Biomaterial Database

Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. 2014

Cassan N Pulaski, and John B Malone, and Catherine Bourguinat, and Roger Prichard, and Timothy Geary, and Danielle Ward, and Thomas R Klei, and Tal Guidry, and George 'Bud' Smith, and Brooke Delcambre, and Jonathan Bova, and Jenny Pepping, and James Carmichael, and Rudolf Schenker, and Romain Pariaut

School of Veterinary Medicine, Louisiana State University and Louisiana Animal Disease Diagnostic Laboratory, Baton Rouge, 70803, LA, USA. cpulaski@vetmail.lsu.edu.

BACKGROUND Strains of Dirofilaria immitis suspected of lack of efficacy (LOE) to macrocyclic lactone (ML) preventive drugs have been increasingly reported in dogs by practicing veterinarians since 2005 in the Lower Mississippi Delta region. If proven, and not controlled in the early stages, the emergence of ML drug resistance threatens to become a widespread problem in the US that may limit the effectiveness of current preventive drug treatment methods. METHODS To validate practice reports, a statewide survey of Louisiana veterinarians was done to define the extent of the problem and identify focal 'hotspots' of reported ML LOEs using Geographic Information Systems (GIS) methods. The present study then utilized microfilariae (Mf) from two canine field cases from different state locations that fit criteria for a high index of suspicion of LOE against heartworms by ML drugs. Blood containing Mf from the canine field cases was used to infect and produce L3 in Aedes aegypti for experimental infection of two groups of dogs, each of which contained two laboratory dogs, one treated with prophylactic ivermectin (12 μg/kg) monthly for 6 months at twice the label dose (6 μg/kg), and one untreated control. RESULTS Both treated and untreated dogs from Group I and Group II developed patent D. immitis infections by 218 DPI and 189 DPI, respectively, as evidenced by a positive occult heartworm antigen test and microfilaremia by the Knott's test. Mf counts gradually increased post-patency in test and control dogs. Infective larvae raised from microfilariae from the treated Group I dog were used to successfully establish a second generation isolate, confirming heritability of resistance in the face of a monthly ivermectin challenge dose of 24 μg/kg, given monthly for 3 months. CONCLUSIONS These experimental infection studies provide in vivo evidence of the existence of ML drug resistance in dogs infected by D. immitis L3 from suspect field LOE cases in the Lower Mississippi Delta. Results encourage further work on mechanisms underlying the emergence of ML resistance in D. immitis and development of evidence-based resistance management strategies for heartworm preventives in order to extend the useful life of current drugs.

UI	MeSH Term	Description	Entries
D007559	Ivermectin	A mixture of mostly avermectin H2B1a (RN 71827-03-7) with some avermectin H2B1b (RN 70209-81-3), which are macrolides from STREPTOMYCES avermitilis. It binds glutamate-gated chloride channel to cause increased permeability and hyperpolarization of nerve and muscle cells. It also interacts with other CHLORIDE CHANNELS. It is a broad spectrum antiparasitic that is active against microfilariae of ONCHOCERCA VOLVULUS but not the adult form.	Eqvalan,Ivomec,MK-933,Mectizan,Stromectol,MK 933,MK933
D008145	Louisiana	State bounded by Arkansas on the north, by Mississippi on the east, the Gulf of Mexico on the south and Texas on the west.
D008297	Male		Males
D008922	Mississippi	State bounded on the north by Tennessee, on the east by Alabama, on the south by Louisiana and Gulf of Mexico, and on the west by Arkansas and Louisiana.
D004183	Dirofilaria immitis	A filarial parasite primarily of dogs but occurring also in foxes, wolves, and humans. The parasite is transmitted by mosquitoes.	Dog Heartworm,Dirofilaria immitides,Dog Heartworms,Heartworm, Dog,Heartworms, Dog,immitis, Dirofilaria
D004184	Dirofilariasis	Infection with nematodes of the genus DIROFILARIA, usually in animals, especially dogs, but occasionally in man.	Heartworm Disease,Dirofilariases,Disease, Heartworm
D004195	Disease Models, Animal	Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases.	Animal Disease Model,Animal Disease Models,Disease Model, Animal
D004283	Dog Diseases	Diseases of the domestic dog (Canis familiaris). This term does not include diseases of wild dogs, WOLVES; FOXES; and other Canidae for which the heading CARNIVORA is used.	Canine Diseases,Canine Disease,Disease, Canine,Disease, Dog,Diseases, Canine,Diseases, Dog,Dog Disease
D004285	Dogs	The domestic dog, Canis familiaris, comprising about 400 breeds, of the carnivore family CANIDAE. They are worldwide in distribution and live in association with people. (Walker's Mammals of the World, 5th ed, p1065)	Canis familiaris,Dog
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug