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Objectives: Studies examining time to positivity (TTP) of blood cultures as a risk factor for death have shown conflicting results. The study objective was to examine the effect of TTP on all-cause-30-day case-fatality among a population-based cohort of patients with bloodstream infections (BSI)., Methods: A retrospective cohort study including all residents of Queensland, Australia with incident monomicrobial BSI managed in the publicly funded healthcare system from 2000 to 2019 was performed. Clinical, TTP and all-cause 30-day case-fatality information was obtained from state-wide sources., Results: A cohort of 88 314 patients was assembled. The median TTP was 14 hours, with 5th, 25th, 75th, and 95th percentiles of 4, 10, 20, and 53 hours, respectively. The TTP varied significantly by BSI aetiology. The 30-day all-cause case-fatality rate was 2606/17 879 (14.6%), 2834/24 272 (11.7%), 2378/20 359 (11.7%), and 2752/22 431 (12.3%) within the first, second, third, and fourth TTP quartiles, respectively (p < 0.0001). After adjustment for age, sex, onset, comorbidity, and focus of infection, TTP within 10 hours (first quartile) was associated with a significantly increased risk for death (odds ratio 1.43; 95% CI, 1.35-1.50; p < 0.001). After adjustment for confounding variables (odds ratio; 95% CI), TTP within the first quartile for Staphylococcus aureus (1.56; 1.41-1.73), Streptococcus pneumoniae (1.91; 1.49-2.46), β-hemolytic streptococci (1.23; 1.00-1.50), Pseudomonas species (2.23; 1.85-2.69), Escherichia coli (1.37; 1.23-1.53), Enterobacterales (1.38; 1.16-1.63), other Gram-negatives (1.68; 1.36-2.06), and anaerobes (1.58; 1.28-1.94) increased the risk for case-fatality., Discussion: This population-based analysis provides evidence that TTP is an important determinant of mortality among patients with BSI., (Copyright © 2024 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Clinical trials of treatments for serious infections commonly use the primary endpoint of all-cause mortality. However, many trial participants survive their infection and this endpoint may not truly reflect important benefits and risks of therapy. The win ratio uses a hierarchical composite endpoint that can incorporate and prioritize outcome measures by relative clinical importance., Methods: The win ratio methodology was applied post hoc to outcomes observed in the MERINO trial, which compared piperacillin-tazobactam with meropenem. We quantified the win ratio with a primary hierarchical composite endpoint, including all-cause mortality, microbiological relapse, and secondary infection. A win ratio of 1 would correspond to no difference between the 2 antibiotics, while a ratio <1 favors meropenem. Further analyses were performed to calculate the win odds and to introduce a continuous outcome variable in order to reduce ties., Results: With the hierarchy of all-cause mortality, microbiological relapse, and secondary infection, the win ratio estimate was 0.40 (95% confidence interval [CI], .22-.71]; P = .002), favoring meropenem over piperacillin-tazobactam. However, 73.4% of the pairs were tied due to the small proportion of events. The win odds, a modification of the win ratio accounting for ties, was 0.79 (95% CI, .68-.92). The addition of length of stay to the primary composite greatly minimized the number of ties (4.6%) with a win ratio estimate of 0.77 (95% CI, .60-.99; P = .04)., Conclusions: The application of the win ratio methodology to the MERINO trial data illustrates its utility and feasibility for use in antimicrobial trials., Competing Interests: Potential conflicts of interest. D. L. P. has received research funding from Shionogi, Merck, Gilead, bioMérieux, BioVersys, and Pfizer; has received consulting fees from the AMR Action Fund, CARB-X, Aurobac, Innoviva, GSK, Pfizer, Merck, Cepheid, bioMérieux, and Spero; has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Merck, bioMérieux, and Cepheid; reports receipt of consumables for use in clinical trial from bioMérieux and receipt of antibiotics for use in clinical trials from Pfizer and Shionogi; and reports an unpaid role on the board of the Australasian Society of Infectious Diseases. M. H. is an employee of Pfizer and holds Pfizer stock options. Y. M. has received honoraria from Pfizer. P. N. A. H. reports research grants from Gilead; served on an advisory board for Sandoz; received honoraria from OpGen, Gilead, and Pfizer; and received travel support and accommodation for a speaking event from Pfizer. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Although Proteus species are occasional causes of serious infections, their epidemiology has not been well defined. The objective was to describe the overall and species-specific occurrence and determinants of Proteus species bloodstream infection (BSI) in a large Australian population., Methods: All Queensland residents with Proteus species BSI identified within the publicly funded healthcare system between 2000 and 2019 were included., Results: A total of 2,143 incident episodes of Proteus species BSI were identified among 2,079 Queensland residents. The prevalence of comorbid illness differed with higher Charlson comorbidity scores observed with P. penneri and P. vulgaris, and higher prevalence of liver disease with P. penneri, higher comorbid cancer with P. vulgaris, and lower diabetes and renal disease prevalence with P. mirabilis BSIs., Conclusion: This study provides novel information on the epidemiology of Proteus species BSI., Competing Interests: Declaration of competing interest P.H. participated as an advisory board member for both MSD and Sandoz, payment was paid to the University of Queensland. K.B.L and F.E. have no conflicts of interest, (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neonatal meningitis is a devastating disease associated with high mortality and neurological sequelae. Escherichia coli is the second most common cause of neonatal meningitis in full-term infants (herein NMEC) and the most common cause of meningitis in preterm neonates. Here, we investigated the genomic relatedness of a collection of 58 NMEC isolates spanning 1974-2020 and isolated from seven different geographic regions. We show NMEC are comprised of diverse sequence types (STs), with ST95 (34.5%) and ST1193 (15.5%) the most common. No single virulence gene profile was conserved in all isolates; however, genes encoding fimbrial adhesins, iron acquisition systems, the K1 capsule, and O antigen types O18, O75, and O2 were most prevalent. Antibiotic resistance genes occurred infrequently in our collection. We also monitored the infection dynamics in three patients that suffered recrudescent invasive infection caused by the original infecting isolate despite appropriate antibiotic treatment based on antibiogram profile and resistance genotype. These patients exhibited severe gut dysbiosis. In one patient, the causative NMEC isolate was also detected in the fecal flora at the time of the second infection episode and after treatment. Thus, although antibiotics are the standard of care for NMEC treatment, our data suggest that failure to eliminate the causative NMEC that resides intestinally can lead to the existence of a refractory reservoir that may seed recrudescent infection., Competing Interests: NN, MP, SH, KP, LA, BF, SA, TM, PH, SB, SS, HB, PT, AB, BW, AI, MS No competing interests declared, (© 2023, Nhu et al.)

Background: A prompt diagnosis of bacteraemia and sepsis is essential. Markers to predict the risk of persistent bacteraemia and metastatic infection are lacking. SeptiCyte RAPID is a host response assay stratifying patients according to the risk of infectious vs sterile inflammation through a scoring system (SeptiScore). In this study we explore the association between SeptiScore and persistent bacteraemia as well as metastatic and persistent infection in the context of a proven bacteraemia episode., Methods: This is a prospective multicentre observational 14-month study on patients with proven bacteraemia caused by Staphylococcus aureus or Gram-negative bacilli. Samples for assessment by SeptiCyte were collected with paired blood cultures for 4 consecutive days after the index blood culture., Results: We included 86 patients in the study, 40 with S. aureus and 46 with Gram-negative bacilli bacteraemia. SeptiScores over the follow-up were higher in patients with Gram-negative compared to S. aureus bacteraemia (median 6.4, IQR 5.5-7.4 vs 5.6 IQR 5.1-6.2, p  = 0.002). Higher SeptiScores were found to be associated with positive blood cultures at follow-up (AUC = 0.86, 95%CI 0.68-1.00) and with a diagnosis of metastatic infection at day 1 and 2 of follow-up (AUC = 0.79, 95%CI 0.57-1.00 and AUC = 0.82, 95%CI 0.63-1.00 respectively) in the context of Gram-negative bacteraemia while no association between SeptiScore and the outcomes of interest was observed in S. aureus bacteraemia. Mixed models confirmed the association of SeptiScore with positive blood cultures at follow-up ( p  = 0.04) and metastatic infection ( p  = 0.03) in the context of Gram-negative bacteraemia but not S. aureus bacteraemia after adjusting for confounders., Conclusions: SeptiScores differ in the follow-up of S. aureus and Gram-negative bacteraemia. In the setting of Gram-negative bacteraemia SeptiScore demonstrated a good negative predictive value for the outcomes of interest and might help rule out the persistence of infection defined as metastatic spread, lack of source control or persistent bacteraemia.

Purpose: Early recognition and effective treatment of sepsis improves outcomes in critically ill patients. However, antibiotic exposures are frequently suboptimal in the intensive care unit (ICU) setting. We describe the feasibility of the Bayesian dosing software Individually Designed Optimum Dosing Strategies (ID-ODS™), to reduce time to effective antibiotic exposure in children and adults with sepsis in ICU., Methods: A multi-centre prospective, non-randomised interventional trial in three adult ICUs and one paediatric ICU. In a pre-intervention Phase 1, we measured the time to target antibiotic exposure in participants. In Phase 2, antibiotic dosing recommendations were made using ID-ODS™, and time to target antibiotic concentrations were compared to patients in Phase 1 (a pre-post-design)., Results: 175 antibiotic courses (Phase 1 = 123, Phase 2 = 52) were analysed from 156 participants. Across all patients, there was no difference in the time to achieve target exposures (8.7 h vs 14.3 h in Phase 1 and Phase 2, respectively, p = 0.45). Sixty-one courses in 54 participants failed to achieve target exposures within 24 h of antibiotic commencement (n = 36 in Phase 1, n = 18 in Phase 2). In these participants, ID-ODS™ was associated with a reduction in time to target antibiotic exposure (96 vs 36.4 h in Phase 1 and Phase 2, respectively, p < 0.01). These patients were less likely to exhibit subtherapeutic antibiotic exposures at 96 h (hazard ratio (HR) 0.02, 95% confidence interval (CI) 0.01-0.05, p < 0.01). There was no difference observed in in-hospital mortality., Conclusions: Dosing software may reduce the time to achieve target antibiotic exposures. It should be evaluated further in trials to establish its impact on clinical outcomes., (© 2024. The Author(s).)

The past decade has seen an increase in the prevalence of sequence type (ST) 45 methicillin-resistant Staphylococcus aureus (MRSA), yet the underlying drivers for its emergence and spread remain unclear. To better understand the worldwide dissemination of ST45 S. aureus, we performed phylogenetic analyses of Australian isolates, supplemented with a global population of ST45 S. aureus genomes. Our analyses revealed a distinct lineage of multidrug-resistant ST45 MRSA harbouring qacA, predominantly found in Australia and Singapore. Bayesian inference predicted that the acquisition of qacA occurred in the late 1990s. qacA was integrated into a structurally variable region of the chromosome containing Tn552 (carrying blaZ) and Tn4001 (carrying aac(6')-aph(2")) transposable elements. Using mutagenesis and in vitro assays, we provide phenotypic evidence that qacA confers tolerance to chlorhexidine. These findings collectively suggest both antimicrobial resistance and the carriage of qacA may play a role in the successful establishment of ST45 MRSA., (© 2024. The Author(s).)

Background: Bloodstream infections (BSIs) caused by carbapenem-resistant Enterobacterales (CRE) are a global health concern. Rapid identification of CRE may improve patient outcomes and reduce inappropriate antibiotic prescription. The use of risk-scoring tools (RSTs) can be valuable for optimizing the decision-making process for empirical antibiotic therapy of suspected CRE bacteraemia. These tools can also be used to triage use of expensive rapid diagnostic methods., Methods: We systematically reviewed the relevant literature in PubMed/MEDLINE, CINAHL, Cochrane, Web of Science, Embase and Scopus up to 1 November 2022 to identify RSTs that predict CRE BSIs. The literature review and analysis of the articles were performed by two researchers; any inconsistencies were resolved through discussion., Results: We identified 9 RSTs developed for early prediction of CRE BSIs and only logistic regression was used for most studies. These RSTs were quite different from each other in terms of their performance and the variables they included. They also had notable limitations and very few of them were externally validated., Conclusions: RSTs for early prediction of CRE BSIs have limitations and lack of external validity outside the local setting in which they were developed. Future studies to identify optimal RSTs in high and low CRE-endemic settings are warranted. Approaches based on rapid diagnostics and RSTs should be compared with a treatment approach using both methods in a randomized controlled trial., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Persistent Staphylococcus aureus bacteremia is associated with metastatic infection and adverse outcomes, whereas gram-negative bacteremia is normally transient and shorter course therapy is increasingly advocated for affected patients. Whether the prolonged detection of pathogen DNA in blood by culture-independent systems could have prognostic value and guide management decisions is unknown., Methods: We performed a multicenter, prospective, observational study on 102 patients with bloodstream infection (BSI) to compare time to bloodstream clearance according to T2 magnetic resonance and blood cultures over a 4-day follow-up. We also explored the association between duration of detectable pathogens according to T2 magnetic resonance (magnetic resonance-DNAemia [MR-DNAemia]) and clinical outcomes., Results: Time to bloodstream clearance according to T2 magnetic resonance was significantly longer than blood culture clearance (HR, .54; 95% CI, .39-.75) and did not differ according to the causative pathogen (P = .5). Each additional day of MR-DNAemia increased the odds of persistent infection (defined as metastatic infection or delayed source control) both in the overall population (OR, 1.98; 95% CI, 1.45-2.70) and in S. aureus (OR, 1.92; 95% CI, 1.12-3.29) and gram-negative bacteremia (OR, 2.21; 95% CI, 1.35-3.60). MR-DNAemia duration was also associated with no improvement in Sequential Organ Failure Assessment score at day 7 from infection onset (OR, 1.76; 95% CI, 1.21-2.56)., Conclusions: T2 magnetic resonance may help diagnose BSI in patients on antimicrobials with negative blood cultures as well as to identify patients with metastatic infection, source control failure, or adverse short-term outcome. Future studies may inform its usefulness within the setting of antimicrobial stewardship programs., Competing Interests: Potential conflicts of interest. D. L. P. has received research funding from Shionogi, Merck, bioMerieux, BioVersys, and Pfizer and has received consulting fees from the AMR Action Fund, CARB-X, Aurobac, Pfizer, Merck, Cepheid, bioMerieux, and Spero and reports a role on the board of the Australasian Society for Infectious Diseases. P. N. A. H. reports research grants from Gilead; has served on advisory boards for OpGen, Merck, and Sandoz; and has received honoraria from OpGen, Sandoz, Pfizer, and bioMerieux. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We aimed to evaluate the performance of Oxford Nanopore Technologies (ONT) sequencing from positive blood culture (BC) broths for bacterial identification and antimicrobial susceptibility prediction. Patients with suspected sepsis in four intensive care units were prospectively enrolled. Human-depleted DNA was extracted from positive BC broths and sequenced using ONT (MinION). Species abundance was estimated using Kraken2, and a cloud-based system (AREScloud) provided in silico predictive antimicrobial susceptibility testing (AST) from assembled contigs. Results were compared to conventional identification and phenotypic AST. Species-level agreement between conventional methods and AST predicted from sequencing was 94.2% (49/52), increasing to 100% in monomicrobial infections. In 262 high-quality AREScloud AST predictions across 24 samples, categorical agreement (CA) was 89.3%, with major error (ME) and very major error (VME) rates of 10.5% and 12.1%, respectively. Over 90% CA was achieved for some taxa (e.g., Staphylococcus aureus ) but was suboptimal for Pseudomonas aeruginosa . In 470 AST predictions across 42 samples, with both high quality and exploratory-only predictions, overall CA, ME, and VME rates were 87.7%, 8.3%, and 28.4%. VME rates were inflated by false susceptibility calls in a small number of species/antibiotic combinations with few representative resistant isolates. Time to reporting from sequencing could be achieved within 8-16 h from BC positivity. Direct sequencing from positive BC broths is feasible and can provide accurate predictive AST for some species. ONT-based approaches may be faster but significant improvements in accuracy are required before it can be considered for clinical use.IMPORTANCESepsis and bloodstream infections carry a high risk of morbidity and mortality. Rapid identification and susceptibility prediction of causative pathogens, using Nanopore sequencing direct from blood cultures, may offer clinical benefit. We assessed this approach in comparison to conventional phenotypic methods and determined the accuracy of species identification and susceptibility prediction from genomic data. While this workflow holds promise, and performed well for some common bacterial species, improvements in sequencing accuracy and more robust predictive algorithms across a diverse range of organisms are required before this can be considered for clinical use. However, results could be achieved in timeframes that are faster than conventional phenotypic methods., Competing Interests: Lukas Lüftinger and Stephan Beisken are employees of Ares Genetics. Patrick Harris reports research grants from Gilead, has served on advisory boards for OpGen, Merck, and Sandoz, and has received honoraria from OpGen, Sandoz, Pfizer, and BioMerieux. David Paterson reports grants from Shionogi, Pfizer, Merck and bioMerieux, and consultancies with the AMR Action Fund, Entasis, QPex, Spero, VenatoRx, Pfizer, Merck, Gilead, bioMerieux, and Accelerate Diagnostics. Jason Roberts reports grants from Qpex, Gilead, Pfizer, Sandoz, MSD, Summit Pharma, and Cipla. Adam Irwin has received research grants and honoraria from Gilead, and honoraria from bioMerieux unrelated to this work.

Objectives: The objective of this systematic review and meta-analysis was to estimate the global prevalence of multi-drug resistant (MDR) Pseudomonas aeruginosa causing ventilator-associated pneumonia (VAP)., Methods: The systematic search was conducted in four databases. Original studies describing MDR P. aeruginosa VAP prevalence in adults from 2012- 2022 were included. A meta-analysis, using the random effects model, was conducted for overall, subgroups (country, published year, study duration, and study design), and European data, respectively. Univariate meta-regression based on pooled estimates was also conducted. Systematic review registered in International Prospective Register of Systematic Review (CRD42022384035)., Results: In total of 31 studies, containing a total of 7951 cases from 16 countries, were included. The overall pooled prevalence of MDR among P. aeruginosa causing VAP was 33% (95% confidence interval [CI] 27.7-38.3%). The highest prevalence was for Iran at 87.5% (95% CI 69-95.7%), and the lowest was for the USA at 19.7% (95% CI 18.6-20.7%). The European prevalence was 29.9% (95% CI 23.2-36.7%)., Conclusions: This review indicates that the prevalence of MDR P. aeruginosa in patients with VAP is generally high and varies significantly between countries; however, data are insufficient for many countries. The data in this study can provide a reference for VAP management and drug customisation strategies., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Existing tools for phylogeographic and epidemiological visualisation primarily provide a macro-geographic view of epidemic and pandemic transmission events but offer little support for detailed investigation of outbreaks in healthcare settings. Here, we present HAIviz, an interactive web-based application designed for integrating and visualising genomic epidemiological information to improve the tracking of healthcare-associated infections (HAIs). HAIviz displays and links the outbreak timeline, building map, phylogenetic tree, patient bed movements, and transmission network on a single interactive dashboard. HAIviz has been developed for bacterial outbreak investigations but can be utilised for general epidemiological investigations focused on built environments for which visualisation to customised maps is required. This paper describes and demonstrates the application of HAIviz for HAI outbreak investigations.

Background: Vibrio species bloodstream infections have been associated with significant mortality and morbidity. Limited information is available regarding the epidemiology of bloodstream infections because of Vibrio species in the Australian context., Aims: The objective of this study was to define the incidence and risk factors for developing Vibrio species bloodstream infections and compare differences between different species., Methods: All patients with Vibrio spp. isolated from positive blood cultures between 1 January 2000 and 31 December 2019 were identified by the state-wide Pathology Queensland laboratory. Demographics, clinical foci of infections and comorbid conditions were collected in addition to antimicrobial susceptibility results., Results: About 100 cases were identified between 2000 and 2019 with an incidence of 1.2 cases/1 million person-years. Seasonal and geographical variation occurred with the highest incidence in the summer months and in the tropical north. Increasing age, male sex and multiple comorbidities were identified as risk factors. Vibrio vulnificus was isolated most frequently and associated with the most severe disease. Overall case fatality was 19%., Conclusions: There is potential for increasing cases of Vibrio species infections globally with ageing populations and climate change. Ongoing clinical awareness is required to ensure optimal patient outcomes., (© 2023 Royal Australasian College of Physicians.)

Objectives: This population-based study aimed to investigate the risk factors and effect of extended-spectrum beta-lactamase (ESBL) production on clinical outcomes in Escherichia coli bloodstream infection (BSI) patients., Methods: The study population was defined as patients aged ≥15 years with E. coli BSI in Queensland, Australia, from 2000 to 2019. Outcomes were defined as 30-day case fatality, hospital length of stay (LOS), and recurrent E. coli BSI., Results: A total of 27,796 E. coli BSIs were identified, of which 1112 (4.0%) were ESBL-producers. Patients with ESBL-Ec BSI were more frequently older, male, with comorbidity, recurrent E. coli BSI, and less likely with community-associated community-onset infections as compared to non-ESBL-Ec BSI patients. The standardized mortality rate of ESBL-Ec BSI increased 8-fold from 2000 to 2019 (1 to 8 per million residents) and case fatality was 12.8% (n = 142) at 30 days from positive blood culture. Patients with ESBL-Ec BSI were not at higher risk of 30-day case fatality (adjusted hazard ratio [HR] = 0.98, 95% CI: 0.83-1.17), but had higher risk of recurring episodes (adjusted subdistribution HR = 1.58, 95% CI: 1.29-1.92) and observed 14% longer LOS (adjusted incidence rate ratio = 1.14, 95% CI: 1.10-1.18) than non-ESBL-Ec BSI patients., Conclusion: In this large patient cohort, ESBL-Ec BSI did not increase case fatality risk but observed higher hospital LOS and recurrent E. coli BSI than non-ESBL-Ec BSI. Clinical resources are warranted to account for the higher morbidity risk associated with ESBL production and incidence., Competing Interests: Declarations of competing interest DLP has received research grants from Merck, Pfizer, bioMerieux, and Shionogi outside of the submitted work. He has also received personal fees from AMR Action Fund, Merck, Pfizer, Shionogi, Spero, Lysovant, The Medicines Company, Entasis, VenatoRx, QPex, bioMerieux, and Accelerate, and is conducting a study on E. coli vaccination sponsored by Janssen. PNAH has received research grants from Merck, Sharpe, and Dohme (MSD), Sandoz, and Shionogi Ltd, outside of the submitted work, and has served on advisory boards for OpGen, Merck, and Sandoz and received speakers fees from Pfizer, OpGen, and Sandoz paid to the University of Queensland. The remaining authors have no competing interests to declare., (Copyright © 2023. Published by Elsevier Ltd.)

Knowledge of the epidemiology of bloodstream infection (BSI) in haematology patients is essential to guide patient management. We investigated the epidemiology of BSI in patients with haematological malignancies in Queensland over the last 20 years (2000-2019), including all episodes diagnosed by the state-wide microbiology service. We identified 7749 BSI in 5159 patients, 58% associated with neutropenia. Gram-negatives were the main causative pathogens (58.3%), more frequent in neutropenic than non-neutropenic patients (3308/5309, 62.3% vs 1932/3678, 52.5%, p < 0.001). Amongst 8987 isolates the most common were E. coli (15.4%) and Pseudomonas spp. (14.2%). Pseudomonas spp. (16.6% vs 10.7%, p < 0.001), Klebsiella spp. (11.6% vs 6.8%, p < 0.001), viridans-group streptococci (4.4% vs 1.2%, p < 0.001) and E. faecium (2.4% vs 0.9%, p < 0.001) were more common in neutropenic than non-neutropenic patients, while S. aureus was less common (5.9% vs 15.6%, p < 0.001). Several antimicrobial resistance rates increased over time and had higher prevalence in neutropenic than non-neutropenic patients, including ciprofloxacin-resistant E. coli (94/758, 12.4% vs 42/506, 8.3%, p = 0.021), trimethoprim-sulfamethoxazole-resistant E. coli (366/764, 47.9% vs 191/517, 36.9%, p < 0.001), penicillin-resistant streptococci (51/236, 21.6% vs 28/260, 10.8%, p < 0.001) and vancomycin-resistant enterococci (46/250, 18.4% vs 9/144, 6.3%, p < 0.001). Carbapenem-resistant Pseudomonas spp. (OR 7.32, 95%CI 2.78-19.32) and fungi, including yeasts and moulds (OR 3.33, 95%CI 2.02-5.48) were associated to the highest odds of 30-day case-fatality at a multivariable logistic regression analysis. Neutropenia was associated with survival (OR 0.66, 95%CI 0.55-0.78). Differences were observed in the BSI epidemiology according to neutropenic status, with an overall increase of resistance over time associated to adverse outcome., (© 2023. The Author(s).)

The continued emergence and transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants requires ongoing genetic surveillance to support public health responses. The expansion of reliable next generation sequence (NGS) platforms has enabled the rapid characterisation of the constant emergence of new SARS-CoV-2 variants using nasopharyngeal swab specimens. Several studies have assessed the ability of COVIDSeq to type earlier SARS-CoV-2 strains (pre-Delta) rapidly and successfully, however, there is limited data showing suitability against Omicron variants. In the present study, we evaluated the performance of the Illumina COVIDSeq Assay as a streamlined amplicon-based NGS platform for detection and typing of Omicron variants. Our results demonstrate the high performance of SARS-CoV-2 sequencing using the COVIDSeq approach, with good repeatability, reproducibility and sensitivity for samples approaching C T 31. The COVIDSeq approach was 100% concordant with samples previously characterized by sequencing methods. The quick library preparation process and high throughput kit made it ideal for reflex testing, with a total time required for sequencing and analysis of approximately two days. This study demonstrates the effectiveness and versatility of the amplicon-based NGS characterisation method for SARS-CoV-2, providing a foundation for further research and development of custom-designed amplicon panels targeting different microorganisms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Piperacillin-tazobactam (PTZ) is one of the most common antibiotics administered to hospitalized patients. Its broad activity against gram-negative, gram-positive, and anaerobic pathogens; efficacy in clinical trials across diverse infection types and patient populations; and generally favorable toxicity profile make it a particularly appealing antibiotic agent. PTZ susceptibility interpretive criteria (ie, breakpoints) for the Enterobacterales were initially established in 1992, as the drug was undergoing approval by the US Food and Drug Administration. In the ensuing 30 years, changes in the molecular epidemiology of the Enterobacterales and its impact on PTZ susceptibility testing, mounting pharmacokinetic/pharmacodynamic data generated from sophisticated techniques such as population pharmacokinetic modeling and Monte Carlo simulation, and disturbing safety signals in a large clinical trial prompted the Clinical Laboratory and Standards Institute (CLSI) to review available evidence to determine the need for revision of the PTZ breakpoints for Enterobacterales. After an extensive literature review and formal voting process, the susceptibility criteria were revised in the 2022 CLSI M100 document to the following: ≤8/4 µg/mL (susceptible), 16/4 µg/mL (susceptible dose-dependent), and ≥32/4 µg/mL (resistant). Herein, we provide a brief overview of the CLSI process of antibiotic breakpoint revisions and elaborate on the available data that ultimately led to the decision to revise the PTZ breakpoints., Competing Interests: Potential conflicts of interest. P. N. A. H. has received research grants from Merck & Co, Inc., Sandoz Pharmaceuticals, and Shionogi, Inc.; speaker's fees from Phizer, Inc., Sumitomo Corporation, and Sandoz Pharmaceuticals; and has served on advisory boards for Merck & Co, Inc. and Sandoz Pharmaceuticals. A. J. M. serves on the Advisory Board for Merck & Co, Inc. and Qpex Biopharma, and reports consulting fees from Merck & Co, Inc., Qpex Biopharma, and Melinta Therapeutics. E. W. serves on the speaker's bureau for AbbVie, Inc, Astellas Pharma, Melinta Therapeutics, and Shionogi, Inc., and on the advisory board for Shionogi, Inc., and Merck & Co, Inc.; and reports consulting fees from bioMerieux, Inc.. R. M. H. is a consultant for Roche, Pattern Bioscience, bioMerieux, Inc., Torus Biosystems, Merck & Co, Inc., Qpex Biopharma, and Melinta Therapeutics and reports grants or contracts from bioMerieux, Inc., Momentum Bioscience, International Health Management Associates (IHMA), Qiagen, Pattern Bioscience, and Specific Diagnostics; and stock or stock options include Accelerate Diagnostics, Specific Diagnostics, and NGD Diagnostics. All authors serve as unpaid volunteers for the CLSI. There was no external support for this work. P. D. T. reports no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: There is a lack of international consensus as to whether high- or low-level disinfection (HLD or LLD) is required for ultrasound (US) transducers used during percutaneous procedures. This study compared the effectiveness of LLD to HLD on US transducers contaminated with microorganisms from skin., Methods: Two identical linear US transducers repeatedly underwent either LLD or HLD during the study. Randomization determined which of these transducers was applied to left and right forearms of each participant. Swabs taken from transducers before and after reprocessing were plated then incubated for 4-5 days, after which colony forming units (CFU) were counted and identified. The primary hypothesis was the difference in the proportion of US transducers having no CFUs remaining after LLD and HLD would be less than or equal to the noninferiority margin of -5%., Results: Of the 654 recruited participants 73% (n = 478) had microbial growth from both transducers applied to their left and right forearms before reprocessing. These were included in the paired noninferiority statistical analysis where, after disinfection, all CFUs were eliminated in 100% (95% CI: 99.4-100.0%) of HLD transducer samples (n = 478) and 99.0% (95% CI: 97.6-99.7%) of LLD transducer samples (n = 473). The paired difference in the proportion of transducers having all CFUs eliminated between LLD and HLD was -1.0% (95% CI: -2.4 to -0.2%, P-value <.001)., Conclusions: Disinfection with LLD is noninferior to HLD when microorganisms from skin have contaminated the transducer. Therefore, using LLD for US transducers involved in percutaneous procedures would present no higher infection risk compared with HLD., (© 2023 The Authors. Journal of Ultrasound in Medicine published by Wiley Periodicals LLC on behalf of American Institute of Ultrasound in Medicine.)

Background: The clinical and genomic epidemiology of melioidosis varies across regions., Aim: To describe the clinical and genetic diversity of B. pseudomallei across Queensland, Australia., Methods: Whole genome sequencing of clinical isolates stored at the melioidosis reference lab from 1996-2020 was performed and analysed in conjunction with available clinical data., Results: Isolates from 292 patients were analysed. Bacteraemia was present in 71% and pneumonia in 65%. The case-fatality rate was 25%. Novel sequence types (ST) accounted for 51% of all isolates. No association was identified between the variable virulence factors assessed and patient outcome. Over time, the proportion of First Nation's patients declined from 59% to 26%, and the proportion of patients aged >70 years rose from 13% to 38%., Conclusion: This study describes a genomically diverse and comparatively distinct collection of B. pseudomallei clinical isolates from across Queensland, Australia. An increasing incidence of melioidosis in elderly patients may be an important factor in the persistently high case-fatality in this region and warrants further investigation and directed intervention., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gassiep et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: Although Klebsiella aerogenes (formerly Enterobacter aerogenes) and Enterobacter cloacae share many phenotypic characteristics, controversy exists as to whether they cause clinically distinguishable infections. The objective of this study was to determine the comparative incidence, determinants, and outcomes of K. aerogenes and E. cloacae bloodstream infections (BSI)., Methods: Population-based surveillance was conducted among residents aged ≥ 15 years of Queensland, Australia during 2000-2019., Results: Overall 695 and 2879 incident K. aerogenes and E. cloacae BSIs were identified for incidence rates of 1.1 and 4.4 per 100,000 population, respectively. There was a marked increase in incidence associated with older age and with males with both species. Patients with K. aerogenes BSIs were older, were more likely male, to have community-associated disease, and to have a genitourinary source of infection. In contrast, E. cloacae were more likely to have co-morbid diagnoses of liver disease and malignancy and be associated with antimicrobial resistance. Enterobacter cloacae were significantly more likely to have repeat episodes of BSI as compared to K. aerogenes. However, no differences in length of stay or all cause 30-day case-fatality were observed., Conclusion: Although significant demographic and clinical differences exist between K. aerogenes and E. cloacae BSI, they share similar outcomes., (© 2023. The Author(s).)

Background: Cefiderocol is generally active against carbapenem-resistant Klebsiella spp. (CRK) with higher MICs against metallo-beta-lactamase producers. There is a variation in cefiderocol interpretive criteria determined by EUCAST and CLSI. Our objective was to test CRK isolates against cefiderocol and compare cefiderocol susceptibilities using EUCAST and CLSI interpretive criteria., Methods: A unique collection ( n  = 254) of mainly OXA-48-like- or NDM-producing CRK bloodstream isolates were tested against cefiderocol with disc diffusion (Mast Diagnostics, UK). Beta-lactam resistance genes and multilocus sequence types were identified using bioinformatics analyses on complete bacterial genomes., Results: Median cefiderocol inhibition zone diameter was 24 mm (interquartile range [IQR] 24-26 mm) for all isolates and 18 mm (IQR 15-21 mm) for NDM producers. We observed significant variability between cefiderocol susceptibilities using EUCAST and CLSI breakpoints, such that 26% and 2% of all isolates, and 81% and 12% of the NDM producers were resistant to cefiderocol using EUCAST and CLSI interpretive criteria, respectively., Conclusions: Cefiderocol resistance rates among NDM producers are high using EUCAST criteria. Breakpoint variability may have significant implications on patient outcomes. Until more clinical outcome data are available, we suggest using EUCAST interpretive criteria for cefiderocol susceptibility testing.

Background: Bloodstream infections may occur as a complication of colorectal cancer or be a marker for its occult presence. The objectives of this study were to quantify the overall and etiology-specific risks for incident colorectal cancer-associated bloodstream infection., Methods: Population-based surveillance for community-onset bloodstream infection was conducted among adults aged 20 years and older in Queensland, Australia between 2000 and 2019. Statewide databases were used to identify patients with incident colorectal cancer and collect clinical and outcome information., Results: After exclusion of 1794 patients with prior colorectal cancer, a cohort of 84,754 patients was assembled, of which 1030 had colorectal cancer-associated bloodstream infection and 83,724 had no colorectal cancer. Bloodstream infection was associated with a 16-fold annualized increased risk for diagnosis of colorectal cancer (incidence rate ratio 16.1; 95% confidence interval [CI], 15.1-17.1) in the adult population. Patients who had colorectal cancer-associated bloodstream infection were more likely to be older and male, have hospital-onset and polymicrobial infections, and have fewer non-cancer-related comorbidities. The organisms associated with highest risk for colorectal cancer included Clostridium species (relative risk [RR] 6.1; 95% CI, 4.7-7.9); especially C. septicum (RR 25.0; 95% CI, 16.9-35.7), Bacteroides species (RR 4.7; 95% CI, 3.8-5.8); especially B. ovatus (RR 11.8; 95% CI, 2.4-34.5), Gemella species (RR 6.5; 95% CI, 3.0-12.5), Streptococcus bovis group (RR 4.4; 95% CI, 2.7-6.8); especially S. infantarius subsp. coli (RR 10.6; 95% CI, 2.9-27.3), Streptococcus anginosus group (RR 1.9; 95% CI, 1.3-2.7), and Enterococcus species (RR 1.4; 95% CI, 1.1-1.8)., Conclusion: Although much attention has been afforded to S. bovis group over the past decades, there are many other isolates associated with higher risk for colorectal cancer-associated bloodstream infections., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Scedosporium and Lomentospora species are environmental moulds that are virulent in immunocompromised hosts and rarely cause bloodstream infection (BSI). Patients with Scedosporium and Lomentospora species BSI were identified by the state public laboratory service in Queensland, Australia, over a 20-year period. Twenty-two incident episodes occurred among 21 residents; one patient had a second episode 321 days following the first. Of these, 18 were Lomentospora prolificans, three were Scedosporium apiospermum complex and one was a nonspeciated Scedosporium species. Seventeen (81%) patients died during their index admission, and all-cause mortality at 30, 90 and 365 days was 73%, 82% and 91% respectively. All 20 patients with haematological malignancy died within 365 days of follow-up with a median time to death of 9 days (interquartile range, 6-20 days) following diagnoses of BSI., (© 2023 Royal Australasian College of Physicians.)

Extended-spectrum-beta-lactamase (ESBL)-producing Enterobacterales as a cause of community-acquired uncomplicated urinary tract infection (UTI) is on the rise. Currently, there are minimal oral treatment options. New combinations of existing oral third-generation cephalosporins paired with clavulanate may overcome resistance mechanisms seen in these emerging uropathogens. Ceftriaxone-resistant Escherichia coli and Klebsiella pneumoniae containing CTX-M-type ESBLs or AmpC, in addition to narrow-spectrum OXA and SHV enzymes, were selected from blood culture isolates obtained from the MERINO trial. Minimum inhibitory concentration (MIC) values of third-generation cephalosporins (cefpodoxime, ceftibuten, cefixime, cefdinir), both with and without clavulanate, were determined. One hundred and one isolates were used with ESBL, AmpC and narrow-spectrum OXA genes (e.g. OXA-1, OXA-10) present in 84, 15 and 35 isolates, respectively. Susceptibility to oral third-generation cephalosporins alone was very poor. Addition of 2 mg/L clavulanate reduced the MIC 50 values (cefpodoxime MIC 50 2 mg/L, ceftibuten MIC 50 2 mg/L, cefixime MIC 50 2 mg/L, cefdinir MIC 50 4 mg/L) and restored susceptibility (33%, 49%, 40% and 21% susceptible, respectively) in a substantial number of isolates. This finding was less pronounced in isolates co-harbouring AmpC. In-vitro activity of these new combinations may be limited in real-world Enterobacterales isolates co-harbouring multiple antimicrobial resistance genes. Pharmacokinetic/pharmacodynamic data would be useful for further evaluation of their activity., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Introduction: The BALANCE study is a randomised clinical trial (3626 participants) designed to assess the non-inferiority of 7 days (short-course) antibiotic therapy compared with 14 days of therapy for bacteraemia using the pragmatic endpoint of 90-day survival. Based on pilot study data, approximately 30% of enrolees will have a urinary tract infection (UTI) as the source of bacteraemia., Methods and Analysis: We aim to assess the non-inferiority of short-course antibiotic therapy for patients with bacteraemia UTIs.Participating sites in four countries will be invited to join this substudy. All participants of this substudy will be enrolled in the main BALANCE study. The intervention will be assigned and treatment administered as specified in the main protocol.We will include participants in this substudy if the probable source of their infection is a UTI, as judged by the site principal investigator, and they have a urine microscopy and culture indicative of a UTI. Participants will be excluded if they have an ileal loop, vesicoureteric reflux or suspected or confirmed prostatitis.The primary outcome is the absence of a positive culture on a test-of-cure urine sample collected 6-12 days after cessation of antimicrobials, with a non-inferiority margin of 15%. Secondary outcomes include the clinical resolution of infection symptoms at test-of-cure., Ethics and Dissemination: The study has been approved in conjunction with the main BALANCE study through the relevant ethics review process at each participating site. We will disseminate the results through the Australasian Society for Infectious Diseases, Canadian Critical Care Trials Group, the Association for Medical Microbiology and Infectious Diseases Canada Clinical Research Network (AMMI Canada CRN) and other collaborators., Universal Trial Number: U1111-1256-0874., Main Balance Trial Registration: NCT03005145., Trial Registration Number: Australian Clinical Trial Register: ACTRN12620001108909., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To investigate an outbreak of vancomycin-resistant Enterococcus faecium (VREfm) sequence type 78 (ST78) in a large tertiary Australian hospital. A collection of 63 VREfm ST78 isolates, identified during a routine genomic surveillance program, were subjected to genomic epidemiological analysis based on whole-genome sequencing (WGS) data. The population structure was reconstructed using phylogenetic analysis, and a collection of publicly available VREfm ST78 genomes were used to provide global context. Core genome single nucleotide polymorphism (SNP) distances and available clinical metadata were used to characterize outbreak clusters and reconstruct transmission events. In silico genotyping confirmed that all study isolates were vanB -type VREfm carrying virulence characteristics of the hospital-associated E. faecium. Phylogenetic analysis identified two distinct phylogenetic clades, only one of which was responsible for a hospital outbreak. Four outbreak subtypes could be defined with examples of recent transmissions. Inference on transmission trees suggested complex transmission routes with unknown environmental reservoirs mediating the outbreak. WGS-based cluster analysis with publicly available genomes identified closely related Australian ST78 and ST203 isolates, highlighting the capacity for WGS to resolve complex clonal relationships between the VREfm lineages. Whole genome-based analysis has provided a high-resolution description of an outbreak of vanB -type VREfm ST78 in a Queensland hospital. Combined routine genomic surveillance and epidemiological analysis have facilitated better understanding of the local epidemiology of this endemic strain, providing valuable insight for better targeted control of VREfm. IMPORTANCE Vancomycin-resistant Enterococcus faecium (VREfm) is a leading cause of health care-associated infections (HAIs) globally. In Australia, the spread of hospital-adapted VREfm is largely driven by a single clonal group (clonal complex [CC]), CC17, to which the lineage ST78 belongs. While implementing a genomic surveillance program in Queensland, we observed increased incidence of ST78 colonizations and infections among patients. Here, we demonstrate the use of real-time genomic surveillance as a tool to support and enhance infection control (IC) practices. Our results show that real-time whole-genome sequencing (WGS) can efficiently disrupt outbreaks by identifying transmission routes that in turn can be targeted using resource-limited interventions. Additionally, we demonstrate that by placing local outbreaks in a global context, high-risk clones can be identified and targeted prior to them becoming established within clinical environments. Finally, the persistence of these organism within the hospital highlights the need for routine genomic surveillance as a management tool to control VRE transmission., Competing Interests: The authors declare no conflict of interest.

Melioidosis is an infectious disease caused by the bacterium Burkholderia pseudomallei. Although this environmental organism is endemic in certain regions of Australia, it is not considered endemic in Southern Queensland, where the last case was reported 21 years ago. We report a climate change-associated outbreak of melioidosis occurring during two La Niña events in a region previously considered nonendemic for B. pseudomallei. During a 15-month period, 14 cases of locally acquired melioidosis were identified. Twelve patients were adults (> 50 years), with diabetes mellitus the most common risk factor in 6 of 12 patients (50%). Eleven patients (79%) had direct exposure to floodwaters or the flooded environment. This study suggests an association between climate change and an increased incidence of melioidosis. In addition, this is the first report of environmental sampling and whole-genome analysis to prove endemicity and local acquisition in this region.

Elizabethkingia meningoseptica is an uncommonly encountered multidrug-resistant gram-negative bacterium that causes infections primarily among vulnerable hosts. A true opportunistic pathogen, its ability to cause severe sepsis and complicated infection in selected patients has been noted. Very limited preclinical and clinical data exist with regard to suitable therapeutic options. In this study, we present the case of prolonged bloodstream and central nervous system infection due to E. meningoseptica treated with dose-optimized combination antibiotic therapy, with evidence of microbiological (including development of adaptive resistance mechanisms) and clinical failure.

Background: Due to their prevalence worldwide, the β-lactamases CTX-M and plasmid-mediated CMY-2 are important antimicrobial resistance enzymes in a clinical setting. While culture- and PCR-based detection methods exist for these targets, they are time consuming and require specialist equipment and trained personnel to carry out., Methods: In this study, three rapid diagnostic single-plex and a prototype triplex assay were developed, using recombinase polymerase amplification with lateral flow detection (RPA-LF), and tested for their sensitivity and specificity using two isolate DNA panels ( n  = 90 and n  = 120 isolates). In addition, the RPA-LF assays were also tested with a small number of faecal extract samples ( n  = 18)., Results: The RPA-LF assays were able to detect bla CXT-M-group-1 , bla variants with high sensitivity (82.1%-100%) and specificity (100%) within a short turnaround time (15-20 min for amplification and detection).CTX-M-group-9 and bla CMY-2-type variants with high sensitivity (82.1%-100%) and specificity (100%) within a short turnaround time (15-20 min for amplification and detection)., Conclusions: RPA-LF assays developed in this study have the potential to be used at or close to the point of care, as well as in low-resource settings, producing rapid results to support healthcare professionals in their treatment decisions., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: There is increasing morbidity and mortality attributed to escalating incidence of Escherichia coli bloodstream infection (BSI). The epidemiology of E. coli BSI is dynamic and differs across populations. This study aimed to describe this epidemiology in Queensland, Australia., Methods: Incident E. coli BSIs (new or recurring ≥30 days from previous BSI) in adult (≥15 years) Queenslanders were identified from 2000 to 2019 using Queensland Health databases. Incidence rates, crude and standardized by age and gender, were calculated. Negative binomial regressions were performed to determine predictors of E. coli BSI incidence., Results: From 2000 to 2019, 30 350 E. coli BSIs in 27 793 patients were detected; the standardized incidence rate almost doubled from 34.1 to 65.9 cases per 100 000 residents. Predictors of higher incidence rate were older age (≥65 years), comorbidity, and community-onset infection. Despite holding these factors constant, the incidence rate was estimated to increase 4% (adjusted incidence rate ratio [IRR], 1.04; 95% CI, 1.03-1.04) annually over the study period. Approximately 4.2% of E. coli isolates produced extended-spectrum beta-lactamase (ESBL-Ec), with most (95%) detected after 2010. The incidence rate of ESBL-Ec increased 25% (IRR, 1.25%; 95% CI, 1.2-1.3) annually, significantly faster than that of non-producers. Amikacin and carbapenems remain effective in vitro against ESBL-Ec BSI in Queensland., Conclusions: The rise in E. coli BSIs is driven both by a higher infection rate and shifting epidemiology toward community-onset infections. These are likely attributed to an aging Australian population with increasing chronic comorbidity. The rapid expansion of ESBL-Ec in recent years is concerning and should be acknowledged for its implication in the community., Competing Interests: Potential conflicts of interest. D.L.P. has received research grants from Merck, Pfizer, and Shionogi outside of the submitted work. He has also received personal fees from Merck, Pfizer, Shionogi, Shionogi, Lysovant, The Medicines Company, Entasis, VenatoRx, Biomerieux, and Accelerate and is conducting a study on E. coli vaccination sponsored by Janssen. P.N.A.H. has received research grants from Merck, Sharpe and Dohme (MSD), Sandoz, and Shionogi Ltd outside of the submitted work, as well as personal fees from Pfizer and Sandoz. All other authors report no potential conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Prospective whole-genome sequencing (WGS)-based surveillance may be the optimal approach to rapidly identify transmission of multi-drug resistant (MDR) bacteria in the healthcare setting., Methods: We prospectively collected methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), carbapenem-resistant Acinetobacter baumannii (CRAB), extended-spectrum beta-lactamase (ESBL-E), and carbapenemase-producing Enterobacterales (CPE) isolated from blood cultures, sterile sites, or screening specimens across three large tertiary referral hospitals (2 adult, 1 paediatric) in Brisbane, Australia. WGS was used to determine in silico multi-locus sequence typing (MLST) and resistance gene profiling via a bespoke genomic analysis pipeline. Putative transmission events were identified by comparison of core genome single nucleotide polymorphisms (SNPs). Relevant clinical meta-data were combined with genomic analyses via customised automation, collated into hospital-specific reports regularly distributed to infection control teams., Results: Over 4 years (April 2017 to July 2021) 2660 isolates were sequenced. This included MDR gram-negative bacilli (n = 293 CPE, n = 1309 ESBL), MRSA (n = 620), and VRE (n = 433). A total of 379 clinical reports were issued. Core genome SNP data identified that 33% of isolates formed 76 distinct clusters. Of the 76 clusters, 43 were contained to the 3 target hospitals, suggesting ongoing transmission within the clinical environment. The remaining 33 clusters represented possible inter-hospital transmission events or strains circulating in the community. In 1 hospital, proven negligible transmission of non-multi-resistant MRSA enabled changes to infection control policy., Conclusions: Implementation of routine WGS for MDR pathogens in clinical laboratories is feasible and can enable targeted infection prevention and control interventions., Competing Interests: Potential conflicts of interest. P. N. A. H. reports research grants from Merck, Sandoz, and Shionogi, outside the submitted work; has served on advisory boards for Sandoz and Merck, and has received speaker's fees from Pfizer, Sandoz, and Sumitomo. D. L. P reports research grants from Merck, Pfizer, and Shionogi outside the submitted work; has received honoraria for advisory board membership from Merck, Pfizer, Shionogi, GSK, QPex, Entasis, VenatoRx, BioMerieux, and Accelerate. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Staphylococcus aureus bacteraemia is associated with a high morbidity and mortality. Time to effective antibiotics is key to reducing mortality. Current practices yield preliminary susceptibilities approximately 16-18 h after blood culture positivity. Molecular diagnostics could reduce the time from blood culture positivity to organism identification as MRSA or MSSA. The objective was to assess the performance of the GeneXpert in identifying MRSA/MSSA from blood culture bottles in the BACT/ALERT VIRTUO system. Eighty-eight blood culture bottles with Gram-positive cocci resembling staphylococci were analysed at Pathology Queensland using the Cepheid Xpert MRSA/SA BC system. The identification and susceptibilities from standard operating procedures were compared with the results from the Xpert MRSA/SA Blood Culture assay and routine laboratory practice. The overall positive percent agreement between the GeneXpert and standard laboratory practice was 94.1% (95% CI 85.6-98.37%) and the negative percent agreement was 100% (95% CI 83.16-100%). The Cepheid Xpert accurately identifies MRSA, MSSA and coagulase-negative staphylococci. The discordant results were from rarely occurring clinical isolates and were expected limitations of the assay. This kit has the potential to reduce the time to effective antibiotics and minimise the use of unnecessary antibiotics and associated costs., (Copyright © 2022 Royal College of Pathologists of Australasia. All rights reserved.)

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., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Peripheral intravenous catheters (PIVCs) are ubiquitous in acute care settings however failure rates are unacceptably high, with around half failing before prescribed treatment is complete. The most effective dressing and securement option to prolong PIVC longevity is unclear., Objectives: To determine feasibility of conducting a definitive randomized controlled trial (RCT) investigating evidence-based securement bundles (medical adhesive tapes and supplementary securement products) to reduce PIVC failure., Methods: In this pilot non-masked 3-group RCT, adults requiring a PIVC for >24 hrs were randomized to Standard care (bordered polyurethane dressing plus non-sterile tape over extension tubing), Securement Bundle 1 (two sterile tape strips over PIVC hub plus Standard care) or Securement Bundle 2 (Bundle 1 plus tubular bandage) with allocation concealed until study entry., Exclusions: laboratory-confirmed positive blood culture, current/high-risk of skin tear, or study product allergy., Primary Outcome: feasibility (eligibility, recruitment, retention, protocol fidelity, participant/staff satisfaction)., Secondary Outcomes: PIVC failure, PIVC dwell time, adverse skin events, PIVC colonization and cost., Results: Of 109 randomized participants, 104 were included in final analyses. Feasibility outcomes were met, except eligibility criterion (79%). Absolute PIVC failure was 38.2% (13/34) for Bundle 2, 25% (9/36) for Bundle 1 and 23.5% (8/34) for Standard care. Incidence rate ratio for PIVC failure/1000 catheter days, compared to Standard care, was 1.1 (95% confidence interval [CI] 0.4-2.7) and 2.1 (95% CI 0.9-5.1) for Bundles 1 and 2, respectively., Conclusions: A large RCT testing securement bundles is feasible, with adjustment to screening processes. Innovative dressing and securement solutions are needed to reduce unacceptable PIVC failure rates. Trial registration ACTRN12619000026123., Competing Interests: Declaration of Competing Interest AC's employer on her behalf has received investigator-initiated research grant from Cardinal Health (unrelated to the current project). AJU's employer on her behalf has received investigator‐initiated research grants and speaker fees from 3 M, Becton Dickinson-Bard, Cardinal Health (unrelated to the current project). NM's employer has received on her behalf investigator‐initiated research grants unrestricted educational grants and from Becton Dickinson-Bard, and Cardinal Health; and a consultancy payment from Becton Dickinson-Bard for expert advice (unrelated to the current project). ENL's employer has received on her behalf, an investigator-initiated research grant from Cardinal Health and a conference scholarship attendance supported by Angiodynamics (unrelated to the current project). CR's employer has received on her behalf investigator‐initiated research or educational grants from Becton Dickinson‐Bard; and consultancy payments for educational lectures/expert advice from 3 M, Becton Dickinson‐Bard, BBraun (unrelated to the current project). JG, EM, CB, PNAH – no conflicts of interest to declare, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aeromonas species can cause severe bloodstream infection (BSI) however, few studies have examined their epidemiology in non-selected populations. The objective of this study was to describe the incidence and determinants of Aeromonas species BSI in Queensland, Australia. A retrospective population-based cohort study was conducted during 2000-2019. Aeromonas species BSI were identified by laboratory surveillance and clinical and outcome information through data linkages to statewide databases. A total of 407 incident Aeromonas species BSI were identified with an age- and sex-standardized incidence of 5.2 per million residents annually. No trend in annual incidence rate during two decades of surveillance was demonstrated. Significant variable monthly occurrences were observed with highest rates during warmer, wetter months, and lowest rates during winter and dry periods. There was significant variability in incidence accordingly to region and climate zones, with higher rates observed in tropical north regions and lowest in southeastern corner. The highest incidence was observed in very remote and hot areas in Queensland. Cases were infrequent in children and risk was highest in elderly and males. Seventy-eight patients died within 30 days with a case-fatality rate of 19%. Older age, non-focal infection, higher Charlson score, and monomicrobial bacteremia were independent risk factors for death. Demographic and climatic changes may increase the burden of these infections in future years.

Escherichia coli is a versatile commensal and pathogenic member of the human microflora. As the primary causative pathogen in urosepsis, E. coli places an immense burden on healthcare systems worldwide. To further exacerbate the issue, multi drug resistance (MDR) has spread rapidly through E. coli populations, making infections more troublesome and costlier to treat. This paper aimed to review the literature concerning the development of MDR in uropathogenic E. coli (UPEC) and explore the existing evidence of current and emerging treatment strategies. While some MDR strains maybe treated with β-lactam-β-lactamase inhibitor combinations as well as cephalosporins, cephamycin, temocillin and fosfomycin, current treatment strategies for many MDR UPEC strains are reliant on carbapenems. Carbapenem overreliance may contribute to the alarming dissemination of carbapenem-resistance amongst some UPEC communities, which has ushered in a new age of difficult to treat infections. Alternative treatment options for carbapenem resistant UPEC may include novel β-lactam-β-lactamase or carbapenemase inhibitor combinations, cefiderocol, polymyxins, tigecycline, aminoglycosides or fosfomycin. For metallo-β-lactamase producing strains (e.g., NDM, IMP-4), combinations of cefazidime-avibacam with aztreonam have been used. Additionally, the emergence of new antimicrobials brings new hope to the treatment of such infections. However, continued research is required to successfully bring these into the clinic for the treatment of MDR E. coli urosepsis.

The application of direct metagenomic sequencing from positive blood culture broth may solve the challenges of sequencing from low-bacterial-load blood samples in patients with sepsis. Forty prospectively collected blood culture broth samples growing Gram-negative bacteria were extracted using commercially available kits to achieve high-quality DNA. Species identification via metagenomic sequencing and susceptibility prediction via a machine-learning algorithm (AREScloud) were compared to conventional methods and other rapid diagnostic platforms (Accelerate Pheno and blood culture identification [BCID] panel). A two-kit method (using MolYsis Basic and Qiagen DNeasy UltraClean kits) resulted in optimal extractions. Taxonomic profiling by direct metagenomic sequencing matched conventional identification in 38/40 (95%) samples. In two polymicrobial samples, a second organism was missed by sequencing. Prediction models were able to accurately infer susceptibility profiles for 6 common pathogens against 17 antibiotics, with an overall categorical agreement (CA) of 95% (increasing to >95% for 5/6 of the most common pathogens, if Klebsiella oxytoca was excluded). The performance of whole-genome sequencing (WGS)-antimicrobial susceptibility testing (AST) was suboptimal for uncommon pathogens (e.g., Elizabethkingia ) and some β-lactamase inhibitor antibiotics (e.g., ticarcillin-clavulanate). The time to pathogen identification was the fastest with BCID (1 h from blood culture positivity). Accelerate Pheno provided a susceptibility result in approximately 8 h. Illumina-based direct sequencing methods provided results in time frames similar to those of conventional culture-based methods. Direct metagenomic sequencing from blood cultures for pathogen detection and susceptibility prediction is feasible. Additional work is required to optimize algorithms for uncommon species and complex resistance genotypes as well as to streamline methods to provide more rapid results.

Background: The objective of this study was to examine the occurrence, determinants, and outcome of S. aureus bloodstream infections (BSI) diagnosed based on single versus multiple positive initial cultures., Methods: All adults with first episodes of mono-microbial S. aureus BSI in Queensland during 2000-2019 were included., Results: 10,855 (67%) and 5,421 (33%) were diagnosed based on one and multiple positive initial cultures, respectively. Patients with multiple positive initial cultures were significantly younger, more likely to have community-associated disease, have a shorter time to culture positivity, less likely to have methicillin-resistant S. aureus BSI, and have a different distribution of comorbid medical illnesses and clinical foci. The 30-day all-cause case-fatality rate was 18% and single positive initial culture was an independent risk factor for death., Conclusions: Among patients with S. aureus BSI, those diagnosed by single positive initial blood cultures have different clinical features and a higher risk for death., Competing Interests: Declaration of competing interest The authors declare they have no conflicts of interest, (Copyright © 2022 Elsevier Inc. All rights reserved.)

Although obesity is a major healthcare problem that is increasing in many populations worldwide, there are limited studies that have examined its contribution to infectious diseases morbidity and mortality. The aim of this study was to examine the clinical determinants and outcomes of bloodstream infections among patients with obesity. All adults within the publicly funded healthcare system in Queensland, Australia, identified with a BSI during 2017-2019 were included and the presence of obesity was based on discharge International Classification of Diseases (ICD-10) codes. Clinical features, microbiology, and outcomes were compared among obese and non-obese subjects. A total of 24,602 incident BSI were identified among 21,613 Queensland residents; of which 4,579 (21.2%) and 17,034 (78.8%) were classified as obese or non-obese, respectively. Obese patients were less likely to have community associated infections and were more likely to be younger, female, have higher comorbidity scores, and have bone and joint or soft tissue infections as compared to non-obese subjects. Obese patients had a lower proportion of Escherichia coli BSI and higher proportions of b-haemolytic streptococci. Although obese patients had longer hospital admissions and more repeat incident BSI within 1 year, they had lower overall case fatality. In a logistic regression model, obesity was associated with a lower risk for 30-day case fatality (adjusted odds ratio 0.51, 95% confidence interval 0.45-0.58). Obesity is associated with significant differences in the determinants and outcome of BSI. Increasing rates of obesity is likely to influence the epidemiology of BSI in populations., (© 2022. The Author(s).)

The dissemination of Escherichia coli producing extended-spectrum beta-lactamase (ESBL-Ec) is evident in the community. A population-based spatial analysis is necessary to investigate community risk factors for ESBL-Ec occurrence. The study population was defined as individuals with ESBL-Ec isolated in Queensland, Australia, from 2010 to 2019. Choropleth maps, global Moran's index and Getis-Ord Gi* were used to describe ESBL-Ec distribution and identify hot spots. Multivariable Poisson regression models with or without spatially structured random effects were performed. A total of 12 786 individuals with ESBL-Ec isolate were identified. The crude incidence rate increased annually from 9.1 per 100 000 residents in 2010 to 49.8 per 100 000 residents in 2019. The geographical distribution of ESBL-Ec changed from random to clustered after 2014, suggesting presence of community-specific factors that can enhance occurrence. Hot spots were more frequently identified in Outback and Far North Queensland, future public health measures to reduce transmission should prioritise these communities. Communities with higher socioeconomic status (RR = 0.66, 95% CI 0.55-0.79, per 100 units increase) and higher proportion of residents employed in the agricultural industry (RR = 0.79, 95% CI 0.67-0.95, per 10% increase) had lower ESBL-Ec incidence. Risk factors for occurrence appear differential between remote and city settings and this should be further investigated.

Carbapenems are recommended for the treatment of urosepsis caused by extended-spectrum β-lactamase (ESBL)-producing, multidrug-resistant Escherichia coli ; however, due to selection of carbapenem resistance, there is an increasing interest in alternative treatment regimens including the use of β-lactam-aminoglycoside combinations. We compared the pharmacodynamic activity of piperacillin-tazobactam and amikacin as mono and combination therapy versus meropenem monotherapy against extended-spectrum β-lactamase (ESBL)-producing, piperacillin-tazobactam resistant E. coli using a dynamic hollow fiber infection model (HFIM) over 7 days. Broth-microdilution was performed to determine the MIC of E. coli isolates. Whole genome sequencing was conducted. Four E. coli isolates were tested in HFIM with an initial inoculum of ~10 7 CFU/mL. Dosing regimens tested were piperacillin-tazobactam 4.5 g, 6-hourly, plus amikacin 30 mg/kg, 24-hourly, as combination therapy, and piperacillin-tazobactam 4.5 g, 6-hourly, amikacin 30 mg/kg, 24-hourly, and meropenem 1 g, 8-hourly, each as monotherapy. We observed that piperacillin-tazobactam and amikacin monotherapy demonstrated initial rapid bacterial killing but then led to amplification of resistant subpopulations. The piperacillin-tazobactam/amikacin combination and meropenem experiments both attained a rapid bacterial killing (~4-5 log 10 ) within 24 h and did not result in any emergence of resistant subpopulations. Genome sequencing demonstrated that all ESBL-producing E. coli clinical isolates carried multiple antibiotic resistance genes including bla CTX-M-15 , bla OXA-1 , bla . These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.EC , bla TEM-1 , and aac(6')-Ib-cr . These results suggest that the combination of piperacillin-tazobactam/amikacin may have a potential role as a carbapenem-sparing regimen, which should be tested in future urosepsis clinical trials.

Background: Case reports and small series indicate that Achromobacter species bloodstream infection (BSI) is most commonly a complication of hospitalization among patients with chronic lung disease. The aim of the present study was to determine the incidence, risk factors, and outcomes of Achromobacter sp. BSI in an Australian population., Methods: Retrospective, laboratory-based surveillance was conducted in Queensland, Australia (population ≈ 5 million) during 2000-2019. Clinical and outcome data were obtained by linkage to state hospital admissions and vital statistics databases. BSI diagnosed within the community or within the first two calendar days of stay in hospital were classified as community-onset. Community-onset BSIs were grouped into community-associated and healthcare-associated., Results: During more than 86 million person-years of surveillance, 210 incidents of Achromobacter sp. BSI occurred among 195 individuals for an overall age-and sex-standardized annual incidence of 2.6 per million residents. Older individuals and males were at highest risk (2.9 vs. 2.0 per million, IRR for males 1.5; 95% CI, 1.1-1.9; p = 0.008). Most (153; 73%) cases were of community-onset of which 100 (48%) and 53 (25%) were healthcare- and community-associated, respectively. An increasing proportion of community-onset cases were observed during twenty years of surveillance. Underlying medical illnesses were common with median (interquartile range) Charlson Comorbidity Index (CCI) scores of 3 (1-5). CCI scores of 0, 1, 2, and 3+ were observed in 37 (18%), 27 (13%), 40 (19%), and 105 (50%) of cases, respectively. All but one of the cases were admitted to hospital for a median (interquartile range) length of stay of 12 (5-34) days. All-cause case-fatality rates in hospital by day 30 and by day 90 were 30 (14%), 28 (13%), and 42 (20%), respectively. The 90-day case-fatality rate increased with increasing comorbidity and was 3% (1/37), 11% (3/27), 25% (10/40), and 27% (28/105) among those with Charlson Comorbidity Indices of 0, 1, 2, and 3+, respectively ( p = 0.004)., Conclusions: Although comorbidity is an important determinant of risk, most Achromobacter sp. BSI are of community-onset and one-fifth of cases occur in patients without significant underlying chronic co-morbidities. This study highlights the value of population-based methodologies to define the epidemiology of an infectious disease.

An attributing factor to Enterobacterales producing extended-spectrum beta-lactamase (ESBL-E) community spread is human-to-human transmission. This systematic review and meta-analysis aimed to estimate the duration of ESBL-E carriage in the community and the rate of household transmission. Literature search was performed on PubMed, EMBASE, and Scopus. Dose-response meta-analysis was planned to model the proportion of ESBL-E carriers and household transmission over time. Twenty-six studies ( n  = 2,505 participants) were included. The median carriage duration was 2 months. Approximately 22% (95% confidence interval: 16-28) had persistent carriage after 12 months. Travelers had significantly shorter carriage (median 1-2 months) than discharged hospital patients (median 6 months) at all measured time points. There were insufficient data to robustly meta-analyze household transmission. Nonetheless, five longitudinal studies reported 18.4% to 35.2% of contacts acquired ESBL-E within 4 to 36 months from hospital discharge of index case. Transmission events from travelers to their contacts appeared lower. Travelers with travel-acquired ESBL-E had significantly faster decolonization rate than discharged patients, suggesting that travel-associated import of multidrug-resistant pathogen may have limited contribution to community transmission of ESBL-E. The substantial prevalence of persistent carriers warrant consideration for additional measures to mitigate exposure risk of ESBL-E from discharged patients in the community and from readmitting patients in the hospital.

Although recent reports of extensively antibiotic-resistant strains have highlighted the importance of Morganella morganii as an emerging pathogen, the epidemiology of serious infections due to this organism is not well defined. The objective of this study was to determine the incidence, determinants, and outcomes of Morganella morganii bloodstream infections (BSIs). Retrospective, population-based surveillance for Morganella morganii BSIs was conducted in Queensland, Australia, in 2000 to 2019; 709 cases were identified, for an annual incidence of 9.2 cases per million population. Most cases were of community onset, with 280 (39.5%) community-associated cases and 226 (31.9%) health care-associated cases. Morganella morganii BSIs were rare in children and young adults, and the incidence increased markedly with advancing age. The most common foci of infection were skin and soft tissue (131 cases [18.5%]), genitourinary (97 cases [13.7%]), and intraabdominal (90 cases [12.7%]). Most patients (580 cases [81.8%]) had at least one comorbid medical illness, with diabetes mellitus (250 cases [35.3%]), renal disease (208 cases [29.3%]), and congestive heart failure (167 cases [23.6%]) being most prevalent. Resistance to one or more of quinolones, co-trimoxazole, aminoglycosides, or carbapenems was observed in 67 cases (9.5%), and this did not change significantly over the study. The 30-day all-cause case fatality rate was 21.2%, and increasing age, nonfocal infection, heart failure, dementia, and cancer were independently associated with increased risk of death. Morganella morganii BSIs are increasing in our population, and elderly male subjects and individuals with comorbidities are at highest risk. Although antibiotic resistance is not a major contributor to the current burden in Queensland, ongoing surveillance is warranted. IMPORTANCE Recent reports of extensively antibiotic-resistant strains have highlighted the importance of Morganella morganii as an emerging pathogen. Despite its present and evolving importance as an agent of human disease, there is a limited body of literature detailing the epidemiology of serious infections due to Morganella morganii. Therefore, the objectives of this study were to examine the incidence and determinants of Morganella morganii BSIs and to examine risk factors for death in a large Australian population in 2000 to 2019.

Background: Small case series and reports suggest that Sphingomonas paucimobilis is predominantly a cause of nosocomial bloodstream infections (BSI) with very low associated mortality. Our objective was to describe the epidemiology and outcome of Sphingomonas species BSI in a large Australian population., Methods: We included all residents of Queensland, Australia, with BSI because of Sphingomonas species identified within the publicly funded system from 2000 to 2019., Results: A total of 282 incident episodes of Sphingomonas species BSI were identified for an age- and sex-adjusted incidence of 3.2 per million population annually. Incidence rates were highest in the tropical regions of the state. Most (94%) of the isolates were confirmed as Sphingomonas paucimobilis. In addition, 77% of the infections were community-onset, of which 48% were community-associated, and 30% were healthcare-associated. The very young, the old, and male patients were at the highest risk. Patients with community-associated disease were, on average, younger, had fewer co-morbidities, and were less likely to have polymicrobial infections. At least 1 co-morbidity was identified in 62% of patients, with malignancy, diabetes, and lung disease most prevalent. The overall all-cause 30-day case-fatality rate was 6%., Conclusion: Sphingomonas paucimobilis BSI is a predominantly community-onset disease associated with a significant risk of death., Competing Interests: Conflict of interest The authors declare they have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)