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The objective of this study was to determine the minimum inhibitory concentrations (MICs) and pharmacodynamic profiles of four ionophores (lasalocid, monensin, narasin and salinomycin) against staphylococcal isolates from clinical cases of human and veterinary staphylococcal infections, and to determine the effect of methicillin resistance on the antimicrobial activity of ionophores. Broth microdilution MIC testing was used to determine antimicrobial activity against 156 staphylococcal isolates of human and veterinary origin. Pharmacodynamic profiles were examined using time‐kill kinetics profiles against an ATCC type strain of Staphylococcus aureus and a clinical isolate of methicillin‐resistant Staphylococcus pseudintermedius. All tests were performed in accordance with CLSI guidelines. All four ionophores demonstrated antimicrobial activity against methicillin‐resistant staphylococci at concentrations similar to those observed for methicillin‐susceptible isolates of the same species. Testing of human and veterinary MRSA isolates also showed that MIC values were not influenced by the host origin of the isolates. Pharmacodynamic profiles were similar for both isolates tested across all four ionophores, with similar reductions in viable cell counts being observed over an 18‐ to 24‐hr period. Lasalocid, monensin, narasin and salinomycin all demonstrated antimicrobial activity against staphylococcal isolates of human and veterinary origins, with activity being unaffected by methicillin resistance status, although some Staphylococcus species‐specific effects were observed that require further investigation. [ABSTRACT FROM AUTHOR]

The authors reflect on the benzalkonium chloride (BAC) intoxication in cats. Topics discussed include the importance of the toxicosis, effect of intoxication to the behavioural predisposition of cats, and use of BAC as an environmental disinfectant. Also mentioned are the BAC toxidrome, adverse effects, and prevention of intoxication.

Doxapram is marketed as a respiratory stimulant and is used by some veterinarians to help with neonatal apnoea, especially in puppies delivered by caesarean. There is a lack of consensus as to whether the drug is effective and data on its safety are limited. Doxapram was compared to placebo (saline) in newborn puppies in a randomized, double‐blinded clinical trial using two outcome measures: 7‐day mortality rate and repeated APGAR score measurements. Higher APGAR scores have been positively correlated with survival and other health outcomes in newborns. Puppies were delivered by caesarean and a baseline APGAR score was measured. This was immediately followed by a randomly allocated intralingual injection of either doxapram or isotonic saline (of the same volume). Injection volumes were determined by the weight of the puppy and each injection was administered within a minute of birth. The mean dose of doxapram administered was 10.65 mg/kg. APGAR scores were measured again at 2, 5, 10 and 20 min. One hundred and seventy‐one puppies from 45 elective caesareans were recruited into this study. Five out of 85 puppies died after receiving saline and 7 out of 86 died after receiving doxapram. Adjusting for the baseline APGAR score, the age of the mother and whether the puppy was a brachycephalic breed, there was insufficient evidence to conclude a difference in the odds of 7‐day survival for puppies that received doxapram compared to those that received saline (p =.634). Adjusting for the baseline APGAR score, the weight of the mother, the litter size, the mother's parity number, the weight of the puppy and whether the puppy was a brachycephalic breed, there was insufficient evidence to conclude a difference in the probability of a puppy having an APGAR score of ten (the maximum APGAR score) between those that received doxapram compared to those that received saline (p =.631). Being a brachycephalic breed was not associated with an increased odds of 7‐day mortality (p =.156) but the effect of the baseline APGAR score on the probability of having an APGAR score of ten was higher for brachycephalic than non‐brachycephalic breeds (p =.01). There was insufficient evidence that intralingual doxapram provided an advantage (or disadvantage) compared to intralingual saline when used routinely in puppies delivered by elective caesarean and that were not apnoeic. [ABSTRACT FROM AUTHOR]

Otitis externa (OE) is a frequently reported disorder in dogs associated with secondary infections by Staphylococcus, Pseudomonas and yeast pathogens. The presence of biofilms may play an important role in the resistance of otic pathogens to antimicrobial agents. Biofilm production of twenty Staphylococcus pseudintermedius and twenty Pseudomonas aeruginosa canine otic isolates was determined quantitatively using a microtiter plate assay, and each isolate was classified as a strong, moderate, weak or nonbiofilm producer. Minimum biofilm eradication concentration (MBEC) of two ionophores (narasin and monensin) and three adjuvants (N‐acetylcysteine (NAC), Tris‐EDTA and disodium EDTA) were investigated spectrophotometrically (OD570nm) and quantitatively (CFU/ml) against selected Staphylococcus and Pseudomonas biofilm cultures. Concurrently, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of planktonic cultures were assessed. 16/20 of the S. pseudintermedius clinical isolates were weak biofilm producers. 19/20 P. aeruginosa clinical isolates produced biofilms and were distributed almost equally as weak, moderate and strong biofilm producers. While significant antibiofilm activity was observed, no MBEC was achieved with narasin or monensin. The MBEC for NAC ranged from 5,000–10,000 µg/ml and from 20,000–80,000 µg/ml against S. pseudintermedius and P. aeruginosa, respectively. Tris‐EDTA eradicated P. aeruginosa biofilms at concentrations ranging from 6,000/1,900 to 12,000/3,800 µg/ml. The MBEC was up to 16‐fold and eightfold higher than the MIC/MBC of NAC and Tris‐EDTA, respectively. Disodium EDTA reduced biofilm growth of both strains at concentrations of 470 µg/ml and higher. It can be concluded that biofilm production is common in pathogens associated with canine OE. NAC and Tris‐EDTA are effective antibiofilm agents in vitro that could be considered for the treatment of biofilm‐associated OE in dogs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The transdermal delivery of 2 fluorescent probes with similar molecular weight but different lipophilicity, into and through the skin from 2 commercially available transdermal bases, pluronic lecithin organogel, and Lipoderm ® has been evaluated. First, in vitro penetration of fluorescein sodium and fluorescein (free acid) through porcine skin was evaluated. Retention and depth distribution profiles in skin were obtained by tape stripping and then followed by optical sectioning using multiphoton microscopy. The results showed that Lipoderm ® led to an enhanced penetration of the hydrophilic compound, fluorescein sodium. For the lipophilic compound fluorescein (free acid), Lipoderm ® performed similar to pluronic lecithin organogel base, where minimal drug was detected in either receptor phase. The skin retention and depth distribution results also showed that the hydrophilic fluorescein sodium had high skin retention with Lipoderm ® , whereas fluorescein (free acid) had very low penetration and retention with increasing skin depth. Moreover, optical sectioning by multiphoton microscopy revealed an uneven distribution of probes across the skin in the x-y plane for both transdermal bases. This work showed that a hydrophilic compound has significantly increased skin penetration and retention when formulated with Lipoderm ® , and the skin retention of the probe was the main determinant of its skin flux. [ABSTRACT FROM AUTHOR]

Background Topical antimicrobial preparations are of utmost importance in treating suspected and confirmed meticillin-resistant Staphylococcus pseudintermedius ( MRSP) infections due to the increasing incidence of widespread resistance to systemic antimicrobials. Lasalocid is active against MRSP in vitro and this may become an important topical antimicrobial for the treatment of canine pyoderma. Hypothesis/Objectives To determine effects of various formulation types on penetration and retention of lasalocid applied to canine skin in vitro. Animals Normal canine skin was collected from the thorax of five dogs that had been euthanized on the basis of health and/or intractable behavioural issues. Methods Solution, lotion and ointment containing 2% lasalocid were applied to ex vivo canine skin. Transdermal penetration was assessed for a 24 h period and retention of lasalocid was assessed at the conclusion of the study. Results The solution had significantly higher skin retention of lasalocid and proportion of applied dose retained in skin than lotion and ointment (Tukey-Kramer Honest Significant Difference test, P < 0.01). Lasalocid could not be detected in the receptor fluid of any Franz cell at any time point. Conclusions and clinical importance Lasalocid was not identified in the receptor fluid of any sample, indicating that systemic absorption of the active ingredient in vivo is unlikely. Lasalocid may be useful in the treatment of MRSP infections if in vivo studies support safety and efficacy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The majority of antimicrobials that are produced are administered to animals, particularly food animals. While the overall impact of antimicrobial use in animals on antimicrobial resistance in humans and the environment is unclear, it undeniably has a role. Yet, some degree of antimicrobial use in animals is necessary for animal health and welfare purposes. Balancing the benefits and risks of antimicrobial use in animals is challenging because of the complexity of the problem and limitations in available data. However, a range of measures can be implemented to reduce, refine and optimize antimicrobial use in animals, with a goal of minimizing the impact on human and environmental health while maintaining necessary therapeutic use in animals. A pandemic instrument can provide the necessary foundation for the whole-of-society and whole-of government One Health approach that is required to strengthen surveillance, communication, collaboration, and action. [ABSTRACT FROM AUTHOR]

POLICY FOR EVALUATION OF A MANUSCRIPT INVOLVING CIAS Manuscripts involving CIAs should be subject to editorial assessment prior to being sent for peer review. For example, studies involving clinical trials where CIAs are used but where other non-CIA drugs would have been more appropriate. [Extracted from the article]

(a-c) Minimal inhibitory concentration (MIC), fractional inhibitory concentration index (FICI) and dose reduction index (DRI) of the combination effect of (a) narasin and N-acetylcysteine (NAC), (b) narasin and Tris-EDTA and (c) narasin and disodium EDTA (a-c) Minimal inhibitory concentration (MIC), fractional inhibitory concentration index (FICI) and dose reduction index (DRI) of the combination effect of (a) monensin and N-acetylcysteine (NAC), (b) monensin and Tris-EDTA and (c) monensin and disodium EDTA for various bacterial isolates (a-c) Minimal inhibitory concentration (MIC), fractional inhibitory concentration index (FICI) and dose reduction index (DRI) of the combination effect of (a) monensin and N-acetylcysteine (NAC), (b) monensin and Tris-EDTA and (c) monensin and disodium EDTA for various bacterial isolates (a-c) Minimal inhibitory concentration (MIC), fractional inhibitory concentration index (FICI) and dose reduction index (DRI) of the combination effect of (a) monensin and N-acetylcysteine (NAC), (b) monensin and Tris-EDTA and (c) monensin and disodium EDTA for various bacterial isolates. [Extracted from the article]

Robenidine (E)‐N′‐((E)‐1‐(4‐chlorophenyl)ethylidene)‐2‐(1‐(4‐chlorophenyl)ethylidene)hydrazine‐1‐carboximidhydrazide displays methicillin‐resistant Staphyoccoccus aureus (MRSA) and vancomycin‐resistant Enterococci (VRE) MICs of 2 μg mL−1. Herein we describe the structure‐activity relationship development of a novel series of guanidine to 2‐aminopyrimidine isosteres that ameliorate the low levels of mammalian cytotoxicity in the lead compound while retaining good antibiotic activity. Removal of the 2‐NH2 pyrimidine moiety renders these analogues inactive. Introduction of a central 2‐NH2 triazine moiety saw a 10‐fold activity reduction. Phenyl to cyclohexyl isosteres were inactive. The 4‐BrPh and 4‐CH3Ph with MIC values of 2 and 4 μg mL−1, against MRSA and VRE respectively, are promising candidates for future development. [ABSTRACT FROM AUTHOR]

Abstract: Increasing reports of multidrug‐resistant bacterial infections in animals has created a need for novel antimicrobial agents that do not promote cross‐resistance to critically important antimicrobial classes used in human medicine. In response to the recent emergence of antimicrobial resistance in several bovine mastitis pathogens, in vitro antimicrobial susceptibility was determined for four polyether ionophores (lasalocid, monensin, narasin and salinomycin) against Staphylococcus spp. and Streptococcus spp. isolated from clinical cases. In addition, erythrocyte haemolysis and WST‐1 cell proliferation assays were used to assess in vitro mammalian cell cytotoxicity and biofilm susceptibility testing was performed using the minimum biofilm eradication concentration (MBEC™) biofilm assay. Lasalocid, monensin, narasin and salinomycin exhibited bacteriostatic antimicrobial activity against all pathogens tested, including methicillin‐resistant staphylococci, with MIC90 values <16 μg/ml. Narasin and monensin displayed the least toxicity against mammalian cell lines and all compounds significantly reduced viable cell numbers in a Staphylococcus aureus biofilm. Based on in vitro characterization, all four ionophores offer potentially novel treatments against bovine mastitis but in vivo studies will be essential to determine whether acceptable safety and efficacy is present following intramammary administration. [ABSTRACT FROM AUTHOR]

Highlights • Examining whether limiting antimicrobial use in food animals decreases antimicrobial resistance in food animals and humans. • 89 studies showed limiting antimicrobials given to animals reduces antimicrobial resistance in animals. • 4 studies indicated withdrawing antimicrobials in food animals results in decreased antimicrobial resistance in humans. • Studies needed on effect of stopping antimicrobial use in food animals, particularly on resistance in human bacterial flora. ABSTRACT Background Large quantities of antimicrobials are given to food animals, particularly in feed, potentially increasing antimicrobial resistance in humans. However, the magnitude of this effect is unclear. Methods We searched PubMed, Embase and Web of Science for studies on interventions that limited antimicrobial use in food animals, in any setting and context, to reduce antimicrobial resistance 1) in those food animals; and 2) in humans. We validated our strategy by testing whether it identified known relevant studies. Data from included studies were extracted into pre-designed and pilot-tested forms. Results We included 104 articles containing 93 studies. Heterogeneity (different animal species, environs, antimicrobial classes, interventions, administration routes, sampling, and methods), was considerable, precluding meta-analysis. The evidence was therefore synthesised narratively. A total of 89 studies (3 directly, 86 indirectly) addressed whether limiting antimicrobial exposure in food animals led to decreased antimicrobial resistance in those animals. The evidence was adequate to conclude this, although the magnitude of the effect could not be quantified. Four studies (1 directly, 3 indirectly) examined whether withdrawal of antibiotics changed resistance of potential pathogens in retail food for human consumption, and in bacteria of humans themselves. The direct (observational) study of broiler hatchery in ovo antimicrobial injection found a credible effect in terms of size reduction and time sequences. Interpretation Limiting antimicrobial use in food animals reduces antimicrobial resistance in food animals, and probably reduces antimicrobial resistance in humans. The magnitude of the effect cannot be quantified. [ABSTRACT FROM AUTHOR]

There are very few articles in the literature describing continuous models of bacterial infections that mimic disease pathogenesis in humans and animals without using separate cohorts of animals at each stage of disease. In this work, we developed bioluminescent mouse models of partial-thickness scald wound infection and sepsis that mimic disease pathogenesis in humans and animals using a recombinant luciferase-expressing Staphylococcus aureus strain (Xen29). Two days post-scald wound infection, mice were treated twice daily with a 2% topical mupirocin ointment for 7 days. For sepsis experiments, mice were treated intraperitoneally with 6 mg/kg daptomycin 2 h and 6 h post-infection and time to moribund monitored for 72 h. Consistent bacterial burden data were obtained from individual mice by regular photon intensity quantification on a Xenogen IVIS Lumina XRMS Series III biophotonic imaging system, with concomitant significant reduction in photon intensities in drug-treated mice. Post-mortem histopathological examination of wounds and bacterial counts in blood correlated closely with disease severity and total flux obtained from Xen29. The bioluminescent murine models provide a refinement to existing techniques of multiple bacterial enumeration during disease pathogenesis and promote animal usage reduction. The models also provide an efficient and information-rich platform for preclinical efficacy evaluation of new drug classes for treating acute and chronic human and animal bacterial infections. [ABSTRACT FROM AUTHOR]

Antimicrobial resistance and antimicrobial stewardship are of ever-increasing importance in veterinary medicine. Multidrug-resistant infections of the canine skin and ear continue to emerge, but the use of antibiotic classes of critical importance to human medicine may not represent good antimicrobial stewardship. Repurposing of old drugs that are not used in human medicine is one approach that addresses both these issues. In this study, the minimal inhibitory concentration (MIC) of monensin for 111 bacterial and yeast canine otitis isolates was determined using microdilution methodology according to Clinical Laboratory Standards Institute (CLSI) guidelines. Monensin was effective against all Gram-positive bacteria including the multidrug-resistant staphylococcal strains with MICs ranging from 1 to 4 μg/ml, but lacked antimicrobial activity against Gram-negative bacteria and yeast isolates. Monensin has potential to be incorporated as one of the main components in an otic formulation. [ABSTRACT FROM AUTHOR]

Background: Antimicrobial resistance and antimicrobial stewardship are of ever‐increasing importance in veterinary medicine. Re‐purposing of old drugs that are not used in human medicine is one approach that addresses the emergence of multidrug resistance in canine skin and ear infections, and can reduce the use of critically important human antibiotic classes. Hypothesis/Objectives: To determine the antimicrobial activity of narasin, a polyether ionophore conventionally used as a rumen modifier and anticoccidial agent in production animals, against common clinical isolates of canine otitis externa (OE). Animals/Isolates: Clinical isolates (n = 110) from canine OE were tested, including 17 meticillin‐susceptible Staphylococcus pseudintermedius (MSSP), 13 multidrug‐resistant Staphylococcus pseudintermedius (MDRSP), and 20 each of β‐haemolytic Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis and Malassezia pachydermatis. Methods: Bacterial and yeast isolates were subcultured, suspended in broth and inoculated into 96‐well plates. Organisms were tested against concentrations of narasin ranging from 0.03 to 128 μg/mL. Minimal inhibitory concentrations (MICs) were determined after overnight incubation. Results: Narasin MICs for staphylococcal and streptococcal isolates ranged from 0.06 to 0.25 μg/mL; MIC50 and MIC90 values for both organisms were 0.125 μg/mL. No MICs were achieved for Pseudomonas or Proteus isolates. There was a weak antifungal effect against M. pachydermatis isolates (MIC 32 to >128 μg/mL). Conclusions and Clinical Relevance: Narasin was effective against Gram‐positive bacteria and had antifungal activity at higher concentrations against M. pachydermatis. However, the lack of Gram‐negative activity would prevent its use as a sole antimicrobial agent in cases of canine OE. [ABSTRACT FROM AUTHOR]

The spread of multidrug resistance among bacterial pathogens poses a serious threat to public health worldwide. Recent approaches towards combating antimicrobial resistance include repurposing old compounds with known safety and development pathways as new antibacterial classes with novel mechanisms of action. Here we show that an analog of the anticoccidial drug robenidine (4,6-bis(2-((E)-4-methylbenzylidene)hydrazinyl)pyrimidin-2-amine; NCL195) displays potent bactericidal activity against Streptococcus pneumoniae and Staphylococcus aureus by disrupting the cell membrane potential. NCL195 was less cytotoxic to mammalian cell lines than the parent compound, showed low metabolic degradation rates by human and mouse liver microsomes, and exhibited high plasma concentration and low plasma clearance rates in mice. NCL195 was bactericidal against Acinetobacter spp and Neisseria meningitidis and also demonstrated potent activity against A. baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae and Enterobacter spp. in the presence of sub-inhibitory concentrations of ethylenediaminetetraacetic acid (EDTA) and polymyxin B. These findings demonstrate that NCL195 represents a new chemical lead for further medicinal chemistry and pharmaceutical development to enhance potency, solubility and selectivity against serious bacterial pathogens. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop an in vitro release model for intramammary drug delivery system (IMDS) evaluation. This study was the first to establish an in vitro–in vivo correlation with investigation of an IMDS containing lasalocid. Three different methods including the standard United States Pharmacopeia dissolution method with apparatus 2, a modified United States Pharmacopeia method using a dialysis bag, or a specifically designed enhancer cell system, were assessed for the release study. Full cream milk and water were selected as the release media. In vivo evaluation was carried out by administering lasalocid IMDS into the udder of lactating Holstein dairy cows. Milk samples were collected and analyzed at selected time points after treatment. Dissolution data were fitted to various kinetic models. The results indicated that the release rate of lasalocid from IMDS was controlled by factors other than diffusion, which could include the sedimentation of lasalocid to the interface and the wetting of lasalocid particles by water at the interface of oil in the formulation and release media. The results obtained in vivo and in vitro were consistent. The in vitro assessment supports formulation design for early stage development and potentially for in vivo performance analysis. [ABSTRACT FROM AUTHOR]

The present review discusses the pharmaceutical impact of the anatomy and physiology of the canine gastrointestinal tract to provide a comprehensive guide to the theories and challenges associated with the development of oral drug delivery systems for dogs. Novel pharmaceutical technologies applied to veterinary drugs are discussed indicating the advantages and benefits for animals. There are currently immense research and development efforts being funneled into novel canine health products. Such products are being used to overcome limitations of drugs that display site-dependent absorption or possess poor biopharmaceutical properties. Techniques that are employed to increase bioavailability of the Biopharmaceutics Classification System class II drugs are discussed in this article. Furthermore, an overview of palatable oral formulations for dog care is provided as an approach to easy administration. In vitro and in vivo evaluation and correlation of oral drug formulations in dogs are also addressed. This article assesses the outlook of canine oral drug development recognizing substantial growth forecasts of the dog care market. [ABSTRACT FROM AUTHOR]

Robenidine, 1 (2,2'-bis[(4-chlorophenyl)methylene]carbonimidic dihydrazide), was active against MRSA and VRE with MIC's of 8.1 and 4.7 μM, respectively. SAR revealed tolerance for 4-Cl isosteres with 4-F (8), 3-F (9), 3-CH3 (22), and 4-C(CH3)3 (27) (23.7-71 μM) and with 3-Cl (3), 4-CH3 (21), and 4-CH(CH3)2 (26) (8.1-13.0 μM). Imine carbon alkylation identified a methyl/ethyl binding pocket that also accommodated a CH2OH moiety (75; 2,2'-bis[1-(4-chlorophenyl)-2-hydroxyethylidene]carbonimidic dihydrazide). Analogues 1, 27 (2,2'-bis{[4-(1,1-dimethylethyl)phenyl]methylene}carbonimidic dihydrazide), and 69 (2,2'-bis[1-(4-chlorophenyl)ethylidene]carbonimidic dihydrazide hydrochloride) were active against 24 clinical MRSA and MSSA isolates. No dose-limiting cytotoxicity at ≥2× MIC or hemolysis at ≥8× MIC was observed. Polymyxin B addition engendered Escherichia coli and Pseudomonas aeruginosa Gram-negative activity MIC's of 4.2-21.6 μM. 1 and 75 displayed excellent microsomal stability, intrinsic clearance, and hepatic extraction ratios with T1/2 > 247 min, CLint < 7 μL/min/mg protein, and EH < 0.22 in both human and mouse liposomes for 1 and in human liposomes for 75. [ABSTRACT FROM AUTHOR]

This study describes a neonatal mouse model of Giardia infection for development of novel antigiardials. Mice were infected with the axenically cultured Assemblage A BAH2c2 strain, with 10 5 trophozoites per animal recovered. This model proved to be robust and consistent for use in preliminary drug efficacy trials and drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel RID-HPLC method development for NAR quantification without derivatization. • Forced degradation was performed to detect degradation peaks and stability of NAR. • The developed method was validated as per FDA guidelines and applied to feed premix. • Greenness profile of the developed method was evaluated using GAPI and AGREE tools. 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. [ABSTRACT FROM AUTHOR]

The article discusses a case of feline permethrin intoxication which was initially treated with Ringer's lactate solution, infused at 7.2 milliliter per hour (ml/h) with 27.8 milligrams (mg) prednisolone succinate given as a separate injection.

• NCL195 synergises with low colistin concentrations to kill Gram-negative bacteria (GNB). • The dual action of NCL195 + colistin against GNB is time- and concentration-dependent. • NCL195 + colistin combination also kills colistin-resistant GNB. • NCL195 represents a new chemical class against infections by GNB. • NCL195 + colistin could represent a good example of antimicrobial stewardship. In this study, the potential of using the novel antibiotic NCL195 combined with subinhibitory concentrations of colistin against infections caused by Gram-negative bacteria (GNB) was investigated. We showed synergistic activity of the combination NCL195 + colistin against clinical multidrug-resistant GNB pathogens with minimum inhibitory concentrations (MICs) for NCL195 ranging from 0.5–4 μg/mL for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa , whereas NCL195 alone had no activity. Transmission electron microscopy of the membrane morphology of E. coli and P. aeruginosa after single colistin or combination drug treatment showed marked ultrastructural changes most frequently in the cell envelope. Exposure to NCL195 alone did not show any change compared with untreated control cells, whereas treatment with the NCL195 + colistin combination caused more damage than colistin alone. Direct evidence for this interaction was demonstrated by fluorescence-based membrane potential measurements. We conclude that the synergistic antimicrobial activity of the combination NCL195 + colistin against GNB pathogens warrants further exploration for specific treatment of acute GNB infections. [ABSTRACT FROM AUTHOR]

Background: An antibiotic adjuvant is a chemical substance used to modify or augment the effectiveness of primary antimicrobial agents against drug‐resistant micro‐organisms. Its use provides an alternative approach to address the global issue of antimicrobial resistance and enhance antimicrobial stewardship. Hypothesis/Objectives: To determine the antimicrobial activity of a panel of potential antimicrobial adjuvants against common pathogens associated with canine otitis externa (OE). Animals/Isolates: A number of type strains and clinical isolates (n = 110) from canine OE were tested including Staphylococcus pseudintermedius, β‐haemolytic Streptococcus spp., Pseudomonas aeruginosa, Proteus mirabilis and Malassezia pachydermatis. Methods and materials: Antimicrobial activities of monolaurin, monocaprin, N‐acetylcysteine (NAC), polymyxin B nonapeptide, Tris‐EDTA, Tris‐HCL and disodium EDTA were tested using microdilution methodology according to CLSI guidelines. Results: N‐acetylcysteine, Tris‐EDTA and disodium EDTA had antimicrobial activity against both type strains and otic pathogens. The other adjuvants tested had limited to no efficacy. NAC had a minimal inhibitory concentration (MIC) range of 2,500–10,000 μg/mL for the various organisms. Pseudomonas aeruginosa isolates were eight times more susceptible to disodium EDTA in the presence of Tris‐HCL in comparison to disodium EDTA alone. Malassezia pachydermatis isolates were most susceptible to Tris‐EDTA (MIC90 = 190/60 μg/mL) and disodium EDTA (MIC90 = 120 μg/mL). Conclusions and clinical relevance: N‐acetylcysteine, Tris‐EDTA and disodium EDTA have intrinsic antimicrobial activity and represent promising adjuvants that could be used to enhance the efficacy of existing antibiotics against Gram‐negative and multidrug‐resistant bacterial infections. These agents could be combined with other antimicrobial agents in a multimodal approach for mixed ear infections in dogs. [ABSTRACT FROM AUTHOR]