Moxidectin: heartworm disease prevention in dogs in the face of emerging macrocyclic lactone resistance

Savadelis, Molly D.; McTier, Tom L.; Kryda, Kristina; Maeder, Steven; Woods, Debra J.

doi:10.1186/s13071-021-05104-7

Cited by 21 publications

(19 citation statements)

References 52 publications

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“…Recapitulation of a resistance phenotype has been observed in an in vitro system in which canine peripheral blood mononuclear cells and the neutrophil fraction within, adhere to D. immitis larvae in the presence of physiologically relevant nM concentrations of ML 27 . Importantly, an ML-resistant isolate of D. immitis showed diminished killing by ivermectin in NSG mice, while retaining a higher susceptibility to moxidectin 28 , 29 , thus demonstrating that the NSG/ D. immitis model was suitable for evaluating compounds for efficacy against ML-susceptible and resistant isolates of D. immitis .…”

Section: Discussionmentioning

confidence: 94%

A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice

Hess

Eberhard

Segura-Lepe

et al. 2023

Sci Rep

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Heartworm disease, caused by Dirofilaria immitis, remains a significant threat to canines and felines. The development of parasites resistant to macrocyclic lactones (ML) has created a significant challenge to the control of the infection. The goal of this study was to determine if mice lacking a functional immune response would be susceptible to D. immitis. Immunodeficient NSG mice were susceptible to the infection, sustaining parasites for at least 15 weeks, with infective third-stage larvae molting and developing into the late fourth-stage larvae. Proteomic analysis of host responses to the infection revealed a complex pattern of changes after infection, with at least some of the responses directed at reducing immune control mechanisms that remain in NSG mice. NSG mice were infected with isolates of D. immitis that were either susceptible or resistant to MLs, as a population. The susceptible isolate was killed by ivermectin whereas the resistant isolate had improved survivability, while both isolates were affected by moxidectin. It was concluded that D. immitis survives in NSG mice for at least 15 weeks. NSG mice provide an ideal model for monitoring host responses to the infection and for testing parasites in vivo for susceptibility to direct chemotherapeutic activity of new agents.

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Section: Discussionmentioning

confidence: 94%

A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice

Hess

Eberhard

Segura-Lepe

et al. 2023

Sci Rep

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“…Thus, azaquinazolines or other novel anti-Wolbachia chemistry with similar rapid killing activity, as identified in high throughput industrial screening [53], might hold promise as new heartworm preventative or curative candidates and now can be triaged for activity utilising our novel D. immitis NSG/NXG mouse model. We used a high single parenteral dose of moxidectin, mimicking extended-release formulations used in dogs [37], to evaluate the D. immitis NSG/NXG mouse model as a preventative drug screen. We demonstrated, using multiple batches of different MLsusceptible D. immitis isolates, in different evaluating laboratories, that injected moxidectin mediated significant 65-89% reductions in larvae assessed between 13-27 days postexposure.…”

Section: Discussionmentioning

confidence: 99%

“…Moxidectin is a front-line ML preventative used in various oral, topical or injectable formulations as monthly, biannual or annual heartworm prophylaxis in dogs [37]. We selected a single high dose subcutaneous injection of moxidectin (2.5mg/kg) for evaluation of larvicidal efficacy in NSG/NXG mice (emulating route of delivery and dose of long-acting injectable formulations of moxidectin in dogs).…”

Section: Immitis Nsg Mouse Infections Can Be Used To Evaluate Prevent...mentioning

confidence: 99%

A dirofilariasis mouse model for heartworm preclinical research

Marriott

Dagley

Hegde

et al. 2023

Preprint

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Use of experimental cats and dogs in veterinary heartworm preclinical drug research is increasing. As a potential alternative primary in vivo heartworm preventative drug screen, we assessed lymphopenic mice with ablation of the interleukin-2/7 common gamma chain (gc) as susceptible to the larval development phase of D. immitis. Non-obese diabetic (NOD) Severe Combined ImmunoDeficient (SCID)gc-/-(NSG / NXG) mice consistently yielded viable D. immitis larvae at 2-4 weeks post-infection across multiple experiments, different batches of infectious larvae inoculates, different isolates of D. immitis and at independent laboratories. Mice did not display any overt clinical signs associated with infection up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, the natural site of this stage of heartworm in dogs. Larvae retrieved from NSG / NXG mice were mid-L4 stage of development. Compared with 14-day in vitro propagated larvae, in vivo derived L4 were significantly larger and contained expanded Wolbachia endobacteria titres, determined by QPCR and Fluorescent in situ Hybridisation (FISH). We established an ex vivo 6-day L4 paralytic screening system against nematodicidal agents (moxidectin, levamisole) which highlighted discrepancies in relative drug sensitivities in comparison with in vitro reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70-90% in D. immitis L4 following 2-7 day oral in vivo exposures of NSG / NXG infected mice with doxycycline or the rapid-acting investigational anti-Wolbachia drug, AWZ1066S. We validated the NSG / NXG mouse model as a filaricide drug screen by in vivo treatments with single injections of moxidectin, which mediated 60-88% reduction in L4 larvae at 14-28 days. Future adoption of the mouse model as a first-line efficacy screen will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround and reduced costs whilst simultaneously decreasing need for experimental cat or dog use.

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“…Focusing on the dogs that were administered moxidectin (microspheres, 500 µg/kg s.c.) at the time of diagnosis of D. immitis infection, the high initial dose was potentially sufficient to clear even ML-resistant D. immitis microfilariae. Higher doses such as 24 µg/kg of moxidectin or higher have been experimentally shown to improve D. immitis prevention with known ML-resistant D. immitis and are already formulated and approved for use in dogs (McTier et al, 2019a;Savadelis et al, 2022). Moxidectin (microspheres) has been shown to significantly improve prevention in a field trial in the Lower Mississippi River Valley region, which is known for its high prevalence of ML-resistance (McTier et al, 2019b).…”

Section: Discussionmentioning

confidence: 99%

Exploration of the sensitivity to macrocyclic lactones in the canine heartworm (Dirofilaria immitis) in Australia using phenotypic and genotypic approaches

Power

Šlapeta

2022

Preprint

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Canine heartworm disease is a potentially deadly cardiopulmonary disease caused by the mosquito-borne filarial nematode Dirofilaria immitis. In Australia, the administration of macrocyclic lactone (ML) drugs has successfully reduced the prevalence of D. immitis infection. However, the recent re-emergence of D. immitis in dogs in Queensland, Australia and the identification of ML-resistant isolates in the USA poses an important question of whether ML-resistance has emerged in this parasite in Australia. The aim of this study was to utilise phenotypic and genotypic assays to determine the presence of ML-resistant D. immitis in Australia. To do this, we surveyed 45 (n=45) dogs from Queensland and New South Wales across 3 years (2019-2022) for the presence of D. immitis infection using an antigen test, quantitative Modified Knott's test, and qPCR targeting both D. immitis and the D. immitis symbiont Wolbachia. A phenotypic assay utilising a microfilarial suppression test for 23/45 dogs was coupled with genetic testing of filtered microfilariae for SNPs previously associated with ML-resistance in isolates from the USA. Sixteen (16/45) dogs tested positive for D. immitis infection despite reportedly receiving 'rigorous' heartworm prevention for 12 months prior to the study. The phenotypic and genotypic assays in this study did not unequivocally demonstrate the presence of ML-resistant D. immitis in Australia. Although the failure of 16 dogs to reduce microfilaremia by >90% after ML treatment was considered phenotypic evidence of suspect ML-resistance, no genotypic evidence was discovered using the genetic SNP analysis. It is possible that the presence of ML-resistance in this study was masked by the high initial dose of moxidectin (microspheres, 500 ug/kg s.c.) administered to eighteen (18/23) dogs at the time of diagnosis, which had the potential to clear any ML-resistant D. immitis microfilariae prior to post-ML treatment sampling.

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Moxidectin: heartworm disease prevention in dogs in the face of emerging macrocyclic lactone resistance

Cited by 21 publications

References 52 publications

A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice

A rodent model for Dirofilaria immitis, canine heartworm: parasite growth, development, and drug sensitivity in NSG mice

A dirofilariasis mouse model for heartworm preclinical research

Exploration of the sensitivity to macrocyclic lactones in the canine heartworm (Dirofilaria immitis) in Australia using phenotypic and genotypic approaches

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