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Plasma Levels of Rifampin Correlate with the Tuberculosis Drug Activity Assay
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.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden.
Karolinska Inst, Sweden; Karolinska Univ Hosp Solna, Sweden.
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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. Vol. 62, no 5, article id e00218-18
Keywords [en]
pharmacokinetics; Mycobacterium tuberculosis; rifampin; isoniazid
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:liu:diva-147915DOI: 10.1128/AAC.00218-18ISI: 000431341200022PubMedID: 29483112OAI: oai:DiVA.org:liu-147915DiVA, id: diva2:1209578
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
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)
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Supervisors
Available from: 2019-04-24 Created: 2019-04-24 Last updated: 2020-05-06Bibliographically approved

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Niward, KatarinaPaues, Jakob

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