https://www.cell.com/trends/parasitology/pdf/S1471-4922(04)00204-1.pdf

Drug resistance in nematodes of veterinary importance: a status report

The detection of anthelmintic resistance in nematodes of veterinary importance.

The avermectins are a complex of chemically related agents which exhibit extraordinarily potent anthelmintic activity. They are produced by a novel species of actinomycete, NRRL 8165, which we have named Streptomyces avermitilis. The morphological and cultural characteristics which differentiate the producing organism from other species are described. The avermectins have been identified as a series of macrocyclic lactone derivatives which, in contrast to the macrolide or polyene antibiotics, lack significant antibacterial or antifungal activity. The avermectin complex is fully active against the gastrointestinal nematode Nematospiroides dubius when fed to infected mice for 6 days at 0.0002% of the diet. Fermentation development, including medium modification and strain selection, resulted in increasing the broth yields from 9 to 500 mug/ml.

Avermectins, New Family of Potent Anthelmintic Agents: Producing Organism and Fermentation

Ivermectin is the 22,23-dihydro derivative of avermectin B1, a macrocyclic lactone produced by an actinomycete, Streptomyces avermitilis. It is active at extremely low dosage against a wide variety of nematode and arthropod parasites, apparently by virtue of its action on the mediation of neurotransmission by gamma-aminobutyric acid. It is now in commercial use in various countries for the treatment and control of parasites in cattle, horses, and sheep, and is expected to become available for use in swine and dogs. Since studies with the drug in man are in a preliminary stage, it is not yet known whether ivermectin will be useful in human medicine.

https://science.sciencemag.org/content/sci/221/4613/823.full.pdf

Ivermectin: A potent new antiparasitic agent

Ivermectin and abamectin, members of the avermectin family of compounds, were introduced to the market in the 1980's as a veterinary antiparasitic drug and agricultural pesticide, respectively. Their acceptance and commercial success have been remarkable; both are highly effective and in worldwide use. The efficacy of ivermectin in river blindness has expanded the interest in its use in human medicine. In response to the intense scientific and industrial interest in ivermectin and abamectin and the likelihood that they will be forerunners of an expanding family of drugs, this comprehensive monograph satisfies the need for a review and synthesis of current knowledge about the use of these substances in crop protection as well as in cattle, sheep, swine, horses, dogs, cats, birds, fish, reptiles, and in man. This overview presents chemical, biochemical, and microbiological data, as well as pharmacological, safety, and environmental aspects and covers practical use of the compounds as antiparasitic and pesticide agents, as well as the available safety data that have emerged from the clinical experience with human applications.

Ivermectin and abamectin.

When given to sheep as a single oral dose at 0.1 mg/kg, the B(1a) component of the avermectins caused a reduction of >95% in the numbers of Haemonchus contortus, Ostertagia circumcincta (including inhibited L(4) larvae), Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia oncophora, and Oesophagostomum columbianum. When given to cattle as a single oral dose at 0.1 mg/kg, avermectin B(1a) was >95% effective in reducing the numbers of Haemonchus placei, Ostertagia ostertagi (including inhibited L(4) larvae), T. axei, T. colubriformis, C. oncophora, Cooperia punctata, Oesophagostomum radiatum, and Dictyocaulus viviparus. Avermectin B(1a) was similarly effective, with the exception of a detectable loss in activity against adult C. oncophora, when administered to cattle as a parenteral injection. Some of these ruminant parasites were fully susceptible to dosages of avermectin B(1a) at 0.025 mg/kg, e.g., D. viviparus, O. radiatum, O. ostertagi, and H. contortus. Avermectin B(1a) removed 83 to 100% of Ancylostoma caninum from dogs given a single oral dose of 0.003 to 0.005 mg/kg. The poultry nematodes Capillaria obsignata and immature Ascaridia galli were effectively removed by avermectin B(1a) at 0.05 and 0.1 mg/kg, respectively, but 0.1 mg/kg was not effective for Heterakis gallinarum. Thus, the avermectins would appear to have unprecedented potency and spectrum of biological activity.

Avermectins, new family of potent anthelmintic agents: efficacy of the B1a component.

Eprinomectin: a novel avermectin for use as a topical endectocide for cattle.

To determine whether there is mutual resistance to avermectin and milbemycin anthelmintics, ivermectin and moxidectin sheep drenches were tested against ivermectin-resistant and susceptible isolates of Ostertagia circumcincta and Trichostrongylus colubriformis in sheep. None of the isolates had been exposed to moxidectin previously. The dosage of ivermectin required to remove 95 per cent of the ivermectin-resistant O circumcincta and T colubriformis were 23 times and six times larger, respectively, than the dosages required to remove the same percentage of susceptible isolates. The dosages of moxidectin required to remove 95 per cent of the ivermectin-resistant O circumcincta and T colubriformis were 31 times and nine times larger, respectively, than the dosages required to remove the same percentage of susceptible isolates. It is concluded that the worms resistant to ivermectin were also resistant to moxidectin.

Mutual resistance to avermectins and milbemycins: oral activity of ivermectin and moxidectin against ivermectin-resistant and susceptible nematodes

Paraherquamide, an oxindole alkaloid metabolite of Penicillium paraherquei, was tested against the common gastrointestinal nematode species of sheep at 0.25, 0.5, 1.0, and 2.0 mg/kg, per os. It was highly efficacious (greater than or equal to 98% reduction) as a single oral treatment dosages greater than or equal to 0.5 mg/kg against adult Haemonchus contortus, Ostertagia circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis and Cooperia curticei, and the L4 stage of Cooperia spp. Noteworthy is the fact the isolate of H. contortus used was ivermectin-resistant and the isolate of T. colubriformis used was ivermectin- and benzimidazole-resistant. This suggests a different mode of action for paraherquamide relative to ivermectin and the benzimidazoles. The adult stage of Oesophagostomum columbianum was the dosage-limiting parasite with 79% efficacy recorded at the highest treatment level (2.0 mg/kg). Extrapolation from the O. columbianum response curve suggests a dosage in excess of 4.0 mg/kg would be required to attain 95% efficacy.

C.H. Eary

Papers

Avermectins, new family of potent anthelmintic agents: efficacy of the B1a component.

Eprinomectin: a novel avermectin for use as a topical endectocide for cattle.

Mutual resistance to avermectins and milbemycins: oral activity of ivermectin and moxidectin against ivermectin-resistant and susceptible nematodes

Anthelmintic activity of paraherquamide in sheep.

The anthelmintic efficacy of ivermectin in experimentally infected cattle