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Tuberculosis: drug resistance, fitness, and strategies for global control

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Abstract

Directly observed standardized short-course chemotherapy (DOTS) regimes are an effective treatment for drug susceptible tuberculosis disease. Surprisingly, DOTS has been reported to reduce the transmission of multi-drug resistant tuberculosis, and standardized short-course chemotherapy regimens with first-line agents have been found to be adequate treatments for some patients with drug resistant tuberculosis, including multi-drug resistance. These paradoxical observations and the apparent heterogeneity in treatment outcome of multi-drug resistant tuberculosis when using standard regimens may be due in part to limitations of in vitro drug susceptibility testing based on unique but mistakenly used techniques in diagnostic mycobacteriology. Experimental data and mathematical models indicate that the fitness cost conferred by a resistance determinant is the single most important parameter which determines the spread of drug resistance. Chromosomal alterations that result in resistance to first-line antituberculosis agents, e.g. isoniazid, rifampicin, streptomycin, may or may not be associated with a fitness cost. Based on work in experimental models and from observations in clinical drug resistant isolates a picture emerges in which, among the various resistance mutations that appear with similar rates, those associated with the least fitness cost are selected in the population.

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Acknowledgements

We apologize to all colleagues whose work could not be cited due to space limitations. We are indebted to our coworkers and collaborators with whom we had the privilege to share ideas and views. We are thankful to Paul van Helden for thoughtful and critical discussions. We thank A. Makovec for typing the manuscript. Work in the authors laboratories has been supported by the German Research Council, the Bundesministerium für Forschung und Technologie (Germany), the European Commission, the Swiss National Research Foundation, the Bundesamt für Gesundheit (Switzerland), the University of Zurich, and the Niedersächsischer Verein zur Bekämpfung der Tuberkulose (Germany).

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  1. Burkhard Springer

    Present address: Institut für Medizinische Mikrobiologie und Hygiene, Beethovenstrasse 6, 8010, Graz, Austria

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  1. Nationales Zentrum für Mykobakterien, Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 32, 8006, Zürich, Switzerland

    Erik C. Böttger & Burkhard Springer

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  1. Erik C. Böttger
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Correspondence to Erik C. Böttger.

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Böttger, E.C., Springer, B. Tuberculosis: drug resistance, fitness, and strategies for global control. Eur J Pediatr 167, 141–148 (2008). https://doi.org/10.1007/s00431-007-0606-9

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