Quantitative In Vitro Drug Potency and Drug Susceptibility Evaluation of Leishmania SSP. from Patients Unresponsive to Pentavalent Antimony Therapy

Joan E. JacksonDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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John D. TallyDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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William Y. EllisDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Yemane B. MebrahtuDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Phillip G. LawyerDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Joab B. WereDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Steven G. ReedDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Daniel M. PaniskoDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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B. L. LimmerDivision of Experimental Therapeutics, Walter Reed Army Institute of Research, Kenya Medical Research Institute, U.S. Army Medical Research Unit, Seattle Biomedical Research Institute, Toronto General Hospital, Washington, DC, Kenya

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Quantitative in vitro drug sensitivity of 32 Leishmania isolates (16 from patients failing pentavalent antimony [SbV] therapy) was determined using a radiorespirometric microtechnique (RAM). Of 30 isolates with histories, 22 (73%) RAM tests agreed with patient history; the remaining 8 (27%) did not. There was no difference in RAM drug sensitivity:clinical correlation between 15 isolates tested blindly and 15 with known clinical history (4 did not agree with clinical history in both). Test sensitivity appeared to be limited only by the sensitivity of the Leishmania to SbV and could be detected at 2 µg/ml Sb (about 10% of serum drug level). An isolate from a patient with untreated self-healing cutaneous disease was drug resistant. Using RAM, parasite drug sensitivity can be quantified apart from patient physiologic and immunologic variables intrinsic to clinical data. Potency differed a maximum of 100% (weight% Sb:weight% Sb) among drug lots and also between Glucantime® and Pentostam®. Potency changes between drug lots were not explainable based on Sb content or test-to-test variability. This microtest offers a rapid method for evaluating the drug sensitivity of patient isolates and for determining of the activity of pentavalent antimonials and other candidate anti-leishmanials prior to the initiation of therapy.

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