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

Published online by Cambridge University Press:  04 June 2015

ADRIAN J. WOLSTENHOLME ,
CHRISTOPHER C. EVANS ,
PABLO D. JIMENEZ  and
ANDREW R. MOORHEAD
ADRIAN J. WOLSTENHOLME*
Affiliation:
Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
CHRISTOPHER C. EVANS
Affiliation:
Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
PABLO D. JIMENEZ
Affiliation:
Calle 169 B No. 75-73 casa 130, Bogotá, Colombia and European Scientific Counsel for Companion Animal Parasites, The Mews Studio, Portland Road, Malvern, Worcestershire, WR14 2TA, United Kingdom
ANDREW R. MOORHEAD
Affiliation:
Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA
*
* Corresponding author. Department of Infectious Diseases, College of Veterinary Medicine, 501 D.W. Brooks Drive, Athens, GA 30602, USA. E-mail: adrianw@uga.edu
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Summary

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.

Keywords

Dirofilaria immitisivermectinresistancerefugia
Type
Review Article
Information
Parasitology , Volume 142 , Issue 10 , September 2015 , pp. 1249 - 1259
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Copyright
Copyright © Cambridge University Press 2015 

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References

REFERENCES

Accardi, M. V., Beech, R. N. and Forrester, S. G. (2012). Nematode cys-loop GABA receptors: biological function, pharmacology and sites of action for anthelmintics. Invertebrate Neuroscience 12, 3–12.CrossRefGoogle ScholarPubMed
Al-Azzam, S. I., Fleckenstein, L., Cheng, K. J., Dzirnianski, M. T. and McCall, J. W. (2007). Comparison of the pharmacokinetics of moxidectin and ivermectin after oral administration to beagle dogs. Biopharmaceutics & Drug Disposition 28, 431–438.Google Scholar
Alibu, V. P., Richter, C., Voncken, F., Marti, G., Shahi, S., Renggli, C. K., Seebeck, T., Brun, R. and Clayton, C. (2006). The role of Trypanosoma brucei MRPA in melarsoprol susceptibility. Molecular and Biochemical Parasitology 146, 38–44.CrossRefGoogle ScholarPubMed
Amarante, A. F. T., Pomroy, W. E., Charleston, W. A. G., Leathwick, D. M. and Tornero, M. T. T. (1997). Evaluation of a larval development assay for the detection of anthelmintic resistance in Ostertagia circumcincta . International Journal for Parasitology 27, 305–311.Google Scholar
Ardelli, B. F., Guerriero, S. B. and Prichard, R. K. (2006). Ivermectin imposes selection pressure on P-glycoprotein from Onchocerca volvulus: linkage disequilibrium and genotype diversity. Parasitology 132, 375–386.Google Scholar
Atkins, C. E., Murray, M. J., Olavessen, L. J., Burton, K. W., Marshall, J. W. and Brooks, C. C. (2014). Heartworm ‘lack of effectiveness’ claims in the Mississippi delta: computerized analysis of owner compliance - 2004–2011. Veterinary Parasitology 206, 106–113.Google Scholar
Barker, E. N., Langton, D. A., Helps, C. R., Brown, G., Malik, R., Shaw, S. E. and Tasker, S. (2012). Haemoparasites of free-roaming dogs associated with several remote Aboriginal communities in Australia. Bmc Veterinary Research 8, 55.CrossRefGoogle ScholarPubMed
Bazzocchi, C., Mortarino, M., Grandi, G., Kramer, L. H., Genchi, C., Bandi, C., Genchi, M., Sacchi, L. and McCall, J. W. (2008). Combined ivermectin and doxycycline treatment has microfilaricidal and adulticidal activity against Dirofilaria immitis in experimentally infected dogs. International Journal for Parasitology 38, 1401–1410.Google Scholar
Beech, R., Levitt, N., Cambos, M., Zhou, S. F. and Forrester, S. G. (2010). Association of ion-channel genotype and macrocyclic lactone sensitivity traits in Haemonchus contortus . Molecular and Biochemical Parasitology 171, 74–80.CrossRefGoogle ScholarPubMed
Blackhall, W. J., Liu, H. Y., Xu, M., Prichard, R. K. and Beech, R. N. (1998 a). Selection at a P-glycoprotein gene in ivermectin- and moxidectin-selected strains of Haemonchus contortus . Molecular and Biochemical Parasitology 95, 193–201.CrossRefGoogle Scholar
Blackhall, W. J., Pouliot, J. F., Prichard, R. K. and Beech, R. N. (1998 b). Haemonchus contortus: selection at a glutamate-gated chloride channel gene in ivermectin- and moxidectin-selected strains. Experimental Parasitology 90, 42–48.Google Scholar
Blackhall, W. J., Prichard, R. K. and Beech, R. N. (2003). Selection at a gamma-aminobutyric acid receptor gene in Haemonchus contortus resistant to avermectins/milbemycins. Molecular and Biochemical Parasitology 131, 137–145.Google Scholar
Blackhall, W. J., Prichard, R. K. and Beech, R. N. (2008). P-glycoprotein selection in strains of Haemonchus contortus resistant to benzimidazoles. Veterinary Parasitology 152, 101–107.Google Scholar
Blagburn, B. L., Dillon, A. R., Arther, R. G., Butler, J. M. and Newton, J. C. (2011). Comparative efficacy of four commercially available heartworm preventive products against the MP3 laboratory strain of Dirofilaria immitis . Veterinary Parasitology 176, 189–194.Google Scholar
Bourguinat, C., Pion, S. D. S., Kamgno, J., Gardon, J., Duke, B. O. L., Boussinesq, M. and Prichard, R. K. (2007). Genetic selection of low fertile Onchocerca volvulus by ivermectin treatment. PLoS Neglected Tropical Diseases 1, e72.Google Scholar
Bourguinat, C., Keller, K., Bhan, A., Peregrine, A., Geary, T. and Prichard, R. (2011 a). Macrocyclic lactone resistance in Dirofilaria immitis . Veterinary Parasitology 181, 388–392.Google Scholar
Bourguinat, C., Keller, K., Blagburn, B., Schenker, R., Geary, T. G. and Prichard, R. K. (2011 b). Correlation between loss of efficacy of macrocyclic lactone heartworm anthelmintics and P-glycoprotein genotype. Veterinary Parasitology 176, 374–381.Google Scholar
Bourguinat, C., Keller, K., Prichard, R. K. and Geary, T. G. (2011 c). Genetic polymorphism in Dirofilaria immitis . Veterinary Parasitology 176, 368–373.Google Scholar
Bowman, D. D. (2012). Heartworms, macrocylic lactones, and the specter of resistance to prevention in the United States. Parasites & Vectors 5, 138.Google Scholar
Bowman, D. D. and Atkins, C. E. (2009). Heartworm biology, treatment and control. Veterinary Clinics Small Animal 39, 1127–1158.CrossRefGoogle ScholarPubMed
Bowman, D. D. and Mannella, C. (2011). Macrocyclic lactones and Dirofilaria immitis microfilariae. Topics in Companion Animal Medicine 26, 160–172.Google Scholar
Bowman, D., Little, S. E., Lorentzen, L., Shields, J., Sullivan, M. P. and Carlin, E. P. (2009). Prevalence and geographic distribution of Dirofilaria immitis, Borrelia burgdorferi, Ehrlichia canis, and Anaplasma phagocytophilum in dogs in the United States: results of a national clinic-based serologic survey. Veterinary Parasitology 160, 138–148.Google Scholar
Coles, G. C., Jackson, F., Pomroy, W. E., Prichard, R. K., von Samson-Himmelstjerna, G., Silvestre, A., Taylor, M. A. and Vercruysse, J. (2006). The detection of anthelmintic resistance in nematodes of veterinary importance. Veterinary Parasitology 136, 167–185.CrossRefGoogle ScholarPubMed
Cuervo, P. F., Sierra, R. M. Y., Waisman, V., Gerbeno, L., Sidoti, L., Albonico, F., Mariconti, M., Mortarino, M., Pepe, P., Cringoli, G., Genchi, C. and Rinaldi, L. (2013). Detection of Dirofilaria immitis in mid-western arid Argentina. Acta Parasitologica 58, 612–614.Google Scholar
Demeler, J., Kuttler, U., El-Abdellati, A., Stafford, K., Rydzik, A., Varady, M., Kenyon, F., Coles, G., Hoglund, J., Jackson, F., Vercruysse, J. and von Samson-Himmelstjerna, G. (2010). Standardization of the larval migration inhibition test for the detection of resistance to ivermectin in gastro intestinal nematodes of ruminants. Veterinary Parasitology 174, 58–64.CrossRefGoogle ScholarPubMed
Demeler, J., Gill, J. H., von Samson-Himmelstjerna, G. and Sangster, N. C. (2013). The in vitro assay profile of macrocyclic lactone resistance in three species of sheep trichostrongyloids. International Journal for Parasitology-Drugs and Drug Resistance 3, 109–118.Google Scholar
Dupuy, J., Derlon, A. L., Sutra, J. F., Cadiergues, M. C., Franc, M. and Alvinerie, M. (2004). Pharmacokinetics of selamectin in dogs after topical application. Veterinary Research Communications 28, 407–413.CrossRefGoogle ScholarPubMed
Eng, J. K. L., Blackhall, W. J., Osei-Atweneboana, M. Y., Bourguinat, C., Galazzo, D., Beech, R. N., Unnasch, T. R., Awadzi, K., Lubega, G. W. and Prichard, R. K. (2006). Ivermectin selection on β-tubulin: evidence in Onchocerca volvulus and Haemonchus contortus . Molecular and Biochemical Parasitology 150, 229–235.Google Scholar
Evans, C. C., Moorhead, A. R., Storey, B. E., Wolstenholme, A. J. and Kaplan, R. M. (2013). Development of an in vitro bioassay for measuring susceptibility to macrocyclic lactone anthelmintics in Dirofilaria immitis . International Journal for Parasitology-Drugs and Drug Resistance 3, 102–108.Google Scholar
Freeman, A. S., Nghiem, C., Li, J., Ashton, F. T., Guerrero, J., Shoop, W. L. and Schad, G. A. (2003). Amphidial structure of ivermectin-resistant and susceptible laboratory and field strains of Haemonchus contortus . Veterinary Parasitology 110, 217–226.Google Scholar
Fryxell, R. T. T., Lewis, T. T., Peace, H., Hendricks, B. B. M. and Paulsen, D. (2014). Identification of avian malaria (Plasmodium sp.) and canine heartworm (Dirofilaria immitis) in the mosquitoes of Tennessee. Journal of Parasitology 100, 455–462.Google Scholar
Geary, T. G., Bourguinat, C. and Prichard, R. K. (2011). Evidence for macrocyclic lactone anthelmintic resistance in Dirofilaria immitis . Topics in Companion Animal Medicine 26, 186–192.Google Scholar
Gilleard, J. S. (2013). Haemonchus contortus as a paradigm and model to study anthelmintic drug resistance. Parasitology 140, 1506–1522.Google Scholar
Gilleard, J. S. and Beech, R. N. (2007). Population genetics of anthelmintic resistance in parasitic nematodes. Parasitology 134, 1133–1147.CrossRefGoogle ScholarPubMed
Godel, C., Kumar, S., Koutsovoulos, G., Ludin, P., Nilsson, D., Comandatore, F., Wrobel, N., Thompson, M., Schmid, C. D., Goto, S., Bringaud, F., Wolstenholme, A., Bandi, C., Epe, C., Kaminsky, R., Blaxter, M. and Maser, P. (2012). The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets. FASEB Journal 26, 4650–4661.CrossRefGoogle ScholarPubMed
Gokbulut, C., Karademir, U., Boyacioglu, M. and McKellar, Q. A. (2006). Comparative plasma dispositions of ivermectin and doramectin following subcutaneous and oral administration in dogs. Veterinary Parasitology 135, 347–354.CrossRefGoogle ScholarPubMed
Guerrero, J., McCall, J. W. and Genchi, C. (2002). The use of macrocyclic lactones in the control and prevention of heartworm and other parasites in dogs and cats. In Macrocyclic Lactones in Antiparasitic Therapy (ed. Vercruysse, J. and Rew, R. S.), pp. 353–370. CABI Publishing, Wallingford, UK.Google Scholar
Hampshire, V. A. (2005). Evaluation of efficacy of heartworm preventive products at the FDA. Veterinary Parasitology 133, 191–195.Google Scholar
Hernando, G. and Bouzat, C. (2014). Caenorhabditis elegans neuromuscular junction: GABA receptors and ivermectin action. Plos ONE 9, e95072.CrossRefGoogle ScholarPubMed
Kaplan, R. M., Vidyashankar, A. N., Howell, S. B., Neiss, J. M., Williamson, L. H. and Terrill, T. H. (2007). A novel approach for combining the use of in vitro and in vivo data to measure and detect emerging moxidectin resistance in gastrointestinal nematodes of goats. International Journal for Parasitology 37, 795–804.Google Scholar
Knight, D. H. and Lok, J. B. (1998). Seasonality of heartworm infection and implications for chemoprophylaxis. Clinical Techniques Small Animal Practice 13, 77–82.CrossRefGoogle ScholarPubMed
Kotani, T. and Powers, K. G. (1982). Developmental stages of Dirofilaria immitis in the dog. American Journal of Veterinary Research 43, 2199–2206.Google Scholar
Kotze, A. C., Le Jambre, L. F. and O'Grady, J. (2006). A modified larval migration assay for detection of resistance to macrocyclic lactones in Haemonchus contortus, and drug screening with Trichostrongylidae parasites. Veterinary Parasitology 137, 294–305.Google Scholar
Krause, R. M., Buisson, B., Bertrand, S., Corringer, P. J., Galzi, J. L., Changeux, J. P. and Bertrand, D. (1998). Ivermectin: a positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Molecular Pharmacology 53, 283–294.Google Scholar
Labarthe, N. and Guerrero, J. (2005). Epidemiology of heartworm: what is happening in South America and Mexico? Veterinary Parasitology 133, 149–156.Google Scholar
Labarthe, N. V., Paiva, J. P., Reifur, L., Mendes-de-Almeida, F., Merlo, A., Pinto, C. J. C., Juliani, P. S., de Almeida, M. A. O. and Alves, L. C. (2014). Updated canine infection rates for Dirofilaria immitis in areas of Brazil previously identified as having a high incidence of heartworm-infected dogs. Parasites & Vectors 7, 493.Google Scholar
Lallemand, E., Lespine, A., Alvinerie, M., Bousquet-Melou, A. and Toutain, P. L. (2007). Estimation of absolute oral bioavailability of moxidectin in dogs using a semi-simultaneous method: influence of lipid co-administration. Journal of Veterinary Pharmacology and Therapeutics 30, 375–380.CrossRefGoogle ScholarPubMed
Lee, A. C. Y., Montgomery, S. P., Theis, J. H., Blagburn, B. L. and Eberhard, M. L. (2010). Public health issues concerning the widespread distribution of canine heartworm disease. Trends in Parasitology 26, 168–173.Google Scholar
Levy, J. K., Lappin, M. R., Glaser, A. L., Birkenheuer, A. J., Anderson, T. C. and Edinboro, C. H. (2011). Prevalence of infectious diseases in cats and dogs rescued following Hurricane Katrina. Javma-Journal of the American Veterinary Medical Association 238, 311–317.Google Scholar
Little, S. E., Beall, M. J., Bowman, D. D., Chandrashekar, R. and Stamaris, J. (2014 a). Canine infection with Dirofilaria immitis, Borrelia burgdorferi, Anaplasma spp., and Ehrlichia spp. in the United States, 2010–2012. Parasites & Vectors 7, 257.Google Scholar
Little, S. E., Munzing, C., Heise, S. R., Allen, K. E., Starkey, L. A., Johnson, E. M., Meinkoth, J. and Reichard, M. V. (2014 b). Pre-treatment with heat facilitates detection of antigen of Dirofilaria immitis in canine samples. Veterinary Parasitology 203, 250–252.CrossRefGoogle ScholarPubMed
Lok, J. B., Knight, D. H., Selavka, C. M., Eynard, J., Zhang, Y. and Bergman, R. N. (1995). Studies of reproductive competence in male Dirofilaria immitis treated with milbemycin oxime. Tropical Medicine and Parasitology 46, 235–240.Google Scholar
Maia, C., Coimbra, M., Ramos, C., Cristovao, J. M., Cardoso, L. and Campino, L. (2015). Serological investigation of Leishmania infantum, Dirofilaria immitis and Angiostrongylus vasorum in dogs from southern Portugal. Parasites & Vectors 8, 152.Google Scholar
McCall, J. W. (2005). The safety-net story about macrocylic lactone heartworm preventives: a review, an update and recommendations. Veterinary Parasitology 133, 197–206.Google Scholar
McCall, J. W., Kramer, L., Genchi, C., Guerrero, J., Dzimianski, M. T., Mansour, A., McCall, S. D. and Carson, B. (2014). Effects of doxycycline on heartworm embryogenesis, transmission, circulating microfilaria, and adult worms in microfilaremic dogs. Veterinary Parasitology 206, 5–13.CrossRefGoogle ScholarPubMed
McCavera, S., Walsh, T. K. and Wolstenholme, A. J. (2007). Nematode ligand-gated chloride channels: an appraisal of their involvement in macrocyclic lactone resistance and prospects for developing molecular markers. Parasitology 134, 1111–1121.Google Scholar
McKay, T., Bianco, T., Rhodes, L. and Barnett, S. (2013). Prevalence of Dirofilaria immitis (Nematoda: Filarioidea) in mosquitoes from northeast Arkansas, the United States. Journal of Medical Entomology 50, 871–878.Google Scholar
McKellar, Q. A. and Gokbulut, C. (2012). Pharmacokinetic features of the antiparasitic macrocyclic lactones. Current Pharmaceutical Biotechnology 13, 888–911.Google Scholar
Moreno, Y., Nabhan, J. F., Solomon, J., Mackenzie, C. D. and Geary, T. G. (2010). Ivermectin disrupts the function of the excretory-secretory apparatus in microfilariae of Brugia malayi . Proceedings of the National Academy of Sciences of the United States of America 107, 20120–20125.Google Scholar
Mottier, M. D. and Prichard, R. K. (2008). Genetic analysis of a relationship between macrocyclic lactone and benzimidazole anthelmintic selection on Haemonchus contortus . Pharmacogenetics and Genomics 18, 129–140.Google Scholar
Njue, A. I., Hayashi, J., Kinne, L., Feng, X.-P. and Prichard, R. K. (2004). Mutations in the extracellular domain of glutamate-gated chloride channel α3 and β subunits from ivermectin-resistant Cooperia oncophora affect agonist sensitivity. Journal of Neurochemistry 89, 1137–1147.CrossRefGoogle ScholarPubMed
Otranto, D., Dantas-Torres, F., Brianti, E., Traversa, D., Petric, D., Genchi, C. and Capelli, G. (2013). Vector-borne helminths of dogs and humans in Europe. Parasites & Vectors 6, 16–0.Google Scholar
Penezic, A., Selakovic, S., Pavlovic, I. and Cirovic, D. (2014). First findings and prevalence of adult heartworms (Dirofilaria immitis) in wild carnivores from Serbia. Parasitology Research 113, 3281–3285.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2001). Genetic variability following selection of Haemonchus contortus with anthelmintics. Trends in Parasitology 17, 445–453.CrossRefGoogle ScholarPubMed
Prichard, R. K. (2005). Is anthelmintic resistance a concern for heartworm control? What can we learn from the human filariasis control programs? Veterinary Parasitology 133, 243–253.Google Scholar
Pulaski, C. N., Malone, J. B., Bourguinat, C., Prichard, R., Geary, T., Ward, D., Klei, T. R., Guidry, T., Smith, G. B., Delcambre, B., Bova, J., Pepping, J., Carmichael, J., Schenker, R. and Pariaut, R. (2014). Establishment of macrocylic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasites & Vectors 7, 494.Google Scholar
Rao, V. T. S., Siddiqui, S. Z., Prichard, R. K. and Forrester, S. G. (2009). A dopamine-gated ion channel (HcGGR3*) from Haemonchus contortus is expressed in the cervical papillae and is associated with macrocyclic lactone resistance. Molecular and Biochemical Parasitology 166, 54–61.Google Scholar
Sarasola, P., Jernigan, A. D., Walker, D. K., Castledine, J., Smith, D. G. and Rowan, T. G. (2002). Pharmacokinetics of selamectin following intravenous, oral and topical administration in cats and dogs. Journal of Veterinary Pharmacology and Therapeutics 25, 265–272.Google Scholar
Sassnau, R., Czajka, C., Kronefeld, M., Werner, D., Genchi, C., Tannich, E. and Kampen, H. (2014). Dirofilaria repens and Dirofilaria immitis DNA findings in mosquitoes in Germany: temperature data allow autochthonous extrinsic development. Parasitology Research 113, 3057–3061.Google Scholar
Shahi, S. K., Krauth-Siegel, R. L. and Clayton, C. E. (2002). Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei . Molecular Microbiology 43, 1129–1138.Google Scholar
Simon, F., Morchon, R., Gonzalez-Miguel, J., Marcos-Atxutegi, C. and Siles-Lucas, M. (2009). What is new about animal and human dirofilariosis? Trends in Parasitology 25, 404–409.Google Scholar
Snyder, D. E., Wiseman, S., Bowman, D. D., McCall, J. W. and Reinemeyer, C. R. (2011 a). Assessment of the effectiveness of a combination product of spinosad and milbemycin oxime on the prophylaxis of canine heartworm infection. Veterinary Parasitology 180, 262–266.Google Scholar
Snyder, D. E., Wiseman, S., Cruthers, L. R. and Slone, R. L. (2011 b). Ivermectin and milbemycin oxime in experimental adult heartworm (Dirofilaria immitis) infection of dogs. Journal of Veterinary Internal Medicine 25, 61–64.Google Scholar
Storey, B., Marcellino, C., Miller, M., Maclean, M., Mostafa, E., Howell, S., Sakanari, J., Wolstenholme, A. and Kaplan, R. (2014). Utilization of computer processed high definition video imaging for measuring motility of microscopic nematode stages on a quantitative scale: ‘The Worminator’. International Journal for Parasitology: Drugs and Drug Resistance 4, 233–243.Google Scholar
Tandon, R. and Kaplan, R. M. (2004). Evaluation of a larval development assay (DrenchRite(R)) for the detection of anthelmintic resistance in cyathostomin nematodes of horses. Veterinary Parasitology 121, 125–142.Google Scholar
Tolnai, Z., Szell, Z., Sproch, A., Szeredi, L. and Sreter, T. (2014). Dirofilaria immitis: an emerging parasite in dogs, red foxes and golden jackals in Hungary. Veterinary Parasitology 203, 339–342.Google Scholar
Urdaneta-Marquez, L., Bae, S. H., Janukavicius, P., Beech, R., Dent, J. and Prichard, R. (2014). A dyf-7 haplotype causes sensory neuron defects and is associated with macrocyclic lactone resistance worldwide in the nematode parasite Haemonchus contortus . International Journal for Parasitology 44, 1063–1071.CrossRefGoogle ScholarPubMed
Van Wyk, J. A. (2001). Refugia – overlooked as perhaps the most potent factor concerning the development of anthelmintic resistance. Onderstepoort Journal of Veterinary Research 68, 55–67.Google Scholar
Vatta, A. F., Dzimianski, M., Storey, B. E., Camus, M. S., Moorhead, A. R., Kaplan, R. M. and Wolstenholme, A. J. (2014). Ivermectin-dependent attachment of neutrophils and peripheral blood mononuclear cells to Dirofilaria immitis microfilariae in vitro . Veterinary Parasitology 206, 38–42.Google Scholar
Venco, L., McCall, J. W., Guerrero, J. and Genchi, C. (2004). Efficacy of long-term monthly administration of ivermectin on the progress of naturally acquired heartworm infections in dogs. Veterinary Parasitology 124, 259–268.Google Scholar
Vezzani, D., Carbajo, A. E., Fontanarrosa, M. F., Scodellaro, C. F., Basabe, J., Cangiano, G. and Eiras, D. F. (2011 a). Epidemiology of canine heartworm in its southern distribution limit in South America: risk factors, inter-annual trend and spatial patterns. Veterinary Parasitology 176, 240–249.Google Scholar
Vezzani, D., Mesplet, M., Eiras, D. F., Fontanarrosa, M. F. and Schnittger, L. (2011 b). PCR detection of Dirofilaria immitis in Aedes aegypti and Culex pipiens from urban temperate Argentina. Parasitology Research 108, 985–989.Google Scholar
von Samson-Himmelstjerna, G., Walsh, T. K., Donnan, A. A., Carriere, S., Jackson, F., Skuce, P. J., Rohn, K. and Wolstenholme, A. J. (2009). Molecular detection of benzimidazole resistance in Haemonchus contortus as a tool for routine field diagnosis. Parasitology 136, 349–358.Google Scholar
Wang, D. M., Bowman, D. D., Brown, H. E., Harrington, L. C., Kaufman, P. E., McKay, T., Nelson, C. T., Sharp, J. L. and Lund, R. (2014). Factors influencing US canine heartworm (Dirofilaria immitis) prevalence. Parasites & Vectors 7, 264.Google Scholar
Williamson, S. M., Storey, B., Howell, S., Harper, K. M., Kaplan, R. M. and Wolstenholme, A. J. (2011). Candidate anthelmintic resistance-associated gene expression and sequence polymorphisms in a triple-resistant field isolate of Haemonchus contortus . Molecular and Biochemical Parasitology 180, 99–105.Google Scholar
Wolstenholme, A. J. (2012). Glutamate-gated chloride channels. Journal of Biological Chemistry 287, 40232–40238.Google Scholar
Wolstenholme, A. J. and Kaplan, R. M. (2012). Resistance to macrocyclic lactones. Current Pharmaceutical Biotechnology 13, 873–887.Google Scholar
Wolstenholme, A. J. and Rogers, A. T. (2005). Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology 131, S85–S95.Google Scholar
Wolstenholme, A. J., Fairweather, I., Prichard, R. K., von Samson-Himmelstjerna, G. and Sangster, N. (2004). Drug resistance in veterinary helminths. Trends in Parasitology 20, 469–476.Google Scholar
Yancey, C. B., Hegarty, B. C., Qurollo, B. A., Levy, M. G., Birkenheuer, A. J., Weber, D. J., Diniz, P. and Breitschwerdt, E. B. (2014). Regional seroreactivity and vector-borne disease co-exposures in dogs in the United States from 2004–2010: utility of canine surveillance. Vector-Borne and Zoonotic Diseases 14, 724–732.Google Scholar
Yates, D. M. and Wolstenholme, A. J. (2004). An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis . International Journal for Parasitology 34, 1075–1081.Google Scholar