Parasiticides play a crucial role in animal health. The need for innovative ectoparasiticides for companion animals has been growing, driven by the risks posed by parasites to both animals and humans. We detail here the discovery pathway of tigolaner, an ectoparasiticide, offering up to 13 weeks protection against fleas and ticks to cats. Felpreva® employs this active ingredient for ectoparasite control together with the endoparasiticides emodepside and praziquantel. It was approved by the European Medicines Agency in November 2021. The discovery of tigolaner resulted from research at Bayer focused on finding novel molecules inhibiting GABA-gated chloride channels (GABA-Cls), with an improved toxicological profile and resistance-breaking potential when compared to dieldrin and fipronil. A high-throughput in vitro screening campaign on GABA-Cls, followed by a "mix-match" synthetic approach, led to the identification of several lead compounds acting as allosteric modulators. The GABA lead class compounds showed a different binding site when compared to fipronil. They have a unique chemotype based on a pyrazole moiety. Further variations of the central ring led to the discovery of tigolaner. Selected structure-activity relationships from the project are presented. Some synthetic pathways for tigolaner and its analogs are also described. This publication also outlines the efficacy of tigolaner against various parasites, making it a key compound of the Felpreva® product.

Tungiasis is a neglected tropical disease which is common in impoverished communities. In sub-Saharan Africa, it is caused by female sand fleas, Tunga penetrans, and pigs are amongst the major domestic animal reservoirs. Depending on the environment, tungiasis occurs throughout the year or preferentially in the dry seasons. This study investigated changes in sand flea abundance and associated morbidity in pigs during a dry season. Tunga penetrans lesions were counted and staged in 35 pigs amongst 22 households with at least one affected pig. Five weekly examinations were performed per animal during a dry season. Enrolment of pigs into the study lasted 17 days and examination was performed for 43 days. The severity score for acute pig tungiasis (SSAPT) was determined for each visit. Generalised linear mixed models (GLMM) were fitted on an absolute time scale to understand factors influencing the changes in abundance of sand flea lesions and SSAPT. The prevalence/abundance of tungiasis-associated lesions increased from 57.1

BACKGROUND:Zoonotic tungiasis caused by Tunga penetrans remains a serious public and animal health problem among endemic villages in Uganda and many sub Saharan African countries. Studies on human and animal tungiasis-related knowledge and treatment practices in endemic communities have never been undertaken, a limitation to development of sustainable control measures.METHODS:A cross sectional study using semi-structured questionnaires (Supplementary file S1) was conducted among 236 animal rearing households in 10 endemic villages in Bugiri District, South-Eastern Uganda. Focus group discussions and observation checklists were used to validate and clarify the findings.RESULTS:Most respondents knew the aetiology (89.4%), clinical signs (98%) and the ecology of T. penetrans as well as the major risk factors of human tungiasis (65.2%). In contrast, very few respondents were aware of animal tungiasis. Only 4.8% of those with infected animals on the compound knew that some of their animals were infected and 13.6% of the respondents had ever seen tungiasis-affected animals. Pigs (13.1%, n=31) and dogs (0.85%, n=2) were the only T. penetrans animal hosts known to animal owners. Affected humans were treated by extraction of embedded sand fleas using non-sterile sharp instruments in all households that reported occurrence of human tungiasis at least once (n=227). Also, affected animals were mainly treated by mechanical removal of embedded sand fleas in households that have ever experienced animal tungiasis (four out of 12; 33.3%). In a few instances, plant and animal pesticides (n=3) and other chemicals such as grease, paraffin and wood preservative (n=3) were also used to treat animal tungiasis.CONCLUSION:The study revealed a high level of knowledge on human tungiasis but inadequate knowledge on the zoonotic nature of tungiasis. Commonly applied methods for treatment of human and animal tungiasis are a health hazard by themselves. Concerted i.e. One Health-based efforts aiming at promoting appropriate treatment of tungiasis, adequate living conditions and increased awareness on tungiasis in the communities are indicated in order to eliminate tungiasis-associated disease.

Towards the improvement of stakeholders’ awareness of animal tungiasis, we report 10 unusual severe clinical cases of pig tungiasis which were associated with very high infection intensities of T. penetrans in an endemic area.

Tungiasis ensues from the penetration and burrowing of female sand fleas (Tunga spp.; Siphonaptera: Tungidae) in the skin of mammals. There are few case reports of severe tungiasis in goats and in these cases the Tunga species were not in most cases clearly identified. Two cases of severe tungiasis caused by Tunga penetrans in goat kids from tungiasis-endemic rural Uganda are reported. These are the first severe cases of tungiasis in goats reported from outside South America.

Background: Tunga penetrans (Insecta, Siphonaptera, Tungidae) causes severe morbidity among heavily infected humans and animals in Latin America and sub-Saharan Africa. The clinical pathology of tungiasis in animals has never been studied systematically.Methods: This was a cross-sectional study conducted between January to March 2015, aimed at describing tungiasis-associated clinical pathology in 121 and 20 T. penetrans-infected pigs and dogs, living in nine and five endemic rural villages respectively located in Bugiri District, Busoga, Uganda.Results: The parasite load of infected animals ranged from one to 246 (median 8) and one to eight (median 2) in pigs and dogs, respectively. In pigs 99.3 % and in dogs 100 % of the lesions were located on feet. In pigs, hind legs were significantly more affected than front legs (90.9 % vs. 57.9 %; p = 0.002) and also had more lesions than the front legs (median 5 vs. 1; p = 0.0001). However, in dogs localization of lesions between front and hind legs never differed significantly (front, 50 % vs. hind, 65 %; p = 0.51) and so were the number of lesions (median front = 0.5 vs. median hind = 2; p = 0.7). Acute and chronic clinical pathology coexisted. The most common disease manifestations in pigs were hoof wall erosions (68.6 %), tissue necrosis of hoof wall and skin (66.1), pain at infection sites (47.9 %), hoof deformity (45.5 %), fissures (44.6 %) and edema (44.6 %). In dogs, tungiasis mainly presented with pain at attachment site (80 %), ulcers (55 %), necrosis (30 %) as well as hyperemia and edema (both 15 %). One pig had lost dew claws while two had loose detaching claws. Despite a lower number of sand fleas, a higher proportion of infected dogs (20 %) than pigs (5.8 %) exhibited functional limb use difficulties (p = 0.05).Conclusions: The pattern of clinical manifestations in pigs and dogs were very similar to those reported from affected humans and rats. The important morbidity associated with animal tungiasis makes the disease a serious veterinary health problem in sub-Saharan Africa warranting treatment and control for optimal animal production.

This letter advises the imminent formation of the Companion Animal Parasites Council for the Tropics (CAPCT). The CAPCT consists of region-specific (e.g., Asia-Pacific, Latin America and Caribbean, Africa) experts comprising academics, veterinarians, parasitologists, physicians and allied industry partners that will work together to inform, guide and develop best-practice recommendations for the optimal diagnosis, treatment and control of companion animal parasites in the tropics, with the aim of protecting the health of pets and that of the public.

The susceptibility of 12 field-collected isolates and 4 laboratory strains of cat fleas, Ctenocephalides felis was determined by topical application of some of the insecticides used as on-animal therapies to control them. In the tested field-collected flea isolates the LD50 values for fipronil and imidacloprid ranged from 0.09 to 0.35 ng/flea and 0.02 to 0.19 ng/flea, respectively, and were consistent with baseline figures published previously. The extent of variation in response to four pyrethroid insecticides differed between compounds with the LD50 values for deltamethrin ranging from 2.3 to 28.2 ng/flea, etofenprox ranging from 26.7 to 86.7 ng/flea, permethrin ranging from 17.5 to 85.6 ng/flea, and d-phenothrin ranging from 14.5 to 130 ng/flea. A comparison with earlier data for permethrin and deltamethrin implied a level of pyrethroid resistance in all isolates and strains. LD50 values for tetrachlorvinphos ranged from 20.0 to 420.0 ng/flea. The rdl mutation (conferring target-site resistance to cyclodiene insecticides) was present in most field-collected and laboratory strains, but had no discernible effect on responses to fipronil, which acts on the same receptor protein as cyclodienes. The kdr and skdr mutations conferring target-site resistance to pyrethroids but segregated in opposition to one another, precluding the formation of genotypes homozygous for both mutations.

BACKGROUND:Animal tungiasis is believed to increase the prevalence and parasite burden in humans. Animal reservoirs of Tunga penetrans differ among endemic areas and their role in the epidemiology of tungiasis had never been investigated in Uganda. METHODS AND FINDINGS:To identify the major animal reservoirs of Tunga penetrans and their relative importance in the transmission of tungiasis in Uganda, a cross sectional study was conducted in animal rearing households in 10 endemic villages in Bugiri District. T. penetrans infections were detected in pigs, dogs, goats and a cat. The prevalences of households with tungiasis ranged from 0% to 71.4% (median 22.2) for animals and from 5 to 71.4% (median 27.8%) for humans. The prevalence of human tungiasis also varied among the population of the villages (median 7%, range 1.3-37.3%). Pig infections had the widest distribution (nine out of 10 villages) and highest prevalence (median 16.2%, range 0-64.1%). Pigs also had a higher number of embedded sand fleas than all other species combined (p < 0.0001). Dog tungiasis occurred in five out of 10 villages with low prevalences (median of 2%, range 0-26.9%). Only two goats and a single cat had tungiasis. Prevalences of animal and human tungiasis correlated at both village (rho = 0.89, p = 0.0005) and household (rho = 0.4, p < 0.0001) levels. The median number of lesions in household animals correlated with the median intensity of infection in children three to eight years of age (rho = 0.47, p < 0.0001). Animal tungiasis increased the odds of occurrence of human cases in households six fold (OR = 6.1, 95% CI 3.3-11.4, p < 0.0001). CONCLUSION:Animal and human tungiasis were closely associated and pigs were identified as the most important animal hosts of T. penetrans. Effective tungiasis control should follow One Health principles and integrate ectoparasites control in animals.

Hepatozoon canis is an apicomplexan parasite of dogs, which is known to become infected by ingesting Rhipicephalus sanguineus adult ticks. To investigate the possibility of H. canis transovarial and transstadial transmission from larvae to nymphs, engorged adult female ticks were collected from a private animal shelter in southern Italy, where H. canis infection is highly prevalent. Female ticks (n = 35) and egg batches were tested by PCR for H. canis. All eggs examined were PCR-negative whereas 88.6% of females from the environment tested positive. Additionally, fed larvae (n = 120) from a dog naturally infected by H. canis were dissected at different time points post collection (i.e. 0, 10, 20 and 30 days). Molted nymphs dissected at 20 days post collection revealed immature oocysts displaying an amorphous central structure in 50% of the specimens, and oocysts containing sporocysts with sporozoites were found in 53.3% of the nymphs dissected at 30 days post collection. This study demonstrates that H. canis is not transmitted transovarially, but it is transmitted transstadially from larvae to nymphs of R. sanguineus and develops sporozoites in oocysts that may infect dogs.

In 2001, an international surveillance initiative was established, utilising a validated larval development inhibition assay to track the susceptibility of cat flea isolates to imidacloprid. In 2009, an Australian node was incorporated into the programme, joining laboratories in the United States and Europe. Field isolates of Ctenocephalides felis eggs were submitted to participating laboratories and, where egg quantity and quality was sufficient, were placed in the imidacloprid discriminating dose bioassay for evaluation. Between 2002 and 2012, a total of 2,307 cat flea isolates were received across all sites; 1,685 submissions (73 %) were suitable for placement into the bioassay. In the Northern Hemisphere, isolate submission rate was influenced by season, with highest numbers submitted between June and October. In Australia, pets with flea infestations could be sourced year-round, and submission rate was largely influenced by programme factors and not climate. A total of 1,367 valid assays were performed between 2002 and 2012 (assay validity data was not recorded in 2001); adult flea emergence 5 % or greater at 3 ppm imidacloprid was observed in 38 of these assays (2.8 %). For these isolates that reached the threshold for further investigation, re-conduct of the assay using either a repeat challenge dose of 3 ppm of imidacloprid or a dose response probit analysis confirmed their susceptibility to imidacloprid. From 2009 to 2012, the Australian node performed valid assays on 97 field isolates from a total of 136 submissions, with no adult emergence observed at the 3-ppm imidacloprid discriminating dose. In addition to reviewing the data generated by this twelve-year initiative, this paper discusses lessons learned from the coordination and evolution of a complex project across geographically dispersed laboratories on three continents.

The medical as well as the veterinary importance of parasitic arthropods or ectoparasites in general terms, is characterized by the primary or secondary impact on the health of humans and companion animals alike. The parasitic arthropods addressed here are those ectoparasites belong to the class of insects, such as fleas and sand flies, or the subclass of acarids, such as ticks. These parasitic arthropods interact intensively with their hosts by blood feeding. Fleas, sand flies and ticks hold the vector capacity to transmit pathogens such as virus, bacteria or protozoa to cats, dogs and humans. The diseases caused by these pathogens are summarized under the terms canine vector-borne diseases (CVBD), feline vector-borne diseases (FVBD) or metazoonoses. In small animal practice, it is important to understand that the transmitted pathogen may either lead to a disease with clinical signs, or more often to asymptomatic, clinically healthy, or silent infections. Blocking of the vector–host interactions, the blood feeding and subsequently the transmission of pathogens during blood feeding is a key element of CVBD control. The focus of this review is on the current knowledge of the epidemiology of parasitic vectors and three important CVBDs they transmit; rickettsiosis, tick borreliosis and canine leishmaniosis from a European perspective, and how veterinary medicine may contribute to the challenges of CVBDs and their control. Prevention of CVBDs is fundamentally based on ectoparasite control. Ectoparasite management in cats and dogs is important not only for the health and well-being of the individual companion animal but for public health in general and is therefore a perfect example of the ‘One health’ approach.

Hepatozoon canis is among the most widespread tick-borne protozoa infecting domestic and wild carnivores. Its distribution is related to the occurrence of its major vector, the brown dog tick Rhipicephalus sanguineus. However, the role of Ixodes ricinus as a vector of H. canis has been hypothesized. In the present study, the development of H. canis was investigated in I. ricinus and R. sanguineus nymphs collected from a naturally infested dog. All I. ricinus ticks examined (n = 133) were negative by cytological examination at days 20, 30, and 90 post collection, although H. canis DNA was detected in one nymph at day 20 and in 2 nymphs at day 30 post collection. On the other hand, H. canis sporogony was documented by cytology, and H. canis DNA was detected by PCR in R. sanguineus at day 30 post collection. These results indicate that H. canis sporogony does not occur in I. ricinus, but in R. sanguineus, suggesting that I. ricinus does not act as a vector of H. canis.

The human-animal bond has been a fundamental feature of mankind's history for millennia. The first, and strongest of these, man's relationship with the dog, is believed to pre-date even agriculture, going back as far as 30,000 years. It remains at least as powerful today. Fed by the changing nature of the interactions between people and their dogs worldwide and the increasing tendency towards close domesticity, the health of dogs has never played a more important role in family life. Thanks to developments in scientific understanding and diagnostic techniques, as well as changing priorities of pet owners, veterinarians are now able, and indeed expected, to play a fundamental role in the prevention and treatment of canine disease, including canine vector-borne diseases (CVBDs).The CVBDs represent a varied and complex group of diseases, including anaplasmosis, babesiosis, bartonellosis, borreliosis, dirofilariosis, ehrlichiosis, leishmaniosis, rickettsiosis and thelaziosis, with new syndromes being uncovered every year. Many of these diseases can cause serious, even life-threatening clinical conditions in dogs, with a number having zoonotic potential, affecting the human population.Today, CVBDs pose a growing global threat as they continue their spread far from their traditional geographical and temporal restraints as a result of changes in both climatic conditions and pet dog travel patterns, exposing new populations to previously unknown infectious agents and posing unprecedented challenges to veterinarians.In response to this growing threat, the CVBD World Forum, a multidisciplinary group of experts in CVBDs from around the world which meets on an annual basis, gathered in Nice (France) in 2011 to share the latest research on CVBDs and discuss the best approaches to managing these diseases around the world.As a result of these discussions, we, the members of the CVBD Forum have developed the following recommendations to veterinarians for the management of CVBDs.

Ectoparasites in the dog and cat: parasitology and aetiopathogenesis of the most important vector-borne diseases having a zoonotic aspect Ectoparasites are those parasites belonging to the class of insects (such as fleas, lice, sandflies and mosquitoes) or the subclass of acarids (e.g. ticks or mites) that live on or in the skin of dogs or cats. The medical importance of ectoparasites is characterized by the primary or secondary impact on the pets' health. Furthermore, the capability of ectoparasites to function as a vector for pathogens transmittable to pets or humans are summarized under the terms canine vector-borne diseases (CVBD) and feline vector-borne diseases (FVBD) or metazoonoses. Parasitic arthropods are effective vectors and in the present article selected vector-borne pathogens are reviewed with a special emphasis on the vector host interactions, the epidemiology of the vector, the pathophysiology of the disease, diagnosis, and vector prophylaxis. Ectoparasite control is discussed with respect to not only the health and well-being of the individual pet but public health, too. Thus, ectoparasite control is a perfect example of the 'One health' initiative.

Background: Phlebotomine sand flies are blood-sucking insects that can transmit Leishmania parasites. Hosts bitten by sand flies develop an immune response against sand fly salivary antigens. Specific anti-saliva IgG indicate the exposure to the vector and may also help to estimate the risk of Leishmania spp. transmission. In this study, we examined the canine antibody response against the saliva of Phlebotomus perniciosus, the main vector of Leishmania infantum in the Mediterranean Basin, and characterized salivary antigens of this sand fly species.Methodology/Principal Findings: Sera of dogs bitten by P. perniciosus under experimental conditions and dogs naturally exposed to sand flies in a L. infantum focus were tested by ELISA for the presence of anti-P. perniciosus antibodies. Antibody levels positively correlated with the number of blood-fed P. perniciosus females. In naturally exposed dogs the increase of specific IgG, IgG1 and IgG2 was observed during sand fly season. Importantly, Leishmania-positive dogs revealed significantly lower anti-P. perniciosus IgG2 compared to Leishmania-negative ones. Major P. perniciosus antigens were identified by western blot and mass spectrometry as yellow proteins, apyrases and antigen 5-related proteins.Conclusions: Results suggest that monitoring canine antibody response to sand fly saliva in endemic foci could estimate the risk of L. infantum transmission. It may also help to control canine leishmaniasis by evaluating the effectiveness of anti-vector campaigns. Data from the field study where dogs from the Italian focus of L. infantum were naturally exposed to P. perniciosus bites indicates that the levels of anti-P. perniciosus saliva IgG2 negatively correlate with the risk of Leishmania transmission. Thus, specific IgG2 response is suggested as a risk marker of L. infantum transmission for dogs.

With rising numbers of dogs taken abroad or being imported, arthropod-borne diseases in dogs (canine vector-borne diseases - CVBD) have increased in frequency in German veterinary practices. First autochthonous cases point to the growing probability that some CVBD, formerly reckoned as exotic, are on their way to become endemic in Germany. Knowledge of the prevalence of the pathogens in the countries of origin and of possible means of prophylaxis is necessary to prevent further spread, especially concerning zoonotic CVBD. In this study, 4,681 dogs without clinical symptoms that had either been travelled to or imported from endemic areas were examined. The samples were sent in within 2004-2009 from animal welfare organisations or private persons via veterinary offices. Most of the dogs were imported from Spain, Portugal, Hungary, Romania and Italy. Overall, Babesia cards (24 %) was detected as the most prevalent pathogen, followed by Anaplasma spp. (18 %), Leishmania infantum (12 %) and Ehrlichia canis (10 %). In 56 % of these dogs no antibodies or pathogens were found. In 29 %, one pathogen could be detected, and 15 % of the dogs had infections with 2-5 pathogens. Additionally, 331 dogs designed for relocation to Germany were tested in endemic areas in Portugal. Only 13 % of these were negative for all pathogens tested. 24 % were positive for one of the pathogens, and 63 % showed multiple infections with 2-6 pathogens. In the Portuguese dogs, only L. infantum and microfilariae had a comparatively lower prevalence. The other pathogens were detected even more frequently (B. coins: 58 %, E. canis: 25 %, Anaplasma spp.: 30 %, Rickettsia spp.: 63 %). In addition to the study on prevalences of CVBDs results of an examination of the preventive effect of Imidacloprid 10 %/Permethrin 50 % (dermal spot-on) are presented.