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University of Groningen

Optimizing levofloxacin dose in the treatment of multidrug-resistant tuberculosis

Ghimire, Samiksha

IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from

it. Please check the document version below.

Document Version

Publisher's PDF, also known as Version of record

Publication date:

2019

Link to publication in University of Groningen/UMCG research database

Citation for published version (APA):

Ghimire, S. (2019). Optimizing levofloxacin dose in the treatment of multidrug-resistant tuberculosis: An

integrated PK/PD approach. University of Groningen.

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Optimizing Levofloxacin Dose

in the Treatment

of Multidrug-Resistant Tuberculosis

An Integrated PK/PD Approach

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Ghimire, S.

Optimizing levofloxacin dose in the treatment of multidrug-resistant tuberculosis An integrated PK/PD approach

Thesis, University of Groningen, The Netherlands

Publication of this thesis was financially supported by University of Groningen, Univer-sity Medical Center Groningen, Graduate School of Medical Sciences, Eric Bleumink Fund, KNCV Tuberculosis Foundation, Royal Dutch Pharmacists Association (KNMP) and Stichting Beatrixoord Noord-Nederland.

Cover: Randy Wind

Layout: Lovebird design.

www.lovebird-design.com Printing: Eikon +

ISBN: (printed book) 978-94-034-1531-4 ISBN: (ebook) 978-94-034-1530-7

© Copyright 2019 S.Ghimire, Groningen, The Netherlands

All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, by photocopying, recording or otherwise, without the prior written permission of the author.

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Optimizing levofloxacin dose in the

treatment of multidrug-resistant

tuberculosis

An integrated PK/PD approach

PhD thesis

to obtain the degree of PhD at the

University of Groningen

on the authority of the

Rector Magnificus Prof. E. Sterken

and in accordance with

the decision by the College of Deans.

This thesis will be defended in public on

Wednesday 10 April 2019 at 16:15

by

Samiksha Ghimire

born on 7 November 1988

in Saptari, Nepal

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Supervisors

Prof. J.W.C. Alffenaar

Prof. D.J. Touw

Prof. T.S. van der Werf

Assessment committee

Prof. L.G. Visser

Prof. K. Taxis

Prof. Y. Stienstra

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The woods are lovely, dark and deep,

But I have promises to keep,

And miles to go before I sleep,

And miles to go before I sleep.

Robert Frost,

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Table of Contents

Chapter 1 General introduction and scope of thesis 9

Chapter 2 Pharmacokinetics/dynamics-based optimization

of levofloxacin administration in the treatment

of multi-drug resistant tuberculosis 25

Chapter 3 Incorporating therapeutic drug monitoring in

WHO’s hierarchy of tuberculosis diagnostics! 55

Chapter 4 Treatment outcomes of MDR-TB patients in Nepal

on a levofloxacin containing standardized

regi-men: retrospective single center study 63

Chapter 5a Determination of levofloxacin in human serum

using liquid chromatography tandem mass

spec-trometry 81

Chapter 5b Cross validation of a liquid chromatography

tan-dem mass spectrometry method for quantification

of levofloxacin in saliva 101

Chapter 6a Levofloxacin pharmacokinetics and

pharmaco-dynamics and outcome in MDR-TB patients 111

Chapter 6b Evaluation of saliva as a potential alternative

sam-pling matrix for therapeutic drug monitoring of

levofloxacin in MDR-TB patients 121

Chapter 7 Discussion and future perspectives 141

Chapter 8 Summary

159

Samenvatting 165

Acknowledgements

172

About the author 173

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