"Hurts less, lasts longer"; a qualitative study on experiences of young people receiving high-dose subcutaneous injections of benzathine penicillin G to prevent rheumatic heart disease in New Zealand.

BACKGROUND: Four-weekly intramuscular (IM) benzathine penicillin G (BPG) injections to prevent acute rheumatic fever (ARF) progression have remained unchanged since 1955. A Phase-I trial in healthy volunteers demonstrated the safety and tolerability of high-dose subcutaneous infusions of BPG which resulted in a much longer effective penicillin exposure, and fewer injections. Here we describe the experiences of young people living with ARF participating in a Phase-II trial of SubCutaneous Injections of BPG (SCIP). METHODOLOGY: Participants (n = 20) attended a clinic in Wellington, New Zealand (NZ). After a physical examination, participants received 2% lignocaine followed by 13.8mL to 20.7mL of BPG (Bicillin-LA®; determined by weight), into the abdominal subcutaneous tissue. A Kaupapa Maori consistent methodology was used to explore experiences of SCIP, through semi-structured interviews and observations taken during/after the injection, and on days 28 and 70. All interviews were recorded, transcribed verbatim, and thematically analysed. PRINCIPAL FINDINGS: Low levels of pain were reported on needle insertion, during and following the injection. Some participants experienced discomfort and bruising on days one and two post dose; however, the pain was reported to be less severe than their usual IM BPG. Participants were 'relieved' to only need injections quarterly and the majority (95%) reported a preference for SCIP over IM BPG. CONCLUSIONS: Participants preferred SCIP over their usual regimen, reporting less pain and a preference for the longer time gap between treatments. Recommending SCIP as standard of care for most patients needing long-term prophylaxis has the potential to transform secondary prophylaxis of ARF/RHD in NZ and globally.

Systematic review of household transmission of Strep A: A potential site for prevention that has eluded attention.

BACKGROUND: Despite being the sixth most common infectious disease globally, transmission of Streptococcus pyogenes (Strep A) within the household remains an understudied driver of infection. We undertook a systematic review to better understand the transmission of Strep A between people within the home while highlighting opportunities for prevention. METHODS: A search strategy was applied to five databases between September 2022 and March 2023. Results were limited to those published between January 2000 and March 2023. Texts were reviewed by two authors and the following data extracted: article details (title, author, year), study type, transmission year, country, participant age/s, infection status, molecular testing, and transmission mode. Funding was provided by the Australian National Health and Medical Research Council (NHMRC, grant number GNT2010716). RESULTS: The final analysis comprised 28 texts. Only seven studies (25.0%) provided sufficient detail to identify the Strep A transmission mode. These were contact (4), vehicle (bedding; clothing; other fabric, and medical equipment, [2]), and contact with animals (1). All others were classified as household (specific mode unascertainable). Most articles reported outbreaks involving invasive Strep A infections. CONCLUSIONS: There is limited literature regarding household transmission of Strep A. Understanding transmission in this setting remains imperative to guide control methods.

Searching for Strep A in the clinical environment during a human challenge trial: a sub-study protocol.

Streptococcus pyogenes (also known as group A Streptococcus , Strep A) is an obligate human pathogen with significant global morbidity and mortality. Transmission is believed to occur primarily between individuals via respiratory droplets, but knowledge about other potential sources of transmission via aerosols or the environment is limited. Such knowledge is required to design optimal interventions to control transmission, particularly in endemic settings. We aim to detail an experimental methodology to assess the transmission potential of Strep A in a clinical environment. We will examine potential sources of transmission in up to 20 participants recruited to the Controlled human infection for penicillin against Streptococcus pyogenes (CHIPS) Trial. Three approaches to understanding transmission will be used: the use of selective agar settle plates to capture possible droplet or airborne spread of Strep A; measurement of the possible distance of Strep A droplet spread during conversation; and environmental swabbing of personal and common high-touch items to detect the presence of Strep A on hard and soft surfaces. All methods are designed to allow for an assessment of transmission potential by symptomatic, asymptomatic and non-cases. Ethical approval has been obtained through Bellberry Human Research Ethics Committee (approval 2021-03-295). Trial registration number: ACTRN12621000751875. Any results elicited from these experiments will be of benefit to the scientific literature in improving our knowledge of opportunities to prevent Strep A transmission as a direct component of the primordial prevention of rheumatic fever. Findings will be reported at local, national and international conferences and in peer-reviewed journals.

Qualitative assessment of healthy volunteer experience receiving subcutaneous infusions of high-dose benzathine penicillin G (SCIP) provides insights into design of late phase clinical studies.

INTRODUCTION: Secondary prophylaxis to prevent rheumatic heart disease (RHD) progression, in the form of four-weekly intramuscular benzathine benzylpenicillin G (BPG) injections, has remained unchanged since 1955. Qualitative investigations into patient preference have highlighted the need for long-acting penicillins to be delivered less frequently, ideally with reduced pain. We describe the experience of healthy volunteers participating in a phase-I safety, tolerability and pharmacokinetic trial of subcutaneous infusions of high-dose benzathine penicillin G (BPG)-the SCIP study (Australian New Zealand Clinical Trials Registry ACTRN12622000916741). METHODS: Participants (n = 24) received between 6.9 mL to 20.7 mL (3-9 times the standard dose) of BPG as a single infusion into the abdominal subcutaneous tissues via a spring-driven syringe pump over approximately 20 minutes. Semi-structured interviews at four time points were recorded, transcribed verbatim and thematically analysed. Tolerability and specific descriptors of the experience were explored, alongside thoughts on how the intervention could be improved for future trials in children and young adults receiving monthly BPG intramuscular injections for RHD. RESULTS: Participants tolerated the infusion well and were able describe their experiences throughout. Most reported minimal pain, substantiated via quantitative pain scores. Abdominal bruising at the infusion site did not concern participants nor impair normal activities. Insight into how SCIP could be improved for children included the use of topical analgesia, distractions via television or personal devices, a drawn-out infusion time with reduced delivery speed, and alternative infusion sites. Trust in the trial team was high. CONCLUSION: Qualitative research is an important adjunct for early-phase clinical trials, particularly when adherence to the planned intervention is a key driver of success. These results will inform later-phase SCIP trials in people living with RHD and other indications.

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.

'Hesitant compliers': Qualitative analysis of concerned fully-vaccinating parents.

OBJECTIVE: Some parents are hesitant about vaccines and yet still vaccinate their children. Vaccine behaviours are not fixed and parents who are concerned but nonetheless adherent to standard schedules could switch to an unconventional schedule, delaying or cherry-picking vaccines. There is a need to better understand vaccine hesitancy in specific contexts, acknowledging cultural and geographical variation, to ensure interventions targeting hesitancy are well directed and received. METHODS: To identify the behaviours, knowledge and attitudes of 'hesitant compliers' in Perth, Western Australia, nine one-on-one in-depth interviews were conducted with vaccinating parents of children (<5 years) who were identified as being hesitant. Interview transcripts were analysed qualitatively and themes developed inductively, following a constructivist paradigm. RESULTS: Parents saw vaccination as important for themselves and their community, despite their limited knowledge of vaccine preventable diseases. Parents reported concerns about potential side effects, and worried about the safety of the measles-mumps-rubella (MMR) and seasonal influenza vaccines. Concerned about the role of anti-vaccination information in the community, some sought to isolate themselves from parents who did not vaccinate, although others were concerned that this could entrench non-vaccinators' behaviours. Parents' views were all underlaid by two pivotal 'vaccine-related events' that had occurred in the community: the severe injury of a baby from seasonal influenza vaccination in 2010, and the death of a baby from whooping cough in 2015. CONCLUSIONS: Parents interpreted pivotal vaccine-related events in the community as requiring them to take personal responsibility for vaccine decisions. Their reports of continued vaccine fears (evident in international studies in recent decades) demonstrate that vaccine scares have long lasting effects. With vaccine rates high and stable, current strategies appear to be have little impact on addressing parental vaccine concerns. Further research is required to determine the prevalence of hesitancy amongst vaccinating parents and identify critical points for intervention.