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. In doing so, we hope to shift the systemic effect from nihilism and despair, to one of hopeful realism about disruptive or unprofessional behaviour. We suggest that solutions lie in cultural change to ensure systemic awareness, responsiveness and early intervention, and an understanding of what systemic failure looks like in this context. Staff education, policies and procedures that outline a consistent reporting and review process including triaging the problem, its source, its effects, and the attempted solutions, are also crucial. Finally, assessment and intervention from appropriately mental-health-trained personnel are required, recognising that this is a complex mental health problem. We are not doing anyone any favours by ignoring, acting as bystanders, or otherwise turning a blind eye to disruptive or unprofessional behaviour; otherwise, we share culpability.

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" (fu ), 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). This metric is used to propose pharmacokinetic/pharmacodynamic (PK/PD) breakpoints required for the interpretation of Antimicrobial Susceptibility Testing. Based on Monte Carlo simulations of the PK/PD index, area under the unbound concentration time curve/minimum inhibitory concentration (fAUC/MIC), computation of PTA from total plasma concentrations scaled by fu ineluctably leads to biased estimates. The bias is greater if the variability associated with fu is added, instead of removing it during this scaling. The explanation for the bias is that total plasma drug concentrations are intrinsically more variable than the corresponding free concentrations. This is due to the variability of antimicrobial binding for total, but not for free plasma concentrations. In consequence, the greater variability always leads to underestimation of the PK/PD cutoff (i.e., the critical MIC that is guaranteed for a given percentile of the population). A further consequence is an increase in calculated dosage required to attain the targeted quantile. This erroneous approach, of using free antimicrobial drug fraction, is not limited to the derivation of PK/PD cutoff, but may also have consequences for antimicrobials drug safety in clinical patients.

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. We compared these with the results of a single summary question regarding occupational exposure. RESULTS: A total of 2772 individuals were included. Some exposure estimates, including "gases and vapors" and "dust and fumes" exposures resulted in associations with effect estimates over two times the estimated effect size when compared with a single summary question. CONCLUSIONS: Use of occupational hazard categories can identify important associations with COPD morbidity while use of single-point measures may underestimate important differences in health risks.

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. The programme structure and activities allowed participants to learn from a range of senior decision-makers about policy and strategic developments and processes. However, the evaluation also highlighted that some pervasive myths still exist around medical leadership and management which, if not addressed, will hamper efforts to fully engage doctors in taking on strategic leadership roles. CONCLUSION: Clinical leadership programmes are valuable, but must be carefully managed to extract the full value from them.

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.

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.

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. This review describes the evolution and ultimate downfall of Materia Medica concepts and practices. Its survival for more than two millennia reflected the impact of religion and dogmas on therapy. The consignment of Materia Medica to history was signified by publication of the first modern book of veterinary pharmacology and therapeutics by Meyer Jones in 1953. Previously, the dominance of Materia Medica was linked to an hippiatry culture, which was shared with farriers and quacks. The Pasteurian and pharmacological revolutions of the second half of the nineteenth century led to its gradual abandonment. This review explains why the existence of authentically active substances, such as opioid analgesics, cardiotonics and general anesthetics either were not used for those actions or were badly prescribed, in part because of historical precedence and in part from lack of pathophysiological knowledge to justify rational use. The modern concept of dosage, in particular inter-species differences, was not understood. There were also major dogmas, supporting false indications, such as failure to recognize pain as a symptom to be treated, whereas inflammation was only a disease symptom involving excess of activity of the blood system, which had to be vigorously addressed by bleeding and purging. This review covers a well-defined period, ranging from Bourgelat, who wrote the first book of Materia Medica for veterinary studies to the first edition of Meyer Jones textbook in 1953, which marked the end of Materia Medica and the beginning of pharmacology in veterinary medicine.

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.

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 0.90-1.11. Bioequivalence was concluded. In a previous publication, we questioned the ability of an ABE trial to guarantee the switchability within patients of the new and old levothyroxine formulations. It was suggested that the two formulations should be compared using the conceptual framework of individual bioequivalence. The present paper is a response to those claiming that, despite the fact that ABE analysis does not formally address the switchability of the two formulations, future patients will nevertheless be fully protected. The basis for this claim is that the ABE study was established in a large trial and analyzed using a stringent a priori acceptance interval of equivalence. These claims are questionable, because the use of a very large number of subjects nullifies the implicit precautionary intention of the European guideline when, for a Narrow Therapeutic Index drug, it recommends shortening the a priori acceptance interval from 0.80-1.25 to 0.90-1.11.

Semi-Mechanistic Modeling of Florfenicol Time-Kill Curves and in silico 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 (fAUC/MIC or fT% > MIC) and its target value for predicting clinical efficacy in vivo. 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 (Pasteurella multocida and Mannheimia haemolytica) to support justification of its PK/PDbreakpoint and clinical breakpoint. Individual TKC assays were performed with 6 field strains of each pathogen (initial inoculum 107 CFU/mL with sampling at times at 0, 1, 2, 4, 8, and 24 h). Semi-mechanistic modeling (Phoenix NLME) allowed precise estimation of bacteria growth system (KGROWTH, natural growth rate; KDEATH, death rate; BMAX, maximum possible culture size) and florfenicol pharmacodynamic parameters (EMAX, efficacy additive to KDEATH; EC50, potency; Gamma, sensitivity). PK/PD simulations (using the present TKC model and parameters of a florfenicol population pharmacokinetic model) predicted the time-course of bacterial counts under different exposures. Of two licensed dosage regimens, 40 mg/kg administered once was predicted to be superior to 20 mg/kg administered at 48 h intervals. Furthermore, we performed in silico dose fractionation with doses 0 - 80 mg/kg administered in 1, 2 or 4 administrations over 96 h and for MICs of 0.5, 1, 2, 4 mg/L with 2 inoculum sizes 105 and 107 CFU/mL. Regression analysis (Imax model) demonstrated that i) fAUC/MIC outperformed fT% > MIC as PK/PD index and ii) maximum efficacy (IC90%) was obtained when the average free plasma concentration over 96 h was equal to 1.2 to 1.4 times the MIC of Pasteurella multocida and Mannheimia haemolytica, respectively.

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/PDCO) value of florfenicol for calf pathogens was determined for long acting formulations (MSD Nuflor® and a bioequivalent generic product). PK/PDCO 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). A virtual population of 5,000 florfenicol disposition curves was generated by Monte Carlo Simulations (MCS) over the 96 h of the assumed duration of action of the formulations. From this population, the maximum predicted MIC, for which 90% of calves can achieve some a priori selected critical value for two PK/PD indices, AUC/MIC and T>MIC, was established. Numerical values were established for two bacterial species of the bovine respiratory disease (BRD) complex, Pasteurella multocida and Mannheimia haemolytica. It was concluded that the PK/PDCO of florfenicol for both AUC/MIC and T>MIC was 1 mg/L.