The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs

A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)‐infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high‐performance liquid chromatography with tandem mass spectrometry (LC‐MS/MS) method. The mean maximum plasma concentration (C_max) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for C_max of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half‐life t_1/2el = 126 h in plasma and t_1/2el = 165 h in lung, as well as longer drug persistent in infected pigs, was found.     

Pulmonary pharmacokinetics of tulathromycin in swine. Part 2: Intra‐airways compartments

The objective of this study was to assess the pharmacokinetics of tulathromycin in pulmonary and bronchial epithelial lining fluid (PELF and BELF) from pigs. Clinically healthy pigs were allocated to two groups of 36 animals each. All animals were treated with tulathromycin (2.5 mg/kg/i.m). Animals in group 2 were also challenged intratracheally with lipopolysaccharide from Escherichia coli 3 h prior to tulathromycin administration. Both PELF and BELF samples were harvested using bronchoalveolar lavage fluid and bronchial micro‐sampling probes, respectively. Samples were taken for 17 days post‐tulathromycin administration. No statistical differences in the concentration of tulathromycin were observed in PELF between groups. The concentration vs. time profile in BELF was evaluated only in Group 1. Tulathromycin distributed rapidly and extensively into the airway compartments. The time to maximal (T_max) concentration was 6 h postdrug administration in PELF but 72 h post‐tulathromycin administration for BELF. In group 2, the T_max was seen at 24 h post‐tulathromycin administration. The area under the concentration time curve (h*ng/mL) was 522 000, 348 000 and 1 290 000 for PELF_Group‐1, PELF_Group‐2, and BELF_Group‐1, respectively. Tulathromycin not only distributed rapidly into intra‐airway compartments at relatively high concentrations but also resided in the airway lining fluid for a long time (>4 days).     

An acute reversible experimental model of pneumonia in pigs: time‐related histological and clinical signs changes

The objective of this study was to evaluate the long‐term survival rates, clinical response, and lung gross and microscopic changes in pigs treated intratracheally with lipopolysaccharide of Escherichia coli 0111:B4 (LPS‐Ec). Healthy pigs were randomly allocated to three groups: (i) no‐LPS‐Ec (n = 1), (ii) LPS‐Ec‐T1 (1 mg/mL, 10 mL/pig) (n = 7), and (iii) LPS‐Ec‐T2 (0.5 mg/mL, 10 mL/pig) (n = 6). Two pigs from each dose group were euthanized at 24 (n = 3 for T1), 48 and 144 h post‐LPS‐Ec challenge. LPS‐Ec‐treated animals showed macroscopic lesions in middle lobes of the lung. A reversible recruitment of macrophages and neutrophils was observed at 24, 48, and 144 h post‐LPS‐Ec challenge. The highest cellular infiltration level was observed at 24 h after challenge. The highest clinical scores were evident in both experimental dose levels within 3 and 5 h after LPS‐Ec administration. Administration of LPS‐Ec, under the conditions evaluated, can be used to induce a reproducible model of acute pulmonary inflammation in pigs.     

Tulathromycin enhances humoral but not cellular immune response in pigs vaccinated against swine influenza

The effect of a standard, single dose therapy with tulathromycin was investigated on the postvaccinal humoral and cellular immune response in pigs vaccinated against swine influenza. Forty‐five pigs, divided into 3 groups, were used (control not vaccinated (C, n = 15), control vaccinated (CV, n = 15), and experimentally received tulathromycin (TUL, n = 15)). For vaccination of pigs, an inactivated, commercial vaccine was used. Pigs from TUL group received single dose of tulathromycin intramuscularly, at the recommended dose (2.5 mg/kg body weight). Pigs from TUL and CV groups were vaccinated at 8 and 10 weeks of age. The specific humoral and cellular immune response against swine influenza virus (SIV) was evaluated. The results of present study showed that humoral postvaccinal response after vaccination against SIV can be modulated by treatment with tulathromycin. In pigs from TUL group, the significantly higher titers of anti‐SIV‐specific antibodies were observed 4 and 6 weeks after booster dose of vaccine. Simultaneously, T‐cell‐mediated immune response against SIV was not affected by tulathromycin. Our recent study confirmed the importance of defining the modulatory activity of tulathromycin because of its influence on the immune response to vaccines. Since the antibodies against hemagglutinin are crucial for the protection against SIV, the present observations should prompt further studies on the practical significance of recent results in terms of clinical implications (postvaccinal protection) in the field conditions.     

Pharmacokinetics of tulathromycin in nonpregnant adult ewes

The objectives of this study were to determine plasma concentrations and pharmacokinetic parameters of tulathromycin after a single subcutaneous administration in the cervical region in sheep using the cattle labeled dose of 2.5 mg/kg. Six adult healthy ewes were administered tulathromycin on day 0. Blood samples were collected just prior to dosing and at selected time points for 360 h. Plasma samples were analyzed to determine tulathromycin concentrations, and noncompartmental analysis was performed for pharmacokinetic parameters. The mean maximum plasma concentration was 3598 ng/mL, the mean time to maximum concentration was 1.6 h, and the apparent elimination half‐life ranged from 68.1 to 233.1 h (mean 118 h). When comparing our results to goats and cattle, it appears sheep are more similar to cattle in regard to the concentrations observed and pharmacokinetic parameters. In summary, the pharmacokinetics of tulathromycin in sheep appear to be similar enough to those in goats and cattle to recommend similar dosing (2.5 mg/kg SC), assuming that the target pathogens have similar inhibitory concentrations.     

Vaccination mitigates the impact of PRRSv infection on the pharmacokinetics of ceftiofur crystalline‐free acid in pigs

The pharmacokinetics of intramuscularly administered ceftiofur crystalline‐free acid (CCFA) were determined in pigs that were clinically healthy (n = 8), vaccinated with a Porcine reproductive and respiratory syndrome modified live virus (PRRS MLV) (n = 10), challenged with wild‐type porcine reproductive and respiratory syndrome virus (PRRSv) VR‐2385 (n = 10), or vaccinated with PRRS MLV and later challenged with wild‐type PRRSv VR‐2385 (n = 10). Animals were given a single dose of CCFA intramuscularly at 5 mg/kg body weight. Blood was collected at 0 (pretreatment), 0.25, 0.5, 1, 6, 12, 24, 48, 96, 144, 192, and 240 h postinjection. Plasma was analyzed using liquid chromatography‐mass spectrometry. Plasma concentration–time curves for each group were evaluated with noncompartmental modeling. When compared to control animals, those receiving the PRRSv wild‐type challenge only had a lower AUC_0‐last, higher Cl/F, and higher Vz/F. The PRRSv wild‐type challenge only group had the longest T_1/2λ. The C_max did not differ among all four treatments. Control animals had no statistically significant differences from animals vaccinated with PRRS MLV alone or animals vaccinated with PRRS MLV and later challenged with wild‐type PRRSv. Our results suggest that PRRSv wild‐type infection has the potential to alter CCFA pharmacokinetics and PRRS MLV vaccination may attenuate those changes.     

Pharmacokinetics and lung tissue concentrations of tulathromycin in swine

The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.     

Relationships between body temperatures and inflammation indicators under physiological and pathophysiological conditions in pigs exposed to systemic lipopolysaccharide and dietary deoxynivalenol

We studied the constancy of the relationship between rectal and intraabdominal temperature as well as their linkage to inflammatory markers (leucocyte counts, kynurenine‐to‐tryptophan ratio (Kyn–Trp ratio), tumour necrosis factor alpha (TNF‐α) in healthy and in pigs exposed to lipopolysaccharide (LPS) and/or deoxynivalenol (DON). Barrows (n = 44) were fed 4 weeks either a DON‐contaminated (4.59 mg DON/kg feed) or a control (CON) diet and equipped with an intraabdominal temperature logger and a multicatheter system (V.portae hepatis, V.lienalis, Vv.jugulares) facilitating infusion of 0.9% NaCl (CON) or LPS (7.5 μg/kg BW) and simultaneous blood sampling. Body temperatures were measured and blood samples taken every 15 min for leucocyte counts, TNF‐α and Kyn–Trp ratio. Combination of diet and infusion created six groups: CON_CON_jug.‐CON_por., CON_CON_jug.‐LPS_por., CON_LPS_jug.‐CON_por., DON_CON_jug.‐CON_por., DON_CON_jug.‐LPS_por., DON_LPS_jug.‐CON_por.. The relationship between both temperatures was not uniform for all conditions. Linear regression revealed that an intraabdominal increase per 1°C increase in rectal temperature was ~25% higher in all LPS‐infused pigs compared to NaCl‐infusion, albeit diet and site of LPS infusion modified the magnitude of this difference. Inflammatory markers were only strongly present under LPS influence and showed a significant relationship with body temperatures. For example, leucocyte counts in clinically inconspicuous animals were only significantly correlated to core temperature in DON‐fed pigs, but in all LPS‐infused groups, irrespective of diet and temperature method. In conclusion, the gradient between body core and rectal temperature is constant in clinically inconspicuous pigs, but not under various pathophysiological conditions. In the latter, measurement of inflammatory markers seems to be a useful completion.     

COMPUTED TOMOGRAPHIC FEATURES OF LUNG LOBE TORSION

The imaging features of lung lobe torsion in 10 dogs (nine complete, one partial torsion) acquired with a helical single‐slice computed tomography (CT) unit are described. Attenuation values of normal, rotated, and adjacent collapsed lung lobes before and after intravenous contrast medium administration were compared. Affected lung lobes were: left cranial (5), right middle (3), right cranial (1), and left caudal (1). CT findings in nine dogs with complete lung lobe torsion included pleural effusion and an abruptly ending bronchus. In eight of these dogs, enlargement, consolidation, emphysema of the affected lung lobe, and mediastinal shift to the contralateral side were present. Rotated lung lobes did not enhance, whereas adjacent collapsed and aerated lung lobes did (P<0.05). Apnea induced with hyperventilation or breath‐hold is essential to reduce motion artefacts and obtain a diagnostic study.     

Pharmacokinetics of tulathromycin in plasma and milk samples after a single subcutaneous injection in lactating goats (Capra hircus)

Eight adult female dairy goats received one subcutaneous administration of tulathromycin at a dosage of 2.5 mg/kg body weight. Blood and milk samples were assayed for tulathromycin and the common fragment of tulathromycin, respectively, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of tulathromycin was analyzed by a noncompartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single‐dose administration of tulathromycin were as follows: C_max (121.54 ± 19.01 ng/mL); T_max (12 ± 12–24 h); area under the curve AUC_0→∞ (8324.54 ± 1706.56 ng·h/mL); terminal‐phase rate constant λz (0.01 ± 0.002 h⁻¹); and terminal‐phase rate constant half‐life t_1/2λz (67.20 h; harmonic). Mean milk pharmacokinetic parameters (±SD) following 45 days of sampling were as follows: C_max (1594 ± 379.23 ng/mL); T_max (12 ± 12–36 h); AUC_0→∞ (72,250.51 ± 18,909.57 ng·h/mL); λz (0.005 ± 0.001 h⁻¹); and t_1/2λz (155.28 h; harmonic). All goats had injection‐site reactions that diminished in size over time. The conclusions from this study were that tulathromycin residues are detectable in milk samples from adult goats for at least 45 days following subcutaneous administration, this therapeutic option should be reserved for cases where other treatment options have failed, and goat milk should be withheld from the human food chain for at least 45 days following tulathromycin administration.     

In vitro anti‐LPS dose determination of ketorolac tromethamine and in vivo safety of repeated dosing in healthy horses

Flunixin meglumine (FM) is a commonly used Nonsteroidal anti‐inflammatory drug (NSAID) in horses, but clinical efficacy is often unsatisfactory. Ketorolac tromethamine (KT) demonstrates superior efficacy compared to other NSAIDs in humans, but its anti‐inflammatory effects have not been investigated in the horse. Safety of repeated dosing of KT has not been evaluated. The first objective was to conduct a dose determination study to verify that a previously described dosage of KT would inhibit Lipopolysaccharide (LPS)‐induced eicosanoid production in vitro, and to compare KT effects of this inhibition to those of FM. Then, a randomized crossover study was performed using nine healthy horses to evaluate plasma concentrations of KT and FM following IV administration. Administered dosages of KT and FM were 0.5 mg/kg and 1.1 mg/kg, respectively. Safety following six repeated doses of KT was assessed. Ketorolac tromethamine and FM suppressed LPS‐induced Thromboxane B₂ (TXB₂) and Prostaglandin E₂ (PGE₂) production in vitro for up to 12 hr. Intravenous administration produced plasma concentrations of KT and FM similar to previous reports. No adverse effects were observed. A KT dosage of 0.5 mg/kg IV inhibited LPS‐induced eicosanoids in vitro, and repeated dosing for up to 3 days appears safe in healthy horses. Investigation of in vivo anti‐inflammatory and analgesic effects of KT is warranted.     

Study of pharmacokinetics of an in situ forming gel system for controlled delivery of florfenicol in pigs

To reduce florfenicol (FFC) administration frequency in veterinary use, the drug was currently developed into in situ forming gel. Twelve pigs were randomly divided into two groups (six pigs per group). A single i.m. dose of 40 mg/kg body weight (b.w.) was given to pigs, group one was given FFC in situ forming gel, and group two was given FFC conventional injection. High‐performance liquid chromatography (HPLC) was used to determine FFC plasma concentrations. There were significant differences (P < 0.01) between FFC in situ forming gel and conventional injection, in pharmacokinetic parameters MRT (mean retention time) (57.79 ± 2.88) h versus (15.94 ± 1.29) h, AUC (area under the concentration–time curve) (421.54 ± 8.97) μg·h/mL versus (168.16 ± 4.59) μg·h/mL, t_max (time of occurrence of c_max) (9.00 ± 2.68) h versus (4.33 ± 0.82) h, c_max (maximum plasma concentration) (6.87 ± 0.66) μg/mL versus (12.01 ± 0.66) μg/mL, t_1/2λz (terminal elimination half‐life) (38.04 ± 2.20) h versus (9.15 ± 2.71) h. The results demonstrated that the in situ forming gel system could shorten dosing interval of FFC and thus achieved less frequent administration during long‐term treatment.     

Pharmacokinetics and lung and muscle concentrations of tulathromycin following subcutaneous administration in white‐tailed deer (Odocoileus virginianus)

Respiratory tract infections are common in farmed North American white‐tailed deer (Odocoileus virginianus). Tulathromycin is approved for use in cattle but not deer but is often employed to treat deer. The pharmacokinetic properties and lung and muscle concentrations of tulathromycin in white‐tailed deer were investigated. Tulathromycin was administered to 10 deer, and then, serum, lung, and muscle tulathromycin concentrations were measured using liquid chromatography–mass spectrometry (LC–MS). The mean maximal serum tulathromycin concentration in deer was 359 ng/mL at 1.3 h postinjection. The mean area under the serum concentration–time curve, apparent volume of distribution, apparent clearance, and half‐life was 4883 ng·h/mL, 208 L/kg, 0.5 L/h/kg, and 281 h (11.7 days), respectively. The maximal tulathromycin concentration in lung and muscle homogenate from a single animal was 4657 ng/g (14 days) and 2264 ng/g (7 days), respectively. The minimum concentrations in lung and muscle were 39.4 ng/g (56 days) and 9.1 ng/g (56 days), respectively. Based on similarity in maximal serum concentrations between deer and cattle and high lung concentrations in deer, we suggest the recommended cattle dosage is effective in deer. Tissue concentrations persisted for 56 days, suggesting a need for longer withdrawal times in deer than cattle. Further tissue distribution and depletion studies are necessary to understand tulathromycin persistence in deer tissue; clinical efficacy studies are needed to confirm the appropriate dosage regimen in deer.     

Effects of dietary supplementation of bacteriophages against enterotoxigenic Escherichia coli (ETEC) K88 on clinical symptoms of post‐weaning pigs challenged with the ETEC pathogen

The present study was performed to investigate the effects of dietary supplementation of bacteriophages (phages) against enterotoxigenic Escherichia coli (ETEC) K88 as a therapy against the ETEC infection in post‐weaning pigs. Two groups of post‐weaning pigs aged 35 days, eight animals per group, were challenged with 3.0 × 10¹⁰ colony forming units of ETEC K88, a third group given the vehicle. The unchallenged group and one challenged group were fed a basal nursery diet for 14 days while the remaining challenged group was fed the basal diet supplemented with 1.0 × 10⁷ plaque forming units of the phage per kg. Average daily gain (ADG), goblet cell density and villous height:crypt depth (VH:CD) ratio in the intestine were less in the challenged group than in the unchallenged group within the animals fed the basal diet (p < 0.05); the reverse was true for rectal temperature, faecal consistency score (FCS), E. coli adhesion score (EAS) in the intestine, serum interleukin‐8 (IL‐8) and tumour necrosis factor‐α (TNF‐α) concentrations and digesta pH in the stomach, caecum and colon. The ETEC infection symptom within the challenged animals was alleviated by the dietary phage supplementation (p < 0.05) in ADG, FCS, EAS in the jejunum, serum TNF‐α concentration, digesta pH in the colon, goblet cell density in the ileum and colon and VH:CD ratio in the ileum. Moreover, the infection symptom tended to be alleviated (p < 0.10) by the phage supplementation in rectal temperature, EAS in the ileum and caecum, and VH:CD ratio in the duodenum and jejunum. However, EAS in the colon, digesta pH in the stomach and caecum, and goblet cell density in the jejunum did not change due to the dietary phage. Overall, results indicate that the phage therapy is effective for alleviation of acute ETEC K88 infection in post‐weaning pigs.     

Correlation between oral fluid and plasma oxytetracycline concentrations after intramuscular administration in pigs

The penetration of oxytetracycline (OTC) into the oral fluid and plasma of pigs and correlation between oral fluid and plasma were evaluated after a single intramuscular (i.m.) dose of 20 mg/kg body weight of long‐acting formulation. The OTC was detectable both in oral fluid and plasma from 1 hr up to 21 day after drug administration. The maximum concentrations (C_max) of drug with values of 4021 ± 836 ng/ml in oral fluid and 4447 ± 735 ng/ml in plasma were reached (T_max) at 2 and 1 hr after drug administration respectively. The area under concentration–time curve (AUC), mean residence time (MRT) and the elimination half‐life (t_1/2β) were, respectively, 75613 ng × hr/ml, 62.8 hr and 117 hr in oral fluid and 115314 ng × hr/ml, 31.4 hr and 59.2 hr in plasma. The OTC concentrations were remained higher in plasma for 48 hr. After this time, OTC reached greater level in oral fluid. The strong correlation (r = .92) between oral fluid and plasma OTC concentrations was observed. Concentrations of OTC were within the therapeutic levels for most sensitive micro‐organism in pigs (above MIC values) for 48 hr after drug administration, both in the plasma and in oral fluid.     

Effect of Endobronchial Challenge with Actinobacillus pleuropneumoniae Serotype 10 of Pigs Vaccinated with Bacterins Consisting of A. pleuropneumoniae Serotype 10 Grown under NAD‐Rich and NAD‐Restricted Conditions

The efficacy of two bacterins containing an Actinobacillus pleuropneumoniae serotype 10 strain was evaluated. The bacterial cells constituting bacterin 1 and 2 were grown under nicotinamide adenine dinucleotide (NAD)‐rich (low‐adherence capacity to alveolar epithelial cell cultures) and NAD‐restricted (high‐adherence capacity to alveolar epithelial cell cultures) conditions, respectively. Ten pigs were vaccinated twice with the bacterin 1 and nine pigs with the bacterin 2. Ten control animals were injected twice with a saline solution. Three weeks after the second vaccination, all pigs were endobronchially inoculated with 106.5 colony‐forming units (CFU) of an A. pleuropneumoniae serotype 10 strain. In the bacterin 1 and 2 group, three and two pigs died after inoculation, respectively. Only two pigs of the control group survived challenge. Surviving pigs were killed at 7 days after challenge. The percentage of pigs with severe lung lesions (>10% of the lung affected) was 100% in the control group, 70% in the bacterin 1 group and 22% in the bacterin 2 group. Actinobacillus pleuropneumoniae was isolated from the lungs of all animals. The mean bacterial titres of the caudal lung lobes were 7.0 × 10⁶ CFU/g in the control group, 6.3 × 10⁵ CFU/g in the bacterin 1 group and 1.3 × 10⁶ CFU/g in the bacterin 2 group. It was concluded that both bacterins induced partial protection against severe challenge. Furthermore, there are indications that the bacterin 2, containing A. pleuropneumoniae bacteria grown under conditions resulting in high in vitro adhesin, induced better protection than the bacterin 1.     

Reduced lung lesions in pigs challenged 25 weeks after the administration of a single dose of Mycoplasma hyopneumoniae vaccine at approximately 1 week of age

Two independent studies assessed the duration of immunity of an inactivated adjuvanted Mycoplasma hyopneumoniae vaccine against mycoplasmal pneumonia in seronegative (study A, n = 52) and seropositive (study B, n = 52) pigs. The pigs were allocated randomly to treatment and were then injected with a single dose of either the vaccine or a placebo at approximately 1 week of age. Twenty-five weeks after treatment administration, the pigs were challenged with a virulent strain (LI 36, Strain 232) of M. hyopneumoniae and the extent of lung lesions consistent with mycoplasmal pneumonia was assessed 4 weeks later.In study A, the geometric mean lung lesion score (expressed as least squares mean percentages of lung lesions) was significantly (P = 0.0001) lower in vaccinated (0.3%, n = 20) than in control pigs (5.9%, n = 24) seronegative to M. hyopneumoniae at enrolment; similarly, in study B, the extent of lung lesions was significantly reduced (P = 0.0385) in seropositive vaccinated pigs (2.0%, n = 22) compared to controls (4.5%, n = 26). At the end of the investigation period, 4 weeks after challenge, mean antibody sample-to-positive (S/P) ratios were significantly higher both in seronegative (P = 0.0012) and seropositive (P = 0.0001) vaccinated pigs (mean values = 0.77 and 0.81, respectively) than in controls (mean values = 0.51 and 0.38, respectively).     

Efficacy of tulathromycin in the treatment of respiratory disease in pigs caused by Actinobacillus pleuropneumoniae

The efficacy of a single dose of tulathromycin, a novel triamilide antimicrobial of the macrolide class, given at 2.5 mg/kg or 5 mg/kg bodyweight, or three daily doses of ceftiofur, given at 3 mg/kg bodyweight, was evaluated in pigs with respiratory disease induced experimentally with Actinobacillus pleuropneumoniae. On day 0, 100 pigs with clinical signs of respiratory disease were randomly assigned to groups of 25 pigs, which were treated with either saline, one of the doses of tulathromycin, or ceftiofur. The pigs' rectal temperatures and clinical scores for respiratory signs and general attitude were recorded daily until day 10. Animals withdrawn from the study for welfare reasons were recorded. On day 10, the animals remaining in the study were weighed, euthanased and examined postmortem. Three of the animals treated with saline and one of those treated with 2.5 mg/kg tulathromycin were withdrawn from the study, but none of those treated with 5 mg/kg tulathromycin or ceftiofur were withdrawn. The least squares mean bodyweight gains of the pigs treated with the antimicrobial agents were significantly (P<0.05) higher than that of the saline-treated group, and the least squares mean percentages of the total lung involvement and incidence of respiratory disease associated with A. pleuropneumoniae were significantly (P<0.05) lower, but there were no significant differences between the three groups of pigs treated with the antimicrobial agents.     

Standard PK/PD concepts can be applied to determine a dosage regimen for a macrolide: the case of tulathromycin in the calf

The pharmacokinetic (PK) profile of tulathromycin, administered to calves subcutaneously at the dosage of 2.5 mg/kg, was established in serum, inflamed (exudate), and noninflamed (transudate) fluids in a tissue cage model. The PK profile of tulathromycin was also established in pneumonic calves. For Mannheimia haemolytica and Pasteurella multocida, tulathromycin minimum inhibitory concentrations (MIC) were approximately 50 times lower in calf serum than in Mueller–Hinton broth. The breakpoint value of the PK/pharmacodynamic (PD) index (AUC_(0–24 h)/MIC) to achieve a bactericidal effect was estimated from in vitro time‐kill studies to be approximately 24 h for M. haemolytica and P. multocida. A population model was developed from healthy and pneumonic calves and, using Monte Carlo simulations, PK/PD cutoffs required for the development of antimicrobial susceptibility testing (AST) were determined. The population distributions of tulathromycin doses were established by Monte Carlo computation (MCC). The computation predicted a target attainment rate (TAR) for a tulathromycin dosage of 2.5 mg/kg of 66% for M. haemolytica and 87% for P. multocida. The findings indicate that free tulathromycin concentrations in serum suffice to explain the efficacy of single‐dose tulathromycin in clinical use, and that a dosage regimen can be computed for tulathromycin using classical PK/PD concepts.     

Effects of experimentally induced respiratory disease on the pharmacokinetics and tissue residues of tulathromycin in meat goats

Tulathromycin is a macrolide antibiotic commonly used for the treatment of respiratory disease in food animal species including goats. Recent research in pigs has suggested that the presence of disease could alter the pharmacokinetics of tulathromycin in animals with respiratory disease. The objectives of this study were (a) compare the plasma pharmacokinetics of tulathromycin in healthy goats as well as goats with an induced respiratory disease; and (b) to compare the tissue residue concentrations of tulathromycin marker in both groups. For this trial, disease was induced with Pasteurella multocida. Following disease induction, tulathromycin was administered. Samples of plasma were collected at various time points up to 312 hr posttreatment, when study animals were euthanized and tissue samples were collected. For PK parameters in plasma, V_z (control: 28.7 ± 11.9 ml/kg; experimental: 57.8 ± 26.6 ml/kg) was significantly higher (p = 0.0454) in the experimental group than the control group, and nonsignificant differences were noted in other parameters. Among time points significantly lower plasma concentrations were noted in the experimental group at 168 hr (p = 0.023), 216 hr (p = 0.036), 264 hr (p = 0.0017), 288 hr (p = 0.0433), and 312 hr (p = 0.0486). None of the goats had tissue residues above the US bovine limit of 5 µg/g at the end of the study. No differences were observed between muscle, liver, or fat concentrations. A significantly lower concentration (p = 0.0095) was noted in the kidneys of experimental goats when compared to the control group. These results suggest that the effect of respiratory disease on the pharmacokinetics and tissue residues appear minimal after experimental P. multocida infection, however as evidenced by the disparity in C_max, significant differences in plasma concentrations at terminal time points, as well as the differences in kidney concentrations, there is the potential for alterations in diseased versus clinical animals.