Herd immunity, vaccination and moral obligation.

The public health benefits of herd immunity are often used as the justification for coercive vaccine policies. Yet, 'herd immunity' as a term has multiple referents, which can result in ambiguity, including regarding its role in ethical arguments. The term 'herd immunity' can refer to (1) the herd immunity threshold, at which models predict the decline of an epidemic; (2) the percentage of a population with immunity, whether it exceeds a given threshold or not; and/or (3) the indirect benefit afforded by collective immunity to those who are less immune. Moreover, the accumulation of immune individuals in a population can lead to two different outcomes: elimination (for measles, smallpox, etc) or endemic equilibrium (for COVID-19, influenza, etc). We argue that the strength of a moral obligation for individuals to contribute to herd immunity through vaccination, and by extension the acceptability of coercion, will depend on how 'herd immunity' is interpreted as well as facts about a given disease or vaccine. Among other things, not all uses of 'herd immunity' are equally valid for all pathogens. The optimal conditions for herd immunity threshold effects, as illustrated by measles, notably do not apply to the many pathogens for which reinfections are ubiquitous (due to waning immunity and/or antigenic variation). For such pathogens, including SARS-CoV-2, mass vaccination can only be expected to delay rather than prevent new infections, in which case the obligation to contribute to herd immunity is much weaker, and coercive policies less justifiable.

Ethics of antibiotic allergy.

Antibiotic allergies are commonly reported among patients, but most do not experience reactions on rechallenge with the same agents. These reported allergies complicate management of infections in patients labelled as having penicillin allergy, including serious infections where penicillin-based antibiotics are the first-line (most effective and least toxic) treatment option. Allergy labels are rarely questioned in clinical practice, with many clinicians opting for inferior second-line antibiotics to avoid a perceived risk of allergy. Reported allergies thereby can have significant impacts on patients and public health, and present major ethical challenges. Antibiotic allergy testing has been described as a strategy to circumvent this dilemma, but it carries limitations that often make it less feasible in patients with acute infections or in community settings that lack access to allergy testing. This article provides an empirically informed ethical analysis of key considerations in this clinical dilemma, using Staphylococcus aureus bacteraemia in patients with penicillin allergies as a case study. We argue that prescribing first-line penicillin-based antibiotics to patients with reported allergies may often present a more favourable ratio of benefits to risks, and may therefore be more ethically appropriate than using second-line drugs. We recommend changes to policy-making, clinical research and medical education, in order to promote more ethically acceptable responses to antibiotic allergies than the status quo.

Quantifying the impact of individual and collective compliance with infection control measures for ethical public health policy.

Infectious disease control measures often require collective compliance of large numbers of individuals to benefit public health. This raises ethical questions regarding the value of the public health benefit created by individual and collective compliance. Answering these requires estimating the extent to which individual actions prevent infection of others. We develop mathematical techniques enabling quantification of the impacts of individuals or groups complying with three public health measures: border quarantine, isolation of infected individuals, and prevention via vaccination/prophylaxis. The results suggest that (i) these interventions exhibit synergy: They become more effective on a per-individual basis as compliance increases, and (ii) there is often substantial "overdetermination" of transmission. If a susceptible person contacts multiple infectious individuals, an intervention preventing one transmission may not change the ultimate outcome (thus, risk imposed by some individuals may erode the benefits of others' compliance). These results have implications for public health policy during epidemics.

The Staphylococcus aureus Network Adaptive Platform Trial Protocol: New Tools for an Old Foe.

Staphylococcus aureus bloodstream (SAB) infection is a common and severe infectious disease, with a 90-day mortality of 15%-30%. Despite this, <3000 people have been randomized into clinical trials of treatments for SAB infection. The limited evidence base partly results from clinical trials for SAB infections being difficult to complete at scale using traditional clinical trial methods. Here we provide the rationale and framework for an adaptive platform trial applied to SAB infections. We detail the design features of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial that will enable multiple questions to be answered as efficiently as possible. The SNAP trial commenced enrolling patients across multiple countries in 2022 with an estimated target sample size of 7000 participants. This approach may serve as an exemplar to increase efficiency of clinical trials for other infectious disease syndromes.

Ethics and antibiotic resistance.

INTRODUCTION OR BACKGROUND: Antibiotic resistance raises ethical issues due to the severe and inequitably distributed consequences caused by individual actions and policies. SOURCES OF DATA: Synthesis of ethical, scientific and clinical literature. AREAS OF AGREEMENT: Ethical analyses have focused on the moral responsibilities of patients to complete antibiotic courses, resistance as a tragedy of the commons and attempts to limit use through antibiotic stewardship. AREAS OF CONTROVERSY: Each of these analyses has significant limitations and can result in self-defeating or overly narrow implications for policy. GROWING POINTS: More complex analyses focus on ethical implications of ubiquitous asymptomatic carriage of resistant bacteria, non-linear outcomes within and between patients over time and global variation in resistant disease burdens. AREAS TIMELY FOR DEVELOPING RESEARCH: Neglected topics include the harms of antibiotic use, including off-target effects on the human microbiome, and the lack of evidence guiding most antibiotic prescription decisions.

Imagination and remembrance: what role should historical epidemiology play in a world bewitched by mathematical modelling of COVID-19 and other epidemics?

Although every emerging infectious disease occurs in a unique context, the behaviour of previous pandemics offers an insight into the medium- and long-term outcomes of the current threat. Where an informative historical analogue exists, epidemiologists and policymakers should consider how the insights of the past can inform current forecasts and responses.

Coronavirus Human Infection Challenge Studies: Assessing Potential Benefits and Risks.

Human infection challenge studies (HCS) have been proposed as a means to accelerate SARS-CoV2 vaccine development and thereby help to mitigate a prolonged global public health crisis. A key criterion for the ethical acceptability of SARS-CoV2 HCS is that potential benefits outweigh risks. Although the assessment of risks and benefits is meant to be a standard part of research ethics review, systematic comparisons are particularly important in the context of SARS-CoV2 HCS in light of the significant potential benefits and harms at stake as well as the need to preserve public trust in research and vaccines. In this paper we explore several considerations that should inform systematic assessment of SARS-CoV-2 HCS. First, we detail key potential benefits of SARS-CoV-2 HCS including, but not limited to, those related to the acceleration of vaccine development. Second, we identify where modelling is needed to inform risk-benefit (and thus ethical) assessments. Modelling will be particularly useful in (i) comparing potential benefits and risks of HCS with those of vaccine field trials under different epidemiological conditions and (ii) estimating marginal risks to HCS participants in light of the background probabilities of infection in their local community. We highlight interactions between public health policy and research priorities, including situations in which research ethics assessments may need to strike a balance between competing considerations.

A Scenario-Based Survey of Expert Echocardiography Recommendations for Patients With Staphylococcus aureus Bacteremia at Varying Risk for Endocarditis.

Importance: Echocardiography to detect infective endocarditis is regarded as a key quality indicator in the care of patients with Staphylococcus aureus bacteremia, but its application varies markedly between reported series. Understanding the reasons for this variation in practice is important to improve the use of this investigation. Objective: To identify expert clinicians' preferred echocardiography strategy for a variety of S aureus bacteremia scenarios in a hypothetical setting free from extrinsic constraints. Design, Setting, and Participants: Anonymous web-based survey study comprising 50 text-based scenarios describing patients with S aureus bacteremia and various combinations of risk factors for endocarditis. Other variables included patient age and the presence of an extracardiac focus of infection warranting prolonged treatment. The survey was emailed to participants between September 2018 and March 2019. Each respondent was asked to recommend 1 of 6 echocardiography strategies for up to 8 randomly selected scenarios. Respondents were primarily infectious diseases physicians, and more than half reported an annual caseload of more than 20 cases of S aureus bacteremia. Main Outcomes and Measures: The proportion of respondents selecting each of the 6 echocardiography strategies was calculated alongside Wilson score confidence intervals. Modified Fleiss κ statistics were used to described interrespondent variability. Generalized estimating equations were used to assess the associations between respondent- and scenario-level variables and the recommendation of an echocardiography strategy with a low negative likelihood ratio for infective endocarditis (ie, a highly exclusionary strategy). Results: A total of 656 respondents from 24 countries provided 4837 echocardiography recommendations across the 50 scenarios. Echocardiography recommendations were associated with scenarios' burden of endocarditis risk (multivariate odds ratio per point of the VIRSTA score, 1.4; 95% CI, 1.4-1.5; P < .001). Poor interrespondent agreement was seen across all scenarios (modified Fleiss κ, 0.06; 95% CI, 0.05-0.07) but was most notable for scenarios with a lower risk of endocarditis (modified Fleiss κ, 0.04; 95% CI, 0.03-0.05). The presence of an extracardiac focus of infection was also associated with the choice of echocardiography strategy (odds ratio for highly exclusionary strategy, 0.51; 95% CI, 0.45-0.58). Respondent location in continental Europe was associated with recommendations in favor of a highly exclusionary strategy (odds ratio, 1.8; 95% CI, 1.3-2.5) compared with location in Australia or New Zealand. Conclusions and Relevance: In this study, expert clinicians demonstrated active stratification by risk of endocarditis when making echocardiography recommendations for hypothetical patients with S aureus bacteremia. Substantial disagreement existed as to whether patients at lower risk of endocarditis should undergo transesophageal echocardiography-based echocardiography strategies.

Early transthoracic echocardiography has useful prognostic value in left-sided native valve endocarditis despite limited diagnostic performance.

To investigate the prognostic implications of findings on early transthoracic echocardiography (TTE) in patients with definite left-sided native valve infective endocarditis (LNVIE). We reviewed a 10-year retrospective cohort of consecutive patients with definite LNVIE treated at a tertiary cardiothoracic centre. TTE studies performed within the first seven days of the index blood culture (for culture-positive cases) or hospital admission (for culture-negative cases) were reviewed for the presence of valvular vegetations, perivalvular abscesses, aortic or mitral regurgitation of moderate or greater severity or a bicuspid aortic valve. Six-week outcomes included all-cause mortality, cardiac surgery for endocarditis or new embolic cerebral infarction. Early TTE was performed in 118 of 151 episodes of definite LNVIE at a median of two days after the index blood culture or hospital admission. Findings on these studies included valvular vegetations or abscesses in 74 patients, moderate or severe aortic or mitral regurgitation in 67 patients and a bicuspid aortic valve in 19 patients. The presence of any of these findings conferred a relative risk of any adverse six-week outcome of 4.80 (95% confidence interval 1.6-17, p = 0.001). The presence of a bicuspid aortic valve appeared particularly predictive of the need for cardiac surgery, including for clinically occult paravalvular abscesses. Early TTE can be used to stratify patients with LNVIE by the risk of major endocarditis-related adverse outcomes occurring within the first six weeks of treatment.

Benefit of Echocardiography in Patients With Staphylococcus aureus Bacteremia at Low Risk of Endocarditis.

BACKGROUND: The risk of endocarditis among patients with Staphylococcus aureus bacteremia is not uniform, and a number of different scores have been developed to identify patients whose risk is less than 5%. The optimal echocardiography strategy for these patients is uncertain. METHODS: We used decision analysis and Monte Carlo simulation using input parameters taken from the existing literature. The model examined patients with S aureus bacteremia whose risk of endocarditis is less than 5%, generally those with nosocomial or healthcare-acquired bacteremia, no intracardiac prosthetic devices, and a brief duration of bacteremia. We examined 6 echocardiography strategies, including the use of transesophageal echocardiography, transthoracic echocardiography, both modalities, and neither. The outcome of the model was 90-day survival. RESULTS: The optimal echocardiography strategy varied with the risk of endocarditis and the procedural mortality associated with transesophageal echocardiography. No echocardiography strategy offered an absolute benefit in 90-day survival of more than 0.5% compared with the strategy of not performing echocardiography and treating with short-course therapy. Strategies using transesophageal echocardiography were never preferred if the mortality of this procedure was greater than 0.5%. CONCLUSIONS: In patients identified to be at low risk of endocarditis, the choice of echocardiography strategy appears to exert a very small influence on 90-day survival. This finding may render test-treatment trials unfeasible and should prompt clinicians to focus on other, more important, management considerations in these patients.

Clinical variation in the use of echocardiography in Staphylococcus aureus bacteraemia: a multi-centre cohort study.

The objective of this investigation was to assess whether between-hospital variation in echocardiography usage for patients with Staphylococcus aureus bacteraemia (SAB) is explained by differences in patients' pre-test probability of endocarditis. This was a retrospective cohort study at three neighbouring hospitals in Australia. Consecutive episodes of SAB were reviewed for the presence of three endocarditis risk factors (community onset, prolonged bacteraemia and the presence of an intracardiac prosthetic device) and the performance and results of all echocardiography studies within 30 days. Multivariate logistic regression was used to examine the effect of hospital site on the performance of (i) transoesophageal and (ii) transthoracic echocardiography controlling for major endocarditis risk factors. Significant variation in echocardiography usage was demonstrated between sites in a total cohort of 1167 episodes of SAB. None of the three sites were found to exhibit echocardiography usage that could be considered consistent with current guidelines, and each differed from the guidelines in different ways. Hospital site, rather than endocarditis risk factors, was the strongest predictor of transthoracic echocardiography use; however, the use of transoesophageal echocardiography was strongly predicted by endocarditis risk factors. Variation in echocardiography use between these hospitals is not adequately explained by differences in the risk factor profile of their SAB cohorts.

Criteria for Identifying Patients With Staphylococcus aureus Bacteremia Who Are at Low Risk of Endocarditis: A Systematic Review.

This systematic review examines the methods and results of recent studies reporting clinical criteria able to identify patients with Staphylococcus aureus bacteremia who are at very low risk of endocarditis. We searched PubMed, EMBASE, and the Cochrane Collaboration CENTRAL database for articles published after March 1994 using a combination of MeSH and free text search terms for S. aureus AND bacteremia AND endocarditis. Studies were included if they presented a combination of clinical and microbiological criteria with a negative likelihood ratio of ≤0.20 for endocarditis. We found 8 studies employing various criteria and reference standards whose criteria were associated with negative likelihood ratios between 0.00 and 0.19 (corresponding to 0%-5% risk of endocarditis at 20% background prevalence). The benefit of echocardiography for patients fulfilling these criteria is uncertain.