Macrocyclic lactones were introduced in the early 1980s (first representative was ivermectin) and since then several veterinary parasites have developed resistance or tolerance to this chemical class, e.g. heartworms of dogs and cats, several gastrointestinal roundworms (nematodes) of livestock and horses, cattle ticks, etc. The most relevant resistant species are:

See below for DETAILS.

There are reports on other parasites that have developed resistance to macrocyclic lactones, but so far, such cases remain restricted to limited regions and/or do not represent a global threat for domestic animals yet, and thus are not particularly analyzed in this article. Recommended measures to handle these cases are more or less the same as for the most critical ones: Rotation to chemical classes with different modes of action that remain effective and/or Integrated Pest Management. The following cases can be mentioned:

Multiresistance is spreading. In 2010 one sheep property was reported in Brazil where gastrointestinal roundworms were simultaneously resistant to 7 different chemical classes (levamisole, benzimidazoles, macrocyclic lactones, nitroxinil, disophenol, trichlorfon and closantel). In 2021 a study in cattle farms in Brazil reported multiresistance of gastrointestinal roundworms to 4 chemical classes of anthelmintics in 95% of the twenty farms investigated: macrocyclic lactones, levamisole, benzimidazoles, and closantel.

Ivermectin is the most used veterinary antiparasitic worldwide. There are thousands of generic brands used in livestock, horses and pets. It is used in all imaginable formulations: pour-ons, feed additives, drenches and injectables for livestock, oral pastes and gels for horses, tablets, pills, etc, oral suspensions and injectables for pets, etc. It is both used alone or in combination with many other active ingredients.

Other macrocycic lactones used in veterinary medicine are abamectin, doramectin (not used in pets), eprinomectin, milbemycin oxime (used only in pets), moxidectin, and selamectin (used only in pets)

It is a general rule that compounds that belong to the same chemical class show so-called cross-resistance among them, i.e., if a parasite develops resistance to one compound, it will be more or less resistant to other compounds of the same chemical class.

Parasites with resistance to macrocyclic lactones

  • Heartworms (Dirofilaria immitis) in dogs

    • OCCURRENCE. Resistant cases on heartworm microfilariae to ivermectin and other macrocyclic lactones have been repeatedly reported in the USA since the mid 2010s, mainly in the South and Southeast. This means that dogs treated with an approved preventative became infested with adult worms, i.e. that microfilariae in their blood were able to develop to adult worms. Basically all macrocyclic lactones are affected, (so-called cross-resistance) although different formulations (e.g. for oral, injectable or topical administration) may show different degrees of tolerance, and some may still be active, e.g. because the blood levels they achieve may be higher and/or last longer after a single administration. Little is now yet about how many dogs are affected by such resistance in the concerned regions.
    • OUTLOOK. Resistance will not disappear, as it always happened before with resistance. Since it has taken very long to appear (about 30 years) some specialists believe that spreading and strengthening may be relatively slow. Although no cases of heartworm resistance to ivermectin have been reported in cats so far, it's probably only a matter of time for this to happen in affected regions.
    • RECOMMENDED MEASURES. Compliance, i.e. strictly following the use recommendations are crucial, because incorrect use is the most frequent cause of product failure, and because chronic under-dosing may favor resistance development. Since heartworm microfilariae are transmitted by mosquitoes, exposure of dogs to mosquitoes should be diminished, either by avoiding places where mosquitoes are particularly abundant, or by reducing the chances of contact of the dogs with the mosquitoes (e.g. using mosquito nets, repellents, etc.).
    • ALTERNATIVE PARASITICIDES for ROTATION. Unfortunately there are no real chemical alternatives to macrocyclic lactones for the chemical prevention of heartworm microfilariae.
  • Gastrointestinal roundworms in catte, sheep and goats

  • Cattle ticks: Rhipicephalus (Boophilus) spp.

    • OCCURRENCE. Resistance of R. microplus to ivermectin has been reported in most countries in Latin America (e.g. in Argentina, Brazil, Mexico and Uruguay) and also in India. For other related species resistance to ivermectin has been reported e.g. in Egypt (R. annulatus) and South Africa (R. decoloratus). The problem seems to be just beginning. To our knowledge no ivermectin resistance has been reported yet for R. australis in Australia or other parts of Asia. Cross-resistance with all other macrocyclic lactones used in livestock must be assumed (abamectin, doramectin, eprinomectin, moxidectin).
    • OUTLOOK. Problems are likely to worsen everywhere. Resistance will continue to spread and to strengthen, particularly where macrocyclic lactones are massively used to control these ticks. 
    • RECOMMENDED MEASURES. The most reasonable measure is to switch to Integrated Pest Management (IPM) and/or to implement whatever preventative measures that reduce the use of any chemicals (see the article on Rhipicephalus (Boophilus) in this site). Where alternative chemicals of another chemical classes are still working against these ticks, rotation is usually a good option, i.e. to stop using macrocyclic lactones and to use other products with active ingredients of those still effective chemical classes during several years.
    • ALTERNATIVE PARASITICIDES for ROTATION. There are several chemical classes of parasiticides that are effective for the control of cattle ticks. However, most of them are ectoparasiticides that will not control gastrointestinal roundworms, and they are not available for drench or injectable administration, but only for topical use (dipping, pour-on, spraying, etc.).
      • Amitraz. Amitraz is only available for dipping or spraying. However, resistance of cattle ticks to amitraz is already quite frequent worldwide  and spreading, following its increased use as an alternative to synthetic pyrethroids. It controls only ticks as well as lice and mites to some extent. It does not control flies or gastrointestinal roundworms.
      • Fipronil. Fipronil is approved for the control of cattle ticks in some countries (e.g. Latin America and India) but in others not (e.g. Australia, USA). It is available only as a pour-on. Usually it has a very long withholding period of at least 12 weeks. It does not control gastrointestinal roundworms. However, resistance of cattle ticks to fipronil has also been reported in in Latin American countries (e.g. Argentina, Brazil, Mexico, Uruguay) and in India.
      • Fluazuron. Fluazuron is available for cattle tick control in most countries where these ticks are a problem. However, it is very specific for ticks and does not control other external parasites or gastrointestinal roundworms. It is available only as a pour-on. Some cases of resistance of cattle ticks to fluazuron have been already reported in Brazil.
      • Organophosphates (chlorpyrifos, coumaphos, diazinon, ethion, dichlorvos, etc.). In the past (up to the 1990s) organophosphates were used a lot worldwide for tick control. They were progressively abandoned for safety reasons when less toxic compounds were introduced. Availability today is strongly reduced because many products have been banned by the authorities or discontinued by the manufacturers. Organophosphates are used mainly for dipping or spraying. Most organophosphates are also effective against external parasites other than ticks (lice, mites, flies, etc.). Used topically they are not effective against gastrointestinal roundworms. Resistance of cattle ticks to organophosphates was well established before they were replaced and it must be assumed that it remains present in many regions.
      • Synthetic pyrethroids (e.g. cypermethrin, deltamethrin, permethrin, etc.). Synthetic pyrethroids are only available for topical use (dipping, spraying, pour-on). They control numerous external parasites (ticks, mites, lice, flies, etc.), but are ineffective against gastrointestinal roundworms. Following their massive use worldwide from the 1980s onwards, resistance of cattle ticks and other external parasites to synthetic pyrethroids is strongly established worldwide and is often extremely high, making them completely useless.
  • Gastrointestinal roundworms in horses

    • Cyathostomins = small strongyles = small red worms a group of about 50 species of gastrointestinal roundworms that affect horses, donkeys and other equids worldwide.
    • Horse roundworm (Parascaris equorum).
    • OCCURRENCE. Tolerance of cyathostomins to macrocyclic lactones, manifested as a low but significant worm egg output after treatment (determined after fecal egg counts) is not yet widespread, but has been already reported in Europe (e.g. in the UK, Germany, Italy), the USA, and Brazil. Resistance of Parascaris equorum to macrocyclic lactones has also been reported in numerous countries. Cross-resistance among all macrocyclic lactones used in horses (mainly abamectin, doramectin, ivermectin, moxidectin) must be assumed.
    • OUTLOOK. Problems are likely to worsen everywhere. Resistance will continue to spread and to strengthen, because little is done in most regions to reduce their use and to encourage non-chemical control and prevention.
    • RECOMMENDED MEASURES. The most recommended measure is to switch to Integrated Pest Management (IPM) and/or to implement whatever preventative measures that reduce the use of any chemicals. Where alternative chemicals of other chemical classes are still working against these worms, rotation is usually a good option, i.e. to stop using macrocyclic lactones and to use other products of still effective chemical classes during several years. However, these worms have already developed resistance to some of the alternative chemical classes as well.
      • Benzimidazoles (e.g. febantel, fenbendazole, oxibendazole, mebendazole, etc.). Resistance of cyathostomins to benzimidazoles is already very frequent and high as well. In a survey from 2009, resistance to benzimidazoles was confirmed in >80% of the investigated yards in UK and Germany. It is known to be also quite frequent in the US, Australia, India and in many other countries, including Latin America.
      • Tetrahydropyrimidines (mainly pyrantel). They are not effective against some important gastrointestinal worm species (narrow spectrum of activity). Cases of resistance of cyathostomins to pyrantel have been reported in Europe and the USA, but so far it is much less frequent and severe than resistance to benzimidazoles. Cases of resistance of Parascaris spp to pyrantel have been reported in Sweden (2018). For the time being resistance of these horse parasites to pyrantel seems not to be an issue in most regions.
      • Piperazine derivatives. Piperazine is a narrow-spectrum anthelmintic used in pets and livestock effective against some gastrointestinal roundworms (particularly against ascarids, e.g. Parascaris equorum).
      • Other anthelmintics such as levamisole and closantel that may still control these worms are not available for horses in most countries.

Where available, follow national or regional recommendations for delaying resistance development or for handling already confirmed cases.

To evaluate resistance problems it must also be considered that innovation in the field of livestock parasiticides has strongly decreased in the last decades.

This means that the likelihood that new chemical classes with new modes of action against resistant parasites become available is quite slim. The reason is that, in the last decades, almost all animal health companies have focused their R&D investments in the much more profitable business of pet parasiticides. As a consequence, regarding resistance management in livestock and horses, almost nothing really new (i.e. with a new mode of action) has been introduced in the last decades: all new products (mostly new formulations or mixtures) have been basically "more of the same".

If you want to learn more about resistance, read one of the following articles in this site:

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