The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis.

Abstract

Prevention of heartworm disease caused by Dirofilaria immitis in domestic dogs and cats relies on a single drug class, the macrocyclic lactones (MLs). Recently, it has been demonstrated that ML-resistant D. immitis are circulating in the Mississippi Delta region of the USA, but the prevalence and impact of these resistant parasites remains unknown. We review published studies that demonstrated resistance in D.immitis, along with our current understanding of its mechanisms. Efforts to develop in vitro tests for resistance have not yet yielded a suitable assay, so testing infected animals for microfilariae that persist in the face of ML treatment may be the best current option. Since the vast majority of D. immitis populations continue to be drug-sensitive, protected dogs are likely to be infected with only a few parasites and experience relatively mild disease. In cats, infection with small numbers of worms can cause severe disease and so the clinical consequences of drug resistance may be more severe. Since melarsomine dihydrochloride, the drug used to remove adult worms, is not an ML, the ML-resistance should have no impact on our ability to treat diseased animals. A large refugium of heartworms that are not exposed to drugs exists in unprotected dogs and in wild canids, which may limit the development and spread of resistance alleles.

Ivermectin – Old Drug, New Tricks?

“…However, applying this blanket approach has resulted in rapid selection for parasitic nematodes that are capable of surviving drug treatment. Anthelmintic resistance is now a major global problem in the control of gastrointestinal roundworms of sheep, cattle, and horses [47], and there are now reports of IVM resistance in the canine heartworm, D. immitis [48]. Concurrently, reports of reduced embryostatic effects of IVM on O. volvulus in Ghana and Cameroon have raised concerns that IVM resistance may evolve in human parasites 49, 50, 51.…”

How do the macrocyclic lactones kill filarial nematode larvae?

“…Given the importance of the macrocyclic lactones in the control of heartworm and human filariases, together with the emergence of resistance to the drugs in D. immitis (Bourguinat et al 2015; Wolstenholme et al 2015; Pulaski 2014; Geary et al 2011) and reports of reduced drug efficacy in some Onchocerca volvulus patients (Osei-Atweneboana et al 2011) it is essential that we understand how they work against these parasites. Bioinformatic analysis indicates that filarial species have lost many genes encoding ligand-gated ion channels, including many of the GluCl-encoding genes, when compared to other nematodes (Williamson et al 2007; Beech and Neveu 2015).…”

Polymorphism in ion channel genes of Dirofilaria immitis : Relevant knowledge for future anthelmintic drug design

“…In terms of economic factors, in the USA alone, with over 80 million dogs, and with heartworm drugs costing US $75–100/dog per year (Godel et al., 2012), there exists an attractive market for heartworm drug development. Any new pharmaceutical for heartworm control may also benefit efforts to control filarial and potentially other parasitic infections in humans (Wolstenholme et al., 2015). …”