Effect of meloxicam or robenacoxib administration timing on renal function and postoperative analgesia in cats undergoing ovariohysterectomy: A randomized, blinded, controlled clinical trial.

We evaluated the effect of administration timing of meloxicam and robenacoxib on renal function, platelet cyclo-oxygenase and perioperative analgesia in 60 cats undergoing ovariohysterectomy, in a prospective randomized blinded controlled study. Twelve cats were randomly allocated to one subcutaneous treatment group: meloxicam (0.2 mg/kg) or robenacoxib (2 mg/kg) at admission (MA, RA), at induction (MI, RI) and robenacoxib at the end of surgery (RE). All cats received the same anaesthesia protocol. Plasma renin activity (PRA), plasma creatinine, drug concentrations and serum thromboxane (TxB2) were measured sequentially. Anaesthesia significantly increased PRA, as activity at end of the surgery was higher than 2 h later (mean ± SD: 26.6 ± 2.8 versus 10.0 ± 3.9 ng/mL/h). PRA remained higher at 2 h post-surgery in admission groups compared to induction groups (p = .01). Serum TxB2 was lower with meloxicam than robenacoxib (p = .001), and was lower in the MA than each robenacoxib group at catheter placement. Admission groups (16/24 from RA and MA groups) received earlier rescue analgesia than other groups (p = .033). In conclusion, the renin-angiotensin system was activated during anaesthesia despite cyclo-oxygenase inhibition, possibly due to hypotension or surgical stimulation. There was no effect of drug or timing on the markers of renal function but one cat receiving meloxicam at induction had suspected IRIS grade II acute kidney injury.

Cross-sectional survey of sleep, fatigue and mental health in veterinary anaesthesia personnel.

OBJECTIVE: To evaluate the sleep quality, prevalence of fatigue and depressive symptoms in veterinary anaesthesia personnel. STUDY DESIGN: Anonymous online voluntary survey. METHODS: Sleep quality, fatigue, depressive symptoms and self-perceived burnout were scored using the Pittsburgh Sleep Quality Index (PSQI), Fatigue Severity Scale (FSS), Patient Health Questionnaire-9 (PHQ-9) and single-item burnout measure, respectively. Demographic data and questions about work-related fatigue, out-of-hours duty, transport and rest periods were included. PSQI, FSS and PHQ-9 scores were compared using Spearman rank correlation tests. RESULTS: Responses from 393 participants were obtained from an estimated population of 1374 including diplomates of the American and European Colleges of Veterinary An(a)esthesia and Analgesia (43.9%), residency-trained veterinarians (15.6%), residents-in-training (13.8%) and veterinary technicians and nurses (12.0%), from 32 countries. Most were employed in clinical university teaching hospitals (54.2%) or clinical private practice (41.5%). PSQI scores > 5 were reported by 71.2% of respondents, with 52.4% reporting insufficient sleep to meet their job demands. Many showed high or borderline fatigue (56.4%), and 74.7% reported mistakes due to work-related fatigue. Major depressive symptoms (PHQ-9 score ≥ 10) were found in 42.7%, with 19.2% reporting they had thought about suicide or self-harm in the previous 2 weeks. Over half (54.8%) met the criteria for burnout and more veterinary nurses and technicians suffered from burnout than other roles, with 79.6% of this group affected (p < 0.001). Scores for PSQI and FSS [r (388) = 0.40, p < 0.001]; PSQI and PHQ-9 [r (389) = 0.23, p < 0.001]; and FSS and PHQ-9 [r (387) = 0.24, p < 0.001] were all positively correlated. CONCLUSIONS AND CLINICAL RELEVANCE: This survey demonstrates a high prevalence of poor sleep, fatigue, depressive symptoms and burnout in veterinary anaesthesia personnel, and more should be done to improve the health of those in the profession.

Quantitative Pharmacodynamic Characterization of Resistance versus Heteroresistance of Colistin in E. coli Using a Semimechanistic Modeling of Killing Curves.

Heteroresistance corresponds to the presence, in a bacterial isolate, of an initial small subpopulation of bacteria characterized by a significant reduction in their sensitivity to a given antibiotic. Mechanisms of heteroresistance versus resistance are poorly understood. The aim of this study was to explore heteroresistance in mcr-positive and mcr-negative Escherichia coli strains exposed to colistin by use of modeling killing curves with a semimechanistic model. We quantify, for a range of phenotypically (susceptibility based on MIC) and genotypically (carriage of mcr-1 or mcr-3 or mcr-negative) different bacteria, a maximum killing rate (Emax) of colistin and the corresponding potency (EC50), i.e., the colistin concentrations corresponding to Emax/2. Heteroresistant subpopulations were identified in both mcr-negative and mcr-positive E. coli as around 0.06% of the starting population. Minority heteroresistant bacteria, both for mcr-negative and mcr-positive strains, differed from the corresponding dominant populations only by the maximum killing rate of colistin (differences for Emax by a factor of 12.66 and 3.76 for mcr-negative and mcr-positive strains, respectively) and without alteration of their EC50s. On the other hand, the resistant mcr-positive strains are distinguished from the mcr-negative strains by differences in their EC50, which can reach a factor of 44 for their dominant population and 22 for their heteroresistant subpopulations. It is suggested that the underlying physiological mechanisms differ between resistance and heteroresistance, with resistance being linked to a decrease in the affinity of colistin for its site of action, whereas heteroresistance would, rather, be linked to an alteration of the target, which will be more difficult to be further changed or destroyed.

Pharmacology, safety, efficacy and clinical uses of the COX-2 inhibitor robenacoxib.

Robenacoxib is a veterinary-approved non-steroidal anti-inflammatory drug (NSAID) of the coxib group. It possesses anti-hyperalgesic, anti-inflammatory and anti-pyretic properties. Robenacoxib inhibits the cyclooxygenase (COX)-2 isoform of COX selectively (in vitro IC50 ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats). At registered dosages (2 mg/kg subcutaneously in dogs and cats, 1-4 mg/kg orally in dogs and 1-2.4 mg/kg orally in cats), robenacoxib produces significant inhibition of COX-2 whilst sparing COX-1. The pharmacokinetic (PK) profile of robenacoxib is characterized by a high degree of binding to plasma proteins (>98%) and moderate volume of distribution (at steady state, 240 ml/kg in dogs and 190 ml/kg in cats). In consequence, the terminal half-life in blood (<2 h) is short, despite moderate body clearance (0.81 L/kg/h) in dogs and low clearance (0.44 L/kg/h) in cats. Excretion is principally in the bile (65% in dogs and 72% in cats). Robenacoxib concentrates in inflamed tissues, and clinical efficacy is achieved with once-daily dosing, despite the short blood terminal half-life. In dogs, no relevant breed differences in robenacoxib PK have been detected. Robenacoxib has a wide safety margin; in healthy laboratory animals daily oral doses 20-fold (dog, 1 month), eight-fold (cat, 6 weeks) and five-fold (dog, 6 months) higher than recommended clinical doses were well tolerated. Clinical efficacy and safety have been demonstrated in orthopaedic and soft tissue surgery, and in musculoskeletal disorders in dogs and cats.

Effect of theatre temperature on body temperature during anaesthesia for routine neutering of domestic rabbits (Oryctolagus cuniculus).

OBJECTIVE: To investigate the effect of theatre temperature on body temperature in rabbits undergoing castration or ovariohysterectomy surgery during general anaesthesia. STUDY DESIGN: Prospective, clinical study. ANIMALS: A group of 88 rabbits presented for elective neutering. METHODS: Rabbits were divided into male (31/54) and female (23/54) groups and assigned to one of two theatre temperatures via coin toss. Theatre temperature was 23 °C (±2 °C) for group A (n = 37/54) and 28 °C (±2 °C) for group B (n = 17/54). During anaesthesia and recovery, theatre temperature and rectal temperature were recorded every 5 minutes. Time to resumption of feeding and passing faeces were recorded. Data are presented as median (interquartile range) or mean (± standard deviation). Statistical analyses comprised a mixed-effects model, with Sidak's multiple comparison test for post-hoc testing and Fisher's exact test; p < 0.05. RESULTS: A total of 54 rabbits completed the study, with median age 6 (4-9) months and median weight 1.53 (1.30-1.79) kg. In rabbits undergoing castration, theatre temperature did not significantly affect body temperature. Mean temperatures immediately after induction were 38.6 °C and 38.7 °C and at the end of the procedure 38.5 °C and 38.5 °C for group A and group B, respectively. In rabbits undergoing ovariohysterectomy, mean temperatures immediately after induction were 38.3 °C and 38.8 °C and at the end of the procedure 38.1 °C and 39.2 °C for group A and group B, respectively. Rabbits undergoing ovariohysterectomy at an ambient temperature of 28 °C had a significantly higher final temperature, mean ± 1.15 °C (95% confidence interval, 0.47-1.83), compared with 23 °C (p = 0.001). Theatre temperature did not affect return to feeding or defaecating. CONCLUSIONS AND CLINICAL RELEVANCE: During anaesthesia an ambient theatre temperature of 28 °C may reduce the risk of hypothermia in rabbits undergoing ovariohysterectomy or similarly invasive surgery.

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

OBJECTIVES: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications. METHODS: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed. RESULTS: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)]. CONCLUSIONS: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.

Medium-chain triglycerides dietary supplement improves cognitive abilities in canine epilepsy.

OBJECTIVE: Cognitive impairments (CI) have recently been identified in canine epilepsy patients. A medium-chain triglyceride (MCT) enriched diet has been demonstrated to improve cognition in aged dogs and seizure control in canine epilepsy. This study evaluates the short-term effects of MCT-oil consumption on cognitive abilities in dogs with epilepsy, a naturally occurring animal model. METHODS: A 6-month multicenter, prospective, randomized, double-blinded, controlled cross-over diet trial was conducted comparing dietary supplementation (DS) of MCT oil to a control oil. Allocation to dietary oil supplements, consisting of 9% total caloric intake, was block-randomized and supplemented into each dogs' diet for 3 months followed by a respective switch of DS-oil for a further 3 months. Noninvasive cognitive tests and a validated psychometric tool were utilized to evaluate cognitive function and perturbations associated with dietary intervention. RESULTS: Twenty-nine dogs completed the trial, of which 18 completed noninvasive cognitive testing. Spatial-working memory (P = 0.008), problem-solving ability (P = 0.048), and owner-reported trainability (P = 0.041) were significantly improved during MCT-oil supplementation compared to control-DS. SIGNIFICANCE: MCT-oil DS improves cognition in dogs with epilepsy when compared to a control-DS. MCT supplementation may represent a promising option to address CI associated with epilepsy.

A history of antimicrobial drugs in animals: Evolution and revolution.

The evolutionary process of antimicrobial drug (AMD) uses in animals over a mere eight decades (1940-2020) has led to a revolutionary outcome, and both evolution and revolution are ongoing, with reports on a range of uses, misuses and abuses escalating logarithmically. As well as veterinary therapeutic perspectives (efficacy, safety, host toxicity, residues, selection of drug, determination of dose and measurement of outcome in treating animal diseases), there are also broader, nontherapeutic uses, some of which have been abandoned, whilst others hopefully will soon be discontinued, at least in more developed countries. Although AMD uses for treatment of animal diseases will continue, it must: (a) be sustainable within the One Health paradigm; and (b) devolve into more prudent, rationally based therapeutic uses. As this review on AMDs is published in a Journal of Pharmacology and Therapeutics, its scope has been made broader than most recent reviews in this field. Many reviews have focused on negative aspects of AMD actions and uses, especially on the question of antimicrobial resistance. This review recognizes these concerns but also emphasizes the many positive aspects deriving from the use of AMDs, including the major research-based advances underlying both the prudent and rational use of AMDs. It is structured in seven sections: (1) Introduction; (2) Sulfonamide history; (3) Nontherapeutic and empirical uses of AMDs (roles of agronomists and veterinarians); (4) Rational uses of AMDs (roles of pharmacologists, clinicians, industry and regulatory controls); (5) Prudent use (residue monitoring, antimicrobial resistance); (6) International and inter-disciplinary actions; and (7) Conclusions.

Determination of colistin in luminal and parietal intestinal matrices of chicken by ultra-high-performance liquid chromatography-tandem mass spectrometry.

Justification for continued use of colistin in veterinary medicine, for example medicated water, relies on pharmacokinetic/pharmacodynamic (PK/PD) studies that require accurate measurement of colistin content in the digestive tract. A method for the detection and quantification of colistin in poultry intestinal material was developed and validated. Colistin is not absorbed after oral administration, and the biophase is the gastrointestinal tract. Extraction of colistin from the matrix was achieved using solid-phase extraction with a methanol:water (1:2; v/v) solution. Polymyxin B was used as an internal standard. Colistin A and colistin B, the main components of colistin, were separated, detected and measured using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). The method was validated for linearity/quadraticity between 1.1 (LOQ) and 56.7 mg/kg. Mean accuracy was between 82.7% and 107.7% with inter- and intra-day precision lower than 13.3% and 15% respectively. Freeze-thaw, long-term and bench storage were validated. Incurred samples following colistin treatment in poultry at the approved clinical dose of 75,000 IU/kg in drinking water and oral gavage were quantifiable and in line with expected intestinal transit times. The method is considered appropriately accurate and precise for the purposes of pharmacokinetic analysis in the gastrointestinal tract.

The pharmacokinetic/pharmacodynamic paradigm for antimicrobial drugs in veterinary medicine: Recent advances and critical appraisal.

Pharmacokinetic/pharmacodynamic (PK/PD) modelling is the initial step in the semi-mechanistic approach for optimizing dosage regimens for systemically acting antimicrobial drugs (AMDs). Numerical values of PK/PD indices are used to predict dose and dosing interval on a rational basis followed by confirmation in clinical trials. The value of PK/PD indices lies in their universal applicability amongst animal species. Two PK/PD indices are routinely used in veterinary medicine, the ratio of the area under the curve of the free drug plasma concentration to the minimum inhibitory concentration (MIC) (fAUC/MIC) and the time that free plasma concentration exceeds the MIC over the dosing interval (fT > MIC). The basic concepts of PK/PD modelling of AMDs were established some 20 years ago. Earlier studies have been reviewed previously and are not reconsidered in this review. This review describes and provides a critical appraisal of more recent, advanced PK/PD approaches, with particular reference to their application in veterinary medicine. Also discussed are some hypotheses and new areas for future developments.First, a brief overview of PK/PD principles is presented as the basis for then reviewing more advanced mechanistic considerations on the precise nature of selected indices. Then, several new approaches to selecting PK/PD indices and establishing their numerical values are reviewed, including (a) the modelling of time-kill curves and (b) the use of population PK investigations. PK/PD indices can be used for dose determination, and they are required to establish clinical breakpoints for antimicrobial susceptibility testing. A particular consideration is given to the precise nature of MIC, because it is pivotal in establishing PK/PD indices, explaining that it is not a "pharmacodynamic parameter" in the usual sense of this term.

Perioperative pharmacokinetics and pharmacodynamics of meloxicam in emus (Dromaius novaehollandiae) of different age groups using nonlinear mixed effect modelling.

Meloxicam is a widely used nonsteroidal anti-inflammatory drug in avian species. However, variability in pharmacokinetic (PK) and pharmacodynamic (PD) parameters in birds warrants species-specific studies for dose and dosing interval optimization. We performed a perioperative PK study of meloxicam (0.5 mg/kg, intravenously) on emus of three different age groups: 3 chicks (5 weeks old, 3.5 kg), 4 juveniles (26 weeks old, 18.8 kg) and 6 adults (66 weeks old, 38.8 kg). A two-compartment population PK model including weight as a significant covariate on clearance and central volume of distribution (V1) best fitted the data. The typical values (20 kg bird) for clearance and V1 were 0.54 L/kg/h and 0.095 L/kg. Both parameters significantly decreased with increasing weight/age. Meloxicam potency and selectivity for COX-1 and COX-2 were measured in whole blood assays (TxB2 production endpoint). Meloxicam was partially selective in emus (IC50 COX-1:COX-2 = 9.1:1). At the current empirical dose (0.5 mg/kg/24 hr), plasma meloxicam concentration is above IC50 of COX-2 for only 2 hr. PK/PD predicted dose required for 80% COX-2 inhibition over 24 hr were 3.4, 1.4 and 0.95 L/kg/day in chicks, juveniles and adult emus, respectively. The safety, therapeutic efficacy and practicality of modifying the daily dose or dose interval should be considered for dose recommendations in emus.

Analysis of teaching methods in anaesthesia in the undergraduate curriculum of four veterinary universities.

OBJECTIVE: To design a holistic audit tool to assess the effectiveness of anaesthesia teaching strategies, and thereby to study veterinary undergraduate teaching methods in different geographical areas. STUDY DESIGN: Qualitative study using interviews of university staff and students to identify common themes and differences in teaching veterinary anaesthesia. METHODS: An audit was performed using an audit tool in four veterinary universities (École Nationale Vétérinaire d'Alfort, France; Royal Veterinary College, UK; University of Buenos Aires, Argentina; and Alma mater studiorum - Università di Bologna, Italy). First, an open-question interview of anaesthesia head of service (60-90 minutes) identified the pedagogical strategies in order to conceive a subsequent semi-directive interview formulated as a SWOT analysis (Strength/Weaknesses/Opportunity/Threats). Second, the SWOT reflection was conducted by a second staff member and focussed on: 1) general organization; 2) topics for pre-rotation teaching; 3) teaching methods for clinical rotation; and 4) assessment methods. Qualitative analysis of the interview responses was performed with semi-structured interviews. Finally, the students evaluated their teaching through a students' questionnaire generated from the output of both interviews. RESULTS: A group of nine lecturers and 106 students participated in the study at four different sites. Preclinical teaching ranged from 13 to 24 hours (median 15 hours). Clinical teaching ranged from 4 to 80 hours (median 60 hours). Overall, all faculties perceived time as a limitation and attempted to design strategies to achieve the curriculum expectations and optimize teaching using more time-efficient exercises. Large animal anaesthesia teaching was found to be a common area of weakness. Internal feedback was delivered to each university, whereas generalized results were shared globally. CONCLUSIONS: This preliminary study proved the generalizability of the protocol used. Recruiting a larger pool of universities would help to identify and promote efficient teaching strategies and innovations for training competent new graduates in an ever-expanding curriculum.

Faculty's Perception of a Research Project Embedded in the Undergraduate Veterinary Curriculum.

In this article, we describe faculty's perception of a research project embedded in the final year of the undergraduate veterinary curriculum and look at factors associated with overall perceptions of the project. We hypothesized that faculty would have a dichotomous attitude toward the research project, with faculty viewing it either positively or negatively, and that this opinion of the project would be largely influenced by the background of the faculty member-in particular, her or his role at the Royal Veterinary College. We explored this hypothesis via a questionnaire consisting of 26 questions in categorical format, Likert-scale format, and ranking format. The questions addressed faculty demographics, faculty's perceptions of the project, and generic skills. Faculty had an overall positive view of the project and found it to be a useful part of the undergraduate curriculum (83.3% found it to be useful or very useful). Faculty's perception of the project was influenced by their role at the college (p = .017), the species with which they primarily work (p = .05), and their opinion on the time spent supervising the final-year project (p = .003). We concluded that faculty view research as an important and useful part of the undergraduate veterinary curriculum.

A double-blinded randomised dietary supplement crossover trial design to investigate the short-term influence of medium chain fatty acid (MCT) supplement on canine idiopathic epilepsy: study protocol.

BACKGROUND: Epilepsy is the most common brain disease in dogs. Recently, diets have been reported to have a positive impact on seizure activity and behaviour in various species including dogs with idiopathic epilepsy (IE). Historically, classic high fat ketogenic diets (KD) and medium chain triglycerides (MCT) KD have been successfully used to manage drug-resistant epilepsy. Similarly, an MCT enriched diet has been shown to improve seizure control and behavioural comorbidities in some dogs with IE. However, it is unknown whether an MCT dietary supplement (DS) may provide similar positive effects. METHODS: A 6-month prospective, randomised, double-blinded, placebo-controlled, crossover, multicentre dietary trial is designed comparing a 9% metabolic energy based calculated medium-chain triglyceride (MCT) oil supplement to a conventional 'control' DS. Only dogs which will have an International Veterinary Epilepsy Task Force Tier II level like diagnosis of IE which satisfied the following inclusion criteria are included: age between 6 months and ≤ 12 years; weighing between 4 and ≤ 65 kg; unremarkable interictal neurological examinations; no clinically significant findings on routine laboratory diagnostics; unremarkable brain MRI scan; have had at least 3 seizures in the previous 3 months prior to enrolment; treated with at least one ASD and being classified as resistant. All dogs are fed initially for 90 ± 2 days with either the control oil or the MCT oil alongside their normal diet, followed by 97 ± 2 days with the other supplement including a 7-day washout period. Overall, the aim is to recruit thirty-six patients at five different centres and to investigate the effect of MCTs as DS on seizure activity, tolerability, behavioural comorbidities and quality of life (QoL). DISCUSSION: Dietary interventions are rarely studied in a standardised form in veterinary medicine. The background diet, the cohort of animals and ASD received is standardised in this prospective diet trial to ensure representative data about the potential effect of MCT DS. If the study data confirms former findings, this would provide further evidence for the efficacy of MCTs as a management option for canine epilepsy. This publication should offer a repository of trial conditions and variable description with forecasted statistical analysis.

Differential susceptibility to tetracycline, oxytetracycline and doxycycline of the calf pathogens Mannheimia haemolytica and Pasteurella multocida in three growth media.

For clinical isolates of bovine Mannheimia haemolytica and Pasteurella multocida, this study reports minimum inhibitory concentration (MIC) differences for tetracycline, oxytetracycline and doxycycline between cation-adjusted Mueller-Hinton broth (CAMHB), foetal bovine serum (FBS) and Roswell Park Memorial Institute (RPMI) medium. MICs were determined according to CLSI standards and additionally using five overlapping sets of twofold dilutions. Matrix effect: (a) free drug MICs and minimum bactericidal concentrations (MBC) for all drugs were significantly higher in FBS than in CAMHB for both pathogens (p < 0.001); (b) MICs and MBCs were higher for CAMHB and FBS compared to RPMI for P. multocida only. Net growth rate for P. multocida in CAMHB was significantly slower than in FBS and higher than in RPMI, correlating to MIC and MBC ranking. Drug effect: doxycycline MICs and MBCs were significantly lower (p < 0.001) in both CAMHB and FBS than tetracycline and oxytetracycline for both pathogens. Only for M. haemolytica were oxytetracycline MIC and MBC significantly lower than tetracycline, precluding the use of tetracycline to predict oxytetracycline susceptibility in this species. Determining potencies of tetracyclines in a physiological medium, such as FBS, is proposed, when the objective is correlation with pharmacokinetic data for dosage determination.

A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.

The alpha(α)2 -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).

Population variability in animal health: Influence on dose-exposure-response relationships: Part II: Modelling and simulation.

During the 2017 Biennial meeting, the American Academy of Veterinary Pharmacology and Therapeutics hosted a 1-day session on the influence of population variability on dose-exposure-response relationships. In Part I, we highlighted some of the sources of population variability. Part II provides a summary of discussions on modelling and simulation tools that utilize existing pharmacokinetic data, can integrate drug physicochemical characteristics with species physiological characteristics and dosing information or that combine observed with predicted and in vitro information to explore and describe sources of variability that may influence the safe and effective use of veterinary pharmaceuticals.

Evaluation of the dynamic predictors of fluid responsiveness in dogs receiving goal-directed fluid therapy.

OBJECTIVES: Goal-directed fluid therapy (GDFT) based on pulse pressure variation (PPV) was used in anaesthetized dogs undergoing abdominal surgeries. The aims were 1) to evaluate the success rate of the PPV ≥13% in detecting fluid responsiveness [delta stroke volume (ΔSV) ≥10%]; 2) to assess the correlation between PPV, systolic pressure variation (SPV), Plethysmograph Variability Index (PVI) and central venous pressure (CVP) and 3) to establish the threshold value for the PVI that would predict a PPV value of ≥13% and indirectly discriminate responders from nonresponders to fluid therapy. STUDY DESIGN: Clinical, prospective, interventional study. ANIMALS: A total of 63 client-owned dogs scheduled for abdominal procedures. METHODS: PPV and SPV were calculated manually from the invasive blood pressure trace on the Datex monitor. PVI was recorded from the Masimo pulse oximeter. Fluid challenge (10 mL kg-1 Compound Sodium Lactate) was performed when PPV was ≥13% and/or mean arterial pressure (MAP) < 60 mmHg. Fluid responsiveness was assessed by the transoesophageal Doppler probe. Cardiovascular parameters (heart rate, MAP, PPV, SPV, PVI, SV and if available, CVP) were measured before and after each fluid intervention. RESULTS: PPV ≥ 13% reliably predicted fluid responsiveness in 82.9% of cases. There was positive correlation between PPV and SPV (r = 0.84%), PPV and logPVI (r = 0.46) as well as SPV and logPVI (r = 0.45). Noninvasive PVI value ≥13% should predict PPV threshold value (13%) with 97% sensitivity and 68% specificity. There was no statistically significant correlation between PPV and CVP. CONCLUSIONS: PPV is a useful clinical tool to detect occult hypovolaemia and predict cardiovascular response to fluid challenge. Use of PPV is recommended as a part of GDFT in dogs undergoing abdominal procedures.

Prediction of marbofloxacin dosage for the pig pneumonia pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida by pharmacokinetic/pharmacodynamic modelling.

BACKGROUND: Bacterial pneumonia in pigs occurs widely and requires antimicrobial therapy. It is commonly caused by the pathogens Actinobacillus pleuropneumoniae and Pasteurella multocida. Marbofloxacin is an antimicrobial drug of the fluoroquinolone class, licensed for use against these organisms in the pig. In recent years there have been major developments in dosage schedule design, based on integration and modelling of pharmacokinetic (PK) and pharmacodynamic (PD) data, with the objective of optimising efficacy and minimising the emergence of resistance. From in vitro time-kill curves in pig serum, PK/PD breakpoint Area under the curve (AUC) 24h /minimum inhibitory concentration (MIC) values were determined and used in conjunction with published PK, serum protein binding data and MIC distributions to predict dosages based on Monte Carlo simulation (MCS). RESULTS: For three levels of inhibition of growth, bacteriostasis and 3 and 4log10 reductions in bacterial count, mean AUC24h/MIC values were 20.9, 45.2 and 71.7 h, respectively, for P. multocida and 32.4, 48.7 and 55.5 h for A. pleuropneumoniae. Based on these breakpoint values, doses for each pathogen were predicted for several clinical scenarios: (1) bacteriostatic and bactericidal levels of kill; (2) 50 and 90% target attainment rates (TAR); and (3) single dosing and daily dosing at steady state. MCS for 90% TAR predicted single doses to achieve bacteriostatic and bactericidal actions over 48 h of 0.44 and 0.95 mg/kg (P. multocida) and 0.28 and 0.66 mg/kg (A. pleuropneumoniae). For daily doses at steady state, and 90% TAR bacteriostatic and bactericidal actions, dosages of 0.28 and 0.59 mg/kg (P. multocida) and 0.22 and 0.39 mg/kg (A. pleuropneumoniae) were required for pigs aged 12 weeks. Doses were also predicted for pigs aged 16 and 27 weeks. CONCLUSIONS: PK/PD modelling with MCS approaches to dose determination demonstrates the possibility of tailoring clinical dose rates to a range of bacterial kill end-points.