Publications (36) View all
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Article: Increasing failure of miltefosine in the treatment of kala-azar in Nepal and the potential role of parasite drug resistance, re-infection or non-compliance.
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ABSTRACT: Background. Miltefosine (MIL), the only oral drug for visceral leishmaniasis (VL), is currently the 1(st) line therapy in the VL elimination program of the Indian subcontinent. Given the paucity of anti-VL drugs and the looming threat of resistance, there is an obvious need for close monitoring of clinical efficacy of MIL.Methods. In a cohort study of 120 VL patients treated with MIL in Nepal, we monitored the clinical outcomes up to 12 after completion of therapy and explored the potential role of drug compliance, parasite drug resistance and re-infection.Results. The initial cure rate was 95.8% (95% C.I. ±3.6%)and relapse rate at six and twelve months was 10.8% (95% C.I.±5.6%) and 20.0% (95% C.I.±7.2%) respectively. No significant clinical risk factors of relapse apart from age<12 years were found. Parasite fingerprints of pre-treatment and relapse bone marrow isolates within 8 patients were similar, suggesting that clinical relapses were not due to re-infection with a new strain. The mean promastigote MIL-susceptibility (IC(50)) of isolates from definite cures was similar to that of relapses. Although more tolerant strains were observed, parasite resistance, as currently measured, is thus not likely involved in MIL treatment failure. Moreover, MIL blood levels at the end of treatment were similar in cured and relapsed patients.Conclusion. Relapse in one fifth of the MIL treated patients observed in our study is an alarming signal for the VL elimination campaign, urging for further review and cohort monitoring.Clinical Infectious Diseases 02/2013; · 9.15 Impact Factor -
Dataset: 2005 trstmh
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Article: Drug-resistant microorganisms with a higher fitness - can medicines boost pathogens?
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ABSTRACT: Drug-resistant microorganisms (DRMs) are generally thought to suffer from a fitness cost associated with their drug-resistant trait, inflicting them a disadvantage when the drug pressure reduces. However, Leishmania resistant to pentavalent antimonies shows traits of a higher fitness compared to its sensitive counterparts. This is likely due the combination of an intracellular pathogen and a drug that targets the parasite's general defense mechanisms while at the same time stimulating the host's immune system, resulting in a DRM that is better adapted to withstand the host's immune response. This review aims to highlight how this fitter DRM has emerged and how it might affect the control of leishmaniasis. However, this unprecedented example of fitter antimony-resistant Leishmania donovani is also of significance for the control of other microorganisms, warranting more caution when applying or designing drugs that attack their general defense mechanisms or interact with the host's immune system.Critical Reviews in Microbiology 09/2012; · 6.27 Impact Factor -
Article: Genetic markers for SSG resistance in Leishmania donovani and SSG treatment failure in visceral leishmaniasis patients of the Indian subcontinent.
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ABSTRACT: The current standard to assess pentavalent antimonial (SSG) susceptibility of Leishmania is a laborious in vitro assay of which the result has little clinical value because SSG-resistant parasites are also found in SSG-cured patients. Candidate genetic markers for clinically relevant SSG-resistant parasites identified by full genome sequencing were here validated on a larger set of clinical strains. We show that 3 genomic locations suffice to specifically detect the SSG-resistant parasites found only in patients experiencing SSG treatment failure. This finding allows the development of rapid assays to monitor the emergence and spread of clinically relevant SSG-resistant Leishmania parasites.The Journal of Infectious Diseases 06/2012; 206(5):752-5. · 6.41 Impact Factor -
Article: Molecular mechanisms of drug resistance in natural Leishmania populations vary with genetic background.
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ABSTRACT: The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability.PLoS Neglected Tropical Diseases 02/2012; 6(2):e1514. · 4.69 Impact Factor
