Phenotypic Evidence of Emerging Ivermectin Resistance in Onchocerca volvulus

Onchocerciasis, commonly known as river blindness, is caused by the filarial nematode Onchocerca volvulus and is transmitted by a blackfly vector. Over 37 million people are thought to be infected, with over 90 million at risk. Infection predominantly occurs in sub-Saharan Africa. Foci also exist in the Arabian Peninsula and Central and South America. Ivermectin, the sole pharmaceutical available for mass chemotherapy, has been used on a community basis for annual or semi-annual treatment since 1987. Multiple treatments with ivermectin kill the microfilariae that are responsible for the pathology of onchocerciasis. More importantly, ivermectin suppresses the reproductive activity of the adult female worms, thus delaying or preventing the repopulation of the skin with new microfilariae and thereby reducing transmission. This study extends earlier reports of sub-optimal responses to ivermectin by examining repopulation levels of microfilaria one year after treatment, worm burdens per nodule, the age structure of adult female worms recovered from nodules, and the reproductive status of adult female worms 90 days after ivermectin treatment. In some communities which have shown a pattern of sub-optimal response to treatment, the data is consistent with an emergence of ivermectin non response or resistance manifested by a loss of the effect of ivermectin on the suppression of parasite reproduction

Identification of the amino-acetonitrile derivative monepantel (AAD 1566) as a new anthelmintic drug development candidate

Anthelmintic resistance has become a global phenomenon in gastro-intestinal nematodes of farm animals, including multi-drug resistance against the three major classes of anthelmintics. There is an urgent need for an anthelmintic with a new mode of action. The recently discovered amino-acetonitrile derivatives (AADs) offer a new class of synthetic chemicals with anthelmintic activity. The evaluation of AADs was pursued applying in vitro assays and efficacy and tolerability studies in rodents, sheep, and cattle. Amongst various suitable compounds, AAD 1566 eliminated many tested pathogenic nematode species, both at larval and adult stages, at a dose of 2.5 mg/kg bodyweight in sheep and 5.0 mg/kg bodyweight in cattle. The same doses were sufficient to cure animals infected with resistant or multi-drug-resistant nematode isolates. These findings, complemented by the good tolerability and low toxicity to mammals, suggest that AAD 1566, monepantel, would be a suitable anthelmintic drug development candidate

Monepantel y control de Haemonchus contortus en ovinos. Evaluación de la eficacia luego de cuatro años de uso en condiciones de refugio reducido

La resistencia de los nematodes ovinos a los antihelmínticos está generalizada en el centro-norte de la Argentina y la mayor preocupación actual es el aumento y dispersión de Haemonchus contortus portando alelos con resistencia múltiple. Actualmente los únicos antihelmínticos de amplio espectro sin documentación de resistencia en nuestro país son el monepantel y derquantel. Con la primera de estas drogas ya se han registrado casos de resistencia en Uruguay y Brasil por lo que es crítica la información actualizada sobre la actividad en el campo de estos antihelmínticos. Este estudio informa sobre la eficacia del monepantel luego de cuatro años de uso de esta droga sobre un aislamiento de H. contortus con resistencia múltiple (lactonas macrociclicas, closantel, levamisol y benzimidazoles) y bajo condiciones de refugio reducido. Se realizaron dos experiencias A y B (años 2014 y 2016 respectivamente) con corderos naturalmente parasitados y seleccionados en función del número de huevos por gramo de heces (≥ 250) los que fueron tratados con monepantel (2,5 mg/Kg oral). El test de reducción en el conteo de huevos post tratamiento comparando diversas fórmulas indicó que en ambas experiencias, la droga mantuvo una eficacia mayor al 97 % y que permanece activa para controlar este aislamiento de H. contortus luego de cuatro años de uso y bajo las particulares condiciones en las que se realizaron estos estudios. SUMMARY. Monepatel and the control of Haemonchus contortus in sheep. Efficacy assessment after four years of use in reduced refugia. Resistance to anthelmintics in sheep nematode is widespread in central-northern Argentina and current major concern is the rise and spread of Haemonchus contortus carrying multiple resistance alleles. Currently, monepantel and derquantel are the only broad-spectrum anthelmintics without documentation of resistance in our country. With the first of these drugs, have already been registered cases of resistance in Uruguay and Brazil so it is critical update on the activity in the field of these anthelmintics. This study aims to test the effectiveness of monepantel after four years of use of this drug on an isolation of H. contortus with multiple resistance (macrocyclic lactones, closantel, levamisole and benzimidazole) and under conditions of reduced refugia. Two experiences, A and B (2014 and 2016 respectively), were carried out with lambs naturally parasitized and selected by the number of eggs per gram of feces (≥ 250). In both experiences, the test of reduction in egg counts after treatment with monepantel (2.5 mgr/Kg orally) comparing various formulas indicated that the drug remained with efficacy greater than 97% after four years of use to control this isolation of H. contortus under the field conditions of these studie

Eficacia del monepantel para el control de aislamientos de Haemonchus contortus y Trichostrongylus spp con resistencia múltiple (ivermectina y febendazole) en caprinos

El monepantel es un nuevo antihelmíntico registrado en nuestro país exclusivamente para el control de los nematodes gastrointestinales de los ovinos y su uso ha sido direccionado mayormente hacia el control de parásitos resistentes a las clases de antihelmínticos disponibles actualmente. Estos mismos nematodes también parasitan a los caprinos, pero en estos rumiantes la pato-fisiología y la respuesta a los antihelmínticos es diferente, lo cual resulta en un mayor parasitismo y complejidad en el manejo de la resistencia. La presente comunicación informa sobre la eficacia del monepantel en dos hatos caprinos mantenidos bajo condiciones de campo y parasitados naturalmente por los géneros de nematodes gastrointestinales más comunes del área central de la Argentina (Haemonchus y Trichostrongylus) y portando alelos de resistencia múltiple (ivermectina y febendazole). El test de reducción en el conteo de huevos post tratamiento comparando diversas fórmulas, indicaron que en todos los hatos el monepantel por vía oral y a la dosis de 3,75 mg/kg de peso (1,5 veces mayor a la dosis ovina), resultó en eficacias del 99% al 100 %. Se realizan breves consideraciones sobre el uso potencial de esta droga en caprinos. SUMMARY. Monepantel effectiveness against Haemonchus contortus and Trichostrongylus spp. with multiple resistance (ivermectin and febendazole) in goats. Monepantel is a new anthelmintic registered in Argentina exclusively for control of gastrointestinal nematodes of sheep and mostly directed toward controlling resistant parasites to current available classes of anthelmintics. The same nematodes also parasitize goats but pathophysiology and response are different in these hosts resulting in more severe parasitism and complexity in handling anthelmintic resistance. This report assess the efficacy of monepantel in goats maintained under field conditions and naturally parasitized by most common gastrointestinal nematodes from central Argentina (Haemonchus and Trichostrongylus) carrying alleles of multiple resistance (ivermectin and febendazole). According to the egg count reduction test, efficacies of 99% to 100% were observed after monepantel treatment at 3.75 mg/kg orally (1.5 ovine dose)

Pequeños estróngilos de los equinos. Eficacia clínica y periodo de reaparición de huevos luego del tratamiento con moxidectina y pirantel

El control de los pequeños estróngilos de los equinos (grupo Ciatostoma) se basa casi exclusivamente en la aplicación de antihelmínticos. En nuestro país, el desarrollo de resistencia generalizada a los bencimidazoles, está limitando las alternativas químicas disponibles a las lactonas macrocíclicas (ivermectina y moxidectina) y al pirantel, consideradas como drogas de larga y corta acción respectivamente. La información actualizada sobre la actividad de estas drogas en el campo es crítica para determinar su eficacia y detectar el desarrollo de fenómenos de resistencia a los antihelmínticos. En los equinos el período de reaparición de huevos (PRH) luego del tratamiento es considerado como un indicador temprano de la presencia de resistencia. En el presente trabajo se evaluó la eficacia clínica y el PRH luego de tratamientos con moxidectina y pirantel en equinos adultos de cinco establecimientos de las provincias de Santa Fe y Córdoba naturalmente parasitados por pequeños estróngilos. La eficacia clínica determinada al día 15 pos tratamiento utilizando un test de reducción en el conteo de huevos, osciló entre el 99,8 y el 100% para la moxidectina y entre el 98,9 y el 98,8% para el pirantel. Por su parte en el presente estudio el PRH fue de al menos 100 días para la moxidectina y de 35 días para el pirantel. Estos resultados indican que ambas drogas se muestran activas para el control de estos nematodes y que las poblaciones estudiadas (alguna de ellas resistentes a bencimidazoles) permanecen actualmente susceptibles a la moxidectina así como al pirantel. Esta última droga es de uso limitado en nuestro país, pero su inclusión en los programas de control contra los pequeños estróngilos podría reducir la dependencia y la presión de selección sobre las lactonas macrocíclicas y contribuir a mantener la vida útil de las mismas. SUMMARY. Small strongyles in horses. Clinical efficacy and egg reappearance period after moxidectin and pyrantel treatment. The control of the small strongyles (Ciathostoma group) in horses is based on the application of anthelmintics. In our country, the development of generalized resistance to benzimidazoles is limiting the chemical alternatives available to macrocyclic lactones (ivermectin and moxidectin) and to pyrantel, considered as long-acting and short-acting drugs respectively. Updated information on the activity of these drugs in the field, is critical for determining its efficacy and detecting the development of anthelmintic resistance. In these horse nematodes the period of egg reappearance (ERP) after treatment is considered as an early indicator of the presence of resistance. The present study evaluated the clinical efficacy and ERP after moxidectin and pirantel treatments in adult horses naturally parasitized by small strongyles from five farms from Santa Fe and Córdoba provinces. Clinical efficacy determined at day 14 or 15 post treatment using a test of reduction in the egg count ranged from 98.9 to 98.8% for the pirantel and 99.8 to 100% for moxidectin. The ERP was at least 100 days for moxidectin and 35 days for the pirantel. These results indicate that both drugs are active for the control of these nematodes and that the populations studied (some of them resistant to benzimidazoles) remain currently susceptible to moxidectin as well as to pyrantel. This last drug is of limited use in Argentina, but its inclusion in the control programs against the small strongyls could reduce the dependence and the selection pressure on the macrocyclic lactones and contribute to maintain the useful life of the same ones

Seroprevalence of Ehrlichia canis, Ehrlichia chaffeensis and Ehrlichia ewingii in dogs in North America

Background: This study evaluated the exposure of dogs to three different Ehrlichia spp. in the south and central regions of the United States where vector-borne disease prevalence has been previously difficult to ascertain, particularly beyond the metropolitan areas. Methods: Dog blood samples (n = 8,662) were submitted from 14 veterinary colleges, 6 private veterinary practices and 4 diagnostic laboratories across this region. Samples were tested for E. canis, E. chaffeensis and E. ewingii specific antibodies using peptide microtiter ELISAs. Results: Overall, E. canis, E. chaffeensis and E. ewingii seroprevalence was 0.8%, 2.8%, and 5.1%, respectively. The highest E. canis seroprevalence (2.3%) was found in a region encompassing Arkansas, Louisiana, Oklahoma, Tennessee and Texas. E. chaffeensis seroreactivity was 6.6% in the central region (Arkansas, Kansas, Missouri, and Oklahoma) and 4.6% in the southeast region (Georgia, Maryland, North Carolina, South Carolina, Tennessee and Virginia). Seroreactivity to E. ewingii was also highest in the central region (14.6%) followed by the southeast region (5.9%). The geospatial pattern derived from E. chaffeensis and E. ewingii seropositive samples was similar to previous reports based on E. chaffeensis seroreactivity in white-tailed deer and the distribution of human monocytic ehrlichiosis (HME) cases reported by the CDC. Conclusions: The results of this study provide the first large scale regional documentation of exposure to E. canis, E. chaffeensis and E. ewingii in pet dogs, highlighting regional differences in seroprevalence and providing the basis for heightened awareness of these emerging vector-borne pathogens by veterinarians and public health agencies