With impressive reproductive capabilities, ability to persist in the environment and as pathogenic vectors, fleas are considered to be the most important ectoparasite of dogs and cats (Abdullah et al, 2019). Of the 2500 species worldwide, Ctenocephalides felis (cat flea), Ctenocephalides canis, Pulex simulans and Echidnophaga gallinacea are seen as significant, because of their ability to infest companion animals in large numbers (Blagburn and Dryden, 2009). Among the species mentioned above, the cat flea is the most dominant species affecting cats and dogs. Most investigations that have been carried out focus on this species, therefore the following discussion will be largely limited to the cat flea.
Morphology and lifecycle
Fleas are laterally flattened, dark brown insects around 2–5 mm in size. Although fleas are wingless (Figure 1), they are highly mobile because of their strong hind legs adapted for jumping (Wright and Elsheikha, 2014). Adult fleas are obligate blood-feeders. Once a host is found, feeding can occur within minutes, subsequently followed by mating. Egg production then begins within 24 to 36 hours of the first blood meal, with up to 50 eggs being laid per egg laying adult female per day. As the eggs are non-adhesive, host movement causes eggs to fall into the environment. Eggs hatch into larvae within 1 to 10 days (Blagburn and Dryden, 2009). Larvae must feed on the blood-rich faeces of adult fleas, known as ‘flea dirt’, in order to successfully undergo two moults and enter the pupal stage (Figure 2). The third stage larvae spin a sticky cocoon covered in environmental debris, in which they moult into flea pupae and mature into adult fleas (Dobler and Pfeffer, 2011). The pre-emerged adults can remain dormant for several months until stimulated by vibrations, carbon dioxide and/or heat. Under most household conditions, the lifecycle is completed within 3 to 8 weeks, but can extend up to 174 days depending on environmental conditions (Blagburn and Dryden, 2009). Colder temperatures in winter can kill off fleas and immature stages residing outdoors. However, fleas inside the home will survive (Beugnet et al, 2004). Fleas are ubiquitous and exposure to flea infestation is hard to avoid. Companion animals that are kept indoors still require treatment as fleas can be brought into the home by other animals or on the owner's clothing. As a result, both the European Scientific Counsel of Companion Animal Parasites (ESCCAP) and the Companion Animal Parasite Council (CAPC, 2020) recommend all year round protection against fleas.
Impact on the hosts
The blood-feeding behaviour of fleas causes direct irritation, resulting in intense pruritus and anaemia in cases of severe infestation (Taenzler et al, 2014). Repeated exposure can lead to the development of flea allergic dermatitis (FAD) in dogs and cats (Dryden et al, 2013a) and it is estimated that 50% of dermatological cases are associated with fleas (Beugnet et al, 2012). FAD is caused by an exaggerated immune response to flea salivary antigens injected during the flea's feeding, which leads to hypersensitivity. If left untreated, skin changes attributed to self-trauma, such as alopecia and crusts, may develop (Stanneck et al, 2012a). The patient may then also develop a secondary infection.
Apart from these direct effects on the animal itself, fleas can act as vectors for a range of zoonotic pathogens. Cat scratch disease is caused by the bacteria Bartonella henselae, which is spread among cats by C. felis. Transmission to humans occurs when flea faeces containing the bacteria are introduced via bites and scratches or rubbed into skin abrasions (Rust, 2017). C. felis has also been responsible for the transmission of the bacteria Rickettsia typhi and Rickettsia felis via flea bites, causing acute febrile illness in humans (Nelson et al, 2018). In addition, fleas are the intermediate host in the lifecycle of the double-pored dog tapeworm Dipylidium caninum. Dogs and cats, become infected when they ingest fleas containing the infective stage cysticercoid during their grooming activities (Abdullah et al, 2019). Humans, particularly children, can be also infected when they accidentally ingest infected fleas during contact with dogs or cats.
Anti-flea products
Numerous antiparasitic drugs targeting fleas known as adulticides, pulicides or insecticides are available on the market for use in companion animals (Table 1). Insecticides can be administered orally, topically or subcutaneously. Some topical preparations work on the skin surface, while others are absorbed transdermally into the circulation to work systemically. Molecules that act on nerve axons of adult fleas are known as adulticides, whereas molecules that interfere with egg development or other off-host lifecycle stages are termed insect growth regulators (IGRs) or insect development inhibitors (IDIs) (Marchiondo et al, 2013).
Table 1. Selected examples of anti-flea insecticides.
| Example of product | Active Ingredient | Formulation |
|---|---|---|
| Advantage® | Imidacloprid | Spot-on (dogs and cats) |
| Seresto® | Imidacloprid + flumethrin | Collar (dogs and cats) |
| Frontline Combo® | Fipronil + S-methoprene | Spot-on (dogs and cats) |
| Stronghold® | Selamectin | Spot-on (dogs and cats) |
| Activyl® | Indoxacarb | Spot-on (dogs and cats) |
| Bravecto® | Fluralaner | Tablet (dogs), spot-on (dogs and cats) |
| Credelio® | Lotilaner | Tablets (dogs and cats) |
| Simparica® | Sarolaner | Tablets (dogs) |
| NexGard® | Afoxolaner | Tablets (dogs) |
| Program® | Lufenuron | Tablets (dogs and cats); injection and oral suspension (cats) |
Over the past decades the discovery of new molecules, combination of different insecticides in a product and availability of different formulations have expanded the anti-flea product market significantly (Taenzler et al, 2016). For this reason, it would not be feasible to have a complete list of flea products that are currently on the market. The following compounds and example products containing them are frequently used for flea control in the UK.
Imidacloprid (e.g. Advantage®, Elanco UK AH Ltd)
Imidacloprid, a neo-nicotinoid insecticide, has been available as a spot-on treatment since 1996 (Stanneck et al, 2012a). The compound is absorbed by fleas and binds to postsynaptic nicotinic acetylcholine (nACh) receptors inducing nerve membrane depolarisation resulting in spastic paralysis. Residual activity lasts for approximately 1 month, with fleas dying within 24 hours after contact. It also indirectly affects larvae through skin debris falling into the environment from imidacloprid-treated animals (Mehlhorn et al, 1999; Beugnet and Franc, 2012).
Imidacloprid + flumethrin (Seresto®, Elanco UK AH Ltd)
Flumethrin is the only pyrethroid that is not toxic to cats (Linnett, 2008). It acts by inducing nerve cell depolarisation via sodium channels causing death of the insect (Blagburn and Dryden, 2009). Although it is mainly used as an acaricide, it has synergistic effects against insects when combined with imidacloprid (Stanneck et al, 2012a, 2012b). The preparation is available in a collar that slowly releases the active ingredients onto the animal's coat, providing protection for up to 8 months (Stanneck et al, 2012c).
Fipronil + S-methoprene (Frontline Combo®, Boehringer Ingelheim Animal Health UK Ltd)
Fipronil is a topical adulticide that blocks gamma-aminobutyric acid (GABA) receptors (Wismer and Means, 2018). After application to the skin, fipronil accumulates in sebaceous glands and epithelial layers, where it is gradually distributed over the skin surface (Cochet et al, 1997). It is also available as a combination with the IGR S-methoprene, which provides benefits from the additional control of immature stages (Beugnet and Franc, 2012; Dryden et al, 2013b). The activity of this IGR is stimulated when fipronil concentrations fall and when a few adult fleas survive to lay eggs (Beugnet and Franc, 2010).
Selamectin (e.g. Stronghold®, Zoetis)
Selamectin, a broad-spectrum macrocyclic lactone, is a topical formulation effective against both internal and external parasites (Blagburn and Dryden, 2009). It is absorbed through the skin into the blood plasma, where maximum post-administration concentrations are reached at 15 hours in cats and 72 hours in dogs (Sarasola et al, 2002). Skin debris from treated animals and selamectin passed in flea faeces are effective in disrupting the development of immature stages, either through contact or feeding on contaminated matter (McTier et al, 2000).
Indoxacarb (Activyl®, Virbac)
Indoxacarb is a topically applied product and following ingestion or contact by fleas it undergoes bioactivation within the insect (Fisara et al, 2014). Esterase and amidase enzymes metabolise indoxacarb into a more potent form that blocks sodium channels resulting in lethal paralysis (Beugnet and Franc, 2012). Indoxacarb has also been shown to have larvicidal activity and reduce the viability of flea eggs (Dryden et al, 2013a).
Isoxazoline-class ectoparasiticides
Isoxazolines are the latest class of insecticidal drugs, which are licensed for ectoparasite (fleas and ticks) control in dogs and cats. The oral route of administration of isoxazolines offers not only stable performance but also decreases drug exposure for other animals and the pet owners. Isoxazolines inhibit ligand-gated chloride channels, such as those gated by the neurotransmitter GABA, resulting in uncontrolled nervous activity and death of the insects (Wismer and Means, 2018). A number of isoxazoline products have been developed in recent years. For example, fluralaner (Bravecto®, MSD Animal Health) is distributed systemically, irrespective of oral or topical administration, targeting fleas during feeding (Taenzler et al, 2016). Fluralaner provides immediate and persistent flea killing activity for 12 weeks (Ranjan et al. 2018). Also, it kills fleas within 8 hours of attachment before egg production, thus preventing re-infestation (Williams et al, 2014). Lotilaner (Credelio®, Elanco UK AH Ltd) is approved for the prevention and treatment of fleas, and treatment and control of tick infestations in dogs. It starts killing adult fleas and ticks within 4 hours of administration. Sarolaner (Simparica®, Zoetis) is effective against fleas and ticks on dogs when dosed monthly. It kills adult fleas on dogs within 4 hours after treatment and can achieve 100% kill rate against pre-existing experimental flea infestations within 12 hours (Six et al, 2016). Afoxolaner (NexGard®, Boehringer Ingelheim Animal Health UK Ltd) is indicated for treatment of infestations by C. felis and C. canis in dogs for 5 weeks. NexGard kills fleas within 8 hours, and thus prevents egg production and household contamination. Like other isoxazolines, fleas must attach to the host and begin feeding in order to be exposed to afoxolaner.
Insect growth regulators: lufenuron and S-methoprene
IGRs can be further categorised into juvenile hormone analogues and chitin synthesis inhibitors. Juvenile hormone analogues such as S-methoprene, inhibit egg hatching and larvae moulting into pupae (Beugnet and Franc, 2010). By impairing cuticle formation, polymerisation, and deposition, the chitin synthesis inhibitor lufenuron inhibits egg hatching and larval development for up to 6 months following subcutaneous administration (Jacobs et al, 2001; Wismer and Means, 2018).
Current approaches for flea control
Recent advancements in flea control combine adulticides, and the ovicidal and larvicidal effects of IGRs for use on both animals and environment (Ritzhaupt et al, 2002). Interruption of the flea lifecycle at multiple stages inhibits flea reproduction and prevents the flea population from being maintained (Rust, 2017). Non-chemical measures such as vacuuming and washing infested bedding at 60°C, mechanically removes eggs, larvae and pupae. Although adult fleas pose a direct problem to the host, most of the flea population is composed of the immature stages found in the home. If this population is not eradicated, any adult fleas killed on the animal will be replaced from this reservoir of juvenile stages (Perrins and Hendricks, 2007; Wright and Elsheikha, 2014).
Reasons for treatment failure
The reasons why flea infestations remain frequent in companion animals despite the considerable number of anti-flea products is of interest. When treatment fails this is most likely caused by product performance or pet owner-related behaviour (Halos et al, 2014). Poor performance could be caused by drug inefficacy, for instance flea perceived resistance, innate reduced susceptibility or residual speed of kill. If residual activity of a product is not sufficient to last until the next application, fleas will continue to reproduce and control will breakdown (Wright, 2016). The time after application of the adulticide at which fleas survive long enough in the presence of the product to lay eggs is known as the ‘reproductive break point’. If the reproductive break point is reached then flea control will fail.
Previous studies on treatment failure have mainly focused on resistance or reduced susceptibility in older insecticides. Resistance of C. felis to organophosphates, carbamates and pyrethroids has been reported (Bossard et al, 2002; Coles and Dryden, 2014). Although reduced susceptibilities of certain C. felis strains to imidacloprid and fipronil have been documented, there is little evidence to suggest that resistance is widespread in the field. Resistance has not yet been demonstrated in newer formulations (Rust et al, 2018).
There is an assumption on the part of owners to attribute treatment failure to poor drug efficacy (Beck et al, 2014). A successful flea control programme involves the removal of fleas from the infected host and environment (Perrins and Hendricks, 2007). Owner adherence to drug administration at regular intervals is essential to prevent reinfestation (Halos et al, 2014; Fink et al, 2016). Therefore, non-adherence can result in suboptimal pharmacotherapy and potentially treatment failure (Lavan et al, 2017). Common reasons for treatment failure include:
- Insufficient frequency of application — many pet owners have a busy lifestyle and it can be easy for flea treatment doses to be missed or not applied on time. The use of sebum stripping shampoos is likely to increase the required frequency of application of spot-on products containing fipronil and imidacloprid
- Poor compliance — if pet owners are having difficulty administering a product or are not shown how to administer a new product effectively, then correct dosage and frequency of drug treatment may not occur. If finances are an issue, then pet owners may compromise on dosing frequency recommendations beyond license claim statements and/or veterinary advice. Discussing pet owner treatment preferences and demonstrating to clients how to administer products will help to improve compliance. Practice healthcare plans, where cost of flea treatments are spread over time, can also be beneficial
- Not all pets in the house being treated — cat fleas are highly adaptable and capable of infesting and reproducing on a variety of mammals as well as cats, including dogs, rabbits and ferrets. Clients may not realise that rabbits and ferrets may be infested with cat fleas and it is important therefore to ensure all pets in the house have been treated with an appropriate product. Clients may also not mention stray or owned cats that visit the house from elsewhere. Unless they are all treated, or access to the house prevented, then flea control will fail
- Wildlife — wildlife harbouring cat fleas may be brought into homes as casualties for rehabilitation or inhabit outbuildings
- Other varieties of fleas being present — bird and rodent fleas may invade homes from abandoned nests and outbuildings, leading to infestations that are not directly linked to flea infestations on pets. In these cases, elimination of environmental sources of flea infestation are the key to control
- Outdoor re-exposure — fleas may be seen on pets because they are visiting animal burrows or other people's homes with infestations leading to acquisition of adult fleas. Flea products can take up to 24 hours to kill fleas and still provide effective control in a household but as a result, live fleas from other sources may still be seen. This gives the impression that flea control is failing. It takes at least 3 to 4 months to get rid of an existing flea infestation.
Conclusion
Flea control challenges continue to occur. Fleas are not only serious pests to companion pets, but are also associated with public health concerns. Many treatment and preventative products have been developed and proven to be safe and effective in the management of flea infestation. However, the success of flea control programmes varies widely for different reasons and treatment failure is not uncommon in clinical practice. Failure to untangle the reasons for poor flea treatment outcomes will have possible implications with respect of the pet owner's experience and satisfaction. Chemotherapeutic products are and will remain the mainstay of any flea treatment protocol. Therefore, we should be more proactive and mitigate the factors that can prevent anti-flea products from achieving their maximum therapeutic potential.
KEY POINTS
- Fleas are serious pests and flea control challenges continue to occur.
- Successful flea control relies mainly on the use of effective anti-flea products and pet owners adhering to treatment recommendations.
- The failure to reach adequate flea control is more likely due to poor owner compliance rather than lack of drug efficacy.
- Veterinary staff should be proactive in providing rationale for the use of anti-flea products and reassure owners of their effectiveness with the aim of maximising compliance.
- There is a need to gain a better understanding of how owner compliance might be optimised as part of a strategy to improve flea control success in dogs and cats.