Macrocyclic Lactones and Dirofilaria immitis Microfilariae

Abstract

Although there has been extensive veterinary focus on both the effectiveness of macrocyclic lactones for heartworm prevention in dogs and their adulticidal effects, little attention has been directed to their effects on heartworm microfilariae. With routine use of macrocyclic lactones, in some cases knowingly, in dogs with existing heartworm infections, veterinarians should recognize the benefits, and possible complications, arising from this behavior. Macrocyclic lactones remain our only class of heartworm prevention available, and preserving their effectiveness is critical. Drugs in this class share common traits: there are currently no Food and Drug Administration-approved microfilaricides in the US marketplace, but because all macrocyclic lactones have microfilaricidal properties (to varying degrees), they are widely used by veterinarians for this purpose. Originally formulated to be used in dogs without patent heartworm infections, all have been demonstrated as safe to use at label doses, and higher, in microfilaremic dogs. All of the product labels indicate that dogs should be tested for heartworm infection before starting preventive therapy. Although microfilaricidal, microfilariae reduction may take many months to occur, and some dogs may never clear. The effects of macrocyclic lactones on the numbers of circulating microfilariae may be due to several different underlying causes (i.e., direct effect on the nervous system, affecting stages found in the uterus of the female worms), but the details of all mechanisms by which microfilariae are killed and/or cleared in dogs treated with macrocyclic lactones have not yet been fully elucidated. Some 10% to 20% of heartworm-infected dogs that begin monthly heartworm preventive treatment without adulticide therapy will have the continued and persistent presence of circulating microfilariae, and the concern is that this may be selecting for resistance to these molecules. The veterinary literature now includes evidence of increased genotypic homozygosity in specific dogs in one area of the country for a marker gene associated with macrocyclic lactone resistance in nematodes of ruminants. This article will review the biology of microfilariae, as well as the evolution of diagnostic testing for heartworm infection. The effects of macrocyclic lactones on microfilaria behavior and survival will be discussed, as well as the use and effects of macrocyclic lactones in microfilaremic dogs, with or without adulticide treatment. The effect of doxycycline on heartworm microfilariae, optimal testing methodologies, and verification of effective clearance of microfilariae after adulticide treatment and microfilaricidal therapy so that dogs do not remain a potential source of infection for other dogs are all covered.