Tildipirosin

Tildipirosin(Zuprevo) is a novel 16-membered macrolide for treatment, control, and prevention of bovine respiratory disease; inhibits protein synthesis on the ribosome (IC50= 0.23 ± 0.01 μM).

Pharmacokinetics of tildipirosin in pig tonsils.[Pubmed:26935349]

J Vet Pharmacol Ther. 2016 Apr;39(2):199-201.

The penetration of antimicrobials in pig tonsils is hardly known. The objective of the study was to quantify the Tildipirosin (TD) penetration in tonsils. Animals were randomly divided into six groups (control, T1, T2 (1), T2(5), T2(10), and T2(15)) of eight animals. T1 and T2 groups received a dose of 2 and 4 mg of TD/kg bw in one shot (Zuprevo(R) MSD Animal Health), respectively, and the control group received 2 mL of saline solution. The animals were sacrificed by intravenous administration of pentobarbital sodium 24 h after finishing the treatment for the control, T1, and T2(1) groups, whereas animals of T2(5), T2(10), and T2(15) groups were sacrificed at 5, 10, and 15 days, post-treatment, respectively. Tonsils and blood samples were taken at necropsy to obtain plasma, and the Tildipirosin concentration was determined by high-performance liquid chromatography with tandem mass spectrometry detection. The concentration in plasma was always significantly lower than in tonsil. Average TD tonsil concentrations increased significantly in a dose-dependent manner, and the tonsil TD vs. plasma TD concentration ratio was approximately 75 for the doses of 2 and 4 mg of TD/kg bw at 24 h post-treatment. Moreover, the maximum concentration of Tildipirosin in tonsil was observed at 1 day postadministration, and this concentration decreased gradually from this day until 15 days postadministration for the dose of 4 mg of TD/kg bw. Finally, the ratio AUCtonsil/AUCplasma was 97.9, and the T1/2 (h) was clearly higher in tonsil than in plasma.

Clinical disease and lung lesions in calves experimentally inoculated with Histophilus somni five days after metaphylactic administration of tildipirosin or tulathromycin.[Pubmed:27027834]

Am J Vet Res. 2016 Apr;77(4):358-66.

OBJECTIVE: To compare clinical disease and lung lesions in calves experimentally inoculated with Histophilus somni 5 days after metaphylactic administration of Tildipirosin or tulathromycin. ANIMALS Twenty-four 3-month-old Holstein and Holstein-crossbreed steers. PROCEDURES: Calves were randomly allocated to 3 groups of 8 calves. On day 0, calves in group 1 received Tildipirosin (4 mg/kg, SC), calves in group 2 received tulathromycin (2.5 mg/kg, SC), and calves in group 3 received isotonic saline (0.9% NaCl) solution (1 mL/45 kg, SC; control). On day 5, calves were inoculated with 10 mL of a solution containing H somni strain 7735 (1.6 x 10(9) CFUs/mL, intrabronchially; challenge). Calves were clinically evaluated on days 5 through 8 and euthanized on day 8. The lungs were grossly evaluated for evidence of pneumonia, and bronchial secretion samples underwent bacteriologic culture. RESULTS: The mean clinical score for each group was significantly increased 12 hours after challenge, compared with that immediately before challenge, and was significantly lower for Tildipirosin-treated calves on days 6, 7, and 8, compared with those for tulathromycin-treated and control calves. The mean percentage of lung consolidation for Tildipirosin-treated calves was significantly lower than those for tulathromycin-treated and control calves. Histophilus somni was isolated from the bronchial secretions of some tulathromycin-treated and control calves but was not isolated from Tildipirosin-treated calves. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that metaphylactic administration of Tildipirosin to calves 5 days prior to H somni challenge prevented subsequent culture of the pathogen from bronchial secretions and was more effective in minimizing clinical disease and lung lesions than was metaphylactic administration of tulathromycin.

Efficacy of tildipirosin metaphylaxis for the prevention of respiratory disease, otitis and mortality in pre-weaned Holstein calves.[Pubmed:28093111]

Vet J. 2017 Jan;219:44-48.

The aim of this study was to evaluate the efficacy of two metaphylactic approaches (long acting antibiotic injected once at 10 days of life or twice at 10 and 35 days of life) on the prevention of bovine respiratory disease (BRD), otitis and mortality in high-risk group-housed pre-weaned Holstein heifer calves. The antibiotic of choice for the metaphylactic approach was a long acting macrolide (Tildipirosin) administered subcutaneously at the base of the neck at a dose of 1 mL per 45 kg body weight. A clinical trial was carried out on one dairy farm with random allocation of newborn calves to one of three treatments: (1) control (CTR); (2) one injection at 10 days of life (M1); and (3) two injections at 10 and 35 days of life (M2). Study heifers (n = 795) were reared in group pens of 25 calves per pen and fed unrestricted acidified non-saleable milk from day 1 to day 65 of life. Cox proportional hazard and general linear mixed models were used to evaluate the effect of treatment on mortality, BRD and otitis, and average daily weight gain. The birth weights, proportions of calves with inadequate transfer of passive immunity, proportions of calves born from primiparous dams and proportions of calves born from assisted parturitions were not different among CTR, M1 and M2 treatments. A significantly lower hazard of being affected with BRD and/or otitis (but not for BRD or otitis alone) was observed for M1 (hazard ratio, HR = 0.70, P = 0.009) and M2 (HR = 0.72, P = 0.01) when compared to the CTR group. Metaphylactic treatments had no effect on mortality, otitis and average daily weight gain during the pre-weaning period.

A microbiological assay to estimate the antimicrobial activity of parenteral tildipirosin against foodborne pathogens and commensals in the colon of beef cattle and pigs.[Pubmed:26538405]

J Vet Pharmacol Ther. 2016 Jun;39(3):277-86.

Tildipirosin (TIP) is a novel 16-membered-ring macrolide authorized for the treatment of bovine and swine respiratory disease. The pH dependency of macrolide antimicrobial activity is well known. Considering that the pH in the colon contents of growing beef cattle and pigs is usually below pH 7.0, the minimum inhibitory concentrations (MIC) of TIP against foodborne bacterial pathogens such as Campylobacter (C.) coli, C. jejuni and Salmonella enterica and commensal species including Enterococcus (E.) faecalis, E. faecium and Escherichia coli were determined under standard (pH 7.3 +/- 1) or neutral as well as slightly acidic conditions. A decrease in pH from 7.3 to 6.7 resulted in an increase in MICs of TIP. Except for the MICs > 256 mug/mL observed in the resistant subpopulation of the C. coli and the Enterococcus species, the MIC ranges increased from 2-8 mug/mL to 64-> 256 mug/mL for Salmonella enterica and E. coli, from 8-16 mug/mL to 32-128 mug/mL for the two Campylobacter species, and from 4-32 mug/mL to 128-> 256 mug/mL for both Enterococcus species. To estimate the antimicrobial activity of TIP in the colon contents of livestock during recommended usage of the parenterally administered TIP (Zuprevo((R)) ), and to compare this with the increased MICs at the slightly acidic colonic pH, we developed and validated a microbiological assay for TIP and used this to test incurred faecal samples collected from cattle and pigs. Microbiological activity of luminal TIP was determined in aqueous supernatants from diluted faeces, using standard curves produced from TIP-spiked faecal supernatants. The limit of quantification (LOQ) for TIP was 1 mug/mL (ppm). In a cattle study (n = 14), 3 of 28 faecal samples collected 24 and 48 h post-treatment were found to contain TIP above the LOQ (concentrations of 1.3-1.8 ppm). In another cattle study (n = 12) with faecal samples collected at 8, 24 and 48 h post-treatment, TIP concentrations were above the LOQ in 4 of the 8 h samples (1.2-2.6 ppm) and one of the 24-h samples (1.3 ppm). In a pig study (n = 12) with faecal samples collected 24, 48 and 72 h post-treatment, only one sample contained TIP above the LOQ (concentration 1.5 ppm). In another pig study (n = 12), with samples collected at 8, 24 48 and 96 h post-treatment, TIP concentrations were above the LOQ in one 8-h sample (1.1 ppm) and two 24-h samples (2.3 and 2.5 ppm). None of the 48-h and 96-h samples from these 4 studies contained measurable TIP concentrations. Thus, in cattle and pigs, only a small fraction of faecal samples collected up to 24 h postdosing contained measurable microbiologically active TIP, with its maximum limited to 2.6 mug/mL. This is several log2 dilution steps below the MICs of TIP against foodborne pathogens and commensals collected under acidic conditions comparable with those in the colonic contents and may explain a lack of intestinal dysbacteriosis with parenteral Tildipirosin in livestock.