycobacterium tuberculosis (drug effects, isolation & purification)
• Prospective Studies
• Serum Bactericidal Test
• Tuberculosis, Multidrug-Resistant (blood, drug therapy, epidemiology)
• Observational Studies as Topic