Ivermectin-Based Mass Drug Administration for Scabies in Northern India: A Single-Arm Community Intervention Trial.

Background: Scabies and impetigo cause direct health effects and contribute to severe infectious and immune-mediated complications. Ivermectin-based mass drug administration can reduce scabies and impetigo prevalence in island settings with high prevalence, but the effectiveness in moderate-prevalence settings is not known. Methods: We conducted a single-arm, before-after community intervention trial. Mass drug administration was offered to the entire population of 4 villages in Uttarakhand, India. The treatment consisted of 2 doses, given 7 days apart, of oral ivermectin (∼200 µg/kg), or topical 5% permethrin if ivermectin was contraindicated. The primary outcome was the prevalence of scabies at 12 months compared with baseline, as diagnosed using clinical assessment and the 2020 International Alliance for the Control of Scabies criteria. Secondary outcomes included the prevalence of impetigo at each time point. The trial was registered with the Australian and New Zealand Trials Registry (ACTRN12619001712190). Results: In January 2020, 1211 participants were enrolled (100% of the estimated village population). Treatment coverage was high-1204 (99.4%) and 1177 (97.2%) received 1 and 2 doses, respectively. Scabies was diagnosed in 91 participants (7.5%) and impetigo in 15 (1.2%). In February 2021, 1190 (98.3% of baseline) participants re-enrolled, and of these 11 had scabies (0.9%; relative risk reduction, 87.7%; 95% CI, 77.1%-93.4%) and 5 had impetigo (0.4%; relative risk reduction, 66.1%; 95% CI, 7.0%-87.6%). Conclusions: A single round of ivermectin-based mass drug administration substantially reduced the prevalence of scabies and impetigo in this setting with moderate scabies prevalence in northern India.

NEARER SCAN (LENO BESIK) evaluation of a task-sharing echocardiographic active case finding programme for rheumatic heart disease in Australia and Timor-Leste: protocol for a hybrid type II effectiveness-implementation study.

INTRODUCTION: Rheumatic heart disease (RHD) is underdiagnosed globally resulting in missed treatment opportunities and adverse clinical outcomes. We describe the protocol for a study which aims to co-design, implement and conduct an evaluation of a task-sharing approach to echocardiographic active case finding for early detection and management of RHD in high-risk settings in Australia and Timor-Leste. METHODS AND ANALYSIS: Echocardiograms will be obtained by trained local staff using hand-held echocardiographic devices employing the 'Single Parasternal Long Axis view with a Sweep of the Heart' (SPLASH) technique and interpreted by experts remote from the site of acquisition. Approximately 1500 children and pregnant women will be screened across high-risk communities in Australia and Timor-Leste over an 18-month period. The study will use a type II effectiveness-implementation hybrid design. A tailored package of implementation strategies will be co-designed with communities and health services and mapped onto a Theory of Change framework. The clinical effectiveness will be assessed as the change in the proportion of the target population that are prescribed secondary prophylaxis for RHD by the end of the study compared with baseline. The implementation will be assessed as the adoption, penetration, sustainability, fidelity and cost of the programme with a mixed-methods theory-based and economic evaluation. Data will include numbers of normal, abnormal and uninterpretable SPLASH echocardiograms obtained, numbers of participants progressing through the cascade of care, interviews with staff and programme costs. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Human Research Ethics Committee of the NT Department of Health and Menzies School of Health Research, Darwin (HREC-2022-4479), the Western Australian Aboriginal Health Ethics Committee (HREC-1237) and the Instituto Nasional Saude Publika Timor-Leste Ethics and Technical Committee (03-UEPD/INSP-TL/V/2023). Informed consent is required to be enrolled. Study findings will be disseminated in the communities involved and submitted for publication. TRIAL REGISTRATION NUMBER: NCT06002243.

Systematic review of the evidence for treatment and management of common skin conditions in resource-limited settings: An update.

INTRODUCTION: The skin is the largest and most visible organ of the human body. As such, skin infections can have a significant impact on overall health, social wellbeing and self-image. In 2019, we published a systematic review of the treatment, prevention and public health control of skin infections including impetigo, scabies, crusted scabies and tinea in resource-limited settings where skin infections are endemic. This current review serves as an update to assess the evidence for treatment of these conditions as well as atopic dermatitis, molluscum contagiosum and head lice in endemic settings. The data from this systematic review have supported an update to the Australian National Healthy Skin guidelines. METHODS: A systematic review was conducted using two separate searches in MEDLINE, PubMed, Embase, CINAHL, Cochrane and Web of Science. The first search was an update of the 2018 systematic review using the same search strategy for the same skin conditions to identify emerging literature from 2018 to 2022. The second search strategy used the same key terms but with the addition of atopic dermatitis, head lice and molluscum contagiosum from 1960 to 2022. Eligible studies included Indigenous peoples and populations in resource-limited settings with a diagnosis of impetigo, scabies, crusted scabies, tinea capitis, atopic dermatitis, molluscum contagiosum or who presented with head lice. Studies conducted in high-income countries were excluded. Articles were screened for inclusion independently by one author with a second group of reviewers independently double screening. Data extraction and an in-depth quality assessment conducted by one author and checked by two others. RESULTS: Of 1466 original articles identified, 68 studies were included and key findings outlined for impetigo, scabies, crusted scabies, atopic dermatitis, head lice and molluscum contagiosum. Recommendations for each condition based on the available evidence are provided. CONCLUSION: The importance of assessing literature relevant to the populations with heavy burden of skin infections is outlined in this systematic review. We have summarised updates to this literature, which may benefit in developing guidelines for skin infection management similar to the National Healthy Skin Guidelines for Australia.

Costs of primary healthcare presentations and hospital admissions for scabies and related skin infections in Fiji, 2018-2019.

Scabies and related bacterial skin and soft tissue infections (SSTIs) are highly prevalent in many tropical, low- and middle-income settings. These skin conditions contribute to higher healthcare costs and burdens on healthcare systems. The Big Skin Health Intervention Fiji Trial ("Big SHIFT") carried out surveillance for scabies and SSTIs from July 2018 to June 2019 in the Northern Division of Fiji, an area with high prevalence of scabies, prior to a division-wide ivermectin-based mass drug administration (MDA) campaign. Using data from Big SHIFT, we sought to estimate the annual direct healthcare costs of scabies and related SSTIs for the Northern Division and extrapolate these costs to the national level. We categorized SSTIs as being potentially scabies-related or unlikely scabies-related, based on a previous study. The analysis used a health system perspective, with the main resource use categories of outpatient visits, bed days during admissions, medicines, and diagnostic tests. We extrapolated the total annual number of cases and direct healthcare costs for all divisions in Fiji based upon previous scabies and impetigo prevalence data across all divisions. The average cost per PHC presentation for scabies was US$17.7, and for potentially scabies-related SSTI was $18.3. The average cost per hospital admission for a potentially scabies-related SSTI case was $439. The estimated annual healthcare costs of scabies and related SSTIs in Fiji was US$3.0 million, with cost per capita of $3.3. Scabies and related SSTIs lead to a heavy economic burden in Fiji and prevention would reduce these healthcare costs.

Humoral and cellular immune responses in vaccinated and unvaccinated children following SARS-CoV-2 Omicron infection.

Objectives: The immune response in children elicited by SARS-CoV-2 Omicron infection alone or in combination with COVID-19 vaccination (hybrid immunity) is poorly understood. We examined the humoral and cellular immune response following SARS-CoV-2 Omicron infection in unvaccinated children and children who were previously vaccinated with COVID-19 mRNA vaccine. Methods: Participants were recruited as part of a household cohort study conducted during the Omicron predominant wave (Jan to July 2022) in Victoria, Australia. Blood samples were collected at 1, 3, 6 and 12 months following COVID-19 diagnosis. Humoral immune responses to SARS-CoV-2 Spike proteins from Wuhan, Omicron BA.1, BA.4/5 and JN.1, as well as cellular immune responses to Wuhan and BA.1 were assessed. Results: A total of 43 children and 113 samples were included in the analysis. Following Omicron infection, unvaccinated children generated low antibody responses but elicited Spike-specific CD4 and CD8 T-cell responses. In contrast, vaccinated children infected with the Omicron variant mounted robust humoral and cellular immune responses to both ancestral strain and Omicron subvariants. Hybrid immunity persisted for at least 6 months post infection, with cellular immune memory characterised by the generation of Spike-specific polyfunctional CD8 T-cell responses. Conclusion: SARS-CoV-2 hybrid immunity in children is characterised by persisting SARS-CoV-2 antibodies and robust CD4 and CD8 T-cell activation and polyfunctional responses. Our findings contribute to understanding hybrid immunity in children and may have implications regarding COVID-19 vaccination and SARS-CoV-2 re-infections.

Scabies: a clinical update.

Scabies is the most common neglected tropical disease with cutaneous manifestations, disproportionately affecting socially disadvantaged populations living in overcrowded settings. Scabies infestation is characterised by a generalised intractable pruritus, and is often complicated by secondary bacterial infection, which can lead to a range of complications. Scabies is a clinical diagnosis and requires an adequate degree of suspicion. The use of dermoscopy may improve diagnostic accuracy. In Australia, the first-line treatment recommended for scabies is topical permethrin 5% cream, applied to the whole body and repeated in one week. Oral ivermectin is subsidised by the Pharmaceutical Benefits Scheme with streamlined authority for patients who have completed and failed treatment with topical therapy, have a contraindication to topical treatment or have crusted scabies. Early identification and prompt initiation of treatment is key to minimise the disease burden of scabies.

Trimodal skin health programme for childhood impetigo control in remote Western Australia (SToP): a cluster randomised, stepped-wedge trial.

BACKGROUND: Skin infections affect physical health and, through stigma, social-emotional health. When untreated, they can cause life-threatening conditions. We aimed to assess the effect of a holistic, co-designed, region-wide skin control programme on the prevalence of impetigo. METHODS: The SToP (See, Treat, and Prevent Skin Sores and Scabies) trial is a pragmatic, open-cohort, stepped-wedge cluster randomised trial involving participants aged 0-18 years in nine remote communities of the Kimberley, Western Australia. The trial involves programmatic interventions in three domains: See (skin checks and skin infection recognition training), Treat (skin infection treatment training, sulfamethoxazole-trimethoprim for impetigo, and ivermectin for scabies), and Prevent (co-designed health promotion and environmental health). Four clusters, defined as pragmatic aggregations of communities, were randomised in two steps to progressively receive the activities during ten visits. The primary outcome was the proportion of school-aged children (aged 5-9 years) with impetigo. We adopted an intention-to-treat analysis and compared the intervention with the control (usual care before the start of intervention) states to derive a time and cluster averaged effect using Bayesian modelling. This study is registered with Australian New Zealand Clinical Trials Registry, ACTRN12618000520235. FINDINGS: Between Sept 19, 2018, and Nov 22, 2022, 915 children were consented and 777 (85%) had skin checks performed on at least one of ten possible visits between May 5, 2019, and Nov 22, 2022. Of the participants, 448 (58%) of 777 were aged 5-9 years at one or more of the visit timepoints and were eligible for primary outcome assessment. A decline in impetigo occurred across all clusters, with the greatest decline during the observational period of baseline skin checks before commencement of the interventional trial activities activities. The mean (95% credible interval) for the conditional posterior odds ratio for observing impetigo in the intervention compared with the control period was 1·13 (0·71-1·70). The probability that the intervention reduced the odds of observing impetigo was 0·33. INTERPRETATION: A decreased prevalence of impetigo during the observational period before the commencement of trial activities was sustained across the trial, attributable to the trimodal skin health initiative. Although the prevalence of impetigo reduced, there is no direct evidence to attribute this to the individual effects of the trial activities. The wholistic approach inclusive of skin checks collectively contributed to the sustained reduction in impetigo. FUNDING: Western Australia Department of Health, Australian National Health and Medical Research Council, and Healthway.

Transmission potential of Streptococcus pyogenes during a controlled human infection trial of pharyngitis.

Controlled human infection (CHI) models can provide insights into transmission of pathogens such as Streptococcus pyogenes (Strep A). As part of the Controlled Human Infection with Penicillin for Streptococcus pyogenes (CHIPS) trial, we explored the potential for transmission among participants deliberately infected with the Strep A emm75 strain. Three approaches to understanding transmission were employed: the use of agar settle plates to capture possible droplet or airborne spread of Strep A; measurement of distance droplets could spread during conversation; and environmental swabbing of high-touch items to detect Strep A on surfaces. Of the 60 (27%) CHIPS trial participants across five cohorts, 16 were enrolled in this sub-study; availability of study staff was the primary reason for selection. In total, 189 plates and 260 swabs were collected. Strep A was grown on one settle plate from a participant on the second day, using plates placed 30 cm away. This participant received the placebo dose of penicillin and had met the primary endpoint of pharyngitis. Whole-genome sequencing identified this to be the challenge strain. Strep A was not detected on any swabs. In this small sample of CHI participants, we did not find evidence of Strep A transmission by the airborne route or fomites, and just one instance of droplet spread while acutely symptomatic with streptococcal pharyngitis. Although these experiments provide evidence of minimal transmission within controlled clinical settings, greater efforts are required to explore Strep A transmission in naturalistic settings.IMPORTANCEStreptococcus pyogenes remains a significant driver of morbidity and mortality, particularly in under-resourced settings. Understanding the transmission modalities of this pathogen is essential to ensuring the success of prevention methods. This proposed paper presents a nascent attempt to determine the transmission potential of Streptococcus pyogenes nested within a larger controlled human infection model.

Chains of misery: surging invasive group A streptococcal disease.

PURPOSE OF REVIEW: We describe the epidemiology of the recent global surge in invasive group A streptococcal (GAS) disease and consider its proximate and distal causes. We highlight important knowledge gaps regarding clinical management and discuss potential strategies for prevention. RECENT FINDINGS: Rates of invasive GAS (iGAS) disease were increasing globally prior to the COVID-19 pandemic. Since mid-2022, following the worst years of the pandemic in 2020 and 2021, many countries with systems to monitor GAS syndromes have reported surges in cases of iGAS concurrent with increased scarlet fever, pharyngitis, and viral co-infections. The emergence of the hypervirulent M1 UK strain as a cause of iGAS, particularly in high income countries, is concerning. New data are emerging on the transmission dynamics of GAS. GAS remains universally susceptible to penicillin but there are increasing reports of macrolide and lincosamide resistance, particularly in invasive isolates, with uncertain clinical consequences. Intravenous immunoglobulin is used widely for streptococcal toxic shock syndrome and necrotizing soft tissue infections, although there is limited clinical evidence, and none from a completed randomized controlled trial. Intensive and expensive efforts at population-level control of GAS infections and postinfectious autoimmune complications have been only partially successful. The great hope for control of GAS diseases remains vaccine development. However, all modern vaccine candidates remain in the early development stage. SUMMARY: In many countries, iGAS rates surged from mid-2022 in the aftermath of pandemic control measures and physical distancing. The emergence of a dominant hypervirulent strain is an important but incomplete explanation for this phenomenon. Clinical management of iGAS remains highly empirical and new data has not emerged. A vaccine remains the most likely means of achieving a sustainable reduction in the burden of iGAS.

Acceptability of a nationwide scabies mass drug administration (MDA) program in Fiji: a qualitative interview-based study.

Background: Fiji has among the highest global reported prevalence of scabies. Mass drug administration (MDA) has been identified as a potentially effective strategy to control scabies, but acceptability of MDA from the perspectives of people receiving and delivering scabies MDA programs remains underexplored in Fiji and globally. Methods: A qualitative study was conducted after completion of the national MDA campaign. Participants included 44 community members and 12 key informants across the Central and Western Divisions of Fiji. Semi-structured face-to-face and virtual interviews were conducted in August and September 2023. An interpretive research approach was adopted, and data were analysed using deductive and inductive techniques. Findings: We identified several barriers and facilitators to scabies MDA acceptability. Facilitators included prior experiences of scabies and knowledge of the potential health benefit of MDA, community attitudes to MDA and neighbours' adherence practices, endorsement of MDA by community leaders, community consultation and exposure to community sensitisation, and involvement of local key informants during planning and implementation. Barriers included a lack of trust in MDA campaigns, religious beliefs, limited reach of community sensitisation, and challenges to implementing MDA in urban locations. Interpretation: This is the first qualitative study documenting acceptability of a nationwide scabies-MDA globally. It identified diverse socio-structural factors that influenced MDA implementation and acceptability. Future MDA programs could benefit from widespread community sensitisation, tailored approaches to urban and rural MDA design and delivery, and the inclusion of communities in the co-design and implementation of MDA programs. Funding: The National Health and Medical Research Council (NHMRC) investigator grant-LR and the Macquarie Group Foundation 50th Celebration Awards-AS.

Living with rheumatic fever and rheumatic heart disease in Victoria, Australia: A qualitative study.

BACKGROUND: In Victoria, Australia, children with Pacific Islander ('Pacific') ethnicities are overrepresented in acute rheumatic fever (ARF) and rheumatic heart disease (RHD). In June 2023, ARF and RHD became notifiable in Victoria. To inform public health and clinical practice, we described young Pacific patients' and their caregivers' understandings and experiences of ARF/RHD, and identified possible ways to improve the delivery of clinical care. METHODS: We established a project reference group including local Pacific people to guide this research. Pacific patients who attended an ARF/RHD clinic at The Royal Children's Hospital, Melbourne, were invited to participate, as were their caregivers. A Samoan researcher conducted qualitative 'talanoa' (conversational) interviews with patients and caregivers. A second researcher conducted semi-structured interviews with treating clinicians and other stakeholders. Interview transcripts underwent thematic analysis guided by the Tuilaepa Youth Mentoring Services Pacific Youth Wellbeing Framework. RESULTS: We interviewed 27 participants. This included nine patients and nine caregivers, all of whom were Samoan. These 18 participants expressed a desire to learn more about ARF/RHD and connect with other affected people. While some shared their experiences of having well-liked and trusted healthcare providers, patients often struggled to have two-way clinical conversations. The need to support clinicians working with high-risk populations to improve their awareness of ARF was identified. Receiving treatment on time was a top priority for affected families, despite injection pain, inconvenience and financial costs. The need to support continuity of care for young adult patients was raised by participants. CONCLUSIONS: Pacific people living with ARF/RHD and their families require additional support to receive high quality management in Victoria. Introducing a patient register and a specialist RHD nurse would enhance access to treatment, as would removing cost barriers, improving clinical awareness of ARF/RHD and creating Victoria-specific patient resources.

Ivermectin therapy for young children with scabies infection: a multicentre phase 2 non-randomized trial.

Background: Ivermectin, an effective treatment for scabies, is not licensed for children weighing <15 kg. Pharmacokinetic modelling has shown a 3 mg dose in young children (2-4 years, weighing 10-14 kg) achieves comparable drug exposure to a 200 µg/kg dose in children aged ≥5 years. This trial evaluated a 3 mg dose in young children. Methods: Multicentre, phase 2 trial in five health centres in Lao PDR. Children aged 2-4 years, weighing 10-14 kg with scabies received 3 mg ivermectin and had two plasma concentrations determined (Clinicaltrials.gov ID NCT05500326). On day 14, clinical outcomes and adverse effects were assessed, and a second dose given to complete treatment. The primary outcome was the mean plasma ivermectin exposure (AUC0-∞) after the first dose (compared to a historical control of Indigenous Australian children aged ≥5 years weighing ≥15 kg receiving 200 µg/kg). Secondary outcomes were clinical improvement and adverse effects. Findings: Overall, 100 children with a median age of 3.0 years (IQR 2.6-3.9) and weight of 11.9 kg (IQR 11.0-13.1) were enrolled. The mean observed ivermectin AUC0-∞ was comparable to the historical control group aged 5-11 years (815 µg h/L vs 953 µg h/L, p = 0.256). Complete resolution of scabies occurred in 90/99 children by day 14. Adverse effects were mild, occurring in 7/99. Interpretation: A 3 mg ivermectin dose in children aged 2-4 years and weighing 10-14 kg achieved a mean plasma AUC0-∞ comparable to older children, was highly effective in treating scabies and well tolerated. This study supports extending ivermectin treatment to younger children improving global efforts to control this neglected disease. Funding: Project funding provided by a Thrasher Foundation Early Career Research Award.

Evaluation of a multiplex-qPCR for paediatric pleural empyema-An observational study in hospitalised children.

Pleural empyema is a serious complication of pneumonia in children. Negative bacterial cultures commonly impede optimal antibiotic therapy. To improve bacterial identification, we developed a molecular assay and evaluated its performance compared with bacterial culture. Our multiplex-quantitative PCR to detect Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus and Haemophilus influenzae was assessed using bacterial genomic DNA and laboratory-prepared samples (n = 267). To evaluate clinical performance, we conducted the Molecular Assessment of Thoracic Empyema (MATE) observational study, enrolling children hospitalised with empyema. Pleural fluids were tested by bacterial culture and multiplex-qPCR, and performance determined using a study gold standard. We determined clinical sensitivity and time-to-organism-identification to assess the potential of the multiplex-qPCR to reduce the duration of empiric untargeted antibiotic therapy. Using spiked samples, the multiplex-qPCR demonstrated 213/215 (99.1%) sensitivity and 52/52 (100%) specificity for all organisms. During May 2019-March 2023, 100 children were enrolled in the MATE study; median age was 3.9 years (IQR 2-5.6). A bacterial pathogen was identified in 90/100 (90%) specimens by multiplex-qPCR, and 24/100 (24%) by bacterial culture (P <0.001). Multiplex-qPCR identified a bacterial cause in 68/76 (90%) culture-negative specimens. S. pneumoniae was the most common pathogen, identified in 67/100 (67%) specimens. We estimate our multiplex-qPCR would have reduced the duration of untargeted antibiotic therapy in 61% of cases by a median 20 days (IQR 17.5-23, range 1-55). Multiplex-qPCR significantly increased pathogen detection compared with culture and may allow for reducing the duration of untargeted antibiotic therapy.

Global epidemiological comparison of Streptococcus pyogenes emm-types associated with pharyngitis and pharyngeal carriage.

OBJECTIVES: To test the prevailing dogma that Streptococcus pyogenes emm-types that cause pharyngitis are the same as those associated with the carriage, using a global dataset. METHODS: Drawing on our systematic review of the global distribution of S. pyogenes emm-types and emm-clusters from 1990 to 2023, we compared the distribution and diversity of strains associated with pharyngitis and pharyngeal carriage, in the context of local United Nations Development Programme Human Development Index (HDI) values. RESULTS: We included 20 222 isolates from 71 studies done in 34 countries, with the vast majority of carriage strain data from studies in 'Low HDI' settings (550/1293; 43%). There was higher emm-type diversity for carriage than pharyngitis strains (Simpson Reciprocal Index of diversity 28.9 vs. 11.4). Compared with pharyngitis strains, carriage emm-types were disproportionately from emm-clusters E and D, usually described as 'generalist' or 'skin' strains. DISCUSSION: A limited number of studies have compared S. pyogenes strains from cases of pharyngitis compared with carriage. Our understanding of strains associated with carriage is the poorest for high-income settings. In low and medium HDI countries, we found greater strain associated with pharyngeal carriage than pharyngitis. Improving our understanding of S. pyogenes carriage epidemiology in the pre-vaccine era will help to decipher the direct and potential indirect effects of vaccines.

A highly sensitive 3base™ assay for detecting Streptococcus pyogenes in saliva during controlled human pharyngitis.

Streptococcus pyogenes (Group A Streptococcus; GAS) is a Gram-positive bacterium responsible for substantial human mortality and morbidity. Conventional diagnosis of GAS pharyngitis relies on throat swab culture, a low-throughput, slow, and relatively invasive 'gold standard'. While molecular approaches are becoming increasingly utilized, the potential of saliva as a diagnostic fluid for GAS infection remains largely unexplored. Here, we present a novel, high-throughput, sensitive, and robust speB qPCR assay that reliably detects GAS in saliva using innovative 3base™ technology (Genetic Signatures Limited, Sydney, Australia). The assay has been validated on baseline, acute, and convalescent saliva samples generated from the Controlled Human Infection for Vaccination Against Streptococcus (CHIVAS-M75) trial, in which healthy adult participants were challenged with emm75 GAS. In these well-defined samples, our high-throughput assay outperforms throat culture and conventional qPCR in saliva respectively, affirming the utility of the 3base™ platform, demonstrating the feasibility of saliva as a diagnostic biofluid, and paving the way for the development of novel non-invasive approaches for the detection of GAS and other oropharyngeal pathogens.

Intramuscular versus enteral penicillin prophylaxis to prevent progression of rheumatic heart disease: Study protocol for a noninferiority randomized trial (the GOALIE trial).

BACKGROUND: Rheumatic Heart Disease (RHD) persists as a major cardiovascular driver of mortality and morbidity among young people in low-and middle-income countries. Secondary antibiotic prophylaxis (SAP) with penicillin remains the cornerstone of RHD control, however, suboptimal treatment adherence undermines most secondary prevention programs. Many of the barriers to optimal SAP adherence are specific to the intramuscular form of penicillin and may potentially be overcome by use of oral penicillin. This noninferiority trial is comparing the efficacy of intramuscular to oral penicillin SAP to prevent progression of mild RHD at 2 years. METHODS/DESIGN: The Intramuscular vs Enteral Penicillin Prophylaxis to Prevent Progression of Rheumatic Heart Disease (GOALIE) trial is randomizing Ugandan children aged 5 to 17 years identified by echocardiographic screening with mild RHD (Stage A or B as defined by 2023 World Heart Federation criteria) to Benzathine Benzyl Penicillin G (BPG arm, every-28-day intramuscular penicillin) or Phenoxymethyl Penicillin (Pen V arm, twice daily oral penicillin) for a period of 2 years. A blinded echocardiography adjudication panel of 3 RHD experts and 2 cardiologists is determining the echocardiographic stage of RHD at enrollment and will do the same at study completion by consensus review. Treatment adherence and study retention are supported through peer support groups and case management strategies. The primary outcome is the proportion of children in the Pen V arm who progress to more advanced RHD compared to those in the BPG arm. Secondary outcomes are patient-reported outcomes (treatment acceptance, satisfaction, and health related quality of life), costs, and cost-effectiveness of oral compared to intramuscular penicillin prophylaxis for RHD. A total sample size of 1,004 participants will provide 90% power to demonstrate noninferiority using a margin of 4% with allowance for 7% loss to follow-up. Participant enrollment commenced in October 2023 and final participant follow-up is expected in December 2026. The graphical abstract (Fig. 1) summarizes the flow of echocardiographic screening, participant enrollment and follow-up. DISCUSSION: The GOALIE trial is critical in global efforts to refine a pragmatic approach to secondary prevention for RHD control. GOALIE insists that the inferiority of oral penicillin be proven contemporarily and against the most important near-term clinical outcome of progression of RHD severity. This work also considers other factors that could influence the adoption of oral prophylaxis and change the calculus for acceptable efficacy including patient-reported outcomes and costs. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05693545.

Burden of antimicrobial prescribing in primary care attributable to sore throat: a retrospective cohort study of patient record data.

BACKGROUND: Reducing antibiotic use in Australia, and the subsequent impact on antimicrobial resistance, requires multiple, sustained approaches with appropriate resources and support. Additional strategies to reduce antibiotic prescribing include effective vaccines, against pathogens such as Streptococcus pyogenes, the most common bacterial cause of sore throat. As part of efforts towards assessing the benefits of introducing new strategies to reduce antimicrobial prescribing, we aimed to determine the burden of antimicrobial prescribing for sore throat in general practice. METHODS: General practice activity data from 2013 - 2017 derived from the first 8 practices participating in the 'Primary Care Audit, Teaching and Research Open Network' (Patron) program were analysed according to reason for visit (upper respiratory tract infection, URTI, or sore throat) and antibiotic prescription. The main outcome measures were percentage of sore throat or URTI presentations with antibiotic prescription by age. RESULTS: A total of 722,339 visits to general practice were made by 65,449 patients; 5.7% of visits were for URTI with 0.8% meeting the more specific criteria for sore throat. 66.1% of sore throat visits and 36.2% of URTI visits resulted in antibiotic prescription. Penicillin, the recommended antibiotic for sore throat when indicated, was the antibiotic of choice in only 52.9% of sore throat cases prescribed antibiotics. Broader spectrum antibiotics were prescribed more frequently in older age groups. CONCLUSIONS: Frequency of antibiotic prescribing for sore throat is high and broad, despite Australian Therapeutic guideline recommendations. Multiple, sustained interventions to reduce prescribing, including availability of effective S. pyogenes vaccines that could reduce the incidence of streptococcal pharyngitis, could obviate the need to prescribe antibiotics and support ongoing efforts to promote antimicrobial stewardship.

Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

Antibiotics to eradicate Streptococcus pyogenes pharyngeal carriage in asymptomatic children and adults: A systematic review.

Streptococcus pyogenes (S. pyogenes) is a Gram-positive bacteria which causes a spectrum of diseases ranging from asymptomatic infection to life-threatening sepsis. Studies report up to 2000 times greater risk of invasive S. pyogenes disease in close contacts of index cases within 30-days of symptom onset. Despite this, there is variability in the management of asymptomatic carriage of S. pyogenes and those at risk of secondary cases of invasive S. pyogenes infection. OBJECTIVE: Our systematic review assessed the efficacy of different antibiotic regimens used for eradication of S. pyogenes from the pharynx in asymptomatic individuals. METHODS: We searched Pubmed, EMBASE (1974-), OVID Medline (1948-) and the Cochrane CENTRAL registry. We included randomised controlled trials (RCTs) with asymptomatic participants with >50% with pharyngeal cultures positive with S. pyogenes at baseline. Only studies with microbiological methods including culture (+/- polymerase chain reaction, PCR) were included. We included studies published in English. Each included study was assessed by two independent reviewers for data extraction and risk of bias. RESULTS: Of 1166 unique records identified, three RCTs were included in the review. Two of the three included RCTs found oral clindamycin for 10-days was the most efficacious regimen, compared to intramuscular benzathine penicillin G followed by 4 days of oral rifampicin, or monotherapy using benzathine penicillin, phenoxymethylpenicillin or erythromycin. Two RCTs were assessed as being at high risk of bias, with the third study demonstrating low/some risk of bias. CONCLUSIONS: Current available evidence for the optimal antibiotic in eradicating pharyngeal S. pyogenes carriage is limited. Future RCTs should include penicillin, first-generation cephalosporins, rifampicin, macrolides (such as azithromycin) and clindamycin.