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Veterinary products with macrocyclic lactones, registered in the USA or Europe for heartworm prevention in dogs and cats *.
Source publication
Dirofilaria immitis infection is one of the most severe parasitic diseases in dogs. Prevention is achieved by the administration of drugs containing macrocyclic lactones (MLs). These products are very safe and highly effective, targeting the third and fourth larval stages (L3, L4) of the parasite. Until 2011, claims of the ineffectiveness of MLs, r...
Contexts in source publication
Context 1
... to the impact of heartworms on the health of pets, the complexity, risk, and cost of the treatment, and the zoonotic implications, heartworm prevention in dogs is imperative. Currently, there are many veterinary products in the market approved for this purpose and all of them contain a single drug class, i.e., the macrocyclic lactones (MLs) ( Table 1). These drugs, when administered according to label instructions, are very safe and effective at preventing heartworm disease. ...Context 2
... are many forms available on the market, i.e., spot-ons, chewables, tablets, and injectables, some of them as single active ingredient products but most of them as combinations of antiparasitics, often in the form of endo-ectoparasiticides. The majority of these formulations are licensed for heartworm prevention by monthly administration but there are also injectable forms of MOX for administration every 6 or every 12 months (extended-release injectable forms) (Table 1). ...Citations
... During a blood meal from a heartworm-infected host, the mosquito ingests microfilariae, i.e., the stage that circulates in the bloodstream of infected animals after being produced by adult female heartworms. Microfilariae develop inside the arthropod to first-stage larvae (L1) and then molt twice to second (L2), and finally to the infective third-stage larvae (L3) in a period of 8-29 days, depending on the environmental temperature and mosquito species (9). The infective larvae migrate to the mouthparts of the mosquito and can be transmitted during another blood meal to a mammalian host, as they pass in a pool of mosquito hemolymph deposited at the site of the bite and enter the definitive host through the wound (9,10). ...
... Microfilariae develop inside the arthropod to first-stage larvae (L1) and then molt twice to second (L2), and finally to the infective third-stage larvae (L3) in a period of 8-29 days, depending on the environmental temperature and mosquito species (9). The infective larvae migrate to the mouthparts of the mosquito and can be transmitted during another blood meal to a mammalian host, as they pass in a pool of mosquito hemolymph deposited at the site of the bite and enter the definitive host through the wound (9,10). In the definitive host, L3 remain close to the site of inoculation and molt to the fourth-stage larvae (L4) within 3-5 days post-infection. ...
... With high worm burdens, worms can reside in the right atrium, right ventricle, and the vena cava, causing caval syndrome. Caval syndrome provokes valvular dysfunction, blood flow impairment, hemolysis, liver, kidney, and heart failure, and often results in the death of the dog (9,13). The pathophysiologic impact of D. immitis mainly depends on the number of worms present in the pulmonary arteries and duration of infection, the size of the dog relative to number of adult heartworms, and the individual immune response to the infection (9). ...
Macrocyclic lactones (MLs) are the only drug class currently licensed for heartworm disease prophylaxis. Macrocyclic lactones kill third- and fourth-stage larvae of Dirofilaria immitis, thus preventing the development of adult worms in dogs, which are responsible for heartworm disease, a potentially life-threatening condition. Despite considerable overlap in terms of endectocide spectrum, several important differences distinguish moxidectin from other MLs. Moxidectin has beneficial pharmacokinetic characteristics, such as a longer half-life and greater tissue distribution compared to ivermectin. Additionally, moxidectin has a greater margin of safety compared to ivermectin in dogs with ABCB1 (previously MDR1) gene-defect, which is commonly recognized in collies and other breeds. Multiple laboratory studies have shown that moxidectin is more effective than other commonly used heartworm preventives against resistant strains of D. immitis. This improved efficacy benefits individual dogs and helps reduce the risk of spreading resistant strains within the community. Despite the presence of proven resistant strains in the United States, non-compliance with preventive measures remains a major factor contributing to the diagnosis of heartworm disease in dogs. In retrospective analyses, the oral moxidectin combination product Simparica Trio® (sarolaner, moxidectin, and pyrantel) was associated with increased compliance, resulting in more time of protection compared to dogs receiving flea/tick and heartworm preventive products separately. Compliance with the extended-release moxidectin injectables ProHeart® 6 and ProHeart® 12 was higher than with monthly heartworm preventives, as they provide 6 months or a full year of protection with one single injection, respectively, and revenues remain in the veterinary clinics as injectable moxidectin cannot be sourced through online retailers.
... infection is relatively simple and straightforward with the administration of macrocyclic lactones. Macrocyclic lactones are highly effective against the L3 and L4 stages of Dirofilaria spp., and they have a 'reach-back' efficacy, killing the parasite 30-60 days post-infection (Nolan and Lok, 2012;Diakou and Prichard, 2021). As such, dogs that visit an enzootic area should receive a preventive dosage of a macrocyclic lactone at the latest 30 days after their arrival to that area and continue monthly dosing until 30 days after their return home. ...
... As such, dogs that visit an enzootic area should receive a preventive dosage of a macrocyclic lactone at the latest 30 days after their arrival to that area and continue monthly dosing until 30 days after their return home. Dogs that are imported from an enzootic area should be tested for heartworm, both with the modified Knott's test for the detection and identification of circulating microfilariae ( Figure 2) and by serology for antigen detection (Diakou and Prichard, 2021). These tests should be repeated at least once, 6-9 months later, given that D. immitis has a long prepatent period and a dog may test negative early after its import despite being infected. ...
In the modern world, country borders do not represent boundaries for the transmission of pathogens. This is also true for parasites that may travel with animals, particularly pets. Dogs and cats are moving across countries more than ever before as a result of adoption, commerce and travels with owners. In addition, climate change supports the establishment of parasites, particularly those transmitted by invertebrate intermediate hosts and vectors, into areas which were previously considered non-enzootic. Therefore, it is important for veterinarians to keep a vigilant eye on such parasitic infections in dogs and cats, be able to recognise compatible signs and feel confident in ordering specific diagnostic tests. This article presents parasites prevalently reported as imported from one European country to another. Furthermore, common clinical manifestations and diagnostic tests are summarised and the preventive measures that should be advised to pet owners are discussed. Raising awareness among veterinary practitioners and pet owners about the risk of parasites spreading in new areas is imperative for controlling and delaying globalisation of important, and potentially lethal, parasitic diseases.
... To date, all preventive drugs used to control D. immitis belong to the ML class, which act efficiently against the third (L3) and fourth (L4) larval stages in a sort of "reach-back" efficacy, i.e. MLs act against parasites that have been already inoculated into the host by the vector in the 30-40 days before dosing (Nolan and Lok, 2012;Diakou and Prichard, 2021). ...
... The phenomenon of D. immitis resistance is an alarming condition with the potential to widely jeopardize effective heartworm prevention. Resistance to MLs has emerged in the Lower Mississippi region of the USA and its precise extent cannot be unequivocally defined (Diakou and Prichard, 2021). Recent studies genotyping D. immitis isolates from random and suspected cases in Europe have so far failed to identify any resistant genotypes (Diakou et al., 2018;Curry et al., 2022;Kumar et al., 2024). ...
... Recent studies genotyping D. immitis isolates from random and suspected cases in Europe have so far failed to identify any resistant genotypes (Diakou et al., 2018;Curry et al., 2022;Kumar et al., 2024). Nevertheless, there is a reasonable concern that resistance to ML may spread to new areas, either by introduction of resistant strains through animal and mosquito movements (e.g., trade of goods) or by an independent evolutionary process, as it occurred in the USA (Diakou and Prichard, 2021). ...
... Heartworm product-related complaints were first submitted to the FDA Center for Veterinary Medicine; however, most reports of preventive failure were linked to a lack of full compliance to recommended prophylaxis (Hampshire, 2005). Since the initial observation of reduced ML effectiveness, subsequent studies have confirmed the emergence of resistance to MLs in D. immitis (Pulaski et al., 2014;Bourguinat et al., 2015;Diakou & Prichard, 2021). The heritability of drug resistance was confirmed (Pulaski et al., 2014) indicating that it has a genetic basis. ...
... MLs are periodically administered either as monthly administered oral or topical formulations, or an annually administered slow-release injectable formulation (Diakou and Prichard, 2021). It is currently recommended in Australian heartworm preventative guidelines for all dogs to be administered MLs year-round for dirofilariosis prevention (Korman et al., 2014). ...
... Even a single missed or delayed monthly preventive dose can lead to heartworm disease (3). The monthly heartworm preventives do not display prospective or residual efficacy against D. immitis, but rather have a "reach-back" efficacy against past inoculations (9), which is 30 days (10). ...
... Although resistance against macrocyclic lactones has been confirmed in some strains of D. immitis in the Lower Mississippi River Valley (LMRV) (9,11), non-compliance is the main contributor for heartworm disease in dogs (12). Approximately only a third of all medicalized dogs in the USA receive one or more doses of heartworm preventive annually (13). ...
Background
This study had two objectives: first, to examine the association between the history of heartworm preventive purchase compliance and the risk of positive heartworm tests, and second to preliminarily investigate the long-term cardiac outcomes of heartworm disease in dogs that had undergone successful adulticidal therapy.
Methods
A retrospective cohort study design was used for both analyses, using anonymous transaction data from Covetrus (retrospective analysis 1) and anonymized medical records from Banfield Pet Hospital (retrospective analysis 2), both including canine patients across the USA. The first analysis examined the relative risk (RR) of a positive heartworm test in dogs with lapses in heartworm preventive purchase history compared to dogs that had no history of a preventive purchase six to 24 months prior to the test. In the second analysis, a long-term evaluation of structured diagnostic codes pertaining to cardiac diseases and risk assessment of outcomes was performed in dogs that had previously been successfully treated for heartworm disease compared to dogs that never had a positive heartworm test.
Results
83,478 unique patients were included in the first analysis. Compared to 32,413 dogs with no history of a heartworm preventive purchase, 44,410 dogs with lapses in monthly preventive purchases had a reduced risk of testing positive for heartworm disease (RR = 0.36, p < 0.0001). Dogs (n = 6,655) with lapses in injectable heartworm preventive administration had a decreased risk of a positive test versus dogs with no preventive purchases (RR = 0.15, p < 0.0001), as well as versus dogs with lapses in monthly heartworm preventive purchases (RR = 0.28, p = 0.0024). In the second analysis, 6,138 patients treated for heartworm infection were found to have significantly (p < 0.001) elevated risks of right heart failure (RR = 3.59), left heart failure (RR = 1.83), or cardiomyopathy (RR = 2.79) compared to 4,022,752 patients that never had a positive heartworm test.
Conclusion
This study highlights the importance of compliance with heartworm preventive guidelines, to reduce the risk of heartworm disease in dogs, which is not only a potentially life-threatening condition in the short-term but also associated with long-term negative cardiac outcomes.
... Heartworm product-related complaints were first submitted to the FDA Center for Veterinary Medicine; however, most reports of preventive failure were linked to a lack of full compliance to recommended prophylaxis (Hampshire, 2005). Since the initial observation of reduced ML effectiveness, subsequent studies have confirmed the emergence of resistance to MLs in D. immitis (Pulaski et al., 2014;Bourguinat et al., 2015;Diakou & Prichard, 2021). The heritability of drug resistance was confirmed (Pulaski et al., 2014) indicating that it has a genetic basis. ...
... Currently, there are many veterinary products in the market approved for the treatment and prevention of the disease. They contain a single drug class, i.e., the macrocyclic lactones, which, when administered according to label instructions, are proven to be very safe and effective at preventing heartworm disease (Diakou and Prichard, 2021).This communication describes the detailed clinical, investigative, confirmatory and therapeutic management of canine dirofilariasis in a dog in Nagaland. ...
Dirofilariasis is one of the most clinically important diseases in dogs. It is also called as heart-worm disease, which is a non-contagious parasitic disease caused by filarial or small thread-like worms, Dirofilaria immitis, and D. repens of the family Onchocercidae (Nelson et al., 2014; Adebayo et al., 2022). It is an arthropod-borne disease. The mosquitoes belonging to the genera Culex, Aedes, Anopheles, and Mansonia are principally responsible for the transmission of this disease (Borthakur et al., 2016). Transmission of the parasite occurs when a potential vector bites dogs during a blood meal. It takes about 6-7 months for the third-stage larvae (L3) to become adult parasites after entering the blood vessels of the hosts (Koutsu et al., 2022). After maturation, the adult worms reproduce and produce microfilariae (pre-L1), which are released in the host blood vessels and taken up by a feeding mosquito (Thilakarathne et al., 2023), and completed the lifecycle of the parasite.
... Resistance to MLs is increasingly recognised as a threat to D. immitis control, particularly in the USA, where drug failures and resistant isolates have been defined and characterised (Pulaski et al., 2014;Maclean et al., 2017;Diakou and Prichard, 2021). Understanding the genetic determinants of drug resistance has been challenging, partly due to a lack of high quality genome resources and a poor understanding of how genetic variation is distributed within and between populations under drug pressure. ...
The heartworm, Dirofilaria immitis, is a filarial parasitic nematode responsible for significant morbidity and mortality in wild and domesticated canids. Resistance to macrocyclic lactone drug prevention represents a significant threat to parasite control and has prompted investigations to understand the genetic determinants of resistance. This study aimed to improve the genomic resources of D. immitis to enable a more precise understanding of how genetic variation is distributed within and between parasite populations worldwide, which will inform the likelihood and rate by which parasites, and in turn, resistant alleles, might spread. We have guided the scaffolding of a recently published genome assembly for D. immitis (ICBAS_JMDir_1.0) using the chromosomal-scale reference genomes of Brugia malayi and Onchocerca volvulus, resulting in an 89.5 Mb assembly composed of four autosomal- and one sex-linked chromosomal-scale scaffolds representing 99.7% of the genome. Publicly available and new whole-genome sequencing data from 32 D. immitis samples from Australia, Italy and the USA were assessed using principal component analysis, nucleotide diversity (Pi) and absolute genetic divergence (Dxy) to characterise the global genetic structure and measure within- and between-population diversity. These population genetic analyses revealed broad-scale genetic structure among globally diverse samples and differences in genetic diversity between populations; however, fine-scale subpopulation analysis was limited and biased by differences between sample types. Finally, we mapped single nucleotide polymorphisms previously associated with macrocyclic lactone resistance in the new genome assembly, revealing the physical linkage of high-priority variants on chromosome 3, and determined their frequency in the studied populations. This new chromosomal assembly for D. immitis now allows for a more precise investigation of selection on genome-wide genetic variation and will enhance our understanding of parasite transmission and the spread of genetic variants responsible for resistance to treatment.
... Importantly, chemoprophylaxis with MLs, including ivermectin, is the current standard preventive administrated to dogs and cats and this approach has proven its efficacy to prevent heartworm disease in endemic regions. However, resistances to MLs has been reported in the United States and its development is of concern in Europe [35]. Therefore, chemoprophylaxis with a DAF-12 inhibitor alone or combined with MLs could be a promising strategy to overcome the emergence of resistance to MLs because DAF-12 antagonists and MLs would have different mechanisms of action. ...
... Therefore, chemoprophylaxis with a DAF-12 inhibitor alone or combined with MLs could be a promising strategy to overcome the emergence of resistance to MLs because DAF-12 antagonists and MLs would have different mechanisms of action. Indeed, DAF-12 antagonists would alter the development of filarial larvae while MLs are thought to block the excretory-secretory apparatus of the parasites, thus preventing the secretion of immunomodulatory molecules [35,36]. Though caution should be taken in the development of DAF-12 antagonists as they may face cross reactivity with mammalian nuclear receptors such as FXR, the mammalian DAF-12 homolog which responds to bile acids or intermediates of the bile acids synthesis pathways. ...
Nematode parasites enter their definitive host at the developmentally arrested infectious larval stage (iL3), and the ligand-dependent nuclear receptor DAF-12 contributes to trigger their development to adulthood. Here, we characterized DAF-12 from the filarial nematodes Brugia malayi and Dirofilaria immitis and compared them with DAF-12 from the non-filarial nematodes Haemonchus contortus and Caenorhabditis elegans. Interestingly, Dim and BmaDAF-12 exhibit high sequence identity and share a striking higher sensitivity than Hco and CelDAF-12 to the natural ligands Δ4- and Δ7-dafachronic acids (DA). Moreover, sera from different mammalian species activated specifically Dim and BmaDAF-12 while the hormone-depleted sera failed to activate the filarial DAF-12. Accordingly, hormone-depleted serum delayed the commencement of development of D. immitis iL3 in vitro. Consistent with these observations, we show that spiking mouse charcoal stripped-serum with Δ4-DA at the concentration measured in normal mouse serum restores its capacity to activate DimDAF-12. This indicates that DA present in mammalian serum participate in filarial DAF-12 activation. Finally, analysis of publicly available RNA sequencing data from B. malayi showed that, at the time of infection, putative gene homologs of the DA synthesis pathways are coincidently downregulated. Altogether, our data suggest that filarial DAF-12 have evolved to specifically sense and survive in a host environment, which provides favorable conditions to quickly resume larval development. This work sheds new light on the regulation of filarial nematodes development while entering their definitive mammalian host and may open the route to novel therapies to treat filarial infections.
