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The Roles of Stochasticity and Life History in the Evolutionary Research Collection Doctoral Thesis Within-host population dynamics and the evolution of drug resistance in bacterial infections Author(s): Cadosch, Dominique Richard Publication Date: 2016 Permanent Link: https://doi.org/10.3929/ethz-a-010795126 Rights / License: In Copyright - Non-Commercial Use Permitted This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library DISS. ETH NO. 23499 WITHIN-HOSTPOPULATIONDYNAMICSANDTHEEVOLUTION OFDRUGRESISTANCEINBACTERIALINFECTIONS A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZÜRICH (Dr. sc. ETH Zürich) presented by DOMINIQUERICHARDCADOSCH M.Sc. ETH Zürich, Switzerland born on 30.05.1984 citizen of Vaz/Obervaz GR, Switzerland accepted on the recommendation by Prof. Dr. Sebastian Bonhoeffer, examiner Prof. Dr. Theodore H. Cohen, co-examiner PD Dr. Roland Regoes, co-examiner 2016 To my parents, Ruth and Edgar Cadosch, for their sedulous support and guidance. “I have a friend who’s an artist and has sometimes taken a view which I don’t agree with very well. He’ll hold up a flower and say "look how beautiful it is," and I’ll agree. Then he says "I as an artist can see how beautiful this is but you as a scientist take this all apart and it becomes a dull thing," and I think that he’s kind of nutty. First of all, the beauty that he sees is available to other people and to me too, I believe. Although I may not be quite as refined aesthetically as he is ... I can appreciate the beauty of a flower. At the same time, I see much more about the flower than he sees. I could imagine the cells in there, the complicated actions inside, which also have a beauty. I mean it’s not just beauty at this dimension, at one centimeter; there’s also beauty at smaller dimensions, the inner structure, also the processes. The fact that the colors in the flower evolved in order to attract insects to pollinate it is interesting; it means that insects can see the color. It adds a question: does this aesthetic sense also exist in the lower forms? Why is it aesthetic? All kinds of interesting questions which the science knowledge only adds to the excitement, the mystery and the awe of a flower. It only adds. I don’t understand how it subtracts.” Richard Feynman v CONTENTS summary1 zusammenfassung3 1 general introduction5 2 the role of adherence and retreatment in de novo emer- gence of mdr-tb 11 3 alternative treatment strategies for tuberculosis 39 4 considering antibiotic stress-induced mutagenesis 61 5 general discussion 77 acknowledgements 103 curriculum vitae 105 vii SUMMARY This thesis investigates the influence of population dynamics of bacterial infections and their treatment on the probability of the emergence of drug resistance. In partic- ular the study of the effects of suboptimal patient compliance, various treatment reg- imens and the possibility of antibiotic stress-induced mutagenesis call for a deeper understanding of the mechanisms at play. The work presented in this study uses mathematical models that incorporate pharmacokinetics and -dynamics, as well as the effect of bacterial traits to make predictions about the evolution of drug resistance. All dynamics are being simulated at the within-host level. Chapter 1 is a general introduction of the central themes of this thesis. It gives a short overview over the advent of the study of population dynamics as a field of research. The global significance of tuberculosis and the problems that arise due to the frequent occurrence of drug resistance are being explained. I also address the issue of suboptimal treatment adherence and rationalize the value of mathematical modeling to tackle the questions in the following chapters. In Chapter 2, we investigate how adherence to the treatment regimen and the use of a standard retreatment regimen are involved in the emergence of multidrug- resistant tuberculosis (MDR-TB). MDR-TB is characterized by its resistance against isoniazid and rifampicin, two important first-line drugs. To answer the question whether there is a considerable probability for the de novo emergence of MDR-TB we simulate patients with various degrees of adherence to a standard treatment regimen containing a combination of four drugs. Patients who do not achieve complete clear- ance of the infection undergo a prolonged retreatment regimen with an additional fifth drug. Chapter 3 explores proposed alternative strategies for the treatment of pulmonary tuberculosis. We extend the previously established model and introduce more de- tailed absorption pharmacokinetics. This extension of the model enables us to inves- tigate the potential benefit and effects of extended-release formulations of rifampicin. Extended-release formulations show a much lower absorption and thus exhibit a lower but longer time-concentration profile. Such formulations are compared in daily or intermittent treatment regimens with conventional rifampicin formulations and their influence on the probability of treatment failure and the emergence of drug resistance are recorded. Furthermore, we also tested the advantage and risks involved with increased rifampicin doses. Chapter 4 then deals with the concept of antibiotic stress-induced mutagenesis (ASIM). The concept of stress-induced mutagenesis describes the increase of the bacterial mutation rate in response to a stress, such as the exposure to certain an- tibiotics. We propose a model to simulate the increase of the mutation rate in a drug concentration-dependent manner. With this ASIM model we then investigate how much a model with a fixed mutation rate would underestimate the risk for the emergence of a drug resistance mutation. Lastly, we study whether the regimen of administering a stress-inducing drug and a non-stress-inducing drug has an influ- ence on the emergence of resistance if we consider ASIM. 1 2 summary Finally, in Chapter 5 I put the results and conclusions from the preceding chapters in a bigger perspective. Furthermore, I present some future directions that could be explored with further research. ZUSAMMENFASSUNG Diese Dissertation untersucht den Einfluss von Populationsdynamik in bakteriel- len Infektionen und deren Behandlung auf die Wahrscheinlichkeit des Auftretens von Medikamentenresistenz. Im Besonderen die Analyse der Effekte suboptimaler Patienten-Adhärenz, die Anwendung unterschiedlicher Behandlungsstrategien und die Möglichkeit stress-bedingter Mutagenese durch Antibiotika verlangen nach ei- nem tiefgreifenderem Verständnis für die zugrundeliegenden Wirkmechanismen. Die Arbeit, welche in dieser Dissertation vorgestellt wird nutzt mathematische Model- le, welche Pharmakokinetik und Pharmakodynamik, sowie Effekte von bakteriellen Merkmalen beinhalten, um Prognosen in Bezug auf die Evolution von Medikamen- tenresistenz aufstellen zu können. Alle Dynamiken werden dabei jeweils auf der Ebene eines einzelnen Patienten simuliert. Kapitel 1 ist eine allgemeine Einführung in die zentralen Themen dieser Disserta- tion. Das Kapitel gibt einen kurzen Überblick über die Ursprünge der Erforschung von Populationsdynamiken. Die globale Bedeutung von Tuberkulose sowie die Pro- bleme, welche durch das häufige Auftreten von Medikamentenresistenz entstehen, werden erklärt. Ich spreche auch die Thematik von suboptimaler Adhärenz an sowie den Wert von mathematischer Modellierung, um die Fragestellungen der folgenden Kapitel anzupacken. In Kapitel 2 untersuchen wir, wie Adhärenz während der Behandlung und die An- wendung einer standardisierten Nachbehandlung involviert sind in das Auftreten von multiresistenter Tuberkulose (engl. multi-drugresistant tuberculosis; MDR-TB). MDR-TB ist gekennzeichnet durch die Resistenz gegenüber Isoniazid und Rifampi- cin, zwei wichtigen standardmässig eingesetzten Antibiotika. Um die Frage zu beant- worten, ob es eine nennenswerte Wahrscheinlichkeit gibt für das Auftreten de novo MDR-TB, simulieren wir Patienten mit unterschiedlichen Adhärenzen gegenüber ei- ner Behandlungsstrategie mit einer Kombination von vier Medikamenten. Patienten, in denen die Infektion nicht vollständig sterilisiert wurde, werden einer längeren Nachbehandlung mit einem zusätzlichen fünften Medikament unterzogen. Kapitel 3 erforscht alternative Behandlungsvorschläge für Lungentuberkulose. Wir erweitern das zuvor etablierte Modell und führen eine detailiertere Absorptions- Pharmakokinetik ein. Diese Erweiterung des Modells ermöglicht es uns, die poten- tiellen Vorteile und Auswirkungen eines Retard-Präparats von Rifampicin zu un- tersuchen. Retardarzneiformen zeichnen sich durch eine verlangsamte Absorption aus und weisen deshalb eine niedrigeres aber gestrecktes Konzentrationsprofil. Sol- che Arzeneiformen werden in täglichen und intermittierenden Behandlungsregimes verglichen mit konventionellen Rifampicin-Präparaten und die Wahrscheinlichkeiten für ein Behandlungsversagen sowie das Auftreten von Medikamentenresistenz wer- den ermittelt. Des Weiteren testen wir ebenfalls die Vorteile und Risiken die mit erhöhten Rifampicindosen verbunden sind. Kapitel 4 behandelt das Konzept von stressbedingter Mutagenese durch Antibio- tika (engl. antibiotic stress-induced mutagenesis; ASIM). Das Konzept von stressbe- dingter Mutagenese beschreibt den Anstieg der bakteriellen Mutationsrate als Reakti- 3 4 zusammenfassung on auf einen äusseren Stressreiz, wie die Exposition gegenüber gewissen Antibiotika. Wir stellen ein Modell vor, um den Anstieg der Mutationsrate in Abhängigkeit zur Medikamentenkonzentration zu simulieren. Mit
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