Are we enrolling the right patients? A scoping review of external validity and generalizability of clinical trials in bloodstream infections.

BACKGROUND: Having a representative population in randomized clinical trials (RCTs) improves external validity and generalizability of trial results. There are limited data examining differences between RCT-enrolled and real-world populations in bloodstream infections (BSI). OBJECTIVES: We conducted a scoping review aiming to review studies assessing generalizability of BSI RCT populations, to identify sub-groups that have been systematically under-represented and to explore approaches to improve external validity of future RCTs. SOURCES: MEDLINE, Embase, and Cochrane Library databases were searched for terms related to external validity or generalizability, BSI, and clinical trials in papers published up to 1 August 2023. Studies comparing enrolled versus nonenrolled patients, or papers discussing external validity or generalizability in the context of BSI RCTs were included. CONTENT: Sixteen papers were included in the final review. Five compared RCT-enrolled and nonenrolled participants from the same source population. There were significant differences between the two groups in all studies, with nonenrolled patients having a greater comorbidity burden and consistently worse outcomes including mortality. We identified several barriers to improving generalizability of RCT populations and outlined potential approaches to reduce these barriers, such as alternative/simplified consent processes, streamlining eligibility criteria and follow-up procedures, quota-based sampling techniques, and ensuring diversity in site and study team selection. IMPLICATIONS: Study cohorts in BSI RCTs are not representative of the general BSI patient population. As we increasingly adopt large pragmatic trials in infectious diseases, it is important to recognize the importance of maximizing generalizability to ensure that our research findings are of direct relevance to our patients.

Validating a novel three-times-weekly post-hemodialysis ceftriaxone regimen in infected Indigenous Australian patients-a population pharmacokinetic study.

OBJECTIVES: To describe the total and unbound population pharmacokinetics of a 2 g three-times-weekly post-dialysis ceftriaxone regimen in Indigenous Australian patients requiring hemodialysis. METHODS: A pharmacokinetic study was carried out in the dialysis unit of a remote Australian hospital. Adult Indigenous patients on intermittent hemodialysis (using a high-flux dialyzer) and treated with a 2 g three-times-weekly ceftriaxone regimen were recruited. Plasma samples were serially collected over two dosing intervals and assayed using validated methodology. Population pharmacokinetic analysis and Monte Carlo simulations were performed using Pmetrics in R. The probability of pharmacokinetic/pharmacodynamic target attainment (unbound trough concentrations ≥1 mg/L) and toxicity [trough concentrations (total)  ≥100 mg/L] were simulated for various dosing strategies. RESULTS: Total and unbound concentrations were measured in 122 plasma samples collected from 16 patients (13 female) with median age 57 years. A two-compartment model including protein-binding adequately described the data, with serum bilirubin concentrations associated (inversely) with ceftriaxone clearance. The 2 g three-times-weekly regimen achieved 98% probability to maintain unbound ceftriaxone concentrations ≥1 mg/L for a serum bilirubin of 5 µmol/L. Incremental accumulation of ceftriaxone was observed in those with bilirubin concentrations >5 µmol/L. Three-times-weekly regimens were less probable to achieve toxic exposures compared with once-daily regimens. Ceftriaxone clearance was increased by >10-fold during dialysis. CONCLUSIONS: A novel 2 g three-times-weekly post-dialysis ceftriaxone regimen can be recommended for a bacterial infection with an MIC ≤1 mg/L. A 1 g three-times-weekly post-dialysis regimen is recommended for those with serum bilirubin ≥10 µmol/L. Administration of ceftriaxone during dialysis is not recommended.

Evaluating the use of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the workup of Staphylococcus aureus bacteraemia: a cost-utility analysis.

OBJECTIVES: The use of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with Staphylococcus aureus bacteraemia can improve the diagnosis of infectious foci and guide clinical management. We aimed to evaluate the cost-utility of PET/CT among adults hospitalized with Staphylococcus aureus bacteraemia. METHODS: A cost-utility analysis was conducted from the healthcare payer perspective using a probabilistic Markov cohort model assessing three diagnostic strategies: (a) PET/CT in all patients, (b) PET/CT in high-risk patients only, and (c) routine diagnostic workup. Primary outcomes were quality-adjusted life years (QALYs), costs in Canadian dollars, and an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses were conducted to evaluate parameter uncertainty. RESULTS: Routine workup resulted in an average of 16.64 QALYs from the time of diagnosis at a lifetime cost of $209 060/patient. This was dominated by PET/CT in high-risk patients (i.e. greater effectiveness at lower costs) with average 16.88 QALYs at a cost of $199 552. Compared with PET/CT in high-risk patients only, PET/CT for all patients cost on average $11 960 more but resulted in 0.14 more QALYs, giving an incremental cost-effectiveness ratio of $83 500 (cost per additional QALY gained); however, there was a high degree of uncertainty comparing these two strategies. At a willingness-to-pay threshold of $50 000/QALY, PET/CT in high-risk patients was the most cost-effective strategy in 58.6% of simulations vs. 37.9% for PET/CT in all patients. DISCUSSION: Our findings suggest that a strategy of using PET/CT in high-risk patients is more cost-effective than no PET/CT. Randomized controlled trials should be conducted to evaluate the use of PET/CT in different patient groups.

Influenza-associated hospitalisation and mortality rates among global Indigenous populations; a systematic review and meta-analysis.

BACKGROUND: More than 50 million influenza infections and over 100,000 deaths from influenza occur annually. While Indigenous populations experience an inequitable influenza burden, the magnitude of this inequity has not previously been estimated on a global scale. This study compared rates of influenza-associated hospitalisation and mortality between Indigenous and non-Indigenous populations globally. METHODS: A systematic review and meta-analysis was conducted including literature published prior to 13 July 2021. Eligible articles either reported a rate ratio (RR) comparing laboratory-confirmed influenza-associated hospitalisation and/or mortality between an Indigenous population and a corresponding benchmark population, or reported sufficient information for this to be calculated using publicly available data. Findings were reported by country/region and pooled by country and period (pandemic/seasonal) when multiple studies were available using a random-effects model. The I2 statistic assessed variability between studies. RESULTS: Thirty-six studies (moderate/high quality) were included; all from high or high-middle income countries. The pooled influenza-associated hospitalisation RR (HRR) for indigenous compared to benchmark populations was 5·7 (95% CI: 2·7-12·0) for Canada, 5·2 (2.9-9.3) for New Zealand, and 5.2 (4.2-6.4) for Australia. Of the Australian studies, the pooled HRR for seasonal influenza was 3.1 (2·7-3·5) and for pandemic influenza was 6·2 (5·1-7·5). Heterogeneity was slightly higher among studies of pandemic influenza than seasonal influenza. The pooled mortality RR was 4.1 (3·0-5.7) in Australia and 3·3 (2.7-4.1) in the United States. CONCLUSIONS: Ethnic inequities in severe influenza persist and must be addressed by reducing disparities in the underlying determinants of health. Influenza surveillance systems worldwide should include Indigenous status to determine the extent of the disease burden among Indigenous populations. Ethnic inequities in pandemic influenza illustrate the need to prioritise Indigenous populations in pandemic response plans.

Early oral stepdown antibiotic therapy versus continuing intravenous therapy for uncomplicated Gram-negative bacteraemia (the INVEST trial): study protocol for a multicentre, randomised controlled, open-label, phase III, non-inferiority trial.

BACKGROUND: The incidence of Gram-negative bacteraemia is rising globally and remains a major cause of morbidity and mortality. The majority of patients with Gram-negative bacteraemia initially receive intravenous (IV) antibiotic therapy. However, it remains unclear whether patients can step down to oral antibiotics after appropriate clinical response has been observed without compromising outcomes. Compared with IV therapy, oral therapy eliminates the risk of catheter-associated adverse events, enhances patient quality of life and reduces healthcare costs. As current management of Gram-negative bacteraemia entails a duration of IV therapy with limited evidence to guide oral conversion, we aim to evaluate the clinical efficacy and economic impact of early stepdown to oral antibiotics. METHODS: This is an international, multicentre, randomised controlled, open-label, phase III, non-inferiority trial. To be eligible, adult participants must be clinically stable / non-critically ill inpatients with uncomplicated Gram-negative bacteraemia. Randomisation to the intervention or standard arms will be performed with 1:1 allocation ratio. Participants randomised to the intervention arm (within 72 h from index blood culture collection) will be immediately switched to an oral fluoroquinolone or trimethoprim-sulfamethoxazole. Participants randomised to the standard arm will continue to receive IV therapy for at least 24 h post-randomisation before clinical re-assessment and decision-making by the treating doctor. The recommended treatment duration is 7 days of active antibiotics (including empiric therapy), although treatment regimen may be longer than 7 days if clinically indicated. Primary outcome is 30-day all-cause mortality, and the key secondary outcome is health economic evaluation, including estimation of total healthcare cost as well as assessment of patient quality of life and number of quality-adjusted life years saved. Assuming a 30-day mortality of 8% in the standard and intervention arms, with 6% non-inferiority margin, the target sample size is 720 participants which provides 80% power with a one-sided 0.025 α-level after adjustment for 5% drop-out. DISCUSSION: A finding of non-inferiority in efficacy of oral fluoroquinolones or trimethoprim-sulfamethoxazole versus IV standard of care antibiotics may hypothetically translate to wider adoption of a more cost-effective treatment strategy with better quality of life outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT05199324 . Registered 20 January 2022.

COVID-19 and paediatric health services: A survey of paediatric physicians in Australia and New Zealand.

AIMS: COVID-19 is now a global pandemic. At the time of survey, fewer than 150 children in Australia and New Zealand had documented infection. The aim of this study was to assess attitudes, readiness and confidence in the early stages of the COVID-19 pandemic through an online survey of paediatric physicians and sub-specialists across Australia and New Zealand. METHODS: Multiple email list groups were used to contact paediatric physicians to undertake an online Likert scale survey between 17 and 24 March. Respondents' specialty, experience and work setting were recorded. Ordinal logistic regression was used to determine respondent factors. RESULTS: There were 542 respondents from across Australia and New Zealand: an estimated 11% of the paediatric physician workforce. A minority (36.6%) agreed that their national response had been well coordinated; the majority (92.7%) agreed that senior-level hospital administrators were taking the situation seriously. Most reported a good understanding of the natural history of COVID-19 in children, and knowledge of where to find local information. A large proportion of physicians (86.1%) were worried about becoming infected through their work; few (5.8%) reported that they would not come to work to avoid infection. Closure of school and childcares would reduce the ability to continue work at current capacity for 23.6% of respondents. CONCLUSION: Despite limited experience in pandemics, most paediatric physicians felt informed. Concern about exposure at work is common; most were willing to work regardless. The closure of schools and daycares may have an impact on staffing. Coordination and leadership will be critical.

SToP (See, Treat, Prevent) skin sores and scabies trial: study protocol for a cluster randomised, stepped-wedge trial for skin disease control in remote Western Australia.

INTRODUCTION: Skin is important in Australian Aboriginal culture informing kinship and identity. In many remote Aboriginal communities, scabies and impetigo are very common. Untreated skin infections are painful, itchy and frequently go untreated due to under-recognition and lack of awareness of their potential serious complications. We hypothesise that the skin infection burden in remote Aboriginal communities can be reduced by implementing streamlined training and treatment pathways integrated with environmental health and health promotion activities, tested in the See, Treat, Prevent (SToP skin sores and scabies) trial. METHODS AND ANALYSIS: SToP will evaluate a skin control programme using a stepped-wedge, cluster randomised trial design with three intervention components (the 'SToP activities'): (1) seeing skin infections (development of training resources implemented within a community dermatology model); (2) treating skin infections (employing the latest evidence for impetigo, and scabies treatment); and (3) preventing skin infections (embedded, culturally informed health promotion and environmental health activities). Four community clusters in the remote Kimberley region of Western Australia will participate. Following baseline data collection, two clusters will be randomly allocated to the SToP activities. At 12 months, the remaining two clusters will transition to the SToP activities. The primary outcome is the diagnosis of impetigo in children (5-9 years) at school-based surveillance. Secondary outcome measures include scabies diagnosis, other child health indicators, resistance to cotrimoxazole in circulating pathogenic bacteria, determining the economic burden of skin disease and evaluating the cost effectiveness of SToP activities. ETHICS AND DISSEMINATION: This study protocol was approved by the health ethics review committees at the Child and Adolescent Health Service (Approval number RGS0000000584), the Western Australian Aboriginal Health Ethics Committee (Reference number: 819) and the University of Western Australia (Reference RA/4/20/4123). Study findings will be shared with community members, academic and medical communities via publications and presentations, and in reports to funders. Authorship for all publications based on this study will be determined in line with the Uniform Requirements for Manuscripts Submitted to Biomedical Journals published by the International Committee of Medical Journal Editors. Sharing results with organisations and communities who contributed to the study is paramount. The results of the SToP trial will be shared with participants in a suitable format, such as a single summary page provided to participants or presentations to communities, the Kimberly Aboriginal Health Planning Forum Research Subcommittee and other stakeholders as appropriate and as requested. Communication and dissemination will require ongoing consultation with Aboriginal communities to determine appropriate formats. TRIAL REGISTRATION NUMBER: ACTRN12618000520235.

When Ventricular Cerebrospinal Fluid Assessment Misleads: Basal Meningitis and the Importance of Lumbar Puncture Sampling.

The diagnosis of central nervous system (CNS) infection relies upon analysis of cerebrospinal fluid (CSF). We present 4 cases of CNS infections associated with basal meningitis and hydrocephalus with normal ventricular CSF but grossly abnormal lumbar CSF. We discuss CSF ventricular-lumbar composition gradients and putative pathophysiological mechanisms and highlight clinical clues for clinicians.

Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management.

Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to ß-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.

Impact of ethnicity and socio-economic status on Staphylococcus aureus bacteremia incidence and mortality: a heavy burden in Indigenous Australians.

BACKGROUND: Investigations of the impact of ethnicity and socio-economic status on incidence and outcomes of Staphylococcus aureus bacteraemia are limited. METHODS: We prospectively identified all S. aureus bacteraemia episodes in the Australian New Zealand Cooperative on Outcomes in Staphylococcal Sepsis cohort study between 2007 and 2010. We calculated population level incidence rates using regional postcodes and stratified the analysis by ethnicity, age and socio-economic status indexes. RESULTS: There were 7539 episodes of S. aureus bacteraemia with an annual incidence of 11·2 episodes per 100,000 population. The age-adjusted incidence in the Indigenous population was 62·5 per 100,000 population with an age standardized incidence rate ratio of 5·9 compared to the non-Indigenous population and an incidence rate ratio of 29.2 for community-associated methicillin-resistant S. aureus (MRSA). Populations in the lowest socio-economic status quintile had an increased S. aureus bacteraemia incidence compared to higher quintiles. However, there was a disparity between Indigenous and non-Indigenous populations across all socio-economic status quintiles. The lower 30-day mortality for Indigenous patients (7%) compared to non-Indigenous patients (17%) was explained by differences in age. CONCLUSIONS: Indigenous Australians suffer from a higher rate of S. aureus bacteraemia than non-Indigenous Australians, particularly for community-associated MRSA. Ethnicity and socio-economic status had little impact on subsequent mortality, with other host factors contributing more significantly.

Minim typing--a rapid and low cost MLST based typing tool for Klebsiella pneumoniae.

Here we report a single nucleotide polymorphism (SNP) based genotyping method for Klebsiella pneumoniae utilising high-resolution melting (HRM) analysis of fragments within the multilocus sequence typing (MLST) loci. The approach is termed mini-MLST or Minim typing and it has previously been applied to Streptococcus pyogenes, Staphylococcus aureus and Enterococcus faecium. Six SNPs were derived from concatenated MLST sequences on the basis of maximisation of the Simpsons Index of Diversity (D). DNA fragments incorporating these SNPs and predicted to be suitable for HRM analysis were designed. Using the assumption that HRM alleles are defined by G+C content, Minim typing using six fragments was predicted to provide a D = 0.979 against known STs. The method was tested against 202 K. pneumoniae using a blinded approach in which the MLST analyses were performed after the HRM analyses. The HRM-based alleles were indeed in accordance with G+C content, and the Minim typing identified known STs and flagged new STs. The tonB MLST locus was determined to be very diverse, and the two Minim fragments located herein contribute greatly to the resolving power. However these fragments are refractory to amplification in a minority of isolates. Therefore, we assessed the performance of two additional formats: one using only the four fragments located outside the tonB gene (D = 0.929), and the other using HRM data from these four fragments in conjunction with sequencing of the tonB MLST fragment (D = 0.995). The HRM assays were developed on the Rotorgene 6000, and the method was shown to also be robust on the LightCycler 480, allowing a 384-well high through-put format. The assay provides rapid, robust and low-cost typing with fully portable results that can directly be related to current MLST data. Minim typing in combination with molecular screening for antibiotic resistance markers can be a powerful surveillance tool kit.