A rapid molecular detection tool for toxigenic M1UK Streptococcus pyogenes.

BACKGROUND: The gradual replacement of the Streptococcus pyogenes M1global genotype by a newly emergent M1UK variant is a global public health threat warranting increased surveillance. M1UK differs from progenitor M1global genotype by 27 single nucleotide polymorphisms (SNPs) and is characterised by increased speA superantigen expression in vitro. METHODS: An allele-specific real-time PCR assay was developed for the rapid detection of M1UK strains. The assay was used in combination with whole-genome sequencing to determine emm (sub)type distribution for 51 invasive (n = 9) and non-invasive (n = 42) S. pyogenes clinical isolates. RESULTS: Emm1 was the most prevalent S. pyogenes emm serotype (n = 11) in this set of clinical isolates, with M1UK being the dominant emm1 genotype (4/5 invasive, 3/6 non-invasive isolates). The assay accurately detected M1UK strains. Whole genome sequencing revealed continued presence of Australian M1UK sub-lineages associated with epidemic scarlet fever-causing S. pyogenes in Asia. CONCLUSIONS: Our study establishes a suitable target for detection of the toxigenic M1UK, and confirms the maintenance of M1UK strains in Queensland, Australia. This assay can be deployed in laboratories and provides a valuable, cost-effective tool to enhance surveillance of the expanding M1UK clone.

Characterization of Gram-negative Bloodstream Infections in Hospitalized Australian Children and Their Clinical Outcomes.

BACKGROUND: Gram-negative bloodstream infections (GNBSIs) more commonly occur in children with comorbidities and are increasingly associated with antimicrobial resistance. There are few large studies of GNBSIs in children that relate the clinical presentation, pathogen characteristics, and outcomes. METHODS: A 3-year prospective study of GNBSIs in children aged <18 years was conducted in 5 Australian children's hospitals between 2019 and 2021. The clinical characteristics, disease severity, and outcomes were recorded. Causative pathogens underwent antibiotic susceptibility testing and whole genome sequencing. RESULTS: There were 931 GNBSI episodes involving 818 children. Median age was 3 years (interquartile range, 0.6-8.5). A total of 576/931 episodes (62%) were community onset, though 661/931 (71%) occurred in children with comorbidities and a central venous catheter was present in 558/931 (60%). Central venous catheter (145/931) and urinary tract (149/931) were the most common sources (16% each). One hundred of 931 (11%) children required intensive care unit admission and a further 11% (105/931) developed GNBSIs in intensive care unit. A total of 659/927 (71%) isolates were Enterobacterales, of which 22% (138/630) were third-generation cephalosporin resistant (3GCR). Extended spectrum beta-lactamase genes were confirmed in 65/138 (47%) 3GCR Enterobacterales. Most common extended spectrum beta-lactamase genes were blaCTX-M-15 (34/94, 36%) and blaSHV-12 (10/94, 11%). There were 48 deaths overall and 30-day in-hospital mortality was 3% (32/931). Infections with 3GCR Enterobacterales were independently associated with higher mortality (adjusted odds ratio, 3.2; 95% confidence interval, 1.6-6.4). CONCLUSIONS: GNBSIs in children are frequently healthcare associated and affect children younger than age 5 years. Infections with 3GCR Enterobacterales were associated with worse outcomes. These findings will inform optimal management guidelines and help prioritize future antimicrobial clinical trials.

Serum ganciclovir drug exposure in children receiving standard ganciclovir dosing.

Intravenous ganciclovir (GCV) is used for the treatment of cytomegalovirus (CMV) infection in immunocompromised children. Although the therapeutic target for treatment is unclear, studies have shown a serum area under the concentration-time curve (AUC24h) ≥40 mg/L·h correlates with effective CMV prevention. This study aimed to externally validate existing GCV population pharmacokinetic (PopPK) models and develop a model if needed and evaluate the serum AUC24h achieved with standard GCV dosing and propose an optimized dosing strategy for immunocompromised children. Ganciclovir drug monitoring data from two pediatric hospitals were retrospectively collected, and published pediatric PopPK models were externally validated. The population AUC24h with standard GCV dosing (5 mg/kg twice daily) was calculated, and an optimized dosing strategy was determined using Monte Carlo simulations to achieve an AUC24h between 40 and 100 mg/L·h. Overall, 161 samples from 23 children with a median (range) age of 9.0 years (0.4-17.0) and weight of 28.2 kg (5.6-73.3) were analyzed. Transferability of published pediatric PopPK models was limited. Thus, a one-compartment model with first-order absorption and elimination with weight and serum creatinine as covariates was developed. The median (5th-95th percentiles) steady state AUC24h with standard dosing was 38.3 mg/L·h (24.8-329.2) with 13 children having an AUC24h <40 mg/L·h, particularly those aged <4 years (8/13). An optimized simulated GCV dosing regimen, ranging from 2 to 13 mg/kg twice daily for children with normal renal function, achieved 61%-78% probability of target attainment. Standard GCV dosing likely results in inadequate drug exposure in more than half of the children, particularly those aged <4 years. An optimized dosing regimen has been proposed for clinical validation.

Prevalence of extra-pulmonary tuberculosis in Africa: A systematic review and meta-analysis.

OBJECTIVE: The burden of extra-pulmonary tuberculosis (EPTB) is not well quantified in TB endemic countries such as those in sub-Saharan Africa. This study aimed to quantify that burden via a systematic review of the prevalence of EPTB in African countries. METHODS: Studies were retrieved by searching five databases; 105 studies published between 1990 and 2023 were included. The studies described the prevalence of EPTB among the general population (4 studies), TB patients (68) and patients with other conditions, including HIV (15), meningitis (3), renal failure (3) and other comorbidities, some of which are cancer (12). Due to the low number of studies reporting EPTB in patients with conditions other than TB, the meta-analysis was performed on studies reporting on EPTB among TB patients (68 studies). Meta-analysis was performed on the 68 studies (271,073 participants) using a random-effects model to estimate the pooled prevalence of EPTB. Meta-regression was used to explore possible explanations for heterogeneity according to regions and time periods. RESULTS: The pooled prevalence of EPTB among TB patients was 26% (95% CI 23-29%). There was substantial heterogeneity of prevalence for the five African regions. The Eastern region had the highest prevalence of 32% (95% CI 28-37%) and the lowest in Western Africa, 16% (95% CI 10-24%). There was no significant difference in the prevalence of EPTB between the 3 eleven-year time periods. CONCLUSIONS: Our systematic review and meta-analysis give insight into the burden of EPTB in Africa. This review could inform clinical and programmatic practices-a higher suspicion index for clinicians and more effort for better services. This could contribute to efforts aiming to end TB, which have historically been focused on PTB.Coordinated efforts that target both EPTB and PTB are needed.

Implementing paediatric appropriate use criteria for endotracheal suction to reduce complications in mechanically ventilated children with respiratory infections.

BACKGROUND: Endotracheal suction is used to maintain endotracheal tube patency. There is limited guidance to inform clinical practice for children with respiratory infections. OBJECTIVE: The objective of this study was to determine whether implementation of a paediatric endotracheal suction appropriate use guideline Paediatric AirWay Suction (PAWS) is associated with an increased use of appropriate and decreased use of inappropriate suction interventions. METHODS: A mixed-method, pre-implementation-post-implementation study was conducted between September 2021 and April 2022. Suction episodes in mechanically ventilated children with a respiratory infection were eligible. Using a structured approach, we implemented the PAWS guideline in a single paediatric intensive care unit. Evaluation included clinical (e.g., suction intervention appropriateness), implementation (e.g., acceptability), and cost outcomes (implementation costs). Associations between implementation of the PAWS guideline and appropriateness of endotracheal suction intervention use were investigated using generalised linear models. RESULTS: Data from 439 eligible suctions were included in the analysis. Following PAWS implementation, inappropriate endotracheal tube intervention use reduced from 99% to 58%, an absolute reduction (AR) of 41% (95% confidence interval [CI]: 25%, 56%). Reductions were most notable for open suction systems (AR: 48%; 95% CI: 30%, 65%), 0.9% sodium chloride use (AR: 23%; 95% CI: 8%, 38%) and presuction and postsuction manual bagging (38%; 95% CI: 16%, 60%, and 86%; 95% CI: 73%, 99%), respectively. Clinicians perceived PAWS as acceptable and suitable for use. CONCLUSIONS: Implementation of endotracheal tube suction appropriate use guidelines in a mixed paediatric intensive care unit was associated with a large reduction in inappropriate suction intervention use in paediatric patients with respiratory infections.

A multicentre, retrospective audit of fosfomycin use for urinary tract infections in Australian children and adolescents.

BACKGROUND: Urinary tract infections (UTIs) due to MDR organisms are increasingly common. The lack of paediatric data on efficacious antibiotics makes UTI treatment particularly challenging. Data on the efficacy of fosfomycin use for UTI in children are variable. METHODS: We conducted a retrospective audit of children aged 0-18 years who were treated with fosfomycin for UTI at seven tertiary paediatric hospitals in Australia over a 7 year period, from 2014 to 2020. RESULTS: Ninety-one children with a median age of 5 years (range 2 months to 18 years) received oral fosfomycin for UTI. The majority (57/91, 63%) had one or more comorbidity, with the most common being renal tract anomalies (24/91, 26%). Fifty-nine (65%) had febrile UTI, 14/91 (15%) had pyelonephritis and 1/91 (1%) was bacteraemic. A majority (80/91, 88%) of urinary cultures had an ESBL-producing Gram-negative pathogen isolated. Fosfomycin susceptibility was evident in all 80 isolates tested. For uncomplicated UTI, the most common dose in children aged <1, 1-12 and >12 years was 1, 2 and 3 g, respectively. For complicated UTI, doses of 2 and 3 g were most common. The median duration of fosfomycin administration was 5 days (range 1-82). Clinical cure was achieved in 84/90 (93%); the six with treatment failure had underlying comorbidities. Overall, 2/91 (2%) children experienced drug-related adverse effects comprising gastrointestinal symptoms in both, which resolved after treatment discontinuation. CONCLUSIONS: Fosfomycin is well tolerated and associated with favourable treatment outcomes in children with UTI. Further research on the optimal dosing strategy is required.

Evolving insights into the epidemiology of Moraxella species bloodstream infection from two decades of surveillance in Queensland, Australia.

The epidemiology of Moraxella species bloodstream infection (BSI) is poorly defined due to their rarity. We sought to determine the incidence, risk factors, and outcomes of Moraxella species BSI in a large Australian population. All Moraxella species BSIs in patients admitted to Queensland (population estimate 5 million) public health facilities between 2000 and 2019 and submitted to Queensland pathology laboratory-based surveillance were included. Clinical and hospitalisation data were matched with laboratory-based surveillance data. Incidence rate ratios (IRR) with 95% confidence intervals (CI) were calculated. In total, 375 incident Moraxella species BSI occurred during 86 million person-years of surveillance, with an annualised age and sex standardised incidence of 4.3 per million residents. Isolates were most commonly identified as M. catarrhalis (n = 128; 34%) and community-associated (n = 225; 60%). Incidence was highest in infants, with increasing age associated with lower incidence rate. Males were at higher risk (incidence 2.9 vs. 2.0 per million, IRR1.4; 95% CI, 1.2-1.8), this was most pronounced at age extremes. Two-thirds of adults and 43% of children with Moraxella BSI had at least one comorbid illness. When compared to infections in adults, children were more likely to have community-associated disease, and a head and neck source focus of infection. The all-cause 30-day case-fatality rate was 4% (15/375) and this was significantly higher among adults (14/191; 7% vs 1/183; 1%; p < 0.001). Our findings demonstrate the low burden of Moraxella species BSI in a state-wide cohort, for which young children have the highest risk.

Neonatal Vascular Access Practice and Complications: An Observational Study of 1,375 Catheter Days.

Vascular access devices play vital roles within neonatal care. We aimed to identify neonatal vascular access device insertion and management practices, and describe the incidence and risk factors for complication development. This is a prospective cohort study of neonates requiring vascular access devices over 3 months in an Australian quaternary-referral neonatal intensive care unit. In addition to describing current practices, primary outcomes were device failure, complications, and skin complications. Results are reported using descriptive statistics and with risk factors calculated via Cox proportional hazards regression. A total of 104 neonates required 302 vascular access devices, over 1375 catheter days. Peripheral intravenous catheters (PIVCs) were most used (n = 186; 62%), followed by umbilical venous catheters (n = 52; 17%). Insertion attempts were often undocumented; but for those recorded, 5% of devices (n = 15) required 4 attempts or more. Device failure occurred in 28% (n = 82), at an incidence rate of 62.5 per 1000 catheter days (95% confidence interval [CI] 49.7-75.9). Failure was most frequent in PIVCs (37%; n = 68), peripheral arterial catheters (33%; n = 2), and peripherally inserted central catheters (20%; n = 6). Infiltration and extravasation were the most frequent cause of PIVC failure (12%; n = 35). A birth weight less than 1500 g was associated with a significant decrease in PIVC failure (hazard ratio 0.58; 95% CI 0.34-0.99).

Proof-of-concept, rapid, instrument-free molecular detection of Neisseria gonorrhoeae and ciprofloxacin susceptibility.

OBJECTIVES: To develop instrument-free point-of-care methods using recombinase polymerase amplification (RPA) technology coupled with a simple lateral flow detection system to detect Neisseria gonorrhoeae and susceptibility to ciprofloxacin. METHODS: For identification of gonococcal infection, an RPA-based method was developed targeting the gonococcal porA pseudogene (NG-porA-RPA). For ciprofloxacin susceptibility, predictive WT sequences at codons 91 and 95 of the gonococcal gyrA DNase gene were targeted. Given the known complexities of SNP detection using RPA (e.g. the ability to accommodate mismatches) we trialled several different assays incorporating various additional non-template mismatches in the oligonucleotide sequences to reduce affinity for the mutant (resistant) gyrA sequences. Assays were evaluated using a bank of N. gonorrhoeae (n = 10) and non-gonococcal (n = 5) isolates and a panel of N. gonorrhoeae nucleic acid amplification test (NAAT)-positive clinical sample extracts (n = 40). RESULTS: The NG-porA-RPA assay was specific to N. gonorrhoeae and provided a positive percentage agreement (PPA) of 87.5% (35/40) compared with a commercial N. gonorrhoeae NAAT when applied to the 40 clinical sample extracts. For gyrA, the non-template bases successfully reduced banding intensity for double-mutant strains (mutations at both 91 and 95), but not for rarer single-mutant (91 only) strains. The most promising gyrA assay, NG-gyrA-RPA08, correctly detected 83% (25/30) of infections from NAAT-positive clinical samples confirmed to have WT gyrA sequences based on Sanger sequencing. CONCLUSIONS: These proof-of-concept data show that RPA technology has considerable promise for detecting N. gonorrhoeae and associated antibiotic susceptibility and would offer a diagnostic-based stewardship strategy identified as urgently needed by the WHO.

The Paediatric AirWay Suction (PAWS) appropriateness guide for endotracheal suction interventions.

BACKGROUND/OBJECTIVE: Endotracheal suction is an invasive and potentially harmful technique used for airway clearance in mechanically ventilated children. Choice of suction intervention remains a complex and variable process. We sought to develop appropriate use criteria for endotracheal suction interventions used in paediatric populations. METHODS: The RAND Corporation and University of California, Los Angeles Appropriateness Method was used to develop the Paediatric AirWay Suction appropriateness guide. This included defining key terms, synthesising current evidence, engaging an expert multidisciplinary panel, case scenario development, and two rounds of appropriateness ratings (weighing harm with benefit). Indications (clinical scenarios) were developed from common applications or anticipated use, current practice guidelines, clinical trial results, and expert consultation. RESULTS: Overall, 148 (19%) scenarios were rated as appropriate (benefit outweighs harm), 542 (67%) as uncertain, and 94 (11%) as inappropriate (harm outweighs benefit). Disagreement occurred in 24 (3%) clinical scenarios, namely presuction and postsuction bagging across populations and age groups. In general, the use of closed suction was rated as appropriate, particularly in the subspecialty population 'patients with highly infectious respiratory disease'. Routine application of 0.9% saline for nonrespiratory indications was more likely to be inappropriate/uncertain than appropriate. Panellists preferred clinically indicated suction versus routine suction in most circumstances. CONCLUSION: Appropriate use criteria for endotracheal suction in the paediatric intensive care have the potential to impact clinical decision-making, reduce practice variability, and improve patient outcomes. Furthermore, recognition of uncertain clinical scenarios facilitates identification of areas that would benefit from future research.

MicroPIPE: validating an end-to-end workflow for high-quality complete bacterial genome construction.

BACKGROUND: Oxford Nanopore Technology (ONT) long-read sequencing has become a popular platform for microbial researchers due to the accessibility and affordability of its devices. However, easy and automated construction of high-quality bacterial genomes using nanopore reads remains challenging. Here we aimed to create a reproducible end-to-end bacterial genome assembly pipeline using ONT in combination with Illumina sequencing. RESULTS: We evaluated the performance of several popular tools used during genome reconstruction, including base-calling, filtering, assembly, and polishing. We also assessed overall genome accuracy using ONT both natively and with Illumina. All steps were validated using the high-quality complete reference genome for the Escherichia coli sequence type (ST)131 strain EC958. Software chosen at each stage were incorporated into our final pipeline, MicroPIPE. Further validation of MicroPIPE was carried out using 11 additional ST131 E. coli isolates, which demonstrated that complete circularised chromosomes and plasmids could be achieved without manual intervention. Twelve publicly available Gram-negative and Gram-positive bacterial genomes (with available raw ONT data and matched complete genomes) were also assembled using MicroPIPE. We found that revised basecalling and updated assembly of the majority of these genomes resulted in improved accuracy compared to the current publicly available complete genomes. CONCLUSIONS: MicroPIPE is built in modules using Singularity container images and the bioinformatics workflow manager Nextflow, allowing changes and adjustments to be made in response to future tool development. Overall, MicroPIPE provides an easy-access, end-to-end solution for attaining high-quality bacterial genomes. MicroPIPE is available at https://github.com/BeatsonLab-MicrobialGenomics/micropipe .

Gram-negative neonatal sepsis in low- and lower-middle-income countries and WHO empirical antibiotic recommendations: A systematic review and meta-analysis.

BACKGROUND: Neonatal sepsis is a significant global health issue associated with marked regional disparities in mortality. Antimicrobial resistance (AMR) is a growing concern in Gram-negative organisms, which increasingly predominate in neonatal sepsis, and existing WHO empirical antibiotic recommendations may no longer be appropriate. Previous systematic reviews have been limited to specific low- and middle-income countries. We therefore completed a systematic review and meta-analysis of available data from all low- and lower-middle-income countries (LLMICs) since 2010, with a focus on regional differences in Gram-negative infections and AMR. METHODS AND FINDINGS: All studies published from 1 January 2010 to 21 April 2021 about microbiologically confirmed bloodstream infections or meningitis in neonates and AMR in LLMICs were assessed for eligibility. Small case series, studies with a small number of Gram-negative isolates (<10), and studies with a majority of isolates prior to 2010 were excluded. Main outcomes were pooled proportions of Escherichia coli, Klebsiella, Enterobacter, Pseudomonas, Acinetobacter and AMR. We included 88 studies (4 cohort studies, 3 randomised controlled studies, and 81 cross-sectional studies) comprising 10,458 Gram-negative isolates from 19 LLMICs. No studies were identified outside of Africa and Asia. The estimated pooled proportion of neonatal sepsis caused by Gram-negative organisms was 60% (95% CI 55% to 65%). Klebsiella spp. was the most common, with a pooled proportion of 38% of Gram-negative sepsis (95% CI 33% to 43%). Regional differences were observed, with higher proportions of Acinetobacter spp. in Asia and Klebsiella spp. in Africa. Resistance to aminoglycosides and third-generation cephalosporins ranged from 42% to 69% and from 59% to 84%, respectively. Study limitations include significant heterogeneity among included studies, exclusion of upper-middle-income countries, and potential sampling bias, with the majority of studies from tertiary hospital settings, which may overestimate the burden caused by Gram-negative bacteria. CONCLUSIONS: Gram-negative bacteria are an important cause of neonatal sepsis in LLMICs and are associated with significant rates of resistance to WHO-recommended first- and second-line empirical antibiotics. AMR surveillance should underpin region-specific empirical treatment recommendations. Meanwhile, a significant global commitment to accessible and effective antimicrobials for neonates is required.

Rapid detection of NDM and VIM carbapenemase encoding genes by recombinase polymerase amplification and lateral flow-based detection.

Carbapenemase-producing organisms (CPOs) pose a serious clinical threat and rapid detection tools are essential to aid in patient management. We developed rapid and simple molecular tests to detect blaNDM-type and blaVIM-type carbapenemase genes using recombinase polymerase amplification (RPA) combined with a lateral flow detection. The tests could provide results in approximately 15 min when using DNA extracts, with limits of detection of 9.2 copies/µl for the blaNDM-type assay and 7.5 copies/µl for blaVIM-type assay, and successfully detected all isolates harbouring the carbapenemase encoding genes in a panel of 57 isolates. These RPA tests may be suitable for use in low-resource settings to tailor rapid implementation of infection control precautions and antibiotic stewardship.

Normal saline and lung recruitment with paediatric endotracheal suction (NARES): A pilot, factorial, randomised controlled trial.

BACKGROUND/OBJECTIVE: Endotracheal suction is one of the most common and harmful procuedres performed on mechanically ventilated children. The aim of the study was to establish the feasibility of a randomised controlled trial (RCT) examining the effectiveness of normal saline instillation (NSI) and a positive end-expiratory pressure recruitment manoeuvre (RM) with endotracheal suction in the paediatric intensive care unit. METHODS: Pilot 2 × 2 factorial RCT. The study was conducted at a 36-bed tertiary paediatric intensive care unit in Australia. Fifty-eight children aged less than 16 years undergoing tracheal intubation and invasive mechanical ventilation. (i) NSI or no NSI and (ii) RM or no RM with endotracheal suction . The primary outcome was feasibility; secondary outcomes were ventilator-associated pneumonia (VAP), change in end-expiratory lung volume assessed by electrical impedance tomography, dynamic compliance, and oxygen saturation-to-fraction of inspired oxygen (SpO2/FiO2) ratio. RESULTS/FINDINGS: Recruitment, retention, and missing data feasibility criteria were achieved. Eligibility and protocol adherence criteria were not achieved, with 818 patients eligible and 58 enrolled; cardiac surgery was the primary reason for exclusion. Approximately 30% of patients had at least one episode of nonadherence. Children who received NSI had a reduced incidence of VAP; however, this did not reach statistical significance (incidence rate ratio = 0.12, 95% confidence interval = 0.01-1.10; p = 0.06). NSI was associated with a significantly reduced SpO2/FiO2 ratio up to 10 min after suction. RMs were not associated with a reduced VAP incidence (incidence rate ratio = 0.31, 95% confidence interval = 0.05-1.88), but did significantly improve end-expiratory lung volume at 2 and 5 min after suction, dynamic compliance, and SpO2/FiO2 ratio. CONCLUSION: RMs provided short-term improvements in end-expiratory lung volume and oxygenation. NSI with suction led to a reduced incidence of VAP; however, a definitive RCT is needed to test statistical differences. A RCT of study interventions is worthwhile and may be feasible with protocol modifications including the widening of participant eligibility.

Detection of Epidemic Scarlet Fever Group A Streptococcus in Australia.

Sentinel hospital surveillance was instituted in Australia to detect the presence of pandemic group A Streptococcus strains causing scarlet fever. Genomic and phylogenetic analyses indicated the presence of an Australian GAS emm12 scarlet fever isolate related to United Kingdom outbreak strains. National surveillance to monitor this pandemic is recommended.

Revising Pediatric Vancomycin Dosing Accounting for Nephrotoxicity in a Pharmacokinetic-Pharmacodynamic Model.

This study aimed to suggest an initial pediatric vancomycin dose regimen through population pharmacokinetic-pharmacodynamic modeling. A population pharmacokinetic approach was used to analyze vancomycin concentration-time data from a large pediatric cohort. Pharmacokinetic target attainment for patients with bloodstream isolates was compared with clinical outcome using logistic regression and classification and regression trees. Change in serum creatinine during treatment was used as an indicator of acute nephrotoxicity. Probability of acute kidney injury (50% increase from baseline) or kidney failure (75% increase from baseline) was evaluated using logistic regression. An initial dosing regimen was derived, personalized by age, weight, and serum creatinine, using stochastic simulations. Data from 785 hospitalized pediatric patients (1 day to 21 years of age) with suspected Gram-positive infections were collected. Estimated (relative standard error) typical clearance, volume of distribution 1, intercompartmental clearance, and volume of distribution 2 were (standardized to 70 kg) 4.84 (2.38) liters/h, 39.9 (8.15) liters, 3.85 (17.3) liters/h, and 37.8 (10.2) liters, respectively. While cumulative vancomycin exposure correlated positively with the development of nephrotoxicity (713 patients), no clear relationship between vancomycin area under the plasma concentration-time curve and efficacy was found (102 patients). Predicted probability of acute kidney injury and kidney failure with the optimized dosing regimen at day 5 was 10 to 15% and 5 to 10%, increasing by approximately 50% on day 7 and roughly 100% on day 10 across all age groups. This study presents the first data-driven pediatric dose selection to date accounting for nephrotoxicity, and it indicates that cumulative vancomycin exposure best describes risk of acute kidney injury and acute kidney failure.

Improving antibiotic prescribing for children in the resource-poor setting.

Antibiotics are a critically important part of paediatric medical care in low- and middle-income countries (LMICs), where infectious diseases are the leading cause of child mortality. The World Health Organization estimates that >50% of all medicines are prescribed, dispensed or sold inappropriately and that half of all patients do not take their medicines correctly. Given the rising prevalence of antimicrobial resistance globally, inappropriate antibiotic use is of international concern, and countries struggle to implement basic policies promoting rational antibiotic use. Many barriers to rational paediatric prescribing in LMICs persist. The World Health Organization initiatives, such as 'Make medicines child size', the Model List of Essential Medicines for Children and the Model Formulary for Children, have been significant steps forward. Continued strategies to improve access to appropriate drugs and formulations, in conjunction with improved evidence-based clinical guidelines and dosing recommendations, are essential to the success of such initiatives on both a national and an international level. This paper provides an overview of these issues and considers future developments that may improve LMIC antibiotic prescribing.

Getting Up to Speed: Rapid Pathogen and Antimicrobial Resistance Diagnostics in Sepsis.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Time to receive effective therapy is a primary determinant of mortality in patients with sepsis. Blood culture is the reference standard for the microbiological diagnosis of bloodstream infections, despite its low sensitivity and prolonged time to receive a pathogen detection. In recent years, rapid tests for pathogen identification, antimicrobial susceptibility, and sepsis identification have emerged, both culture-based and culture-independent methods. This rapid narrative review presents currently commercially available approved diagnostic molecular technologies in bloodstream infections, including their clinical performance and impact on patient outcome, when available. Peer-reviewed publications relevant to the topic were searched through PubMed, and manufacturer websites of commercially available assays identified were also consulted as further sources of information. We have reviewed data about the following technologies for pathogen identification: fluorescence in situ hybridization with peptide nucleic acid probes (Accelerate PhenoTM), microarray-based assay (Verigene®), multiplex polymerase chain reaction (cobas® eplex, BioFire® FilmArray®, Molecular Mouse, Unyvero BCU SystemTM), matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (Rapid MBT Sepsityper®), T2 magnetic resonance (T2Bacteria Panel), and metagenomics-based assays (Karius©, DISQVER®, Day Zero Diagnostics). Technologies for antimicrobial susceptibility testing included the following: Alfed 60 ASTTM, VITEK® REVEALTM, dRASTTM, ASTar®, Fastinov®, QuickMIC®, ResistellTM, and LifeScale. Characteristics, microbiological performance, and issues of each method are described, as well as their clinical performance, when available.

Trends in Enterobacterales Bloodstream Infections in Children.

OBJECTIVES: Enterobacterales bloodstream infections (E-BSI) cause a significant burden of disease in children and are associated with antimicrobial resistance. We assessed temporal changes in the population-based incidence of E-BSI in children in Queensland, Australia. METHODS: We conducted a cohort study of incidents of E-BSI occurring in children in Queensland between 2000 and 2019, with a total population of 19.7 million child years. Infections were linked to clinical outcomes in hospital admissions and vital statistics databases. We estimated age- and sex-standardized E-BSI incidence rates over time. Secondary outcomes included the proportion of extended-spectrum ß-lactamase phenotypes per year, hospital length of stay, and mortality. RESULTS: We identified 1980 E-BSI in 1795 children. The overall age- and sex-standardized incidence rate was 9.9 cases per 100 000 child years, which increased from 7.3 to 12.9 over the period studied, an increase of 3.9% (95% confidence interval: 3.1-4.7) per year. There were 3.6 cases of E. coli bloodstream infection per 100 000 child years, increasing annually by 4.7% (3.5-5.9). The Salmonella sp. bloodstream infection incidence was 3.0 cases per 100 000 child years, which increased from 2013 by 13.7% (3.8-24.3) per year. The proportion of extended-spectrum ß-lactamase E. coli increased over time. Mortality and length of stay were higher among children with comorbidities than those without (4.0% vs 0.3%, and 14 vs 4 days, respectively, P < .001). CONCLUSIONS: The age- and sex-standardized incidence of E-BSI almost doubled in Queensland children over 2 decades, driven by increases in Salmonella sp. and E. coli. Increasing resistance of E. coli should prompt the inclusion of children in antimicrobial clinical trials.

Antimicrobial resistance in Enterobacterales, Acinetobacter spp. and Pseudomonas aeruginosa isolates from bloodstream infections in Australian children, 2013-2021.

BACKGROUND: Gram-negative bloodstream infections are associated with significant morbidity and mortality in children. Increasing antimicrobial resistance (AMR) is reported globally, yet efforts to track pediatric AMR at a national level over time are lacking. METHODS: The Australian Group on Antimicrobial Resistance (AGAR) surveillance program captures clinical and microbiological data of isolates detected in blood cultures across Australia. EUCAST 2022 was used for MIC interpretation and the AMR package in R for data analysis. RESULTS: Over a nine-year period, there were 3,145 bloodstream infections with 3,266 gram-negative isolates reported in hospitalized children aged <18 years; 21.0% were from neonates. The median length of stay was 9 days, and 30-day all-cause mortality was 5.2%. A greater odds of death was observed in those with a multi-drug resistant organism (aOR: 2.1, 95%CI: 1.3, 3.3, p: 0.001). Escherichia coli (44.5%) and Klebsiella pneumoniae complex (12.6%) were the two most frequently reported organisms. Overall resistance in Enterobacterales to gentamicin/tobramycin was 11.6%, to ceftazidime/ceftriaxone was 12.9%, and 13.2% to ciprofloxacin. Resistance increased over time.Of 201 Pseudomonas aeruginosa isolates reported, 19.7% were resistant to piperacillin-tazobactam, 13.1% resistant to cefepime/ceftazidime and 9.8% to ciprofloxacin. Of 108 Acinetobacter spp. isolates, one was resistant to meropenem, and two were resistant to ciprofloxacin. Resistance did not increase over time. CONCLUSION: AMR in gram-negative organisms causing bloodstream infections in Australian children is increasing which should be considered when updating guidelines and empiric treatment regimens. Ongoing pediatric-specific national surveillance with pediatric reporting must remain a priority to strengthen antimicrobial stewardship and infection control programs.