The Relevance of Susceptibility Tests, Breakpoints, and Markers
This chapter will cover the challenges that we have in considering drug resistance in the context of use of antileishmanial drugs. This is not just a problem of lack of definition but also absence of suitable models and assays. We do not have the standard
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Introduction: The Challenges In previous chapters (“The Role of the Immune System in Resistance to Infection”, “Vaccination as a Control Measure” and “Leishmania Vaccines: Past, Present, and Future”), the molecular and epidemiological characteristics of resistance to antileishmanial drugs have been described and are mostly based upon testing the in vitro susceptibility (often incorrectly referred to as sensitivity) of defined laboratory strains or clinical field isolates to the current standard antileishmanial drugs: pentavalent antimonials (SbV), miltefosine (MIL), amphotericin-B (AmB), and paromomycin (PMM). Most current research refers to laboratory-generated strains or clones with well-defined characteristics that are linked to molecular changes resulting in reduced susceptibility and cross-resistance to the standard drugs. However, many unresolved issues have to be faced when considering the definition of “resistance” in the context of the use of antileishmanial drugs and characterization of clinical field isolates. A first challenge is not just a problem of lack of definition but is specifically linked to the unavailability of standardized and validated laboratory assays. Although many in vitro “drug screening” models and procedures have indeed been described during the last decade, standard operating procedures (SOPs) that will unequivocally define intrinsic drug “susceptibility” as to the in vitro response of a Leishmania strain/isolate to a standard drug are not yet available. Yet another and even more difficult step is the linkage of the in vitro drug-susceptibility profile
L. Maes • P. Cos Laboratory of Microbiology, Parasitology, and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium S.L. Croft (*) London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, UK e-mail: [email protected] A. Ponte-Sucre et al. (eds.), Drug Resistance in Leishmania Parasites, DOI 10.1007/978-3-7091-1125-3_19, # Springer-Verlag Wien 2013
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to clinical outcome in the treated patient since pharmacokinetic, pharmacodynamic, and host immune phenomena largely define the response of the pathogen to a standard drug (Turnidge and Paterson 2007, Drusano 2004). A second challenge in our concerns about resistance is the absence of definitive knowledge about the mechanisms of action and resistance of most of the current antileishmanial drugs and how this relates to changes in drug susceptibility in clinical isolates from patients who have either responded, relapsed, or not responded to treatment. It is essential not just to be able to relate in vitro susceptibility to particular biochemical and/or molecular changes but also to identify relevant molecular markers that could be used in an epidemiological and clinical setting. The problems around methodologies on resistance markers have not yet been considered for leishmaniasis (Natera et al. 2007), but recent research on antimalarial markers has identified some important issues (Hastings et al. 2010). A third challenge specifically
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