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The trion represents a localized group of neurons with three levels of firing activity. Networks of a small number of trions (with structured interactions and firing dependent on activity at two previous discrete time steps) support a repertoire of hundreds of quasistable, periodic firing patterns (which can be learned). We report striking phenomena with variation in temperature T: There exist a series of phase transitions at precise values T(n), giving new repertoires of periodic firing patterns, and the average time for any initial firing configuration to project onto a firing pattern shows a quite sharp change at each T(n). Near a phase transition, in a Monte Carlo simulation, the temporal evolution wanders back and forth between sets of these firing patterns in contrast to the more structured sequential evolutions far from a T(n). © 1991 The American Physical Society.

Motivated by V. B. Mountcastle's organizational principle for neocortical function, and by M. E. Fisher's model of physical spin systems, we introduce a cooperative model of the cortical column incorporating an idealized substructure, the trion, which represents a localized group of neurons. Computer studies reveal that typical networks composed of a small number of trions (with symmetric interactions) exhibit striking behavior--e.g., hundreds to thousands of quasistable, periodic firing patterns, any of which can be selected out and enhanced with only small changes in interaction strengths by using a Hebb-type algorithm.

We developed a cooperative model of the cortical column incorporating an idealized subunit, the trion (which represents a localized group of neurons), and a discrete time step for firing. We found that networks composed of a small number of trions (with symmetric interactions) supported up to thousands of quasi-stable, periodic firing patterns (MPs) which could be selected out with only small changes in interaction strengths using a Hebb-type algorithm. Here we report a study of the associative recall properties showing striking features: By considering all possible initial firing patterns (for a given set of network connections), we find 1) It takes on the average only 2-5 time steps to recall an MP. 2) Many of the MPs can be individually accessed by thousands of different initial patterns. The variety of examples presented illustrate the rich, general nature of the model.

Tobramycin dosing in patients with cystic fibrosis (CF) is challenged by its high pharmacokinetic (PK) variability and narrow therapeutic window. Doses are typically individualized using two-sample log-linear regression (LLR) to quantify the area under the concentration-time curve (AUC). Bayesian model-informed precision dosing (MIPD) may allow dose individualization with fewer samples; however, the relative performance of these methods is unknown. This single-center retrospective analysis included adult patients with CF receiving tobramycin from 2015 to 2022. Tobramycin concentrations were predicted using LLR or Bayesian estimation with two population PK models (Hennig and Alghanem). Then, both methods were used to estimate the AUC for simulated patients. For Bayesian estimation, AUC estimation with flattened priors and limited sampling strategies were also assessed. Predictions were evaluated using normalized root mean square error (nRMSE), mean percent error (MPE), and accuracy. The data set included 70 treatment courses, with 32 not evaluable by LLR due to detection limits or timing issues. Bayesian estimation demonstrated worse accuracy (47.1%-50.7% vs 75.7%), higher MPE (24.2%-32.4% vs -2.4%), and higher nRMSE (35.0%-39.4% vs 24.8%) than LLR for peak concentrations but performed better on troughs (accuracy: 92.0%-92.9% vs 84.6%). Bayesian estimation with flattened priors and a single sample at 4 h was comparable to LLR performance, with better accuracy (42.9%-68.0% vs 41.1% LLR), comparable MPE (-2.3% to -3.7% vs -0.5%) and nRMSE (11.3%-21.6% vs 17.3%). Bayesian estimation with one concentration and flattened priors can match LLR prediction accuracy. However, popPK models must be improved to better estimate peak samples.

Background: Ceftolozane-tazobactam and ceftazidime-avibactam are preferred treatment options for multidrug-resistant Pseudomonas aeruginosa infections; however, real-world comparative effectiveness studies are scarce. Pharmacokinetic and pharmacodynamic differences between the agents might affect clinical response rates. We aimed to compare the effectiveness of ceftolozane-tazobactam and ceftazidime-avibactam for treatment of invasive multidrug-resistant P aeruginosa infections., Methods: This multicentre, retrospective, observational study was conducted at 28 hospitals in the USA between Jan 1, 2016, and Dec 31, 2023. Eligible patients were adults (age ≥18 years old) with microbiologically confirmed multidrug-resistant P aeruginosa pneumonia or bacteraemia treated with ceftolozane-tazobactam or ceftazidime-avibactam for more than 48 h. Patients were matched (1:1) by study site, severity of illness, time to treatment initiation (≤72 h or >72 h), and infection type. The primary outcome was clinical success at day 30, which was defined as survival, resolution of signs and symptoms of infection with the intended treatment course, and the absence of recurrent infection due to P aeruginosa. Secondary outcomes included all-cause mortality and development of resistance to study drug., Findings: 420 eligible patients were included (210 in each treatment group), of whom 350 (83%) had pneumonia and 70 (17%) had bacteraemia. Baseline demographics, comorbidities, and severity of illness indicators were similar between groups. On treatment initiation, 336 (80%) patients were in the intensive care unit, 296 (70%) were receiving mechanical ventilation, and 168 (40%) required vasopressor support. Clinical success was observed in 128 (61%) of 210 patients treated with ceftolozane-tazobactam and 109 (52%) of 210 patients treated with ceftazidime-avibactam. By conditional logistic regression analysis, the adjusted odds ratio (aOR) of success after treatment with ceftolozane-tazobactam compared with ceftazidime-avibactam was 2·07 (95% CI 1·16-3·70). For patients with pneumonia, clinical success was observed in 110 (63%) of 175 patients in the ceftolozane-tazobactam group and 89 (51%) of 175 patients in the ceftazidime-avibactam group (aOR 2·34 [95% CI 1·22-4·47]). Among patients with bacteraemia, rates of clinical success were 51% (18 of 35 patients) for patients treated with ceftolozane-tazobactam and 57% (20 of 35 patients) for those treated with ceftazidime-avibactam (0·76 [0·23-2·57]). There were no significant differences between groups in 30-day or 90-day mortality. Among patients whose baseline isolates were tested for susceptibility, resistance developed in 22% (38 of 173) of patients treated with ceftolozane-tazobactam and 23% (40 of 177) of patients treated with ceftazidime-avibactam., Interpretation: Treatment with ceftolozane-tazobactam resulted in higher rates of clinical success compared with ceftazidime-avibactam for invasive infections due to multidrug-resistant P aeruginosa. Differences were driven by improved response rates for patients with pneumonia who were treated with ceftolozane-tazobactam. There were no significant differences between study groups with respect to all-cause mortality; treatment-emergent resistance was common with both agents., Funding: Merck Sharp & Dohme., Competing Interests: Declaration of interests RKS has served as a consultant for AbbVie, Biomerieux, Shionogi, Menarini, Merck, Entasis, GlaxoSmithKline, and Venatorx, and has received investigator-initiated funding from Roche, Innoviva, Merck, Melinta, Shionogi, and Venatorx. LMA has served on advisory boards for bioMérieux, Roche, Pfizer, Shionogi, La Jolla/Innoviva, Ferring, and AbbVie, and has received speaker honorarium from Gilead. SLA has served on advisory boards for Shionogi, GlaxoSmithKline, Melinta, and Basilea. AB has served on an advisory board for Beckman Coulter. RB has received travel funds from bioMérieux. KCC has served as a consultant for bioMérieux. KED has served on advisory boards for Shionogi, Spero, Entasis, AbbVie, Melinta, Basilea, and GlaxoSmithKline; has received a speaker honorarium from MAD-ID; and has received travel funds from the Society of Infectious Diseases Pharmacists where she serves as Treasurer. JCG has received honoraria from MJH where he serves as Associate Editor for Clinical Infectious Diseases; has received payment for expert testimony from German, Gallagher & Murtagh; has served on advisory boards for Allergan, GlaxoSmithKline, Merck, Novavax, Qpex, Shionogi, and Spero; reports serving as Editor-in-Chief for Contagion; and has received authorship royalties from JB Learning. ELH has served as a consultant for Wolters-Kluwer. KMH has served on a speaker's bureau for Cepheid Diagnostics and has received travel funds from bioMérieux. KSK has served as a consultant for Merck, GlaxoSmithKline, Allecra, Shionogi, MicuRx, VenatoRx, and AbbVie. WDK has received funding from Merck and Shionogi. AM has received funding from F2G Biotech GmbH. EKM has served as a consultant for Abbvie, Merck, Basilea, Shionogi, Melinta, Ferring, Cidara, Entasis, LabSimply, Pfizer, and GlaxoSmithKline; has received speaker honoraria from GlaxoSmithKline, Shionogi, and Pfizer; has served as a safety monitor for the SNAP Trial and the NIAID Division of Microbiology and Infectious Diseases; and is President of the Society of Infectious Diseases Pharmacists. WRM has received funding from the National Institutes of Health and royalties from UpToDate. JMP has served as a consultant for Merck, Shionogi, Melinta, Entasis, GlaxoSmithKline, and VenatoRx; has received investigator-initiated funding from Merck; and has research grants from Merck, Shionogi, and Melinta. MJS has received funding from Merck, bioMérieux, and Selux Diagnostics; has served as a consultant for Shionogi; and has served on an advisory board for AbbVie. DV has received funding from Merck; has served as a consultant for Utility, Shionogi, Merck, Union, Roche, and Qpex; has received honoraria from Pfizer, Entasis, and Clinical Care Options; and has received fees from the British Society of Antimicrobial Chemotherapy and Universidade Federal do Rio Grande do Sul. MV has served on an advisory board for Shionogi. VV has received funding from the Florida Department of Health; has received honoraria from the American College of Clinical Pharmacy, the American Society of Health-System Pharmacists, ID Week, the American Society of Microbiologists, and Merck; and has received payment for expert testimony from Silver Golub & Teitell. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Current vancomycin monitoring guidelines recommend monitoring 24-hour area under the concentration-time curve (AUC) to minimum inhibitory concentration ratios for patients with serious methicillin-resistant Staphylococcus aureus infections. However, there are sparse data on the safety, feasibility, and efficacy of vancomycin AUC monitoring for outpatients. Traditional AUC pharmacokinetic calculations require 2 concentrations, while bayesian software allows for single-concentration AUC estimations., Methods: We conducted a single-center, quasi-experimental, interrupted time series study of patients enrolled in the outpatient parenteral antimicrobial therapy program at our institution for vancomycin management. Our institution implemented a pharmacist-driven vancomycin AUC monitoring program from September 2019 to February 2020, and again from September 2022 to March 2023. Patients enrolled underwent vancomycin monitoring using an AUC goal of 400-600 mg⋅h/L, estimated through bayesian modeling. Patients enrolled in the outpatient parenteral antimicrobial therapy program from July 2021 through August 2022 for trough-based monitoring were used for comparison. The primary outcome was nephrotoxicity incidence, defined as a serum creatinine increase by ≥0.5 mg/dL or ≥50% during outpatient vancomycin therapy., Results: We enrolled 63 patients in the AUC group and 60 patients in the trough-based group. Nephrotoxicity was significantly lower in the AUC cohort (6.3% vs 23.3%; P = .01). The number of unusable vancomycin concentrations was also significantly lower in the AUC cohort (0% vs 6%; P < .01). There was no difference in composite 90-day all-cause mortality or readmission (33.3% vs 38.3%; P = .56)., Conclusions: Following implementation of a pharmacist-driven AUC monitoring program, patients were less likely to develop nephrotoxicity during outpatient vancomycin therapy., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Dalbavancin has been used off-label to treat invasive bacterial infections in vulnerable populations like people who use drugs (PWUD) because of its broad gram-positive coverage and unique pharmacological properties. This retrospective, multisite study examined clinical outcomes at 90 days in PWUD versus non-PWUD after secondary treatment with dalbavancin for bacteremia, endocarditis, osteomyelitis, septic arthritis, and epidural abscesses., Methods: Patients at 3 teaching hospitals who received dalbavancin for an invasive infection between March 2016 and May 2022 were included. Characteristics of PWUD and non-PWUD, infection highlights, hospital stay and treatment, and outcomes were compared using χ 2 for categorical variables, t test for continuous variables, and nonparametric tests where appropriate., Results: There were a total of 176 patients; 78 were PWUD and 98 were non-PWUD. PWUD were more likely to have a patient-directed discharge (26.9% vs 3.1%; P < .001) and be lost to follow-up (20.5% vs 7.14%; P < .01). Assuming loss to follow-up did not achieve clinical cure, 73.1% of PWUD and 74.5% of non-PWUD achieved clinical cure at 90 days ( P = .08)., Conclusions: Dalbavancin was an effective treatment option for invasive gram-positive infections in our patient population. Despite higher rates of patient-directed discharge and loss to follow-up, PWUD had similar rates of clinical cure at 90 days compared to non-PWUD., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Nontuberculous mycobacteria (NTM) can cause a variety of infections, including serious pulmonary disease. Treatment encompasses polypharmacy, with a targeted regimen of 2-5 active medications, depending on site of infection, species, and clinical characteristics. Medications may include oral, intravenous, and inhalational routes. Medication acquisition can be challenging for numerous reasons, including investigational status, limited distribution models, and insurance prior authorization. Additionally, monitoring and managing adverse reactions and drug interactions is a unique skill set. While NTM is primarily medically managed, clinicians may not be familiar with the intricacies of medication selection, procurement, and monitoring. This review offers insights into the pharmacotherapeutic considerations of this highly complex disease state, including regimen design, medication acquisition, safety monitoring, relevant drug-drug interactions, and adverse drug reactions., Competing Interests: Potential conflicts of interest. C.G.R. has received speaker fees from Insmed. B.C. holds stock or stock options in Pfizer, Merck, Viatris, Organon, and GE HealthCare. M.V.M. serves as a consultant for BD Diagnostics, GSK, and Cidara. M.V.M. has served on an advisory board for Melinta, Pfizer, and Merck. M.V.M. has received research funding from Merck. M.V.M. has received an honorarium from Paratek. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Previous studies identified a rapid decrease in valproate serum concentrations when coadministered with a carbapenem; however, the specific consequences and subsequent therapy adjustments are not well described. We aimed to investigate the clinical and therapeutic implications of the carbapenem-valproate drug-drug interaction., Methods: This retrospective analysis included data from 2 large academic medical centers during January 2017 to June 2022. The primary outcome was incidence of seizures or behavioral events stratified by valproate indication. All adult patient encounters with concomitant administration of any carbapenem antimicrobial and valproate were included. Patients without prolonged exposure to valproate prior to hospitalization, without valproate levels pre- and post-carbapenem administration, with an admitting diagnosis of seizure, with exposure to other agents that decrease valproate concentrations, or who had a seizure during the hospitalization prior to carbapenem exposure were excluded., Results: Two hundred fifty-eight episodes of concomitant use among 78 unique adult patients were included. Valproate was used for seizure control in 41 patients (52.6%) and for mood-related disorders in 37 (47.4%). In those prescribed valproate for its antiepileptic properties, seizures occurred following carbapenem administration in 46.3% of encounters. In those taking valproate for mood-related disorders, 50.8% met the primary endpoint of behavioral disturbance., Conclusions: Our study demonstrates significant clinical implications of the carbapenem-valproate interaction. Clinicians should be aware of this interaction and consider alternative antimicrobial and/or antiepileptic agents whenever possible. Adding or increasing doses of antiepileptic agents and/or consultation with a neurologist prior to concomitant use should be considered when this combination cannot be avoided., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Long-acting lipoglycopeptides such as dalbavancin may have utility in patients with Gram-positive bloodstream infections (BSI), particularly in those with barriers to discharge or who require prolonged parenteral antibiotic courses. A retrospective cohort study was performed to provide further multicenter real-world evidence on dalbavancin use as a sequential therapy for Gram-positive BSI., Methods: One hundred fifteen patients received dalbavancin with Gram-positive BSI, defined as any positive blood culture or diagnosed with infective endocarditis, from 13 centers geographically spread across the United States between July 2015 and July 2021., Results: Patients had a mean (SD) age of 48.5 (17.5) years, the majority were male (54%), with many who injected drugs (40%). The most common infection sources (non-exclusive) were primary BSI (89%), skin and soft tissue infection (SSTI) (25%), infective endocarditis (19%), and bone and joint infection (17%). Staphylococcus aureus accounted for 72% of index cultures, coagulase-negative Staphylococcus accounted for 18%, and Streptococcus species in 16%. Dalbavancin started a median (Q 1 -Q 3 ) of 10 (6-19) days after index culture collection. The most common regimen administered was dalbavancin 1500 mg as one dose for 50% of cases. The primary outcome of composite clinical failure occurred at 12.2%, with 90-day mortality at 7.0% and 90-day BSI recurrence at 3.5%., Conclusions: Dalbavancin may serve as a useful tool in facilitating hospital discharge in patients with Gram-positive BSI. Randomized controlled trials are anticipated to validate dalbavancin as a surrogate to current treatment standards., (© 2024. The Author(s).)

Background: Bacillus cereus is a ubiquitous gram-positive rod-shaped bacterium that can cause sepsis and neuroinvasive disease in patients with acute leukemia or neutropenia., Methods: A single-center retrospective review was conducted to evaluate patients with acute leukemia, positive blood or cerebrospinal fluid test results for B cereus , and abnormal neuroradiographic findings between January 2018 and October 2022. Infection control practices were observed, environmental samples obtained, a dietary case-control study completed, and whole genome sequencing performed on environmental and clinical Bacillus isolates., Results: Five patients with B cereus neuroinvasive disease were identified. All patients had acute myeloid leukemia (AML), were receiving induction chemotherapy, and were neutropenic. Neurologic involvement included subarachnoid or intraparenchymal hemorrhage or brain abscess. All patients were treated with ciprofloxacin and survived with limited or no neurologic sequelae. B cereus was identified in 7 of 61 environmental samples and 1 of 19 dietary protein samples-these were unrelated to clinical isolates via sequencing. No point source was identified. Ciprofloxacin was added to the empiric antimicrobial regimen for patients with AML and prolonged or recurrent neutropenic fevers; no new cases were identified in the ensuing year., Conclusions: B cereus is ubiquitous in the hospital environment, at times leading to clusters with unrelated isolates. Fastidious infection control practices addressing a range of possible exposures are warranted, but their efficacy is unknown and they may not be sufficient to prevent all infections. Thus, including B cereus coverage in empiric regimens for patients with AML and persistent neutropenic fever may limit the morbidity of this pathogen., Competing Interests: Potential conflicts of interest. M. K.: royalties from UpToDate. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: Current infective endocarditis guidelines recommend two different gentamicin synergy dosing strategies for selected Gram-positive organisms. The purpose of this analysis was to evaluate the incidence of acute kidney injury (AKI) with gentamicin synergy dosing, comparing divided-daily and once-daily dosing strategies for infective endocarditis (IE)., Methods: Groups were split into patients who received gentamicin divided-daily dosing and once-daily (3 mg/kg) dosing for Gram-positive IE. The primary outcome was the incidence of AKI defined by RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria after starting gentamicin. A multivariable logistic regression analysis was performed to identify possible independent predictors of developing AKI. Notable secondary outcomes included hospital length of stay, need for gentamicin dose adjustments based on therapeutic drug monitoring, and assessment of each case of AKI using the Naranjo algorithm., Results: The incidence of AKI was significantly higher in the divided-daily group compared with the once-daily group (52.5% versus 13%, P  < 0.01). The divided-dosing group had significantly longer median [IQR] hospital length of stay (19 days [12:29] versus 13.5 days [9:22], P  < 0.01) and a greater number of patients who required dose adjustments (76.2% versus 21.7%, P  < 0.01). The multivariable regression analysis showed that the divided-dosing strategy, duration and institution were independently associated with incidence of AKI., Conclusions: This analysis suggests a lower incidence of AKI in the treatment of endocarditis with gentamicin synergy dosed once-daily compared with a divided-daily dosing. Further studies are warranted to assess if there is a difference in efficacy between gentamicin synergy dosing strategies and in gentamicin compared with no gentamicin regimens for IE., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

In 2010 a single isolate of a trimethoprim-resistant multilocus sequence type 5, Panton-Valentine leucocidin-positive, community-associated methicillin-resistant Staphylococcus aureus (PVL-positive ST5 CA-MRSA), colloquially named WA121, was identified in northern Western Australia (WA). WA121 now accounts for ~14 % of all WA MRSA infections. To gain an understanding of the genetic composition and phylogenomic structure of WA121 isolates we sequenced the genomes of 155 WA121 isolates collected 2010-2021 and present a detailed genomic description. WA121 was revealed to be a single clonally expanding lineage clearly distinct from sequenced ST5 strains reported outside Australia. WA121 strains were typified by the presence of the distinct PVL phage φSa2wa-st5, the recently described methicillin resistance element SCC mec IVo carrying the trimethoprim resistance ( dfrG ) transposon Tn 4791 , the novel β-lactamase transposon Tn 7702 and the epidermal cell differentiation inhibitor (EDIN-A) plasmid p2010-15611-2. We present evidence that SCC mec IVo together with Tn 4791 has horizontally transferred to Staphylococcus argenteus and evidence of intragenomic movement of both Tn 4791 and Tn 7702 . We experimentally demonstrate that p2010-15611-2 is capable of horizontal transfer by conjugative mobilization from one of several WA121 isolates also harbouring a pWBG749-like conjugative plasmid. In summary, WA121 is a distinct and clonally expanding Australian PVL-positive CA-MRSA lineage that is increasingly responsible for infections in indigenous communities in northern and western Australia. WA121 harbours a unique complement of mobile genetic elements and is capable of transferring antimicrobial resistance and virulence determinants to other staphylococci.

A novel pharmacy residency rotation was created to meet the needs of patients enrolled in an outpatient parenteral antimicrobial therapy (OPAT) program but not yet discharged from the inpatient setting. This service resulted in a high number of antimicrobial stewardship interventions identified and accepted by the primary team(s)., Competing Interests: R.S.B. reports travel support from the American College of Clinical Pharmacy. M.V.M. reports receiving grants from Merck; consulting fees from BD Biosciences, Cidara Therapeutics, Glaxo Smith Klein, Melinta Therapeutics, Merck, and Pfizer; honoraria from Paratek; travel support from the American College of Clinical Pharmacy, American Society of Health-System Pharmacists, and Society for Healthcare Epidemiology of America; and the current President of the Massachusetts Society of Health-system Pharmacists. J.C.P. reports participating on advisory board for Shionogi and Gilead Sciences. All other authors report no relevant conflicts of interest., (© The Author(s) 2023.)

In Australia, gonococcal isolates are monitored for antimicrobial susceptibilities. In Western Australia (WA), gonorrhoea notification rates increased by 63 % between 2013 and 2016, with the steepest increase occurring between 2015 and 2016, before stabilizing at this higher baseline between 2017 and 2020. This increased prevalence was associated with antimicrobial-susceptible (AMS) lineages. To understand the provenance of these isolates causing gonorrhoea in WA, whether they were introduced or expanded from endogenous lineages, 741 isolates were collected in 2017 and characterized by both iPLEX typing and whole genome sequencing (WGS). Antibiograms and genocoding of the isolates revealed that AMS isolates were most prevalent in the remote regions, while the urban/rural regions were characterized by antimicrobial-resistant (AMR) isolates. iPLEX typing identified 78 iPLEX genotypes (WA-1 to WA-78) of which 20 accounted for over 88 % of isolates. WA-10 was the most frequently identified genotype in the urban/rural regions whilst WA-29 was the most frequently identified genotype in the remote regions. Genotypes WA-38, WA-52 and WA-13 accounted for 81 % ( n =36/44) of the azithromycin-resistant N. gonorrhoeae (AziR) isolates. A representative isolate of each iPLEX genotype and AMR biotype was whole genome sequenced and analysed using MLST, NG-MAST and NG-STAR, and the novel core genome clustering Ng&#95;cgc&#95;400 typing scheme. Five predominant Bayesian population groups (termed BPG-1 to 5) were identified in the study collection. BPG-1 and BPG-2 were associated with AMS isolates from the remote regions. BPG-1 and BPG-2 were shown to be unique to the remote regions based on a minimum spanning tree against 4000 international isolates. AMS isolates in urban/rural regions were dominated by international lineages. AziR and Cef DS (decreased susceptibility to ceftriaxone) was concentrated in three urban/rural genomic groups (BPG-3, 4 and 5). Azithromycin minimum inhibitory concentrations (0.5-16 mg l -1 ) correlated with the accumulation of mtrR mutations or/and the fraction of 23S rRNA C2611T mutated copies. The majority of isolates in BPG-3, 4 and 5 could be correlated with known AMR lineages circulating globally and nationally. In conclusion, the surge in AMS isolates in WA in 2017 was due to importation of international AMS lineages into urban/rural regions, whilst the local AMS lineages persisted largely in the remote regions. Bridging between the urban/rural and remote regions was relatively rare, but continued surveillance is required to prevent ingress of AMR strains/lineages into the remote regions of WA.

Background: Sepsis guidelines recommend daily review to de-escalate or stop antibiotics in appropriate patients. This randomized, controlled trial evaluated an opt-out protocol to decrease unnecessary antibiotics in patients with suspected sepsis., Methods: We evaluated non-intensive care adults on broad-spectrum antibiotics despite negative blood cultures at 10 US hospitals from September 2018 through May 2020. A 23-item safety check excluded patients with ongoing signs of systemic infection, concerning or inadequate microbiologic data, or high-risk conditions. Eligible patients were randomized to the opt-out protocol vs usual care. Primary outcome was post-enrollment antibacterial days of therapy (DOT). Clinicians caring for intervention patients were contacted to encourage antibiotic discontinuation using opt-out language. If continued, clinicians discussed the rationale for continuing antibiotics and de-escalation plans. To evaluate those with zero post-enrollment DOT, hurdle models provided 2 measures: odds ratio of antibiotic continuation and ratio of mean DOT among those who continued antibiotics., Results: Among 9606 patients screened, 767 (8%) were enrolled. Intervention patients had 32% lower odds of antibiotic continuation (79% vs 84%; odds ratio, 0.68; 95% confidence interval [CI], .47-.98). DOT among those who continued antibiotics were similar (ratio of means, 1.06; 95% CI, .88-1.26). Fewer intervention patients were exposed to extended-spectrum antibiotics (36% vs 44%). Common reasons for continuing antibiotics were treatment of localized infection (76%) and belief that stopping antibiotics was unsafe (31%). Thirty-day safety events were similar., Conclusions: An antibiotic opt-out protocol that targeted patients with suspected sepsis resulted in more antibiotic discontinuations, similar DOT when antibiotics were continued, and no evidence of harm., Clinical Trials Registration: NCT03517007., Competing Interests: Potential conflicts of interest. E. D. A. reports grants or contracts from the University of Maryland (paid to author), University of Chicago (paid to author), CDC Prevention Epicenter Program (paid to institution), Oxford University Clinical Research Unit (paid to author), CDC (paid to institution), and DASON Member Hospital Contracts (paid to institution); royalties or licenses from UpToDate (paid to author); consulting fees from the American College of Clinical Pharmacy (paid to author), Hospital Association of New York State (paid to author), Sarah Moreland Russel Consulting (paid to author), and HealthTrackRX (paid to author); and support for attending meetings and/or travel from the American Society of Microbiology (paid to author), Pew Charitable Trusts (paid to author), and Oxford University Clinical Research Unit (paid to institution). A. E. D. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck & Co (paid to author). M. Z. D. reports grants or contracts from the National Institutes of Health, GSK, Johnson & Johnson, and Contrafect (paid to institution); support for attending meetings and/or travel from GSK; and participation on a data and safety monitoring board or advisory board for GSK (paid to author). D. J. A. reports grants or contracts from Agency for Healthcare Research and Quality (to institution), royalties or licenses from UpToDate Online (paid to author), and other financial or nonfinancial interests from Infection Control Education for Major Sports, LLC (owner). M. K. reports grants or contracts from Agency for Healthcare Research and Quality (paid to institution) and the Massachusetts Department of Public Health (paid to institution) and royalties or licenses from UpToDate (paid to author). R. W. M. reports grants or contracts from the CDC (paid to institution) and the Agency for Healthcare Research and Quality (paid to institution), royalties or licenses from UpToDate, Inc. (paid to author), speaker honoraria for the North Carolina Statewide Program for Infection Control and Epidemiology (paid to author), support for attending meetings and/or travel from the Society for Healthcare Epidemiology of America, and is on the Society for Healthcare Epidemiology of America Board of Trustees. A. P. reports grants from Clinical and Translational Science Award (to Biostatistics, Epidemiology, and Research Design Core, within the Biostatistics and Bioinformatics Department at Duke University). J. C. P. reports serving on the advisory boards for Shionogi, Inc, and Gilead Sciences, Inc. 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.)

Nontuberculous mycobacteria (NTM) are a group of atypical bacteria that may cause a spectrum of clinical manifestations, including pulmonary, musculoskeletal, skin and soft tissue, and cardiac infections. Antimycobacterial medication regimens for NTM infections require multiple agents with prolonged treatment courses and are often associated with poor tolerance in patients and suboptimal clinical outcomes. This review summarizes NTM pharmacotherapy, including treatment concepts, preferred medication regimens according to NTM species and site of infection, and emerging treatment methods for difficult-to-treat species., (© 2023. The Author(s).)

Background: Current vancomycin guidelines recommend early and frequent area-under-the-curve monitoring in patients with obesity. Vancomycin's volume of distribution is likely altered in patients with obesity, which may result in lower serum concentrations initially but lead to accumulation with continued use. The objective of this study was to evaluate the incidence of vancomycin accumulation in patients with obesity and identify potential factors associated with accumulation., Methods: This was a single-center, retrospective, observational study at a tertiary academic medical center. Adult patients with a body mass index (BMI) ≥ 30 kg/m 2 and ≥ 2 vancomycin serum trough concentrations drawn in 2019 were screened for inclusion. The major endpoint was the incidence of vancomycin accumulation defined as ≥ 20% increase in trough concentration within the first 10 days of therapy. Key minor endpoints included incidence of acute kidney injury (AKI) and factors associated with accumulation., Results: Of the 443 patients screened, 162 were included. The median age was 56.5 years (interquartile range [IQR], 43-65.3), and 62.3% were male. The median weight was 112.7 kg (IQR, 99.8-122.6) and the median BMI was 36.8 kg/m 2 (IQR, 33.1-41). The total daily dose median at initiation was 28.7 mg/kg per day (IQR, 25.4-31.2). Accumulation occurred in 99 of 162 patients (61.1%) and AKI occurred in 20 of 140 patients (14.3%). No specific factors were found to be associated with accumulation., Conclusions: Patients with obesity are likely to experience vancomycin accumulation within the first 10 days of therapy. Clinicians should use frequent monitoring of vancomycin and use caution when interpreting early concentrations in patients with obesity., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aim: To evaluate the efficiency of Bayesian modeling software and first-order pharmacokinetic (PK) equations to calculate vancomycin area under the concentration-time curve (AUC) estimations., Methods: Unblinded, crossover, quasi-experimental study at a tertiary care hospital for patients receiving intravenous vancomycin. Vancomycin AUC monitoring was compared using Bayesian modeling software or first-order PK equations. The primary endpoint was the time taken to estimate the AUC and determine regimen adjustments. Secondary endpoints included the percentage of vancomycin concentrations usable for AUC calculations and acute kidney injury (AKI)., Results: Of the 124 patients screened, 34 patients had usable vancomycin concentrations that led to 44 AUC estimations. Without electronic health record (EHR) integration, the time from assessment to intervention in the Bayesian modeling platform was a median of 9.3 min (quartiles Q 1 -Q 3 7.8-12.4) compared to 6.8 min (Q 1 -Q 3 4.8-8.0) in the PK equations group ( p = 0.004). With simulated Bayesian software integration into the EHR, however, the median time was 3.8 min (Q 1 -Q 3 2.3-6.9, p = 0.019). Vancomycin concentrations were usable in 88.2% in the Bayesian group compared to 48.3% in the PK equation group and there were no cases of AKI., Conclusion: Without EHR integration, Bayesian software was more time-consuming to assess vancomycin dosing than PK equations. With simulated integration, however, Bayesian software was more time efficient. In addition, vancomycin concentrations were more likely to be usable for calculations in the Bayesian group.

Introduction: Enterococcus faecium is an opportunistic pathogen that has become one of the leading causes of hospital acquired infection that are resistant to multiple critically important antimicrobials., Aim: The objective of the study was to describe the molecular characteristics and relationship between major strains of E. faecium harbouring the van operon and to determine if the strains had increasing virulence and antimicrobial resistance determinants over time., Methods: E. faecium harbouring the van operon detected using PCR from surveillance rectal swabs of patients that were admitted to high-risk units at a Perth teaching hospital from 2001 to 2015 were retrospectively analysed using a whole genome sequencing and bioinformatics approach., Results: ST18, ST78, ST80, ST173, ST203 and ST555 were identified as the major STs accounting for 93.7% of E. faecium isolates. Except for ST173, major STs identified at Royal Perth Hospital (RPH) have been reported across Australia and internationally. Isolates from each ST formed independently branched phylogenetic clusters with each harbouring unique virulence and antimicrobial resistance profiles. Depending on the ST, different genes conferring resistance to similar antimicrobial classes were identified. Except for ST80 which harboured the vanA type operon, all major strains harboured the vanB operon conferring only vancomycin resistance., Conclusion: Major strains of E. faecium isolated over 15-years showed unique virulome and resistome profiles with no indication of increasing virulence or antimicrobial resistance determinants. Strains were distantly related and the acquisition of different genes encoding similar antimicrobial resistances suggest the independent evolution of each strain., Data Summary: The whole genome sequences of all isolates from this study are accessible from the NCBI-SRA database under project number PRJNA575940 and PRJNA524213. Published reference sequence Aus0004 was obtained from NCBI-SRA under project number PRJNA86649 DOI:10.1128/JB.00259-12., (Crown Copyright © 2021. Published by Elsevier GmbH. All rights reserved.)

Initially reported in Western Australia in the 1980s, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has become a major cause of S. aureus infections globally. We report the complete genome sequences of three of the earliest CA-MRSA strains isolated from remote Australian Indigenous communities in the Kimberley region of Western Australia.

Sequence type 1 (ST1) methicillin-resistant Staphylococcus aureus (MRSA) SCC mec IV[2B] has become one of the most common community-associated MRSA clones in Australia. We report the complete genome sequence of one of the earliest isolated Australian S. aureus ST1-MRSA-IV strains, WBG8287, isolated from an Indigenous Australian patient living in the remote Kimberley region of Western Australia.

Background: Progranulin is a widely expressed pleiotropic growth factor with a central regulatory effect during the early immune response in sepsis. Progranulin signaling has not been systematically studied and compared between sepsis, community-acquired pneumonia (CAP), COVID-19 pneumonia and a sterile systemic inflammatory response (SIRS). We delineated molecular networks of progranulin signaling by next-generation sequencing (NGS), determined progranulin plasma concentrations and quantified the diagnostic performance of progranulin to differentiate between the above-mentioned disorders using the established biomarkers procalcitonin (PCT), interleukin-6 (IL-6) and C-reactive protein (CRP) for comparison., Methods: The diagnostic performance of progranulin was operationalized by calculating AUC and ROC statistics for progranulin and established biomarkers in 241 patients with sepsis, 182 patients with SIRS, 53 patients with CAP, 22 patients with COVID-19 pneumonia and 53 healthy volunteers. miRNAs and mRNAs in blood cells from sepsis patients (n = 7) were characterized by NGS and validated by RT-qPCR in an independent cohort (n = 39) to identify canonical gene networks associated with upregulated progranulin at sepsis onset., Results: Plasma concentrations of progranulin (ELISA) in patients with sepsis were 57.5 (42.8-84.9, Q25-Q75) ng/ml and significantly higher than in CAP (38.0, 33.5-41.0 ng/ml, p < 0.001), SIRS (29.0, 25.0-35.0 ng/ml, p < 0.001) and the healthy state (28.7, 25.5-31.7 ng/ml, p < 0.001). Patients with COVID-19 had significantly higher progranulin concentrations than patients with CAP (67.6, 56.6-96.0 vs. 38.0, 33.5-41.0 ng/ml, p < 0.001). The diagnostic performance of progranulin for the differentiation between sepsis vs. SIRS (n = 423) was comparable to that of procalcitonin. AUC was 0.90 (95% CI = 0.87-0.93) for progranulin and 0.92 (CI = 0.88-0.96, p = 0.323) for procalcitonin. Progranulin showed high discriminative power to differentiate bacterial CAP from COVID-19 (sensitivity 0.91, specificity 0.94, AUC 0.91 (CI = 0.8-1.0) and performed significantly better than PCT, IL-6 and CRP. NGS and partial RT-qPCR confirmation revealed a transcriptomic network of immune cells with upregulated progranulin and sortilin transcripts as well as toll-like-receptor 4 and tumor-protein 53, regulated by miR-16 and others., Conclusions: Progranulin signaling is elevated during the early antimicrobial response in sepsis and differs significantly between sepsis, CAP, COVID-19 and SIRS. This suggests that progranulin may serve as a novel indicator for the differentiation between these disorders., Trial Registration: Clinicaltrials.gov registration number NCT03280576 Registered November 19, 2015., (© 2021. The Author(s).)

Background: Omadacycline is an aminomethylcycline antimicrobial approved by the US Food and Drug Administration in 2018 for community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It has in vitro activity against nontuberculous mycobacteria, including Mycobacterium abscessus complex, but clinical data for this indication are lacking., Methods: Omadacycline use was reviewed at an 804-bed academic medical center. Patients were included if they received omadacycline for culture-proven M abscessus disease in 2019., Results: Four patients received omadacycline for the treatment of culture-positive M abscessus disease in 2019. Two patients had cutaneous disease, 1 had pulmonary disease, and 1 had osteomyelitis and bacteremia. The patients received omadacycline for a median duration of 166 days (range, 104-227) along with a combination of other antimicrobial agents. Omadacycline-containing regimens were associated with a clinical cure in 3 of 4 patients, with 1 patient improving on ongoing treatment. Omadacycline's tolerability was acceptable for patients with M abscessus disease, with 1 patient discontinuing therapy in month 6 due to nausea., Conclusions: Omadacycline is a novel oral option for the treatment of M abscessus disease, for which safe and effective options are needed. Although this case series is promising, further data are required to determine omadacycline's definitive role in the treatment of M abscessus disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Staphylococcus aureus is a serious human and animal pathogen. Multilocus sequence type 612 (ST612) is the dominant methicillin-resistant S. aureus (MRSA) clone in certain South African hospitals and is sporadically isolated from horses and horse-associated veterinarians in Australia. Colonisation and infection by ST612-MRSA is increasing in Western Australia. Whole-genome sequencing was performed for 51 isolates of ST612-MRSA from Western Australian patients and healthcare workers, South African hospital patients, Australian veterinarians and New South Wales horses. Core genome phylogenies suggested that Australian equine and veterinarian-associated ST612-MRSA were monophyletic. Individual Western Australian isolates grouped either with this equine-associated lineage or more diverse lineages related to those in South African hospitals. Bioinformatic analyses of the complete ST612-MRSA reference genome SVH7513 confirmed that ST612-MRSA was closely related to ST8 USA500 MRSA. Common use of rifampicin in South Africa and equine veterinarian practice may favour ST612-MRSA in these settings. Humans and horses colonised with ST612-MRSA are potential reservoirs for MRSA in Australia., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)