Effect of Local Administration of Meglumine Antimoniate and Polyhexamethylene Biguanide Alone or in Combination with a Toll-like Receptor 4 Agonist for the Treatment of Papular Dermatitis due to Leishmania infantum in Dogs

Abstract

Papular dermatitis is a cutaneous manifestation of canine Leishmania infantum infection associated with mild disease. Although it is a typical presentation, nowadays, there is still no established treatment. This study evaluated the safety and clinical efficacy of local meglumine antimoniate, locally administered polyhexamethylene biguanide (PHMB) alone or PHMB in combination with a Toll-like receptor 4 agonist (TLR4a) for the treatment of papular dermatitis due to L. infantum and assessed parasitological and immunological markers in this disease. Twenty-eight dogs with papular dermatitis were divided randomly into four different groups; three of them were considered treatment groups: PHMB (n = 5), PHMB + TLR4a (n = 4), and meglumine antimoniate (n = 10)), and the remaining were considered the placebo group (n = 9), which was further subdivided into two sub-groups: diluent (n = 5) and TLR4a (n = 4). Dogs were treated locally every 12 h for four weeks. Compared to placebo, local administration of PHMB (alone or with TLR4a) showed a higher tendency towards resolution of papular dermatitis due to L. infantum infection at day 15 (χ² = 5.78; df = 2, p = 0.06) and day 30 (χ² = 4.; df = 2, p = 0.12), while local meglumine antimoniate administration demonstrated the fastest clinical resolution after 15 (χ² = 12.58; df = 2, p = 0.002) and 30 days post-treatment (χ² = 9.47; df = 2, p = 0.009). Meglumine antimoniate showed a higher tendency towards resolution at day 30 when compared with PHMB (alone or with TLR4a) (χ² = 4.74; df = 2, p = 0.09). In conclusion, the local administration of meglumine antimoniate appears to be safe and clinically efficient for the treatment of canine papular dermatitis due to L. infantum infection.

Keywords: canine; cutaneous lesions; immunotherapy; leishmaniosis; local treatment; toll-like agonist.

Figure 1

Clinical efficacy of local PHMB on papular dermatitis due to L. infantum at day 0 (a), day 15 (b) showing partial remission, and day 30 (c) full remission. Courtesy of Isaac Carrasco.

Figure 2

Timeline of the procedures performed on each dog at the time of diagnosis and during follow-up. Created with BioRender.com. CBC = complete blood count, BQ = biochemistry panel, Ab = antibody, IFN-γ = Interferon-gamma, IL-17a = Interleukin-17a, LSA = soluble L. infantum antigen, NBT = Nitroblue tetrazolium.

Figure 3

Flowchart displaying the number of dogs included at the time of diagnosis, treatment groups, as well as withdrawn dogs and lost to follow-up during the follow-up period. PHMB = polyhexamethylene biguanide, TLR4a = Toll-like receptor 4 agonist, Control group (n = 9): diluent (n = 5) + TLR4a (n = 4). Lost to follow-up = owners did not want to participate in the study anymore. No visit at this follow-up = owners did not show up at the Veterinary clinic that day. Withdrawn = dog was withdrawn of the study due to the development of systemic disease based on clinical signs and clinicopathological abnormalities, treatment with conventional anti-Leishmania drugs (meglumine antimoniate, miltefosine, or allopurinol), or highly increased antibody levels.

Figure 4

Median concentration with 95% CI (a) IFN-γ and (b) IL-17a concentration after LSA stimulation in cytokine producers and non-producers dogs at the time of diagnosis and prior to administration of local treatment.

Figure 5

Correlation between IL-17a (pg/mL) and IFN-γ (pg/mL) after LSA stimulation in the total of dogs studied at the time of diagnosis and follow-up. Spearman r: 0.59, p < 0.0001.