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Background Otitis externa is a commonly diagnosed dermatological disorder in canines. The pathogens primarily involved in canine otitis externa (COE) include Staphylococcus pseudintermedius, Pseudomonas aeruginosa, Proteus mirabilis, and Malassezia pachydermatis. As COE tends to be superficial, medications delivered topically are often effective and practical in managing the condition. As such, there is a wide variety of approved topical products currently available in the market. The efficacy of topical dosage forms can be dependent on various factors such as the pharmacology of active constituents and the physicochemical properties of the formulation, including pH, viscosity, spreadability, and bio-adhesion. Currently, there is a lack of published literature available on the optimal properties of topical COE products. In this study, we compared the physicochemical properties of nine commercially available otic veterinarian products in Australia used clinically to manage COE. Results Based on our comparative analysis, the pH (6.26 ± 0.04) of an aqueous-based product was similar to a healthy dog’s external auditory canal. Products containing polymers exhibited higher viscosity and bio-adhesion. Spreadability was inversely related to viscosity and Osurnia ® a product with high viscosity demonstrated the lowest spreadability. Aqueous-based otic products showed better syringebility whereas oil-based systems required higher force to expel the products. Variability in droplet size was noted. Derm Otic, Baytril Otic, and Aurizon Ear Drops had the lower standard deviation which indicates they would give a more consistent dose. Conclusions Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.

Refereed/Peer-reviewed While the global market for veterinary products has been expanding rapidly, there is still a lack of specialist knowledge of equine pharmaceutics. In many cases, the basic structure of the gastrointestinal tract (GIT) and integumentary system of the horse shares similarities with those of humans. Generally, the dosage form developed for humans can be repurposed to deliver equine medications; however, due to physiological variation, the therapeutic outcomes can be unpredictable. This is an area that requires more research, as there is a clear deficiency in literature precedence on drug delivery specifically for horses. Through a careful evaluation of equine anatomy and physiology, novel drug delivery systems (NDDSs) can be developed to adequately address many of the medical ailments of the horse. In addition to this, there are key considerations when delivering oral, topical, and parenteral drugs to horses, deriving from age and species variation. More importantly, NDDSs can enhance the duration of action of active drugs in animals, significantly improving owner compliance; and ultimately, enhancing the convenience of product administration. To address the knowledge gap in equine pharmaceutical formulations, this paper begins with a summary of the anatomy and physiology of the equine gastrointestinal, integumentary, and circulatory systems. A detailed discussion of potential dosage-form related issues affecting horses, and how they can be overcome by employing NDDSs is presented.

In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical diversity for the treatment of multidrug-resistant (MDR) bacterial infections. We show that NCL179 exhibits potent bactericidal activity, returning minimum inhibitory concentration/minimum bactericidal concentrations (MICs/MBCs) of 1–2 µg/mL against methicillin-resistant Staphylococcus aureus, MICs/MBCs of 1–2 µg/mL against methicillin-resistant S. pseudintermedius and MICs/MBCs of 2–4 µg/mL against vancomycin-resistant enterococci. NCL179 showed synergistic activity against clinical isolates and reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa in the presence of sub-inhibitory concentrations of colistin, whereas NCL179 alone had no activity. Mice given oral NCL179 at 10 mg/kg and 50 mg/kg (4 × doses, 4 h apart) showed no adverse clinical effects and no observable histological effects in any of the organs examined. In a bioluminescent S. aureus sepsis challenge model, mice that received four oral doses of NCL179 at 50 mg/kg at 4 h intervals exhibited significantly reduced bacterial loads, longer survival times and higher overall survival rates than the vehicle-only treated mice. These results support NCL179 as a valid candidate for further development to treat MDR bacterial infections as a stand-alone antibiotic or in combination with existing antibiotic classes.

Multidrug-resistant (MDR) Gram-negative pathogens, especially Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Enterobacter spp., are recognized by the World Health Organization as the most critical priority pathogens in urgent need of drug development. In this study, the in vitro antimicrobial activity of robenidine analogues NCL259 and NCL265 was tested against key human and animal Gram-negative clinical isolates and reference strains. NCL259 and NCL265 demonstrated moderate antimicrobial activity against these Gram-negative priority pathogens with NCL265 consistently more active, achieving lower minimum inhibitory concentrations (MICs) in the range of 2–16 µg/mL. When used in combination with sub-inhibitory concentrations of polymyxin B to permeabilize the outer membrane, NCL259 and NCL265 elicited a synergistic or additive activity against the reference strains tested, reducing the MIC of NCL259 by 8- to 256- fold and the MIC of NCL265 by 4- to 256- fold. A small minority of Klebsiella spp. isolates (three) were resistant to both NCL259 and NCL265 with MICs > 256 µg/mL. This resistance was completely reversed in the presence of the efflux pump inhibitor phenylalanine-arginine-beta-naphthylamide (PAβN) to yield MIC values of 8–16 µg/mL and 2–4 µg/mL for NCL259 and NCL256, respectively. When NCL259 and NCL265 were tested against wild-type E. coli isolate BW 25113 and its isogenic multidrug efflux pump subunit AcrB deletion mutant (∆AcrB), the MIC of both compounds against the mutant ∆AcrB isolate was reduced 16-fold compared to the wild-type parent, indicating a significant role for the AcrAB-TolC efflux pump from Enterobacterales in imparting resistance to these robenidine analogues. In vitro cytotoxicity testing revealed that NCL259 and NCL265 had much higher levels of toxicity to a range of human cell lines compared to the parent robenidine, thus precluding their further development as novel antibiotics against Gram-negative pathogens.

One approach to combat the increasing incidence of multidrug-resistant (MDR) bacterial pathogens involves repurposing existing compounds with known safety and development pathways as new antibacterial classes with potentially novel mechanisms of action. Here, triclabendazole (TCBZ), a drug originally developed to treat Fasciola hepatica (liver fluke) in sheep and cattle, and later in humans, was evaluated as an antibacterial alone or in combination with sub-inhibitory concentrations of polymyxin B (PMB) against clinical isolates and reference strains of key Gram-positive and Gram-negative bacteria. We show for the first time that in vitro, TCBZ selectively kills methicillin-sensitive and methicillin-resistant Staphylococcus aureus and Staphylococcus pseudintermedius at a minimum inhibitory concentration (MIC) range of 2–4 µg/mL, and vancomycin-resistant enterococci at a MIC range of 4–8 µg/mL. TCBZ also inhibited key Gram-negative bacteria in the presence of sub-inhibitory concentrations of PMB, returning MIC90 values of 1 µg/mL for Escherichia coli, 8 µg/mL for Klebsiella pneumoniae, 2 µg/mL for Acinetobacter baumannii and 4 µg/mL for Pseudomonasaeruginosa. Interestingly, TCBZ was found to be bacteriostatic against intracellular S. aureus but bactericidal against intracellular S. pseudintermedius. Additionally, TCBZ’s favourable pharmacokinetic (PK) and pharmacodynamic (PD) profile was further explored by in vivo safety and efficacy studies using a bioluminescent mouse model of S. aureus sepsis. We show that repeated four-hourly oral treatment of mice with 50 mg/kg TCBZ after systemic S. aureus challenge resulted in a significant reduction in S. aureus populations in the blood to 18 h post-infection (compared to untreated mice) but did not clear the bacterial infection from the bloodstream, consistent with in vivo bacteriostatic activity. These results indicate that additional pharmaceutical development of TCBZ may enhance its PK/PD, allowing it to be an appropriate candidate for the treatment of serious MDR bacterial pathogens.

Refereed/Peer-reviewed Narasin (NAR) is a commonly used ionophoric antibiotic used in the poultry industry, cattle and pig production both for treating coccidiosis and increasing feed conversion efficiency. To ensure safe administration of NAR into the feed is important to avoid toxicity to farm animals caused by incorporation of large doses or non-homogenous mixing, which requires a simple and sensitive chromatographic method to quantify NAR. However, NAR detection by HPLC is challenging as it lacks a chromophore making it less susceptible to UV and fluorescence detection, and the published analytical methods suffer from disadvantages such as the need for complex derivatization or the use of high volumes of hazardous organic solvents. Herein, a novel, simple, rapid, and cost-effective HPLC method is reported to quantify NAR and a study of forced degradation under acidic, basic, temperature, and oxidative conditions are proposed. The separation was performed using a Phenomenex C18 analytical column (4.6 × 150 mm, 5 μm) and the mobile phase composed of 920 mL methanol, 80 mL water and 10 mL glacial acetic acid. A flow rate of 1 mL/min, and sample injection volume of 50 μL was used to detect NAR using the refractive index detector. The HPLC method was validated according to FDA guidelines and was found to be accurate, precise, sensitive and robust. It was shown to be linear at ranges of 200 to 900 µg/mL with a limit of detection (LOD) and limit of quantitation (LOQ) of 7.1 µg/mL and 21.5 µg/mL respectively. The method was successfully used to quantify the drug in its commercial formulation and a forced degradation study was performed under acidic, basic, temperature, and oxidative conditions. The greenness profile of the method was also investigated and compared to reported methods using the green analytical procedure Index (GAPI), and Analytical GREEnness Metric Approach and Software (AGREE) tools. The results indicated the greenness of the developed method.