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A pharmacokinetics/pharmacodynamics (PK/PD) approach was used to determine the best empirical dosage regimen of cefazolin (CEZ) after intramuscular (IM) administration of CEZ in horses. Seven horses received a single IM or intravenous (IV) administration of CEZ of 5 mg/kg bodyweight (BW) according to a crossover design. CEZ plasma concentrations were measured using LC-MS/MS. The plasma concentrations in these seven horses and those of six other horses obtained in a previous study with an IV CEZ dose of 10 mg/kg were modelled simultaneously using NonLinear Mixed-Effect modelling followed by Monte Carlo simulations to establish a rational dosage regimen. A 90% Probability of Target Attainment (PTA) for a PK/PD target of a free plasma concentration exceeding MIC

Updating vaccine strains is essential to control equine influenza. We evaluated the protective efficacy of an inactivated equine influenza vaccine derived from viruses generated by reverse genetics (RG) in horses in an experimental viral challenge study. Wild-type (WT) virus (A/equine/Tipperary/1/2019) and virus generated by RG (consisting of hemagglutinin and neuraminidase genes from A/equine/Tipperary/1/2019 and six other genes from high-growth A/Puerto Rico/8/34) were inactivated by formalin for vaccine use. Twelve 1-year-old naïve horses with no antibodies against equine influenza virus were assigned to three groups (each n = 4): control, WT, and RG. They were vaccinated twice, 4 weeks apart, and were challenged with A/equine/Tipperary/1/2019 2 weeks after the second vaccination. All four horses in the control group and one horse in the WT group had pyrexia for multiple days and respiratory illness, and one horse in the RG group had pyrexia for 2 days without respiratory illness. The mean rectal temperatures and the mean concentrations of serum amyloid A in the WT and RG groups were significantly lower than those in the control group, with no significant differences between them. The WT and RG vaccines significantly reduced viral shedding relative to the control. The protective efficacy of the RG-derived inactivated vaccine against equine influenza virus is comparable to that of the vaccine derived from WT viruses in horses. The RG technique can make it easy to update equine influenza vaccine strains.

Objective To clarify the detailed pharmacokinetics (PK) of orally administered voriconazole in tear fluid (TF) of horses for evaluating the efficacy of voriconazole secreted into TF against equine keratomycosis. Animals studied Five healthy Thoroughbred horses. Procedures Voriconazole was administrated through a nasogastric tube to each horse at a single dose of 4.0 mg/kg. TF and blood samples were collected before and periodically throughout the 24 hours after administration. Voriconazole concentrations in plasma and TF samples were analyzed using liquid chromatography‐electrospray tandem‐mass spectrometry. The predicted voriconazole concentration in both samples following multiple dosing every 24 hours was simulated by the superposition principle. Results The mean maximum voriconazole concentrations in plasma and TF were 3.3 μg/mL at 1.5 h and 1.9 μg/mL at 1.6 h, respectively. Mean half‐life in both samples were 16.4 and 25.2 h, respectively. The ratio of predicted AUC0–24 at steady state in TF (51.3 μg∙h/mL) to previously published minimum inhibitory concentration (MIC) of Aspergillus and Fusarium species was >100 and 25.7, respectively. Conclusions This study demonstrated the detailed single‐dose PK of voriconazole in TF after oral administration and simulated the predicted concentration curves in a multiple oral dosing. Based on the analyses of PK‐PD, the simulation results indicated that repeated oral administration of voriconazole at 4.0 mg/kg/d achieves the ratio of AUC to MIC associated with treatment efficacy against Aspergillus species. The detailed PK‐PD analyses against pathogenic fungi in TF can be used to provide evidence‐based medicine for equine keratomycosis.

Platelet-rich plasma (PRP) therapy has been widely applied in various medical fields including humans and horses. This study aimed to establish an optimal activation method to stably and reproducibly maximize the concentrations of platelet-derived growth factor-BB (PDGF-BB) and transforming growth factor-β1 (TGF-β1) contained in equine PRP. Autologous PRP was prepared from 11 Thoroughbreds. For the activation test, PRP was activated by either a single freeze-thaw cycle (Fr) or adding calcium and autologous serum containing thrombin (Ca). PDGF-BB and TGF-β1 concentrations in Fr, Ca, nonactivated (No), and platelet-poor plasma (PPP) samples were determined using ELISA and compared. For repetitive freeze-thaw test, PRP was subjected to single (Fr1), double (Fr2), triple (Fr3), or quadruple (Fr4) freeze-thaw cycles and the concentrations of both growth factors in samples were compared similarly. The PDGF-BB concentration in Ca was significantly higher than that in other preparations. The TGF-β1 concentrations in Fr and Ca were significantly higher than those in PPP and No, with no significant differences between Fr and Ca. The concentrations of both factors were significantly increased in PRP treated with multiple cycles of freeze-thaw compared with that in PRP treated with a single cycle. No significant differences were noted among Fr2, Fr3, and Fr4. Our findings suggest that activation by adding calcium and autologous serum is optimal for instant use of PRP and that double freeze-thawing is an easier and optimal activation method for cryopreserved PRP.

We aimed to investigate the recent incidence of carpal fractures and the risk factors for recurrent ipsilateral fractures after arthroscopic removal of clinically active unilateral carpal chip fracture fragments in Thoroughbred racehorses.The findings for horses managed under the Japan Racing Association that developed carpal bone fractures between 2014 and 2018 were retrospectively reviewed. The proportion of cases that developed a recurrent carpal fracture in the originally affected joint was calculated, and the risk factors for recurrent fractures were analysed.In total, 2858 carpal fractures were recorded in the study period (incidence, 0.8%). Of the 554 horses that resumed racing after the treatment of the unilateral major carpal chip fracture, 144 had a recurrent fracture (26.0%). Chip fractures of the third carpal bone (odds ratio [OR]: 3.7) or a combination of the distal end of the radius and intermediate carpal bone (OR: 3.0) were associated with a significantly higher risk of recurrent fractures than the distal aspect of the radial carpal bone.The incidence of carpal fractures remained similar to that reported in Japan in the 1990s. The rate of recurrent ipsilateral fractures differed among lesion sites.

OBJECTIVE To determine plasma pharmacokinetics of metronidazole and imipenem following administration of a single dose PO (metronidazole, 15 mg/kg) or IV (imipenem, 10 mg/kg) in healthy Thoroughbreds and simulate pleural fluid concentrations following multiple dose administration every 8 hours. ANIMALS 4 healthy Thoroughbreds. PROCEDURES Metronidazole and imipenem were administered, and samples of plasma and pleural fluid were collected at predetermined time points. Minimum concentrations of metronidazole and imipenem that inhibited growth of 90% of isolates (MIC90), including 22 clinical Bacteroides isolates from horses with pleuropneumonia, were calculated. For the computer simulation, the target ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was > 70, and the target percentage of time per day that the pleural fluid concentration of imipenem exceeded the MIC90 was > 50%. RESULTS Mean ± SD pleural fluid concentrations of metronidazole and imipenem were 12.7 ± 3.3 μg/mL and 12.1 ± 0.9 μg/mL, respectively, 1 hour after administration and 4.9 ± 0.85 μg/mL and 0.3 ± 0.08 μg/mL, respectively, 8 hours after administration. For both antimicrobials, concentrations in the pleural fluid and plasma were similar. The ratio for area under the pleural fluid concentration-versus-time curve during 24 hours to the MIC90 for metronidazole was 84.9, and the percentage of time per day the pleural fluid concentration of imipenem exceeded the MIC90 was 70.9%. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that administration of metronidazole (15 mg/kg, PO, q 8 h) or imipenem (10 mg/kg, IV, q 8 h) resulted in their accumulation in the pleural fluid in healthy horses and concentrations were likely to be effective for the treatment of pneumonia and pleuropneumonia caused by Bacteroides spp.

Background Although Clostridioides difficile-associated diseases (CDAD) is considered to be associated with colitis in horses, few studies have been performed with a focus on the characteristics of CDAD in thoroughbred racehorses. Methods Between 2010 and 2018, a test for C. difficile was performed using faecal samples from 137 thoroughbred racehorses with colitis presenting with diarrhoea and fever. The mortality rate, clinical findings, predisposing factors and the selected treatments were investigated in a retrospective manner. Results Twenty-four cases were diagnosed as CDAD and 113 as non-CDAD. The mortality rate was significantly higher in the CDAD group (83 per cent) than that in the non-CDAD group (34 per cent). The levels of serum amyloid A, blood urea nitrogen and packed cell volume at initial presentation were also significantly higher, and those of total protein and albumin were significantly lower in the CDAD group. The development of CDAD was associated with the administration of antimicrobials, surgery and hospitalisation. No significant improvement in mortality was observed for any of the selected treatment in both groups. Conclusion CDAD in thoroughbred racehorses was identified as a high mortality disease with rapid progression of systemic inflammation and deterioration of the circulatory state. Further investigation is required to improve the treatment.

A retrospective cohort study was conducted to investigate risk factors for the failure of Thoroughbred racehorses to return to racing after an injury of the superficial digital flexor tendon (SDFT). Successful return was defined as the completion of five or more races after SDFT injury. The official Japan Racing Association (JRA) medical records of racehorses with a core-type SDFT injury were reviewed for clinical variables related to the characteristics of the horse and the severity of SDFT injuries at the time of diagnosis. Data on racing outcomes were obtained from the official JRA racing database. Risk factors were screened using univariable logistic regression and subsequent multivariable model building. Forty-nine of 346 (14.2%) horses successfully returned to racing after SDFT injuries. Multivariable model building revealed that an increase in the total number of injured zones (defined as the total number of zones in which the injured hypoechoic area was observed at the time of ultrasonographic diagnosis of SDFT injury) was associated with an increased risk of failure to return to racing after SDFT injury. Horse characteristics, such as age, body mass and sex, were not associated with a successful return to racing. In the rehabilitation of cases with larger (longer) lesions, more effective and careful medical management may be needed for an improvement in the athletic outcomes.

OBJECTIVE To investigate the pharmacokinetics and antihistaminic effects (pharmacodynamics) of olopatadine in a small population of healthy horses after administration via nasogastric tube. ANIMALS 4 healthy adult Thoroughbreds. PROCEDURES Olopatadine (0.1 mg/kg, once) was administered via nasogastric tube. Blood samples were collected at predetermined time points for pharmacokinetic analyses of the drug in plasma. Olopatadine effects were investigated by measurement of cutaneous wheals induced by ID histamine injection (0.1 mL [10 μg]/injection) at predetermined time points. Inhibition effect ratios were calculated on the basis of measured wheal size (area) after versus before olopatadine administration. RESULTS Mean ± SD maximum plasma olopatadine concentration was 48.8 ± 11.0 ng/mL approximately 1.5 hours after administration. Median terminal half-life was 6.11 hours. Mean ± SD maximal effect was 88.2 ± 4.9% inhibition approximately 3.5 hours after drug delivery, and the inhibition effect remained > 80% for 12.5 hours after treatment. No signs of adverse clinical effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested olopatadine may have a strong, long-term inhibitory effect against histamine-induced wheals in the skin of horses. Clinical research with a larger number of horses is warranted.

To determine hemodynamic effects of hydroxyethyl starch (HES) infusion during anesthesia in horses, incremental doses of 6% HES were administered to 6 healthy Thoroughbred horses. Anesthesia was induced with xylazine, guaifenesin and thiopental and maintained with sevoflurane at 2.8% of end-tidal concentration in all horses. The horses were positioned in right lateral recumbency and administered 3 intravenous dose of 6% HES (5 ml/kg) over 15 min with 15-min intervals in addition to constant infusion of lactated Ringer's solution at 10 ml/kg/hr. Hemodynamic parameters were measured before and every 15 min until 90 min after the administration of 6% HES. There was no significant change in heart rate and arterial blood pressures throughout the experiment. The HES administration produced significant increases in mean right atrial pressure, stroke volume, cardiac output (CO) and decrease in systemic vascular resistance (SVR) in a dose-dependent manner. There was no significant change in electrolytes (Na(+), K(+), Cl(-)) throughout the experiment, however, packed cell volume, hemoglobin concentration, and total protein and albumin concentrations decreased in a dose-dependent manner following the HES administration. In conclusion, the HES administration provides a dose-dependent increase in CO, but has no impact upon arterial blood pressures due to a simultaneous decrease in SVR.

Sonoelastography can assess the inner stiffness of tissues. Sonoelastographic evaluation of injured equine superficial digital flexor tendons (SDFTs) is considered to be useful for assessing the stiffness of a lesion even during late-stage rehabilitation. The purpose of this study was to investigate and compare the sonoelastographic appearance of injured SDFTs over time from the onset of the injury. Eighteen horses were classified into three groups according to the length of time from injury onset: group A, within two weeks after injury; group B, approximately five months after injury; and group C, approximately nine months after injury. Longitudinal and transverse images of all injured SDFTs were obtained using grey-scale ultrasonography and sonoelastography. Grey-scale and sonoelastographic images were evaluated by two observers using echogenicity-grading and colour-grading systems, respectively. The authors evaluated the interobserver agreement and compared the grades among the three groups. The results indicated almost perfect interobserver agreement. Significant differences were found in the sonoelastography among the three groups, whereas no significant difference was found in the grey-scale ultrasonography between groups B and C. Sonoelastography is a feasible and useful modality to evaluate the equine injured SDFTs in vivo and to distinguish between them among the different phases even during the chronic phase.

Meticillin-resistant Staphylococcus aureus (MRSA) infections have been confirmed in hospitalised Thoroughbred racehorses at the hospitals of two training centres in Japan since 2009. To investigate the source of infection, the authors examined the rate of nasal MRSA colonisation in 600 healthy Thoroughbred racehorses, 53 veterinarians and 16 office staff at the racehorse hospitals of the two training centres. MRSA was not isolated from healthy Thoroughbred racehorses or hospital office staff. However, MRSA was isolated from 16 veterinarians (30.1 per cent), and the colonisation rate was significantly higher in veterinarians than in the office staff of the same hospitals. Also, 10 of the 16 MRSA strains (62.5 per cent) isolated from veterinarians were classified as type II by staphylococcal cassette chromosome mec (SCCmec) typing and ST5 by multilocus sequence typing. Pulsed-field gel electrophoresis analysis demonstrated that these 10 MRSA strains of SCCmec type II and ST5 were genetically identical or very similar to 9 MRSA strains isolated from infected horses hospitalised at these hospitals between 2009 and 2013. These results indicate that SCCmec type II and ST5 MRSA strains were probably transmitted between veterinarians and infected horses.

The pharmacokinetics of d-chlorpheniramine (CPM), a histamine H1-receptor antagonist, and its ability to inhibit of histamine-induced cutaneous wheal formation, were studied in healthy Thoroughbred horses (n=5). Following an intravenous (IV) dose of 0.5mg/kg bodyweight (BW), plasma drug disposition was very rapid, with the mean terminal half-life and total body clearance calculated as 2.7h and 0.7 L/h/kg, respectively. The observed maximal inhibition of wheal formation following IV doses of 0.1 and 0.5mg/kg BW were 37.8% and 60.6% at 0.5h, respectively. Oral administration of CPM (0.5mg/kg BW) resulted in a bioavailability of 38%, which induced a peak plasma drug concentration at 1h and a maximal inhibition of wheal formation (39%) at 2h. A pharmacokinetic/pharmacodynamic link model showed that CPM in horses has lower efficacy, much lower potency and slightly lower sensitivity than other reported antihistamines. These results indicated that CPM should be administered at frequent intervals or at large dose rates to maintain therapeutic concentrations in horses.

Clostridium difficile is an important cause of acute enterocolitis in horses. We describe five cases of C difficile infection occurring postoperatively in Thoroughbred racehorses. Following diarrhoea or colic accompanied by a marked increase in packed cell volume (to ≥60 per cent) and leucopenia (≤4000 cells/μl) within two to four days after surgery in all five horses, four of them died or were euthanased because of colitis or severe diarrhoea. In these four horses, necrotising entero-typhlo-colitis was revealed by postmortem examination, and C difficile was recovered from the contents of the small and/or large intestine. The remaining horse was euthanased because of marked decline in general condition and the presence of a lung abscess, from which C difficile was isolated. The horse had had severe postoperative diarrhoea before the onset of respiratory disorder; laboratory tests for C difficile were not performed on the faeces. All C difficile isolates were toxin-A-positive, toxin-B-positive and actin-specific ADP-ribosyltransferase (CDT)-positive. The isolates were indistinguishable by pulsed field gel electrophoresis analysis, PCR ribotyping, and slpA sequence typing, and the slpA sequences and PCR ribotype patterns were identical to those of known PCR type 078. This case sequence might have been healthcare-associated infection, although there was about a four-month interval between each disease onset.