Human infections with Leishmania protozoan parasites, transmitted by the bite of phlebotomine sand flies, cause visceral, cutaneous, or mucocutaneous leishmaniasis. Eighty-eight countries are affected, with > 2 million new infections worldwide each year.1 The most severe disease forms are anthroponotic VL due to Leishmania donovani in the Indian subcontinent and parts of central Asia and Africa and zoonotic VL due to Leishmania infantum (Leishmania chagasi) in the Mediterranean, parts of Asia, and Latin America.
Domestic dogs are the only confirmed domestic reservoir of zoonotic VL.2 Reports3–5 from various areas suggest that the geographic range of leishmaniasis in dogs is changing, including detection of new foci in northern Italy and an extension of disease distribution in Israel and France. Moreover, there is some evidence that leishmaniasis in dogs could be enzootic in the United States. Sporadic autochthonous cases of disease have been reported in North America since early 1980.6 Of particular importance is the outbreak of leishmaniasis in Foxhounds at a New York kennel, which was first detected in 1999. A subsequent survey involving Foxhounds, other breeds of dogs, and wild canids revealed that leishmaniasis in dogs is enzootic in 18 states and 2 Canadian provinces. The lack of spread from Foxhounds to the wider dog population or local wild canid population suggests that sand fly transmission could not be involved, and thus infection in these dogs must be maintained by non–sand fly transmission routes.6
Neglected by researchers and funding agencies, leishmaniasis control strategies have varied little for decades, but in recent years, there have been advances in diagnosis, treatment, and prevention of the disease. Advances in prevention include evidence that the incidence of zoonotic VL, both in humans and dogs, can be reduced by treating dogs with dermal application of synthetic pyrethroids.7
In a broad sense, the term prevention includes the application of measures intended to avoid instances of infection by a pathogen or the pathological outcome of such instances. Vaccination against pathogens is regarded as a milestone in the field of infectious disease prevention; however, this important tool is not yet available worldwide for prevention of leishmaniasis in dogs.
Guidelines developed by the Canine Leishmaniasis Working Group for diagnosis, clinical classification, and treatment of leishmaniasis in dogs have been published.8,9 Here, we review preventive strategies by updating guidelines previously published in Italian in Veterinaria, the official journal of the Italian Society of Veterinarians of Companion Animals.10 The guidelines reported here are a result of a thorough review of international literature and, where inadequate or incomplete information existed, the experience of working group members. For completeness, we include a summary of research conducted to produce safe Leishmania vaccines for dogs. Therefore, the guidelines concern available preventive measures against phlebotomine sand flies, the only established Leishmania vector. It should be pointed out, however, that non–sand fly transmission routes have long been suspected and some have been confirmed experimentally, such as transplacental11 and sexual12 routes as well as via blood transfusion,13 although no evidence exists for transmission via saliva or conjunctiva fluids. All these transmission routes could be particularly important in areas in which autochthonous leishmaniasis in dogs has been reported in the absence of sand flies (eg, northern Europe)14 or in which local sand fly species have not yet been implicated in enzootic transmission of leishmaniasis (eg, North America). In such circumstances, our guidelines may not be effective or relevant.
Review of the Veterinary Literature
The PubMed database was searched by use of the following combination of search terms: (dog* OR canine) AND (prevention* OR against OR versus) AND (leishm*) NOT vaccine*. After ruling out 193 publications unrelated to the topic, 19 were included in this review. Moreover, 6 studies reported as abstracts in proceedings of international scientific meetings were examined.
Biological Aspects of Leishmania Vectors
The only established vectors of leishmaniasis are phlebotomine sand flies, including > 40 Phlebotomus species in the Old World and a further 30 Lutzomyia species in the New World.15 In the absence of the vector, stable foci of leishmaniasis do not exist. The hypothesis that transmission of leishmaniasis in the United States and Canada is from dog to dog rather than from sand flies requires confirmation.6 Detected in northeastern states in which leishmaniasis epidemics in dogs have occurred, Lutzomyia shannoni is the most highly suspected vector in the United States, but there may also be other species capable of transmitting the disease.16 In some countries, sand flies also carry and transmit other pathogens such as Bartonella spp, phleboviruses, and some flaviviruses, orbiviruses, and vesiculoviruses.17
Ecological niches of sand flies vary from humid tropical forests to deserts and from cities situated at sea level to high mountain villages. In temperate regions, sand fly activity is limited to the warm season. Despite this diversity, all sand fly species share a number of basic features. They are all nocturnal, resting during the day in dark, humid microhabitats and able to insert themselves into confined spaces to avoid extremes of temperature or humidity. Sand flies generally bite a variety of hosts and should be considered as opportunistic human biters rather than anthropophilic.18 Usual flight ranges are limited to a few hundred meters.19 Because of the wide host range, small size, and silent flight of sand flies, people in Leishmania-endemic areas may be unaware of the insect's presence or role in the epidemiology of the disease, a fact that may compromise leishmaniasis control efforts involving community participation. Despite their small size and delicateness, female sand flies are hematophagous pests, so their control may be required even where they are not active as vectors. Terrestrial larval breeding sites are generally difficult to identify,20 and therefore control measures oriented specifically against immature stages are not feasible, although the effectiveness of a few biological and chemical agents has been determined in laboratory studies.19
Leishmania Vector Control and Preventive Measures
The vectors of leishmaniases may theoretically be controlled through genetic or biological means, but at present, there are few effective methods other than chemical control.21 Such control measures are aimed at reducing sand fly populations and contact with humans by the use of insecticide IRS in houses and animal shelters, insecticide-treated nets for human use, dermal application of repellents in humans, and dermal application of insecticides in dogs. The following is a brief description of each measure, the information for which was obtained from a review by Alexander and Maroli.21
IRS—Indoor residual spraying consists of the application of long-acting insecticides on the walls and roofs of houses and domestic animal shelters and has been successfully used in malaria control since the 1940s. It is also an important method of controlling leishmaniasis. In the past, IRS has been used against these diseases alone in only some regions. In most situations, the purpose of IRS in human dwellings has been to control mosquitoes or other insects and the control of sand flies has been only coincidental. There are several examples of sand flies being affected by control measures directed against other pest species. In the late 1940s, malaria control efforts in Italy through the use of dichlorodiphenyltrichloroethane (ie, DDT) considerably reduced transmission of Leishmania spp. The same occurred in India, Iran, Syria, and Greece. Presently, only 2 countries from the Americas (Brazil and Paraguay) and 3 countries from the Eastern Mediterranean Region (Morocco, Syria, and Iran) are reporting use of the insecticide for leishmaniasis vector control, and that use is mainly through IRS.
Insecticides most extensively used for leishmaniasis vector control from 2003 through 2005, by class of insecticide, are as follows: organophosphate (chlorpyrifos-methyl), carbamate (propoxur), and pyrethroid (α-cypermethrin, cypermethrin, deltamethrin, and L-cyhalothrin). The effectiveness of IRS may depend on the degree to which sand flies have adapted to manmade environments as well as the total area treated. Thus, control of sand flies and thereby leishmaniasis by this method will be much more effective in urban settings in which every house and animal shelter is treated than in rural areas in which relatively few, widely dispersed dwellings are sprayed and the insects that bite humans and domestic animals represent a small proportion of the total vector population.
Among the synthetic insect repellents, the gold standard is N, N-diethyl-3-methylbenzamide (ie, DEET), which is highly effective against hematophagous insects and has been in use for > 50 years. Its efficacy has been established against Leishmania vectors. During the last 10 years, a new piperidine compound, 1-piperidinecarboxylic acid, 2-(2.hydroxyethyl)-1- methylpropylester (KBR 3023), was developed and its efficacy against Phlebotomus duboscqui was established. More recently, the efficacy of the natural neem oil, compared with a 20% KBR 3023 commercial formulationa against the bite of the anthropophilic species Phlebotomus papatasi, was evaluated in human volunteers.22 Results suggested 100% protection by KBR 3023 until 7 hours after application, in contrast with rapid decrease of activity of neem oil, from 100% protection in the first hour to almost none 5 hours after application.
Pharmacological Aspects of Insecticides for Dermal Application in Dogs
Because domestic dogs are the main reservoir host of L infantum throughout the world, much of the focus on controlling zoonotic VL is placed on dogs. The prevention of sand fly bites is an effective tool in protecting dogs from leishmaniasis and reducing the risk of human infections.19,23 In this field, several studies have been conducted on synthetic pyrethroids to be used on animals in topical formulations. These are classified as ectoparasiticides, consisting of registered medical remedies that have undergone rigorous registration procedures like other pharmaceuticals.
The mode of action of synthetic pyrethroids involves 2 main pharmacological aspects. After landing on treated dogs, sand flies may rest on the skin for a period sufficient to absorb a lethal dose of insecticide (effect achieved via toxic effects) or the flies may have only fleeting contact with insecticide-treated skin that is sufficient to cause irritation and disorientation, resulting in reduction of blood-feeding rate (effect achieved via lack of feeding).24 Synthetic pyrethroids used for application in dogs combine the properties of low to moderate mammalian toxic effects, low volatility, and high, fast insecticidal activity.25,26 Modes of application include slow-release protector band (dog collar), spoton formulations, or spray formulations. Safety tests performed after application on dog skin have revealed rare and temporary skin reactions to compounds in some of the smallest breeds with thin delicate skin. Reactions include itchiness and erythema at the site of application.27
In China in the early 1990s, first attempts were made to interrupt VL transmission through use of the pyrethroid deltamethrin in a medicated bath for dogs to prevent sand fly bites.28,29 Later, the insecticidal and nofeeding effects of deltamethrin and permethrin (pyrethroid), alone or in combination, were determined experimentally for 5 competent Leishmania vectors (Phlebotomus perniciosus and P papatasi in the Old World and Lutzomyia longipalpis, Lutzomyia migonei, and Lutzomyia intermedia in the New World; Table 1).24,30–39 The nofeeding effect was evaluated as the percentage of sand fly females unable to ingest a blood meal when in contact with treated dogs, whereas the toxic effect was related to the mortality rate observed at 24 hours after sand fly exposure to treated dogs. In general, the no-feeding effect was high: 84% to 96% of sand flies did not bite on treated dogs, compared with untreated control dogs. Mortality rates in the few fed females ranged from 98.8% to 100%. This outcome is important from the perspective of control of zoonotic VL. In fact, mass treatment of Leishmania-infected dogs would virtually interrupt L infantum transmission because almost all sand flies biting on treated reservoirs would die before transmitting the parasite to other hosts.
Summary of characteristics and outcomes of laboratory trials conducted to evaluate dermal insecticide formulations for the prevention of Leishmania vector bites in dogs.
| Formulation | Vector species used | No. of treated (control) dogs | Effect (%) | Observed period of protection (wk) | Reference No. | |
|---|---|---|---|---|---|---|
| Protective* | Insecticidal† | |||||
| 50% permethrin–10% imidacloprid (spot-on) | Phlebotomus papatasi | 6 (6) | 93 | 46 | 1 | 37 |
| 56 | 29 | 4 | 37 | |||
| Phlebotomus perniciosus | 8 (8) | 90 | 49 | 3 | 36 | |
| Lutzomyia longipalpis | 12 (12) | 90 | NR | 3 | b | |
| 65% permethrin (spot-on) | P perniciosus | 2 (2) | 91 | 67 | 4 | 32 |
| Lutzomyia intermedia | 3 (3) | 49 | 23 | 8 | 34 | |
| 2% permethrin–0.2% pyriproxyfen (spray) | P perniciosus | 3 (3) | 94 | 60 | ND | 30 |
| P perniciosus | 4 (4) | 89 | ND | 3 | 33 | |
| P perniciosus | 4 (4) | 87 | 60 | 4 | 35 | |
| 4% deltamethrin–triphenyl phosphate (collar) | P perniciosus | 5 (2) | 96 | 25–64 | 34 | 24 |
| P perniciosus | 5 (5) | 84 | 42 | 26 | 31 | |
| P papatasi | 7 (0) | 80 | 18 | NR | 39 | |
| L longipalpis | 4 (3) | 96 | 35–90 | 35 | 38 | |
| Lutzomyia migonei | 4 (3) | 96 | 46–91 | 36 | 38 | |
| L intermedia | 5 (3) | 69 | 37 | 8 | 34 | |
Percentage protective effect corresponds to no-feeding effect of the compound evaluated as the percentage of sand fly females unable to ingest a blood meal when in contact with treated dogs.
Insecticidal effect is the mortality rate of sand flies (male and female) at 24 hours after exposure to treated dogs.
ND = Not determined. NR = Not reported.
bRefer to footnote.
Collars—Because of the slow release of the insecticide from the protector band of dog collars, full protective activity is achieved approximately 1 week after application. Use of deltamethrin-impregnated collars results in a potent no-feeding effect against P perniciosus and kills up to 60% of the insects within 2 hours after exposure.24 Dogs wearing collars are reportedly bitten by approximately 80% fewer P papatasi than are unprotected animals.39 The collars also have a no-feeding and insecticidal effect against both Lutzomyia longipalpis and Lutzomyia migonei, New World vectors of zoonotic VL and cutaneous leishmaniasis parasites, respectively.38
In a study40 conducted to compare collars impregnated with deltamethrin or diazinon (a pyrimidine organothiophosphate), the deltamethrin-impregnated collars were effective (> 90% protection) and their effect lasted longer (up to 7 months in 2 different experiments). On the basis of results from laboratory evaluations, it has been suggested that, at least in the temperate regions, deltamethrin-impregnated collars could be expected to protect dogs from most sand fly bites and retain a protective and killing effect for a complete sand fly season. Given the long-term effect of collars (up to 34 weeks), applying them to most dogs in an L infantum focus could reduce contact between vectors and reservoirs sufficiently to reduce the risk of infection for both dogs and humans.24 In particular, the impact of mass use of deltamethrin-impregnated dog collars on the incidence of leishmaniasis in dogs has been evaluated. A village-based intervention trial27 conducted in the Campania region of Italy during 2 consecutive transmission periods revealed that collars confer up to 86% protection against L infantum infection in pet dogs. A study41 performed in Iran revealed that use of dog collars may significantly reduce the incidence of zoonotic VL in dogs and children. Additional intervention trials in which dog collars were evaluated have been conducted in Italy, Brazil, and Tunisia (Table 2).42–49
Summary of characteristics and outcomes of field trials conducted to evaluate the impact of mass use of dermal application of synthetic pyrethroids in dogs on the incidence of leishmaniasis in dogs.
| Formulation | Country | No. of treated (control) dogs | Study duration | Reduction in proportion of dogs with leishmaniasis (%) | Reference No. |
|---|---|---|---|---|---|
| 50% permethrin–10% imidacloprid (spot-on) | Italy | 209* and 204† (218) | 8 mo | 89* and 93† | 48 |
| 65% permethrin (spot-on) | Brazil | 150 (146) | 4 mo | 50 | 49 |
| Italy | 120 (188) | 2 seasons | 84 | 44 | |
| 4% deltamethrin–tripenyl phosphate collar | Italy | 354 (371) | 2 seasons | 50‡ and 86§ | 27 |
| 49 (150) | 1 season | 52 | 42 | ||
| 60 (60) | 2 seasons | 51 | 43 | ||
| 119 (188) | 2 seasons | 84 | 44 | ||
| Tunisia | 42 (32) | 2 seasons | 100 | 47 | |
| Iran | 466 (354) | 6 mo | 54∥ | 41 | |
| Brazil | 1,246 (1,267) | 1 y | 49 | 45 | |
| Approx 900 (600) | 1 y | 58 | c | ||
| 136 (97) | 5 mo | 50 | 46 | ||
| 22,000 (0) | 2 y | 8.6¶ | d |
Treatment applied once a month.
Treatment applied twice a month.
First sand fly season.
Second sand fly season.
A reduction in the incidence of zoonotic VL in humans was also observed (43%).
The prevalence of infection decreased from 12.5% in 2003 to 3.9% in 2005. There was a concomitant decrease in the incidence of leishmaniasis in humans from 34.1/100,000 to 5.4/100,000 over the same period.
c,dRefer to footnotes.
Spot-on formulations—Because of the time necessary for insecticide to spread over the whole body surface, full protective activity of spot-on formulations is achieved at approximately 24 to 48 hours after application. A combination of 10% imidacloprid (a nicotinoid insecticide) and 50% permethrin has been developed in a spot-on dermal topical formulation as a treatment for and prophylactic agent against ticks, fleas, mosquitoes, and phlebotomine sand flies. The no-feeding and insecticidal activity of this spot-on formulation against bites from P papatasi, P perniciosus, and Lutzomyia longipalpis has been determined experimentally, revealing 92.7% to 97.7% protection for 3 weeks (Table 1).36,37,b Therefore, it has been suggested that the combination could be effective in protecting dogs against leishmaniasis. The high effectiveness of this formulation when applied once or twice a month was confirmed in a field study48 conducted in an endemic area of southern Italy (Table 2). Other spot-on formulations, such as a solution containing 65% permethrin, are effective against P perniciosus and Lutzomyia migonei bites for 4 and 8 weeks, respectively.32,34 The effectiveness of this formulation was evaluated also in field trials.44,49 Other chemicals, such as the pyrazole insecticide pyriprole (125 mg/mL) and metaflumizone (an unclassified insecticide; 150 mg/mL) combined with the formamidine amitraz (150 mg/mL) in spot-on formulations, have no or limited efficacy in prevention of P perniciosus from feeding on dogs.50
Spray formulation—Insecticide activity in spray formulations is immediate after application. In the laboratory setting, spray application of permethrin combined with the insect growth regulator pyriproxyfen yields 87% to 94% protection of dogs from sand fly bites for a 3- to 4-week period (Table 1)30,33,35; however, field studies involving this product have not been reported.
Attempts to Produce Safe and Effective Leishmania Vaccines
Among parasitic diseases, leishmaniasis is theoretically considered the most likely to be controlled by vaccination because resolution of leishmaniasis in humans results in strong resistance to reinfection.7 However, development of vaccines has been difficult owing to the antigenic complexity and variability of the organisms, and past attempts to produce safe and effective Leishmania vaccines for dogs had limited success.
Over recent years, several new candidate vaccines against L infantum infection and disease in dogs have been developed.51 In general, it appears that antigen formulations consisting of defined recombinant proteins or polypeptides fail to induce effective immune protection, whereas those consisting of purified Leishmania fractions are most successful.52,53 Two canine vaccines have achieved successful results in phase III trials: the FML-saponin and the LiESAp-MDP vaccine. The glycoprotein-enriched preparation of L donovani promastigotes (FML), which is antigenic for humans and dogs, was formulated with Quillaja saponaria saponin and passed phase I through III trials to become a licensed vaccine in Brazil. The FML was immunogenic, immunoprophylactic, and immunotherapeutic in mice, hamsters, and dogs.54,55 In the first phase III trial,54 4 placebo-treated dogs (n = 30) died and 6 more developed clinical signs of leishmaniasis, as confirmed by parasite analysis and PCR assay. No deaths were detected among 36 vaccinated dogs, but infection was confirmed in 3 (8%) with mild signs of disease, indicating 92% of vaccinated dogs had been protected from infection, with an estimated vaccine efficacy equal to 76%. In the second trial,55 the opportunity for infection was higher. By 2 years after vaccination, 8 of 33 (24%) placebo-treated dogs had died, compared with 1 of 20 (5%) vaccinated dogs, corresponding to 95% protective effect and 80% vaccine efficacy. This protection lasted for at least 3.5 years and was concomitant with a decrease in the incidence of leishmaniasis in humans in the same region, which was a probable consequence of a transmission-blocking activity of the vaccine. It was concluded that the FML-saponin vaccine protected against severe disease and death caused by zoonotic VL. However, serologic discrimination of naturally infected from FML-vaccinated dogs is difficult, and this phenomenon has lead to reluctance to use this vaccine by veterinarians in Brazil, where screening and culling of dogs for leishmaniasis is performed by the Ministry of Health.
The other purified Leishmania vaccine, LiESAp-MDP, is composed of the 54-kDa excreted protein of L infantum and contains muramyl dipeptide as adjuvant. In a small study56 involving kenneled dogs, parasites were detected in the bone marrow of all 3 placebo-treated dogs, whereas they were not detected in all 3 vaccinated dogs. A double-blinded randomized clinical trial56 was performed with the LiESAp-MDP vaccine in naturally exposed dogs in southern France. Two years after vaccination, the incidence of infection in vaccinated dogs was 0.6% (1/165) versus 6.9% (12/175) in control dogs, corresponding to a vaccine efficacy of 92%. In any dog with clinical or serologic evidence of leishmaniasis, infection was confirmed by detection of parasites in bone marrow aspirates cultured in a blood-agar medium and also by use of PCR analysis. Additional field trials of this vaccine are underway in other L infantum endemic areas; a commercial formulation is not yet available.51
Conclusions and Recommendations
Among synthetic pyrethroids, permethrin and deltamethrin have received marketing approval with indications of efficacy with regard to no-feeding and toxic effects against Leishmania vectors (Table 3). Permethrin, alone or in combination with imidacloprid, as a topical (spot-on) treatment and deltamethrin (delta-methrin-triphenylphosphate complex) administered by slow-release collar are recommended for their high efficacy in preventing sand fly bites. The different starting periods of protection activity associated with various permethrin and deltamethrin formulations should be carefully considered when choosing a product. In particular, dog owners that plan to take their pets from nonendemic to endemic areas of leishmaniasis during the sand fly activity period should be advised to take into account that the interval until full protection may vary from immediate to 1 week, depending on the product. Because of a shorter duration of ectoparasiticidal activity, spot-on and spray formulations (3 to 4 weeks' duration) require owners to remember and comply with frequent applications, whereas slow-release collars containing ectoparasiticides do not need to be replaced more than twice a year in environments in which Leishmania vectors are active throughout the year or once a year in temperate areas in which no adult flies are present during cold months.
Commercial products currently labeled for dermal application in dogs for the prevention of Leishmania vector bites.
| Mode of application | Commercial product | Active ingredient | Interval to action after application | Estimated duration of protection |
|---|---|---|---|---|
| Spot-on | Advantixa | 50% permethrin and 10% imidacloprid | 24–48 h | 3 wk |
| Spot-on | Exspote | 65% permethrin | 24–48 h | 4 wk |
| Spray | Duowinf | 2% permethrin and 0.2% pyriproxyfen | Immediate | 3 wk |
| Collar | Scalibore | 4% deltamethrin and triphenyl phosphate | 1 wk | 5 mo |
We recommend that any healthy dogs living in or visiting areas in which leishmaniasis is endemic be protected from phlebotomine bites to prevent Leishmania infections (individual protection). Because dogs receiving treatment for leishmaniasis still can be infectious to sand flies despite clinical cure and reduction in parasite load having been achieved,57,58 we also recommend that any Leishmania-affected dogs living in leishmaniasisendemic areas be protected from phlebotomine bites as a measure to reduce infection risk in the human and canine community (mass protection).
Although preventive treatments ensure high efficacy against sand fly bites, they may not provide 100% protection. Therefore, we recommend examinations for leishmaniasis after potential exposure to Leishmania vectors.8 In leishmaniasis-endemic areas, when dermal application of synthetic pyrethroids is contraindicated (eg, in young puppies, when adverse effects are observed, or when owner compliance is low), alternative preventive measures may include housing pets at dusk in facilities with entrances protected by nets of small mesh (2 to 3 mm). However, it should be considered that no studies on the effectiveness of protective netting for preventing sand fly bites have been reported.
ABBREVIATIONS
| FML | Fucose-mannose ligand |
| IRS | Indoor residual spraying |
| VL | Visceral leishmaniasis |
Bayer AG, Leverkusen, Germany.
Mencke N, Volf P, Volfova V, et al. Comparing the repellent efficacy of a imidacloprid/permethrin spot-on solution against Lutzomyia longipalpis and Phlebotomus papatasi (abstr), in Proceedings. 3rd World Cong Leishmaniosis 2005;169.
Badarò R, Netto EM, Freire J, et al. Preliminary results of a field trial in Bahia State, Brazil, to reduce the risk of human visceral leishmaniasis by controlling leishmaniasis in dogs with delta-methrin-impregnated collars, in Proceedings. 2nd Int Canine Leishmaniasis Forum 2002;97.
Camargo-Neves VL, Rodas LAC, Calemes E, et al. Reduction of the incidence levels of American visceral leishmaniasis in humans and canines with the use of deltamethrin impregnated collars at 4%, in Proceedings. 4th World Cong Leishmaniasis 2009;318.
Intervet/Schering Plough Animal Health, Milan, Italy.
Virbac, Carros, France.
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