Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Phylodynamic signatures in the emergence of community-associated MRSA.

Community-associated, methicillin-resistant Staphylococcus aureus (MRSA) lineages have emerged in many geographically distinct regions around the world during the past 30 y. Here, we apply consistent phylodynamic methods across multiple community-associated MRSA lineages to describe and contrast their patterns of emergence and dissemination. We generated whole-genome sequencing data for the Australian sequence type (ST) ST93-MRSA-IV from remote communities in Far North Queensland and Papua New Guinea, and the Bengal Bay ST772-MRSA-V clone from metropolitan communities in Pakistan. Increases in the effective reproduction number (Re) and sustained transmission (Re > 1) coincided with spread of progenitor methicillin-susceptible S. aureus (MSSA) in remote northern Australian populations, dissemination of the ST93-MRSA-IV genotype into population centers on the Australian East Coast, and subsequent importation into the highlands of Papua New Guinea and Far North Queensland. Applying the same phylodynamic methods to existing lineage datasets, we identified common signatures of epidemic growth in the emergence and epidemiological trajectory of community-associated S. aureus lineages from America, Asia, Australasia, and Europe. Surges in Re were observed at the divergence of antibiotic-resistant strains, coinciding with their establishment in regional population centers. Epidemic growth was also observed among drug-resistant MSSA clades in Africa and northern Australia. Our data suggest that the emergence of community-associated MRSA in the late 20th century was driven by a combination of antibiotic-resistant genotypes and host epidemiology, leading to abrupt changes in lineage-wide transmission dynamics and sustained transmission in regional population centers.

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.

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.

Antibody to Plasmodium falciparum Variant Surface Antigens, var Gene Transcription, and ABO Blood Group in Children With Severe or Uncomplicated Malaria.

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.

Phylodynamic Inference of Bacterial Outbreak Parameters Using Nanopore Sequencing.

Nanopore sequencing and phylodynamic modeling have been used to reconstruct the transmission dynamics of viral epidemics, but their application to bacterial pathogens has remained challenging. Cost-effective bacterial genome sequencing and variant calling on nanopore platforms would greatly enhance surveillance and outbreak response in communities without access to sequencing infrastructure. Here, we adapt random forest models for single nucleotide polymorphism (SNP) polishing developed by Sanderson and colleagues (2020. High precision Neisseria gonorrhoeae variant and antimicrobial resistance calling from metagenomic nanopore sequencing. Genome Res. 30(9):1354-1363) to estimate divergence and effective reproduction numbers (Re) of two methicillin-resistant Staphylococcus aureus (MRSA) outbreaks from remote communities in Far North Queensland and Papua New Guinea (PNG; n = 159). Successive barcoded panels of S. aureus isolates (2 × 12 per MinION) sequenced at low coverage (>5× to 10×) provided sufficient data to accurately infer genotypes with high recall when compared with Illumina references. Random forest models achieved high resolution on ST93 outbreak sequence types (>90% accuracy and precision) and enabled phylodynamic inference of epidemiological parameters using birth-death skyline models. Our method reproduced phylogenetic topology, origin of the outbreaks, and indications of epidemic growth (Re > 1). Nextflow pipelines implement SNP polisher training, evaluation, and outbreak alignments, enabling reconstruction of within-lineage transmission dynamics for infection control of bacterial disease outbreaks on portable nanopore platforms. Our study shows that nanopore technology can be used for bacterial outbreak reconstruction at competitive costs, providing opportunities for infection control in hospitals and communities without access to sequencing infrastructure, such as in remote northern Australia and PNG.

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.

Success of Debridement, Antibiotics, and Implant Retention in Prosthetic Joint Infection Following Primary Total Knee Arthroplasty: Results From a Prospective Multicenter Study of 189 Cases.

BACKGROUND: This study aimed to identify the success rate of debridement, antibiotics, and implant retention (DAIR) for prosthetic joint infection (PJI) in a large prospective cohort of patients undergoing total knee arthroplasty (TKA). The ability for different PJI classification systems to predict success was assessed. METHODS: Prospective data recorded in the Prosthetic Joint Infection in Australia and New Zealand Observational study were analyzed. One hundred eighty-nine newly diagnosed knee PJIs were managed with DAIR between July 2014 and December 2017. Patients were prospectively followed up for 2 years. A strict definition of success was used, requiring the patient being alive with documented absence of infection, no ongoing antibiotics and the index prosthesis in place. Success was compared against the Coventry (early PJI ≤1 month), International Consensus Meeting (early ≤90 days), Auckland (early <1 year), and Tsukayama (early ≤1 month, hematogenous >1 month with <7 days symptoms, chronic >1 month with >7 days symptoms) classifications. RESULTS: DAIR success was 45% (85/189) and was highest in early PJIs defined according to the Coventry (adjusted odds ratio [aOR] = 3.9, P = .01), the International Consensus Meeting (aOR = 3.1, P = .01), and the Auckland classifications (aOR = 2.6, P = .01). Success was lower in both hematogenous (aOR = 0.4, P = .03) and chronic infections (aOR = 0.1, P = .003). CONCLUSION: Time since primary TKA is an important predictor of DAIR success. Success was highest in infections occurring <1 month of the primary TKA and progressively decreased as time since the primary TKA increased.

Invasive Infections Caused by Lancefield Groups C/G and A Streptococcus, Western Australia, Australia, 2000-2018.

Epidemiologic data on invasive group C/G Streptococcus (iGCGS) infections are sparse internationally. Linked population-level hospital, pathology, and death data were used to describe the disease burden in Western Australia, Australia, during 2000-2018 compared with that of invasive group A Streptococcus (GAS, Streptococcus pyogenes) infections. Of 1,270 cases, 866 (68%) occurred in men. Patients with iGCGS infection were older (median age 62 years) than those with invasive GAS (median age 44 years; p<0.0001). The age and sex-adjusted incidence rate ratio by year was 1.08 (95% CI 1.07-1.09). The incidence rate ratio for Indigenous compared with non-Indigenous Australians was 3.6 (95% CI 3.0-4.3). The all-cause 90-day death rate was 9% for iGCGS infection compared with 7% for invasive GAS (p = 0.03). iGCGS infection was more common in men and older persons and had a higher death rate, perhaps reflecting the effect of age and comorbidities on incidence and death.

Piperaquine Pharmacokinetic and Pharmacodynamic Profiles in Healthy Volunteers of Papua New Guinea after Administration of Three-Monthly Doses of Dihydroartemisinin-Piperaquine.

Mass drug administration (MDA) with monthly dihydroartemisinin-piperaquine (DHA-PQP) appears useful in malaria control and elimination strategies. Determining the relationship between consecutive piperaquine phosphate (PQP) exposure and its impact on QT interval prolongation is a key safety consideration for MDA campaigns. Healthy volunteers from Papua New Guinea received a 3-day course of DHA-PQP (2.1/17.1 mg/kg) monthly for 3 consecutive months in a single arm longitudinal study. Plasma PQP concentrations were measured after the third dose of each course (at 52-54 h) and at 0 h of course 3. Twelve-lead electrocardiographic readings were conducted at 0 h, 48 h, 52 h, and day 7 of each course. QT interval corrected by Fridericia's formula (QTcF) was measured at each time point. A pharmacokinetic-pharmacodynamic model using nonlinear mixed effects models was developed to correlate PQP concentrations with QTcF. Ten thousand female and 10,000 male individuals were simulated at each treatment course. Eighty-two participants were included; mean age was 28.3 years (standard deviation [SD] ±12.3 years), and 36 (44%) were female. Pharmacokinetic-pharmacodynamic models were determined with 290 PQP concentrations and 868 QTcF observations. The average baseline QTcF was 392 ms with a between-subject variability SD ±14.4 ms and between-occasion variability SD ±3.64 ms. From the population modeled, only 0.08% of males and 0.45% of females would be at risk of an absolute QTcF of >500 ms. DHA-PQP is safe at standard doses in consecutive months, and the likelihood of severe cardiac events occurring during an MDA campaign is very low. This study has been registered at ClinicalTrials.gov under identifier NCT02605720.

Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling.

BACKGROUND: Acute rheumatic fever (ARF), an autoimmune reaction to Group A Streptococcus (Streptococcus pyogenes; Strep A) infection, can cause rheumatic heart disease (RHD). New formulations of long-acting penicillins are being developed for secondary prophylaxis of ARF and RHD. OBJECTIVES: To evaluate the penicillin G concentrations required to suppress growth of Strep A. METHODS: Broth microdilution MIC and MBC for Strep A strains M75611024, M1T15448 and M18MGAS8232 were determined. All strains were studied in a hollow fibre model (initial inoculum 4 log10 cfu/mL). Constant penicillin G concentrations of 0.008, 0.016 and 0.05 mg/L were examined against all strains, plus 0.012 mg/L against M18MGAS8232. Viable counts were determined over 144 h. Subsequently, all penicillin G-treated cartridges were emptied, reinoculated with 5 log10 cfu/mL and counts determined over a further 144 h. Mathematical modelling was performed. RESULTS: MIC and MBC were 0.008 mg/L for all strains; small subpopulations of M75611024 and M1T15448, but not M18MGAS8232, grew at 1× MIC. Following the first inoculation, 0.008 mg/L achieved limited killing and/or stasis against M75611024 and M1T15448, with subsequent growth to ∼6 log10 cfu/mL. Following both inocula, concentrations ≥0.016 mg/L suppressed M75611024 and M1T15448 to <1 log10 cfu/mL from 6 h onwards with eradication. Concentrations ≥0.008 mg/L suppressed M18MGAS8232 to <1 log10 cfu/mL from 24 h onwards with eradication after both inoculations. Mathematical modelling well described all strains using a single set of parameter estimates, except for different maximum bacterial concentrations and proportions of bacteria growing at 1× MIC. CONCLUSIONS: In the absence of validated animal and human challenge models, the study provides guidance on penicillin G target concentrations for development of new penicillin formulations.

Population pharmacokinetic study of benzathine penicillin G administration in Indigenous children and young adults with rheumatic heart disease in the Northern Territory, Australia.

BACKGROUND: Benzathine penicillin G (BPG) is the cornerstone of secondary prophylaxis to prevent Streptococcus pyogenes infections, which precede acute rheumatic fever (ARF). The paucity of pharmacokinetic (PK) data from children and adolescents from populations at the highest risk of ARF and rheumatic heart disease (RHD) poses a challenge for determining the optimal dosing and frequency of injections and undermines efforts to develop improved regimens. METHODS: We conducted a 6 month longitudinal PK study of young people receiving BPG for secondary prophylaxis. Throat and skin swabs were collected for microbiological culture along with dried blood spot (DBS) samples for penicillin concentrations. DBSs were assayed using LC-MS/MS. Penicillin concentration datasets were analysed using non-linear mixed-effects modelling and simulations performed using published BMI-for-age and weight-for-age data. RESULTS: Nineteen participants provided 75 throat swabs, 3 skin swabs and 216 penicillin samples. Throat cultures grew group C and G Streptococcus. Despite no participant maintaining penicillin concentration >20 ng/mL between doses, there were no S. pyogenes throat infections and no ARF. The median (range) observed durations >20 ng/mL for the low- and high-BMI groups were 14.5 (11.0-24.25) and 15.0 (7.5-18.25) days, respectively. CONCLUSIONS: Few patients at highest risk of ARF/RHD receiving BPG for secondary prophylaxis maintain penicillin concentrations above the target of 20 ng/mL beyond 2 weeks during each monthly dosing interval. These PK data suggest that some high-risk individuals may get inadequate protection from every 4 week dosing. Future research should explore this gap in knowledge and PK differences between different populations to inform future dosing schedules.

Longitudinal changes in serum testosterone and sex hormone-binding globulin in men aged 40-69 years from the UK Biobank.

OBJECTIVE: Testosterone and sex hormone-binding globulin (SHBG) concentrations are reported to decline during male ageing, but whether these changes reflect physiological ageing or age-related comorbidities remains uncertain. We examined longitudinal changes in serum testosterone and SHBG concentrations in middle-aged to older men, concordance between baseline and follow-up values and relationships with concomitant changes in lifestyle and medical factors. DESIGN: Population-based longitudinal cohort study. PARTICIPANTS: Community-dwelling men aged 40-69 years. MEASUREMENTS: Immunoassay serum total testosterone (n = 7812) and SHBG (n = 6491) at baseline (2006-2010) and follow-up (2012-2013). Free testosterone (cFT) was calculated. Bland-Altman analyses and concordance correlation of repeated measurements were conducted. Associations of changes in hormone concentrations with lifestyle and medical factors were explored using Spearman's rank correlation. RESULTS: Over 4.3 years follow-up, there was a negligible mean change (±SE) in serum total testosterone concentration (+0.06 ± 0.03 nmol/L), whereas mean SHBG concentration increased (+3.69 ± 0.12 nmol/L) and cFT decreased (-10.7 ± 0.7 pmol/L). Concordance estimates were 0.67 (95% confidence interval [CI]: 0.66-0.69) for total testosterone, 0.83 (CI = 0.82-0.84) for SHBG and 0.56 (CI = 0.54-0.58) for cFT. Changes in serum total testosterone correlated with changes in SHBG (Spearman's rank ρ = 0.33, CI = 0.30-0.35), and inversely with changes in body mass index (BMI) (ρ = -0.18, CI = -0.20 to -0.16) and waist circumference (ρ = -0.13, CI = -0.15 to -0.11) and in SHBG with changes in BMI (ρ = -0.34, CI = -0.36 to -0.32) and waist circumference (ρ = -0.21, CI = -0.24 to -0.19). CONCLUSION: In relatively healthy middle-aged to older men, mean serum total testosterone concentration is stable with ageing, while mean SHBG concentration increases. Both total testosterone and SHBG concentrations were highly concordant over time.

Stability of benzylpenicillin for continuous intravenous infusions: An isotonic formulation for therapeutic use and a low-dose formulation for clinical trial.

INTRODUCTION: The objectives of this study were to develop a stability-indicating high performance liquid chromatography (HPLC) assay for benzylpenicillin (BPC) in pharmaceutical fluids, and to investigate the stability of (i) isotonic citrate-buffered BPC solutions at the clinically relevant concentration of 30 mg/mL, and (ii) low concentration citrate-buffered BPC intravenous infusions (5-30 µg/mL). METHODS: The stability of isotonic BPC solutions containing 3.4 or 7.2 mg/mL sodium citrate was compared against contemporary hypertonic solutions. The HPLC assay was shown to be stability-indicating following acidic, alkali, oxidative and elevated temperature stress testing. RESULTS: After 7 d storage at 4 °C and 24 h at 35 °C, the concentrations of isotonic BPC 30 mg/mL solutions containing 3.4 and 7.2 mg/mL sodium citrate were 96% and 95% respectively, compared to day 0. After 3 d at 4 °C and 24 h at room temperature (22 °C), the concentrations of isotonic BPC solutions with 3.4 and 7.2 mg/mL sodium citrate were 99% and 96% respectively, compared to day 0. These data were comparable to the hypertonic solutions and meet pharmacopeial stability requirements. Low concentration BPC infusions showed 0.5% and 2.5% degradation after 24 h storage at 22 °C and 35 °C, respectively. CONCLUSIONS: The isotonic BPC 30 mg/mL formulation is simple to prepare and may offer clinical benefits in settings where hypertonic solutions are problematic. This study provides assurance that high- and low-dose isotonic BPC infusions are stable at room temperature and our findings may be applicable to in vitro studies of BPC.

Proposed empiric antibiotic therapy for prosthetic joint infections: an analysis of the Prosthetic Joint Infection in Australia and New Zealand, Observational (PIANO) cohort.

Empiric antibiotic therapy in suspected prosthetic joint infection should cover likely pathogens while avoiding overly broad-spectrum antibiotics. We analysed individual patient data from a large prospective cohort study (Prosthetic Joint Infection in Australia and New Zealand, Observational (PIANO)) and found that causative organisms vary with the presentation type, with early post-operative infections more likely to be polymicrobial (41%) compared with late acute infections (10%). We thus propose empirical regimens tailored to the presentation type and presence or absence of sepsis.

Antifungal use via outpatient parenteral antimicrobial therapy.

BACKGROUND: Antifungal administration via outpatient parenteral antimicrobial therapy (OPAT) is infrequent. As patients with invasive fungal infections (IFIs) receiving OPAT are at high risk of readmissions, careful, risk-based patient selection and monitoring is important. OBJECTIVES: To describe our experience managing IFIs via OPAT, including assessment of risk factors associated with unplanned readmissions. PATIENTS AND METHODS: A retrospective cohort study of outpatients from two tertiary hospitals in Western Australia managed with parenteral antifungals for the treatment of IFIs from 2012 to 2020. Outcomes assessed were unplanned OPAT-related readmissions; adverse events and achievement of treatment aim at the completion of OPAT. RESULTS: Forty-six patients were included, encompassing 696 OPAT days. Twenty-three (50%) patients received intravenous (IV) liposomal amphotericin B (L-AmB), 23 (50%) received IV echinocandins and one (2%) patient received IV fluconazole. One patient received both IV L-AmB and an echinocandin. Unplanned OPAT-related readmissions occurred in 13 (28%) patients and any adverse event occurred in 19 (41%), most commonly nephrotoxicity amongst patients receiving L-AmB. On univariate analysis, unplanned OPAT-related readmissions were more common in Mucorales infection, L-AmB doses of ≥5 mg/kg and otorhinolaryngologic (ENT) infections. At the completion of OPAT, attainment of treatment aims occurred in 28 (61%) patients. CONCLUSIONS: Patients receiving parenteral antifungals via OPAT experience high rates of unplanned readmissions and adverse events. Risk factor identification may facilitate optimal patient selection and establishment of treatment aims.

Wound healing with "spray-on" autologous skin grafting (ReCell) compared with standard care in patients with large diabetes-related foot wounds: an open-label randomised controlled trial.

There is an urgent need for interventions that improve healing time, prevent amputations and recurrent ulceration in patients with diabetes-related foot wounds. In this randomised, open-label trial, participants were randomised to receive an application of non-cultured autologous skin cells ("spray-on" skin; ReCell) or standard care interventions for large (>6 cm2 ), adequately vascularised wounds. The primary outcome was complete healing at 6 months, determined by assessors blinded to the intervention. Forty-nine eligible foot wounds in 45 participants were randomised. An evaluable primary outcome was available for all wounds. The median (interquartile range) wound area at baseline was 11.4 (8.8-17.6) cm2 . A total of 32 (65.3%) index wounds were completely healed at 6 months, including 16 of 24 (66.7%) in the spray-on skin group and 16 of 25 (64.0%) in the standard care group (unadjusted OR [95% CI]: 1.13 (0.35-3.65), P = .845). Lower body mass index (P = .002) and non-plantar wounds (P = .009) were the only patient- or wound-related factors associated with complete healing at 6 months. Spray-on skin resulted in high rates of complete healing at 6 months in patients with large diabetes-related foot wounds, but was not significantly better than standard care (Australian New Zealand Clinical Trials Registry: ACTRN12618000511235).

Revisiting the inoculum effect for Streptococcus pyogenes with a hollow fibre infection model.

Severe, invasive Streptococcus pyogenes (Strep A) infections result in greater than 500,000 deaths annually. First line treatment for such infections is benzylpenicillin, often with the addition of clindamycin, but treatment failure can occur with this regimen. This failure has been partially attributed to the inoculum effect, which presents as reduced antibiotic susceptibility during high bacterial density and plateau-phase growth. Hollow fibre infection models (HFIM) have been proposed as an in vitro alternative to in vivo research to study these effects. To re-evaluate the inoculum effect for benzylpenicillin, clindamycin, linezolid, and trimethoprim-sulfamethoxazole using a Strep A HFIM. Differential antibiotic susceptibility of Strep A was measured in a HFIM starting from low- and high-density inocula with an average difference in bacterial concentration of 56-fold. Dynamic antibiotic concentrations were delivered over 48 h to simulate in vivo human pharmacokinetics in an in vitro model. Differences in antibiotic susceptibility were measured by plate count of colony-forming units over time. Inoculum effects were seen in benzylpenicillin and linezolid at 24 h, and benzylpenicillin, linezolid, and clindamycin at 48 h. The effect size was greatest for continuously infused benzylpenicillin at 48 h with a log10-fold difference of 4.02 between groups. No inoculum effect was seen in trimethoprim-sulfamethoxazole, with a maximal log10-fold difference of 0.40. Inoculum effects were seen using benzylpenicillin, linezolid, and clindamycin, which may predict reduced clinical efficacy following treatment delay. The model has proven robust and largely in agreeance with published data, recommending it for further Strep A study.

Increasing incidence of invasive group A streptococcal disease in Western Australia, particularly among Indigenous people.

OBJECTIVE: To quantify the burden of invasive group A Streptococcus (GAS) disease in Western Australia during 2000-2018. DESIGN, SETTING: Population-based data linkage study: Hospital Morbidity Data Collection (HMDC; all WA public and private hospital records), PathWest pathology data (government-owned pathology services provider), and death registrations. PARTICIPANTS: People with invasive GAS disease, defined by an isolate from a normally sterile site (PathWest) or a hospital-based principal ICD-10-AM diagnosis code (HMDC). MAIN OUTCOME MEASURES: Incidence of invasive GAS disease; median length of hospital stay; all-cause mortality. RESULTS: We identified 2237 cases of GAS disease during 2000-2018; 1283 were in male patients (57%). 1950 cases had been confirmed by GAS isolates from normally sterile tissues (87%; including 1089 from blood [56% of cases] and 750 from tissue [38%]). The age-standardised incidence increased from 2.0 (95% CI, 1.4-2.7) cases per 100 000 population in 2000 to 9.1 (95% CI, 7.9-10.2) cases per 100 000 in 2017 (by year, adjusted for age group and sex: incidence rate ratio [IRR], 1.09; 95% CI, 1.08-1.10). Incidence was consistently higher among Indigenous than non-Indigenous Australians (year-adjusted IRR, 13.1; 95% CI, 11.3-15.1). All-cause 30-day mortality was 5% (116 deaths), and 90-day mortality 7% (156 deaths); 30-day mortality, adjusted for age group and sex, was not statistically significantly different for cases involving Indigenous or non-Indigenous patients (adjusted odds ratio, 0.8; 95% CI, 0.6-1.1). CONCLUSIONS: The incidence of invasive GAS disease in WA increased between 2000 and 2018, particularly among Indigenous Australians. Mandatory notification of invasive GAS disease would therefore be appropriate. The social determinants of differences in incidence should be addressed, and other relevant host, pathogen, and health system factors investigated.

The Australian burden of invasive group A streptococcal disease: a narrative review.

The Australian and New Zealand governments have allocated significant funding to advance efforts towards a group A Streptococcus (Strep A) vaccine. The argument for Strep A vaccine development has to date focussed on prevention of non-invasive disease (e.g. pharyngitis) and immune-mediated complications (especially rheumatic heart disease). Because of the poorer prognosis and theoretically more precisely known burden of invasive, compared to non-invasive disease, exploration of the burden of invasive Strep A disease could lend further support to the vaccine business case. This narrative review critically assesses the Australian incidence of invasive Strep A disease. Case notification data were first assessed through government sources, expressing annual incidence as cases per 100 000 population. Published literature accessed through PubMed and MEDLINE was assessed to March 2020. Where estimates could be updated by replicating reported methods with publicly available data, this was performed. Invasive Strep A disease is currently notifiable in Queensland and the Northern Territory only. The magnitude, degree of certainty and recency of estimates vary by state/territory and between sub-populations, including higher incidence among Indigenous Australians compared to non-Indigenous Australians. According to inpatient records from 2017 to 2018, the Australian incidence of invasive Strep A disease was 8.3 per 100 000. However, this is likely to be an underestimate. Preventing invasive Strep A disease is an important use for a Strep A vaccine. This narrative review highlights deficiencies in our current understanding of the Australian disease burden. These difficulties would be overcome by nationally consistent mandatory case reporting.