Managing anthelmintic resistance in Parascaris spp.: A modelling exercise

Leathwick, Dave M.; Sauermann, Christian W.; Geurden, Thomas; Nielsen, Martin K.

doi:10.1016/j.vetpar.2017.03.026

Cited by 23 publications

(18 citation statements)

References 33 publications

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“…In the case of Cry5B plus tribendimidine or pyrantel, our high dose combination data suggest that the synergy might have a positive effect on delaying resistance since hookworms are obligate parasites—complete elimination from the host blocks the reproductive cycle. Our high-dose results with Cry5B and nAChR agonists are consistent with recent modeling work that predicts the benefits of combining two anthelmintics at high efficacy doses with regards to delaying resistance [ 69 , 70 ].…”

Section: Discussionsupporting

confidence: 89%

In vivo and in vitro studies of Cry5B and nicotinic acetylcholine receptor agonist anthelmintics reveal a powerful and unique combination therapy against intestinal nematode parasites

Miller

Zhang

et al. 2018

PLoS Negl Trop Dis

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BackgroundThe soil-transmitted nematodes (STNs) or helminths (hookworms, whipworms, large roundworms) infect the intestines of ~1.5 billion of the poorest peoples and are leading causes of morbidity worldwide. Only one class of anthelmintic or anti-nematode drugs, the benzimidazoles, is currently used in mass drug administrations, which is a dangerous situation. New anti-nematode drugs are urgently needed. Bacillus thuringiensis crystal protein Cry5B is a powerful, promising new candidate. Drug combinations, when properly made, are ideal for treating infectious diseases. Although there are some clinical trials using drug combinations against STNs, little quantitative and systemic work has been performed to define the characteristics of these combinations in vivo.Methodology/Principal findingsWorking with the hookworm Ancylostoma ceylanicum-hamster infection system, we establish a laboratory paradigm for studying anti-nematode combinations in vivo using Cry5B and the nicotinic acetylcholine receptor (nAChR) agonists tribendimidine and pyrantel pamoate. We demonstrate that Cry5B strongly synergizes in vivo with both tribendimidine and pyrantel at specific dose ratios against hookworm infections. For example, whereas 1 mg/kg Cry5B and 1 mg/kg tribendimidine individually resulted in only a 0%-6% reduction in hookworm burdens, the combination of the two resulted in a 41% reduction (P = 0.020). Furthermore, when mixed at synergistic ratios, these combinations eradicate hookworm infections at doses where the individual doses do not. Using cyathostomin nematode parasites of horses, we find based on inhibitory concentration 50% values that a strongylid parasite population doubly resistant to nAChR agonists and benzimidazoles is more susceptible or “hypersusceptible” to Cry5B than a cyathostomin population not resistant to nAChR agonists, consistent with previous Caenhorhabditis elegans results.Conclusions/SignificanceOur study provides a powerful means by which anthelmintic combination therapies can be examined in vivo in the laboratory. In addition, we demonstrate that Cry5B and nAChR agonists have excellent combinatorial properties—Cry5B combined with nAChR agonists gives rise to potent cures that are predicted to be recalcitrant to the development of parasite resistance. These drug combinations highlight bright spots in new anthelmintic development for human and veterinary animal intestinal nematode infections.

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Section: Discussionsupporting

confidence: 89%

In vivo and in vitro studies of Cry5B and nicotinic acetylcholine receptor agonist anthelmintics reveal a powerful and unique combination therapy against intestinal nematode parasites

Miller

Zhang

et al. 2018

PLoS Negl Trop Dis

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“…Over half of the respondents reported that foals were ≤6 weeks of age when first dosed with an anthelmintic; however, anthelmintic therapy is not recommended in foals <2 months of age as there will be few adult Parascaris or cyathostomin worms present and larvae, including migrating stages, will predominate. For Parascaris , ML drugs, if active against larval stages, will reduce refugia and may increase selection pressure for AR . In the current study, MLs in interval treatment programmes were extensively used by respondents for foals which may be associated with the development of resistance to ivermectin in Parascaris , which has been described recently to occur on Australian stud farms …”

Section: Discussionmentioning

confidence: 83%

A questionnaire study of parasite control in Thoroughbred and Standardbred horses in Australia

Wilkes

Heller

Raidal

et al. 2020

Equine Veterinary Journal

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Background Information regarding parasite control practices currently used on Thoroughbred and Standardbred studs in Australia is lacking. Anthelmintic resistance (AR) is a global problem which has implications for equine health and welfare. Objectives To identify parasite control practices currently used on horse studs in Australia and investigate the frequency of use of management factors that have been associated with the likelihood of promoting or delaying AR. Study design Questionnaire study of equine parasite control on Thoroughbred and Standardbred studs in Australia. Methods An online questionnaire was emailed to 300 studs in Australia. Information obtained included property details, grazing management, anthelmintic use, non‐chemotherapeutic parasite control practices, use of faecal egg counts (FECs) and perceptions of AR. Results Seventy‐five completed questionnaires were received (25% response rate). Macrocyclic lactones (MLs) were the most commonly administered anthelmintics in mares and foals and less than 5% of respondents used targeted treatment regimens. The implementation of pasture hygiene practices was variable. The majority of respondents (97%) considered AR to be important; however, few respondents were aware of the use of FEC reduction tests for monitoring of drug efficacy. Main limitations The potential for nonresponse bias was the main limitation of this study. Conclusions Parasite control strategies on Australian stud farms remain over‐reliant on anthelmintic use. The frequent use of MLs is of concern for the increased selection pressure for AR. There is a lack of awareness of the importance of non‐chemotherapeutic strategies in integrated approaches to parasite control aimed at delaying the development of AR. This study highlights the need for greater veterinary involvement in the implementation of more sustainable parasite control practices with greater emphasis placed on surveillance through FEC testing.

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“…It has been recently suggested that an increased drug variability associated with suboptimal drug concentrations may have implications on the development of IVM resistance [ 11 ]. However, this data is based in modeling studies in veterinary medicine, and still more studies are needed to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, it has been evaluated in co-administration with albendazol for the treatment of soil transmitted helminthiasis (STH) showing an increased efficacy compared to albendazole stand-alone against Trichuris trichiura [ 7 , 8 ], therefore increasing the feasibility of achieving transmission interruption, as shown in modelling exercises [ 9 ]. Due to its alternative mechanism of action, the addition of IVM to a benzimidazole based regimen lowers the threat of emergence of drug resistance [ 10 ], as suggested in modelling studies conducted in veterinary medicine [ 11 ]. Furthermore, the recent finding that the endectocide effect of IVM reduces the survival of Anopheles mosquitoes that feed on an IVM treated person after a single standard oral dose, supports the integration of IVM-based interventions for the control of multiple tropical infectious diseases [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

et al. 2018

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Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.Trial registrationClinicalTrials.gov NCT03173742.

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Managing anthelmintic resistance in Parascaris spp.: A modelling exercise

Cited by 23 publications

References 33 publications

In vivo and in vitro studies of Cry5B and nicotinic acetylcholine receptor agonist anthelmintics reveal a powerful and unique combination therapy against intestinal nematode parasites

In vivo and in vitro studies of Cry5B and nicotinic acetylcholine receptor agonist anthelmintics reveal a powerful and unique combination therapy against intestinal nematode parasites

A questionnaire study of parasite control in Thoroughbred and Standardbred horses in Australia

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

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