A modified larval migration assay for detection of resistance to macrocyclic lactones in Haemonchus contortus, and drug screening with Trichostrongylidae parasites

Kotze, Andrew C.; Jambre, L.F. Le; O’Grady, J.

doi:10.1016/j.vetpar.2006.01.017

Cited by 83 publications

(59 citation statements)

References 14 publications

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“…These results are in full agreement with data from previous in vivo studies, which showed that MOX efficacy is maintained at higher levels than is IVM efficacy as ML resistance develops, as well as in vitro studies on drug-resistant parasitic nematodes, where MOX was more potent than IVM, while EPR was the least potent drug, displaying the highest resistance ratio compared to IVM and MOX (35,(43)(44)(45)(46)(47)(48)(49)(50)(51). These similarities with the ML-selected C. elegans strains clearly show that the model of drug selection pressure in C. elegans can be relevant to studies of the adaptation of parasitic nematodes to ML treatment in the field.…”

Section: Discussionsupporting

confidence: 91%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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cIvermectin and moxidectin are the most widely administered anthelmintic macrocyclic lactones (MLs) to treat human and animal nematode infections. Their widespread and frequent use has led to a high level of resistance to these drugs. Although they have the same mode of action, differences in terms of selection for drug resistance have been reported. Our objective was to study and compare changes occurring upon ivermectin or moxidectin selection in the model nematode Caenorhabditis elegans. C. elegans worms were submitted to stepwise exposure to increasing doses of moxidectin. The sensitivity of moxidectin-selected worms to MLs was determined in a larval development assay and compared with those of wild-type and ivermectin-selected strains. Selection with either ivermectin or moxidectin led to acquired tolerance to ivermectin, moxidectin, and eprinomectin. Importantly, moxidectin was the most potent ML in both ivermectin-and moxidectin-selected strains. Interestingly, this order of potency was also observed in a resistant Haemonchus contortus isolate. In addition, ivermectin-and moxidectin-selected strains displayed constitutive overexpression of several genes involved in xenobiotic metabolism and transport. Moreover, verapamil potentiated sensitivity to ivermectin and moxidectin, demonstrating that ABC transporters play a role in ML sensitivity in ML-selected C. elegans strains. Finally, both ivermectin-and moxidectin-selected strains displayed a dye-filling-defective phenotype. Overall, this work demonstrated that selection with ivermectin or moxidectin led to cross-resistance to several MLs in nematodes and that the induction of detoxification systems and defects in the integrity of amphidial neurons are two mechanisms that appear to affect the responsiveness of worms to both ivermectin and moxidectin.T he broad-spectrum anthelmintic macrocyclic lactones (MLs) are most commonly used in veterinary medicine to treat diseases caused by gastrointestinal nematodes and external parasites in livestock (1, 2). Ivermectin (IVM) was the first ML approved for use in animals and remains today the sole ML registered for use in humans, mainly to treat onchocerciasis through mass chemotherapy. Another ML, moxidectin (MOX), was subsequently commercialized for the veterinary market and is currently being evaluated for possible use against human onchocerciasis (3). Inevitably, the intensive use of these compounds has led to the emergence of resistance in small ruminant, cattle, and some human nematode parasites (4-7). Discovering the mechanisms by which resistance to MLs occurs remains an important challenge today.There is consistent evidence that ATP-binding-cassette (ABC) transporters such as P-glycoproteins (Pgps) play an important role in multidrug resistance (MDR) in many organisms, including several nematode species. Gene expression levels of ABC transporters or allele frequencies were modified after ML selection (8-13), and they are involved in the tolerance of Caenorhabditis elegans (9, 14-16) and parasitic nematodes s...

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Section: Discussionsupporting

confidence: 91%

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Ménez

Alberich

Kansoh

et al. 2016

Antimicrob Agents Chemother

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“…The LC 50 for ivermectin at 24 h (1.8 M) is similar to that for a Cooperia sp. (1.7 M), Haemonchus contortus, and Strongyloides ratti (ϳ1.14 M) (25)(26)(27), although in the last two nematodes, a high-throughput motility assay demonstrated lower IC 50 s (Ͻ0.34 M) (28). Where the filarial nematodes Brugia malayi and Dirofilaria immitis are concerned, the ivermectin IC 50 s ranged from 4.6 to 28.2 M, depending on life stage (27,29).…”

mentioning

confidence: 99%

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

Mounsey

Walton

Innes

et al. 2017

Antimicrob Agents Chemother

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Moxidectin is under consideration for development as a treatment for human scabies. As some arthropods show decreased sensitivity to moxidectin relative to ivermectin, it was important to assess this for Sarcoptes scabiei. In vitro assays showed that the concentration of moxidectin required to kill 50% of mites was lower than that of ivermectin (0.5 M versus 1.8 M at 24 h; P Ͻ 0.0001). This finding provides further support for moxidectin as a candidate for the treatment of human scabies.

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“…Using this method, Rothwell and Sangster (1993) detected resistance to three broad-spectrum anthelminthics in H. contortus. Kotze et al, (2006) used the same principle for larvae of H. contortus migrating through sieves with a mesh size of 20 µm or agarose gels as a method for detecting populations resistant to ivermectin. The differences in larval motility are a basis for another test in which L3 infective larval motility is measured with a micromotility meter (Bennet & Pax, 1987).…”

Section: Methods For Detection Of Anthelminthic Resistancementioning

confidence: 99%

Anthelmintic resistance in parasites of small ruminants: sheep versus goats

et al. 2011

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SummaryAnthelmintic resistance among parasites of sheep and goats has been known to occur for at least four decades. Both species of host have similar genera of nematodes, but the nematodes in goat herds usually develop anthelmintic resistance more rapidly. In vitro tests show higher ED 50 values in goats than in flocks of sheep. Sheep and goats differ in many ways; for example, goats have a higher metabolic rate and require higher dose rates for drugs. The immune system of goats is also different. Additionally, these animals are reared under different management systems, i.e. sheep graze pastures and goats browse bushes, and lambing/kidding periods are different. Most anthelmintics used in goats have not been licensed for this animal species, and correct dose rates have rarely been experimentally determined. Possible explanations for such differences are discussed.

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A modified larval migration assay for detection of resistance to macrocyclic lactones in Haemonchus contortus, and drug screening with Trichostrongylidae parasites

Cited by 83 publications

References 14 publications

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

Acquired Tolerance to Ivermectin and Moxidectin after Drug Selection Pressure in the Nematode Caenorhabditis elegans

In Vitro Efficacy of Moxidectin versus Ivermectin against Sarcoptes scabiei

Anthelmintic resistance in parasites of small ruminants: sheep versus goats

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