Determination of pharmacokinetic-pharmacodynamic cutoff values of oxytetracycline in calves and adult cattle using population pharmacokinetic modeling.

Introduction: A harmonized clinical breakpoint for interpreting antimicrobial susceptibility testing of oxytetracycline in cattle is currently lacking in Europe. This study aimed to establish a pharmacokinetic/pharmacodynamic (PK/PD) cutoff to propose clinical breakpoints, facilitating reliable interpretation of antimicrobial susceptibility results in cattle.

Methods: A meta-analysis of oxytetracycline pharmacokinetic data from 69 cattle was conducted, including 1,730 plasma concentration samples from animals administered 20 mg/kg intramuscularly and/or 20 or 40 mg/kg intravenously.

Pragmatic Systemic Solutions to the Wicked and Persistent Problem of the Unprofessional Disruptive Physician in the Health System.

We have always had and will always have "disruptive" or "dysfunctional" doctors behaving unprofessionally within healthcare institutions. Disruptive physician behaviour (also called "unprofessional behaviour") was described almost 150 years ago, but remains a persistent, wicked problem in healthcare, largely fuelled by systemic inaction. In this Commentary, we aim to explore the following aspects from a systemic lens: (i) the gaps in understanding systemic resistance and difficulty in addressing this issue; and (ii) pragmatic approaches to its management in the healthcare system.

Biased computation of probability of target attainment for antimicrobial drugs.

The medical literature is replete with articles in which there is confusion between "free concentration" and "unbound fraction" (f ), which is the ratio of free to total plasma concentration. The lack of clarity in distinguishing between these two terms has led to biased computations, erroneous interpretations, and misleading recommendations. The problems are highlighted in this paper, taking the example of calculation of Probability of Target Attainment (PTA).

Association of Occupational Exposures and Chronic Obstructive Pulmonary Disease Morbidity.

Objective: The aim of the study is to determine whether aggregate measures of occupational exposures are associated with chronic obstructive pulmonary disease (COPD) outcomes in the Subpopulations and Intermediate Outcome Measures in COPD study cohort.

Methods: Individuals were assigned to six predetermined exposure hazard categories based on self-reported employment history. Multivariable regression, adjusted for age, sex, race, current smoking status, and smoking pack-years determined the association of such exposures to odds of COPD and morbidity measures.

Evaluating the impact of a national strategic leader development programme for UK doctors: myth-busting, mind-changing, mood-enhancing.

Background: The drive towards engaging UK doctors in clinical leadership and management has involved many initiatives at various levels.

Methods: This paper reports on the findings of an in-depth evaluation of a national medical leadership programme for doctors in the late stages of specialty or general practitioner (GP) training or have just become consultants or GPs.

Results: The evaluation clearly demonstrates the impact of this programme and the benefits for the individuals and organisations involved, particularly around stimulating a shift in mood and a major mindset shift in what medical leadership is (and is not) and what they can achieve as medical leaders.

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 IC ratios COX-1:COX-2, 129:1 in dogs, 32:1 in cats).

The Decline and Fall of Materia Medica and the Rise of Pharmacology and Therapeutics in Veterinary Medicine.

Materia Medica is a Latin term, relating to the history of pharmacy. It describes the sources (vegetable, animal and mineral), nature, preparation, and properties of substances or mixtures of substances, which were used as remedies for the treatment of diseases. Bourgelat authored the first veterinary Materia Medica book.

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.

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.

Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

At the request of French Regulatory Authorities, a new formulation of Levothyrox was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90-1.

VetCAST Method for Determination of the Pharmacokinetic-Pharmacodynamic Cut-Off Values of a Long-Acting Formulation of Florfenicol to Support Clinical Breakpoints for Florfenicol Antimicrobial Susceptibility Testing in Cattle.

The PK/PD cut-off (PK/PD) value of florfenicol for calf pathogens was determined for long acting formulations (MSD Nuflor® and a bioequivalent generic product). PK/PD is one of the three MICs considered by VetCAST, a sub-committee of the European Committee on Susceptibility Testing (EUCAST), to establish a Clinical Breakpoint for interpreting Antimicrobial Susceptibility Testing (AST). A population model was built by pooling three pharmacokinetic data sets, obtained from 50 richly sampled calves, receiving one of two formulations (the pioneer product and a generic formulation).

Semi-Mechanistic Modeling of Florfenicol Time-Kill Curves and Dose Fractionation for Calf Respiratory Pathogens.

An important application of time-kill curve (TKC) assays is determination of the nature of the best PK/PD index (AUC/MIC or T% > MIC) and its target value for predicting clinical efficacy . VetCAST (the veterinary subcommittee of EUCAST) herein presents semi-mechanistic TKC modeling for florfenicol, a long acting (96 h) veterinary antimicrobial drug licensed against calf pneumonia organisms ( and ) to support justification of its PK/PD and clinical breakpoint. Individual TKC assays were performed with 6 field strains of each pathogen (initial inoculum 10 CFU/mL with sampling at times at 0, 1, 2, 4, 8, and 24 h).

Levothyrox New and Old Formulations: Are they Switchable for Millions of Patients?

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox. In March 2017, at the request of French authorities, a new formulation of Levothyrox was licensed, with the objective of avoiding stability deficiencies of the old formulation.

Peak Exposures in Epidemiologic Studies and Cancer Risks: Considerations for Regulatory Risk Assessment.

We review approaches for characterizing "peak" exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose-response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. We searched the epidemiologic literature on environmental chemicals classified as carcinogens in which cancer risks were described in relation to "peak" exposures.