Macrocyclic lactone (ML) heartworm preventives differ meaningfully in efficacy against resistant Dirofilaria immitis isolates, while sharing a broadly favorable safety profile at label doses in dogs and cats without MDR1 mutations.

Ivermectin has the most potent safety-net and adulticidal activity among the MLs, milbemycin oxime has the least, and selamectin and injectable moxidectin fall in between. Drug effects with ivermectin are not enhanced by increasing the dose or shortening the dosing interval; continuous monthly treatment is required to produce the full effect, and the earlier treatment is initiated relative to larval age, the more stunted the worms and the shorter their survival time.Veterinary Para…

Against susceptible isolates, all approved MLs provide high efficacy. A single oral dose of moxidectin (NexGard® PLUS, targeting the minimum label dose of 12–24 µg/kg) achieved 100% efficacy against the susceptible SC-20 isolate in dogs.Parasites and V… The four label-approved feline MLs — ivermectin, selamectin, moxidectin (topical, 1% in combination with imidacloprid), and milbemycin oxime — were each approved based on L3 challenge models.Journal of Feli…

Against ML-resistant isolates, moxidectin at higher doses or with more monthly administrations substantially outperforms ivermectin and milbemycin oxime. Against the ZoeLA resistant strain, oral moxidectin at 24 µg/kg for four or six monthly doses achieved ≥96.1% efficacy, while Heartgard® Plus (ivermectin/pyrantel) and Interceptor® Plus (milbemycin oxime/praziquantel) achieved only 18.7% and 21.2%, respectively — neither significantly different from untreated controls.Parasites and V… Against the JYD-34 resistant isolate, the same moxidectin regimen achieved ≥95.9% efficacy versus 63.9% for ivermectin/pyrantel and 54.6% for milbemycin oxime/praziquantel.Parasites and V…

Dose and duration of moxidectin exposure are the key variables against resistant isolates. Five monthly doses of moxidectin at 6 µg/kg provided 83.3–90.2% efficacy against JYD-34, while five monthly doses at 9 µg/kg provided 94.1–98.8% efficacy. Three monthly doses at 30 µg/kg and 50 µg/kg provided 97.9% and 99.0% efficacy, respectively, and a single dose of 100 µg/kg provided 91.1% efficacy.Parasites and V… This underscores that repeated lower-dose administration is an alternative to single high-dose strategies when facing resistant isolates.Parasites and V…

NexGard® PLUS (moxidectin 12–24 µg/kg + afoxolaner + pyrantel) and Simparica Trio® administered for six monthly doses provided comparable efficacy of 99.5% and 99.8%, respectively, against the JYD-34 resistant isolate, with no significant difference between the two products.Parasites and V… The moxidectin dose in NexGard® PLUS was selected to balance efficacy against resistant isolates with safety in MDR1-deficient dogs; collie dogs homozygous for the MDR1 mutation began showing inconsistent signs of ML toxicity when moxidectin was administered once orally at 150 µg/kg.Research in Vet…

Topical moxidectin (1% formulation) is unique among MLs in maintaining detectable serum levels for weeks after administration, unlike other monthly MLs that are largely eliminated before the next dose.Journal of Feli… In cats, this sustained exposure prevented both antibody seroconversion and pulmonary pathology even when treatments were administered only prior to repeated larval inoculation.Journal of Feli…

At label doses, oral MLs do not cause clinically significant retinal or pupillary light reflex dysfunction in dogs. No association was found between oral ML administration and electroretinogram amplitudes, peak times, baseline pupil size, or chromatic pupillary light reflex.Veterinary Opht… The terminal plasma half-life of moxidectin (25.9 days) is substantially longer than ivermectin (3.3 days) or milbemycin oxime (1.2–3.3 days), but accumulation to toxic levels is not expected at monthly label dosing.Veterinary Opht…

The primary safety risk across all MLs is neurotoxicity in animals with deficient P-glycoprotein function due to ABCB1 mutations. In dogs, the ABCB1-1Δ mutation and in cats the ABCB1 1930_1931delTC mutation impair the blood-brain barrier efflux pump, allowing ML accumulation in the CNS and producing signs including mydriasis, hypersalivation, paresis, tremors, seizures, coma, and death.Journal of the…

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