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Lack of correlation between the promastigote back-transformation assay and miltefosine treatment outcome

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dc.contributor.author Hendrickx, S.
dc.contributor.author Eberhardt, E.
dc.contributor.author Mondelaers, A.
dc.contributor.author Rijal, S.
dc.contributor.author Bhattarai, N. R.
dc.contributor.author Dujardin, J. C.
dc.contributor.author Delputte, P.
dc.contributor.author Cos, P.
dc.contributor.author Maes, L.
dc.date.accessioned 2016-02-04T13:11:15Z
dc.date.available 2016-02-04T13:11:15Z
dc.date.issued 2015
dc.identifier.issn 0305-7453
dc.identifier.doi http://dx.doi.org/10.1093/jac/dkv237
dc.identifier.other ITG-B6A
dc.identifier.other DBM
dc.identifier.other U-MOLPAR
dc.identifier.other JIF
dc.identifier.other DOI
dc.identifier.other Abstract
dc.identifier.other UPD60
dc.identifier.uri http://hdl.handle.net/10390/8666
dc.description.abstract OBJECTIVES: Widespread antimony resistance in the Indian subcontinent has enforced a therapy shift in visceral leishmaniasis treatment primarily towards miltefosine and secondarily also towards paromomycin. In vitro selection of miltefosine resistance in Leishmania donovani turned out to be quite challenging. Although no increase in IC50 was detected in the standard intracellular amastigote susceptibility assay, promastigote back-transformation remained positive at high miltefosine concentrations, suggesting a more 'resistant' phenotype. This observation was explored in a large set of Nepalese clinical isolates from miltefosine cure and relapse patients to assess its predictive value for patient treatment outcome. METHODS: The predictive value of the promastigote back-transformation for treatment outcome of a set of Nepalese L. donovani field isolates (n = 17) derived from miltefosine cure and relapse patients was compared with the standard susceptibility assays on promastigotes and intracellular amastigotes. RESULTS: In-depth phenotypic analysis of the clinical isolates revealed no correlation between the different susceptibility assays, nor any clear link to the actual treatment outcome. In addition, the clinical isolates proved to be phenotypically heterogeneous, as reflected by the large variation in drug susceptibility among the established clones. CONCLUSIONS: This in vitro laboratory study shows that miltefosine treatment outcome is not necessarily exclusively linked with the susceptibility profile of pre-treatment isolates, as determined in standard susceptibility assays. The true nature of miltefosine treatment failures still remains ill defined. en_US
dc.language English en_US
dc.subject Protozoal diseases en_US
dc.subject Kala azar en_US
dc.subject Visceral en_US
dc.subject Leishmaniasis en_US
dc.subject Leishmania donovani en_US
dc.subject Vectors en_US
dc.subject Sandflies en_US
dc.subject Phlebotomus argentipes en_US
dc.subject Drug resistance en_US
dc.subject Antimonials en_US
dc.subject Miltefosine en_US
dc.subject Paromomycin en_US
dc.subject Promastigotes en_US
dc.subject Amastigotes en_US
dc.subject Relapses en_US
dc.subject Predictive value en_US
dc.subject Phenotyping en_US
dc.subject In vitro en_US
dc.subject Laboratory techniques and procedures en_US
dc.title Lack of correlation between the promastigote back-transformation assay and miltefosine treatment outcome en_US
dc.type Article en_US
dc.citation.issue 11 en_US
dc.citation.jtitle Journal of Antimicrobial Chemotherapy en_US
dc.citation.volume 70 en_US
dc.citation.pages 3023-3026 en_US
dc.identifier.pmid http://www.ncbi.nlm.nih.gov/pubmed/26253089
dc.citation.jabbreviation J Antimicrob Chemother en_US


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