Evaluation of signal detection algorithms within the Elanco Animal Health Pharmacovigilance database.

Statistical algorithms for detecting safety signals are beginning to be applied to Animal Health Pharmacovigilance (PV) databases. How these signal detection algorithms (SDAs) perform in an animal health PV database is the subject of this report. Statistical methods and SDAs were assessed against a set of known signals in order to identify which SDAs were most appropriate for signal detection using the Elanco Animal Health PV database. A reference set of adverse events that should signal was created for 31 products across four species. Nine SDAs based on five disproportionality statistical methods were evaluated against the reference set. The performance metrics were sensitivity, precision, specificity, accuracy, and F score. For bovine and porcine products, the Observed-to-Expected (O/E) SDA was the closest in terms of geometric distance to 100% sensitivity and 100% precision. For canine and feline products, the Information Component (IC) SDA was geometrically closest to 100% sensitivity and 100% precision. Principal Component Analysis confirmed that the O/E and IC SDAs were unique performers with respect to one another and other SDAs. The performance of the SDAs was dependent on the choice of the statistical method with differences seen between animal species.

Laser Photolysis Kinetic Study of OH Radical Reactions with Methyl tert-Butyl Ether and Trimethyl Orthoformate under Conditions Relevant to Low Temperature Combustion: Measurements of Rate Coefficients and OH Recycling.

Methyl tertiary butyl ether (MTBE) and trimethyl orthoformate (TMOF) are potential biofuel ethers and could replace conventional fossil fuels, or act as additives to aid combustion. Laser flash photolysis with laser-induced fluorescence detection of the OH radical has been used to measure the rate coefficients of the OH reaction with these ethers, from 298 K to approximately 740 K. The temperature dependence of the rate coefficients is parametrized as kOH+MTBE(298-680 K) = 9.8 × 10-13× ( T/298)2.7 × exp(2500/R T) cm3 molecule-1 s-1 and kOH+TMOF(298-744 K) = 8.0 × 10-13 × [( T/298)2.6 + ( T/298)-8.1] × exp[2650/R T] cm3 molecule-1 s-1. The room temperature (298 K) bimolecular rate coefficients were measured as kOH+MTBE = (2.81 ± 0.32) × 10-12 cm3 molecule-1 s-1 and kOH+TMOF = (4.65 ± 0.50) × 10-12 cm3 molecule-1 s-1 where the errors represent statistical uncertainties at the 2σ level in combination with an estimated 10% systematic error. Regeneration of OH radicals was observed for both reactions at higher temperatures in the presence of O2 via biexponential OH decays, which were observed above 489 K and 568 K, for TMOF and MTBE respectively. The OH yield from MTBE/O2, between 620 and 700 K, was invariant with the concentration of oxygen (1015-1018 molecules cm-3) at (36 ± 5)%. Mechanisms for OH regeneration from MTBE are briefly discussed and compared with those in the literature and from dimethyl and diethyl ether. The lower OH yield from MTBE, compared to these other ethers, is most likely due to competition with an HO2 formation channel.

Long-term and acute safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) in juvenile and adult dogs.

BACKGROUND: The combination of milbemycin oxime (MO) and lotilaner (Credelio® Plus) is a novel systemic endectocide that provides month-long effectiveness in dogs after a single oral treatment. The safety of Credelio® Plus flavored chewable tablets was investigated in three target animal safety studies. Two studies (one in juveniles and one in adults) evaluated the long-term safety, and one study evaluated the acute safety of the product when administered orally at the upper end of the recommended dose range (0.75-1.53 mg/kg MO and 20-41 mg/kg lotilaner) and multiples of this dose. METHODS: The objectives of these studies were to determine the long-term and acute safety of MO and lotilaner flavored chewable tablets in healthy dogs. All three studies were randomized, blinded, parallel-group design studies in healthy Beagle dogs. In each of the two long-term studies, 32 dogs were randomized among four groups to untreated controls or to treated groups at target doses of 1X, 3X, or 5X. Treatment was administered on seven (adult dogs) or nine (juvenile dogs) occasions with dosing every 4 weeks. In the acute study, 48 dogs were randomized among four groups to untreated controls or to treated groups at 1X, 3X, or 6X. In all three studies, the control group was administered placebo tablets. All dogs were fed 30 to 45 min prior to treatment and the assessment of safety was based on health observations, complete physical/neurological examinations, and food consumption. For the long-term safety studies, safety assessments also included clinical pathology evaluations (hematology, clinical chemistry and urinalysis), body weight, pharmacokinetic blood collections, and macroscopic and microscopic examinations of collected tissues. RESULTS: MO and lotilaner did not induce any treatment-related adverse effects based on health observations, physical/neurological examinations, or food consumption in the long-term or acute studies. Additionally, in the long-term studies, MO and lotilaner did not induce any treatment-related effects on clinical pathology, body weight, and macroscopic and microscopic examinations. CONCLUSIONS: These three studies demonstrate that Credelio® Plus has a wide safety margin when administered at monthly intervals to puppies and dogs at the high end of the commercial dose band.

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural flea and tick infestations on dogs presented as veterinary patients in Europe.

BACKGROUND: A pivotal randomised, blinded, positive-controlled, multicentre, European field study was conducted to evaluate the effectiveness and safety of a novel combination tablet of lotilaner and milbemycin oxime (Credelio® Plus) administered orally to client-owned dogs naturally infested with fleas and/or ticks. METHODS: In this field study, households with flea- or tick-infested dog(s) were enrolled on Day 0 into the study to provide data for either the tick or flea infestation cohorts. Households were randomised in a 2:1 ratio to receive either the combination investigational product (IP, Credelio Plus® tablets) or the control product (CP: Nexgard Spectra® tablets). Dogs were administered IP (flea cohort n = 135; tick cohort: n = 147) or CP (flea cohort: n = 67; tick cohort: n = 74) once every 4 weeks for a total of three times at a dose rate of 20.0-41.5 mg/kg bodyweight lotilaner and 0.75-1.53 mg/kg bodyweight milbemycin oxime (IP) or as recommended (CP). Percentage reduction was calculated by comparing individual dog flea and tick counts at each assessed post-treatment time point to their respective baseline (pre-treatment) infestation. Resolution of the clinical signs of flea allergy dermatitis (FAD) was assessed in flea-allergic dogs on the days that flea counts were performed. RESULTS: Flea effectiveness of Credelio Plus® after 3 consecutive monthly treatments was 100% against Ctenocephalides felis, C. canis and Pulex irritans. Tick effectiveness of Credelio Plus® over the same time frame was 99.3% for Ixodes ricinus and 100% against Rhipicephalus sanguineus (s.l.). Flea effectiveness of the CP after three consecutive monthly treatments was 100% against C. felis, C. canis and P. irritans. Tick effectiveness of the CP over the same time frame was 99.8% for I. ricinus and 100% against R. sanguineus. Credelio Plus® was well tolerated based on the safety assessments in all treated dogs in this field study. Within both treatment groups there was a reduction in total FAD scores from baseline. CONCLUSIONS: This pivotal European field study demonstrated the excellent effectiveness and safety of a combination of lotilaner and milbemycin oxime (Credelio Plus®) administered orally to dogs naturally infested with fleas and/or ticks.

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) against natural intestinal nematode infections in dogs presented as veterinary patients in Europe.

BACKGROUND: A randomised, blinded, positive controlled, multicentre, Good Clinical Practice-compliant, pivotal field study was conducted to evaluate the effectiveness and safety of a new combination of lotilaner + milbemycin oxime tablets (Credelio® Plus; Elanco Animal Health) administered orally to client-owned dogs naturally infected with intestinal nematodes. METHODS: Client-owned dogs presenting to veterinary clinics from households in France, Hungary and Germany were screened for intestinal nematodes. Dogs with an initial positive faecal egg count that was subsequently confirmed with a follow-up faecal examination to demonstrate the presence of naturally occurring mixed or mono-infections with Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum were enrolled on Day 0 into the study. Households were randomised in an approximately 2:1 ratio to receive either an investigational product (IP; Credelio Plus tablets) or control product (CP; Nexgard Spectra® tablets) as treatment. Dogs were administered the IP (n = 278) or CP (n = 117) once on Day 0 at a dose rate of 0.75-1.56 mg/kg bodyweight milbemycin oxime and 20.0-41.5 mg/kg bodyweight lotilaner (IP) or as recommended (CP). Effectiveness of the IP and CP treatments was based on the post-treatment reduction in geometric mean faecal egg counts on Day 8 (range Day 7-10) after treatment as compared to their pre-treatment nematode faecal egg counts. RESULTS: Geometric mean (GM) faecal egg counts for T. canis, A caninum and T. vulpis were reduced by ≥ 97.2% in the Credelio Plus group and by ≥ 95.3% in the afoxolaner + milbemycin oxime group. There were insufficient data to calculate a percentage reduction in GM faecal egg counts between Day 0 and Day 8 for T. leonina due to low prevalence. Credelio Plus was well tolerated in this field study. Of the 355 total doses administered, 82.3% were accepted free choice in the IP group compared to 80.8% in the CP group. CONCLUSIONS: This study demonstrated effectiveness (≥ 97.2% reduction), safety and tablet acceptance of a combination of milbemycin oxime and lotilaner (Credelio Plus) administered orally to dogs with natural intestinal infections of T. canis, A. caninum and T. vulpis.

Field study to investigate the effectiveness and safety of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the prevention of heartworm disease (Dirofilaria immitis) in client-owned dogs in the USA.

BACKGROUND: Dirofilaria immitis, a globally distributed filarial parasite of dogs, is known to cause serious or fatal cardiopulmonary disease. Client-owned dogs were enrolled in a clinical field study in the USA to evaluate the clinical effectiveness and field safety of an orally administered combination investigational product (IP) containing milbemycin oxime and lotilaner (Credelio® Plus) as compared to a control product (CP) for the prevention of heartworm disease when administered monthly for 11 consecutive months. METHODS: In this 11-month field study, 319 dogs ≥ 8 weeks old confirmed to be heartworm-negative were enrolled from eight geographically distinct US veterinary clinics, including sites in the southern USA and Mississippi River Valley. The dogs were treated with either the IP combination product at 0.75-1.53 mg/kg milbemycin oxime and 20-41.5 mg/kg lotilaner (n = 159) or the CP (Sentinel® Flavor Tabs®; milbemycin oxime/lufenuron) at the label-recommended dose rate (n = 158.) On day 330, effectiveness was evaluated in each dog using antigen and microfilarial (modified Knott's) testing to assess the establishment of any patent adult heartworm infections. RESULTS: All dogs treated with the IP combination product and the CP tested negative (100% prevention) for heartworm infection on day 330. The IP combination product tablets containing milbemycin oxime and lotilaner were well tolerated based on the safety assessments in all treated dogs. CONCLUSIONS: This multi-site clinical study using client-owned dogs demonstrated that monthly use of flavored, chewable tablets containing a combination of milbemycin oxime and lotilaner administered orally under end use conditions is safe for dogs. None of the enrolled dogs developed heartworm infections. Eleven consecutive monthly treatments of the IP provided 100% prevention of heartworm disease caused by D. immitis.

Effectiveness of a novel orally administered combination drug product containing milbemycin oxime and lotilaner (Credelio® Plus) for the treatment of larval and immature adult stages of Ancylostoma caninum in experimentally infected dogs.

BACKGROUND: The hookworm, Ancylostoma caninum, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. Both the immature and adult stages of A. caninum ingest large volumes of blood during the feeding process and can cause severe anemia and death in young dogs, even before patent infections can be diagnosed using routine faecal examination methods. Thus, effective treatment of any pre-patent stages of immature hookworms can reduce or eliminate the risk of clinical disease in infected dogs and additionally reduce environmental contamination of eggs and infective larvae. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to evaluate the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus®) administered orally to dogs experimentally infected with immature (L4 and immature adult [L5]) stages of A. caninum. METHODS: Treatments using the intended global commercial tablet formulation of Credelio Plus were administered in a time frame relative to inoculation with infective larvae so that effectiveness could be assessed against each specific immature stage of A. caninum. In each study, dogs were randomized to one of six (study 1) or four (study 2) treatment groups. Each treatment group contained 8 (study 1) or 10 (study 2) dogs that had been experimentally inoculated with infective A. caninum larvae on day 0 and were dosed once on day 7 or day 11. Enrolled subjects were administered placebo tablets, Credelio Plus tablets, or lotilaner mono tablets to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 days after their respective treatment. All nematodes recovered from the gastrointestinal tract at necropsy were counted by species and stage. RESULTS: For both dose confirmation studies and based on geometric mean worm counts, efficacy of Credelio Plus was ≥ 97.3% against L4 larval stage of A. caninum and ≥ 98.7% against immature adult (L5) A. caninum. CONCLUSIONS: These studies demonstrated that the orally administered Credelio Plus combination tablet was highly efficacious in treating immature (L4 and immature adult [L5]) stages of A. caninum in experimentally infected dogs.

Effectiveness of Credelio® Plus, a novel chewable tablet containing milbemycin oxime and lotilaner for the treatment of larval and immature adult stages of Toxocara canis in experimentally infected dogs.

BACKGROUND: The ascarid, Toxocara canis, is a common and important zoonotic intestinal nematode parasite that infects dogs globally. An effective treatment that kills any pre-patent stages of immature T. canis could additionally reduce or eliminate the development of patent infections that can result in clinical disease in infected dogs and would further reduce environmental contamination of eggs. Two randomized, blinded, GCP-compliant, pivotal laboratory dose confirmation studies were conducted to assess the effectiveness and safety of a new novel combination of lotilaner and milbemycin oxime tablets (Credelio Plus) administered orally to dogs that were experimentally infected with immature (L4 or immature adult [L5]) stages of T. canis. METHODS: The commercial tablet formulation of Credelio Plus® was administered in a time frame relative to inoculation with infective eggs. This allowed for effectiveness to be assessed against each specific immature stage of T. canis. In each study, dogs were randomized and allocated to one of four treatment groups. Each treatment group contained ten dogs that had been experimentally inoculated on Day 0 with infective T. canis eggs and then were dosed once on Day 14 or Day 24 using either placebo tablets or Credelio Plus tablets (IP) to provide minimum dosages of 0.75 mg/kg of milbemycin oxime and 20 mg/kg of lotilaner. All dogs were necropsied 5 or 6 days after their respective treatment. At necropsy, all nematodes recovered from the gastrointestinal tract were counted by species and stage. RESULTS: In both dose confirmation studies using geometric mean worm counts, effectiveness of Credelio Plus was ≥ 98.6% and ≥ 96.8% against L4 larval stage T. canis and immature adult [L5] T. canis in both studies, respectively. CONCLUSIONS: These studies demonstrated that the Credelio Plus combination tablet administered orally to dogs was highly efficacious against experimental infections with L4 and immature adult [L5] stages of T. canis.

Survey of UK pet owners quantifying internal parasite infection risk and deworming recommendation implications.

BACKGROUND: Dogs and cats in the UK are exposed to many internal parasites which can pose risks to the health of both the pet and their owners. By understanding these endemic parasites and the risks they pose, we can assess the lifestyle of pets and recommend the correct deworming frequency. Studies identifying risk factors were discussed in the European Scientific Counsel Companion Animal Parasites (ESCCAP) guidelines. To this date, there has been very little information on how pet owners in the UK deworm their pets and if the protocols they follow align with ESCCAP recommendations. The objective of this study was to look at the current deworming protocols of UK cat and dog owners in conjunction with their lifestyle and risk. METHODS: An online survey was conducted in the UK targeting pet owners who own at least one dog and/or cat and were responsible for product purchase, the pet's health care and veterinary visits. These survey results were analysed against the ESCCAP guidelines and each pet placed into a risk category. By comparing the current deworming frequency with that recommended for their risk category, the compliance of UK pet owners with ESCCAP recommendations was evaluated. RESULTS: A total of 500 dog owners and 500 cat owners completed surveys. Overall, the study found none of the pets fell into risk group A, with all pets meeting the risk level for at least deworming four times a year (risk group B and above). The majority of animals fell into the highest risk category D with 97% of dogs and 68% of cats. The average deworming per year in the UK was 3.1 for dogs and 3.1 cats, below the minimum recommended by ESCCAP. CONCLUSIONS: For both felines and canines, the dosing frequencies are lower than recommended to both reduce zoonotic risk for reducing Toxocara spp. egg-shedding and improve pet health. This research highlights the need for improved education around dog and cat patient risk assessments and greater adherence to recommended deworming aligned with the ESCCAP guidelines.

Efficacy of lotilaner (Credelio™) against the adult cat flea, Ctenocephalides felis and flea eggs following oral administration to dogs.

BACKGROUND: A blinded, randomized, negative controlled laboratory study was conducted to evaluate the efficacy of lotilaner (CredelioTM, Elanco) when administered orally to dogs, against experimentally induced adult flea infestations and flea egg production. METHODS: Twenty dogs were selected for the study and allocated to two treatment groups. Ten dogs were treated with lotilaner (at the lower half of the recommended dose range of 20-43 mg/kg) on Day 0. Ten dogs treated with placebo tablets served as the control group. Each dog was infested with 100 unfed adult C. felis fleas on days -1, 6, 13, 20 and 29. At 24 h post-treatment or post-infestation, each dog was combed for the removal and counting of adult live fleas. Flea eggs were also collected and counted from the pan under each dog cage. RESULTS: Dogs in the lotilaner treated group received a mean dose of 22.6 mg/kg (range 20.2-25.9 mg/kg) and no adverse events were observed in any dog in this study. At each evaluation time point, the lotilaner group provided 100% efficacy against adult live flea counts as compared to the placebo control group. Egg production from lotilaner treated dogs was reduced by 98.5% (geometric mean; 97.4% arithmetic mean) 24 h post-treatment (and 48 h post-flea infestation). No eggs (100% efficacy) were available for collection following infestations on Day 6 onwards from the lotilaner treated dogs. At each evaluation time point, adult live flea counts from the lotilaner treated dogs were significantly lower (P < 0.0001) than from the placebo control group. CONCLUSIONS: In dogs treated with a single dose of lotilaner (mean dose 22.6 mg/kg), 100% of adult fleas were killed within 24 h post-treatment or post-subsequent infestations as compared to the placebo control group, thereby demonstrating that lotilaner kills fleas before they can lay eggs thus preventing subsequent flea infestations for 30 days after treatment. There were no reported adverse events in any dogs, demonstrating that lotilaner tablets were well tolerated at the dose rates assessed in this study.

Increasing incidence of Dirofilaria immitis in dogs in USA with focus on the southeast region 2013-2016.

BACKGROUND: A recent American Heartworm Society (AHS) survey on the incidence of adult heartworm infections in dogs in the United States of America showed a 21.7% increase in the average cases per veterinary clinic from 2013 to 2016. The analysis reported here was performed to see if heartworm testing results available via the Companion Animal Parasite Council (CAPC) aligned with the AHS survey and whether changes in heartworm preventive dispensing accounts for the increased incidence. The resistance of Dirofilaria immitis to macrocyclic lactones (MLs) has been previously reported. METHODS: An analysis of 7-9 million heartworm antigen tests reported annually to the Companion Animal Parasite Council (CAPC) from 2013 to 2016 was conducted and compared to the 2016 AHS survey. A state-by-state analysis across the southeastern USA was also performed. National heartworm preventive dispensing data were obtained from Vetstreet LLC and analyzed. All oral, topical and injectable heartworm preventives were included in this analysis, with injectable moxidectin counting as six doses. RESULTS: Positive antigen tests increased by 15.28% from 2013 to 2016, similar to the 21.7% increase reported by the AHS survey. Incidence in the southeastern USA increased by17.9% while the rest of USA incidence increased by 11.4%. State-by-state analysis across the southeastern USA revealed an increased positive test frequency greater than 10% in 9 of 12 states evaluated. During this time, the overall proportion of dogs receiving heartworm prophylaxis remained relatively unchanged. Approximately 2/3 of the dogs in the USA received no heartworm prevention each year. CONCLUSION: These CAPC data show the rate of positive heartworm tests increasing significantly (P <  0.0001) in the USA from 2013 to 2016, with a higher rate of increase in the southeastern USA than nationally. Only 1/3 of dogs in the USA were dispensed one or more doses of heartworm prevention annually by veterinarians, averaging 8.6 monthly doses/year. Veterinarians and pet owners should work together to follow CAPC and AHS guidelines to protect dogs from infection with D. immitis. Lack of preventive use and the emergence of heartworm resistance to MLs could both be impacting the increased rate of positive heartworm tests in dogs.

Effects of milbemycin oxime, combined with spinosad, when administered orally to microfilaremic dogs infected with adult heartworms (Dirofilaria immitis).

OBJECTIVE To evaluate the safety of PO administration of a milbemycin oxime (MBO) and spinosad product to heartworm (Dirofilaria immitis)-positive microfilaremic dogs. DESIGN Randomized, blinded, complete block trial. ANIMALS 32 purebred Beagles with a patent heartworm infection. PROCEDURES Dogs ranked by sex and microfilaria counts (range, 398 to 1,980 microfilaria/mL) were assigned to 4 groups of 8 to receive 3 treatments PO at 28-day intervals beginning on day 0: placebo (control group) or spinosad-MBO tablets containing MBO at the upper end of the label dose range (0.75 to 1 mg/kg [0.34 to 0.45 mg/lb]; 1× group) or 3 (3× group) or 5 (5× group) times that dose. Blood samples were collected at various points for adult heartworm antigen and Knott tests. Necropsies were performed on day 65, and recovered adult heartworms were counted. RESULTS 1 control dog died from heartworm-associated complications. Other adverse events included mild, transient emesis (1 dog in each of the 1× and 5× groups and 3 dogs in the 3× group). Similar adult heartworm counts (range, 13 to 41) were obtained for all 4 groups. Results of blood antigen and microfilaria tests were positive throughout the study, with 1 exception in each of the 3× and 5× groups. Mean microfilaria counts increased with time in the control group, whereas reductions from baseline in treated groups ranged from 61.5% to 96.4%. CONCLUSIONS AND CLINICAL RELEVANCE The evaluated MBO-spinosad formulation caused no severe adverse events when administered PO to microfilaremic dogs. Although microfilaria counts decreased following treatment, repeated monthly MBO treatments were incompletely microfilaricidal, suggesting MBO should not be used as a microfilaricide.

Survey of European pet owners quantifying endoparasitic infection risk and implications for deworming recommendations.

BACKGROUND: Zoonotic endoparasites pose risks to pets and people. The European Scientific Counsel Companion Animal Parasites (ESCCAP) created risk groupings for dogs (A-D) and for cats (A-B), with the highest risk pets (Group D dogs and Group B cats) receiving the most frequent testing and/or deworming recommendations. Little information exists on current deworming behaviours across Europe, alignment to accepted guidelines and the percentage of dogs and cats falling into ESCCAP groups. The study objectives were to evaluate the reported infection-risk behaviours of dogs and cats and assesses whether deworming frequency reported by pet owners complied with recommended deworming frequencies. METHODS: A total of 5001 pet owners from five different countries (France, Germany, Spain, Sweden and the UK) were surveyed regarding endoparasite infection risk and the frequency of deworming of dogs and cats. For the purposes of this study, ESCCAP risk groups for cats (A-B) were converted into four risk groups (A-D) using the additional risk factors outlined in the ESCCAP guidelines. This allowed direct comparison between cats and dogs as well as grouped higher risk cats into the appropriate deworming frequency. RESULTS: The three most common risk factors identified for dogs were contact with: other dogs, snails or prey; children or the elderly; going off lead outside their own garden. 85-98% of all dogs had risks putting them into Group D, the highest risk group. The three most common risk factors identified for cats were: hunting; catching prey; contact with children or the elderly. Using these revised groups, 33-68% of cats were in Group D. Despite the majority of dogs and cats falling into a risk category where ESCCAP recommends monthly deworming, dogs and cats averaged 2.3 and 2.2 dewormings per year, respectively. This frequency was less than the four times a year dosing frequency demonstrated to be required to reduce zoonotic Toxocara spp. ova shedding. CONCLUSIONS: Overall, 93% of dogs and 54% of cats fell into Group D, the highest risk group. Deworming frequencies were considerably less than recommended by ESCCAP or required to both reduce zoonotic risk and improve pet health. Improved treatment compliance is needed.

Efficacy of lotilaner (Credelio™), a novel oral isoxazoline against naturally occurring mange mite infestations in dogs caused by Demodex spp.

BACKGROUND: The oral systemic efficacy of lotilaner (Credelio™, Elanco) was evaluated against Demodex spp. in naturally infested dogs with generalized demodicosis. METHODS: In this study, 10 dogs with clinical signs of generalized demodicosis and positive for Demodex spp. mites based on skin scrapings were assigned to a single group orally treated with lotilaner (minimum dose of 20 mg/kg) on Days 0, 28 and 56. RESULTS: For lotilaner-treated dogs, pre-treatment mite counts based on skin scrapings performed at five different sites were reduced by > 99.9% (P < 0.0001) up to 56 days after the first and second monthly doses. No live mites were detected after Day 56 out to and including Day 84 post-treatment for 100% efficacy of each dog's Demodex mite infestation. Nine of 10 dogs were 100% mite-free from Day 28 (first evaluation) through Day 84 (end of study) and live mites were only found once on one dog (Day 56) following treatment with lotilaner. All dogs in the lotilaner-treated group showed marked improvement in the clinical signs of demodicosis and there were no drug associated adverse events. A marked improvement in hair re-growth was observed in all the dogs from 6 weeks following initiation of treatment. CONCLUSIONS: In this study lotilaner administered at a minimum oral dose of 20 mg/kg was highly effective in reducing and eliminating live mite counts in dogs with natural infestations of Demodex spp.

A randomized, controlled field study to assess the efficacy and safety of lotilaner flavored chewable tablets (Credelio™) in eliminating fleas in client-owned dogs in the USA.

BACKGROUND: Preclinical studies have shown that the novel isoxazoline, lotilaner (Credelio™, Elanco) administered orally to dogs, produces rapid flea and tick knockdown and sustained speed of kill for at least a month post-treatment with a wide safety margin. A field study was undertaken to validate pre-clinical results. METHODS: Dogs were enrolled at 10 veterinary clinics across the United States. Qualifying households containing up to three dogs and one primary dog with at least 10 fleas were randomized 2:1 to receive lotilaner (Credelio™, Elanco) at the recommended minimum dose of 20 mg/kg, or afoxolaner (Nexgard®, Merial), administered per label, to give a minimum dose of 2.5 mg/kg. Treatments were dispensed on Days 0, 30 and 60 for administration by owners; all household dogs received the same treatment as the primary dog. Post-enrollment flea and tick counts were made on primary dogs on Days 30, 60 and 90, and all dogs were assessed for tablet palatability and safety. RESULTS: For efficacy assessments, data were used from 111 lotilaner-treated dogs and 50 afoxolaner-treated dogs; for safety, 197 and 86 dogs, respectively. Percent reductions from baseline in geometric mean flea counts for the lotilaner group were 99.3, 99.9 and 100% on Days 30, 60 and 90, respectively, and for afoxolaner 98.3, 99.8 and 99.8% (P < 0.001, both groups, all days). On Day 90, 100% of lotilaner-treated dogs and 93% of afoxolaner-treated dogs were flea-free. Too few ticks were present to allow assessment. There were no differences in palatability between products (P = 0.2132), with, respectively, 94% and 96% of lotilaner and afoxolaner treatments accepted when offered by hand, in an empty food bowl or with food. Both treatments were well tolerated, alleviating clinical signs of flea allergy dermatitis (FAD) in dogs affected at enrollment. CONCLUSION: A single owner-administered lotilaner treatment was greater than 99% effective in reducing mean flea counts within 30 days. Three consecutive monthly lotilaner treatments resulted in a 100% reduction in flea infestations, and a substantial reduction in signs of FAD. Lotilaner flavored tablets were readily accepted under field conditions. The absence of treatment-related adverse events confirms the safety of lotilaner in dogs.

Laboratory evaluations of the immediate and sustained efficacy of lotilaner (Credelio™) against four common species of ticks affecting dogs in North America.

BACKGROUND: Effective control of tick infestations on dogs is important to reduce the risk of transmission of bacterial, viral, and protozoal pathogens. Laboratory studies were initiated to determine the efficacy of lotilaner against common ticks infesting dogs in the United States. METHODS: Eight studies investigated the efficacy of lotilaner against ticks. In two studies dogs were infested with both Dermacentor variabilis and Rhipicephalus sanguineus: one additional study was completed for each of these species. Two studies assessed infestations with Amblyomma americanum and two with Ixodes scapularis. In all studies, dogs were ranked and blocked by counts from pre-treatment infestations and randomly allocated, at least eight per group, to be treated orally with lotilaner (minimum dose rate 20 mg/kg), or to be untreated controls. Treatments were administered on Day 0, within 30 min after dogs were fed. In all studies, infestations were performed with 50 adult ticks on Days -2, 7, 14, 21 and 28, and also on Day 35 for R. sanguineus, D. variabilis and I. scapularis. Tick counts were completed 48 h after treatment or after each subsequent challenge. An adequate infestation was defined as at least 25% of the infestation dose recovered from each of at least six control animals at each evaluation. Efficacy calculations for the primary objective were based on geometric means. RESULTS: In all studies, lotilaner was 100% effective against existing infestations. For post-treatment assessments, on only two occasions did efficacy fall below 99%: in one D. variabilis study efficacy was 98.0% on Day 35 and in one I. scapularis study efficacy on Day 16 was 98.4%. Only mild and transient adverse events were observed, and none were considered to be related to treatment. CONCLUSION: Lotilaner was completely effective against existing infestations with four common species of ticks, D. variabilis, R. sanguineus, A. americanum and I. scapularis, that affect dogs in North America, with at least 4 weeks efficacy of 98.0% or more against subsequent challenge infestations. These results show that lotilaner is a highly effective isoxazoline that offers sustained efficacy against ticks through and beyond the one-month end-of-dose treatment interval.

Field evaluation of the efficacy and safety of a combination of spinosad and milbemycin oxime in the treatment and prevention of naturally acquired flea infestations and treatment of intestinal nematode infections in dogs in Europe.

Two separate randomised, blinded, multicentre field trials were conducted to evaluate the efficacy and safety of a combination of spinosad and milbemycin oxime (MO) (Trifexis(®), Elanco Animal Health) in the treatment and prevention of naturally acquired flea infestations and intestinal nematode infections in European dogs. Treatments using Trifexis(®) and each control veterinary product (CVP) were administered once on Day 0 in both field studies. In the flea field trial, 11 veterinary clinics in France participated in the study. On Day 0, whole body flea comb counts were conducted on all dogs being evaluated for enrolment. Dogs with ≥7 fleas on Day 0 were enrolled, treated once on Day 0 with spinosad/MO or the CVP (Stronghold(®); selamectin) and then underwent post-treatment flea counts on Days 14 and 30. There were 150 spinosad/MO treated dogs and 71 CVP treated dogs included in the flea effectiveness population. Effectiveness against fleas (% reduction in geometric means; GM) was 98.97% and 97.37% for the spinosad/MO treated dogs, and 97.43% and 93.96% for the CVP dogs on Days 14 and 30, respectively, compared to the pre-treatment baseline flea counts. Of the spinosad/MO dogs, 89.3% and 80.0% had no live fleas on Days 14 and 30, compared to 77.5% and 70.4% of the CVP dogs, respectively. In the nematode field trial, data from 10 veterinary clinics in France and 19 in Ireland were pooled. Faecal samples from dogs at each clinic were analysed. A positive result at screening (parasite eggs from Toxocara canis, Toxascaris leonina, Trichuris vulpis or Ancylostoma caninum) allowed for enrolment. Dogs were randomised to spinosad/MO or the CVP (Milbemax(®); MO/praziquantel). On Day 8, a post-treatment faecal sample was taken and analysed. Of 2333 dogs screened for nematode eggs, 238 dogs were positive with one or more of these nematodes, and 229 were enrolled in the study. Of the 229 dogs, 151 were treated with a single dose of spinosad/MO, and 77 were treated with a single dose of CVP. Post-treatment effectiveness against all nematodes (% reduction GM) was achieved with reductions of 98.57% and 97.57% for the spinosad/MO treated dogs and CVP dogs, respectively, as compared to the pre-treatment baseline faecal egg counts. Trifexis(®) was shown to be safe and effective against natural infestations of fleas as well as mixed and single intestinal nematode infections in client owned dogs in Europe when administered as a single oral administration at the recommended dose.

Efficacy of milbemycin oxime in combination with spinosad in the treatment of larval and immature adult stages of Ancylostoma caninum and Toxocara canis in experimentally infected dogs.

Ancylostoma caninum and Toxocara canis are two important zoonotic parasites of dogs. The primary objective of these studies were to confirm the oral effectiveness of milbemycin oxime (MO) and spinosad in dogs experimentally infected with immature (L4 and immature adult) stages of T. canis or A. caninum. Both trials were conducted as randomized, blinded, placebo-controlled dose confirmation studies. Treatments using the intended European commercial tablet formulation of Trifexis were administered in a timeframe relative to inoculation so that effectiveness could be assessed against specific immature stages of A. caninum or T. canis. In each study on Day 0, each of 32, 3-4 month old dogs were inoculated with 250 infective eggs of T. canis or 300 infective L3 of the hookworm, A. caninum. All dogs were weighed before their scheduled treatment, randomized to 1 of the 4 treatment groups in each study (8 dogs/group). All dogs were fed just prior to dosing. For T. canis, dogs were treated orally with an MO/spinosad tablet on Day 14 or Day 24. For A. caninum, dogs were treated orally with an MO/spinosad tablet on Day 7 or Day 11. Corresponding control groups in each study received a placebo tablet. Dogs were necropsied 5 or 6 days after their respective treatments. The digestive tract was removed and processed to recover, count, and identify all stages. The GM worm count for the MO/spinosad tablet on Day 14 (L4 T. canis) was 0.0, with efficacy calculated as 100%; however, only 3 of 8 control dogs had adequate infections. The GM worm count for the MO/spinosad tablet on Day 24 (immature adult stage) was 0.30; efficacy calculated at 96.15%. This is based on 5 of the 8 control dogs with adequate infections. In the two A. caninum studies, GM worm counts for the MO/spinosad tablets on Day 7 (L4 efficacy) was 2.37 and 0.8 with efficacy calculated as 98.92% and 99.25%, respectively. The GM count for the group treated with the MO/spinosad combination on Day 11 (immature adult) was 6.19 and 1.4; efficacy calculated at 97.77% and 98.58%, respectively. A minimum MO oral dose of 0.75 mg/kg was highly effective for the treatment of immature stages of T. canis and A. caninum infections in dogs. The ability to kill immature stages of these two parasites before they become patent will benefit dogs, their owners and family members due to reduced exposure to these potentially zoonotic parasites.

Speed of kill efficacy and efficacy of flavored spinosad tablets administered orally to cats in a simulated home environment for the treatment and prevention of cat flea (Ctenocephalides felis) infestations.

The efficacy of spinosad against adult fleas (Ctenocephalides felis) on cats was evaluated in two separate controlled, blinded studies-one to determine flea knockdown and speed of flea kill (SOFK) on experimentally infested cats, another to assess the ability of spinosad to prevent flea infestations in a simulated home environment (SHE) study design. In each study, pre-treatment live flea counts were used as a blocking factor to randomize cats to treatment, and treated in the fed state, with flavored tablets containing either no active ingredient (control) or spinosad (50-100mg/kg in the SOFK study; 50-75 mg/kg body weight in the SHE study). In the SOFK study, 6 cats per group were infested with unfed adult fleas on Day -1. Groups 1-5 received control tablets; groups 6-10 received spinosad tablets. Flea counts were conducted at 0.5, 2, 4, 8 and 24h post-dosing. In the SHE study, 12 flea-free cats per group, treated on Days 0, 30 and 60, were maintained in solid-sided cages with solid carpeted floors. Each cat was infested on Days 1, 7 and 14 with 100 unfed adult fleas. Individual flea comb counts were performed on Days 3, 9, 16, 21, 28, 35, 42, 49, 56, 63, 70, 77, 84, 91 and 95. After each count, except Day 95, up to 300 live fleas were replaced on each cat. To augment flea challenge, the carpeted area in each cage was sprinkled weekly with larval flea growth media (dried blood, yeast). In the SOFK study, reductions in mean flea counts in the spinosad groups were observed at all post-treatment assessments, beginning at 0.5h post-infestation with significant differences (p<0.0001) from vehicle-treated cats from 2h post-treatment when efficacy was >90%, through the final flea counts 24h post-infestation when no fleas were found on spinosad treated cats. In the SHE study, GM post-treatment flea counts in the control group ranged between 38.9 and 107.0 (arithmetic means 58.8-118.1); no live fleas were combed from spinosad-treated cats (100% effectiveness) at any time point post-treatment. No adverse events that were attributable to the treatments were observed in either study. These studies demonstrated that spinosad administered orally to cats is safe and effective, providing >90% efficacy from 2h post-dosing and 100% knockdown at 24h, and preventing infestations over a 95 day study period from a flea-contaminated simulated home environment.

Safety and efficacy of spinosad chewable tablets for treatment of flea infestations of cats.

OBJECTIVE: To compare safety and efficacy of spinosad and selamectin and determine effects of those products on flea allergy dermatitis (FAD) in cats. DESIGN: Randomized clinical trial. Animals-211 client-owned cats. PROCEDURES: Cats with ≥ 5 fleas evaluated at 8 veterinary clinics were allocated to receive spinosad (50 to 100 mg/kg [22.7 to 45.5 mg/lb], PO; n = 139) or selamectin (≥ 6 mg/kg [≥ 2.7 mg/lb], topically; 72) once per month. Flea comb counts and FAD scores were determined on day -1, between days 27 and 33, and between days 85 and 95 (evaluations 1, 2, and 3, respectively); day 0 was the first day of drug administration. RESULTS: The most common adverse event was vomiting (14.3% and 2.4% of spinosad- and selamectin-treated cats, respectively). Evaluation 2 and 3 geometric mean flea counts for spinosad-treated cats were significantly lower than those for selamectin-treated cats. Percentage reductions in flea counts for the spinosad and selamectin groups were 97.5% and 88.8% (evaluation 2) and 99.3% and 97.7% (evaluation 3), respectively. At evaluations 2 and 3, 70.6% and 92.6% of spinosad-treated cats and 29.4% and 64.7% of selamectin-treated cats were free of fleas, respectively. Weighted FAD scores for spinosad- and selamectin-treated cats decreased 94.2% and 80.0% during the study, respectively. Spinosad tablets were successfully administered during 98.1% of treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated spinosad and selamectin both reduced flea counts and FAD scores for cats, although spinosad was more effective. Monthly oral administration of spinosad may be practical for treatment of flea infestations and FAD in cats.