Detection of ivermectin resistance by a larval development test—Back to the past or a step forward?

Dolinská, Michaela Urda; Königová, Alžbeta; Letková, V.; Molnár, Ladislav; Várady, Marián

doi:10.1016/j.vetpar.2013.07.043

Cited by 29 publications

(31 citation statements)

References 28 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 test results were considered significant when p≤0.05. The anthelmintic resistance degree was expressed as a resistance factor (RF) and was calculated as the values of LC 50 and LC 99 of the resistant isolates divided by the respective values of the susceptible isolates (Dolinská et al 2013), resulting in RF50 and RF99. The results of the LDT for the determination of the LC 50 and LC 90 were analyzed statistically by the Probit procedure of the SAS software.…”

Section: Discussionmentioning

confidence: 99%

Target selected treatment with levamisole to control the development of anthelmintic resistance in a sheep flock

et al. 2015

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Levamisole phosphate, chosen based on its 100 % efficacy demonstrated by a previous fecal egg count reduction test (FECRT), was used as the exclusive anthelmintic treatment in the Embrapa Southeast Livestock sheep flock from 2009 to 2014 in a target selected treatment scheme. In the present study, the effectiveness of this nematode control scheme was evaluated after 5 years by FECRT, larval development test (LDT), and a molecular test to assess the development of levamisole resistance in Haemonchus contortus. Animals were submitted to treatments with albendazole, levamisole, closantel, ivermectin, moxidectin, and monepantel. Eggs per gram of feces (EPG) counts and fecal cultures were performed, and anthelmintic efficacy was calculated by the RESO 4.0 program. The helminths of the flock (GIN Embrapa2014) were compared to susceptible (McMaster) and resistant (Embrapa2010) H. contortus isolates in the LDT to estimate the LC50 and LC90 of levamisole and in a molecular test to evaluate the 63-bp indel in the acr8 gene associated with levamisole resistance. In the FECRT, parasites were susceptible to monepantel (99.6 %) and closantel (98.3 %), but resistant to moxidectin (93.8 %), levamisole (70.4 %), ivermectin (48.1 %), and albendazole (0 %). In the coproculture on D14, and the control group presented 80 % H. contortus and 20 % Trichostrongylus sp., while in the monepantel group L1 were observed as well as Oesophagostomum sp. L3. LDT and resistance factors provided good separation between susceptible and resistant parasites. The genotypic frequencies of the 63-bp insertion in the acr8 gene in H. contortus were 11.9, 6.7, and 0 % in GIN Embrapa2014, Embrapa2010, and McMaster isolates, respectively. After 5 years of exclusive use, the nematodes developed resistance to levamisole, detected by FECRT and by increase in LC50 and LC90 for levamisole in the LDT. The 63-bp indel was not confirmed as a molecular marker of levamisole resistance in our isolates. The target selected treatment scheme was effective to control helminths in the sheep flock for 5 years, when levamisole's inefficacy was perceived because of no change in the clinical situation of treated animals. Through this scheme, it was possible to promote reversion towards susceptibility or increase of efficacy for other chemical classes. Thus, this is a valid recommendation to control worms and to delay the development of resistance, preserving other anthelmintic classes for future use.

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“…The present version of the micromotility test is thus unsuitable for measuring levels of resistance under fi eld conditions. As it was demonstrated in the previous studies, the use of avermectin analogs (eprinomectin, ivermectin aglycone) signifi cantly increased the ability of the in vitro tests to differentiate between IVM-resistant and -susceptible isolates (Dolinská et al, 2013). These analogues produce 2 -3 times higher RR compared to IVM, which was not a case of our study in MMT.…”

Section: Discussionmentioning

confidence: 46%

“…The LMIT is suitable only for H. contortus, which seriously limits the utility of this test for monitoring resistance in fi eld surveys. The RFs obtained by LMITs are signifi cantly lower than those obtained by larval development tests (Dolinská et al, 2012(Dolinská et al, , 2013, which may indicate a lower sensitivity of the LMIT for the detection of IVM-resistant parasites. Additionally the cost of the microtiter plates (Millipore), in which the LMIT is performed, is considerable.…”

Section: Discussionmentioning

confidence: 89%

“…Several in vitro tests have been described for testing the anthelmintic activity of MLs for the detection of resistance. These tests depend on an assessment of paralysis in larvae (Gill et al, 1991;Kotze et al, 2006) or of inhibited larval development (Coles et al, 1988;Hubert & Kerboeuf, 1992;Dolinská et al, 2013). A micromotility meter has also been developed to evaluate the motility of various larval and adult nematodes as a criterion of paralysis in the absence or presence of anthelmintics, based on a quantitative measurement of motility by photo-detectors (Folz et al, 1987a).…”

Section: Introductionmentioning

confidence: 99%

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Comparison of two in vitro methods for the detection of ivermectin resistance in Haemonchus contortus in sheep

et al. 2016

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SummaryGastrointestinal parasitic nematodes in sheep cause severe economic losses. Anthelmintics are the most commonly used drugs for prophylaxis and therapy against parasitic helminths. The problem of drug resistance has developed for all commercially available anthelmintics in several genera and classes of helminths. In vitro and in vivo tests are used to detect anthelmintic resistance. Two in vitro methods (larval migration inhibition test and micromotility test) for the detection of ivermectin (IVM) resistance were compared using IVM-resistant and IVM-susceptible isolates of Haemonchus contortus. The degree of resistance for each test was expressed as a resistance factor (RF). The micromotility test was more sensitive for quantitatively measuring the degree of resistance between susceptible and resistant isolates. The RFs for this test for IVM and eprinomectin ranged from 1.00 to 108.05 and from 3.87 to 32.32, respectively.

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Detection of ivermectin resistance by a larval development test—Back to the past or a step forward?

Cited by 29 publications

References 28 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

Target selected treatment with levamisole to control the development of anthelmintic resistance in a sheep flock

Comparison of two in vitro methods for the detection of ivermectin resistance in Haemonchus contortus in sheep

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