An eprinomectin extended-release injection formulation providing nematode control in cattle for up to 150 days

A series of 10 dose confirmation studies was conducted to evaluate the persistent activity of an extended-release injectable (ERI) formulation of eprinomectin against single point challenge infections of gastrointestinal and pulmonary nematodes of cattle. The formulation, selected based on the optimal combination of high nematode efficacy, appropriate plasma profile, and satisfactory tissue residue levels, includes 5% poly(d,l-lactide-co-glycolic)acid (PLGA) and is designed to deliver eprinomectin at a dose of 1.0 mg/kg bodyweight. Individual studies, included 16–30 cattle blocked based on pre-treatment bodyweight and randomly allocated to treatment with either ERI vehicle or saline (control), or the selected Eprinomectin ERI formulation. Treatments were administered once at a dose volume of 1 mL/50 kg bodyweight by subcutaneous injection in front of the shoulder. In each study, cattle were challenged with a combination of infective stages of gastrointestinal and/or pulmonary nematodes 100, 120 or 150 days after treatment and were processed for parasite recovery according to standard techniques 25–30 days after challenge. Based on parasite counts, Eprinomectin ERI (1 mg eprinomectin/kg bodyweight) provided >90% efficacy (p < 0.05) against challenge with Cooperia oncophora and Cooperia surnabada at 100 days after treatment; against challenge with Ostertagia ostertagi, Ostertagia lyrata, Ostertagia leptospicularis, Ostertagia circumcincta, Ostertagia trifurcata, Trichostrongylus axei, and Cooperia punctata at 120 days after treatment; and against challenge with Haemonchus contortus, Bunostomum phlebotomum, Oesophagostomum radiatum and Dictyocaulus viviparus at 150 days after treatment. Results of a study to evaluate eprinomectin plasma levels in cattle treated with the Eprinomectin ERI formulation reveal a characteristic second plasma concentration peak and a profile commensurate with the duration of efficacy. These results confirm that the Eprinomectin ERI formulation can provide high levels of parasite control against a range of nematodes of cattle for up to 5 months following a single treatment.     

LongRange™ (eprinomectin 5%) extended-release injection parasiticide and the utility of extended-activity antiparasitics in cattle

An extended-release injection, which is administered at a rate of 1 mg eprinomectin/kg body weight, has been developed to provide up to 150 days control of parasites of cattle. The product can facilitate the achievement of two of the fundamental aims of parasite control. The first is protection of the host against the negative impact of susceptible parasites in order to ensure control of disease and to enhance performance. The second is to reduce parasite transmission and hence the challenge to animals when grazing. In addition, farmers and veterinarians can benefit from high levels of convenience and hence compliance from a single administration, which also limits handling stress in the cattle. This introductory paper provides some perspective on the practical applications for this extended-release product under various husbandry systems and in different classes of cattle and discusses its role in sustainable parasite control.     

Therapeutic efficacy of eprinomectin extended-release injection against induced infections of developing (fourth-stage larvae) and adult nematode parasites of cattle

The therapeutic efficacy of eprinomectin in an extended-release injection (ERI) formulation was evaluated against induced infections of developing fourth-stage larval or adult gastrointestinal and pulmonary nematodes of cattle in a series of six studies under two identical protocols (three each for developing fourth-stage larvae or adults) conducted in the USA, Germany or the UK (two studies at each location, one per stage).     

Persistent efficacy and production benefits following use of extended-release injectable eprinomectin in grazing beef cattle under field conditions

Seven studies were conducted in commercial grazing operations to confirm anthelmintic efficacy, assess acceptability, and measure the productivity response of cattle to treatment with eprinomectin in an extended-release injectable formulation (ERI) when exposed to nematode infected pastures for 120 days. The studies were conducted under one protocol in the USA in seven locations (Arkansas, Idaho, Louisiana, Minnesota, Missouri, Oregon, and Wisconsin). Each study had 67–68 naturally infected animals for a total of 475 (226 female, 249 male castrate) Angus or beef-cross cattle. The animals weighed 133–335 kg prior to treatment and were approximately 3–12 months of age. The studies were conducted under a randomized block design based on pre-treatment body weights to sequentially form 17 replicates of four animals each within sex in each study. Animals within a replicate were randomly assigned to treatments, one to Eprinomectin ERI vehicle (control) and three to Eprinomectin ERI (5%, w/v eprinomectin). Treatments were administered at 1 mL/50 kg body weight once subcutaneously anterior to the shoulder. All animals in each study grazed one pasture throughout the observation period of 120 days. Cattle were weighed and fecal samples collected pre-treatment and on 28, 56, 84, and 120 days after treatment for fecal egg and lungworm larval counts. Positive fecal samples generally were cultured en masse to determine the nematode genera attributable to the gastrointestinal helminth infection. Bunostomum, Cooperia, Haemonchus, Nematodirus, Oesophagostomum, Ostertagia, and Trichostrongylus, when present, were referred to as strongylids. At all post-treatment sampling intervals, Eprinomectin ERI-treated cattle had significantly (P < 0.05) lower strongylid egg counts than vehicle-treated controls, with ≥95% reduction after 120 days of grazing. Over this same period, Eprinomectin ERI-treated cattle gained more weight (43.9 lb/head) than vehicle-treated controls in all studies. This weight gain advantage was significant (P < 0.05) in six of the studies with the Eprinomectin ERI-treated cattle gaining an average of 42.8% and the control cattle gaining 33.1% of their initial weight. No adverse reactions were observed in the treated animals.     

The efficacy of eprinomectin extended-release injection against naturally acquired nematode parasites of cattle,with special regard to inhibited fourth-stage Ostertagia larvae

The efficacy of eprinomectin in an extended-release injection (ERI) formulation in the treatment of cattle harboring naturally acquired nematode populations (including inhibited nematodes) was evaluated. Five studies were conducted under a similar protocol in the USA, the UK, and in Germany. All study animals were infected by grazing naturally contaminated pastures. The adequacy of pasture infectivity was confirmed by examining tracer calves prior to allocation and treatment of the study animals. The cattle were of various breeds or crosses, weighing 79–491 kg, and aged approximately 6–15 months. In each study, 20 animals were infected by grazing, and then removed from pasture and housed in a manner to preclude further nematode infections for 8–16 days until treatment. Animals were blocked based on descending pre-treatment body weight and randomly allocated to one of two treatments: ERI vehicle (control) at 1 mL/50 kg body weight or eprinomectin 5% (w/v) ERI at 1 mL/50 kg body weight (1.0 mg eprinomectin/kg). Treatments were administered once on Day 0 by subcutaneous injection in front of the shoulder. For parasite recovery and count, all study animals were humanely euthanized 14/15 days after treatment. Cattle treated with eprinomectin ERI had significantly (p < 0.05) fewer of the following nematodes than the controls with overall reduction of parasite counts of ≥94%: adult Dictyocaulus viviparus, Capillaria spp., Cooperia oncophora, Cooperia pectinata, Cooperia punctata, Cooperia surnabada, Haemonchus placei, Nematodirus helvetianus, Oesophagostomum radiatum, Ostertagia lyrata, Ostertagia ostertagi, Trichostrongylus axei, Trichostrongylus colubriformis, Trichuris discolor, Trichuris skrjabini, and Trichuris spp.; developing fourth-stage larvae of Ostertagia spp. and Trichostrongylus spp.; and inhibited fourth-stage larvae of Cooperia spp., Haemonchus spp., Nematodirus spp., Oesophagostomum spp., Ostertagia spp., and Trichostrongylus spp.     

The efficacy of eprinomectin extended-release injection against Hypoderma spp. (Diptera: Oestridae) in cattle

The efficacy of eprinomectin in an extended-release injection (ERI) formulation was determined in cattle harboring naturally acquired infestations of first- or second- and third-stage larvae of Hypoderma spp. in three studies conducted according to the same protocol in the USA (two studies) and Germany (one study). Thirty cattle sourced from herds with a history of Hypoderma infestation were included in each study. Cattle were formed into replicates of three animals each on the basis of pre-treatment anti-Hypoderma antibody titers. Within replicates each animal was randomly allocated to one of the following treatments: ERI vehicle (control) at 1 mL/50 kg bodyweight, administered once on Day 0; Eprinomectin 5% ERI at 1 mL/50 kg bodyweight (1.0 mg eprinomectin/kg), administered once on Day 0 (when larvae were expected to be first instars); or Eprinomectin 5% ERI at 1 mL/50 kg bodyweight (1.0 mg eprinomectin/kg), administered once when larvae were second or third instars (study dependent, Day 73, 119, or 140). Treatments were administered by subcutaneous injection in front of the shoulder. In all studies, emerging and/or expressed Hypoderma larvae were recovered, speciated, and counted and viability was determined. Eprinomectin LAI treatment was 100% (p < 0.05) efficacious against first- and second- or third-stage larvae of Hypoderma bovis (two studies) and Hypoderma lineatum (one study). All animals accepted the treatment well. No adverse reaction to treatments was observed in any animal in any study.     

The treatment of bovine sarcoptic mange (Sarcoptes scabiei var. bovis) using eprinomectin extended-release injection

The efficacy of eprinomectin in an extended-release injection (ERI) formulation was evaluated in cattle harbouring induced infestations of Sarcoptes scabiei var. bovis (sarcoptic mange) in three studies conducted in Germany (two studies) and Austria (one study). A total of 44 cattle were included in the studies, 12 in one study and 16 in each of the other two studies. Approximately eight weeks following initial induced infestation, cattle in each study were formed into replicates of two animals each on the basis of pre-treatment bodyweights. Within replicates the animals were randomly allocated to one of two treatments: ERI vehicle (control) or Eprinomectin 5% (w/v) ERI (1.0 mg eprinomectin/kg). Treatments were administered at 1 mL/50 kg bodyweight by subcutaneous injection in front of the shoulder once on day 0. The number of live mites in skin scrapings was determined prior to treatment and at weekly intervals for eight weeks after treatment. Severity of skin lesions was evaluated and scored when skin scrapings were taken. In all studies, animals were weighed before infestation and again prior to and at 56 days after treatment.     

Field efficacy of minidosed eprinomectin against Hypoderma spp. in dairy cattle

A chemoprophylactic field trial was conducted to assess the efficacy of pour-on eprinomectin applied at the approximate dose of 50 mcg/kg to dairy cattle with naturally occurring hypodermosis. Two-hundred-eleven cattle, selected from two herds with a high prevalence of Hypoderma spp. infestation, were divided in three groups: Group A (N = 71) was treated with pour-on eprinomectin at the recommended dosage of 500 mcg/kg, Group B (N = 64) at the lower dose of 50 mcg/kg, a third group (Group C, N = 76) served as untreated control group. Treatments were performed in November-December 2002 and the animals were examined for the presence of warbles in the following April and June. No larvae emerged in the treated groups, whereas a variable number of warbles (ranging from 1 to 28) were found in control animals. Adverse reactions were not observed in any animal, and only minor side effects were observed. A larger field trial carried out in the following year (1064 treated and 131 untreated control cattle) confirmed the chemoprophylactic efficacy of minidosed eprinomectin against Hypoderma spp. Administration of eprinomectin minidoses in dairy cattle is interesting because of the low costs involved and no need for milk withdrawal.     

Transmission of Babesia spp by the cattle tick (Boophilus microplus) to cattle treated with injectable or pour-on formulations of ivermectin and moxidectin

OBJECTIVE: To assess the efficacy of ivermectin and moxidectin to prevent transmission of Babesia bovis and Babesia bigemina by Boophilus microplus to cattle under conditions of relatively intense experimental challenge. DESIGN: Naive Bos taurus calves were treated with either pour-on or injectable formulations of either ivermectin or moxidectin and then exposed to larvae of B microplus infected with B bovis or larvae or adults of B microplus infected with B bigemina. One calf was used for each combination of haemoparasite, B microplus life stage, drug and application route. PROCEDURE: Groups of calves were treated with the test drugs in either pour-on or injectable formulation and then infested with B microplus larvae infected with B bovis or B bigemina. B bigemina infected adult male ticks grown on an untreated calf were later transferred to a fourth group of animals. Infections were monitored via peripheral blood smears to determine haemoparasite transmission. RESULTS: Cattle treated with either pour-on or injectable formulations of ivermectin and moxidectin became infected with B bovis after infestation with infected larvae. Similarly, larvae infected with B bigemina survived to the nymphal stage to transmit the haemoparasite to animals treated with each drug preparation. Cattle treated with pour-on formulations of ivermectin and moxidectin then infested with adult male ticks infected with B bigemina did not become infected with B bigemina whereas those treated with the injectable formulations of ivermectin and moxidectin did show a parasitaemia. CONCLUSIONS: Injectable or pour-on formulations of ivermectin and moxidectin do not prevent transmission of Babesia to cattle by B microplus. Use of these drugs can therefore not be recommended as a primary means of protecting susceptible cattle from the risk of Babesia infection.     

Influence of urea molasses treated wheat straw fermented with cattle manure on chemical composition and feeding value for growing buffalo calves

The study was conducted to examine the chemical composition of urea–molasses treated wheat straw (WS) fermented with cattle manure (CM) and its feeding value for growing buffalo male calves. Wheat straw treated with varying levels of urea (0%, 2% and 4%) and molasses (2% and 4%) was ensiled with 30% cattle manure (on dry matter basis) for different fermentation periods (20, 30 and 40 days). Fermented wheat straw (FWS) after each fermentation period was analyzed for pH, dry matter (DM), crude protein (CP), true protein (TP), ammonia nitrogen (NH₃-N), acid detergent fiber (ADF) and neutral detergent fiber (NDF). Maximum pH, DM, CP, TP and NH₃-N and minimum NDF contents were observed with 4% urea. The 4% molasses level increased the CP, TP and NH₃-N contents of FWS, but pH, DM and NDF remained unchanged after 40 days of fermentation. The 4% urea × 4% molasses interaction resulted in maximum DM, CP, TP, NH₃-N after 40 days of fermentation period and this combination was used for large scale production of FWS to evaluate its feeding value for calves. Four isonitrogen and isocaloric diets were formulated. The control FWS 0 diet contained no FWS while in FWS 15, FWS 25 and FWS 35 diets concentrate was replaced with 15%, 25% and 35% FWS, respectively. The diets were randomly allotted to four groups of 28 calves 9–12 months of age, seven in each group, in a randomized complete block design to examine the nutrient intake, digestibility, nitrogen balance and weight gain. An increased DM, organic matter (OM), CP and NDF intakes were observed in calves fed FWS diets compared to those fed FWS 0 diet. Nitrogen retention increased significantly with increasing the level of FWS. The DM, OM, CP and NDF apparent digestibilities were non-significant in calves fed different levels of FWS. A linear increase in weight gain was noticed in calves fed diets containing increasing level of FWS.     

Maternal and foetal immune responses of cattle following an experimental challenge with Neospora caninum at day 70 of gestation

The immune responses of pregnant cattle and their foetuses were examined following inoculation on day 70 of gestation either intravenously (iv) (group 1) or subcutaneously (sc) (group 2) with live NC1 strain tachyzoites or with Vero cells (control) (group 3). Peripheral blood mononuclear cell (PBMC) responses to Neospora antigen and foetal viability were assessed throughout the experiment. Two animals from each group were sacrificed at 14, 28, 42 and 56 days post inoculation (pi). At post mortem, maternal lymph nodes, spleen and PBMC and when possible foetal spleen, thymus and PBMC samples were collected for analysis. Inoculation with NC1 (iv and sc) lead to foetal deaths in all group 1 dams (6/6) and in 3/6 group 2 dams from day 28pi; statistically significant (p ≤ 0.05) increases in cell-mediated immune (CMI) responses including antigen-specific cell proliferation and IFN-γ production as well as increased levels of IL-4, IL-10 and IL-12 were observed in challenged dams compared to the group 3 animals. Lymph node samples from the group 2 animals carrying live foetuses showed greater levels of cellular proliferation as well as significantly (p ≤ 0.05) higher levels of IFN-γ compared to the dams in group 2 carrying dead foetuses. Foetal spleen, thymus and PBMC samples demonstrated cellular proliferation as well as IFN-γ, IL-4, IL-10 and IL-12 production following mitogenic stimulation with Con A from day 14pi (day 84 gestation) onwards. This study shows that the generation of robust peripheral and local maternal CMI responses (lymphoproliferation, IFN-γ) may inhibit the vertical transmission of the parasite.     

Urine retention in cattle putatively associated with injection of an ivermectin and closantel anthelmintic formulation into the ischiorectal fossa

Case History: A group of 39, 19–22-month-old Friesian bulls were administered an ivermectin/closantel anthelmintic via intended S/C injection in the ischiorectal fossa on 15 June 2017 (Day 0). Over the next 50 days, 22 affected bulls presented various degrees of anorexia, abdominal pain and urine dribbling. Seventeen bulls were examined by transrectal ultrasonography which revealed urinary bladder distension in all 17, and peritoneal fluid accumulation in some. Overall, eight bulls died or were subjected to euthanasia. On-farm postmortem examination of three bulls revealed urinary bladder rupture.

Clinical Findings: On Day 50 one affected live bull was admitted to Massey University for further investigation. This bull continuously dribbled urine and had an overtly distended urinary bladder as determined by rectal palpation and ultrasonography.

Pathological Findings: Postmortem examination of this bull revealed a markedly distended urinary bladder, massive subcapsular and pericapsular renal oedema with retroperitoneal fluid accumulation, minimal hydronephrosis and no evidence of mechanical urinary outflow obstruction. The right ischiorectal fossa contained multifocal areas of tissue fibrosis that extended into areas innervated by the distal cutaneous branch of the pudendal nerve and the pelvic nerve. Histopathological changes consisted of extensive fibrosis, myonecrosis and neurodegeneration, and evidence of granulation tissue and inflammation at the putative injection site and in surrounding tissues.

Diagnosis: A local inflammatory reaction at the presumed injection site together with localised peripheral neurodegeneration and myelopathy may have led to detrusor-sphincter dyssynergia causing urine retention.

Clinical Relevance: These cases of urine retention and bladder rupture in cattle were of putative iatrogenic origin. Veterinarians should be aware of this rare complication after S/C injections in the ischiorectal fossa.     

Effect of dry period length on the effect of an intramammary teat sealant on the risk of mastitis in cattle treated with antibiotics at drying off

AIM: The aim of this study was to evaluate, under farm conditions, the use of a teat sealant in addition to whole herd dry cow antibiotic therapy on the risk of clinical mastitis in dairy cattle at pasture, and to evaluate the impact of dry period length on that risk and the impact of the teat sealant on that risk.

METHODS: Dairy cows in three herds which used routine whole herd antibiotic therapy were randomly assigned to receive either treatment with an internal teat sealant (n=322) or no additional treatment (n=313) at drying-off between March and May 2010. All clinical mastitis cases during the dry period and to the end of the subsequent lactation were recorded by farm staff; factors affecting risk of clinical mastitis were then analysed using a Cox proportional hazards model.

RESULTS: Median duration of the dry period was 112 days with >25% of cows having a dry period >130 days. The incidence risk of mastitis during lactation for cows treated with teat sealant was 9.9 (95% CI=6.9–13.7) cases per 100 cows compared with 17.9 (95% CI=13.8–22.6) cases per 100 cows for cows treated with antibiotic alone. The addition of a teat sealant to dry cow antibiotic therapy decreased the risk of clinical mastitis only in the first 33 days after calving (Hazard risk 0.24 (95% CI=0.12–0.48)). Length of dry period did not significantly affect the risk of clinical mastitis, or the effect of adding teat sealant to dry cow antibiotic therapy on the risk of clinical mastitis.

CONCLUSIONS: In these herds where, based on the mastitis history, whole herd antibiotic therapy had been recommended, the use of a teat sealant significantly reduced the risk of clinical mastitis. This effect was limited to the first 33 days after calving; subsequently there was no significant effect of treatment. There was no effect of dry period length on risk of clinical mastitis, nor any significant interaction with treatment.

CLINICAL RELEVANCE: Combination therapy with teat sealant and antibiotic was effective under New Zealand conditions in herds using whole herd antibiotic treatment at drying off. Teat sealant reduced risk of clinical mastitis in cattle with dry periods substantially longer than 100 days, and there was no evidence that this effect changed as dry period length increased.