Disposition of gamithromycin in plasma, pulmonary epithelial lining fluid, bronchoalveolar cells, and lung tissue in cattle.

OBJECTIVE: To determine the disposition of gamithromycin in plasma, pulmonary epithelial lining fluid (PELF), bronchoalveolar lavage (BAL) cells, and lung tissue homogenate in cattle. ANIMALS: 33 healthy Angus calves approximately 7 to 8 months of age. PROCEDURES: Calves were randomly assigned to 1 of 11 groups consisting of 3 calves each, which differed with respect to sample collection times. In 10 groups, 1 dose of gamithromycin (6 mg/kg) was administered SC in the neck of each calf (0 hours). The remaining 3 calves were not treated. Gamithromycin concentrations in plasma, PELF, lung tissue homogenate, and BAL cells (matrix) were measured at various points by means of high-performance liquid chromatography with tandem mass spectrometry. RESULTS: Time to maximum gamithromycin concentration was achieved at 1 hour for plasma, 12 hours for lung tissue, and 24 hours for PELF and BAL cells. Maximum gamithromycin concentration was 27.8 µg/g, 17.8 µg/mL, 4.61 µg/mL, and 0.433 µg/mL in lung tissue, BAL cells, PELF, and plasma, respectively. Terminal half-life was longer in BAL cells (125.0 hours) than in lung tissue (93.0 hours), plasma (62.0 hours), and PELF (50.6 hours). The ratio of matrix to plasma concentrations ranged between 4.7 and 127 for PELF, 16 and 650 for lung tissue, and 3.2 and 2,135 for BAL cells. CONCLUSIONS AND CLINICAL RELEVANCE: Gamithromycin was rapidly absorbed after SC administration. Potentially therapeutic concentrations were achieved in PELF, BAL cells, and lung tissue within 30 minutes after administration and persisted for 7 (PELF) to > 15 (BAL cells and lung tissue) days after administration of a single dose.

Occurrence of spvA virulence gene and clinical significance for multidrug-resistant Salmonella strains.

Nontyphoidal Salmonella strains are important reservoirs of antimicrobial resistance. An important issue that has not been investigated is whether the multiresistant Salmonella strains are more virulent than their susceptible counterparts. Salmonella isolates collected from clinical human (n=888) and porcine (n=2,120) cases at the same time period and geographic location were investigated. Antimicrobial susceptibility, PCR analysis for the spvA virulence gene, and pulsed-field gel electrophoresis (PFGE) genotyping were done. Carriage of spvA was associated with multidrug-resistant (MDR) type ACSSuT strains (odds ratio, 7.1; P<0.05), a type often implicated in bacteremic human cases. PFGE revealed that clinical isolates from pigs were more clonally related to those of human origin than the nonclinical porcine isolates. The findings suggest that MDR strains that also carry specific virulence factors are more likely to be of clinical significance.

Longitudinal study of Salmonella dispersion and the role of environmental contamination in commercial swine production systems.

This study investigated the roles of various environmental sources, such as truck-washing systems, waste-processing lagoons, and other sources, as potential contributors to the exposure and dissemination of Salmonella in commercial swine production systems. Four cohorts of nursery age swine herds which originated from distinct farm flows were selected. In addition, cross-sectional sampling of four truck wash stations selected based on the types of disinfectants and sources of water used for sanitizing trucks were tested. Salmonella isolates were recovered from pigs (feces, cecal contents, and mesenteric lymph nodes) and environmental sources (barn floor, lagoon, barn flush, trucks, and holding pens). Antimicrobial susceptibility testing and genotyping were conducted using Kirby-Bauer disk diffusion and amplified fragment length polymorphism, respectively. Salmonella prevalence significantly increased with age from late nursery to slaughter for all of the cohorts (P = 0.007). In two of three instances, all three pig holding pens (lairage) sampled at processing were Salmonella positive. The predominant antibiotypes for all sources included ACSSuT (51.8%), SSuT (16.8%), T (6%), and pansusceptible (7.4%). For the isolates obtained at the farms, the ACSSuT phenotype was 5.6 times more likely to be found in the animals than in the environment (95% confidence interval, 4.4 to 7.2 times). Serogroup B was the most common serogroup (79%), followed by serogroup E (10.4%). Despite the fact that the four production flows were independent, 1 of the 11 genotypic clusters (cluster A1) was commonly detected in any type of sample regardless of its origin. Five of the genotypic clusters (clusters A3, A4, A5, A6, and A7) contained isolates that originated from trucks and lairage swabs and also from cecal contents and/or mesenteric lymph nodes. More interestingly, genotypic clusters A3, A4, and A6 (but not clusters A5 and A7) were not detected on the farms. They originated from the trucks and lairage swabs and then were identified from the cecal contents and/or mesenteric lymph nodes. These findings underscore the significance of various environmental factors, including inadequate truck-washing systems, and emphasize the role of lairage contamination by Salmonella that has food safety significance.

Water-flow variation and pharmacoepidemiology of tetracycline hydrochloride administration via drinking water in swine finishing farms.

OBJECTIVE: To evaluate variation of drinking-water flow rates in swine finishing barns and the relationship between drinker flow rate and plasma tetracycline concentrations in pigs housed in different pens. DESIGN: Cross-sectional (phase 1) and cohort (phase 2) studies. SAMPLE POPULATION: 13 swine finishing farms (100 barns with 7,122 drinkers) in phase 1 and 100 finishing-stage pigs on 2 finishing farms (1 barn/farm) in phase 2. PROCEDURES: In phase 1, farms were evaluated for water-flow variation, taking into account the following variables: position of drinkers within the barn, type of drinker (swing or mounted), pig medication status, existence of designated sick pen, and existence of leakage from the waterline. In phase 2, blood samples were collected from 50 pigs/barn (40 healthy and 10 sick pigs) in 2 farms at 0, 4, 8, 24, 48, and 72 hours after initiation of water-administered tetracycline HCl (estimated dosage, 22 mg/kg [10 mg/lb]). Plasma tetracycline concentrations were measured via ultraperformance liquid chromatography. RESULTS: Mean farm drinker flow rates ranged from 1.44 to 2.77 L/min. Significant differences in flow rates existed according to drinker type and whether tetracycline was included in the water. Mean drinker flow rates and plasma tetracycline concentrations were significantly different between the 2 farms but were not different between healthy and sick pigs. The plasma tetracycline concentrations were typically < 0.3 microg/mL. CONCLUSIONS AND CLINICAL RELEVANCE: Many factors affected drinker flow rates and therefore the amount of medication pigs might have received. Medication of pigs with tetracycline through water as performed in this study had questionable therapeutic value.

Epidemiologic assessment of porcine circovirus type 2 coinfection with other pathogens in swine.

OBJECTIVE: To identify important pathogens and characterize their serologic and pathologic effects in porcine circovirus type 2 (PCV2)-infected pigs in relation to pig age and type of swine production system. DESIGN: Cross-sectional study. ANIMALS: 583 conventionally reared pigs. PROCEDURES: 3- (n = 157), 9- (149), 16- (152), and 24-week-old (125) pigs from 41 different 1-, 2-, and 3-site production systems (5 pigs/age group/farm) were euthanized and necropsied. Pigs with and without PCV2 infection were identified (via PCR assay); infection with and serologic responses to other pathogens and pathologic changes in various tissues (including lungs) were assessed. Logistic regression models were constructed for effects overall and within each age group and type of production system. RESULTS: Compared with PCV2-negative pigs, PCV2-positive pigs were more likely to have swine influenza virus (SIV) type A and Mycoplasma hyopneumoniae infections and sample-to-positive (S:P) ratios for SIV H1N1 from 0.50 to 0.99; also, PCV2-positive pigs had higher serum anti-porcine reproductive and respiratory syndrome virus (PRRSV) antibody titers and more severe lung tissue damage. Infection with SIV (but lower SIV H1N1 S:P ratio) was more likely in 3-week-old PCV2-positive pigs and evidence of systemic disease was greater in 16-week-old PCV2-positive pigs than in their PCV2-negative counterparts. By site type, associations of coinfections and disease effects between PCV2-positive and -negative pigs were greatest in 3-site production systems. CONCLUSIONS AND CLINICAL RELEVANCE: In PCV2-positive pigs, coinfections with SIV, M. hyopneumoniae, and PRRSV are important, having the greatest effect in the early to late nursery phase and in 3-site production systems.

Efficacy of oral afoxolaner plus milbemycin oxime chewables against induced gastrointestinal nematode infections in dogs.

The efficacy of oral afoxolaner plus milbemycin oxime combination chewables against induced gastrointestinal nematode infections in dogs was evaluated in six separate studies. Two studies were performed to evaluate the efficacy of the product against Toxocara canis, two studies evaluated the efficacy against Toxascaris leonina, one study evaluated the efficacy against Ancylostoma braziliense, and one study evaluated the efficacy against Ancylostoma caninum. In the A. caninum study, the efficacy of milbemycin oxime alone and afoxolaner alone was also evaluated. Dogs in all studies were inoculated with infective eggs or larvae and confirmed to have patent infections based on a fecal examination prior to allocation to study group and treatment. Each study utilized a randomized block design with blocks based on pre-treatment body weight. All dogs were assigned to blocks based on body weight, and then each dog within a block was randomly assigned to treatment group. There were two groups of 10 dogs each in the T. canis, T. leonina, and A. braziliense studies: 1) an untreated (control) group and 2) a group treated with afoxolaner plus milbemycin oxime chewables (NexGard Spectra(®), Merial). This group was treated at a dose as close as possible to the minimum effective dose of afoxolaner and milbemycin oxime (2.5mg+0.5mg per kg body weight, respectively) once on Day 0 using whole chews. There were four groups of 10 dogs each in the A. caninum study: 1) untreated (control), 2) NexGard Spectra(®) as described above, 3) milbemycin oxime alone (dose of at least 0.5mg per kg of body weight) and 4) afoxalaner alone (dose of at least 2.5mg per kg body weight). For parasite recovery and counts, dogs were euthanized humanely and necropsied seven days after treatment. The efficacy of the afoxolaner plus milbemycin oxime combination was ≥98% against T. canis, ≥95.8% against T. leonina, and 90.2% against A. braziliense. Efficacy of the combination against A. caninum was 99.7%, while the efficacy of milbemycin oxime alone was 99.6% and the efficacy of afoxolaner alone was 2.1%. Dogs treated with afoxolaner plus milbemycin oxime chewables had significantly (p≤0.0002) fewer nematodes than the untreated controls in all studies. There were no adverse events or other health problems that were related to treatment with Nexgard Spectra(®) in these studies. The results of these controlled studies demonstrate the high efficacy of the afoxolaner plus milbemycin oxime chewables against a broad range of canine intestinal nematode infections.

Efficacy of afoxolaner plus milbemycin oxime chewable tablets against naturally acquired intestinal nematodes in dogs.

The efficacy of oral afoxolaner plus milbemycin oxime combination chewable tablets (NexGard Spectra, Merial) against naturally acquired intestinal nematode infections in dogs was evaluated in six negative control, blinded studies including a total of 114 dogs. Dogs were selected based on a pre-treatment fecal examination indicating patent infections with hookworms (two studies), Toxocara or Toxascaris ascarids (one study each) or Trichuris whipworms (two studies). In each study, dogs were assigned to blocks of two animals each, based on decreasing pre-treatment body weight and were randomly allocated to one of two groups consisting of eight, nine or 10 dogs: untreated (control) or treated with the combination chewable tablet formulation. Chewable tablets were combined to provide doses of actives as close as possible to the minimum effective dose of afoxolaner and milbemycin oxime, i.e., 2.5 mg/kg body weight and 0.5 mg/kg body weight, respectively, once on Day 0. For parasite recovery and count, dogs were euthanized humanely and necropsied seven or eight days after treatment. A single treatment with afoxolaner plus milbemycin oxime chewable tablets provided 94.8% and 90.9% efficacy against adult Ancylostoma braziliense and A. caninum, respectively, 97.8% and 99.4% efficacy against adult Toxocara canis and Toxascaris leonina, respectively, and ≥98.3% efficacy against adult Trichuris vulpis. Compared to untreated controls, nematode counts of the treated dogs were significantly reduced (F-test; p<0.002). In addition, analysis of the pooled data across studies revealed that treatment with afoxolaner plus milbemycin oxime chewable tablets reduced adult Uncinaria stenocephala burdens by 74.9% (p=0.002). All dogs tolerated the treatment well based on clinical observations post-treatment and daily clinical observations. No adverse experiences or other clinical problems related to the treatment were observed throughout the studies. The results of this series of controlled studies demonstrated high efficacy and excellent acceptability and safety of the afoxolaner plus milbemycin oxime chewable tablets when administered for treatment of a broad range of canine intestinal nematode infections.

Efficacy of afoxolaner against Dermacentor variabilis ticks in dogs.

Efficacy of afoxolaner, a novel isoxazoline insecticide/acaricide, against Dermacentor variabilis ticks was confirmed in two laboratory studies. Each study utilized a controlled, randomized block design. One day prior to treatment, beagle dogs were infested with 50 unfed adult ticks. Repeat infestations were performed weekly for four weeks. The number of live ticks remaining on each dog was determined 48 h after treatment and after each subsequent infestation. A single oral treatment with a dose approaching the minimum effective dose of afoxolaner (2.5mg/kg) eliminated the pre-existing infestations by D. variabilis ticks and controlled weekly re-infestations with 99.7-100% efficacy up to Day 23 and >97% efficacy at Day 30.