Serological responses to target Streptococcus pyogenes vaccine antigens in patients with proven invasive beta-haemolytic streptococcal infections.

BACKGROUND: Rising incidence of invasive beta-haemolytic streptococcal (iBHS) infections has prompted consideration of vaccination as a preventative strategy for at-risk populations. The benefits of a vaccine targeting Lancefield group A (Streptococcus pyogenes; Strep A) would increase if cross-species immunity against Lancefield groups C/G (Streptococcus dysgalactiae subspecies equisimilis; SDSE) and B (Streptococcus agalactiae; GBS) was demonstrated. METHODS: A prospective, observational study of adult patients with iBHS infections due to Strep A, SDSE or GBS. Antibody responses to six Strep A candidate antigens were assayed on acute and convalescent sera. A serological response was defined as an increase of >0.2log10 arbitrary units/mL (AU/mL). RESULTS: Sixty-seven participants were enrolled. Thirty-three participants were included in the final analysis (12, 11 and 10 with Strep A, SDSE and GBS, respectively). The median serological response for participants with Strep A was significant for all tested antigens (median >0.2log10 difference between acute and convalescent samples; P<0.05 for all). Those with SDSE had comparable and significant median (IQR) responses to streptolysin-O (0.65 [0.36-1.67], P=0.004), S. pyogenes adhesion and division protein (0.68 [0.36-1.63], P=0.005) and C5a peptidase (ScpA; 0.30 [0.23-1.06]), P=0.004). GBS responses were limited to ScpA only (0.34 [0.08-0.52], P=0.05). CONCLUSION: Patients with invasive Strep A infection mount robust antibody responses to six non-M protein vaccine candidate antigens. Similar significant responses to C5a peptidase in those with invasive SDSE and GBS infection highlight the importance of further research into cross-species protection and immunological correlates of vaccine efficacy.

Artemisinin combination therapy at delivery to prevent postpartum malaria: a randomized open-label controlled trial.: Preventing postpartum malaria.

OBJECTIVES: Although the incidence of malaria is increased in women in endemic areas after delivery compared to non-pregnant women, no studies have assessed the benefit of presumptive antimalarial treatment given postpartum. METHODS: A randomised controlled trial investigating the efficacy of antimalarial treatment in preventing postpartum malaria was performed in healthy PNG mothers immediately following delivery. Participants were randomised 1:1 to no treatment (n=90) or artemisinin combination therapy (ACT), with further 1:1 ACT randomization to artemether-lumefantrine (AL; n=45) or dihydroartemisinin-piperaquine (DP; n=45). Standardised reviews were conducted monthly for six-months, including clinical assessment, malaria screening and haemoglobin measurement. The primary endpoint was incidence of slide-positive malaria within six-months of delivery. RESULTS: Of 183 recruited participants, 151 completed study procedures and were included in per protocol analyses (no treatment n=71, AL n=40, DP, n=40). Those allocated to ACT were significantly less likely to develop slide-positive malaria during the six-month follow-up period compared to those who were untreated (n=17 (21%) versus n=27 (38%); P=0·016; HR 0·49 (95% CI 0·27 to 0·90). There was no significant difference in malaria incidence between the two ACT groups. CONCLUSIONS: A treatment course of ACT at time of delivery halved the incidence of malaria infection during the first 6-months postpartum.

Estimation of two-year hospital costs of hip and knee periprosthetic joint infection treatments using activity-based costing.

Aims: Our aim was to estimate the total costs of all hospitalizations for treating periprosthetic joint infection (PJI) by main management strategy within 24 months post-diagnosis using activity-based costing. Additionally, we investigated the influence of individual PJI treatment pathways on hospital costs within the first 24 months. Methods: Using admission and procedure data from a prospective observational cohort in Australia and New Zealand, Australian Refined Diagnosis Related Groups were assigned to each admitted patient episode of care for activity-based costing estimates of 273 hip PJI patients and 377 knee PJI patients. Costs were aggregated at 24 months post-diagnosis, and are presented in Australian dollars. Results: The mean cost per hip and knee PJI patient was $64,585 (SD $53,550). Single-stage revision mean costs were $67,029 (SD $47,116) and $80,063 (SD $42,438) for hip and knee, respectively. Two-stage revision costs were $113,226 (SD $66,724) and $122,425 (SD $60,874) for hip and knee, respectively. Debridement, antibiotics, and implant retention in hips and knees mean costs were $53,537 (SD$ 39,342) and $48,463 (SD $33,179), respectively. Suppressive antibiotic therapy without surgical management mean costs were $20,296 (SD $8,875) for hip patients and $16,481 (SD $6,712) for knee patients. Hip patients had 16 different treatment pathways and knee patients had 18 treatment pathways. Additional treatment, episodes of care, and length of stay contributed to substantially increased costs up to a maximum of $369,948. Conclusion: Treating PJI incurs a substantial cost burden, which is substantially influenced by management strategy. With an annual PJI incidence of 3,900, the cost burden would be in excess of $250 million to the Australian healthcare system. Treatment pathways with additional surgery, more episodes of care, and a longer length of stay substantially increase the associated hospital costs. Prospectively monitoring individual patient treatment pathways beyond initial management is important when quantifying PJI treatment cost. Our study highlights the importance of optimizing initial surgical treatment, and informs treating hospitals of the resources required to provide care for PJI patients.

Safety of intramuscular tixagevimab-cilgavimab (Evusheld®) administration in patients at risk of iatrogenic haematoma due to haematological disorders.

INTRODUCTION: Traditionally, intramuscular (IM) injections have been avoided in patients with haematological diseases due to the risk of iatrogenic haematoma. Tixagevimab-cilgavimab (Evusheld®) is a novel monoclonal antibody combination used as preexposure prophylaxis against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for those at highest risk of severe infections. It is delivered as two separate IM injections (1.5 mL each). Patients with haematological disease are at higher risk for severe SARS-CoV-2 infections, which may be partially abrogated by the prophylactic inoculation of tixagevimab-cilgavimab. METHODS: A combined retrospective and prospective study of patients under the haematology service at a large metropolitan hospital receiving tixagevimab-cilgavimab was conducted. Tixagevimab-cilgavimab was administered IM to all patients, with platelet and factor replacement provided according to local protocols. Patients completed a numerical pain score daily for seven days following the injection, with scores ≥4/10 prompting an ultrasound to identify iatrogenic gluteal haematomas. RESULTS: The study recruited 131 patients; 66 patients were thrombocytopenic, including 10 patients with a platelet count <30 × 109/L. Fourteen patients (10.7%) received a single platelet transfusion prior to tixagevimab-cilgavimab administration, while two patients received fresh frozen plasma. No gluteal haematomas were identified, and only two patients reported an initial pain score of ≥4/10. CONCLUSIONS: The intramuscular administration of tixagevimab-cilgavimab in patients with haematological diseases was well tolerated and was not associated with iatrogenic haematoma.

Antecedent and persistent symptoms in COVID-19 and other respiratory illnesses: Insights from prospectively collected data in the BRACE trial.

BACKGROUND: Some individuals have a persistence of symptoms following both COVID-19 (post-acute COVID-19 syndrome; PACS) and other viral infections. This study used prospectively collected data from an international trial to compare symptoms following COVID-19 and non-COVID-19 respiratory illness, to identify factors associated with the risk of PACS, and to explore symptom patterns before and after COVID-19 and non-COVID-19 respiratory illnesses. METHODS: Data from a multicentre randomised controlled trial (BRACE trial) involving healthcare workers across four countries were analysed. Symptom data were prospectively collected over 12 months, allowing detailed characterisation of symptom patterns. Participants with COVID-19 and non-COVID-19 respiratory illness episodes were compared, focussing on symptom severity, duration (including PACS using NICE and WHO definitions), and pre-existing symptoms. FINDINGS: Compared to those with a non-COVID-19 illness, participants with COVID-19 had significantly more severe illness (OR 7·4, 95%CI 5·6-9·7). Symptom duration meeting PACS definitions occurred in a higher proportion of COVID-19 cases than non-COVID-19 respiratory controls using both the NICE definition (2·5% vs 0·5%, OR 6·6, 95%CI 2·4-18·3) and the WHO definition (8·8% vs 3·7%, OR 2·5, 95%CI 1·4-4·3). When considering only participants with COVID-19, age 40-59 years (aOR 2·8, 95%CI 1·3-6·2), chronic respiratory disease (aOR 5·5, 95%CI 1·3-23·1), and pre-existing symptoms (aOR 3·0, 95%CI 1·4-6·3) were associated with an increased risk of developing PACS. Symptoms associated with PACS were also reported by participants in the months preceding their COVID-19 or non-COVID-19 respiratory illnesses (32% fatigue and muscle ache, 11% intermittent cough and shortness of breath). INTERPRETATION: Healthcare workers with COVID-19 were more likely to have severe and longer-lasting symptoms than those with a non-COVID-19 respiratory illness, with a higher proportion meeting the WHO or NICE definitions of PACS. Age, chronic respiratory disease, and pre-existing symptoms increased the risk of developing PACS following COVID-19.

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.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial.

OBJECTIVES: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19. DESIGN: Phase III double-blind randomised controlled trial. SETTING: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic. PARTICIPANTS: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG. INTERVENTION: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989). MAIN OUTCOME MEASURES: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion). RESULTS: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group. CONCLUSIONS: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.

A mouldable fibreglass backslab device as a novel approach to offload chronic plantar foot ulcers: A retrospective observational audit.

BACKGROUND: Pressure offloading is a critical component of plantar foot ulcer management, including diabetes-related foot ulcers (DFU). Conventional offloading options such as total contact casting and removable knee-high walkers may be unsuitable or unsuccessful in patients with morbid obesity, intermittent lower limb oedema, high exudative wounds or poor mobility. A mouldable fibreglass backslab device (BSD) may be a practical alternative to be considered in these situations. METHODS: Data were retrospectively collected on 28 patients (29 foot ulcers) with non-healing ulcers who received a BSD to offload their foot ulcer as an extension to standard offloading care. Baseline data included: patient demographics, type of offloading prior to BSD application, date of ulcer onset, days ulcer present prior to BSD application and ulcer size at BSD initiation. Measures of success included ulcer size reduction 12 weeks post-BSD application, time to complete ulcer healing in BSD, time to 50% reduction in ulcer size post-BSD application and total number of days ulcer present. RESULTS: The median (IQR) ulcer area and ulcer duration at baseline for 19 patients (20 ulcers) who used the BSD was 1.65 (0.4-3.8) cm2 and 531 (101-635) days. At 12 weeks, the median (IQR) ulcer area was 0.3 (0-0.55) cm2 with a median (IQR) reduction of 97 (80-100) %. Nine (45%) ulcers achieved complete wound healing (100% reduction in wound size) at 12 weeks post-BSD application, and the remaining 11 (55%) ulcers achieved at least 50% reduction in wound size. The median (IQR) time to complete wound healing and 50% reduction in wound size was 71 (35-134) days and 24 (15-44) days, respectively. Nine patients ceased use of the BSD and reverted to conventional offloading before their wounds had healed. Of these, four patients achieved a 50% reduction in wound size at the 12-week mark with conventional offloading. CONCLUSION: Our preliminary data suggests that a mouldable fibreglass BSD may be a practical offloading option in the management of DFUs, especially when conventional offloading methods are unsuccessful, unsuitable or unacceptable to patients. Higher level evidence is required to demonstrate suitability or efficacy of the BSD compared to current evidence-based recommended offloading methods.

Serological Responses to Streptococcus pyogenes Vaccine Candidate Antigens Suggests That Streptococcus dysgalactiae Is the Predominant Cause of Lower Limb Cellulitis.

Background: A future Streptococcus pyogenes (Strep A) vaccine will ideally prevent a significant burden of lower limb cellulitis; however, natural immune responses to proposed vaccine antigens following an episode of cellulitis remain uncharacterized. Methods: We enrolled 63 patients with cellulitis and 26 with invasive beta hemolytic streptococci infection, using a multiplexed assay to measure immunoglobulin G against Strep A vaccine candidate antigens, including: streptolysin O (SLO), deoxyribonuclease B (DNB), group A carbohydrate (GAC), C5a peptidase (ScpA), cell envelope proteinase (SpyCEP), and adhesion and division protein (SpyAD). Responses in the invasive cohort were used to predict the infecting etiology in the cellulitis cohort. Results: Of 41 patients with cellulitis and paired serological samples, 68.3% had evidence of beta hemolytic streptococci infection by conventional anti-SLO and/or anti-DNB criteria. A positive serological response to at least 1 of the tested antigens was seen in 78.0% of the cellulitis cohort. Individually, anti-SLO (58.5%), anti-SpyAD (46.3%), and anti-ScpA (39.0%) were the most common. Based on principal component analysis, increases in these 3 antibodies, without responses to DNB, GAC, and SpyCEP characterized Streptococcus dysgalactiae subspecies equisimilis (SDSE) infection. Conclusions: SDSE appears to be the predominant cause of lower limb cellulitis. Effective Strep A vaccines incorporating antigens that provide additional cross protection against SDSE may prevent a significant burden of lower limb cellulitis.

Patient-Reported Outcomes Following Periprosthetic Joint Infection of the Hip and Knee: A Longitudinal, Prospective Observational Study.

BACKGROUND: The role of patient-reported outcome measures (PROMs) as tools for monitoring the impact and outcomes of periprosthetic joint infection (PJI) is not well described. This study analyzed the Oxford Hip Score (OHS) or Oxford Knee Score (OKS) in a prospective observational cohort of patients with hip or knee PJI. METHODS: The PIANO (Prosthetic joint Infection in Australia and New Zealand, Observational study) cohort prospectively enrolled patients with newly diagnosed PJI from multiple centers. The OHS and OKS were evaluated at PJI diagnosis (baseline) and at 3, 12, and 24 months. Scores and score changes were examined according to PJI type, patient characteristics, and management. A successful functional outcome at 12 months was defined as an OHS of >38 or OHS of >36 and/or an improvement from baseline of >12 or >9, respectively. RESULTS: Of the 741 participants, PROMs were available at 12 months for 233 with hip and 342 with knee PJI. Significant improvements (p < 0.0001) were seen at 12 months for both the OHS (24.5 to 36) and OKS (25 to 34), with no further improvement at 24 months. Patients with late-acute PJI had a higher median baseline OHS (35; interquartile range [22 to 46]) and OKS (30 [18 to 41]) than those with early PJI (OHS: 19 [15 to 29]; OKS: 22 [16 to 29.5]) or chronic PJI (OHS: 23 [14 to 34]; OKS 22 [14 to 28]). Logistic regression showed that a clinical cure (adjusted odds ratio [aOR] = 1.88, 95% confidence interval [CI] = 1.28 to 2.76, p = 0.001) and early PJI (aOR = 2.56, 95% CI = 1.64 to 4.07, p < 0.0001) independently predicted a successful functional outcome. Chronic renal impairment (aOR = 0.31, 95% CI = 0.13 to 0.71, p = 0.007), congestive cardiac failure (aOR = 0.41, 95% CI = 0.17 to 0.95, p = 0.04), and clinical signs of inflammation (aOR = 0.53, 95% CI = 0.33 to 0.85, p = 0.009) at diagnosis independently predicted failure to achieve a successful functional outcome. CONCLUSIONS: The OHS and OKS varied significantly at baseline and 12 months according to PJI type, emphasizing the need to consider the PJI type when evaluating treatment success. This study highlights superior functional outcomes associated with early PJI and with achievement of a clinical cure. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

"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.

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trial.

Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%-68.2%), compared with 63.4% in the control group (95% CI 61.8%-65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%-20.7%), compared with 18.8% in the control group (95% CI 17.4%-20.2%) a difference of +0.6 percentage points (95% CI -1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.

Patient preferences for prophylactic regimens requiring regular injections in children and adolescents: a systematic review and thematic analysis.

BACKGROUND: At present, limited literature exists exploring patient preferences for prophylactic treatment of acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Given low treatment completion rates to this treatment in Australia, where the burden of disease predominantly affects Aboriginal and Torres Strait Islander people, an improved understanding of factors driving patient preference is required to improve outcomes. Due to limited available literature, this review sought to explore treatment preferences for conditions for which the findings might be generalisable to the ARF/RHD context. OBJECTIVE: Explore treatment preferences of patients, parents/caregivers and healthcare providers towards regular injection regimens in paediatric and adolescent populations for any chronic condition. Findings will be applied to the development of benzathine penicillin G (BPG) prophylactic regimens that are informed by treatment preferences of patients and their caregivers. This in turn should contribute to optimisation of successful BPG delivery. METHODS: A systematic review of databases (Medline, Embase and Global Health) was conducted using a search strategy developed with expert librarian input. Studies were selected using a two-stage process: (1) title and abstract screen and (2) full text review. Data were extracted using a reviewer-developed template and appraised using the JBI Critical Appraisal tool. Data were synthesised according to a thematic analytical framework. RESULTS: 1725 papers were identified by the database search, conducted between 12 February 2022 and 8 April 2022, and 25 were included in the review. Line-by-line coding to search for concepts generated 20 descriptive themes. From these, five overarching analytical themes were derived inductively: (1) ease of use, (2) tolerability of injection, (3) impact on daily life, (4) patient/caregiver agency and (5) home/healthcare interface. CONCLUSIONS: The findings of this review may be used to inform the development of preference-led regular injection regimens for paediatric and adolescent patient cohorts-specifically for BPG administration in ARF/RHD secondary prophylaxis. TRIAL REGISTRATION NUMBER: Patient, parent and health personnel preferences towards regular injection regimes in paediatric and adolescent populations-a protocol for a systematic review. PROSPERO 2021 CRD42021284375. Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284375.

External Validation of the Joint-Specific Bone Involvement, Antimicrobial Options, Coverage of the Soft Tissues, and Host Status (JS-BACH) Classification for Predicting Outcome in Periprosthetic Joint Infections: A Cohort of 653 Patients.

BACKGROUND: Periprosthetic joint infection (PJI) is a devastating complication in hip and knee joint arthroplasty. The "Joint-Specific Bone Involvement, Antimicrobial Options, Coverage of the Soft Tissues, and Host Status (JS-BACH)" classification system was developed in 2021 to stratify the complexity of PJI, and more importantly, to act as a tool to guide referrals to specialist centers. The "JS-BACH" classification has not been validated in an external cohort. This study aimed to do so using a large prospective cohort from Australia and New Zealand. METHODS: We applied the JS-BACH classification to the Prosthetic Joint Infection in Australia and New Zealand Observational (PIANO) cohort. This prospective study of newly diagnosed PJI collected 2-year outcome data from 653 participants enrolled in 27 hospitals. The definition of PJI treatment failure at 24 months was any of the following: death, clinical or microbiological signs of infection, destination prosthesis removed, or ongoing antibiotic use. Individual cases were classified as per JS-BACH into "1: uncomplicated" (n = 268), "2: complex" (n = 330), and "3: limited options" (n = 55). This cohort was similar to the original JS-BACH population in terms of baseline characteristics. However, there was a difference in complexity, with more debridement, antibiotics, and implant retention procedures, fewer revision procedures, and a higher proportion of uncomplicated patients in the PIANO cohort. RESULTS: The risk of treatment failure correlated strongly with the JS-BACH category, with odds ratios (95% confidence interval) for category 2 versus 1 of 1.75 (1.24 to 2.47) and for category 3 versus 1 of 7.12 (3.42 to 16.02). CONCLUSIONS: Despite the PIANO study population being less complicated than the original derivation cohort, the JS-BACH classification showed a clear association with treatment failure in this large external cohort.

Could late-latent syphilis be treated with a single subcutaneous infusion of long-acting penicillin?

Syphilis is an important global health threat and little has changed in its treatment since the mid-20th century. For late-latent or syphilis infection of unknown duration, the standard treatment of multiple intramuscular injections of benzathine penicillin G (BPG) are associated with significant pain and distress to clients and caregivers, negatively impacting on treatment completion. Based on pharmacokinetic modelling from a Phase I study of subcutaneous infusion of high dose BPG (SCIP), we present its feasibility, safety and tolerability for treatment of syphilis in a single infusion. SCIP leads to more sustained penicillin concentrations above the desired target with less reported pain and reduced clinic visits.

Subcutaneous infusion of high-dose benzathine penicillin G is safe, tolerable, and suitable for less-frequent dosing for rheumatic heart disease secondary prophylaxis: a phase 1 open-label population pharmacokinetic study.

Since 1955, the recommended strategy for rheumatic heart disease (RHD) secondary prophylaxis has been benzathine penicillin G [BPG; 1.2 MU (900 mg)] injections administered intramuscularly every 4 weeks. Due to dosing frequency, pain, and programmatic challenges, adherence is suboptimal. It has previously been demonstrated that BPG delivered subcutaneously at a standard dose is safe and tolerable and has favorable pharmacokinetics, setting the scene for improved regimens with less frequent administration. The safety, tolerability, and pharmacokinetics of subcutaneous infusions of high-dose BPG were assessed in 24 healthy adult volunteers assigned to receive either 3.6, 7.2, or 10.8 MU (three, six, and nine times the standard dose, respectively) as a single subcutaneous infusion. The delivery of the BPG to the subcutaneous tissue was confirmed with ultrasonography. Safety assessments, pain scores, and penicillin concentrations were measured for 16 weeks post-dose. Subcutaneous infusion of penicillin (SCIP) was generally well tolerated with all participants experiencing transient, mild infusion-site reactions. Prolonged elevated penicillin concentrations were described using a combined zero-order (44 days) and first-order (t1/2 = 12 days) absorption pharmacokinetic model. In simulations, time above the conventionally accepted target concentration of 20 ng/mL (0.02 µg/mL) was 57 days for 10.8 MU delivered by subcutaneous infusion every 13 weeks compared with 9 days of every 4-weekly dosing interval for the standard 1.2 MU intramuscular dose (i.e., 63% and 32% of the dosing interval, respectively). High-dose SCIP (BPG) is safe, has acceptable tolerability, and may be suitable for up to 3 monthly dosing intervals for secondary prophylaxis of RHD.