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

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

doi:10.1186/preaccept-5912484341258228

Cassan N Pulaski , Thomas R Klei + Show 13 more

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https://doi.org/10.1186/preaccept-5912484341258228

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Abstract

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

Highlights

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
LSU 10a ivermectin (12 μg/kg, monthly for 6 months) LSU 10b untreated control LSU 10-II ivermectin (24 μg/kg, monthly for 3 months) LSU 13a ivermectin (12 μg/kg, monthly for 6 months) LSU 13b untreated control We propose that we have successfully isolated two strains from proven cases of resistance in client-owned dogs in Louisiana that can be used to further study and characterize the emergence of ML resistance by D. immitis
ML drugs for livestock, protected against heartworms, intestinal helminthes and other internal parasites with very striking benefits for dogs [26,27]. This was soon followed by controlled pharmaceutical company experimentation leading to Food and Drug Administration (FDA) approval and marketing in the late 1980’s of current ML drug formulations at the very low dose levels used for prevention of canine heartworms [26,27]. 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

Summary

Introduction

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. Anecdotal reports of increasing LOE cases from the veterinary community in heartworm endemic areas, pharmaceutical firms initiated reimbursement programs in 2004 to cover costs of treatment of LOE cases if owners and their veterinarians could document full compliance with recommended preventive treatment practices. The objectives of studies reported here are to record results of: 1) a 2009 survey to document the experience of veterinarians in Louisiana on potential emerging ML resistance by D. immitis, and 2) establishment of ML resistant isolates of D. immitis in experimentally infected laboratory dogs using L3 raised in Aedes aegypti fed on microfilaremic blood from 2 dogs with a ‘high index of suspicion of resistance’ Several research efforts were initiated, investigating the spatio-temporal scale and dynamics of LOE reports [2], potential in vitro indicators of resistance [3,4], possible genetic markers of resistance via genomic studies [5,6,7,8,9,10] and in vivo experiments, the gold standard, to establish confirmed resistant strains from canine field cases in the laboratory [11,12].

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