Stephen W. Page

Development of an improved Streptococcus uberis experimental mastitis challenge model using different doses and strains in lactating dairy cows

Publisher: Cambridge University Press (CUP)

Date: 20-07-2015

DOI: 10.1017/S0022029915000321

Abstract: Developing a reliable mastitis challenge infection model is required to test new intramammary antimicrobial preparations, other novel bovine mastitis treatments, and study mastitis pathogenesis. Three treatment groups of Holstein Friesian cows in active lactation were administered two doses (10 4 and 10 6 cfu/quarter) on a single occasion with one of the three Streptococcus uberis strains (BFR6019, MFF1283 and SA002) suspended in 5 ml of sterile PBS, administered via intramammary inoculation immediately after milking. All quarters that were challenged with S. uberis strains MLF1283 and BFR6019 showed clinical signs of mastitis on day 1 and 2 after the challenge. Strain SA002 had a lower rate of inducing clinical mastitis which was detected later than day 3 after the challenge. We successfully developed a rapid and reliable model for inducing experimental S. uberis mastitis with 100% success rate in cows in active lactation. On the basis of the correlation results between strains, RAPD fingerprinting results, clinical findings, and a 100% success rate of mastitis induction for low and high doses S. uberis strains MLF1283 and BFR6019, strain virulence seems to be a more important effect than challenge dose in induction of clinical mastitis following experimental challenge.

In vitroActivity of Robenidine Analog NCL195 in Combination With Outer Membrane Permeabilizers Against Gram-Negative Bacterial Pathogens and Impact on Systemic Gram-Positive Bacterial Infection in Mice

Publisher: Frontiers Media SA

Date: 04-08-2020

DOI: 10.3389/FMICB.2020.01556

Evaluation of Benzguinols as Next-Generation Antibiotics for the Treatment of Multidrug-Resistant Bacterial Infections

Publisher: MDPI AG

Date: 16-06-2021

DOI: 10.3390/ANTIBIOTICS10060727

Abstract: Our recent focus on the “lost antibiotic” unguinol and related nidulin-family fungal natural products identified two semisynthetic derivatives, benzguinols A and B, with unexpected in vitro activity against Staphylococcus aureus isolates either susceptible or resistant to methicillin. Here, we show further activity of the benzguinols against methicillin-resistant isolates of the animal pathogen Staphylococcus pseudintermedius, with minimum inhibitory concentration (MIC) ranging 0.5–1 μg/mL. When combined with sub-inhibitory concentrations of colistin, the benzguinols demonstrated synergy against Gram-negative reference strains of Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa (MICs of 1–2 μg/mL in the presence of colistin), whereas the benzguinols alone had no activity. Administration of three intraperitoneal (IP) doses of 20 mg/kg benzguinol A or B to mice did not result in any obvious adverse clinical or pathological evidence of acute toxicity. Importantly, mice that received three 20 mg/kg IP doses of benzguinol A or B at 4 h intervals exhibited significantly reduced bacterial loads and longer survival times than vehicle-only treated mice in a bioluminescent S. aureus murine sepsis challenge model. We conclude that the benzguinols are potential candidates for further development for specific treatment of serious bacterial infections as both stand-alone antibiotics and in combination with existing antibiotic classes.

Antimicrobial resistance in animal and public health: introduction and classification of antimicrobial agents

Publisher: O.I.E (World Organisation for Animal Health)

Date: 04-2012

DOI: 10.20506/RST.31.1.2093

Abstract: Bacteria have a remarkable ability to adapt, evolve and survive by developing resistance to therapeutic compounds. This ability is also shared by other pathogenic agents such as viruses, fungi, and parasites. Even when focusing on bacterial resistance only, this phenomenon is quite complex to analyse due to the ersity of animal species, the ersity of rearing environment, the number of antimicrobial classes available and the ersity of pathogenic bacteria involved. This introductory paper includes developments on the place of antiviral compounds in veterinary medicine and a classification of antimicrobials used in food-producing animals.

Bioluminescent murine models of bacterial sepsis and scald wound infections for antimicrobial efficacy testing

Publisher: Public Library of Science (PLoS)

Date: 16-07-2018

DOI: 10.1371/JOURNAL.PONE.0200195

Robenidine Analogues as Gram-Positive Antibacterial Agents

Publisher: American Chemical Society (ACS)

Date: 10-02-2016

DOI: 10.1021/ACS.JMEDCHEM.5B01797

Abstract: 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.

Diethylstilboestrol—historical background and current regulatory status

Publisher: Wiley

Date: 07-1991

DOI: 10.1111/J.1751-0813.1991.TB03211.X

Abstract: Diethylstilboestrol is a non-steroidal orally active oestrogen that in the past has been widely used in a variety of conditions in both medical and veterinary fields. In recognition of potential systemic availability to man of DES in the tissues of treated food-producing animals, together with an understanding of the potential teratogenic and carcinogenic toxicity of DES in man, the veterinary use of DES has been restricted to oral use in small animals only. Use of DES is prohibited in all food-producing animals.

Gram-Positive and Gram-Negative Antibiotic Activity of Asymmetric and Monomeric Robenidine Analogues

Publisher: Wiley

Date: 19-11-2018

DOI: 10.1002/CMDC.201800463

Abstract: Desymmetrisation of robenidine (1: N',2-bis((E)-4-chlorobenzylidene)hydrazine-1-carboximidhydrazide) and the introduction of imine alkyl substituents gave good antibiotic activity. Of note was the increased potency of two analogues against vancomycin-resistant Enterococci (VRE), one of which returned a MIC of 0.5 μg mL

Physicochemical properties of otic products for Canine Otitis Externa: comparative analysis of marketed products

Publisher: Springer Science and Business Media LLC

Date: 09-02-2023

DOI: 10.1186/S12917-023-03596-2

Abstract: 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. 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. Findings from this work provide considerations for industry researchers or formulation scientists working in the area of otic dosage formulations.

Does antibiotic use in farmed animals pose a risk to human health? — No

Publisher: AMPCo

Date: 03-2012

DOI: 10.5694/MJA12.10364

In vitro antimicrobial activity of seven adjuvants against common pathogens associated with canine otitis externa

Publisher: Wiley

Date: 13-12-2019

DOI: 10.1111/VDE.12712

Abstract: 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. To determine the antimicrobial activity of a panel of potential antimicrobial adjuvants against common pathogens associated with canine otitis externa (OE). 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. 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. 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 (MIC 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.

Advanced Strategies of Drug Delivery via Oral, Topical, and Parenteral Administration Routes: Where do Equine Medications Stand?

Publisher: MDPI AG

Date: 04-01-2023

DOI: 10.3390/PHARMACEUTICS15010186

Abstract: 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.

Key Considerations in Designing Oral Drug Delivery Systems for Dogs

Publisher: Elsevier BV

Date: 05-2016

DOI: 10.1016/J.XPHS.2016.03.007

Abstract: 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.

In vitro antimicrobial activity of narasin against common clinical isolates associated with canine otitis externa

Publisher: Wiley

Date: 24-01-2018

DOI: 10.1111/VDE.12516

Abstract: 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. 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). 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. 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. Narasin MICs for staphylococcal and streptococcal isolates ranged from 0.06 to 0.25 μg/mL MIC 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.

In vitro Antimicrobial Activity of Robenidine, Ethylenediaminetetraacetic Acid and Polymyxin B Nonapeptide Against Important Human and Veterinary Pathogens

Publisher: Frontiers Media SA

Date: 25-04-2019

DOI: 10.3389/FMICB.2019.00837

Chloramphenicol 3. Clinical pharmacology of systemic use in the horse

Publisher: Wiley

Date: 1991

DOI: 10.1111/J.1751-0813.1991.TB09828.X

Abstract: The use of chlor henicol in the horse is now prohibited as horses are classified as food-producing animals. However, chlor henicol has until recently been widely available for oral, intramuscular or intravenous administration. A critical appraisal of the published literature on the use of chlor henicol in the horse clearly demonstrates that there are sound pharmacokinetic and microbiological reasons for concluding that chlor henicol is not an appropriate antibiotic for systemic use. The short half-life of chlor henicol in the horse, together with the broad range of minimum inhibitory concentrations of target pathogens, preclude the use of practical dosage regimens. It can be concluded that the withdrawal of chlor henicol will have no adverse effects on chemotherapy in the horse.

Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs

Publisher: Wiley

Date: 21-05-2016

DOI: 10.1111/JVP.12243

Abstract: Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were ided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma s les and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

Opposing views Does antibiotic use in farmed animals pose a risk to human health?

Publisher: AMPCo

Date: 03-2012

DOI: 10.5694/MJA12.10329

Antimicrobial Stewardship in Veterinary Medicine

Publisher: ASM Press

Date: 23-08-2018

DOI: 10.1128/9781555819804.CH31

In vitro synergistic activity of NCL195 in combination with colistin against Gram-negative bacterial pathogens

Publisher: Elsevier BV

Date: 05-2021

DOI: 10.1016/J.IJANTIMICAG.2021.106323

In Vitro Activity of Robenidine Analogues NCL259 and NCL265 against Gram-Negative Pathogens

Publisher: MDPI AG

Date: 23-09-2022

DOI: 10.3390/ANTIBIOTICS11101301

Abstract: 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.

Preliminary investigations into a novel, long-acting, injectable, intramuscular formulation of omeprazole in the horse

Publisher: Wiley

Date: 17-05-2017

DOI: 10.1111/EVJ.12688

Abstract: Pilot investigations have suggested that a novel, long-acting, injectable i.m. formulation of omeprazole (LA-OMEP) can induce acid suppression for up to 7 days following a single injection. To investigate the pharmacodynamics and assess the clinical efficacy of the LA-OMEP formulation. Part A comprised a pharmacodynamic study. Part B consisted of a pilot clinical trial. Part A enrolled six adult Thoroughbred horses with percutaneous gastrotomy tubes. Intragastric pH was measured for continuous 23-h periods (08.00-07.00 h) for eight consecutive days (days 0-7). A single 2.0-g dose of a 100 mg/mL LA-OMEP formulation was administered at 08.00 h on day 1. In Part B, 26 horses with squamous or glandular gastric disease were enrolled based on routine gastroscopic evaluation. Once enrolled, horses received 2.0 g of the 100 mg/mL LA-OMEP formulation by i.m. injection on days 0 and 7. Repeat gastroscopy was performed on days 14 (23 horses) or 16 (one horse). In Part A, the percentage of time during which pH was above 4 exceeded 66% for days 1-4 in all horses and days 1-7 in four of the six horses studied. In Part B, healing was observed in all 22 (100%, 95% confidence interval [CI] 89-100%) horses with squamous disease and in nine of 12 (75%, 95% CI 47-92%) horses with glandular disease. Improvement, by at least one grade, was observed in all 22 (100%, 95% CI 89-100%) horses with squamous disease and in all 12 (100%, 95% CI 81-100%) horses with glandular disease. No worsening of lesions was observed. Lesion grade decreased over time in both the squamous (P<0.0001) and glandular (P = 0.0024) mucosa. Small s le sizes. The results of the present study compare favourably with previous reports on the pharmacodynamics of omeprazole and the clinical outcomes of trials reporting response to oral omeprazole therapy.

Chloramphenicol 1. Hazards of use and the current regulatory environment

Publisher: Wiley

Date: 1991

DOI: 10.1111/J.1751-0813.1991.TB09826.X

Abstract: Chlor henicol is a broad-spectrum antibiotic which has enjoyed extensive use in both medical and veterinary practice. Shortly after its introduction in the late 1940s, the use of chlor henicol was associated with the induction of an idiosyncratic form of aplastic anaemia in man. This rare and unpredictable adverse effect has since been associated not only with systemic use but with topical applications, as well as occupational exposure. Recognition of the small risk of a potentially fatal adverse reaction, together with the risk of selection of chlor henicol-resistant pathogens, has led to restrictions on the veterinary uses of chlor henicol. In Australia at present, the use of chlor henicol is only permitted in small animals. Its use is specifically prohibited in food-producing animals, including horses.

Antimicrobial prescribing guidelines for poultry

Publisher: Wiley

Date: 29-03-2021

DOI: 10.1111/AVJ.13034

Current and future antimicrobial resistance issues for the Australian pig industry

Publisher: CSIRO Publishing

Date: 2017

DOI: 10.1071/AN17358

Abstract: Antimicrobial use and antimicrobial resistance (AMR) in intensive pig production and its potential impacts to human and animal health are very much under the spotlight, both internationally, and within Australia. While the majority of AMR of medical importance is associated with the exclusive use of antimicrobials in humans, resistance in zoonotic foodborne pathogens such as Salmonella and C ylobacter, and livestock commensal bacteria such as Escherichia coli and Enterococcus spp., is under increased scrutiny. This is primarily due to the current reliance on many of the same drug classes as used in human medicine for treatment and control of bacterial diseases of livestock. Furthermore, the development of multidrug resistance in pathogens such as enterotoxigenic E. coli may drive off-label use of critically important drug classes such as 3rd-generation cephalosporins. This could lead to the emergence and lification of resistance genes of potential public health significance in both pathogens and commensal bacteria. Livestock-associated and community-associated methicillin-resistant Staphylococcus aureus has also recently been detected in Australian pigs as a result of human-to-animal transmission and are a potential public health issue for in-contact piggery workers. Australia is in a unique position compared with many of its international trading partners due to its isolation, ban on importation of livestock and conservative approach to antimicrobial registration, including reservation of the fluoroquinolone class for use in humans and companion animals only. Cross-sectional AMR surveys of pathogens and commensals in healthy pigs have identified only low frequency of resistance to critically important drug classes. Nevertheless, resistance to critically important antimicrobials has emerged and careful antimicrobial stewardship is required to ensure that these low levels do not increase. In this report, we review AMR of significance to the Australian pig industry and identify potential prevention and control measures.

Is antimicrobial administration to food animals a direct threat to human health? A rapid systematic review

Publisher: Elsevier BV

Date: 09-2018

DOI: 10.1016/J.IJANTIMICAG.2018.04.005

Abstract: 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. 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. We included 104 articles containing 93 studies. Heterogeneity (different animal species, environs, antimicrobial classes, interventions, administration routes, s ling, 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. 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.

Antimicrobial prescribing guidelines for pigs

Publisher: Wiley

Date: 04-2020

DOI: 10.1111/AVJ.12940

Antiparasitic drugs

Publisher: Elsevier

Date: 2008

DOI: 10.1016/B978-070202858-8.50012-9

Antigiardial Activity of Novel Guanidine Compounds

Publisher: Wiley

Date: 29-09-2022

DOI: 10.1002/CMDC.202200341

Abstract: From four focused compound libraries based on the known anticoccidial agent robenidine, 44 compounds total were synthesised and screened for antigiardial activity. All active compounds were counter‐screened for antibiotic and cytotoxic action. Of the analogues examined, 21 displayed IC 50 μM, seven with IC 50 .0 μM. Most active were 2,2′‐ bis {[4‐(trifluoromethoxy)phenyl]methylene}carbonimidic dihydrazide hydrochloride ( 30 ), 2,2′‐ bis {[4‐(trifluoromethylsulfanyl)phenyl]methylene}carbonimidic dihydrazide hydrochloride ( 32 ), and 2,2′‐bis[(2‐bromo‐4,5‐dimethoxyphenyl)methylene]carbonimidic dihydrazide hydrochloride ( 41 ) with IC 50 =0.2 μM. The maximal observed activity was a 5 h IC 50 value of 0.2 μM for 41 . The clinically used metronidazole was inactive at this timepoint at a concentration of 25 μM. Robenidine off‐target effects at bacteria and cell line toxicity were removed. Analogue 41 was well tolerated in mice treated orally (100 mg/kg). Following 5 h treatment with 41 , no Giardia regrowth was noted after 48 h.

Effect of an immunomodulatory feed additive on markers of immunity in pasture‐fed dairy cows

Publisher: Wiley

Date: 26-11-2014

DOI: 10.1111/AVJ.12269

Abstract: Infectious diseases in dairy cows often follow a time of nutritional or physiological stress and the subsequent altered immune system function. This study aimed to determine if the immunomodulatory effects of a feed additive previously observed in experimental animals and housed cattle fed total mixed rations could be reproduced in pasture-fed dairy cattle under Australian conditions. The study included 34 pasture-fed dairy cattle given the treatment (n = 17) or placebo (bentonite, n = 17) for an acclimation period of 15 days followed by 60 days of supplementation. Blood tests were taken pre-trial and then 30, 60 and 90 days after acclimation. Blood s les were extracted and preserved in Trizol and analysed for immune markers. Pasture-fed dairy cows in the treatment group had significantly higher levels of the immune markers interleukin-8R and L-selectin in comparison with placebo-fed cows at 60 days after the start of supplementation. The immunomodulatory effects of the additive observed in the current study and the associated enhanced neutrophil function demonstrated by other studies suggest a role in decreasing the rates of mastitis and other infectious diseases of dairy cattle, particularly during times of nutritional or physiological stress.

The publication of studies involving the use of human critically important antimicrobial agents in veterinary species

Publisher: Wiley

Date: 11-08-2021

DOI: 10.1111/JVP.13005

Repurposing Ionophores as novel antimicrobial agents for the treatment of bovine mastitis caused by Gram-positive pathogens

Publisher: Wiley

Date: 04-07-2018

DOI: 10.1111/JVP.12674

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 MIC

Evaluation of Transdermal Drug Permeation as Modulated by Lipoderm and Pluronic Lecithin Organogel

Publisher: Elsevier BV

Date: 02-2018

DOI: 10.1016/J.XPHS.2017.09.008

Abstract: 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

Antibiotic Awareness Week - November 2017

Publisher: Georg Thieme Verlag KG

Date: 2017

DOI: 10.3415/VCOT-17-10-0137

In vitro efficacy and pharmacodynamic profiles of four polyether ionophores against methicillin-resistant Staphylococcus spp

Publisher: Wiley

Date: 18-05-2020

DOI: 10.1111/JVP.12871

Small Animal Clinical Pharmacology

Publisher: Elsevier

Date: 2008

DOI: 10.1016/B978-0-7020-2858-8.X5001-5

Antimicrobial Stewardship in Animals

Publisher: Wiley

Date: 16-08-2013

DOI: 10.1002/9781118675014.CH7

PERMETHRIN SPOT-ON INTOXICATION OF CATS Literature review and survey of veterinary practitioners in Australia

Publisher: SAGE Publications

Date: 2010

DOI: 10.1016/J.JFMS.2009.12.002

Abstract: Survey aims A questionnaire was sent to veterinarians in Australia to determine the approximate number of cats presenting for permethrin spot-on (PSO) intoxication over a 2-year period. Findings Of the 269 questionnaires returned, 255 were eligible for analysis. A total of 207 respondents (81 %) reported cases of PSO intoxication in cats over the previous 2 years. In total, 750 in idual cases were reported, with 166 deaths. While all deaths were generally attributable to intoxication, 39 cats were euthanased because owners were unable to pay the anticipated treatment costs. Brands of PSO implicated included Exelpet Flea (and Tick) Liquidator (Mars Australia) (146 respondents), Bayer Advantix (48), Purina Totalcare Flea Eliminator Line-On (19), Troy Ease-On (six) and Duogard Line-On (Virbac) (four) 67 respondents were not able to identify a specific product. Permethrin spot-on formulations were most commonly obtained from supermarkets (146 respondents), followed by pet stores (43), veterinary practices (16), and a range of other sources including produce stores and friends. The majority of intoxication cases reported involved PSOs labelled for use in dogs with specific label instructions such as ‘toxic to cats’. Owners applied these PSO products to their cats accidentally or intentionally. In some cases, exposure was through secondary contact, such as when a PSO product was applied to a dog with which a cat had direct or indirect contact. Recommendations In the authors' view, because of the likelihood of inappropriate use and toxicity in the non-labelled species, over-the-counter products intended for use in either dogs or cats must have a high margin of safety in all species. Furthermore, PSOs should only be available at points of sale where veterinary advice can be provided and appropriate warnings given. As an interim measure, modified labelling with more explicit warnings may reduce morbidity and mortality.

Giardia duodenalis mouse model for the development of novel antigiardial agents

Publisher: Elsevier BV

Date: 02-2018

DOI: 10.1016/J.MIMET.2017.11.025

Abstract: 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

The World Small Animal Veterinary Association (WSAVA)

Publisher: Wiley

Date: 16-06-2020

DOI: 10.1111/JSAP.13135

Feline Focus

Publisher: SAGE Publications

Date: 07-2011

DOI: 10.1177/1098612X1101300701

Principles of clinical pharmacology

Publisher: Elsevier

Date: 2008

DOI: 10.1016/B978-070202858-8.50003-8

Quality of amoxicillin/clavulanic acid oral formulations for intended veterinary use in the UK, Malaysia, Serbia and Thailand

Publisher: Wiley

Date: 21-06-2023

DOI: 10.1111/JSAP.13648

Abstract: Amoxicillin/clavulanate is the most commonly used oral antimicrobial drug in companion animals. The objective of the study was to detect types and frequency of deficits in the quality of veterinary oral formulations of amoxicillin/clavulanate in various countries. In a prospective study with purposive s ling, amoxicillin/clavulanate tablet formulations for canine use were collected in four countries (wholesalers or veterinary practice) and shipped to a central bioanalytical laboratory. Twenty‐four s les were collected from the UK (nine), Malaysia (nine), Serbia (four) and Thailand (two), yielding 18 different formulations (10 veterinary). Packaging inspection, tablet disintegration and content assay were conducted (validated high‐performance liquid chromatography with ultra‐violet detection) content was acceptable when within the 90% to 120% pre‐specified range (US Pharmacopeia). Secondary packaging was present for 13 of 24 s les and primary packaging integrity was verified for all but one s le. Amoxicillin trihydrate otassium clavulanate label ratio was 4:1, except for three formulations (2:1). Tablet dose strength ranged from 250 to 625 mg. All formulations contained both analytes. For amoxicillin, two of 24 s les were out of specification with 72.8% (Malaysia) and 82.3% (Thailand) of labelled content. For clavulanate, four of 24 s les were out of specification with 46.9% (Serbia), 79.0% (UK), 84.3% (Serbia) and 86.5% (Thailand) of labelled content. One formulation (Thailand) failed for both analytes. Antimicrobial formulations of substandard quality have negative consequences for efficacy in patients and potentially promote antimicrobial resistance. There was evidence of substandard formulations in all countries, not only for amoxicillin but especially for clavulanate this could compromise equitable access to acceptable quality essential veterinary medicines worldwide.

Diethylstilboestrol—clinical pharmacology and alternatives in small animal practice

Publisher: Wiley

Date: 07-1991

DOI: 10.1111/J.1751-0813.1991.TB03212.X

Abstract: Diethylstilboestrol is currently only available in Australia for oral use in dogs and cats. As an orally and systemically active non-steroidal oestrogen, DES has been widely used in small animal veterinary medicine for a variety of indications. A review of the literature reveals that many of the recommendations for use are founded on anecdotal or unreported clinical observations. While many of the uses may be valid, accurate determinations of optimum dosing regimens have not been defined. This is especially unfortunate in view of the potential toxicity of DES to small animals. Nevertheless, particularly in cases of low-dose intermittent administration, oral DES appears indicated at least until data on alternative safe and effective interventions become available.

Nanotechnology and narasin: a powerful combination against acne

Publisher: Royal Society of Chemistry (RSC)

Date: 2023

DOI: 10.1039/D3NR01789C

Abstract: We have unleashed the potential of NAR and its nanoformulation against acne infections. The results of the ex vivo skin deposition study demonstrate the effectiveness of the developed nano gel as a targeted topical therapy for acne.

Adverse drug reactions

Publisher: Elsevier

Date: 2008

DOI: 10.1016/B978-070202858-8.50005-1

The behaviour of doramectin in the gastrointestinal tract, its secretion in bile and pharmacokinetic disposition in the peripheral circulation after oral and intravenous administration to sheep

Publisher: Wiley

Date: 04-08-2000

DOI: 10.1046/J.1365-2885.2000.T01-2-00286.X

Abstract: Sheep were 'compartmentalized' by surgically implanting cannulae in the rumen, abomasum and terminal ileum with a re-entrant cannula inserted between the cystic duct and the duodenum to monitor bile secretion. Doramectin, containing a trace of [3H]-doramectin, was administered both intravenously (i.v.) and intraruminally (i.r.) at a dosage of 150 microg/kg. The pharmacokinetic behaviour of [3H]-labelled products was determined in these pools, and also in peripheral plasma, urine and faeces. Parent doramectin was also determined in plasma, abomasal digesta fluid and bile. Following i.r. administration, [3H] compounds were almost entirely associated with particulate digesta. A 14.5 h half-life in the rumen prolonged the presence of [3H] in the abomasum. Doramectin appeared to be degraded in abomasal digesta because only 24% of abomasal [3H] was attributed to the parent drug. Absorption of doramectin resulted in a systemic availability of 35%, of which 1.6 and 23.6% of the dose was contained in urine and biliary secretions, respectively. Following i.v. administration, almost negligible quantities of [3H] were secreted into the rumen or abomasum and only 2.7% of the dose was excreted in urine, whereas 132% was secreted in bile. This indicated that approximately one-third of biliary metabolites were enterohepatically recycled with biliary metabolites, elevating the proportion of [3H] in fluid digesta in the small intestine. Passage of the i.r.-administered drug through the gastrointestinal tract (GIT) resulted in virtually complete faecal excretion of [3H] within 5 days, whereas the continued secretion of i.v.-administered [3H] in bile prolonged the presence of [3H] in the GIT, with faecal clearance not being complete for at least 10 days. This multi-compartmental study has provided more information on the behaviour of doramectin than can be obtained from examining drug disposition in the peripheral circulation alone. With this knowledge, it is anticipated that opportunities for improving drug performance will be identified.

Benzalkonium chloride intoxication in cats

Publisher: Wiley

Date: 02-2015

DOI: 10.1136/VR.H1119

Development of intramammary delivery systems containing lasalocid for the treatment of bovine mastitis: Impact of solubility improvement on safety, efficacy, and milk distribution in dairy cattle

Publisher: Informa UK Limited

Date: 2015

DOI: 10.2147/DDDT.S74731

Antimicrobial Stewardship in Veterinary Medicine

Publisher: American Society for Microbiology

Date: 06-2018

DOI: 10.1128/MICROBIOLSPEC.ARBA-0023-2017

Abstract: While antimicrobial resistance is already a public health crisis in human medicine, therapeutic failure in veterinary medicine due to antimicrobial resistance remains relatively uncommon. However, there are many pathways by which antimicrobial resistance determinants can travel between animals and humans: by close contact, through the food chain, or indirectly via the environment. Antimicrobial stewardship describes measures that can help mitigate the public health crisis and preserve the effectiveness of available antimicrobial agents. Antimicrobial stewardship programs have been principally developed, implemented, and studied in human hospitals but are beginning to be adapted for other applications in human medicine. Key learning from the experiences of antimicrobial stewardship programs in human medicine are summarized in this article—guiding the development of a stewardship framework suitable for adaptation and use in both companion animal and livestock practice. The antimicrobial stewardship program for veterinary use integrates infection prevention and control together with approaches emphasizing avoidance of antimicrobial agents. The 5R framework of continuous improvement that is described recognizes the importance of executive support highly motivated organizations and teams (responsibility) the need to review the starting position, set objectives, and determine means of measuring progress and success and a critical focus on reducing, replacing, and refining the use of antimicrobial agents. Significant issues that are currently the focus of intensive research include improved detection and diagnosis of infections, refined dosing regimens that are simultaneously effective while not selecting resistance, searches for alternatives to antimicrobial agents, and development of improved vaccines to enhance immunity and reduce disease.

Treating permethrin poisoning in cats

Publisher: Wiley

Date: 06-2013

DOI: 10.1136/VR.F3632

In vitro comparison of the dermal penetration of three different topical formulations containing lasalocid

Publisher: Wiley

Date: 03-05-2017

DOI: 10.1111/VDE.12379

Abstract: 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. To determine effects of various formulation types on penetration and retention of lasalocid applied to canine skin in vitro. 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. 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. 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. Lasalocid was not identified in the receptor fluid of any s le, 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.

Repurposing of the Fasciolicide Triclabendazole to Treat Infections Caused by Staphylococcus spp. and Vancomycin-Resistant Enterococci

Publisher: MDPI AG

Date: 10-08-2021

DOI: 10.3390/MICROORGANISMS9081697

Abstract: 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.

Antibiotic use in animals and humans in Australia

Publisher: AMPCo

Date: 19-12-2020

DOI: 10.5694/MJA2.50463

Discovery of 4,6-bis(2-((E)-benzylidene)hydrazinyl)pyrimidin-2-Amine with Antibiotic Activity

Publisher: Wiley

Date: 07-2019

DOI: 10.1002/OPEN.201800241

In vitro antimicrobial activity of monensin against common clinical isolates associated with canine otitis externa

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.CIMID.2018.05.001

Abstract: 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.

Development of Intramammary Drug Delivery Systems: Novel In Vitro Release Method

Publisher: Elsevier BV

Date: 03-2017

DOI: 10.1016/J.XPHS.2016.11.012

Abstract: 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 s les 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.

Antimicrobial use and stewardship practices on Australian beef feedlots

Publisher: Wiley

Date: 12-11-2020

DOI: 10.1111/AVJ.12889

Abstract: Improving antimicrobial stewardship in the livestock sector requires an understanding of the motivations for antimicrobial use and the quantities consumed. However,detailed information on antimicrobial use in livestock sectors is lacking. This cross-sectional study aimed to better understand antimicrobial use in the beef feedlot sector in Australia. A self-administered questionnaire asking about antimicrobial use and reasons for use was designed and mailed to beef feedlot operators in Australia. Respondents were asked to report the percentage of animals treated, purpose of use, and disease conditions targeted for 26antimicrobial agents. In total, 83 of 517 (16.1%) beef feedlot operators completed the survey. Monensin (61.0%of respondents) and virginiamycin (19.5%of respondents) were the most commonly reported in-feed antimicrobials. In-feed antimicrobial agents were most frequently used by respondents for treatment of gastrointestinal diseases (52.8%). Antimicrobials were used for growth promotion by 42.1% of respondents, with most (85.7%) reporting the use of ionophores(a group of compounds not used in human medicine). Short-acting penicillin(69.1%), short-acting oxytetracycline, and tulathromycin (both 57.3%) werethe most common injectable antimicrobial agents used. Injectable antimicrobials were most frequently used to treat respiratory (72.3%) and musculoskeletal (67.5%) conditions. Overall,the use of antimicrobials was appropriate for the purpose indicated, and there was a strong preference for drugs of low-importance in human medicine. The data described here stand to be a strong influence on the implementation of an antimicrobial stewardship program in the sector.

Use of antimicrobial agents in livestock

Publisher: O.I.E (World Organisation for Animal Health)

Date: 04-2012

DOI: 10.20506/RST.31.1.2106

Abstract: Antimicrobial agents, especially antibacterial agents, are used throughout the world, across a erse array of extensive and intensive livestock production systems, to protect the health and welfare of livestock and to improve their performance. While some agents that are used in livestock belong to classes that have no counterpart in human medicine, this is not the case for the most widely used agents: the tetracyclines, penicillins, macrolides and sulphonamides. Many bacterial diseases of livestock cause devastating losses of animal life and productivity. As a result, their keepers can lose their livelihoods and see a dramatic reduction in income, so there is often a great sense of urgency to treat affected animals early. However, there are a large number of bacterial pathogens that cause disease and it is frequently difficult to reach a conclusive diagnosis prior to instituting treatment. There are many ways in which existing uses of antimicrobial agents can be improved, amongst the most important are increased utilisation of veterinary professional services, the introduction of enhanced infection control measures, improved point-of-care diagnostic tests, and the application of physiologically based population pharmacokinetic-pharmacodynamic modelling.

Biofilm production by pathogens associated with canine otitis externa, and the antibiofilm activity of ionophores and antimicrobial adjuvants

Publisher: Wiley

Date: 10-09-2019

DOI: 10.1111/JVP.12811

Abstract: 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 (OD

The 5Rs approach to antimicrobial stewardship

Publisher: Wiley

Date: 08-2014

DOI: 10.1136/VR.G5327

Aminoguanidines: New leads for treatment of Giardia duodenalis infection

Publisher: Elsevier BV

Date: 08-2019

DOI: 10.1016/J.IJPDDR.2019.04.003

Pharmacology and Therapeutics

Publisher: Wiley

Date: 15-03-2007

DOI: 10.1002/9780470753316.CH73

The effect of doxapram on survival and APGAR score in newborn puppies delivered by elective caesarean: A randomized controlled trial

Publisher: Wiley

Date: 21-05-2023

DOI: 10.1111/JVP.13388

Abstract: 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.

The publication of studies involving the use of human critically important antimicrobial agents in veterinary species: Reply from the authors

Publisher: Wiley

Date: 11-2021

DOI: 10.1111/JVP.13025

In vitro antimicrobial activity of narasin and monensin in combination with adjuvants against pathogens associated with canine otitis externa

Publisher: Wiley

Date: 11-11-2020

DOI: 10.1111/VDE.12803

Abstract: The emergence of antimicrobial resistance represents a serious human and animal health risk. Good antimicrobial stewardship is essential to prolong the lifespan of existing antibiotics, and new strategies are required to combat infections in man and animals. To determine the in vitro interaction of ionophores (narasin or monensin) with antimicrobial adjuvants (N-acetylcysteine (NAC), Tris-EDTA or disodium EDTA) against bacterial strains representing pathogens associated with canine otitis externa (OE). American Type Culture Collection (ATCC) strains Staphylococcus aureus 29213, Pseudomonas aeruginosa 27853 and P. aeruginosa biofilm producer PAO1, and a clinical isolate of Proteus mirabilis from a case of canine OE were tested. A 2D microdilution checkerboard method was used, allowing calculation of fractional inhibitory concentration index (FICI), dose reduction index (DRI) and plotting of isobolograms. The combination of narasin with either Tris-EDTA or disodium EDTA produced additive effects (FICI = 0.75) against P. aeruginosa ATCC 27853 and P. aeruginosa biofilm producer ATCC PAO1. An additive effect (FICI = 0.53-0.75) was found against S. aureus ATCC 29213 when narasin or monensin were combined with NAC. The highest DRI (32-fold) was found with monensin/NAC where the MIC of monensin was reduced from 4 to 0.125 μg/mL. The combination of narasin with Tris-EDTA or disodium EDTA is a promising strategy to inhibit the intrinsic resistance elements of Gram-negative bacteria. These novel combinations potentially could be useful as a multimodal approach to treat mixed infections in canine OE.

Comparison of two transmission electron microscopy methods to visualize drug-induced alterations of gram-negative bacterial morphology

Publisher: MDPI AG

Date: 17-03-2021

DOI: 10.3390/ANTIBIOTICS10030307

Abstract: In this study, we optimized and compared different transmission electron microscopy (TEM) methods to visualize changes to Gram-negative bacterial morphology induced by treatment with a robenidine analogue (NCL195) and colistin combination. Aldehyde-fixed bacterial cells (untreated, treated with colistin or NCL195 + colistin) were prepared using conventional TEM methods and compared with ultrathin Tokuyasu cryo-sections. The results of this study indicate superiority of ultrathin cryo-sections in visualizing the membrane ultrastructure of Escherichia coli and Pseudomonas aeruginosa, with a clear delineation of the outer and inner membrane as well as the peptidoglycan layer. We suggest that the use of ultrathin cryo-sectioning can be used to better visualize and understand drug interaction mechanisms on the bacterial cell membrane.

Clinical pharmacokinetics

Publisher: Elsevier

Date: 2008

DOI: 10.1016/B978-070202858-8.50004-X

Semisynthesis and biological evaluation of a focused library of unguinol derivatives as next-generation antibiotics

Publisher: Royal Society of Chemistry (RSC)

Date: 2021

DOI: 10.1039/D0OB02460K

Abstract: Semisynthetic unguinol derivatives showed potent activity against a panel of methicillin-resistant Staphylococcus aureus strains and are promising candidates for further development.

Impact of a Novel Anticoccidial Analogue on Systemic Staphylococcus aureus Infection in a Bioluminescent Mouse Model

Publisher: MDPI AG

Date: 06-01-2022

DOI: 10.3390/ANTIBIOTICS11010065

Abstract: In this study, we investigated the potential of an analogue of robenidine (NCL179) to expand its chemical ersity 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.

University Of Sydney

Location: Australia

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University Of Technology Sydney

Location: Australia

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Linkage Projects - Grant ID: LP110200770

Start Date: 11-2011

End Date: 12-2016

Amount: $428,000.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP210301109

Start Date: 12-2023

End Date: 12-2026

Amount: $282,339.00

Funder: Australian Research Council

Linkage Projects - Grant ID: LP130100736

Start Date: 09-2013

End Date: 04-2018

Amount: $529,853.00

Funder: Australian Research Council

Industrial Transformation Training Centres - Grant ID: IC220100050

Start Date: 07-2023

End Date: 07-2028

Amount: $4,508,426.00

Funder: Australian Research Council