Keynote Message

Concerns about cases of possible lack of efficacy (LOE) of macrocyclic lactone (ML) heartworm preventives emerged in USA about 15 years ago. However, it was initially unclear as to whether most or all of the LOE cases were due to a lack of compliance with monthly heartworm preventive treatment in endemic regions. However, detailed in vivo clinical studies, with heartworm preventives administered as recommended, have confirmed that ML resistance has emerged in Dirofilaria immitis in North America. The in vivo studies have been supplemented with genome-wide association studies in which ML-resistant populations of the parasite have been compared with susceptible populations in order to determine genetic markers which may be useful for confirming resistance and for epidemiological surveys. The confirmed resistant populations show a number of distinct genetic changes. Most of the confirmed resistance and LOE cases appear to be confined, at present, to the southern regions of the USA where dirofilariasis is hyperendemic. However, it has been shown that dogs can carry resistant parasites to other regions. To date, clear evidence of transmission of resistance in regions out of the southern USA has not been shown. As MLs are the only class of anthelmintics effective for prevention of heartworm disease, and all members of this class (ivermectin, milbemycin oxime, selamectin, moxidectin) are affected by the resistance, the emergence of ML resistance is of particular concern for preventing heartworm disease. Work is ongoing to develop an in vivo microfilarial reduction test as a surrogate for identifying cases of ML resistance, as well as to validate the genetic markers against more isolates confirmed as susceptible or resistant to ML heartworm preventives. Treatments to remove established adult infections, not involving "slow-kill" with ML anthelmintics, such as the use of Immiticide, or anti-Wolbachia therapy using doxycycline, appear to remain effective.

Key References

1.  Hampshire VA. Evaluation of efficacy of heartworm preventive products at the FDA. Veterinary Parasitology. 2005;133:191–195.

2.  Bourguinat C, Keller K, Bhan A, Peregrine AS, Geary TG, Prichard RK.Macrocyclic lactone resistance in Dirofilaria immitis. Veterinary Parasitology. 2011;181:388– 392. DOI: 10.1016/j.vetpar.2011.04.012.

3.  Pulaski CN, Malone JB, Bourguinat C, Prichard R, et al. Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasites & Vectors. 2014;7:494. DOI:10.1186/s13071-014-0494-6.

4.  Bourguinat C, Lee ACY, Lizundia R, Blagburn BL, et al. Macrocyclic lactone resistance in Dirofilaria immitis: failure of heartworm preventives and investigation of genetic markers for resistance.Veterinary Parasitology. 2015;210:167–178. DOI: 10.1016/j.vetpar.2015.04.002.

5.  Geary TG, Bourguinat C, Prichard RK. Evidence for macrocyclic lactone anthelmintic resistance in Dirofilaria immitis. Topics in Companion Animal Medicine. 2011;26:186–192. DOI: 10.1053/j.tcam.2011.09.004.

6.  Wolstenholme AJ, Evans CC, Jimenez PD, Moorhead AR. The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis Parasitology. 2015;142:1249–59. DOI: 10.1017/S003118201500061X.
https://www.cambridge.org/core/journals/parasitology/article/emergence-of-macrocyclic-lactone-resistance-in-the-canine-heartworm-dirofilaria-immitis/D05563B14F5293B43728C39D0F7DF26D