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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 0.1mL 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 percentage 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 percentage 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 health care workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov NCT04327206.
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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.
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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.
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Prioridad del Paciente , Fiebre Reumática , Humanos , Adolescente , Niño , Prioridad del Paciente/psicología , Fiebre Reumática/prevención & control , Fiebre Reumática/tratamiento farmacológico , Penicilina G Benzatina/uso terapéutico , Penicilina G Benzatina/administración & dosificación , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Australia , Inyecciones , Cuidadores/psicologíaRESUMEN
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.
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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.
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Artroplastia de Reemplazo de Cadera , Medición de Resultados Informados por el Paciente , Infecciones Relacionadas con Prótesis , Humanos , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/terapia , Infecciones Relacionadas con Prótesis/diagnóstico , Masculino , Femenino , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Estudios Longitudinales , Artroplastia de Reemplazo de Cadera/efectos adversos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Prótesis de Cadera/efectos adversos , Australia , Prótesis de la Rodilla/efectos adversos , Resultado del Tratamiento , Nueva Zelanda , Anciano de 80 o más AñosRESUMEN
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.
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Penicilina G Benzatina , Cardiopatía Reumática , Humanos , Penicilina G Benzatina/administración & dosificación , Penicilina G Benzatina/uso terapéutico , Masculino , Femenino , Nueva Zelanda , Inyecciones Subcutáneas , Cardiopatía Reumática/prevención & control , Cardiopatía Reumática/tratamiento farmacológico , Adulto , Adolescente , Adulto Joven , Dolor/tratamiento farmacológico , Dolor/prevención & control , Investigación Cualitativa , Fiebre Reumática/prevención & control , Fiebre Reumática/tratamiento farmacológico , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéuticoRESUMEN
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.
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Antibacterianos , Artroplastia de Reemplazo de Cadera , Artroplastia de Reemplazo de Rodilla , Infecciones Relacionadas con Prótesis , Humanos , Infecciones Relacionadas con Prótesis/microbiología , Infecciones Relacionadas con Prótesis/etiología , Infecciones Relacionadas con Prótesis/tratamiento farmacológico , Femenino , Masculino , Anciano , Estudios Prospectivos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Persona de Mediana Edad , Artroplastia de Reemplazo de Cadera/efectos adversos , Nueva Zelanda , Antibacterianos/uso terapéutico , Australia , Prótesis de Cadera/efectos adversos , Prótesis de Cadera/microbiología , Anciano de 80 o más Años , Prótesis de la Rodilla/efectos adversos , Estudios de Cohortes , Reoperación/estadística & datos numéricosRESUMEN
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.
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Sífilis , Humanos , Antibacterianos/uso terapéutico , Infusiones Subcutáneas , Inyecciones Intramusculares , Dolor/tratamiento farmacológico , Penicilina G Benzatina/uso terapéutico , Sífilis/tratamiento farmacológicoRESUMEN
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.
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Fiebre Reumática , Cardiopatía Reumática , Adulto , Humanos , Antibacterianos/farmacocinética , Infusiones Subcutáneas , Dolor/tratamiento farmacológico , Penicilina G Benzatina/efectos adversos , Fiebre Reumática/prevención & control , Cardiopatía Reumática/tratamiento farmacológico , Cardiopatía Reumática/prevención & controlRESUMEN
Prosthetic joint infections (PJI) present a major management challenge for practicing orthopedic surgeons and infectious disease physicians. There are few high-quality data to inform treatment guidelines. The aim of this systematic review was to report the design characteristics and recruitment rates for randomized controlled trials (RCTs) of PJI management. Trials were considered eligible for inclusion if human participants were randomized to any management intervention for PJI. We searched Medline, PubMed, Embase, Web of Science, Cochrane Database, ANZ Clinical Trials Registry, ClinicalTrials.gov, and the EU Clinical Trials Register until the end of May 2023. The systematic review was registered with PROSPERO (CRD42018112646). We identified 15 published RCTs with a total of 1743 participants with PJI. The median (interquartile range [IQR]) number of successfully recruited participants was 63 (38-140), with 0.28 (0.13-0.96) enrolments per site per month. Only four trials (36.4%) achieved the target recruitment. All RCTs applied different primary endpoints and varying definitions of a 'good' outcome. Despite recent improvements, PJI RCTs are characterized by slow recruitment and heterogeneous endpoint assessments, which preclude synthesis in a standard meta-analytic framework. To inform international guidelines, future PJI trials should be run as multi-country trials at high-recruiting sites.
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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.
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Background: Recurrences of herpes simplex virus (HSV) in the orofacial region (herpes labialis or cold sores) impact quality-of-life. We aimed to study whether the bacille Calmette-Guérin (BCG) vaccine can attenuate cold sore recurrences through off-target immunomodulatory effects. Methods: In this nested randomised controlled trial within the multicentre, phase 3 BRACE trial, 6828 healthcare workers were randomised in 36 sites in Australia, the Netherlands, Spain, the United Kingdom and Brazil, to receive BCG-Denmark or no BCG (1:1 ratio using a web-based procedure) and followed for 12 months with 3-monthly questionnaires. Exclusion criteria included contraindication to BCG vaccine or previous vaccination with BCG within the past year, any other live-attenuated vaccine within the last month, or any COVID-specific vaccine. The intervention group received one intradermal dose of 0.1 mL of BCG-Denmark corresponding to 2-8 x 105 colony forming units of Mycobacterium bovis, Danish strain 1331. The primary outcome was the difference in restricted mean survival time (i.e., time to first cold-sore recurrence), in participants with frequent recurrent herpes labialis (≥4 recurrences/year), analysed by intention-to-treat. Secondary outcomes addressed additional questions, including analyses in other sub-populations. Adverse events were monitored closely during the first 3 months and were reported in all participants who received one dose of study drug according to intervention received. The BRACE trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020 and February 18, 2021, 84 individuals with frequent recurrent cold sores were randomly assigned to BCG (n = 38) or control (n = 46). The average time to first cold-sore recurrence was 1.55 months longer in the BCG group (95% CI 0.27-2.82, p = 0.02) than the control group (hazard ratio 0.54, 95% CI 0.32-0.91; intention-to-treat). The beneficial effect of BCG was greater in the as-treated population (difference 1.91 months, 95% CI 0.69-3.12, p = 0.003; hazard ratio 0.45, 95% CI 0.26-0.76). In prespecified subgroup analyses, only sex modified the treatment effect (interaction p = 0.007), with benefit restricted to males. Over 12 months, a greater proportion of participants in the BCG group compared with the control group reported a decrease in duration (61% vs 21%), severity (74% vs 21%), frequency (55% vs 21%), and impact on quality of life (42% vs 15%) of cold sore recurrences. In participants who had ever had a cold sore, there was also a decrease in self-reported burden of recurrences in the BCG group. In participants who had never had a cold sore, there was an increased risk of a first episode in the BCG group (risk difference 1.4%; 95% CI 0.3-2.6%, p = 0.02). There were no safety concerns. Interpretation: BCG-Denmark vaccination had a beneficial effect on herpes labialis, particularly in males with frequent recurrences, but may increase the risk of a first cold sore. Funding: Bill & Melinda Gates Foundation, the 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, and individual donors.
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[This corrects the article DOI: 10.1016/j.heliyon.2023.e15241.].
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OBJECTIVES: To assess the pharmacokinetics, safety, and tolerability of two high-dose, short-course primaquine (PQ) regimens compared with standard care in children with Plasmodium vivax infections. METHODS: We performed an open-label pediatric dose-escalation study in Madang, Papua New Guinea (Clinicaltrials.gov NCT02364583). Children aged 5-10 years with confirmed blood-stage vivax malaria and normal glucose-6-phosphate dehydrogenase activity were allocated to one of three PQ treatment regimens in a stepwise design (group A: 0.5 mg/kg once daily for 14 days, group B: 1 mg/kg once daily for 7 days, and group C: 1 mg/kg twice daily for 3.5-days). The study assessments were completed at each treatment time point and fortnightly for 2 months after PQ administration. RESULTS: Between August 2013 and May 2018, 707 children were screened and 73 met the eligibility criteria (15, 40, and 16 allocated to groups A, B, and C, respectively). All children completed the study procedures. The three regimens were safe and generally well tolerated. The pharmacokinetic analysis indicated that an additional weight adjustment of the conventionally recommended milligram per kilogram PQ doses is not necessary to ensure the therapeutic plasma concentrations in pediatric patients. CONCLUSIONS: A novel, ultra-short 3.5-day PQ regimen has potential benefits for improving the treatment outcomes in children with vivax malaria that warrants further investigation in a large-scale clinical trial.
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Antimaláricos , Malaria Vivax , Humanos , Niño , Primaquina/efectos adversos , Malaria Vivax/tratamiento farmacológico , Antimaláricos/efectos adversos , Resultado del Tratamiento , Hígado , Plasmodium vivaxRESUMEN
BACKGROUND: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s. Patient adherence to IM BPG is poor, largely due to pain, the need for regular injections every 3-4 weeks and health sector delivery challenges in resource-limited settings. There is an urgent need for new approaches for secondary prophylaxis, such as an implant which could provide sustained penicillin concentrations for more than 6 months. METHODS: In this study we developed and evaluated a slow release implant with potential for substantially extended treatment. The side wall of a solid drug rich core was coated with polycaprolactone which acts as an impermeable barrier. The exposed surfaces at the ends of the implant defined the release surface area, and the in vitro release rate of drug was proportional to the exposed surface area across implants of differing diameter. The in vivo pharmacokinetics and tolerability of the implants were evaluated in a sheep model over 9 weeks after subcutaneous implantation. RESULTS: The absolute release rates obtained for the poorly water-soluble benzathine salt were dependent on the exposed surface area demonstrating the impermeability of the wall of the implant. The implants were well-tolerated after subcutaneous implantation in a sheep model, without adverse effects at the implantation site. Gross structural integrity was maintained over the course of the study, with erosion limited to the dual-exposed ends. Steady release of penicillin G was observed over the 9 weeks and resulted in approximately constant plasma concentrations close to accepted target concentrations. CONCLUSION: In principle, a long acting BPG implant is feasible as an alternative to i.m. injections for secondary prophylaxis of RHD. However, large implant size is currently a significant impediment to clinical utility and acceptability.
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Fiebre Reumática , Cardiopatía Reumática , Animales , Ovinos , Penicilina G Benzatina/uso terapéutico , Cardiopatía Reumática/prevención & control , Cardiopatía Reumática/tratamiento farmacológico , Fiebre Reumática/tratamiento farmacológico , Fiebre Reumática/prevención & control , Antibacterianos , Preparaciones de Acción Retardada/uso terapéutico , Inyecciones IntramuscularesRESUMEN
BACKGROUND: Antibodies to variant surface antigens (VSAs) such as Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) may vary with malaria severity. The influence of ABO blood group on antibody development is not understood. METHODS: Immunoglobulin G antibodies to VSAs in Papua New Guinean children with severe (n = 41) or uncomplicated (n = 30) malaria were measured by flow cytometry using homologous P falciparum isolates. Isolates were incubated with ABO-matched homologous and heterologous acute and convalescent plasma. RNA was used to assess var gene transcription. RESULTS: Antibodies to homologous, but not heterologous, isolates were boosted in convalescence. The relationship between antibody and severity varied by blood group. Antibodies to VSAs were similar in severe and uncomplicated malaria at presentation, higher in severe than uncomplicated malaria in convalescence, and higher in children with blood group O than other children. Six var gene transcripts best distinguished severe from uncomplicated malaria, including UpsA and 2 CIDRα1 domains. CONCLUSIONS: ABO blood group may influence antibody acquisition to VSAs and susceptibility to severe malaria. Children in Papua New Guinea showed little evidence of acquisition of cross-reactive antibodies following malaria. Var gene transcripts in Papua New Guinean children with severe malaria were similar to those reported from Africa.