Topical treatment with a commercial formulation containing permethrin and indoxacarb (Activyl® Tick Plus) provided significant anti-feeding efficacy against the sandfly P. perniciosus for up to four weeks after application. The anti-feeding efficacy of > 95% was observed from 2 to 14 days post treatment, with significant anti-feeding effect continuing to 29 days post-treatment. This study confirmed that a topical permethrin and indoxacarb combination treatment could aid in the prevention of sandfly infestation in dogs. Although the frequency of subsequent applications was not determined in this study, the results suggest that treatment would need to be re-applied two to three weeks after initial application to maintain appropriate efficacy and prevent blood feeding, which is consistent with the duration of effects approved for similar permethrin-containing products. Advantix® (Bayer), a combination of imidacloprid and permethrin, is licenced in Europe with an efficacy claim of 2 to 3 weeks against P. papatasi and P. perniciosus. More recently Vectra 3D™ (Ceva), a combination of dinotefuran, permethrin and pyriproxyfen, has been shown to provide an anti-feeding efficacy of > 95% up to 14 days post treatment, with significant anti-feeding effect of > 80% continuing to 28 days post-treatment, compared with the control group.
The short-term insecticidal efficacy (knock-down effect) was significant over one week post treatment, but as expected no persistent immediate insecticidal activity could be evidenced afterwards. The low knock-down effect reported is consistent with the results observed with other permethrin-containing products in studies where the percent of alive sand flies was also evaluated after one hour of exposure[7, 9]. In this study, the number of dead flies was not evaluated 24 hours after insecticide exposure. For this reason, no conclusion can be drawn on the insecticidal activity according to international standards. However, it remains widely recognized that the anti-feeding effect of permethrin, more than its immediate insecticidal potential, is really the true benefit against transmission of L. infantum by phlebotomine vectors.
Prophylactic measures to control the spread of L. infantum have been initiated over the past 15 years through studies that aimed at demonstrating the efficacy of topical treatment of dogs exposed to sandfly bites. Collars, spot-on and spray formulations, containing pyrethroids at various concentrations, have demonstrated both anti-feeding efficacy (repulsive effect of the insecticide resulting in a decreased blood feeding) and insecticide effect (persistent absorption of the insecticide by the insect at toxic doses). The synergic repulsive/toxic action of these insecticides allows both the prevention of sandfly bites and their elimination or reduction, thereby contributing to the prevention of L. infantum transmission. It is widely accepted that collars have longer anti-feeding and toxicological activities (up to 6 months) compared with sprays and spot-on which have to be administered at least once a month. Conversely, the onset of action of the insecticide is immediate with sprays and ranges between 24–48 hours with spot-on formulations, but the full protective activity is achieved within one week with collars, due to a slower release of the active. Data from the literature have shown that the 24-hour post treatment insecticidal effect against P. perniciosus is comparable with deltamethrin 4% collars (25-64%) and permethrin 50%-imidacloprid 10% or permethrin 65% spot on formulations (49-67%). A short-term knock-down effect of 7% was reported with a permethrin 1.9%-pyriproxyfen 0.02% spray. Conversely, the anti-feeding effect seems higher with a permethrin 50%-imidacloprid 10% or permethrin 65% spot on (89-98%) compared to a deltamethrin 4% collar (72-90%) or a permethrin 1.9%-pyriproxyfen 0.02% spray (71%)[3, 5].
Previous studies of permethrin sandfly anti-feeding efficacy, either as the single active ingredient or in various combination spot-on formulations[7–9], have shown a similar pattern of extended blood feeding prevention over two to four weeks after treatment, together with relatively shorter and lower knock-down effect. Molina et al., particularly, demonstrated that 65% permethrin applied to dogs as a spot-on had satisfactory anti-feeding effect (> 65%) lasting 3 weeks and immediate insecticidal effects (> 40%) lasting 2 weeks after initial application, which is consistent with the present results. Similarly, highly comparable results were reported by Miró et al. with a combination of imidacloprid 10% (w/v)/permethrin 50% (w/v) spot-on, with an immediate insecticidal effect (assessed after 1 hour of sand fly exposure) within the first week of application (> 40%), and an anti-feeding effect of over 90% during the first 3 weeks of the study. Recent results obtained with the addition of 4.95% dinotefuran in the combination 36.08% permethrin-0.44% pyriproxyfen have demonstrated both persistent knock-down effect and insecticidal activity 7 days (> 95%), 2 weeks (> 70%) and up to 4 weeks after treatment (about 40%).
Permethrin uptake on contact by arthropods is the major route of the pharmacodynamic effect, and the toxicity of pyrethroids to insects is attributable to their fast cuticular penetration and ‘knock down’ effect. Indoxacarb (the second active ingredient present in the combination) enters the insect primarily through ingestion although it can be absorbed, to a lesser degree, through the insect cuticle. In vitro data show that indoxacarb is toxic to adult blowfly and mosquito larvae. It is therefore likely that the sandfly feeding behavior only exposes the flies to the effects of topically applied permethrin, leading to minimal contribution of indoxacarb to the insecticidal activity.
The topical application of permethrin combined with indoxacarb (Activyl® Tick Plus) was not associated with any local or systemic tolerance issue, supporting the safety profile of this product when used at the recommended dose.