Abstract
Primary and secondary unresponsiveness to meglumine has long been described in human visceral leishmaniasis. However, no studies have been performed to elucidate if these therapeutic failures were due to strain variability in meglumine sensitivity or were related to host factors. We have studied the in vitro sensitivity of 37 strains of Leishmania infantum isolated from 23 patients (11 human immunodeficiency virus-infected and 12 immunocompetent patients) with visceral leishmaniasis. Sensitivity tests were performed by infecting murine macrophages with Leishmania parasites and culturing them in medium containing different concentrations of meglumine. For each test we calculated a 50% effective dose (ED50) corresponding to the meglumine concentration at which 50% of the Leishmania parasites survived. In vitro results were strongly correlated to immediate clinical outcome. All strains requiring an ED50 of >70 microg/ml were related to therapeutic failures, whereas all strains requiring an ED50 of <40 microg/ml corresponded to an initial efficiency of meglumine. Among those patients who were initially improved, relapses occurred in all immunocompromised patients and in most immunocompetent patients who had a short duration of treatment (15 days). Finally, we found that in vitro sensitivity of strains decreased progressively in relapsing patients treated with meglumine. Consequently, the physician may be encouraged to alternate meglumine with other treatments such as amphotericin B or pentamidine, especially in the case of relapsing patients.
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- Alvar J., Molina R., San Andrés M., Tesouro M., Nieto J., Vitutia M., González F., San Andrés M. D., Boggio J., Rodriguez F. Canine leishmaniasis: clinical, parasitological and entomological follow-up after chemotherapy. Ann Trop Med Parasitol. 1994 Aug;88(4):371–378. doi: 10.1080/00034983.1994.11812879. [DOI] [PubMed] [Google Scholar]
- Berman J. D., Lee L. S. Activity of antileishmanial agents against amastigotes in human monocyte-derived macrophages and in mouse peritoneal macrophages. J Parasitol. 1984 Apr;70(2):220–225. [PubMed] [Google Scholar]
- Berman J. D., Wyler D. J. An in vitro model for investigation of chemotherapeutic agents in leishmaniasis. J Infect Dis. 1980 Jul;142(1):83–86. doi: 10.1093/infdis/142.1.83. [DOI] [PubMed] [Google Scholar]
- Bryceson A. D., Chulay J. D., Ho M., Mugambii M., Were J. B., Muigai R., Chunge C., Gachihi G., Meme J., Anabwani G. Visceral leishmaniasis unresponsive to antimonial drugs. I. Clinical and immunological studies. Trans R Soc Trop Med Hyg. 1985;79(5):700–704. doi: 10.1016/0035-9203(85)90197-x. [DOI] [PubMed] [Google Scholar]
- Davidson R. N., Croft S. L. Recent advances in the treatment of visceral leishmaniasis. Trans R Soc Trop Med Hyg. 1993 Mar-Apr;87(2):130-1, 141. doi: 10.1016/0035-9203(93)90457-2. [DOI] [PubMed] [Google Scholar]
- Doenhoff M. J., Modha J., Lambertucci J. R., McLaren D. J. The immune dependence of chemotherapy. Parasitol Today. 1991 Jan;7(1):16–18. doi: 10.1016/0169-4758(91)90079-4. [DOI] [PubMed] [Google Scholar]
- Gramiccia M., Gradoni L., Orsini S. Decreased sensitivity to meglumine antimoniate (Glucantime) of Leishmania infantum isolated from dogs after several courses of drug treatment. Ann Trop Med Parasitol. 1992 Dec;86(6):613–620. doi: 10.1080/00034983.1992.11812717. [DOI] [PubMed] [Google Scholar]
- Grögl M., Oduola A. M., Cordero L. D., Kyle D. E. Leishmania spp.: development of pentostam-resistant clones in vitro by discontinuous drug exposure. Exp Parasitol. 1989 Jul;69(1):78–90. doi: 10.1016/0014-4894(89)90173-2. [DOI] [PubMed] [Google Scholar]
- Hendrickson N., Sifri C. D., Henderson D. M., Allen T., Wirth D. F., Ullman B. Molecular characterization of the ldmdr1 multidrug resistance gene from Leishmania donovani. Mol Biochem Parasitol. 1993 Jul;60(1):53–64. doi: 10.1016/0166-6851(93)90028-v. [DOI] [PubMed] [Google Scholar]
- Neal R. A., Croft S. L. An in-vitro system for determining the activity of compounds against the intracellular amastigote form of Leishmania donovani. J Antimicrob Chemother. 1984 Nov;14(5):463–475. doi: 10.1093/jac/14.5.463. [DOI] [PubMed] [Google Scholar]
- Ouellette M., Papadopoulou B. Mechanisms of drug resistance in Leishmania. Parasitol Today. 1993 May;9(5):150–153. doi: 10.1016/0169-4758(93)90135-3. [DOI] [PubMed] [Google Scholar]
- Peters B. S., Fish D., Golden R., Evans D. A., Bryceson A. D., Pinching A. J. Visceral leishmaniasis in HIV infection and AIDS: clinical features and response to therapy. Q J Med. 1990 Nov;77(283):1101–1111. doi: 10.1093/qjmed/77.2.1101. [DOI] [PubMed] [Google Scholar]
- Piarroux R., Fontes M., Perasso R., Gambarelli F., Joblet C., Dumon H., Quilici M. Phylogenetic relationships between Old World Leishmania strains revealed by analysis of a repetitive DNA sequence. Mol Biochem Parasitol. 1995 Jul;73(1-2):249–252. doi: 10.1016/0166-6851(95)00097-k. [DOI] [PubMed] [Google Scholar]
- Piarroux R., Garnier J. M., Gambarelli F., Dumon H., Kaplanski S., Unal D. Résistance de Leishmania infantum au Glucantime: circonstances de survenue et prise en charge thérapeutique. Arch Pediatr. 1996 Apr;3(4):352–356. doi: 10.1016/0929-693x(96)84691-4. [DOI] [PubMed] [Google Scholar]
- Rioux J. A., Lanotte G., Serres E., Pratlong F., Bastien P., Perieres J. Taxonomy of Leishmania. Use of isoenzymes. Suggestions for a new classification. Ann Parasitol Hum Comp. 1990;65(3):111–125. doi: 10.1051/parasite/1990653111. [DOI] [PubMed] [Google Scholar]
- Wong A. K., Chow L. M., Wirth D. F. A homologous recombination strategy to analyze the vinblastine resistance property of the V-circle in Leishmania. Mol Biochem Parasitol. 1994 Mar;64(1):75–86. doi: 10.1016/0166-6851(94)90136-8. [DOI] [PubMed] [Google Scholar]