Safety and efficacy of a novel oral chewable combination tablet containing sarolaner, moxidectin and pyrantel (Simparica Trio™) against natural flea infestations in client-owned dogs in the USA.

BACKGROUND: One randomized, controlled clinical field study was conducted in 18 general veterinary practices throughout the USA to evaluate the safety and efficacy of a novel oral chewable combination tablet, Simparica Trio™, containing sarolaner, moxidectin and pyrantel for the treatment and prevention of fleas on dogs. METHODS: Client-owned dogs, from households of three or fewer dogs were eligible for enrollment. Four hundred and twenty-two dogs from 251 households were enrolled. Households were randomly assigned in a 2:1 ratio to treatment with either Simparica Trio™ at the minimum label dose of 1.2 mg/kg sarolaner, 24 µg/kg moxidectin and 5 mg/kg pyrantel (as pamoate salt) or afoxolaner (NexGard®, Boehringer-Ingelheim) at the label dose. One dog per household was selected as the primary dog for efficacy evaluations. Treatments were dispensed and dogs were dosed in their home environment on Day 0 and on approximately Day 30. Flea counts and examination for clinical signs of flea allergy dermatitis (FAD) were performed at the initial visit the day before or on Day 0 prior to treatment and on Days 30 and 60. Additionally, all dogs were examined for general health at each visit and blood and urine were collected for clinical pathology at screening and Day 60. RESULTS: Simparica Trio™ reduced geometric mean live flea counts by 99.0% by Day 30 and by 99.7% by Day 60. As a result of the rapid reduction in flea infestations, clinical signs associated with FAD substantially improved following treatment. Simparica Trio™ was well-tolerated and a diverse range of concomitant medications were administered to dogs during the course of the study. Simparica Trio™ chewable tablets were well-accepted by dogs, with the majority of flavored chewable tablets (91.9%) voluntarily consumed by free choice without, or when offered in food. CONCLUSIONS: Simparica Trio™ administered orally once monthly for two consecutive treatments was safe and effective against natural flea infestations and substantially improved clinical signs associated with FAD in client-owned dogs in a field study conducted in the USA.

Laboratory and field studies to investigate the efficacy of a novel, orally administered combination product containing moxidectin, sarolaner and pyrantel for the prevention of heartworm disease (Dirofilaria immitis) in dogs.

BACKGROUND: Dirofilaria immitis is a filarial parasite of dogs that can cause serious or fatal cardiopulmonary disease. Three studies were conducted to evaluate the efficacy and safety of monthly treatment with moxidectin in a chewable tablet product in combination with sarolaner and pyrantel to prevent heartworm disease in dogs after experimental challenge and in a clinical field study in the USA. METHODS: In two laboratory studies, dogs (8 per group) that had been inoculated 30 days prior with 50 third-stage D. immitis larvae were randomized to treatment on Day 0 with placebo or combination product, at the minimum dose of 24 µg/kg moxidectin, 2 mg/kg sarolaner and 5 mg/kg pyrantel (as pamoate salt). Study 2 also included groups treated with tablets containing moxidectin-alone (24 µg/kg) or sarolaner-alone (2 mg/kg). Efficacy was evaluated ~ 5 months after inoculation by adult heartworm counts at necropsy. In the field study, 410 dogs ≥ 8 weeks-old from 23 USA veterinary clinics were treated for 11 months with either combination product at 24-48 µg/kg moxidectin, 2-4 mg/kg sarolaner and 5-10 mg/kg pyrantel (n = 272) or Heartgard® Plus (ivermectin/pyrantel) at the label recommended dose rate (n = 138). Efficacy was evaluated on Day 330 using antigen and microfilaria testing to assess adult heartworm infection. RESULTS: In the laboratory studies, there were no heartworms recovered from any dog treated with the combination product or moxidectin alone and all dogs treated with placebo or sarolaner-alone were infected with 20-44 adult heartworms. In the field study, all dogs treated with the combination product tested negative for heartworm infection on Day 330, whereas two dogs treated with Heartgard® Plus tested positive. The Heartgard® Plus-treated dogs that tested heartworm positive were from the lower Mississippi River Valley region, where heartworm resistance has been confirmed to occur. The combination product was well tolerated in all studies. CONCLUSIONS: In laboratory studies, no heartworms were recovered from dogs treated with a single dose of the novel combination product containing moxidectin, sarolaner and pyrantel. Additionally, in the field study no dog tested positive for adult heartworm infection when dosed with the combination product monthly for 11 months, while two dogs treated with Heartgard® Plus tested positive.

Efficacy of a topical formulation of selamectin plus sarolaner against induced infestations of Amblyomma americanum on cats and prevention of Cytauxzoon felis transmission.

Cytauxzoonosis, caused by infection with Cytauxzoon felis, is the most severe tick-borne disease of cats. The purpose of our study was to determine the efficacy of selamectin (6.0 mg/kg) plus sarolaner (1.0 mg/kg) formulated in combination (Revolution® Plus / Stronghold® Plus, Zoetis) applied topically once a month on cats for three months against induced infestations of Amblyomma americanum adults and to evaluate the effectiveness of the product in preventing the transmission of C. felis. This study was conducted in two phases. Sixteen cats were dosed with selamectin/sarolaner or a placebo (vehicle control) on Days 0, 28, and 56. In phase 1, each cat was infested with 50 (±5) unfed adult A. americanum on Day 4 and tick counts were conducted on Day 6 (48 h post infestation) and Day 7 (72 h post infestation) to evaluate acaricidal efficacy. In phase 2, to confirm acaricidal efficacy and evaluate prevention of C. felis transmission, each cat was infested on Day 60 with 50 (±5) adult A. americanum acquisition fed as nymphs on two C. felis-infected donor cats. Tick counts were conducted on Day 62 (48 h post infestation) and Day 63 (72 h post infestation). Blood samples were collected on Days -9, 60, 70, 76, and 90 and tested for infection with C. felis. Placebo cats were adequately infested on all count days, with least squares (geometric) mean live tick counts ranging from 34.0 (28.8) to 46.1 (46.0). Treatment reduced the least squares (geometric) mean counts compared to placebo by 27.1 (32.1)% and 90.4 (96.8)% on Days 6 and 7, respectively. The corresponding percent reductions were 56.4 (60.6)% and 94.7 (97.3)% on Days 62 and 63, respectively. Least squares mean counts were significantly lower in the treated group compared with the placebo group on all count days (P ≤ 0.0286). All cats were negative for C. felis by PCR prior to study start. In phase 2, seven cats in the control group and no cats in the selamectin/sarolaner group became infected with C. felis (P = 0.0017). Topical treatment with selamectin/sarolaner was >90% effective in reducing A. americanum tick counts 72 h after infestation and prevented the transmission of C. felis from infected ticks following the third of three monthly treatments. Revolution® Plus / Stronghold® Plus offers an option for the control of A. americanum infestations on cats and for preventing the transmission of C. felis to cats.

Efficacy and safety of a new topical formulation of selamectin plus sarolaner in the treatment and control of natural infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States.

A new topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) was evaluated in the treatment and control of naturally occurring infections of Ancylostoma tubaeforme and Toxocara cati in cats presented as veterinary patients in the United States. Three thousand three hundred three (3303) cats were screened in 25 veterinary practices in 15 states and 153 hookworm-positive cats (A. tubaeforme and/or A. braziliense), mainly from Alabama, Mississippi, Texas, and Hawaii, were identified; 135 cats met all the criteria for enrollment and were included on study. The cats were randomly assigned to treatment with Revolution® (at the label dosage, to provide a minimum dosage of 6 mg/kg selamectin) or selamectin plus sarolaner (at a dosage of 6-12 mg/kg plus 1-2 mg/kg, respectively). Treatments were administered at the time of enrollment and repeated 30 days later. Fecal samples were collected for differential fecal egg count prior to the first treatment (Day 0), prior to the second treatment (Day 30), and approximately 30 days later (Day 60). Efficacy was based on the percentage reductions in geometric mean fecal egg count for A. tubaeforme on Day 30 and Day 60 compared with Day 0. Where cats were co-infected with T. cati, efficacy against this species was also evaluated. Efficacy data were evaluated for A. tubaeforme for 40 cats on both Day 30 and Day 60 for the group treated with the selamectin/sarolaner combination and reductions in geometric mean fecal egg counts of 99.4% and 99.7% were demonstrated for Day 30 and Day 60, respectively. For the group treated with selamectin alone, 44 and 40 cats were evaluated and percent reductions for Day 30 and Day 60 were 99.5% and 99.9%, respectively. For T. cati, 14 cats were evaluated in the selamectin/sarolaner-treated group for Day 30 and for Day 60, and the reduction in geometric mean fecal egg count was 100% for both days. There were 11 and 9 cats evaluated for Day 30 and Day 60, respectively, for the selamectin-treated group and the reduction was again 100% for both days. The geometric mean fecal egg counts post-treatment were significantly lower than pre-treatment for both A. tubaeforme and T. cati, for both treatments, and for both periods of interest (P < 0.0001). No serious adverse events related to treatment with either product occurred during the study. Thus, both selamectin alone and the combination product of selamectin/sarolaner were safe and effective when administered on a monthly basis for the treatment and control of natural infections of A. tubaeforme and T. cati. The addition of sarolaner to the formulation did not interfere with the efficacy of selamectin against these nematodes.

The efficacy of a novel topical formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing the development of Dirofilaria immitis in cats.

Three controlled studies were conducted to investigate the efficacy of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) in preventing feline heartworm disease in cats. In all studies, cats were inoculated with 100 Dirofilaria immitis third stage larvae on Day -30. In the first study, cats were treated with selamectin plus sarolaner as a single dose on Day 0 or as three consecutive monthly doses on Days 0, 28 and 56. In the second and third studies, cats were treated with either sarolaner alone on Day 0, selamectin plus sarolaner on Day 0 or selamectin plus sarolaner as three consecutive monthly doses on Days 0, 28 and 56. In all three studies, dosages were 6 mg/kg selamectin plus 1 mg/kg sarolaner or 1 mg/kg sarolaner alone. Control cats were given a placebo containing inert formulation ingredients (vehicle). All treatments were administered at a single site topically to the skin cranial to the scapulae. Cats were humanely euthanized on Day 145/146 (i.e., 175/176 post-inoculation), and adult D. immitis worms were recovered and enumerated. Across the three studies, adult heartworms were recovered from 87 to 100% of control cats, with geometric mean worm counts ranging from 2.1 to 5.4. No adult D. immitis worms were recovered from cats treated with selamectin plus sarolaner. Cats treated with sarolaner alone were not protected against D. immitis infection, showing geometric mean worm counts of 1.9 to 2.4. In these studies, selamectin (6 mg/kg) plus sarolaner (1 mg/kg) was 100% effective in preventing heartworm development in cats when administered topically as one dose 30 days after inoculation or as three consecutive monthly doses starting 30 days post-inoculation. These studies demonstrated that a single topical administration of selamectin plus sarolaner at the recommended dosage was completely effective in preventing the development of D. immitis in cats.

Efficacy and safety of a combination of selamectin plus sarolaner for the treatment and prevention of flea infestations and the treatment of ear mites in cats presented as veterinary patients in the United States.

Two randomised, single-masked, multi-center field studies were conducted in the United States in cats presented as veterinary patients. The first study evaluated the efficacy and safety of a topically applied formulation of selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus, Zoetis) against natural flea infestations; the second study evaluated its efficacy against natural ear mite infestations. The product was administered topically by the cats' owners at the dose range provided in the market product of 6.0-12.0 mg selamectin and 1.0-2.0 mg sarolaner per kg bodyweight. Imidacloprid plus moxidectin (Advantage® Multi for Cats, Bayer) was used as a positive control in both studies at the label dosage. In the flea study, treatments were administered on Days 0, 30, and 60. Efficacy was calculated based on the mean percent reduction of live flea counts on Days 30, 60, and 90 relative to the pre-treatment count. In the ear mite study, a single treatment was applied on Day 0 and efficacy was determined on Days 14 and 30 based on the presence or absence of ear mites. In both studies, patients were randomly allocated to treatments in the ratio of 2:1, selamectin plus sarolaner: imidacloprid plus moxidectin. In the two studies, 405 cats received treatment with selamectin plus sarolaner; of these, 256 cats received three monthly treatments in the flea study. There were no serious adverse reactions to treatment with selamectin plus sarolaner; health issues noted were typical of the normal ailments or minor traumatic injuries expected in the general cat population and were similar in both treatment groups. Efficacy against fleas based on geometric (arithmetic) means was 97.2% (95.9%), 99.5% (99.4%), and 99.8% (99.8%) in the selamectin plus sarolaner group and was 79.7% (70.5%), 91.4% (77.3%), and 95.5% (87.4%) in the imidacloprid plus moxidectin group on Days 30, 60, and 90, respectively. Flea counts for the selamectin plus sarolaner group were significantly lower than the counts for the imidacloprid plus moxidectin group at all time-points after treatment administration on Day 0 (P < 0.001). Treatment reduced the clinical signs of flea allergy dermatitis (alopecia, dermatitis/pyodermatitis, erythema, pruritus, scaling, and papules) in affected cats by 86.7%-100% in the selamectin plus sarolaner group and by 66.7%-100% in the imidacloprid plus moxidectin group. In the ear mite study, a single application of selamectin plus sarolaner resulted in the clearance of mites from 87.5% of cats within 14 days and 94.4% of cats within 30 days of treatment. The respective percentages of mite-free cats in the imidacloprid plus moxidectin group were 64.0% and 72.0%. There were significantly more cats with no mites noted in the selamectin plus sarolaner group than in the imidacloprid plus moxidectin group on Day 14 and Day 30 (P ≤ 0.018). Selamectin plus sarolaner (Revolution® Plus/Stronghold® Plus) administered topically at monthly intervals for three months was well tolerated and highly effective for the treatment and prevention of natural infestations of fleas on cats presented as veterinary patients. Clinical signs of flea allergy dermatitis improved in affected cats following treatment administration. A single topical treatment was also safe and highly effective for the treatment of ear mite infestations in naturally infested cats.

Efficacy of a novel oral formulation of sarolaner (Simparica™) against five common tick species infesting dogs in the United States.

The efficacy of a single oral treatment with sarolaner (Simparica™, Zoetis), a novel isoxazoline compound, was evaluated against five tick species known to infest dogs in the United States. A total of 10 laboratory studies, two against each species, were conducted using adult purpose-bred mongrels or Beagle dogs. In each study, 16 dogs were randomly allocated to one of two treatment groups based on pre-treatment host-suitability tick counts. Dogs were infested with approximately 50 unfed adult Amblyomma americanum, Amblyomma maculatum, Dermacentor variabilis, Ixodes scapularis or Rhipicephalus sanguineus ticks on Days -2, 5, 12, 19, 26 and 33. On Day 0, dogs were treated with a placebo or a sarolaner tablet providing a minimum dose of 2 mg/kg. Tick counts were conducted 48h after treatment and after each subsequent weekly re-infestation. There were no treatment-related adverse reactions during any of the studies. Dogs in the placebo-treated group maintained tick infestations throughout the studies. Geometric mean live tick counts were significantly lower (P≤0.0001) in the sarolaner-treated group compared to the tick counts in the placebo group at all timepoints. Treatment with sarolaner resulted in ≥99.6% efficacy against existing infestations of all five tick species within 48h. The efficacy against weekly post-treatment re-infestations of all tick species was ≥96.9% for at least 35 days after treatment. Thus, a single dose of sarolaner administered orally at the minimum dosage of 2mg/kg, resulted in excellent efficacy within 48h against existing tick infestations, and against weekly re-infestations for 35 days after treatment. These studies confirmed that administration of the minimum dose of sarolaner will provide rapid treatment of existing infestations and give at least one month of control against re-infestation by the common tick species affecting dogs in the US.

Effect of linezolid on the 50% lethal dose and 50% protective dose in treatment of infections by Gram-negative pathogens in naive and immunosuppressed mice and on the efficacy of ciprofloxacin in an acute murine model of septicemia.

Murine models of infection were used to study the effect of linezolid on the virulence of Gram-negative bacteria and to assess potential pharmacodynamic interactions with ciprofloxacin in the treatment of these infections, prompted by observations from a recent clinical trial. Naive and immunosuppressed mice were challenged with Klebsiella pneumoniae 53A1109, K. pneumoniae GC6658, and Pseudomonas aeruginosa UC12120 in acute sepsis and pulmonary infection models, using different serial dilutions of these pathogens (groups of 8 animals each). Linezolid (100 mg/kg/dose) was administered orally at 0.5 and 4.0 h postchallenge in the sepsis model and at 4 h postchallenge followed by 2 days of twice-daily treatment in the pulmonary model. Further, ciprofloxacin alone and in combination with oral linezolid was investigated in the sepsis model. Survival was assessed for 4 and 10 days postchallenge in the systemic and respiratory models, respectively. The data were fitted to a nonlinear regression analysis to determine 50% lethal doses (LD(50)s) and 50% protective doses (PD(50)s). A clinically relevant, high-dose regimen of linezolid had no significant effect on LD(50) in these models. This lack of effect was independent of immune status. A combination of oral ciprofloxacin with linezolid yielded lower PD(50)s than oral ciprofloxacin alone (ciprofloxacin in combination, 8.4 to 32.7 mg/kg; oral ciprofloxacin, 39.4 to 88.3 mg/kg). Linezolid did not improve the efficacy of subcutaneous ciprofloxacin (ciprofloxacin in combination, 2.0 to 2.4 mg/kg; subcutaneous ciprofloxacin, 2.0 to 2.8 mg/kg). In conclusion, linezolid does not seem to potentiate infections caused by Gram-negative pathogens or to interact antagonistically with ciprofloxacin.