Pre-extensively Drug-Resistant Congenital Tuberculosis in an Extremely Premature Baby.

We describe a case of congenital tuberculosis in an extremely premature baby, with rapid molecular detection of a pre-extensively drug-resistant (XDR) pattern of drug resistance. The baby was treated successfully with a regimen including bedaquline and delamanid, drugs not previously described in the treatment of congenital tuberculosis (TB).

Chains of misery: surging invasive group A streptococcal disease.

PURPOSE OF REVIEW: We describe the epidemiology of the recent global surge in invasive group A streptococcal (GAS) disease and consider its proximate and distal causes. We highlight important knowledge gaps regarding clinical management and discuss potential strategies for prevention. RECENT FINDINGS: Rates of invasive GAS (iGAS) disease were increasing globally prior to the COVID-19 pandemic. Since mid-2022, following the worst years of the pandemic in 2020 and 2021, many countries with systems to monitor GAS syndromes have reported surges in cases of iGAS concurrent with increased scarlet fever, pharyngitis, and viral co-infections. The emergence of the hypervirulent M1UK strain as a cause of iGAS, particularly in high income countries, is concerning. New data are emerging on the transmission dynamics of GAS. GAS remains universally susceptible to penicillin but there are increasing reports of macrolide and lincosamide resistance, particularly in invasive isolates, with uncertain clinical consequences. Intravenous immunoglobulin is used widely for streptococcal toxic shock syndrome and necrotizing soft tissue infections, although there is limited clinical evidence, and none from a completed randomized controlled trial. Intensive and expensive efforts at population-level control of GAS infections and postinfectious autoimmune complications have been only partially successful. The great hope for control of GAS diseases remains vaccine development. However, all modern vaccine candidates remain in the early development stage. SUMMARY: In many countries, iGAS rates surged from mid-2022 in the aftermath of pandemic control measures and physical distancing. The emergence of a dominant hypervirulent strain is an important but incomplete explanation for this phenomenon. Clinical management of iGAS remains highly empirical and new data has not emerged. A vaccine remains the most likely means of achieving a sustainable reduction in the burden of iGAS.

A Systematic Review of Human Challenge Trials, Designs, and Safety.

BACKGROUND: Few studies have assessed participant safety in human challenge trials (HCTs). Key questions regarding HCTs include how risky such trials have been, how often adverse events (AEs) and serious adverse events (SAEs) occur, and whether risk mitigation measures have been effective. METHODS: A systematic search of PubMed and PubMed Central for articles reporting on results of HCTs published between 1980 and 2021 was performed and completed by 7 October 2021. RESULTS: Of 2838 articles screened, 276 were reviewed in full. A total of 15 046 challenged participants were described in 308 studies that met inclusion criteria; 286 (92.9%) of these studies reported mitigation measures used to minimize risk to the challenge population. Among 187 studies that reported on SAEs, 0.2% of participants experienced at least 1 challenge-related SAE. Among 94 studies that graded AEs by severity, challenge-related AEs graded "severe" were reported by between 5.6% and 15.8% of participants. AE data were provided as a range to account for unclear reporting. Eighty percent of studies published after 2010 were registered in a trials database. CONCLUSIONS: HCTs are increasingly common and used for an expanding list of diseases. Although AEs occur, severe AEs and SAEs are rare. Reporting has improved over time, though not all papers provide a comprehensive report of relevant health impacts. We found very few severe symptoms or SAEs in studies that reported them, but many HCTs did not report relevant safety data. This study was preregistered on PROSPERO as CRD42021247218.

Using a bedside test to detect genetic susceptibility to aminoglycoside-induced hearing loss: Has the future arrived?

Aminoglycosides are among the most commonly prescribed antibiotics in hospitalised Australian adults and children. A proportion of individuals with an underlying genetic predisposition to aminoglycoside-induced hearing loss (AIHL) can develop bilateral sensorineural hearing loss that is immediate and profound after just a single standard dose of an aminoglycoside. A recent publication described the use of a rapid point-of-care test (POCT) in a neonatal nursery in the United Kingdom for real-time detection of infants at risk of AIHL, in whom exposure to aminoglycosides could then be avoided. This proof of concept study should provide a catalyst for further development of similar assays that would be suitable for Australia's genetically diverse population. The barriers to mitigating the impact of AIHL on Australian children are not primarily technical, but involve a lack of data on the prevalence of the MT-RNR1 mutations in our current neonatal and paediatric populations and intensive care nurseries.

Acute rheumatic fever and rheumatic heart disease in children and adolescents in Victoria, Australia.

AIM: To describe the epidemiology and clinical profile of children and adolescents with acute rheumatic fever (ARF) and rheumatic heart disease (RHD) in Victoria, Australia. METHODS: A retrospective audit was undertaken of children and adolescents with ARF and RHD attending the Royal Children's and Monash Children's Hospitals in Victoria, Australia between 2010 and 2019. Potential cases were identified by searching multiple sources for relevant ICD-10-AM codes and keywords, then reviewed manually. For confirmed cases, we collected data on patient demographics, clinical features, comorbidities and management. RESULTS: Of 179 participants included, there were 108 Victorian residents and 71 non-Victorian residents. 126 had at least one episode of ARF during the study period and 128 were diagnosed with RHD. In the Victorian resident group, the overall incidence of ARF was 0.8 per 100 000 5-14 year olds. This incidence was higher in Victorian Aboriginal and/or Torres Strait Islander (3.8 per 100 000) and Pacific Islander (32.1 per 100 000) sub-populations. Of 83 Victorian residents who had an ARF episode, 11 (13%) had a recurrence. Most Victorian residents with RHD had mixed aortic and mitral valve pathology (69.4%) and moderate to severe disease (61.9%). Most non-Victorian residents were Aboriginal and/or Torres Strait Islander people (80.3%) and were commonly transferred for tertiary or surgical management of RHD (83.1%). CONCLUSIONS: ARF and RHD continue to affect the health of significant numbers of children and adolescents living in Victoria, including severe and recurrent disease. Specialised services and a register-based control program may help to prevent complications and premature death.

Characteristics, management and changing incidence of children with empyema in a paediatric intensive care unit.

AIM: Paediatric intensive care unit (PICU) admissions for empyema increased following the 13-valent pneumococcal conjugate vaccine (PCV13). We describe the clinical characteristics, management and outcomes for children with empyema and compare incidence before and after PCV13. METHODS: Retrospective study of patients <18 years admitted to The Royal Children's Hospital Melbourne PICU with empyema between January 2016 and July 2019. We investigated the incidence of empyema during two time periods: 2007-2010 (pre-PCV13) and 2016-2019 (post-PCV13). RESULTS: Seventy-one children (1.9% of all PICU admissions) were admitted to PICU with empyema between 2016 and 2019. Sixty-one (86%) had unilateral disease, 11 (16%) presented with shock and 44 (62%) were ventilated. Streptococcus pneumoniae and group A Streptococcus were the most commonly identified pathogens. Forty-five (63%) were managed with video-assisted thoracoscopic surgery (VATS). There was a 31% reduction in empyema hospitalisations as a proportion of all hospitalisations (IRR 0.69, 95% CI 0.59-0.8), but a 2.8-fold increase in empyema PICU admissions as a proportion of all PICU admissions (95% CI 2.2-3.5, P < 0.001). For the PICU cohort, this was accompanied by reduction in PIM2 probability of death (median 1% vs. 1.9%, P = 0.02) and duration of intubation (median 69 h vs. 126.5 h, P = 0.045). CONCLUSIONS: In children with empyema in PICU 62% required ventilation, 16% had features of shock and 63% received VATS. Empyema admissions, as a proportion of all PICU admissions, increased in the era post-PCV13 compared to pre-PCV13 despite no increase in illness severity at admission.

A Systematic Review and Meta-analysis of Upper Airway Swab Collection for Detection of Viral and Bacterial Pathogens by Individuals or Caregivers Compared to Health Care Workers.

Self- or caregiver collection of upper airway swabs reduces infectious exposures of health care workers (HCWs) and the need to redeploy clinical staff to testing roles. We aimed to determine whether self- or caregiver collection has adequate diagnostic performance for detection of viral and bacterial upper airway pathogens. We did a systematic review and meta-analysis of studies comparing diagnostic accuracy of self- or caregiver-collected upper airway swabs collected by patients or caregivers compared to HCWs. All study types except case reports and series were included if sufficient data were presented to calculate sensitivity, specificity, and Cohen's kappa. Studies published from 1946 to 17 August 2020 were included in the search. We did a meta-analysis to assess pooled sensitivity and specificity. Twenty studies were included in the systematic review and 15 in the meta-analysis. The overall sensitivity of swabs collected by patients or caregivers compared to HCWs was 91% (95% confidence interval [CI], 87 to 94), and specificity was 98% (95% CI, 96 to 99). Sensitivity ranged from 65% to 100% and specificity from 73% to 100% across the studies. All but one study concluded that self- or caregiver-collected swabs were acceptable for detection of upper airway pathogens. Self- and caregiver collection of upper airway swabs had reassuring diagnostic performance for multiple pathogens. There are numerous potential benefits of self- and caregiver-collected swabs for patients, families, researchers, and health systems. Further research to optimize implementation of sample collection by patients and caregivers is warranted.

An emm-type specific qPCR to track bacterial load during experimental human Streptococcus pyogenes pharyngitis.

BACKGROUND: Streptococcus pyogenes causes a profound global burden of morbidity and mortality across its diverse clinical spectrum. To support a new controlled human infection ('challenge') model seeking to accelerate S. pyogenes vaccine development, we aimed to develop an accurate and reliable molecular method for quantifying bacterial load from pharyngeal swabs collected during experimental human pharyngitis. METHODS: Combined sequential RNA + DNA extraction from throat swabs was compared to traditional separate RNA-only and DNA-only extractions. An emm-type specific qPCR was developed to detect the emm75 challenge strain. Results from the qPCR were compared to culture, using throat swab samples collected in a human challenge study. RESULTS: The qPCR was 100% specific for the emm75 challenge strain when tested against a panel of S. pyogenes emm-types and other respiratory pathogens. Combined RNA + DNA extraction had similar yield to traditional separate extractions. The combined extraction method and emm75 qPCR had 98.8% sensitivity compared to culture for throat swabs collected from challenge study participants. CONCLUSIONS: We have developed a reliable molecular method for measuring S. pyogenes bacterial load from throat swabs collected in a controlled human infection model of S. pyogenes pharyngitis. TRIAL REGISTRATION: NCT03361163 on 4th December 2017.

Payment in challenge studies: ethics, attitudes and a new payment for risk model.

Controlled Human Infection Model (CHIM) research involves the infection of otherwise healthy participants with disease often for the sake of vaccine development. The COVID-19 pandemic has emphasised the urgency of enhancing CHIM research capability and the importance of having clear ethical guidance for their conduct. The payment of CHIM participants is a controversial issue involving stakeholders across ethics, medicine and policymaking with allegations circulating suggesting exploitation, coercion and other violations of ethical principles. There are multiple approaches to payment: reimbursement, wage payment and unlimited payment. We introduce a new Payment for Risk Model, which involves paying for time, pain and inconvenience and for risk associated with participation. We give philosophical arguments based on utility, fairness and avoidance of exploitation to support this. We also examine a cross-section of the UK public and CHIM experts. We found that CHIM participants are currently paid variable amounts. A representative sample of the UK public believes CHIM participants should be paid approximately triple the UK minimum wage and should be paid for the risk they endure throughout participation. CHIM experts believe CHIM participants should be paid more than double the UK minimum wage but are divided on the payment for risk. The Payment for Risk Model allows risk and pain to be accounted for in payment and could be used to determine ethically justifiable payment for CHIM participants.Although many research guidelines warn against paying large amounts or paying for risk, our empirical findings provide empirical support to the growing number of ethical arguments challenging this status quo. We close by suggesting two ways (value of statistical life or consistency with risk in other employment) by which payment for risk could be calculated.

Incidence of acute rheumatic fever and rheumatic heart disease in Melbourne, Australia from 1937 to 2013.

AIM: Acute rheumatic fever (ARF) most commonly presents in children aged 5-14 years old. Lifelong rheumatic heart disease (RHD) can result. This study investigated time trends in ARF and RHD using inpatient data from the Royal Children's Hospital, Melbourne (RCH). METHODS: A retrospective cohort study covering the period 1937-2013 was conducted using records from RCH, a quaternary paediatric hospital in Melbourne, Victoria, Australia. Patient data were identified using RCH classification of diseases coding for ARF or RHD for years <1952. For the period 1952-1987, this system was used in addition to identifying International Classification of Disease (ICD) discharge codes that corresponded to ARF or RHD. From 1988-2013, only ICD codes were used to identify patient data. Descriptive epidemiological analyses were performed, including incidence rate calculations using historical census population denominator data. Analyses focussed on children in the peak age group. RESULTS: Among children aged five to 14 years, a total of 4337 RCH admissions with ARF/RHD occurred for 3015 patients. A sharp decline in first ARF/RHD hospitalisations at RCH occurred from 1959, following a peak mean annual incidence rate during 1944-1947 of 40.1/100 000 children (95% confidence interval (CI): 36.6-43.9; P < 0.05). Over 1996-2013, the mean annual incidence rate was 1.6/100 000 (95% CI: 1.3-1.8) and reached 2.3/100 000 (95% CI: 1.3-3.7) in 2005. CONCLUSION: The burden of ARF and RHD treated at RCH declined following the 1940s, mirroring changes seen in North America and Europe. Despite this, inpatient treatment for these conditions continued to be provided right up until the end of the study period.

International survey of paediatric infectious diseases consultants on the management of community-acquired pneumonia complicated by pleural empyema.

AIM: Community-acquired pneumonia (CAP) complicated by pleural empyema is an important paediatric problem. Antibiotic management decisions are made on the basis of little available data and without strong specific recommendations in guidelines. METHODS: This was an online survey of paediatric infectious diseases (PID) physicians disseminated by major international professional organisations, examining empiric and targeted antibiotic choice, switch to oral antibiotics and duration of treatment for two hypothetical cases of contrasting severity. RESULTS: This study included 183 responses, mostly from North America, Western Europe and Australia/New Zealand. Increased disease severity was significantly associated with broader-spectrum and combination empiric and targeted antibiotic treatment, empiric methicillin-resistant Staphylococcus aureus (MRSA) coverage and both longer intravenous (IV) and total duration of antibiotic treatment. Empirical MRSA coverage was also associated with local prevalence. Clinical progress was most important for determining the timing of the switch from IV to oral antibiotics. Few respondents chose antibiotics with activity against organisms associated with atypical pneumonia (e.g. Mycoplasma, Chlamydia), and most did not choose agents that inhibit protein synthesis (e.g. clindamycin), even in the case of a severe invasive group A streptococcal infection. Some variation in targeted treatment choices reflected areas of uncertainty, such as Streptococcus pneumoniae susceptibility breakpoints, comparative effectiveness of anti-staphylococcal penicillins and first-generation cephalosporins for serious S. aureus infections and linezolid and vancomycin for MRSA pneumonia. CONCLUSIONS: This international survey of PID physicians highlights the priority targets for clinical research to improve antibiotic treatment of CAP complicated by empyema. Interventions that might be studied include empirical antibiotic guidelines stratified by case severity, adjunctive empirical use of agents that inhibit protein synthesis (e.g. clindamycin) and approaches to encourage rapid IV-to-oral switch and shorter total antibiotic treatment.

Australia-wide point prevalence survey of the use and appropriateness of antimicrobial prescribing for children in hospital.

OBJECTIVES: To describe antimicrobial use in hospitalised Australian children and to analyse the appropriateness of this antimicrobial use. DESIGN: Multicentre single-day hospital-wide point prevalence survey, conducted in conjunction with the Antimicrobial Resistance and Prescribing in European Children study. SETTING: Eight children's hospitals across five Australian states, surveyed during late spring and early summer 2012. PATIENTS: Children and adolescents who were inpatients at 8 am on the day of the survey. MAIN OUTCOME MEASURES: Quantity and quality of antimicrobial prescribing. RESULTS: Of 1373 patients, 631 (46%) were prescribed at least one antimicrobial agent, 198 (31%) of whom were < 1 year old. The highest antimicrobial prescribing rates were in haematology and oncology wards (76% [95/125]) and paediatric intensive care units (55% [44/80]). Of 1174 antimicrobial prescriptions, 550 (47%) were for community-acquired infections, 175 (15%) were for hospital-acquired infections and 437 (37%) were for prophylaxis. Empirical treatment accounted for 72% of antimicrobial prescriptions for community-acquired infections and 58% for hospital-acquired infections (395 and 102 prescriptions, respectively). A total of 915 prescriptions (78%) were for antibacterials; antifungals and antivirals were predominantly used for prophylaxis. The most commonly prescribed antibacterials were narrow-spectrum penicillins (18% [164 prescriptions]), ß-lactam-ß-lactamase inhibitor combinations (15% [136]) and aminoglycosides (14% [128]). Overall, 957 prescriptions (82%) were deemed appropriate, but this varied between hospitals (range, 66% [74/112]) to 95% [165/174]) and specialties (range, 65% [122/187] to 94% [204/217]). Among surgical patients, 65 of 187 antimicrobial prescriptions (35%) were deemed inappropriate, and a common reason for this was excessive prophylaxis duration. CONCLUSION: A point prevalence survey is a useful cross-sectional method for quantifying antimicrobial use in paediatric populations. The value is significantly augmented by adding assessment of prescribing quality.

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

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

Global Streptococcus pyogenes strain diversity, disease associations, and implications for vaccine development: a systematic review.

The high strain diversity of Streptococcus pyogenes serves as a major obstacle to vaccine development against this leading global pathogen. We did a systematic review of studies in PubMed, MEDLINE, and Embase that reported the global distribution of S pyogenes emm-types and emm-clusters from Jan 1, 1990, to Feb 23, 2023. 212 datasets were included from 55 countries, encompassing 74 468 bacterial isolates belonging to 211 emm-types. Globally, an inverse correlation was observed between strain diversity and the UNDP Human Development Index (HDI; r=-0·72; p<0·0001), which remained consistent upon subanalysis by global region and site of infection. Greater strain diversity was associated with a lower HDI, suggesting the role of social determinants in diseases caused by S pyogenes. We used a population-weighted analysis to adjust for the disproportionate number of epidemiological studies from high-income countries and identified 15 key representative isolates as vaccine targets. Strong strain type associations were observed between the site of infection (invasive, skin, and throat) and several streptococcal lineages. In conclusion, the development of a truly global vaccine to reduce the immense burden of diseases caused by S pyogenes should consider the multidimensional diversity of the pathogen, including its social and environmental context, and not merely its geographical distribution.

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.

Mycobacterium ulcerans challenge strain selection for a Buruli ulcer controlled human infection model.

Critical scientific questions remain regarding infection with Mycobacterium ulcerans, the organism responsible for the neglected tropical disease, Buruli ulcer (BU). A controlled human infection model has the potential to accelerate our knowledge of the immunological correlates of disease, to test prophylactic interventions and novel therapeutics. Here we present microbiological evidence supporting M. ulcerans JKD8049 as a suitable human challenge strain. This non-genetically modified Australian isolate is susceptible to clinically relevant antibiotics, can be cultured in animal-free and surfactant-free media, can be enumerated for precise dosing, and has stable viability following cryopreservation. Infectious challenge of humans with JKD8049 is anticipated to imitate natural infection, as M. ulcerans JKD8049 is genetically stable following in vitro passage and produces the key virulence factor, mycolactone. Also reported are considerations for the manufacture, storage, and administration of M. ulcerans JKD8049 for controlled human infection.