Population pharmacokinetic meta-analysis to support dosing regimen in dogs for surgical antimicrobial prophylaxis

The Pharmacokinetic/Pharmacodynamic of antimicrobial drugs (AMD) for surgical prophylaxis has been poorly studied, hampering evidence-based decision making around AMD dosing and timing. Our objective is to use PK/PD principles to inform (i) the timing of administration and (ii) the interval for re-administration of AMD used peri-operatively in dogs. Raw plasma concentrations of cefazolin, cefuroxime, cephalexin, amoxicillin and ampicillin were retrieved from original intravenous studies performed in dogs. Staphylococci and E. coli were identified as possible intraoperative contaminants and their Epidemiological cutoffs (ECOFF) were retrieved from the EUCAST database. Individual PK data were refitted with non-linear mixed effect models (Phoenix). We performed Monte Carlo simulation to compute i) the 95th percentile of time of peak concentration in the peripheral compartment (informing timing between administration and first incision) and ii) the duration for which at least 90% of dogs maintain a free plasma concentration above ECOFF (informing timing of re-administration: 1.5 to 4h). Cefazolin (22-25 mg/kg), cefuroxime (20 mg/kg) and amoxicillin (16.7 mg/kg) reached peak peripheral concentrations within 30 minutes, but cephalexin (15 mg/kg) and ampicillin (20 mg/kg) required 45 and 90 minutes, respectively. For staphylococci, cefazolin and cefuroxime require re-administration every 2h, whereas cephalexin and both amoxicillin and ampicillin can be readministered every 3 and 4 hours, respectively. For E. coli, only cefazolin provided adequate perioperative coverage with 2-hourly administration, where cefuroxime and cephalexin failed uniformly. Alternatively, ampicillin and amoxicillin (sick dogs) may cover E. coli contaminations, but only if readministered every 1.5h. These PK-derived conclusions provide a rationale for perioperative AMD administration timing

Large-scale statistical analysis of Mycobacterium tuberculosis genome sequences identifies compensatory mutations associated with multi-drug resistance

Tuberculosis (TB), caused by Mycobacterium tuberculosis, has a significant impact on global health worldwide. The development of multi-drug strains that are resistant to the first-line drugs isoniazid and rifampicin threatens public health security. Rifampicin and isoniazid resistance are largely underpinned by mutations in rpoB and katG respectively and are associated with fitness costs. Compensatory mutations are considered to alleviate these fitness costs and have been observed in rpoC/rpoA (rifampicin) and oxyR’-ahpC (isoniazid). We developed a framework (CompMut-TB) to detect compensatory mutations from whole genome sequences from a large dataset comprised of 18,396 M. tuberculosis samples. We performed association analysis (Fisher’s exact tests) to identify pairs of mutations that are associated with drug-resistance, followed by mediation analysis to identify complementary or full mediators of drug-resistance. The analyses revealed several potential mutations in rpoC (N=47), rpoA (N=4), and oxyR’-ahpC (N=7) that were considered either ‘highly likely’ or ‘likely’ to confer compensatory effects on drug-resistance, including mutations that have previously been reported and validated. Overall, we have developed the CompMut-TB framework which can assist with identifying compensatory mutations which is important for more precise genome-based profiling of drug-resistant TB strains and to further understanding of the evolutionary mechanisms that underpin drug-resistance

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

Short-term induced hyperinsulinaemia and dexamethasone challenge do not affect circulating total adiponectin concentrations in insulin-sensitive ponies

BackgroundHypoadiponectinaemia is a risk factor for endocrinopathic laminitis, but the directionality and nature of its association with insulin dysregulation is unclear.ObjectivesTo investigate the effects of short-term induced hyperinsulinaemia and dexamethasone challenge on circulating [total adiponectin] and whole blood expression of adiponectin (AdipoR1 and AdipoR2), insulin, and insulin-like growth factor 1 (IGF-1) receptors in insulin-sensitive ponies.Study designIn vivo experiment.MethodsSix never-laminitic, insulin-sensitive, native-breed UK ponies first underwent a dexamethasone challenge (0.08 mg/kg i.v.) with blood samples collected every 15 min over 3 h. After a 14-day washout period, hyperinsulinaemia was induced for 9 h via a euglycaemic-hyperinsulinaemic clamp (EHC), with blood samples collected every 30 min. Serum [insulin], plasma [total adiponectin], and plasma [IGF-1] were measured using validated assays and receptor gene expression was assessed via quantitative polymerase chain reaction (qPCR). Finally, whole blood was incubated with 10-1000 ng/mL dexamethasone for 3 h at 37 degrees C to investigate its direct effects on gene expression.ResultsThere were no adverse effects observed during either protocol. Dexamethasone challenge did not alter circulating [insulin] or [total adiponectin] at any time-point, but significantly upregulated AdipoR1 and IGF-1R expression at 150 and 180 min. Ex vivo incubation of whole blood with dexamethasone did not alter expression of the genes examined. There was no change in [total adiponectin] or expression of the genes examined associated with EHC-induced hyperinsulinemia.Main limitationsThis was a small sample size that included only native-breed ponies; total adiponectin was measured rather than high-molecular-weight adiponectin.ConclusionsShort-term induced hyperinsulinaemia and dexamethasone challenge did not affect circulating [total adiponectin] in insulin-sensitive ponies. However, dexamethasone administration was associated with upregulation of two receptors linked to adiponectin signalling, suggesting that a physiological response occurred possibly to counteract dexamethasone-associated changes in tissue insulin sensitivity

Isolated discrete upper septal thickening in a non-referral cat population of senior and young cats

Introduction/objectives: Discrete upper septal thickening (DUST) is a phenotype of elderly people. The cardiac phenotype in senior cats has been incompletely described. We aimed to characterize the echocardiographic phenotype of senior cats, specifically to determine prevalence of DUST and hypertrophic cardiomyopathy (HCM).Animals: One hundred and forty-nine healthy, normotensive cats.Materials and methods: Prospective cross-sectional study. Senior (>= nine years) and young (= 6 mm. An interventricular septum ratio (basal-to-mid septal thickness ratio) was calculated. We assessed for associations between clinical and echocardiographic variables and DUST. Data are presented as mean (+/- SD), median (range), or frequency (percentage).Results: One-hundred and two senior and 47 young cats were enrolled. Aortoseptal angle (AoSA) was steeper in senior cats (137 degrees (+/- 14.5) vs. 145 degrees (+/- 12.3) in young cats, p=0.002). Eighteen cats had DUST (18/149, 12%), fourteen senior, and four young cats (p=0.4). Cats with DUST had steeper AoSA (125 degrees (+/- 8.3) vs. 142 degrees (+/- 13.7), p<0.0001) and higher interventricular septum ratio (1.4 (1.2-2.0) vs. 1.0 (0.7-1.8)). Univariable analysis showed decreased odds of DUST with greater AoSA (OR 0.9, p<0.0001), age was not associated with DUST. Twenty-nine senior cats had HCM (28.4%).Discussion/conclusions: Prevalence of DUST was 12%. There was no association between age and DUST. Smaller/steeper AoSA was the main factor associated with DUST. There was a high prevalence of HCM in this senior population