The effects of oclacitinib treatment on antimicrobial usage in allergic dogs in primary practice: an Australia wide case-control study.

BACKGROUND: Canine allergic dermatitis is a common diagnosis in veterinary practices which can lead to secondary infections requiring treatment with antimicrobials. A previous study suggested that dogs treated with oclacitinib in an Australian referral hospital required fewer courses of antimicrobial therapy compared to dogs receiving other anti-pruritic treatments. This study aimed to quantify the effect of oclacitinib treatment on the use of antimicrobials and other therapies in general practice veterinary clinics across Australia. A retrospective case-controlled review of patient records was designed to investigate the number of courses of antimicrobials and other therapies in dogs that received oclacitinib (Apoquel®), compared with those who received an anti-pruritic treatment that was not oclacitinib. RESULTS: The target population included canine patients with a presumptive diagnosis of allergic dermatitis presenting between 2008 and 2018 to general practices contributing to the VetCompass Australia database. Patient records of interest were identified using search terms relating to allergic dermatitis, resulting in over 700,000 observations. Multivariable logistic regression models were developed to determine whether cases were prescribed fewer antimicrobial courses than controls, after adjusting for the presence of concurrent skin infections or infectious agents in ears. Our results indicate that fewer antimicrobial courses were prescribed in the cases compared to the controls. After adjusting for the concurrent skin infections, there was a significant reduction in the use of cefovecin [OR:0.62(0.39-0.98), P = 0.043], chlorhexidine [OR:0.57(0.42-0.77), P < 0.001], neomycin [OR:0.4(0.28-0.56), P < 0.001] and amoxycillin clavulanic acid (AMC) [OR: 0.55(0.39-0.78), P = 0.001] in cases compared to controls. CONCLUSION: This study demonstrates a potential sparing effect of oclacitinib on the prescription of antimicrobials for the treatment of allergic skin diseases in dogs. This information may assist in the planning of treatment for canine allergic dermatitis, with consideration for antimicrobial stewardship.

Site-Selective Chemoenzymatic Modification on the Core Fucose of an Antibody Enhances Its Fcγ Receptor Affinity and ADCC Activity.

Fc glycosylation profoundly impacts the effector functions of antibodies and often dictates an antibody's pro- or anti-inflammatory activities. It is well established that core fucosylation of the Fc domain N-glycans of an antibody significantly reduces its affinity for FcγRIIIa receptors and antibody-dependent cellular cytotoxicity (ADCC). Previous structural studies have suggested that the presence of a core fucose remarkably decreases the unique and favorable carbohydrate-carbohydrate interactions between the Fc and the receptor N-glycans, leading to reduced affinity. We report here that in contrast to natural core fucose, special site-specific modification on the core fucose could dramatically enhance the affinity of an antibody for FcγRIIIa. The site-selective modification was achieved through an enzymatic transfucosylation with a novel fucosidase mutant, which was shown to be able to use modified α-fucosyl fluoride as the donor substrate. We found that replacement of the core l-fucose with 6-azide- or 6-hydroxy-l-fucose (l-galactose) significantly enhanced the antibody's affinity for FcγRIIIa receptors and substantially increased the ADCC activity. To understand the mechanism of the modified fucose-mediated affinity enhancement, we performed molecular dynamics simulations. Our data revealed that the number of glycan contacts between the Fc and the Fc receptor was increased by the selective core-fucose modifications, showing the importance of unique carbohydrate-carbohydrate interactions in achieving high FcγRIIIa affinity and ADCC activity of antibodies. Thus, the direct site-selective modification turns the adverse effect of the core fucose into a favorable force to promote the carbohydrate-carbohydrate interactions.