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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
Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
Fudan Univ, Peoples R China; Fudan Univ, Peoples R China.
Xiamen City Ctr Dis Control, Peoples R China.
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2018 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 8, no 9, article id e023899Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018. Vol. 8, no 9, article id e023899
Keywords [en]
tuberculosis; clinical pharmacology; public health; microbiology
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:liu:diva-153393DOI: 10.1136/bmjopen-2018-023899ISI: 000450417800153PubMedID: 30287613Scopus ID: 2-s2.0-85054436449OAI: oai:DiVA.org:liu-153393DiVA, id: diva2:1271502
Note

Funding Agencies|Swedish Heart Lung Foundation [20150508]; Swedish National Research Council [540-2013-8797]; National Research Foundation of China [81361138019]

Available from: 2018-12-17 Created: 2018-12-17 Last updated: 2019-05-01Bibliographically approved
In thesis
1. Towards individualised treatment of tuberculosis
Open this publication in new window or tab >>Towards individualised treatment of tuberculosis
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Each year, around 10 million of individuals develop active tuberculosis (TB). Worldwide, TB is the leading cause of death from an infectious agent surpassing both malaria and HIV. Current treatment regimens are long and therefore encompass a risk of nonadherence and development of acquired drug-resistance, reflected in the increase of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. Indeed, this calls for prudent use of existing TB drugs and improvement of TB treatment strategies. The aim of this thesis was to investigate the current drug susceptibility testing (DST) breakpoints for Mycobacterium tuberculosis (M. tuberculosis), the pharmacokinetics and pharmacodynamics (PK/PD) of TB treatment and to explore the role of therapeutic drug monitoring (TDM) for optimising TB treatment.

Drug resistance in M. tuberculosis is expressed over a continuous scale and for some drugs it may be identified as low- and high-level resistance. This has been poorly reflected in currently used binary susceptibility breakpoints for TB drugs. Results from genome sequencing and phenotypic DST of ofloxacin and levofloxacin were compared in study I and current breakpoints were found to misclassify up to 25% of M. tuberculosis isolates with resistance mutations in gyrA as susceptible to fluoroquinolones. This finding may have implications for the classification of XDR-TB, treatment of MDR-TB and the evaluation of fluoroquinolones in clinical studies.

Study II was a prospective cohort study of susceptible TB in Sweden, where drug concentrations of first-line TB drugs were measured along with the susceptibility level of the bacteria defined by the minimum inhibitory concentration (MIC) of M. tuberculosis. First-line drug concentrations below the reference range (16-42%) were common and most pronounced for rifampicin (13/31, 42%). An exploratory investigation of PK/PD parameters displayed a wide distribution of ratios between drug exposures and MICs. Rifampicin exhibited higher level of individual fluctuations over time during TB treatment compared with isoniazid. In study III the plasma drug concentrations of rifampicin were compared to the tuberculosis drug activity assay (TDA) and results showed that rifampicin drug levels, but not drug levels of the other first-line drugs, correlated with TDA. Patients with rifampicin drug levels below 8 mg/L had significantly lower median TDA. This finding supports the use of TDA as a potential indicator for low rifampicin exposure in resource-constrained settings without access to drug concentration analysis. The study design in study II has been further developed in study IV, which is a prospective cohort study of MDR-TB in China, where drug exposure will be explored in relation to individual bacterial MIC and measurements of treatment outcome.

In summary, the work in this thesis emphasises the importance of reliable DST of M. tuberculosis and the need to re-evaluate the currently used breakpoints. Therapeutic drug monitoring (TDM) based on drug concentrations and MICs is a useful tool to avoid suboptimal drug exposure and to individualise TB treatments. Such strategies may improve treatment regimens and avoid further development of resistance.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 94
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1662
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-156494 (URN)10.3384/diss.diva-156494 (DOI)9789176851289 (ISBN)
Public defence
2019-05-23, Hugo Theorell, Hus 448, Universitetssjukhuset, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2019-04-24Bibliographically approved

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