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Yisha Li,1 Margaret Ragland,1 Erin Austin,2 Kendra Young,1 Katherine Pratte,3 John E Hokanson,1 Terri H Beaty,4 Elizabeth A Regan,3 Stephen I Rennard,5 Christina Wern,6 Michael R Jacobs,7 Ruth Tal-Singer,8 Barry J Make,3 Gregory L Kinney1 On Behalf of theCOPDGene investigators1Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 2Mathematical and Statistical Sciences, University of Colorado Denver, Denver, CO, USA; 3National Jewish Health, Denver, CO, USA; 4Bloomberg School of Public Health, University of John Hopkins, Baltimore, MD, USA; 5Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NB, USA; 6Department of Clinical Pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA; 7School of Pharmacy, Temple University, PA, Pennsylvania, USA; 8COPD Foundation, Washington, D.C., USACorrespondence: Gregory L KinneyDepartment of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USATel +1 303-724-4437Email GREG.KINNEY@CUANSCHUTZ.EDUPurpose: Medication patterns include all medications in an individual’s clinical profile. We aimed to identify chronic co-morbidity treatment patterns through medication use among COPDGene participants and determine whether these patterns were associated with mortality, acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and quality of life.Materials and Methods: Participants analyzed here completed Phase 1 (P1) and/or Phase 2 (P2) of COPDGene. Latent class analysis (LCA) was used to identify medication patterns and assign individuals into unobserved LCA classes. Mortality, AECOPD, and the St. George’s Respiratory Questionnaire (SGRQ) health status were compared in different LCA classes through survival analysis, logistic regression, and Kruskal–Wallis test, respectively.Results: LCA identified 8 medication patterns from 32 classes of chronic comorbid medications. A total of 8110 out of 10,127 participants with complete covariate information were included. Survival analysis adjusted for covariates showed, compared to a low medication use class, mortality was highest in participants with hypertension+diabetes+statin+antiplatelet medication group. Participants in hypertension+SSRI+statin medication group had the highest odds of AECOPD and the highest SGRQ score at both P1 and P2.Conclusion: Medication pattern can serve as a good indicator of an individual’s comorbidities profile and improves models predicting clinical outcomes.Keywords: COPDGene, co-morbidities, latent class analysis, medication patterns, mortality

The antipneumococcal activity of MEN 10700 was compared with those of nine other compounds by MIC and time-kill kinetics. MIC90s (mg/L) of 202 penicillin-susceptible, -intermediate and -resistant pneumococci were: 0.06, 1.0 and 2.0 (MEN 10700); 0.06, 0.5-1.0 and 2.0 (amoxycillin ± clavulanate); 0.06, 0.5 and 4.0 (cefotaxime); 0.1 25, 0.5 and 2.0 (cefepime); 0.01 6, 0.125 and 0.25 (imipenem); 0.03, 0.5 and 1.0 (meropenem); 2.0 (ciprofloxacin); 0.1 25, >64.0 and >64.0 (clarithromycin); and 0.5 (vancomycin). Time-kill kinetics showed that MEN 10700, at 4 x MIC, was bactericidal for all 12 isolates tested at 4 x MIC. Kinetics of other β-lactams were similar to those of MEN 10700, relative to MICs. Ciprofloxacin, at 4 x MIC, was uniformly bactericidal after 24 h. Clarithromycin exhibited slow kill kinetics, after 24 h. Vancomycin was bactericidal against 11/12 isolates at 2 x MIC after 24 h. [ABSTRACT FROM PUBLISHER]

An agar dilution MIC method was used to test the activity of gatifloxacin, a new broad-spectrum fluoroquinolone, compared with ciprofloxacin, levofloxacin, sparfloxacin, trovafloxacin, amoxycillin, cefuroxime, ceftriaxone and clarithromycin against 71 penicillin-susceptible, 81 penicillin-intermediate and 55 penicillin-resistant pneumococci. Quinolone activity was unaffected by penicillin susceptibility, with MIC50/MIC90s (mg/L) of 0.25/0.5 for gatifloxacin; 1/2 for ciprofloxacin; 1/2 for levofloxacin; 0.25/0.5 for sparfloxacin; 0.125/0.25 for trovafloxacin. β-Lactam and clarithromycin MICs rose with those of penicillin G; MIC50/MIC90 values (mg/lL) for penicillin-susceptible, -intermediate and -resistant strains were: 0.03/0.06, 0.25/1, 2/4 for penicillin G; 0.03/0.03, 0.125/1, 2/4 for amoxycillin; 0.03/0.125, 0.5/4, 8/16 for cefuroxime; 0.03/0.03, 0.25/0.5, 2/4 for ceftriaxone; 0.03/0.06, 0.03/>64, 1/>64 for clarithromycin. Time-kill testing of four penicillin-susceptible, four -intermediate and four -resistant strains showed that levofloxacin at the MIC, gatifloxacin and sparfloxacin at 2 x MIC, and trovafloxacin and ciprofloxacin at 4 x MIC were bactericidal (99.9% killing) for all strains after 12 h and 24 h. By contrast, amoxycillin, cefuroxime and ceftriaxone showed bactericidal activity after 24 h against all strains at 4, 8 and 4 x MIC, respectively. Against ten organisms with clarithromycin MICs of 0.03-4.0 mg/L, clarithromycin was bactericidal against seven strains at 8 x MIC after 24 h. Quinolones showed more rapid killing at lower concentrations and earlier time periods than did β-lactams and clarithromycin. [ABSTRACT FROM PUBLISHER]

To investigate the ability of four in-vitro methods to test trovafloxacin activity, this study evaluated susceptibility of 101 isolates of each of Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus and Streptococcus pneumoniae to trovafloxacin by agar dilution, microdilution, Etest and disc diffusion methodologies. MIC50 and MIC90 values were very similar for all three species with all four methods. For S. aureus and P. aeruginosa, good correlation was obtained between breakpoints of  17 mm, 14-16 mm and  13 mm with agar and microdilution MICs. For both species, Etests yielded susceptibility rates lower than the other three methods. For pneumococci, excellent correlation was obtained with all four methods. [ABSTRACT FROM PUBLISHER]

The activity of erythromycin, azithromycin and clarithromycin against 112 anaerobes was tested by the Oxyrase agar dilution MIC method at pH 7.2 without supplemental CO2 and by an agar dilution MIC method in CO2 with media adjusted to pH 8.0. MICs (mg/L) of erythromycin, azithromycin and clarithromycin against Bacteroides fragilis ATCC 25285 and Bacteroides thetaiotaomicron ATCC 29741 were similar by the two methods. MICs for 94 clinical isolates tested by the two methods were within two dilutions of each other. Eighteen additional isolates required CO2, and did not grow in Oxyrase. With the exception of fusobacteria, with which azithromycin yielded the lowest MICs, clarithromycin has the lowest MICs with both methods. These results show that the pH effect of incubation in CO2 can be avoided by using the Oxyrase method, or by incubating in CO2 with pH adjusted to 8.0. The latter method has the advantage of allowing testing of strains requiring CO2. [ABSTRACT FROM PUBLISHER]

Ledaborbactam (formerly VNRX-5236), a bicyclic boronate β-lactamase inhibitor with activity against class A, C, and D β-lactamases, is under development as an orally bioavailable etzadroxil prodrug (VNRX-7145) in combination with ceftibuten for the treatment of urinary tract infections. At ceftibuten breakpoints of ≤1 mg/L (EUCAST) and ≤8 mg/L (CLSI), 92.5% and 99.0%, respectively, of 200 carbapenem-resistant Klebsiella pneumoniae isolates, predominantly K. pneumoniae carbapenemase producing, were susceptible to ceftibuten-ledaborbactam (ledaborbactam tested at a fixed concentration of 4 mg/L) compared to 4.5% and 30.5%, respectively, to ceftibuten alone.

We characterized the molecular determinants of meropenem-vaborbactam (MV) non-susceptibility among non-metallo-β-lactamase-producing KPC- Klebsiella pneumoniae (KPC- KP ). Whole-genome sequencing was performed to identify mutations associated with MV non-susceptibility. Isolates with elevated MV MICs were found to have mutations encoding truncated or altered OmpK36 porins and increased bla KPC copy numbers. KPC- KP isolates with decreased susceptibility to MV were detected among a collection of isolates predating the availability of MV., Competing Interests: The authors declare no conflict of interest.

Taniborbactam, a bicyclic boronate β-lactamase inhibitor with activity against Klebsiella pneumoniae carbapenemase (KPC), Verona integron-encoded metallo-β-lactamase (VIM), New Delhi metallo-β-lactamase (NDM), extended-spectrum beta-lactamases (ESBLs), OXA-48, and AmpC β-lactamases, is under clinical development in combination with cefepime. Susceptibility of 200 previously characterized carbapenem-resistant K. pneumoniae and 197 multidrug-resistant (MDR) Pseudomonas aeruginosa to cefepime-taniborbactam and comparators was determined by broth microdilution. For K. pneumoniae (192 KPC; 7 OXA-48-related), MIC 90 values of β-lactam components for cefepime-taniborbactam, ceftazidime-avibactam, and meropenem-vaborbactam were 2, 2, and 1 mg/L, respectively. For cefepime-taniborbactam, 100% and 99.5% of isolates of K. pneumoniae were inhibited at ≤16 mg/L and ≤8 mg/L, respectively, while 98.0% and 95.5% of isolates were susceptible to ceftazidime-avibactam and meropenem-vaborbactam, respectively. For P. aeruginosa , MIC 90 values of β-lactam components of cefepime-taniborbactam, ceftazidime-avibactam, ceftolozane-tazobactam, and meropenem-vaborbactam were 16, >8, >8, and >4 mg/L, respectively. Of 89 carbapenem-susceptible isolates, 100% were susceptible to ceftolozane-tazobactam, ceftazidime-avibactam, and cefepime-taniborbactam at ≤8 mg/L. Of 73 carbapenem-intermediate/resistant P. aeruginosa isolates without carbapenemases, 87.7% were susceptible to ceftolozane-tazobactam, 79.5% to ceftazidime-avibactam, and 95.9% and 83.6% to cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively. Cefepime-taniborbactam at ≤16 mg/L and ≤8 mg/L, respectively, was active against 73.3% and 46.7% of 15 VIM- and 60.0% and 35.0% of 20 KPC-producing P. aeruginosa isolates. Of all 108 carbapenem-intermediate/resistant P. aeruginosa isolates, cefepime-taniborbactam was active against 86.1% and 69.4% at ≤16 mg/L and ≤8 mg/L, respectively, compared to 59.3% for ceftolozane-tazobactam and 63.0% for ceftazidime-avibactam. Cefepime-taniborbactam had in vitro activity comparable to ceftazidime-avibactam and greater than meropenem-vaborbactam against carbapenem-resistant K. pneumoniae and carbapenem-intermediate/resistant MDR P. aeruginosa ., Competing Interests: Robert A. Bonomo reports grants from Venatorx, Entasis, Merck, Wockhardt, and Shionogi outside the submitted work. David A. Six, Greg Moeck, and Tsuyoshi Uehara are employees of Venatorx Pharmaceuticals, Inc.

Surgically removed bowels from Crohn's disease patients exhibit a novel form of micropathologies known as cavernous fistulous tract microlesions (CavFT), resembling fissures. We announce the genomes/plasmids and antimicrobial resistance genes of six CavFT bacterial isolates representing the Bacteroidota genera Bacteroides and Phocaeicola . Plasmids were identified in Bacteroides cellulosilyticus and Phocaeicola vulgatus ., Competing Interests: The authors declare no conflict of interest.

Complex bacterial glycoconjugates drive interactions between pathogens, symbionts, and their human hosts. Glycoconjugate biosynthesis is initiated at the membrane interface by phosphoglycosyl transferases (PGTs), which catalyze the transfer of a phosphosugar from a soluble uridine diphosphosugar (UDP-sugar) substrate to a membrane-bound polyprenol-phosphate (Pren-P). The two distinct superfamilies of PGT enzymes (polytopic and monotopic) show striking differences in their structure and mechanism. We designed and synthesized a series of uridine bisphosphonates (UBPs), wherein the diphosphate of the UDP and UDP-sugar is replaced by a substituted methylene bisphosphonate (CXY-BPs; X/Y = F/F, Cl/Cl, ( S )-H/F, ( R )-H/F, H/H, CH 3 /CH 3 ). UBPs and UBPs incorporating an N -acetylglucosamine (GlcNAc) substituent at the β-phosphonate were evaluated as inhibitors of a polytopic PGT (WecA from Thermotoga maritima ) and a monotopic PGT (PglC from Campylobacter jejuni ). Although CHF-BP most closely mimics diphosphate with respect to its acid/base properties, the less basic CF 2 -BP conjugate more strongly inhibited PglC, whereas the more basic CH 2 -BP analogue was the strongest inhibitor of WecA. These surprising differences indicate different modes of ligand binding for the different PGT superfamilies, implicating a modified P-O - interaction with the structural Mg 2+ . For the monoPGT enzyme, the two diastereomeric CHF-BP conjugates, which feature a chiral center at the P α -CHF-P β carbon, also exhibited strikingly different binding affinities and the inclusion of GlcNAc with the native α-anomer configuration significantly improved binding affinity. UBP-sugars are thus revealed as informative new mechanistic probes of PGTs that may aid development of novel antibiotic agents for the exclusively prokaryotic monoPGT superfamily.

Transfusion of bacterially contaminated platelets, although rare, is still a major cause of mortality and morbidity despite the introduction of many methods to limit this over the past 20 years. The methods used include improved donor skin disinfection, diversion of the first part of donations, use of apheresis platelet units rather than whole-blood derived pools, primary and secondary testing by culture or rapid test, and use of pathogen reduction. Primary culture has been in use the US since 2004, using culture 24 h after collection of volumes of 4-8 mL from apheresis collections and whole-blood derived pools inoculated into aerobic culture bottles, with limited use of secondary testing by culture or rapid test to extend shelf-life from 5 to 7 days. Primary culture was introduced in the UK in 2011 using a "large-volume, delayed sampling" (LVDS) protocol requiring culture 36-48 h after collection of volumes of 16 mL from split apheresis units and whole-blood derived pools, inoculated into aerobic and anaerobic culture bottles (8 mL each), with a shelf-life of 7 days. Pathogen reduction using amotosalen has been in use in Europe since 2002, and was approved for use in the US in 2014. In the US, recent FDA guidance, effective October 2021, recommended several strategies to limit bacterial contamination of platelet products, including pathogen reduction, variants of the UK LVDS method and several two-step strategies, with shelf-life ranging from 3 to 7 days. The issues associated with bacterial contamination and these strategies are discussed in this review.

The BACT/ALERT® MP Reagent System is a broth culture medium for optimal detection and recovery of mycobacteria from clinical samples. The MP formulation was recently modified to improve detection and recovery times. A multicenter prospective matched pair study design was conducted to validate the performance of improved MP (MP-I) versus current MP (MP-C) bottles utilizing nonsterile and normally sterile samples, except blood, from patients suspected of having mycobacterial infections. A total of 1488 clinical samples were collected to obtain 212 mycobacteria samples by either or both MP culture bottles. MP-I and MP-C sensitivities were 86.6% and 81.4%, respectively, but the difference was not significant (P = 0.163) while specificities were 96.8% and 93.8%, respectively, and that difference was significant (P = 0.002). Overall recovery was 94.34% for MP-I and 88.68% for MP-C (recovery was 100% for both bottles with 52 seeded samples). Overall performance of MP-I was better than MP-C for sensitivity, specificity, and recovery., Competing Interests: Declaration of Competing Interest HPD, KM, JK, CDG, and DHP are employees of bioMérieux, Inc. SG was an employee of bioMérieux, Inc and has since relocated to another institution. As this was a Clinical Trial, bioMérieux employees were involved in study design and data analysis. Study sites were responsible for testing and data collection. This study was funded by bioMérieux, Inc. BACT/ALERT® MP Reagent Systems are FDA 510(k) cleared., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi's) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH 2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications., 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 Ltd.. All rights reserved.)

Multidrug-resistant (MDR) Pseudomonas aeruginosa infections are a major clinical challenge. Many isolates are carbapenem resistant, which severely limits treatment options; thus, novel therapeutic combinations, such as imipenem-relebactam (IMI/REL), ceftazidime-avibactam (CAZ/AVI), ceftolozane-tazobactam (TOL/TAZO), and meropenem-vaborbactam (MEM/VAB) were developed. Here, we studied two extensively drug-resistant (XDR) P. aeruginosa isolates, collected in the United States and Mexico, that demonstrated resistance to IMI/REL. Whole-genome sequencing (WGS) showed that both isolates contained acquired GES β-lactamases, intrinsic PDC and OXA β-lactamases, and disruptions in the genes encoding the OprD porin, thereby inhibiting uptake of carbapenems. In one isolate (ST17), the entire C terminus of OprD deviated from the expected amino acid sequence after amino acid G388. In the other (ST309), the entire oprD gene was interrupted by an IS Pa 1328 insertion element after amino acid D43, rendering this porin nonfunctional. The poor inhibition by REL of the GES β-lactamases (GES-2, -19, and -20; apparent K i of 19 ± 2 μM, 23 ± 2 μM, and 21 ± 2 μM, respectively) within the isolates also contributed to the observed IMI/REL-resistant phenotype. Modeling of REL binding to the active site of GES-20 suggested that the acylated REL is positioned in an unstable conformation as a result of a constrained Ω-loop.

Background: Pseudomonas aeruginosa is a persistent and difficult-to-treat pathogen in many patients, especially those with Cystic Fibrosis (CF). Herein, we describe a longitudinal analysis of a series of multidrug resistant (MDR) P. aeruginosa isolates recovered in a 17-month period, from a young female CF patient who underwent double lung transplantation. Our goal was to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence evolution over time., Methods: Twenty-two sequential P. aeruginosa isolates were obtained within a 17-month period, before and after a double-lung transplant. At the end of the study period, antimicrobial susceptibility testing, whole genome sequencing (WGS), phylogenetic analyses and RNAseq were performed in order to understand the genetic basis of the observed resistance phenotypes, establish the genomic population diversity, and define the nature of sequence changes over time., Results: The majority of isolates were resistant to almost all tested antibiotics. A phylogenetic reconstruction revealed 3 major clades representing a genotypically and phenotypically heterogeneous population. The pattern of mutation accumulation and variation of gene expression suggested that a group of closely related strains was present in the patient prior to transplantation and continued to change throughout the course of treatment. A trend toward accumulation of mutations over time was observed. Different mutations in the DNA mismatch repair gene mutL consistent with a hypermutator phenotype were observed in two clades. RNAseq performed on 12 representative isolates revealed substantial differences in the expression of genes associated with antibiotic resistance and virulence traits., Conclusions: The overwhelming current practice in the clinical laboratories setting relies on obtaining a pure culture and reporting the antibiogram from a few isolated colonies to inform therapy decisions. Our analyses revealed significant underlying genomic heterogeneity and unpredictable evolutionary patterns that were independent of prior antibiotic treatment, highlighting the need for comprehensive sampling and population-level analysis when gathering microbiological data in the context of CF P. aeruginosa chronic infection. Our findings challenge the applicability of antimicrobial stewardship programs based on single-isolate resistance profiles for the selection of antibiotic regimens in chronic infections such as CF., Competing Interests: The authors have declared that no competing interests exist.

The Acuitas antimicrobial resistance (AMR) gene panel is a qualitative, multiplex, nucleic acid-based in vitro diagnostic test for the detection and differentiation of 28 antimicrobial resistance markers associated with not susceptible results (NS; i.e., intermediate or resistant) to one or more antimicrobial agents among cultured isolates of select Enterobacterales , Pseudomonas aeruginosa, and Enterococcus faecalis. This study was conducted at four sites and included testing of 1,224 deidentified stocks created from 584 retrospectively collected isolates and 83 prospectively collected clinical isolates. The Acuitas results were compared with a combined reference standard including whole-genome sequencing, organism identification, and phenotypic antimicrobial susceptibility testing. The positive percent agreement (PPA) for FDA-cleared AMR targets ranged from 94.4% for MCR-1 to 100% for armA , CTX-M-2, DHA, IMP, OXA-9, SHV, vanA , and VEB. The negative percent agreement (NPA) for the majority of targets was ≥99%, except for AAC, AAD, CMY-41, P. aeruginosa gyrA mutant, Sul1, Sul2, and TEM targets (range, 96.5% to 98.5%). Three AMR markers did not meet FDA inclusion criteria (GES, SPM, and MCR-2). For each organism, 1 to 22 AMR targets met the minimum reportable PPA/NPA and correlated with ≥80% positive predictive value with associated NS results for at least one agent (i.e., the probability of an organism carrying an AMR marker testing NS to the associated agent). We demonstrate that the Acuitas AMR gene panel is an accurate method to detect a broad array of AMR markers among cultured isolates. The AMR markers were further associated with expected NS results for specific agent-organism combinations.

Direct antimicrobial susceptibility testing (AST) of positive blood cultures with Gram-negative bacteria produces results within 24 h, compared to 48 to 96 h with conventional methods. Positive clinical blood cultures were studied, supplemented with contrived blood cultures inoculated with a spectrum of resistant isolates. Bacterial inocula used for direct AST were quantitated. Direct AST was performed using MicroScan NM43 trays inoculated directly from positive blood cultures (100 μL in 25 mL water) and incubated using a WalkAway instrument, with trays read after 16 h. Reference AST was performed the following day from growth on solid medium using the same trays. Agreement of AST results between direct and reference methods, with and without the use of three expert rules for β-lactams, was evaluated using FDA categorical agreement criteria. Of 86 specimens tested (41 clinical specimens and 45 contrived specimens), the mean bacterial load in positive blood cultures was 8.98 log 10 CFU/mL. Fifteen isolates contained extended-spectrum β-lactamases, and 27 contained carbapenemases. Of 1,985 pairs of AST categorical results for 25 antimicrobials, 55.0% were susceptible, 4.7% intermediate, and 40.4% resistant by reference testing. Overall categorical agreement was 92.3%, with 5.3% minor errors, 1.9% major errors, and 0.4% very major errors. Agreement was higher for non-β-lactam agents (95.8%) than for β-lactam agents (90.3%; P  < 0.0001). Application of expert rules increased agreement for β-lactam agents to 94.6%. The methods used achieved the study goal of producing accurate, cost-effective AST results directly from positive blood cultures using MicroScan trays with a 16-h incubation time without the need for additional testing. Use of three expert β-lactam rules improved accuracy.

Rationale: High-flow nasal therapy (HFNT) has beneficial effects in patients hospitalized with acute hypoxemic respiratory failure. HFNT has not been extensively studied following hospitalization for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD)., Objective: We explored the feasibility of conducting a multicentered trial to evaluate the use of HFNT to increase the time to next moderate/ severe exacerbation in patients recently hospitalized for a COPD exacerbation. In this pilot study we measured the hours of home daily HFNT use, maximally tolerated flow rates and temperature, and side effects for a period of 90 days., Methods: Patients were enrolled in a 90-day, open-labeled pilot study of HFNT to determine the safety and feasibility of home use for daily outpatient COPD management. Patients ≥ 40 years of age with prior hospitalization within the past 12 weeks for an AECOPD were enrolled. COPD was the primary diagnosis in all patients., Results: Thirty patients presented for HFNT titration. Two dropped out; 1 after receiving a lung transplant and the other was lost to follow-up. The remaining 28 patients completed 90 days of HFNT. None withdrew from HFNT due to intolerance. Use of HFNT averaged 6.8 (2.1) hours daily., Conclusions: Daily home HFNT for up to 3 months is feasible in COPD patients following hospitalization for AECOPD. Improvements observed in disease-specific quality of life, respiratory symptoms, and 6-minute walk distance suggest the need for a prospective multicenter controlled clinical trial., (JCOPDF © 2021.)

This paper evaluates for the first time the spatial distribution of a wide group of organic (phthalates, nitro, aliphatic, halogen, aromatic, phenol and amino compounds) and inorganic pollutants along the Liffey river in Dublin city. The work takes into account the effect of short-term weather conditions on the occurrence of these contaminants. The results showed that rainfall conditions affect the levels of pollutants along the river in the days following a rainfall event. In addition, the tributaries entering the river Liffey were not found to impact its water quality. In relation to organic pollutants, 2,4,6-trichlorophenol, 2-nitrophenol and phthalate compounds were found in many water samples between concentrations of 0.21 and 2.17 μg L -1 . On the other hand, dimethyl phthalate was present in certain samples at levels around 100 μg L -1 . The levels of these contaminants in the river were lower than the toxicity values reported in the literature. Regarding inorganic pollutants, nitrates were detected from 0.59 to 6.81 mg L -1 increasing from upstream to downstream. Based on the chemical nature and applications of detected pollutants, the river contamination can be mainly related to agricultural, industrial activities as well as diffuse urban contributions. These vary with location within a short distance and have the potential to impact aquatic biodiversity as the chemical composition changes with rainfall events., (© 2021. The Author(s).)

Serious infections caused by multidrug-resistant (MDR) organisms (Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii) present a critical need for innovative drug development. Herein, we describe the preclinical evaluation of YU253911, 2, a novel γ-lactam siderophore antibiotic with potent antimicrobial activity against MDR Gram-negative pathogens. Penicillin-binding protein (PBP) 3 was shown to be a target of 2 using a binding assay with purified P. aeruginosa PBP3. The specific binding interactions with P. aeruginosa were further characterized with a high-resolution (2.0 Å) X-ray structure of the compound's acylation product in P. aeruginosa PBP3. Compound 2 was shown to have a concentration >1 μg/ml at the 6 h time point when administered intravenously or subcutaneously in mice. Employing a meropenem resistant strain of P. aeruginosa, 2 was shown to have dose-dependent efficacy at 50 and 100 mg/kg q6h dosing in a mouse thigh infection model. Lastly, we showed that a novel γ-lactam and β-lactamase inhibitor (BLI) combination can effectively lower minimum inhibitory concentrations (MICs) against carbapenem resistant Acinetobacter spp. that demonstrated decreased susceptibility to 2 alone., 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 © 2021. Published by Elsevier Masson SAS.)

Introduction: Until recently antimicrobial susceptibility testing (AST) methods based on the demonstration of phenotypic susceptibility in 16-24 h remained largely unchanged., Areas Covered: Advances in rapid phenotypic and molecular-based AST systems., Expert Opinion: AST has changed over the past decade, with many rapid phenotypic and molecular methods developed to demonstrate phenotypic or genotypic resistance, or biochemical markers of resistance such as β-lactamases associated with carbapenem resistance. Most methods still require isolation of bacteria from specimens before both legacy and newer methods can be used. Bacterial identification by MALDI-TOF mass spectroscopy is now widely used and is often key to the interpretation of rapid AST results. Several PCR arrays are available to detect the most frequent pathogens associated with bloodstream infections and their major antimicrobial resistance genes. Many advances in whole-genome sequencing of bacteria and fungi isolated by culture as well as directly from clinical specimens have been made but are not yet widely available. High cost and limited throughput are the major obstacles to uptake of rapid methods, but targeted use, continued development and decreasing costs are expected to result in more extensive use of these increasingly useful methods.

Parabacteroides distasonis is the type strain for the genus Parabacteroides , a group of gram-negative anaerobic bacteria that commonly colonize the gastrointestinal tract of numerous species. First isolated in the 1930s from a clinical specimen as Bacteroides distasonis , the strain was re-classified to form the new genus Parabacteroides in 2006. Currently, the genus consists of 15 species, 10 of which are listed as 'validly named' ( P. acidifaciens, P. chartae, P. chinchillae, P. chongii, P. distasonis, P. faecis, P. goldsteinii, P. gordonii, P. johnsonii , and P. merdae ) and 5 'not validly named' ( P. bouchesdurhonensis, P. massiliensis, P. pacaensis, P. provencensis , and P. timonensis ) by the List of Prokaryotic names with Standing in Nomenclature. The Parabacteroides genus has been associated with reports of both beneficial and pathogenic effects in human health. Herein, we review the literature on the history, ecology, diseases, antimicrobial resistance, and genetics of this bacterium, illustrating the effects of P. distasonis on human and animal health.

The evolution of resistance to antimicrobial agents in gram-negatives has challenged the role of the clinical microbiology laboratory to implement new methods for their timely detection. Recent development has enabled the use of novel methods for more rapid pathogen identification, antimicrobial susceptibility testing, and detection of resistance markers. Commonly used methods improve the rapidity of resistance detection from both cultured bacteria and specimens. This review focuses on the commercially available systems available together with their technical performance and possible clinical impact., Competing Interests: Disclosure A. Endimiani is a consultant for (Merck Sharp and Dohme AG). M.R. Jacobs and D.D. Rhoads received grant support from bioMérieux and OpGen. A. Ramette received travel grants from Oxford Nanopore Technologies to attend scientific conferences. The sponsor had no role in the design, execution, interpretation, or writing of the study. A. Endimiani and A. Ramette are supported by the Swiss National Science Foundation (SNF), NRP72 National Research Programme, Antimicrobial Resistance (SNF grant no. 177378). A. Endimiani also is supported by SNF grant no. 170063., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)