scholarly journals Treatment of canine visceral leishmaniasis with Milteforan™ induces Leishmania infantum resistance to miltefosine and amphotericin B

2021 ◽  
Author(s):  
Gustavo Gonçalves ◽  
Monique Paiva Campos ◽  
Alessandra Silva Gonçalves ◽  
Lia Carolina Soares Medeiros ◽  
Fabiano Borges Figueiredo
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Infantum ◽  
Cross Resistance ◽  
Canine Visceral Leishmaniasis ◽  
In Vitro Susceptibility ◽  
Meglumine Antimoniate ◽  
Parasite Fitness ◽  
The Impact

Visceral leishmaniasis (VL) is the most severe form of leishmaniasis and is caused by Leishmania infantum in the Americas. Since the use of Milteforam™ was authorized to treat canine visceral leishmaniasis (CVL) in Brazil in 2017, there has also been fear of the emergence of parasites resistant to this drug and, through cross-resistance mechanisms, to meglumine antimoniate and amphotericin B. Additionally, the literature shows that acquisition of resistance is followed by increased parasite fitness, with higher rates of proliferation, infectivity and metacyclogenesis, which are determining factors for parasite virulence. In this context, this study aims to analyze the impact of treating a dog with Milteforan™ on the generation of parasites resistant to miltefosine, meglumine antimoniate, and amphotericin B. To this end, in vitro susceptibility tests were conducted against these drugs with T0 (parasites isolated from the dog before treatment with Milteforan™), T1 (after one course of treatment), and T2 (after two courses of treatment) isolates. The rates of cell proliferation, infectivity, and metacyclogenesis of the isolates were also evaluated. The results indicate a gradual increase in parasite resistance to miltefosine and amphotericin B with increasing the number of treatment courses. A trend increase in the metacyclogenesis rate of the parasites was also observed as drug resistance increased. Therefore, treatment of CVL with Milteforan™ induces resistance to miltefosine and amphotericin B as well as changes in parasite fitness, and may have an impact on animal and human public health.

scholarly journals Increased Leishmania infantum resistance to miltefosine and amphotericin B after treatment of a dog with miltefosine and allopurinol

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Gustavo Gonçalves ◽  
Monique Paiva Campos ◽  
Alessandra Silva Gonçalves ◽  
Lia Carolina Soares Medeiros ◽  
Fabiano Borges Figueiredo
Keyword(s):  
Amphotericin B ◽  
Leishmania Infantum ◽  
Resistance Mechanisms ◽  
Canine Leishmaniasis ◽  
Cross Resistance ◽  
In Vitro Susceptibility ◽  
Meglumine Antimoniate ◽  
Number Of Treatment ◽  
The Impact

Abstract Background Leishmania infantum is the most important etiological agent of visceral leishmaniasis in the Americas and Mediterranean region, and the dog is the main host. Miltefosine was authorized to treat canine leishmaniasis (CanL) in Brazil in 2017, but there is a persistent fear of the emergence of parasites resistant not only to this drug but, through cross-resistance mechanisms, also to meglumine antimoniate and amphotericin B. Additionally, the literature shows that acquisition of resistance is followed by increased parasite fitness, with higher rates of proliferation, infectivity and metacyclogenesis, which are drivers of parasite virulence. In this context, the aim of this study was to analyze the impact of treating a dog with miltefosine and allopurinol on the generation of parasites resistant to miltefosine, amphotericin B and meglumine antimoniate. Methods In vitro susceptibility tests were conducted against miltefosine, amphotericin B and meglumine antimoniate with T0 (parasites isolated from a dog before treatment with miltefosine plus allopurinol), T1 (after 1 course of treatment) and T2 (after 2 courses of treatment) isolates. The rates of cell proliferation, infectivity and metacyclogenesis of the isolates were also evaluated. Results The results indicate a gradual increase in parasite resistance to miltefosine and amphotericin B with increasing the number of treatment courses. An increasing trend in the metacyclogenesis rate of the parasites was also observed as drug resistance increased. Conclusion The data indicates an increased L. infantum resistance to miltefosine and amphotericin B after the treatment of a dog with miltefosine plus allopurinol. Further studies with a larger number of L. infantum strains isolated from dogs with varied immune response profiles and undergoing different treatment regimes, are advocated. Graphical Abstract

scholarly journals Miltefosine susceptibility of isolates of Leishmania (Leishmania) infantum from dogs of the municipality of Embu-Guaçu, Brazil

2018 ◽  
Author(s):  
Bianca Alves Ferreira ◽  
Adriano Cappellazzo Coelho ◽  
Paulo César Cotrim ◽  
Edite Hatsumi Yamashiro Kanashiro ◽  
Mussya Cisotto Rocha
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Infantum ◽  
Sao Paulo ◽  
Metropolitan Region ◽  
Parasitic Disease ◽  
Canine Visceral Leishmaniasis ◽  
Highly Effective ◽  
The City

Visceral leishmaniasis (VL) is a parasitic disease caused by the protozoan Leishmania (L.) infantum. In Brazil, the number of cases of the disease has increased in the last years. The treatment of leishmaniasis in Brazil consists of the use of pentavalent antimonials and amphotericin B. Recently, miltefosine has been shown to be highly effective against VL in Asia. Although, this drug is not used in the treatment of VL in Brazil, miltefosine is approved for use in the treatment of canine visceral leishmaniasis (CVL). In this study, we evaluate the susceptibility to miltefosine in vitro of isolates of L. (L.) infantum from dogs of municipality of Embu-Guaçu, located in the metropolitan region of the city of São Paulo.

scholarly journals Resistance to Experimental Visceral Leishmaniasis in Mice Infected With Leishmania infantum Requires Batf3

2020 ◽  
Vol 11 ◽  
Author(s):  
Manuel Soto ◽  
Laura Ramírez ◽  
José Carlos Solana ◽  
Emma C. L. Cook ◽  
Elena Hernández-García ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Infantum ◽  
Rational Design ◽  
Leucine Zipper ◽  
Basic Leucine Zipper ◽  
Vector Borne ◽  
The Impact ◽  
Deficient Mice

Unveiling the protective immune response to visceral leishmaniasis is critical for a rational design of vaccines aimed at reducing the impact caused by this fatal, if left untreated, vector-borne disease. In this study we sought to determine the role of the basic leucine zipper transcription factor ATF-like 3 (Batf3) in the evolution of infection with Leishmania infantum, the causative agent of human visceral leishmaniasis in the Mediterranean Basin and Latin America. For that, Batf3-deficient mice in C57BL/6 background were infected with an L. infantum strain expressing the luciferase gene. Bioluminescent imaging, as well as in vitro parasite titration, demonstrated that Batf3-deficient mice were unable to control hepatic parasitosis as opposed to wild-type C57BL/6 mice. The impaired microbicide capacities of L. infantum-infected macrophages from Batf3-deficient mice mainly correlated with a reduction of parasite-specific IFN-γ production. Our results reinforce the implication of Batf3 in the generation of type 1 immunity against infectious diseases.

scholarly journals Investigation of susceptibility to paromomycin in isolates from dogs of Leishmania (Leishmania) infantum

2019 ◽  
Author(s):  
Viviane da Luz Oliveira ◽  
Adriano Cappellazzo Coelho ◽  
Edite H. Y. Kanashiro ◽  
Mussya C. Rocha ◽  
Paulo C. Cotrim
Keyword(s):  
Side Effects ◽  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Infantum ◽  
Sao Paulo ◽  
Parasitic Disease ◽  
Effectiveness Rate ◽  
Alternative Drug ◽  
The City

In Brazil, visceral leishmaniasis (VL) is a parasitic disease caused by the protozoan Leishmania (Leishmania) infantum. This disease is serious and may be lethal if not treated. The treatment of leishmaniasis in Brazil consists in the use of pentavalent antimonials and/or amphotericin B. These drugs are toxic, have several side effects and the effectiveness of treatment has decreased in the last years. Paromomycin is an alternative drug already used in the treatment of VL in Asia with effectiveness rate higher than 90%. In this project, we aimed to evaluate the susceptibility in vitro to paromomycin of isolates of L. (L.) infantum from dogs of the city of Embu-Guaçu, State of São Paulo.

scholarly journals In Vitro Susceptibility of Field Isolates of Leishmania donovani to Miltefosine and Amphotericin B: Correlation with Sodium Antimony Gluconate Susceptibility and Implications for Treatment in Areas of Endemicity

2008 ◽  
Vol 53 (2) ◽  
pp. 835-838 ◽  
Author(s):  
Dhiraj Kumar ◽  
Arpita Kulshrestha ◽  
Ruchi Singh ◽  
Poonam Salotra
Keyword(s):  
Amphotericin B ◽  
Gene Expression Analysis ◽  
Leishmania Donovani ◽  
Resistance Mechanisms ◽  
Cross Resistance ◽  
In Vitro Susceptibility ◽  
Field Isolates ◽  
Antimony Resistance ◽  
Sodium Antimony Gluconate

ABSTRACT Indian Leishmania donovani isolates (n = 19) from regional zones representing various levels of antimony resistance displayed significantly (P < 0.01) correlated results with respect to in vitro susceptibility to the antileishmanial drugs sodium antimony gluconate, amphotericin B, and Miltefosine, raising the possibility of cross-resistance mechanisms operating in the field isolates. The results of gene expression analysis of LdMT and LdRos3 were suggestive of alternate mechanisms of Miltefosine susceptibility in the isolates.

scholarly journals Immunoprophylactic Potential of a New Recombinant Leishmania infantum Antigen for Canine Visceral Leishmaniasis: An In Vitro Finding

2021 ◽  
Vol 11 ◽  
Author(s):  
Rômulo Pessoa-e-Silva ◽  
Lays Adrianne Mendonça Trajano-Silva ◽  
Victor Vaitkevicius-Antão ◽  
Wagner José Tenório dos Santos ◽  
Franklin Barbalho Magalhães ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Infantum ◽  
Mononuclear Cells ◽  
Study Groups ◽  
No Production ◽  
Soluble Antigen ◽  
Mrna Levels ◽  
Canine Visceral Leishmaniasis ◽  
Peripheral Blood Mononuclear

The development and application of safe and effective immunoprophylactic/immunotherapeutic agents against canine visceral leishmaniasis (CanL) have been pointed out as the only means for the real control of the disease. Thus, this study aimed to evaluate the in vitro cellular immune response of dogs, elicited by the new recombinant proteins of Leishmania infantum, Lci10 and Lci13, in order to investigate their potential for vaccinology. Twenty-four dogs were submitted to clinical, parasitological, serological and molecular tests, and then separated into two study groups: 12 infected (InD) and 12 non-infected dogs (NInD), and six of each group were directed for Lci10 and Lci13 evaluation. Peripheral blood mononuclear cells (PBMC) were cultured and stimulated with Lci10 (10 μg/ml) or Lci13 (5 μg/ml), and with L. infantum soluble antigen (LSA) (25 μg/ml) or no stimulus (NS) as controls. Afterwards, the mRNA levels of different cytokines were quantified through qPCR, and Nitric Oxide (NO) production was assessed in the culture supernatants. Significant differences were considered when p ≤ 0.05. The comparative analysis revealed that, in the NInD group, Lci13 promoted a significant increase in the expression of IFN-γ in relation to LSA (p = 0.0362), and the expression of this cytokine in NInD was significantly higher than that presented in the InD (p = 0.0028). A negative expression for TGF-β was obtained in both groups. Lci13 also induced a greater production of NO in relation to the NS sample in the NInD group. No significant differences were observed after stimulation with Lci10. In conclusion, the results suggest a protective role of Lci13 for uninfected animals, thus with a potential for immunoprophylaxis. The results will help to direct the antigen Lci13 for further studies (pre-clinical trials), in order to determine its immunogenicity and reactogenicity effects, as a way to consolidate its real applicability for vaccinology against CanL.

scholarly journals Precise editing using CRISPR-Cas9 to explore the contribution of clinically-derived mutations to antifungal resistance in the pathogenic yeast Candida parapsilosis

2021 ◽  
Vol 3 (12) ◽  
Author(s):  
Sophie Hartuis ◽  
Estelle Robert ◽  
Lisa Lombardi ◽  
Geraldine Butler ◽  
Patrice Le Pape ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Candida Parapsilosis ◽  
Diploid Species ◽  
Antifungal Resistance ◽  
Cross Resistance ◽  
Pathogenic Yeast ◽  
In Vitro Susceptibility ◽  
Fluconazole Resistance ◽  
The Impact

Introduction Candida parapsilosis is both a commensal/saprophytic yeast of the human skin and an opportunistic pathogen which can be responsible for life-threatening infections. The increasing reports of clonal outbreaks involving azole-resistant C. parapsilosis in the clinical setting is worrisome and urges for a better understanding of antifungal resistance in this species. Previous studies have identified mutations in key genes which can explain acquired fluconazole resistance. Reverse genetics approaches are now warranted to confirm their involvement and to determine whether they can affect other clinically-licensed antifungals. Here, we used a CRISPR-Cas9 technique to study the relative contributions of clinically-derived mutations to antifungal resistance and provide answers to these questions. Materials and Methods Six clinically-derived mutations were selected (ERG11Y132F, ERG11K143R,ERG11R398I, TAC1G650E, MRR1G583R, ERG3G111R) to be engineered in two C. parapsilosis fluconazole-susceptible backgrounds (ATCC22019, STZ5) using a previously described CRISPR-Cas9 method. In vitro susceptibility of the transformants to fluconazole, voriconazole, posaconazole, isavuconazole and micafungin was determined by Etest®. Results/Discussion The impact on fluconazole susceptibility was highly variable depending on the residue/gene involved, but roughly similar between the two genetic backgrounds. All but two(ERG11R398I, ERG3G111R) conferred fluconazole resistance, though the highest MIC increase was observed for MRR1G583R (≥650 fold). As expected in a diploid species, we noted an impact of allelic dosage. Some kind of cross-resistance to the other azoles was noted from some mutations, although the impact was lower for posaconazole and isavuconazole, except for MRR1G583R which led to multi-azole resistance. Finally, ERG3G111R increased tolerance to both azoles and echinocandins.

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