BackgroundTo curb increasing resistance rates, responsible antimicrobial use (AMU) is needed, both in human and veterinary medicine. In human healthcare, antimicrobial stewardship programmes (ASPs) have been implemented worldwide to improve appropriate AMU. No ASPs have been developed for and implemented in companion animal clinics yet.ObjectivesThe objective of the present study was to implement and evaluate the effectiveness of an ASP in 44 Dutch companion animal clinics. The objectives of the ASP were to increase awareness on AMU, to decrease total AMU whenever possible and to shift AMU towards 1st choice antimicrobials, according to Dutch guidelines on veterinary AMU.MethodsThe study was designed as a prospective, stepped-wedge, intervention study, which was performed from March 2016 until March 2018. The multifaceted intervention was developed using previous qualitative and quantitative research on current prescribing behaviour in Dutch companion animal clinics. The number of Defined Daily Doses for Animal (DDDAs) per clinic (total, 1st, 2nd and 3rd choice AMU) was used to quantify systemic AMU. Monthly AMU data were described using a mixed effect time series model with auto-regression. The effect of the ASP was modelled using a step function and a change in the (linear) time trend.ResultsA statistically significant decrease of 15% (7%-22%) in total AMU, 15% (5%-24%) in 1st choice AMU and 26% (17%-34%) in 2nd choice AMU was attributed to participation in the ASP, on top of the already ongoing time trends. Use of 3rd choice AMs did not significantly decrease by participation in the ASP. The change in total AMU became more prominent over time, with a 16% (4%-26%) decrease in (linear) time trend per year.ConclusionsThis study shows that, although AMU in Dutch companion animal clinics was already decreasing and changing, AMU could be further optimised by participation in an antimicrobial stewardship programme.
-Gremmels, J. Cytochrome P450-mediated hepatic metabolism of new fluorescent substrates in cats and dogs. J. vet. Pharmacol. Therap. 33,[519][520][521][522][523][524][525][526][527] This study aimed to investigate the biotransformation of cat liver microsomes in comparison to dogs and humans using a high throughput method with fluorescent substrates and classical inhibitors specific for certain isozymes of the human cytochrome P450 (CYP) enzyme family. The metabolic activities associated with CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A were measured. Cat liver microsomes metabolized all substrates selected for the assessment of cytochrome P450 activity. The activities associated with CYP3A and CYP2B were higher than the activities of the other measured CYPs. Substrate selectivity could be demonstrated by inhibition studies with a-naphthoflavone (CYP1A), tranylcypromine ⁄ quercetine (CYP2C), quinidine (CYP2D), diethyldithiocarbamic acid (CYP2E) and ketoconazole (CYP3A) respectively. Other prototypical inhibitors used for characterization of human CYP activities such as furafylline (CYP1A), tranylcypromine (CYP2B) and sulfaphenazole (CYP2C) did not show significant effects in cat and dog liver microsomes. Moreover, IC50-values of cat CYPs differed from dog and human CYPs underlining the interspecies differences. Gender differences were observed in the oxidation of 7-ethoxy-4-trifluoromethylcoumarin (CYP2B) and 3-[2-(N, N-diethyl-N-methylamino)ethyl]-7-methoxy-4-methylcoumarin (CYP2D), which were significantly higher in male cats than in females. Conversely, oxidation of the substrates dibenzylfluorescein (CYP2C) and 7-methoxy-4-trifluoromethylcoumarin (CYP2E) showed significant higher activities in females than in male cats. Overall CYP-activities in cat liver microsomes were lower than in those from dogs or humans, except for CYP2B. The presented difference between feline and canine CYP-activities are useful to establish dose corrections for feline patients of intensively metabolized drugs licensed for dogs or humans.
Cytochrome P450 (CYP) proteins constitute a large ancient family of oxidative enzymes essential for the efficient elimination of a wide variety of clinically used drugs. Polymorphic variants of human CYP2D6 are associated with the conversion rate and efficacy of several drugs such as antidepressants. Polymorphisms of the canine orthologue CYP2D15 are of interest because these antidepressants are also used in dogs with behavioral problems and the outcome of the treatment is variable. However, the annotated CYP2D15 gene is incomplete and inaccurately assembled in CanFam3.1, hampering DNA sequence analysis of the gene in individual dogs. We elucidated the complete exon–intron structure of CYP2D15 to enable comprehensive genotyping of the gene using genomic DNA. We surveyed variations of the gene in four diverse dog breeds and identified novel polymorphisms in exon 2 in border collies. Further investigation to establish the impact of these canine CYP2D15 polymorphisms on interindividual variability in expression and function of this metabolizing enzyme is now feasible. Further knowledge of CYP pharmacogenetics will help individualize therapy and thereby increase therapeutic efficacy, especially in the use of antidepressants in veterinary behavioral medicine.
INTRODUCTIONThe cytochrome P450 superfamily constitutes a multigene membrane-bound enzyme system which catalyses oxidations of both xenobiotics and relevant endogenous compounds [1]. Several constitutional factors (gender, age, species, strain, pathological and physiological conditions) might contribute, together with induction and inhibition phenomena (which are classified as exogenous or xenobiotic-dependent factors) to the modulation of the overall biotransformation capacity [2]. In a previous study, differences in the expression of the liver the cytochrome P450 3A subfamily was reported in Limousine and Piedmontese cattle breeds [3]. The expression of main P450dependent drug metabolising enzyme (DME) activities (both at the catalytic and protein expression levels) were measured in the liver of three different breeds of beef cattle. MATERIALS AND METHODSMicrosomal subcellular fractions were prepared, from the liver of male Charollais (C: n = 10), Blonde d'Aquitaine (B: n = 7) and Piedmontese (P: n = 8) cattle, about 13-18 months old. Total P450 content and main P450-dependent DME activities were measured using known model substrates, according to previously published protocols [4,5]. In addition, cytochrome P450 1A (CYP1A), 2B (CYP2B), 2C (CYP2C) and 3A (CYP3A) apoprotein levels were measured in pooled microsomes by immunoblotting (using polyclonal antibodies directed toward the respective rat and/or human P450 isoforms) [3]. The densitometric analysis of visualised bands was performed by ImageJ 1.34s (NIH). Statistical analysis of data was performed using ANOVA, followed by a post-test (Tukey-Kramer multiple comparisons test: GraphPad InstatÒ 3.06 for Windows). RESULTSSignificant differences in the total liver P450 content between breeds were not found. Lower CYP1A, CYP2B and CYP2E1 DME activity was noticed in P (P < 0.05, P < 0.01, P < 0.001, depending from the substrate used) vs. C or A (P < 0.05, P < 0.001). At the protein level, significantly lower amounts of CYP2B were found in P and C vs. B (P < 0.01). No statistically significant differences in CYP1A, 2C and 3A content were found. DISCUSSIONIt is known that several non-pharmacogenetic factors, such as age, gender, species, disease factors or exposure to environmental pollutants, might contribute to the expression and regulation of hepatic P450 in domestic animals [2]. Studies related to the expression of DME in farm animals might be very helpful in food safety assessment and also for drug registration [4,6]. This is of particular importance in cattle, which represent an important source of animal-derived food products. In this respect, studies on DME expression in ruminants have already been published [6][7][8][9][10]. Data obtained in the present study demonstrate that, mostly at the catalytical activity level, some differences exist between different breeds of cattle, confirming what has been observed previously in liver CYP3A expression in P vs. Limousine cattle [3]. Further immunological investigations for each level of P450 protein have already be...
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