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Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis.
PLoS Negl Trop Dis. 2012; 6(5):e1657.PN

Abstract

BACKGROUND

With widespread resistance to antimonials in Visceral Leishmaniasis (VL) in the Indian subcontinent, Miltefosine (MIL) has been introduced as the first line therapy. Surveillance of MIL susceptibility in natural populations of Leishmania donovani is vital to preserve it and support the VL elimination program.

METHODOLOGY AND PRINCIPAL FINDINGS

We measured in vitro susceptibility towards MIL and paromomycin (PMM) in L. donovani isolated from VL and PKDL, pre- and post-treatment cases, using an amastigote-macrophage model. MIL susceptibility of post-treatment isolates from cured VL cases (n = 13, mean IC(50)±SD = 2.43±1.44 µM), was comparable (p>0.05) whereas that from relapses (n = 3, mean IC(50) = 4.72±1.99 µM) was significantly higher (p = 0.04) to that of the pre-treatment group (n = 6, mean IC(50) = 1.86±0.75 µM). In PKDL, post-treatment isolates (n = 3, mean IC(50) = 16.13±2.64 µM) exhibited significantly lower susceptibility (p = 0.03) than pre-treatment isolates (n = 5, mean IC(50) = 8.63±0.94 µM). Overall, PKDL isolates (n = 8, mean IC(50) = 11.45±4.19 µM) exhibited significantly higher tolerance (p<0.0001) to MIL than VL isolates (n = 22, mean IC(50) = 2.58±1.58 µM). Point mutations in the miltefosine transporter (LdMT) and its beta subunit (LdRos3) genes previously reported in parasites with experimentally induced MIL resistance were not present in the clinical isolates. Further, the mRNA expression profile of these genes was comparable in the pre- and post-treatment isolates. Parasite isolates from VL and PKDL cases were uniformly susceptible to PMM with respective mean IC(50) = 7.05±2.24 µM and 6.18±1.51 µM.

CONCLUSION

The in vitro susceptibility of VL isolates remained unchanged at the end of MIL treatment; however, isolates from relapsed VL and PKDL cases had lower susceptibility than the pre-treatment isolates. PKDL isolates were more tolerant towards MIL in comparison with VL isolates. All parasite isolates were uniformly susceptible to PMM. Mutations in the LdMT and LdRos3 genes as well as changes in the expression of these genes previously correlated with experimental resistance to MIL could not be verified for the field isolates.

Authors+Show Affiliations

National Institute of Pathology, Indian Council of Medical Research, Safdarjung Hospital Campus, New Delhi, India.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22629478

Citation

Bhandari, Vasundhra, et al. "Drug Susceptibility in Leishmania Isolates Following Miltefosine Treatment in Cases of Visceral Leishmaniasis and Post Kala-azar Dermal Leishmaniasis." PLoS Neglected Tropical Diseases, vol. 6, no. 5, 2012, pp. e1657.
Bhandari V, Kulshrestha A, Deep DK, et al. Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Negl Trop Dis. 2012;6(5):e1657.
Bhandari, V., Kulshrestha, A., Deep, D. K., Stark, O., Prajapati, V. K., Ramesh, V., Sundar, S., Schonian, G., Dujardin, J. C., & Salotra, P. (2012). Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. PLoS Neglected Tropical Diseases, 6(5), e1657. https://doi.org/10.1371/journal.pntd.0001657
Bhandari V, et al. Drug Susceptibility in Leishmania Isolates Following Miltefosine Treatment in Cases of Visceral Leishmaniasis and Post Kala-azar Dermal Leishmaniasis. PLoS Negl Trop Dis. 2012;6(5):e1657. PubMed PMID: 22629478.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Drug susceptibility in Leishmania isolates following miltefosine treatment in cases of visceral leishmaniasis and post kala-azar dermal leishmaniasis. AU - Bhandari,Vasundhra, AU - Kulshrestha,Arpita, AU - Deep,Deepak Kumar, AU - Stark,Olivia, AU - Prajapati,Vijay Kumar, AU - Ramesh,V, AU - Sundar,Shyam, AU - Schonian,Gabriele, AU - Dujardin,Jean Claude, AU - Salotra,Poonam, Y1 - 2012/05/22/ PY - 2012/01/16/received PY - 2012/04/11/accepted PY - 2012/5/26/entrez PY - 2012/5/26/pubmed PY - 2012/8/31/medline SP - e1657 EP - e1657 JF - PLoS neglected tropical diseases JO - PLoS Negl Trop Dis VL - 6 IS - 5 N2 - BACKGROUND: With widespread resistance to antimonials in Visceral Leishmaniasis (VL) in the Indian subcontinent, Miltefosine (MIL) has been introduced as the first line therapy. Surveillance of MIL susceptibility in natural populations of Leishmania donovani is vital to preserve it and support the VL elimination program. METHODOLOGY AND PRINCIPAL FINDINGS: We measured in vitro susceptibility towards MIL and paromomycin (PMM) in L. donovani isolated from VL and PKDL, pre- and post-treatment cases, using an amastigote-macrophage model. MIL susceptibility of post-treatment isolates from cured VL cases (n = 13, mean IC(50)±SD = 2.43±1.44 µM), was comparable (p>0.05) whereas that from relapses (n = 3, mean IC(50) = 4.72±1.99 µM) was significantly higher (p = 0.04) to that of the pre-treatment group (n = 6, mean IC(50) = 1.86±0.75 µM). In PKDL, post-treatment isolates (n = 3, mean IC(50) = 16.13±2.64 µM) exhibited significantly lower susceptibility (p = 0.03) than pre-treatment isolates (n = 5, mean IC(50) = 8.63±0.94 µM). Overall, PKDL isolates (n = 8, mean IC(50) = 11.45±4.19 µM) exhibited significantly higher tolerance (p<0.0001) to MIL than VL isolates (n = 22, mean IC(50) = 2.58±1.58 µM). Point mutations in the miltefosine transporter (LdMT) and its beta subunit (LdRos3) genes previously reported in parasites with experimentally induced MIL resistance were not present in the clinical isolates. Further, the mRNA expression profile of these genes was comparable in the pre- and post-treatment isolates. Parasite isolates from VL and PKDL cases were uniformly susceptible to PMM with respective mean IC(50) = 7.05±2.24 µM and 6.18±1.51 µM. CONCLUSION: The in vitro susceptibility of VL isolates remained unchanged at the end of MIL treatment; however, isolates from relapsed VL and PKDL cases had lower susceptibility than the pre-treatment isolates. PKDL isolates were more tolerant towards MIL in comparison with VL isolates. All parasite isolates were uniformly susceptible to PMM. Mutations in the LdMT and LdRos3 genes as well as changes in the expression of these genes previously correlated with experimental resistance to MIL could not be verified for the field isolates. SN - 1935-2735 UR - https://www.unboundmedicine.com/medline/citation/22629478/Drug_susceptibility_in_Leishmania_isolates_following_miltefosine_treatment_in_cases_of_visceral_leishmaniasis_and_post_kala_azar_dermal_leishmaniasis_ L2 - https://dx.plos.org/10.1371/journal.pntd.0001657 DB - PRIME DP - Unbound Medicine ER -