Journal Article

Amphotericin B resistance in Leishmania amazonensis: In vitro and in vivo characterization of a Brazilian clinical isolate

Aoki, Juliana I., Branco, Nilson, Soares, Gustavo H. C., de la Roca, Stephane, Coelho, Adriano C., Ferreira, Bianca A., Lima, Mayara I. S., Coser, Elizabeth M.

2024

Overview

In Brazil, Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The state of Maranhão in the Northeast of Brazil is prevalent for these clinical forms of the disease and also has high rates of HIV infection. Here, we characterized the drug susceptibility of a L . amazonensis clinical isolate from a 46-year-old man with diffuse cutaneous leishmaniasis coinfected with HIV from this endemic area. This patient underwent several therapeutic regimens with meglumine antimoniate, liposomal amphotericin B, and pentamidine, without success. In vitro susceptibility assays against promastigotes and intracellular amastigotes demonstrated that this isolate had low susceptibility to amphotericin B, when compared with the reference strain of this species that is considered susceptible to antileishmanial drugs. Additionally, we investigated whether the low in vitro susceptibility would affect the in vivo response to amphotericin B treatment. The drug was effective in reducing the lesion size and parasite burden in mice infected with the reference strain, whereas those infected with the clinical isolate and a resistant line (generated experimentally by stepwise selection) were refractory to amphotericin B treatment. To evaluate whether the isolate was intrinsically resistant to amphotericin B in animals, infected mice were treated with other drugs that had not been used in the treatment of the patient (miltefosine, paromomycin, and a combination of both). Our findings demonstrated that all drug schemes were able to reduce lesion size and parasite burden in animals infected with the clinical isolate, confirming the amphotericin B-resistance phenotype. These findings indicate that the treatment failure observed in the patient may be associated with amphotericin B resistance, and demonstrate the potential emergence of amphotericin B-resistant L . amazonensis isolates in an area of Brazil endemic for cutaneous leishmaniasis.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amastigotes / Amphotericin B / Amphotericin B - pharmacology / Amphotericin B - therapeutic use / Animals / Antifungal agents / Antiprotozoal Agents - pharmacology / Antiprotozoal Agents - therapeutic use / Brazil / Care and treatment / Cutaneous leishmaniasis / Drug dosages / Drug Resistance / Drugs / Experiments / Health services / HIV / HIV Infections - complications / HIV Infections - drug therapy / Human immunodeficiency virus / Humans / In vivo methods and tests / Leishmania / Leishmania - classification / Leishmania - drug effects / Leishmania - isolation & purification / Leishmania amazonensis / Leishmania mexicana - drug effects / Leishmania mexicana - isolation & purification / Leishmaniasis / Leishmaniasis, Cutaneous - drug therapy / Leishmaniasis, Cutaneous - parasitology / Leishmaniasis, Diffuse Cutaneous - drug therapy / Leishmaniasis, Diffuse Cutaneous - parasitology / Lesions / Male / Meglumine antimoniate / Mice / Mice, Inbred BALB C / Middle Aged / Miltefosine / Parasites / Parasitic diseases / Parasitic Sensitivity Tests / Paromomycin / Patients / Pentamidine / Performance evaluation / Phenotypes / Physiological aspects / Promastigotes / Protozoa / Sterols / Susceptibility / Testing / Vector-borne diseases