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

Gonçalves, Gustavo Henrique; Campos, Monique Paiva; Gonçalves, Alessandra Silva; Medeiros, Lia Carolina Soares; Figueiredo, Fabiano Borges

doi:10.1186/s13071-021-05100-x

Cited by 14 publications

(8 citation statements)

References 29 publications

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“…However, after a few months, the treated dog relapses, needing to go through another therapeutic treatment with the same drug. Therefore, it is common for dogs that have already received three or more treatments with miltefosine to experience increasingly rapid relapses that lead to cases of parasitic resistance to the drug 13 . In this context, many veterinarians use drugs such as allopurinol, 14 domperidone, 15 and antifungals 16 to keep the patient stable for longer periods of time.…”

Section: Discussionmentioning

confidence: 99%

LaSap vaccine: Immunotherapy and immunochemotherapy associated with allopurinol in dogs naturally infected with Leishmania infantum

Clasta,

Rivas,

Souza

et al. 2024

Parasite Immunology

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Canine visceral leishmaniasis is a parasitic zoonosis that has a profound impact on public health in countries where it is endemic. Chemotherapeutic treatments cannot keep dogs stable for long periods, and the risk of generating parasitic resistance must be considered. Forty‐four symptomatic and naturally infected dogs with Leishmania infantum were tested with two treatment protocols (i) immunotherapy with LaSap vaccine and (ii) immunochemotherapy with LaSap vaccine plus allopurinol. At 90 days after the end of the treatment, it was verified that, although both protocols had generated significant clinical improvements with a greater production of IFN‐γ/IL‐10, in relation to the parasite load, mainly in the skin, the dogs treated only with immunotherapy maintained the same profile. These results indicate that LaSap is a good strategy to control dog parasitism.

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Section: Discussionmentioning

confidence: 99%

LaSap vaccine: Immunotherapy and immunochemotherapy associated with allopurinol in dogs naturally infected with Leishmania infantum

Clasta,

Rivas,

Souza

et al. 2024

Parasite Immunology

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“…The authors do not have a clear explanation for this event, especially because the retrospective feature of the study did not allow an in-depth examination of the dogs that relapsed. Indeed, the factors that can determine the lower efficacy of the therapy are several and can be linked to the immune response profile of the dog [ 29 ], but especially to the changes of the parasite [ 23 , 30 , 31 ]. There is no doubt that, in patients requiring more than one treatment, it is useful to alternate the anti- Leishmania molecules in order to limit the development of the drug-resistance.…”

Section: Discussionmentioning

confidence: 99%

“…Instead, the combined therapy of miltefosine and leishmaniostatic allopurinol is a protocol of documented efficacy [ 18 , 19 ] and is considered among those the first choice for CanL therapy [ 4 , 20 ]. Nevertheless, the Miltefosine-Allopurinol (MIL-AL) protocol is sometimes considered a second-choice treatment when compared to meglumine-antimoniate—allopurinol combination, mainly for the risk of earlier relapses [ 21 , 22 ] or the development of parasite drug resistance [ 23 ]. The aim of this study was to evaluate the efficacy of the MIL-AL protocol during a long-term follow-up with an average duration of nine years.…”

Section: Introductionmentioning

confidence: 99%

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Gizzarelli

Manzillo

Inglese³

et al. 2023

Pathogens

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Miltefosine-Allopurinol (MIL-AL) combination is reported to be one of the most effective treatments for canine leishmaniosis, thanks to its oral administration and MIL-documented low impact on renal function. However, MIL-AL is considered a second-choice treatment when compared to meglumine-antimoniate—allopurinol combination, mainly due to the risk of earlier relapses. The aim of this study was to evaluate the efficacy of the MIL-AL protocol during a long-term follow-up with an average duration of nine years. Dogs were living in Southern Italy (Puglia, Italy) in an area considered endemic for Canine leishmaniosis (CanL). Inclusion criteria were clinical and/or clinicopathological signs consistent with CanL; positive result to Leishmania quantitative ELISA; and negativity to the most frequent canine vector-borne infections. All dogs received 2 mg/kg MIL for 28 days, and 10 mg/kg AL, BID, for a period varying between 2 and 12 months. Ancillary treatments were allowed according to the clinical condition of the dog. A total clinical score and a total clinicopathological score were calculated at each time point by attributing one point to each sign or alteration present and then by adding all points. Improvement after each treatment was defined by the reduction of at least 50% of the total score. A survival analysis (Kaplan–Meier curve) was performed for quantifying the probability of the events occurring during the study follow-up. The following events were considered: decreased and negative ELISA results; improvement/recovery of the clinical and clinicopathological alterations; and relapse of leishmaniasis. One hundred seventy-three dogs (75f and 98m) were retrospectively included in the study by examining their clinical records since the first diagnosis of CanL. One hundred forty-three (83%) dogs were under five years of age. The mean duration of the follow-up period was 5.4 (±1.1) years with a minimum of 3.2 years and a maximum of 9 years. All dogs received a first treatment of MIL-AL at inclusion; then, during the follow-up course, 30 dogs required a second treatment, 2 dogs required a third treatment and 1 dog required a fourth and a fifth treatment. The mean time interval between the first and the second treatment was 27.2 (±18.3) months. After the first treatment, all dogs had decreased ELISA levels, in an average interval of 2.6 (±1.6) months. One hundred seventy dogs (98%) experienced a clinical improvement (mean time 3.0 ± 4.9 months); 152 (88%) dogs were considered clinically recovered after a mean time of 16.7 ± 13.5 months. A similar trend was observed for clinicopathological alterations; interestingly, proteinuria decreased in most dogs (p < 0.0001—Chi-square for trends). Thirty dogs experienced relapses, the earliest after 4.8 months. The mean time without relapse was 90.4 (±2.5) months. In relapsed dogs, the mean time for clinical improvement after the second treatment was 8.6 (±12.6) months, whereas it was 11.0 (±15.4) months for clinicopathological alterations. Five dogs had limited gastrointestinal side effects associated with MIL treatment. The present study confirms that the MIL-AL protocol can be considered one of the most effective treatments for CanL therapy, mainly for its capacity to provide a long-time clinical improvement in a large majority of treated dogs. As reported in the literature, the clinical stabilization of dogs does not occur immediately after treatment, probably due to the particular pharmacokinetic properties of MIL. The efficacy of MIL-AL decreases in dogs that need more than one treatment, suggesting the necessity to alternate anti-Leishmania drugs for the treatment of relapses. Side effects were transient and slight, even in dogs that required several treatments.

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“…Although the symptoms are reduced, the parasites are not completely eliminated from the dog ( Andrade et al, 2011 ). Furthermore, cases of induced resistance have been observed ( Gonçalves et al, 2021 ) and there have been reports of animals that remained susceptible to infection by the invertebrate vector despite reaching clinical cure ( Chappuis et al, 2007 ).…”

mentioning

confidence: 99%

Therapeutic success and failure in using miltefosine to treat dogs naturally infected with Leishmania infantum

Gonçalves,

Campos,

Gonçalves

et al. 2024

Rev. Bras. Parasitol. Vet.

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In urban environments, domestic dogs (Canis familiaris) are a major reservoir for the parasite Leishmania infantum. Miltefosine has been used as the standard treatment for canine visceral leishmaniasis in Brazil. However, therapeutic failures have been reported. In the present study, two dogs (CG03 and CG06) with a diagnosis of infection by L. infantum underwent two cycles of treatment with miltefosine (Milteforan™ - Virbac®). Analyses showed increases in the parasite load of both CG03 and CG06, even after treatment. The clinical score of CG03 dropped from 1 to 0 (after one round of treatment), such that this dog became asymptomatic. CG06 showed clinical worsening, such that its score increased from 1 to 2. After the second therapeutic round, the parasite load in CG03 was found to have decreased, but it was still higher than before drug treatment even though this dog was physically asymptomatic. There was no decrease in the parasite load in CG06 and there was clinical worsening. The clinical response of these dogs to the treatment differed, but the parasite load remained high in both cases, which poses a risk to public health, making it essential take measures to prevent the sandfly vector from accessing the dog.

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

Cited by 14 publications

References 29 publications

LaSap vaccine: Immunotherapy and immunochemotherapy associated with allopurinol in dogs naturally infected with Leishmania infantum

LaSap vaccine: Immunotherapy and immunochemotherapy associated with allopurinol in dogs naturally infected with Leishmania infantum

Retrospective Long-Term Evaluation of Miltefosine-Allopurinol Treatment in Canine Leishmaniosis

Therapeutic success and failure in using miltefosine to treat dogs naturally infected with Leishmania infantum

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