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Towards individualised treatment of tuberculosis
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology, Infection and Inflammation. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Infectious Diseases.
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: urn:nbn:se:liu:diva-156494DOI: 10.3384/diss.diva-156494ISBN: 9789176851289 (print)OAI: oai:DiVA.org:liu-156494DiVA, id: diva2:1306623
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
List of papers
1. Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
Open this publication in new window or tab >>Susceptibility testing breakpoints for Mycobacterium tuberculosis categorize isolates with resistance mutations in gyrA as susceptible to fluoroquinolones: implications for MDR-TB treatment and the definition of XDR-TB.
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2016 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 71, no 2, p. 333-338Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES: Fluoroquinolones (FQs) are important in the treatment of MDR-TB and in the definition of XDR-TB. Our objective was to investigate how discrepancies in the phenotypic and genotypic methods for antimicrobial susceptibility testing could affect the interpretation of antimicrobial susceptibility test results.

METHODS: We analysed MICs of ofloxacin and levofloxacin in Middlebrook 7H10 broth (7H10) as well as sequencing of the quinolone resistance-determining region of the gyrA gene and the MTBDRsl assay in 75 resistant isolates, including MDR and XDR strains of Mycobacterium tuberculosis.

RESULTS: Among 75 resistant isolates, 27 had mutations associated with FQ resistance. Among isolates with resistance mutations in gyrA, 26% (seven of 27) were susceptible to levofloxacin and ofloxacin by phenotypic testing at 1 mg/L and 2 mg/L. The most common mutation was in codon 94 and these isolates had significantly increased MICs of levofloxacin (2-8 mg/L) compared with isolates with mutations in codon 90 (0.25-2 mg/L, P < 0.05). The sensitivity and specificity for the MTBDRsl assay compared with gyrA sequencing were 96% and 98%, respectively.

CONCLUSION: Current critical concentrations may classify up to 26% of isolates with gyrA mutations as susceptible to FQs due to a close relationship between susceptible and resistant populations. These results should be considered while improving clinical breakpoints for M. tuberculosis and may have an impact on the definition of XDR-TB.

National Category
Infectious Medicine
Identifiers
urn:nbn:se:liu:diva-124557 (URN)10.1093/jac/dkv353 (DOI)000372427600008 ()26538509 (PubMedID)
Note

Funding agencies: Heart and Lung Foundation; Swedish Society of Antimicrobial Chemotherapy (SSAC); Swedish Medical Association; Marianne and Marcus Wallenberg Foundation

Available from: 2016-02-03 Created: 2016-02-03 Last updated: 2019-04-24
2. Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
Open this publication in new window or tab >>Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting
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2018 (English)In: Journal of Antimicrobial Chemotherapy, ISSN 0305-7453, E-ISSN 1460-2091, Vol. 73, no 10, p. 2838-2845Article in journal (Refereed) Published
Abstract [en]

Background: Therapeutic drug monitoring (TDM) could improve current TB treatment, but few studies have reported pharmacokinetic data together with MICs. Objectives: To investigate plasma concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol along with MICs. Methods: Drug concentrations of rifampicin, isoniazid, pyrazinamide and ethambutol were analysed pre-dose and 2, 4 and 6 h after drug intake at week 2 in 31 TB patients and MICs in BACTEC 960 MGIT were determined at baseline. The highest plasma concentrations at 2, 4 and 6 h post-dose (C-high) were determined, as well as estimates of C-high/MIC and area under the concentration-time curve (AUC(0-6))/MIC including the corresponding ratios based on calculated free-drug concentrations. This trial was registered at www.clinicaltrials.gov (NCT02042261). Results: After 2 weeks of treatment, the median C-high values for rifampicin, isoniazid, pyrazinamide and ethambutol were 10.0, 5.3, 41.1 and 3.3 mg/L respectively. Lower than recommended drug concentrations were detected in 42% of the patients for rifampicin (amp;lt;8 mg/L), 19% for isoniazid (amp;lt;3 mg/L), 27% for pyrazinamide (amp;lt;35 mg/L) and 16% for ethambutol (amp;lt;2 mg/L). The median Chigh/MIC values for rifampicin, isoniazid, pyrazinamide and ethambutol were 164, 128, 1.3 and 2.5, respectively, whereas the AUC(0-6)/MIC was 636 (range 156-2759) for rifampicin and 351 (range 72-895) for isoniazid. Conclusions: We report low levels of first-line TB drugs in 16%-42% of patients, in particular for rifampicin. There was a wide distribution of the ratios between drug exposures and MICs. The future use of MIC determinations in TDM is dependent on the development of a reference method and clinically validated pharmacokinetic/pharmacodynamic targets.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2018
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-153707 (URN)10.1093/jac/dky268 (DOI)000452914200032 ()30124844 (PubMedID)
Note

Funding Agencies|Research Council of Southeast Sweden; Region of Ostergotland; Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Swedish Research Council; Stockholm County Council [ALF20160331]

Available from: 2019-01-07 Created: 2019-01-07 Last updated: 2019-05-02
3. Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
Open this publication in new window or tab >>Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
Show others...
2018 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 62, no 5, article id e00218-18Article in journal (Refereed) Published
Abstract [en]

The plasma tuberculosis drug activity (TDA) assay may be an alternative tool for therapeutic drug monitoring in resource-limited settings. In tuberculosis (TB) patients (n = 30), TDA and plasma levels of first-line drugs were analyzed 2 h post-dose, 2 weeks after treatment initiation. Patients with plasma levels of rifampin lower than 8 mg/liter had a significantly lower median TDA (1.40 versus 1.68, P = 0.0013). TDA may be used to identify TB patients with suboptimal rifampin levels during TB treatment.

Place, publisher, year, edition, pages
AMER SOC MICROBIOLOGY, 2018
Keywords
pharmacokinetics; Mycobacterium tuberculosis; rifampin; isoniazid
National Category
Pharmacology and Toxicology
Identifiers
urn:nbn:se:liu:diva-147915 (URN)10.1128/AAC.00218-18 (DOI)000431341200022 ()29483112 (PubMedID)
Note

Funding Agencies|Research Council of Southeast Sweden (FORSS); Marianne and Marcus Wallenberg Foundation; Swedish Heart and Lung Foundation; Region of Ostergotland, Sweden; Swedish Research Council

Available from: 2018-05-23 Created: 2018-05-23 Last updated: 2019-05-01
4. 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
Open this publication in new window or tab >>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
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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
Keywords
tuberculosis; clinical pharmacology; public health; microbiology
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-153393 (URN)10.1136/bmjopen-2018-023899 (DOI)000450417800153 ()30287613 (PubMedID)2-s2.0-85054436449 (Scopus ID)
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

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Output format
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