Fleas and ticks are common ectoparasites in dogs and cats and are present in many areas of the world, in differing intensity depending on the climatic conditions. Fleas are present in all areas of Europe, with Ctenocephalides felis being the most frequent flea species on our companion animals followed by Ctenocephalides canis. The main European tick species are Rhipicephalus sanguineus (dog); Ixodes ricinus (cat and dog), Dermacentor reticulatus (dog) and Rhipicephalus turanicus (cat). The latter species is not very well recognized but recently acknowledged to be the species present on cats instead of the nearly identical but very dog specific R. sanguineus . Fleas tend to occur from spring to winter and are capable of acting as vectors for several diseases, e.g. bartonellosis and tapeworms, and can cause flea allergic dermatitis (FAD). Ticks peak from early spring to late autumn and are important vectors for several diseases, e.g. borreliosis, anaplasmosis, ehrlichiosis and babesiosis. In humans they can transmit tick encephalitis, borreliosis and anaplasmosis. Both fleas and ticks play an important role as vectors . Therefore, effective measures against these parasites are important in preventing feline, canine and human disease .
While there are many authorized products containing different active ingredients for the prevention of fleas, there are only a few products available against ticks. Products containing fipronil are almost the only option for tick treatment of cats and dogs as the other common acaricides, permethrin and amitraz, are indicated for dogs only [4, 5] and are contraindicated for use in cats due to serious safety concerns. Flumethrin, the acaricidal active component in Kiltix® collars (propoxur 10%/flumethrin 2.25%), is a highly potent acaricide known to be safe in various animal species including cattle, sheep and dogs but also cats: the Kiltix® collar was, up to-date the only broadly marketed pyrethroid containing formulation suitable for cats.
Formulations of these active ingredients are generally designed for topical application with the most common versions being collars and low volume fluids (spot ons): Collars have been used frequently for the treatment and prevention of flea and tick infestations in dogs and cats in the past decades in Europe and abroad [6, 7]. However, with the launch of spot-on topical formulations and concerns about the perceived potential risk for free roaming cats to be trapped by any salient piece of wood or other rigid material, collars have been less involved in the growing market for flea and tick control.
Seresto® (Bayer Animal Health), a new collar for dogs and cats, provides long term broad spectrum parasiticidal activity by combining the insecticidal properties of imidacloprid with the acaricidal properties of flumethrin. The collar matrix system ensures that both active ingredients are slowly and continuously released from the collar towards the animal thereby avoiding peak concentrations and ensuring that acaricidal/insecticidal concentrations of both active ingredients are present in the cat's or dog's hair coat during the entire efficacy period. The active ingredients spread from the site of direct contact over the entire skin surface of the treated animal .
Following application of the collar, both active ingredients remain on the outer surface of the animal's skin and hair coat, enabling them to come into contact with the target parasites and display their efficacy. The neonicotinoid imidacloprid interacts with the nicotinic acetylcholine receptors (nAChRs) on the post-synaptic membrane , while flumethrin, as an α-cyano-(type II)-pyrethroid, exhibits excitatory efficacy by blocking the voltage gated axonic sodium channels . As recently described in laboratory studies , imidacloprid and flumethrin have synergistic efficacy on insects, in particular fleas. Both active ingredients are well known on the ectoparasiticide market: imidacloprid has been the insecticidal active ingredient in products such as Advantage®, Advantix® and Advocate® since 1996 while flumethrin has been registered since 1986 for animal use and has already been used extensively in livestock animals (esp. cattle). It has also been used for more than a decade in the EU as an active ingredient in companion animal products (dogs and in parts of the EU also cats): Kiltix® collar .
As usual for clinical field studies, a full set of laboratory efficacy and safety studies was a prerequisite for conducting the herein described studies. According to a set of preceding laboratory in-vivo studies the collar provides long term (8 month) prevention for cats and dogs against ticks (cats: I. ricinus, R. turanicus (= the Rhipicephalus species on cats, ) dogs: I. ricinus, I. scapularis, R. sanguineus, D. reticulatus) and fleas (C. felis,) [10, 11]. The collar proved also to be effective against the tick species Amblyomma americanum (USA) and Dermacentor variabilis (USA) [10, 11]. The collar's safety has been shown in longterm, overdosage studies following the guideline on target animal safety (VICH GL43) as well as US EPA requirements at up to 5 times the target dose in both cats and dogs, 10 week old kittens and 7 week old puppies . Additionally, to this standard study set, a specific product safety concern for cats was addressed before study start: their particular sensitivity towards pyrethroids . This sensitivity is generally explained by a reduced enzyme pattern for hydrolysis of pyrethroid-esters in cats, and by toxic metabolites developing during the pyrethroid degradation process combined with the reduced glucuronidation and therefore excretion capacity of the feline liver [14–16]. Opposite to e.g. permethrin and deltamethrin, the metabolism of flumethrin is simple without the need for glucuronidation. Flumethrin itself or its main metabolite flumethrin acid can be excreted without conjugation via feces . Moreover, flumethrin acid is pharmacologically inactive . The decreased feline glucuronidation rate is therefore toxicologically irrelevant . Accordingly the NOAEL (No Observed Adverse Effect Level) for flumethrin is identical for dogs and cats . The already rather low flumethrin toxicity in cats is complemented in this new product by two other aspects: only a very low hair coat concentration of this highly effective acaricide is necessary for high efficacy against ticks, and this low amount is released steadily from the collar without peak concentrations . These three aspects together form the basis for the collar to be a useful application form for an effective and safe cat acaricide.
This results in a special benefit of the imidacloprid 10%/flumethrin 4.5% collar when tick and flea treatment is necessary in mixed cat and dog households. As the cat and dog products are identical, dogs living closely together with cats can be protected against ectoparasites without safety concerns about cats potentially ingesting critical amounts of active ingredient through mutual grooming.
Besides the classical target animal safety evaluation, the particular pharmaceutical application via a collar bears another safety relevant aspect for cats which was taken into account and tested before the collar was used in the discussed field study: in contrast to dogs, which usually wear constantly leather or chain collars, cats are less often equipped with these accessories by their owners. The reason for this is the different behaviour of this species; free roaming cats displaying the full range of their hunting instinct are known to roam through wood, scrub or other wayless terrain and to pass through particularly narrow apertures when hunting their prey. Cat owners often fear that cats may be captured or strangulated by a collar, which may get caught on any salient piece of wood or other rigid material, and so cats are perceived to be more at risk wearing a collar. The new collar has an integral safety-closure ratchet mechanism that is constructed to yield at approximately 50 Newton (~5 kg) traction [Jiritschka W, Imidacloprid/Flumethrin - collar: Determination of force needed to re-open the collar using the integral closing system, unpublished], and allows the collar to be widened by the distance to the next rib. Widening by two or three rib spaces will usually easily allow a cat to escape from the collar in the unlikely case that it gets trapped. 50 Newton is the force a 2 kg cat needs to jump to a height of just 40 cm. This is easily brought to bear by even a small cat, which seriously wants to escape from somewhere but is strong enough to keep the collar on the cat's neck under normal circumstances and to prevent the cat from accidentally losing it. Additionally the collar design prevents the collar from widening to the extent that can occur in certain elastic collars, where cats may be endangered by getting the front leg stuck in the over-widened collar; in this case severe skin damage may occur as the leg becomes hooked at the elbow and cannot be retracted by the animal itself.
A second, backup security feature for cats is represented by the "pre-determined breaking point" of the cat collar. In contrast to the approximate 140 Newton (~14 kg) traction necessary to break the cat collar itself, this pre-determined area breaks at approximately 80 Newton (~8 kg) [Jiritschka W, Imidacloprid/Flumethrin - collar: Determination of force needed to disrupt the collar, unpublished]. So even in cases where the safety-closure mechanism is blocked by any unfortunate accident, the animal has an increased chance to escape by breaking the collar.
The extended safety profile described above and initial efficacy data of the new collar in both cats and dogs was a prerequisite to apply for permission to use it in pets naturally infested with fleas and ticks under field conditions. The objective of the present therapeutic confirmatory, controlled, randomised, blocked, multi-centre and multi-regional field study was accordingly to confirm the long-term efficacy and safety of the combination of "imidacloprid 10%/flumethrin 4.5%" administered by collar for the treatment of natural infestations of fleas and/or ticks in cats and dogs, presenting as patients in European veterinary practices and based on statistical non-inferiority as compared with a licensed collar product for cats and dogs. Statistical non-inferiority of the imidacloprid/flumethrin collar (IVP) compared to the control product (CP) was shown if the lower limit of the two-sided 97.5% confidence interval of the difference between IVP and CP was greater than -15%.