Coverage gaps in empiric antibiotic regimens used to treat serious bacterial infections in neonates and children in Southeast Asia and the Pacific.

Background: High levels of antimicrobial resistance (AMR) are propagating deaths due to neonatal and paediatric infections globally. This is of particular concern in Southeast Asia and the Pacific, where healthcare resources are constrained and access to newer agents to treat multidrug-resistant pathogens is limited. Methods: To assess the coverage provided by commonly prescribed empiric antibiotic regimens for children in low- and middle-income countries in Southeast Asia and the Pacific, we built a weighted incidence syndromic combination antibiogram (WISCA), parameterised using data obtained from a systematic review of published literature incorporating WHO-defined SEARO and WPRO regions in Ovid MEDLINE, EMBASE, Global Health and PubMed. Susceptibility data for bacterial pathogens were extracted to provide coverage estimates for pre-specified antibiotics (aminopenicillins, gentamicin, third-generation cephalosporins and carbapenems), reported at the regional level. Findings: 6648 bacterial isolates from 11 countries across 86 papers were included in the Bayesian WISCA model, which weighted bacterial incidence and antimicrobial susceptibility of relevant isolates. Coverage provided by aminopenicillins in neonatal sepsis/meningitis was 26% (80% credible interval: 16-49) whilst gentamicin coverage was 45% (29-62). Third-generation cephalosporin coverage was only 29% (16-49) in neonatal sepsis/meningitis, 51% (38-64) in paediatric sepsis and 65% (51-77) in paediatric meningitis. Carbapenems were estimated to provide the highest coverage: 81% (65-90) in neonatal sepsis/meningitis, 83% (72-90) in paediatric sepsis and 79% (62-91) in paediatric meningitis. Interpretation: These findings reveal alarmingly high rates of resistance to commonly prescribed empirical therapies for neonatal and paediatric sepsis and meningitis in the Asia-Pacific region. Funding: This research was funded in whole, or in part, by the Wellcome Trust [220211]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. PCMW is supported by a National Health and Medical Research Council (NHMRC) Investigator Grant. NHMRC had no involvement in the design or conduct of the research.

Pragmatic Adaptive Trial for Respiratory Infection in Children (PATRIC) Clinical Registry protocol.

INTRODUCTION: Acute respiratory infections (ARI) are the most common cause of paediatric hospitalisation. There is an urgent need to address ongoing critical knowledge gaps in ARI management. The Pragmatic Adaptive Trial for Respiratory Infections in Children (PATRIC) Clinical Registry will evaluate current treatments and outcomes for ARI in a variety of paediatric patient groups. The registry will provide a platform and data to inform a number of PATRIC clinical trials, testing various interventions in ARI treatment and management to optimise paediatric ARI care. METHODS AND ANALYSIS: The PATRIC Clinical Registry is a single-centre, prospective observational registry recruiting from a tertiary paediatric Emergency Department in Western Australia. Through characterising demographic, clinical, treatment and outcome data, the PATRIC Clinical Registry will improve our understanding of antibiotic utilisation and ARI outcomes in children. ETHICS AND DISSEMINATION: The PATRIC Clinical Registry is conducted in accordance with the Declaration of Helsinki, and the International Council for Harmonisation (ICH) Guidelines for Good Clinical Practice (CPMP/ICH/13595) July 1996. Approval is provided by the Child and Adolescent Health Service Human Research Ethics Committee (HREC). Study results will be communicated by presentation and publication (HREC: RGS0000003078.) TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12619000903189. UTN: U1111-1231-3365.

Transparent reporting of adaptive clinical trials using concurrently randomised cohorts.

Adaptive clinical trials have designs that evolve over time because of changes to treatments or changes to the chance that participants will receive these treatments. These changes might introduce confounding that biases crude comparisons of the treatment arms and makes the results from standard reporting methods difficult to interpret for adaptive trials. To deal with this shortcoming, a reporting framework for adaptive trials was developed based on concurrently randomised cohort reporting. A concurrently randomised cohort is a subgroup of participants who all had the same treatments available and the same chance of receiving these treatments. The reporting of pre-randomisation characteristics and post-randomisation outcomes for each concurrently randomised cohort in the study is recommended. This approach provides a transparent and unbiased display of the degree of baseline balance and the randomised treatment comparisons for adaptive trials. The key concepts, terminology, and recommendations underlying concurrently randomised cohort reporting are presented, and its routine use in adaptive trial reporting is advocated.

FeBRILe3: Safety Evaluation of Febrile Infant Guidelines Through Prospective Bayesian Monitoring.

OBJECTIVES: Despite evidence supporting earlier discharge of well-appearing febrile infants at low risk of serious bacterial infection (SBI), admissions for ≥48 hours remain common. Prospective safety monitoring may support broader guideline implementation. METHODS: A sequential Bayesian safety monitoring framework was used to evaluate a new hospital guideline recommending early discharge of low-risk infants. Hospital readmissions within 7 days of discharge were regularly assessed against safety thresholds, derived from historic rates and expert opinion, and specified a priori (8 per 100 infants). Infants aged under 3 months admitted to 2 Western Australian metropolitan hospitals for management of fever without source were enrolled (August 2019-December 2021), to a prespecified maximum 500 enrolments. RESULTS: Readmission rates remained below the prespecified threshold at all scheduled analyses. Median corrected age was 34 days, and 14% met low-risk criteria (n = 71). SBI was diagnosed in 159 infants (32%), including urinary tract infection (n = 140) and bacteraemia (n = 18). Discharge occurred before 48 hours for 192 infants (38%), including 52% deemed low-risk. At study completion, 1 of 37 low-risk infants discharged before 48 hours had been readmitted (3%), for issues unrelated to SBI diagnosis. In total, 20 readmissions were identified (4 per 100 infants; 95% credible interval 3, 6), with >0.99 posterior probability of being below the prespecified noninferiority threshold, indicating acceptable safety. CONCLUSIONS: A Bayesian monitoring approach supported safe early discharge for many infants, without increased risk of readmission. This framework may be used to embed safety evaluations within future guideline implementation programs to further reduce low-value care.

Histo-blood group antigen profile of Australian Aboriginal children and seropositivity following oral rotavirus vaccination.

BACKGROUND: Histo-blood group antigens (HBGAs) may influence immune responses to rotavirus vaccination. METHODS: HBGA phenotyping was determined by detection of antigens A, B, H and Lewis a and b in saliva using enzyme-linked immunosorbent assay. Secretor status was confirmed by lectin antigen assay if A, B and H antigens were negative or borderline (OD ± 0.1 of threshold of detection). PCR-RFLP analysis was used to identify the FUT2 'G428A' mutation in a subset. Rotavirus seropositivity was defined as serum anti-rotavirus IgA ≥ 20 AU/mL. RESULTS: Of 156 children, 119 (76 %) were secretors, 129 (83 %) were Lewis antigen positive, and 105 (67 %) were rotavirus IgA seropositive. Eighty-seven of 119 (73 %) secretors were rotavirus seropositive, versus 4/9 (44 %) weak secretors and 13/27 (48 %) non-secretors. CONCLUSIONS: Most Australian Aboriginal children were secretor and Lewis antigen positive. Non-secretor children were less likely to be seropositive to rotavirus antibodies following vaccination, but this phenotype was less common. HBGA status is unlikely to fully explain underperformance of rotavirus vaccines among Australian Aboriginal children.

Modeling COVID-19 disease processes by remote elicitation of causal Bayesian networks from medical experts.

BACKGROUND: COVID-19 is a new multi-organ disease causing considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain opaque. Better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have described its pathophysiology. METHODS: In early 2020, we began developing such causal models. The SARS-CoV-2 virus's rapid and extensive spread made this particularly difficult: no large patient datasets were publicly available; the medical literature was flooded with sometimes conflicting pre-review reports; and clinicians in many countries had little time for academic consultations. We used Bayesian network (BN) models, which provide powerful calculation tools and directed acyclic graphs (DAGs) as comprehensible causal maps. Hence, they can incorporate both expert opinion and numerical data, and produce explainable, updatable results. To obtain the DAGs, we used extensive expert elicitation (exploiting Australia's exceptionally low COVID-19 burden) in structured online sessions. Groups of clinical and other specialists were enlisted to filter, interpret and discuss the literature and develop a current consensus. We encouraged inclusion of theoretically salient latent (unobservable) variables, likely mechanisms by extrapolation from other diseases, and documented supporting literature while noting controversies. Our method was iterative and incremental: systematically refining and validating the group output using one-on-one follow-up meetings with original and new experts. 35 experts contributed 126 hours face-to-face, and could review our products. RESULTS: We present two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology. CONCLUSIONS: Our method demonstrates an improved procedure for developing BNs via expert elicitation, which other teams can implement to model emergent complex phenomena. Our results have three anticipated applications: (i) freely disseminating updatable expert knowledge; (ii) guiding design and analysis of observational and clinical studies; (iii) developing and validating automated tools for causal reasoning and decision support. We are developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.

Predicting the causative pathogen among children with pneumonia using a causal Bayesian network.

BACKGROUND: Pneumonia remains a leading cause of hospitalization and death among young children worldwide, and the diagnostic challenge of differentiating bacterial from non-bacterial pneumonia is the main driver of antibiotic use for treating pneumonia in children. Causal Bayesian networks (BNs) serve as powerful tools for this problem as they provide clear maps of probabilistic relationships between variables and produce results in an explainable way by incorporating both domain expert knowledge and numerical data. METHODS: We used domain expert knowledge and data in combination and iteratively, to construct, parameterise and validate a causal BN to predict causative pathogens for childhood pneumonia. Expert knowledge elicitation occurred through a series of group workshops, surveys and one-on-one meetings involving 6-8 experts from diverse domain areas. The model performance was evaluated based on both quantitative metrics and qualitative expert validation. Sensitivity analyses were conducted to investigate how the target output is influenced by varying key assumptions of a particularly high degree of uncertainty around data or domain expert knowledge. RESULTS: Designed to apply to a cohort of children with X-ray confirmed pneumonia who presented to a tertiary paediatric hospital in Australia, the resulting BN offers explainable and quantitative predictions on a range of variables of interest, including the diagnosis of bacterial pneumonia, detection of respiratory pathogens in the nasopharynx, and the clinical phenotype of a pneumonia episode. Satisfactory numeric performance has been achieved including an area under the receiver operating characteristic curve of 0.8 in predicting clinically-confirmed bacterial pneumonia with sensitivity 88% and specificity 66% given certain input scenarios (i.e., information that is available and entered into the model) and trade-off preferences (i.e., relative weightings of the consequences of false positive versus false negative predictions). We specifically highlight that a desirable model output threshold for practical use is very dependent upon different input scenarios and trade-off preferences. Three commonly encountered scenarios were presented to demonstrate the potential usefulness of the BN outputs in various clinical pictures. CONCLUSIONS: To our knowledge, this is the first causal model developed to help determine the causative pathogen for paediatric pneumonia. We have shown how the method works and how it would help decision making on the use of antibiotics, providing insight into how computational model predictions may be translated to actionable decisions in practice. We discussed key next steps including external validation, adaptation and implementation. Our model framework and the methodological approach can be adapted beyond our context to broad respiratory infections and geographical and healthcare settings.

The AuTOMATIC trial: a study protocol for a multi-arm Bayesian adaptive randomised controlled trial of text messaging to improve childhood immunisation coverage.

BACKGROUND: While most Australian children are vaccinated, delays in vaccination can put them at risk from preventable infections. Widespread mobile phone ownership in Australia could allow automated short message service (SMS) reminders to be used as a low-cost strategy to effectively 'nudge' parents towards vaccinating their children on time. METHODS: AuTOMATIC is an adaptive randomised trial which aims to both evaluate and optimise the use of SMS reminders for improving the timely vaccination of children at primary care clinics across Australia. The trial will utilise high levels of digital automation to effect, including eligibility assessment, randomisation, delivery of intervention, data extraction and analysis, thereby allowing healthcare-embedded trial delivery. Up to 10,000 parents attending participating primary care clinics will be randomised to one of 12 different active SMS vaccine reminder content and timing arms or usual practice only (no SMS reminder). The primary outcome is vaccine receipt within 28 days of the scheduled date for the index vaccine (the first scheduled vaccine after randomisation). Secondary analyses will assess receipt and timeliness for all vaccine occasions in all children. Regular scheduled analyses will be performed using Bayesian inference and pre-specified trial decision rules, enabling response adaptive randomisation, suspension of any poorly performing arms and early stopping if a single best message is identified. DISCUSSION: This study will aim to optimise SMS reminders for childhood vaccination in primary care clinics, directly comparing alternative message framing and message timing. We anticipate that the trial will be an exemplar in using Bayesian adaptive methodology to assess a readily implementable strategy in a wide population, capable of delivery due to the levels of digital automation. Methods and findings from this study will help to inform strategies for implementing reminders and embedding analytics in primary health care settings. TRIAL REGISTRATION: ANZCTR: ACTRN12618000789268 .

Review of the health impact of the oral rotavirus vaccine program in children under 5 years in Australia: 2006 - 2021.

Oral rotavirus vaccines were incorporated into the National Immunisation Program (NIP) for all Australian infants in July 2007. Initially each of the eight jurisdictions implemented Rotarix or RotaTeq rotavirus vaccine, however from July 2017 all states and territories have administered Rotarix only. This review evaluates the health impact of the oral rotavirus vaccine program for Australian children less than 5 years old over the first 15 years of the rotavirus vaccine program, observing long-term changes in rotavirus-related health care attendances, public health notifications, and vaccine effectiveness and safety data for both Rotarix and RotaTeq rotavirus vaccines. We searched Medline for studies published between January 2006 and May 2022 using the search terms 'rotavirus', 'rotavirus vaccine' and 'Australia'. Of 491 items identified, 76 items - 36 peer-reviewed articles and 40 reports - were included in the review. We found evidence that the introduction of the oral rotavirus vaccine program in Australia was associated with a prompt reduction in rotavirus-coded and all-cause gastroenteritis hospitalisations of vaccine-eligible children. In the context of less complete coverage, reduced vaccine timeliness and lower vaccine effectiveness, a less substantial and inconsistent reduction in severe rotavirus disease was observed among Aboriginal and Torres Strait Islander children, particularly those living in rural and remote northern Australia. Additional studies report no evidence for the emergence of non-vaccine serotypes and/ or replacement serotypes in Australia during the vaccine era. While the health impact for young children and consequent cost-savings of the oral rotavirus vaccine program have been high, it is important to find strategies to improve rotavirus vaccine impact for Aboriginal and Torres Strait Islander populations to ensure health benefits for all Australian children.

Systematic review of the effect of additional doses of oral rotavirus vaccine on immunogenicity and reduction in diarrhoeal disease among young children.

Background: Oral rotavirus vaccines have lower effectiveness in high child mortality settings. We evaluated the impact of additional dose(s) schedules of rotavirus vaccine on vaccine immunogenicity and reduction in episodes of gastroenteritis. Methods: We searched Medline (via PubMed), Cochrane databases and ClinicalTrials.gov for randomised controlled trials from 1973 to February 2022, evaluating the immunological and clinical impact of additional dose vs standard dose oral rotavirus vaccine schedules. We extracted immunogenicity - proportion of children with evidence of anti-rotavirus IgA seroresponse, and clinical - proportion of children with at least one episode of severe rotavirus gastroenteritis, outcome data and used random effects meta-analysis where appropriate. We assessed the methodological quality of the studies using the Cochrane risk of bias tool. The study protocol was registered in PROSPERO (CRD42021261058). Findings: We screened 536 items and included 7 clinical trials. Our results suggest moderate to high level evidence that an additional dose rotavirus vaccine schedule improves IgA vaccine immune response, including additional doses administered as a booster dose schedule >6 months old; IgA vaccine seroresponse 74·3% additional dose schedule vs 56·1% standard dose schedule RR 1·3 (95%CI, 1·15 - 1·48), and when administered to children who were seronegative at baseline; IgA vaccine seroresponse 48.2% additional dose schedule vs 29.6% standard dose schedule RR 1.86 (95%CI 1.27 to 2.72). Only one study evaluated reduction in gastroenteritis episodes and found little benefit in first year of life, 1·8% vs 2·0% RR 0·88 (95% CI, 0·52 to 1·48), or second year of life, 1·7% vs 2·9% RR 0·62 (95%CI, 0·31 - 1·23). Interpretation: Administering an additional dose of oral rotavirus vaccines is likely to result in an improved vaccine immune response, including when administered as a booster dose to older children. Evidence of an impact on diarrhoeal disease is needed before additional dose rotavirus vaccine schedules can be recommended as vaccine policy. Funding: BM was funded by the National Health and Medical Research Council, the Royal Australasian College of Physicians Paediatrics and Child Health Division, and the Australian Academy of Science.

Protocol for establishing a core outcome set for evaluation in studies of pulmonary exacerbations in people with cystic fibrosis.

INTRODUCTION: Pulmonary exacerbations are associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no consensus about which outcomes should be evaluated in studies of pulmonary exacerbations or how these outcomes should be measured. Outcomes of importance to people with lived experience of the disease are frequently omitted or inconsistently reported in studies, which limits the value of such studies for informing practice and policy. To better standardise outcome reporting and measurement, we aim to develop a core outcome set for studies of pulmonary exacerbations in people with CF (COS-PEX) and consensus recommendations for measurement of core outcomes. METHODS AND ANALYSIS: Preliminary work for development of COS-PEX has been reported, including (1) systematic reviews of outcomes and methods for measurement reported in existing studies of pulmonary exacerbations; (2) workshops with people affected by CF within Australia; and (3) a Bayesian knowledge expert elicitation workshop with health professionals to ascertain outcomes of importance. Here we describe a protocol for the additional stages required for COS-PEX development and consensus methods for measurement of core outcomes. These include (1) an international two-round online Delphi survey and (2) consensus workshops to review and endorse the proposed COS-PEX and to agree with methods for measurement. ETHICS AND DISSEMINATION: National mutual ethics scheme approval has been provided by the Child and Adolescent Health Service Human Research Ethics Committee (RGS 4926). Results will be disseminated via consumer and research networks and peer-reviewed publications. This study is registered with the Core Outcome Measures in Effectiveness Trials database.

Urinary tract infections in children: building a causal model-based decision support tool for diagnosis with domain knowledge and prospective data.

BACKGROUND: Diagnosing urinary tract infections (UTIs) in children in the emergency department (ED) is challenging due to the variable clinical presentations and difficulties in obtaining a urine sample free from contamination. Clinicians need to weigh a range of observations to make timely diagnostic and management decisions, a difficult task to achieve without support due to the complex interactions among relevant factors. Directed acyclic graphs (DAG) and causal Bayesian networks (BN) offer a way to explicitly outline the underlying disease, contamination and diagnostic processes, and to further make quantitative inference on the event of interest thus serving as a tool for decision support. METHODS: We prospectively collected data on children present to ED with suspected UTIs. Through knowledge elicitation workshops and one-on-one meetings, a DAG was co-developed with clinical domain experts (the Expert DAG) to describe the causal relationships among variables relevant to paediatric UTIs. The Expert DAG was combined with prospective data and further domain knowledge to inform the development of an application-oriented BN (the Applied BN), designed to support the diagnosis of UTI. We assessed the performance of the Applied BN using quantitative and qualitative methods. RESULTS: We summarised patient background, clinical and laboratory characteristics of 431 episodes of suspected UTIs enrolled from May 2019 to November 2020. The Expert DAG was presented with a narrative description, elucidating how infection, specimen contamination and management pathways causally interact to form the complex picture of paediatric UTIs. Parameterised using prospective data and expert-elicited parameters, the Applied BN achieved an excellent and stable performance in predicting Escherichia coli culture results, with a mean area under the receiver operating characteristic curve of 0.86 and a mean log loss of 0.48 based on 10-fold cross-validation. The BN predictions were reviewed via a validation workshop, and we illustrate how they can be presented for decision support using three hypothetical clinical scenarios. CONCLUSION: Causal BNs created from both expert knowledge and data can integrate case-specific information to provide individual decision support during the diagnosis of paediatric UTIs in ED. The model aids the interpretation of culture results and the diagnosis of UTIs, promising the prospect of improved patient care and judicious use of antibiotics.

The short term safety of COVID-19 vaccines in Australia: AusVaxSafety active surveillance, February - August 2021.

OBJECTIVE: To assess the short term safety of the COVID-19 vaccines Comirnaty (Pfizer-BioNTech BNT162b2) and Vaxzevria (AstraZeneca ChAdOx1) in Australia. DESIGN: Prospective observational cohort study; online surveys by AusVaxSafety, a national active vaccine safety surveillance system, three and eight days after vaccination. SETTING, PARTICIPANTS: People aged 16 years or more who received COVID-19 vaccines at sentinel vaccination hubs, general practices, or Aboriginal Community Controlled Health Organisation clinics, 22 February - 30 August 2021. MAIN OUTCOME MEASURES: Primary outcome: proportion of respondents who reported any adverse event following immunisation (AEFI) 0-3 days after vaccination. SECONDARY OUTCOMES: proportions of respondents who reported specific adverse events or medical review for AEFI within seven days of vaccination; impact on usual daily activities; recovery. RESULTS: 4 851 480 people received COVID-19 vaccines at participating sentinel sites during the study period (25% of all COVID-19 vaccine doses administered in Australia to 30 August 2021). 3 035 983 people responded to both surveys (response rate, 62.6%); 35.9% of respondents reported one or more AEFI 0-3 days after Comirnaty dose 1, 54.7% after Comirnaty dose 2, 52.8% after Vaxzevria dose 1, and 22.0% after Vaxzevria dose 2. Local pain, fatigue, headache, and myalgia were the most frequently reported symptoms. After adjusting for demographic characteristics, vaccination site type, jurisdiction, and self-reported medical conditions, the odds of reporting any AEFI were higher for women than men (range of adjusted odd ratios [aORs], by vaccine and dose, 1.53-1.84), for people with a history of anaphylaxis (aOR range, 1.28-1.45), and for people reporting certain underlying conditions, including obesity (aOR range, 1.15-1.75), immunodeficiency (aOR range, 1.04-2.24), or chronic inflammatory disease (aOR range, 1.05-1.75). 0.9% of respondents sought medical advice in the three days following vaccination, most frequently after Comirnaty dose 2 (1.4%) and Vaxzevria dose 1 (1.2%). CONCLUSION: AusVaxSafety active surveillance affirms the short term safety profile of Comirnaty and Vaxzevria vaccines in a large population sample during the first six months of the Australian COVID-19 vaccination program.

Prevalence of respiratory viruses in community-acquired pneumonia in children: a systematic review and meta-analysis.

BACKGROUND: Respiratory viruses are increasingly detected in children with community-acquired pneumonia but prevalence estimates vary substantially. We aimed to systematically review and pool estimates for 22 viruses commonly associated with community-acquired pneumonia. METHODS: We conducted a systematic review and meta-analysis to determine the prevalence of each of the common respiratory viruses detected by any diagnostic method in children aged up to 18 years with community-acquired pneumonia. We searched MEDLINE, PubMed, Embase, Web of Science, and Scopus databases with no language restrictions for relevant published articles and reports published between Jan 1, 1995, and Dec 31, 2019, restricting the review to pre-COVID-19 pandemic years. Three independent reviewers screened articles and extracted data using a predefined protocol. We calculated the pooled prevalence for each virus in childhood pneumonia using DerSimonian-Laird random-effects models. We assessed bias using the Newcastle-Ottawa Scale. The review protocol was registered in PROSPERO (CRD42016034047). FINDINGS: We identified 186 eligible articles that represented 152 209 children up to age 18 years with community-acquired pneumonia. One or more respiratory viruses were detected in 55·0% (95% CI 50·4-59·7) of paediatric patients with a diagnosis of community-acquired pneumonia; heterogeneity was high (I2=99·4%). Respiratory syncytial virus (22·7%, 20·9-24·5) and rhinovirus (22·1%, 19·5-24·7) were the most commonly detected causes of paediatric pneumonia globally, with other viruses detected in 1-9% of cases. There was non-significant variation in prevalence by the country's national income, under-5 mortality rate, or WHO region. INTERPRETATION: Respiratory viruses are frequently detected in community-acquired pneumonia among children of all ages and geographical regions, with non-significant variation by country's national income or region. Further strategies to limit antibiotic use in children with viral pneumonia and develop treatment and prevention approaches targeting common respiratory viruses are expected to have a substantial effect on the residual burden of childhood pneumonia. FUNDING: None.

Immunogenicity of a Third Scheduled Dose of Rotarix in Australian Indigenous Infants: A Phase IV, Double-blind, Randomized, Placebo-Controlled Clinical Trial.

BACKGROUND: Rotarix (GlaxoSmithKline) oral rotavirus vaccine is licensed as 2 doses in the first 6 months of life. In settings with high child mortality rates, clinical protection conferred by 2 doses of Rotarix is reduced. We assessed vaccine immune response when an additional dose of Rotarix was given to Australian Aboriginal children 6 to <12 months old. METHODS: ORVAC is a 2-stage, double-blind, randomized, placebo-controlled trial. Australian Aboriginal children 6 to <12 months old who had received 1 or 2 prior doses of Rotarix rotavirus vaccine were randomized 1:1 to receive an additional dose of Rotarix or matched placebo. The primary immunological end point was seroresponse defined as an anti-rotavirus immunoglobulin A level ≥20 AU/mL, 28-56 days after the additional dose of Rotarix or placebo. RESULTS: Between March 2018 and August 2020, a total of 253 infants were enrolled. Of these, 178 infants (70%) had analyzable serological results after follow-up; 89 were randomized to receive Rotarix, and 89 to receive placebo. The proportion with seroresponse was 85% after Rotarix compared with 72% after placebo. There were no occurrences of intussusception or any serious adverse events. CONCLUSIONS: An additional dose of Rotarix administered to Australian Aboriginal infants 6 to <12 months old increased the proportion with a vaccine seroresponse. CLINICAL TRIALS REGISTRATION: NCT02941107.

Statistical analysis plan for the OPTIMUM study: optimising immunisation using mixed schedules, an adaptive randomised controlled trial of a mixed whole-cell/acellular pertussis vaccine schedule.

OBJECTIVE: The purpose of this double-blind, randomised, controlled trial is to compare allergic outcomes in children following vaccination with acellular pertussis (aP) antigen (standard of care in Australia) given at 2 months of age versus whole cell pertussis (wP) in the infant vaccine schedule. PARTICIPANTS: Up to 3000 Australian infants 6 to <12 weeks of age born ≥32 weeks gestation. INTERVENTIONS: The intervention is a wP containing vaccine as the first scheduled pertussis vaccine dose instead of an aP containing vaccine. OUTCOMES: The primary outcome is a binary indicator of history of IgE-mediated food allergy at the age of 12 months confirmed, where necessary, with an oral food challenge before 18 months of age. Secondary outcomes include (1) history of parent-reported clinician-diagnosed new onset of atopic dermatitis by 6 or 12 months of age with a positive skin prick test to any allergen before 12 months of age, (2) geometric mean concentration in pertussis toxin-specific IgG before and 21 to 35 days after a booster dose of aP at 18 months of age, and (3) sensitisation to at least one allergen by 12 months of age. RESULTS: Operating characteristics of trial decision rules were evaluated by trial simulation. The selected rules for success and futility approximately maintain type I error of 0.05 and achieved power 0.85 for a reduction in the primary outcome from 10% in the control group to 7% in the intervention group. DISCUSSION: A detailed, prospective statistical analysis plan (SAP) is presented for this Bayesian adaptive design. The plan was written by the trial statistician and details the study design, pre-specified adaptive elements, decision thresholds, statistical methods, and the simulations used to evaluate the operating characteristics of the trial. Application of this SAP will minimise bias and supports transparent and reproducible research. TRIAL REGISTRATION: Australia & New Zealand Clinical Trials Registry, ACTRN12617000065392 . Registered on 12 January 2017 STUDY PROTOCOL: https://doi.org/10.1136/bmjopen-2020-042838.

Preferred health outcome states following treatment for pulmonary exacerbations of cystic fibrosis.

BACKGROUND: Treatment for pulmonary exacerbations of cystic fibrosis (CF) can produce a range of positive and negative outcomes. Understanding which of these outcomes are achievable and desirable to people affected by disease is critical to agreeing to goals of therapy and determining endpoints for trials. The relative importance of outcomes resulting from treatment of these episodes are not reported. We aimed to (i) quantify the relative importance of outcomes resulting from treatment for pulmonary exacerbations and (ii) develop patient and proxy carer-reported weighted outcome measures for use in adults and children, respectively. METHODS: A discrete choice experiment (DCE) survey was conducted. Participants were asked to make a series of hypothetical decisions about treatment for pulmonary exacerbations to assess how they make trade-offs between different attributes of health. Data were analysed using a conditional logistic regression model. The correlation coefficients from these data were rescaled to enable generation of a composite health outcome score between 0 and 100 (worst to best health state). RESULTS: 362 individuals participated (167 people with CF and 195 carers); of these, 206 completed the survey (56.9%). Most participants were female and resided in Australia. Difficult/painful breathing had the greatest impact on the preferred health state amongst people with CF and carers alike. Avoidance of gastrointestinal problems also heavily influenced decision-making. CONCLUSIONS: These data should be considered when making treatment decisions and determining endpoints for trials. Further research is recommended to quantify the preferences of children and to determine whether these align with those of their carer(s).

Standardised treatment and monitoring protocol to assess safety and tolerability of bacteriophage therapy for adult and paediatric patients (STAMP study): protocol for an open-label, single-arm trial.

INTRODUCTION: There has been renewed interest in the therapeutic use of bacteriophages (phages); however, standardised therapeutic protocols are lacking, and there is a paucity of rigorous clinical trial data assessing efficacy. METHODS AND ANALYSIS: We propose an open-label, single-arm trial investigating a standardised treatment and monitoring protocol for phage therapy. Patients included will have exhausted other therapeutic options for control of their infection and phage therapy will be administered under Australia's Therapeutic Goods Administration Special Access Scheme. A phage product with high in vitro activity against the targeted pathogen(s) must be available in line with relevant regulatory requirements. We aim to recruit 50-100 patients over 5 years, from any public or private hospitals in Australia. The standardised protocol will specify clinical assessments and biological sampling at scheduled time points. The primary outcome is safety at day 29, assessed by the frequency of adverse events, and overseen by an independent Data Safety Monitoring Board. Secondary outcomes include long-term safety (frequency of adverse events until at least 6 months following phage therapy), and feasibility, measured as the proportion of participants with>80% of minimum data available for analysis. Additional endpoints assessed include clinical response, patient/guardian reported quality of life measures, phage pharmacokinetics, human host immune responses and microbiome analysis. All trial outcomes will be summarised and presented using standard descriptive statistics. ETHICS AND DISSEMINATION: Participant inclusion will be dependent on obtaining written informed consent from the patient or guardian. The trial protocol was approved by the Sydney Children's Hospitals Network Human Research Ethics Committee in December 2021 (Reference 2021/ETH11861). In addition to publication in a peer-reviewed scientific journal, a lay summary of study outcomes will be made available for participants and the public on the Phage Australia website (https://www.phageaustralia.org/). TRIAL REGISTRATION NUMBER: Registered on ANZCTR, 10 November 2021 (ACTRN12621001526864; WHO Universal Trial Number: U1111-1269-6000).

Study protocol for controlled human infection for penicillin G against Streptococcus pyogenes: a double-blinded, placebo-controlled, randomised trial to determine the minimum concentration required to prevent experimental pharyngitis (the CHIPS trial).

INTRODUCTION: Regular intramuscular benzathine penicillin G injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. As the pharmacological correlate of protection remains unknown, it is difficult to recommend changes to this established regimen. Determining the minimum effective penicillin exposure required to prevent Streptococcus pyogenes infection will accelerate development of new long-acting penicillins for RHD prevention as well as inform opportunities to improve existing regimens. The CHIPS trial will address this knowledge gap by directly testing protection afforded by different steady state plasma concentrations of penicillin in an established model of experimental human S. pyogenes pharyngitis. METHODS AND ANALYSIS: This is a double-blinded, placebo-controlled, randomised experimental human infection study. Sixty healthy adult volunteers aged 18-40 years will be recruited and randomised 1:1:1:1:1 to continuous intravenous penicillin infusions targeting five different steady state plasma concentrations of 0 (placebo), 3, 6, 12 and 20 ng/mL via a midline catheter. Each participant's penicillin pharmacokinetic parameters will be established prior to the challenge, to ensure accurate dosing for the continuous infusion. Following the challenge with a well-characterised strain of S. pyogenes, participants will be observed for up to 6 days for the development of pharyngitis and treated with antibiotics prior to discharge. The primary objective is to determine the minimum effective steady-state plasma penicillin concentration required to prevent experimental pharyngitis. Secondary objectives will explore systemic and mucosal immunoinflammatory responses during pharyngitis, bacterial colonisation dynamics, environmental contamination and qualitative evaluation of the participant experience. ETHICS AND DISSEMINATION: Ethical approval has been obtained (Bellberry Human Research Ethics Committee). Findings will be reported in peer-reviewed publications and presented at national/international stakeholder forums. TRIAL REGISTRATION NUMBER: ACTRN12621000751875.