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Lindsay A Petty,1 Oryan Henig,1 Twisha S Patel,2 Jason M Pogue,3 Keith S Kaye1 1Department of Internal Medicine, Division of Infectious Diseases, University of Michigan Medical School, Ann Arbor, MI, USA; 2Department of Pharmacy Services, University of Michigan Hospitals and Health Centers, Ann Arbor, MI, USA; 3Department of Pharmacy Services, Sinai-Grace Hospital, Detroit Medical Center, Detroit, MI, USA Abstract: There has been a worldwide increase in infections caused by drug-resistant Gram-negative pathogens, including carbapenem-resistant Enterobacteriaceae (CRE). Meropenem-vaborbactam, a carbapenem antibiotic and novel boronic acid-based beta-lactamase inhibitor, is a fixed-dose combination product with potent in vitro activity against Enterobacteriaceae that are Klebsiella pneumoniae carbapenemase producers. Meropenem-vaborbactam has been studied in two Phase III trials, Targeting Antibiotic Non-susceptible Gram-negative Organisms (TANGO)-I and TANGO-II. TANGO-I was a multicenter, international Phase III, randomized, double-blind, double-dummy, active-control trial to evaluate the efficacy and safety of meropenem-vaborbactam for the treatment of complicated urinary tract infection, including acute pyelonephritis. Among patients with complicated urinary tract infection and growth of a baseline pathogen, meropenem-vaborbactam was determined to be superior to piperacillin-tazobactam based on the composite outcome of symptom improvement or resolution and microbial eradication at the end of intravenous therapy. TANGO-II was a multicenter, international, Phase III, randomized, prospective, open-label, comparative trial to evaluate the efficacy and safety of meropenem-vaborbactam vs best available therapy for CRE infections. Treatment with meropenem-vaborbactam resulted in higher rates of clinical cure at the end of therapy (64.3%vs 33.3%, P=0.04). Additionally, 28-day all-cause mortality was 17.9% in the meropenem-vaborbactam group compared to 33.3% in the best available therapy group, a relative risk reduction of 46.5% (P=0.03). In addition to meropenem-vaborbactam, three other agents with activity against CRE are in late-stage development: imipenem-relebactam, plazomicin, and cefiderocol. The data from Phase II and III studies will help to further define the role of these agents. Overall, the recent approval of meropenem-vaborbactam and the active pipeline for other agents with broad Gram-negative activity are encouraging developments on the CRE therapeutic front. Keywords: meropenem, vaborbactam, carbapenemase, CRE, UTI, KPC

Among consecutive patients with multidrug-resistant Pseudomonas aeruginosa bacteremia or pneumonia we found those treated with ceftazidime-avibactam were more likely to develop resistance (defined as ≥4-fold increased MIC) than those treated with ceftolozane-tazobactam (40% vs 10%; P = .002). Ceftazidime-avibactam resistance was associated with new mutations in ampC and efflux regulatory pathways., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Paired baseline and post-exposure isolates from 34 patients who developed ceftolozane-tazobactam (TOL-TAZ) resistance following treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections were analyzed to determine if ceftolozane with an alternative β-lactamase inhibitor could restore susceptibility. The median baseline TOL-TAZ MIC was 2 mg/L; 88% of post-exposure isolates harbored new ampC mutations. Median MIC fold-increase from baseline was 32-, 24-, 16-, and 6-fold for ceftolozane-tazobactam, ceftolozane-avibactam (AVI), ceftolozane-relebactam (REL), and ceftolozane-durlobactam (DUR), respectively. Enhanced ceftolozane-durlobactam activity was evident in specific ampC mutations.

The in vitro susceptibility testing interpretive criteria (STIC) for piperacillin/tazobactam (TZP) against Enterobacterales were recently updated by the US Food and Drug Administration, Clinical and Laboratory Standards Institute, and European Committee on Antimicrobial Susceptibility Testing. The United States Committee on Antimicrobial Susceptibility Testing (USCAST) also recently reviewed TZP STIC for Enterobacterales and arrived at different STIC for Enterobacterales. Here, we explain our recommendations and rationale behind them. Based on our review of the available data, USCAST does not recommend TZP STIC for certain Enterobacterales species that have a moderate to high likelihood of clinically significant AmpC production (Enterobacter cloacae, Citrobacter freundii, and Klebsiella aerogenes only) or for third-generation cephalosporin-nonsusceptible Enterobacterales. USCAST recommends a TZP susceptibility breakpoint of ≤ 16/4 mg/L for third-generation cephalosporin-susceptible Enterobacterales and only endorses the use of extended infusion TZP regimens for patients with infections due to these pathogens., Competing Interests: Potential conflicts of interest. T. P. L.: AbbVie (consultant), Cidara (advisor/consultant), Ferring (advisor/consultant/speaker), Genentech (consultant), GlaxoSmithKline (consultant), ICPD (consultant), Melinta (advisor/consultant), Merck (advisor/consultant, grant/research support), Paratek (advisor/consultant), Roche (consultant), Seres (consultant), Shionogi (advisor/consultant/speaker), Wockhardt (grant/research support), and Venatrox (advisor/consultant). S. B.: grants from: A&G Pharmaceutical, Achaogen Inc, Adagio Therapeutics Inc, AiCuris GmbH & Co KG, Albany Medical College, Amplyx Pharmaceuticals Inc, AN2 Therapeutics, Antabio SAS, Apogee Biologics Inc, Arcutis Biotherapeutics Inc, B. Braun Medical Inc, Basilea Pharmaceutica, Biofire Diagnostics LLC, BLC USA, Boston Pharmaceuticals, Bravos Biosciences LLC, Cidara Therapeutics Inc, Cipla USA, Crestone, Cumberland Pharmaceuticals, CXC, Debiopharm International SA, E-Scape Bio Inc, Entasis Therapeutics, Excalibur Pharmaceuticals Inc, Fedora Pharmaceuticals, Genentech, GlaxoSmithKline, Global Antibiotic Research and Development, Hoffmann-La Roche, ICPD Biosciences LLC, ICPD Holdings, ICPD Technologies, Inotrem, Insmed Inc, Iterum Therapeutics Limited, Kaizen Bioscience, KBP Biosciences USA, Lassen Therapeutics, Matinas Biopharma, Meiji Seika Pharma Co Ltd, Melinta Therapeutics, Menarini Ricerche S.p.A, Mutabilis, Nabriva Therapeutics, Novartis Pharmaceuticals Corp, Novobiotic Pharmaceuticals LLC, Paratek Pharmaceuticals Inc, Pfizer Inc, Praxis Precision Medicines Inc, PTC Therapeutics, PureTech Health, Qpex Biopharma, Renibus Therapeutics, Sagimet Biosciences Inc, Schrodinger Inc, Shionogi & Co Ltd, Sfunga Therapeutics, Spero Therapeutics, Spruce Biosciences, Suzhou Sinovent Pharmaceuticals Co, Symbiotica Inc, TauRx Therapeutics, tranScrip Partners LLP, Theravance, University of Wisconsin–Madison, Utility Therapeutics, US Food and Drug Administration, UT Southwestern, Valanbio Therapeutics Inc, Venatorx, Wockhardt Bio AG, and Zogenix International; consultant: GlaxoSmithKline and Shionogi & Co Ltd. P. A.: grants: A&G Pharmaceutical, Achaogen Inc, Adagio Therapeutics Inc, AiCuris GmbH & Co KG, Albany Medical College, Amplyx Pharmaceuticals Inc, AN2 Therapeutics, Antabio SAS, Apogee Biologics Inc, Arcutis Biotherapeutics Inc, B. Braun Medical Inc, Basilea Pharmaceutica, Biofire Diagnostics LLC, BLC USA, Boston Pharmaceuticals, Bravos Biosciences LLC, Cidara Therapeutics Inc, Cipla USA, Crestone, Cumberland Pharmaceuticals, CXC, Debiopharm International SA, E-Scape Bio Inc, Entasis Therapeutics, Excalibur Pharmaceuticals Inc, Fedora Pharmaceuticals, Genentech, GlaxoSmithKline, Global Antibiotic Research and Development, Hoffmann-La Roche, ICPD Biosciences LLC, ICPD Holdings, ICPD Technologies, Inotrem, Insmed Inc, Iterum Therapeutics Limited, Kaizen Bioscience, KBP Biosciences USA, Lassen Therapeutics, Matinas Biopharma, Meiji Seika Pharma Co Ltd, Melinta Therapeutics, Menarini Ricerche S.p.A, Mutabilis, Nabriva Therapeutics, Novartis Pharmaceuticals Corp, Novobiotic Pharmaceuticals LLC, Paratek Pharmaceuticals Inc, Pfizer Inc, Praxis Precision Medicines Inc, PTC Therapeutics, PureTech Health, Qpex Biopharma, Renibus Therapeutics, Sagimet Biosciences Inc, Schrodinger Inc, Shionogi & Co Ltd, Sfunga Therapeutics, Spero Therapeutics, Spruce Biosciences, Suzhou Sinovent Pharmaceuticals Co, Symbiotica Inc, TauRx Therapeutics, tranScrip Partners LLP, Theravance, University of Wisconsin–Madison, Utility Therapeutics, US Food and Drug Administration, UT Southwestern, Valanbio Therapeutics Inc, Venatorx, Wockhardt Bio AG, and Zogenix International; consultant: GlaxoSmithKline, Shionogi & Co Ltd, Spero Therapeutics Inc, Entasis Therapeutics Inc, and JMI Laboratories. D. A.: consultant: Astellas and sFunga. J. P.: consultant: Merck, Shionogi, Melinta, AbbVie, Entasis, and GlaxoSmithKline; grants/research support: Merck, Shionogi, and Melinta. 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.)

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: Guidelines suggest dual antipseudomonal therapy for empiric treatment of pneumonia caused by gram-negative bacteria in intensive care unit (ICU) patients. Additionally, consideration of local susceptibility data and patient-specific risk factors for resistance is recommended for selecting optimal empiric regimens. However, data assessing how to best do this are lacking, and it is unclear whether a local susceptibility data-based or a patient-specific risk factor-based approach will better drive appropriate empiric treatment. This study aims to compare these 2 strategies., Methods: This retrospective study was divided into 2 periods. In period I, gram-negative respiratory cultures from ICU patients were used to develop unit-specific combination antibiograms, and individual patient charts were reviewed to assess the impact of risk factors on antimicrobial susceptibility to develop a risk factor-based treatment algorithm. Optimal empiric regimens based on these 2 strategies were then defined. In period II, these regimens were hypothetically applied to patients to compare rates of appropriate empiric therapy and overuse by the 2 methods., Results: Risk factor-based regimens had a higher appropriateness rate compared to regimens derived from antibiograms (89.9% vs 83.7%). Additionally, applying antibiogram-based regimens resulted in a higher prevalence of antibiotic overuse than a patient-specific risk factor-based approach (69.8% vs 40.3%), with excess overuse driven by a higher frequency of unnecessary use of combination therapy., Conclusions: Both strategies provided high rates of appropriateness in empiric antibiotic selection. However, the patient-specific risk factor-based approach demonstrated a higher rate of appropriate therapy and offered advantages in reducing rates of unnecessary combination therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

We report identification of 5 patients with infections caused by NDM-5-producing Escherichia coli harboring PBP3 mutations that showed reduced susceptibility to aztreonam-avibactam and cefiderocol. Durlobactam, a novel diazabicyclooctane β-lactamase inhibitor, demonstrated minimum inhibitory concentrations ranging from 0.5 to 2 µg/mL supporting future investigations into a potential role in clinical management., Competing Interests: Potential conflicts of interest. S. L. A. reports serving on advisory boards for Entasis, Melinta, Shionogi, and Basilea and receiving consulting fees from GlaxoSmithKline. J. M. P. reports grant support from Merck and serving as a consultant for Merck, Shionogi, Entasis, Abbvie, and GSK. R. K. S. has served as a consultant for Merck, Melinta, Entasis, Abbvie, GlaxoSmithKline, Pfizer, Shionogi, Venatorx, and Roche, and has received investigator-initiated research funding from Merck, Melinta, Shionogi, Roche, and Venatorx. 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 commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: To assess risk factors for carbapenem-resistant Pseudomonas aeruginosa (CR) and extended-β-lactam-resistant P. aeruginosa (EBR) infection/colonization, and to develop and compare tools for predicting isolation of CR and EBR from clinical cultures., Methods: This retrospective study analysed hospitalized patients with positive P. aeruginosa cultures between 2015 and 2021. Two case-control analyses were performed to identify risk factors and develop scoring tools for distinguishing patients with CR versus carbapenem-susceptible (CS) P. aeruginosa and EBR versus CS P. aeruginosa. The performance of institutionally derived scores, externally derived scores and the presence/absence of key risk factors to predict CR and EBR were then compared., Results: A total of 2379 patients were included. Of these, 8.3% had a positive culture for CR, 5.0% for EBR and 86.7% for CS P. aeruginosa. There was substantial overlap in risk factors for CR and EBR. Institutional risk scores demonstrated modestly higher area under the ROC curve values than external scores for predicting CR (0.67 versus 0.58) and EBR (0.76 versus 0.70). Assessing the presence/absence of ≥1 of the two strongest predictors (prior carbapenem use or CR isolation within 90 days) was slightly inferior to scoring tools for predicting CR, and comparable for predicting EBR., Conclusions: Clinicians concerned about CR in P. aeruginosa should consider the likelihood of EBR when making treatment decisions. A simple approach of assessing recent history of CR isolation or carbapenem usage performed similarly to more complex scoring tools and offers a more pragmatic way of identifying patients who require coverage for resistant P. aeruginosa., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: IV fosfomycin is used against MDR Gram-negative bacilli (GNB) but has dose-limiting side effects, especially in patients with impaired kidney function., Objectives: To determine the optimal dosage of IV fosfomycin for patients with varying degrees of kidney function., Methods: Adult patients receiving IV fosfomycin for treatment of GNB were eligible. Five serial blood samples were collected after at least three doses of fosfomycin; plasma was assayed by LC-MS/MS and modelled by population pharmacokinetic analysis. The PTA for AUC24/MIC of 98.9 for Escherichia coli and Klebsiella pneumoniae, and 40.8 for Pseudomonas aeruginosa were computed by Monte Carlo simulations. Cumulative fractions of response (CFR) were analysed for each pathogen using EUCAST MIC distributions., Results: A total of 24 patients were included. Creatinine clearance (CLCR) and gender significantly influenced fosfomycin clearance. The kidney function-adjusted dosing regimens are proposed by using the lowest dose that can achieve ≥90% PTA for AUC24/MIC of 98.9 at an MIC of ≤32 mg/L (EUCAST v.13 susceptibility breakpoint for Enterobacterales). For patients with normal kidney function (CLCR 91-120 mL/min), a dosage of 15 g/day is suggested. This regimen achieved 97.1% CFR against E. coli, whereas CFR was 72.9% for K. pneumoniae and 76.7% for P. aeruginosa., Conclusions: A fosfomycin dosage of 15 g/day with adjustment according to kidney function provided high PTA and CFR when treating E. coli. This dosage is lower than that used in current practice and may improve tolerability. Higher dosages may be needed for P. aeruginosa; however, safety data are limited., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: JAJ has received grant funding from the Society of Infectious Diseases Pharmacists for research on Gram-positive bacterial infections. JMP declares no competing interests.

Meropenem therapy will be open-label, while tobramycin or placebo will be administered in a double-blind fashion. The primary trial endpoint will be a composite hierarchical outcome of 1) 28-day all-cause mortality, 2) ventilator-free days, and 3) modified time to clinical stability, evaluated using a win ratio methodology (see below). Secondary trial outcomes will include frequency of safety events (acute kidney injury), resolution of circulatory shock, recurrent HABP, and emergence of meropenem resistance both during treatment and in cases of recurrent infection. Using simulation studies to inform sample size calculations, we estimate that recruitment of 130 patients per treatment arm would provide at least 80% power to detect a win ratio of 1.50 while preserving a two-sided type 1 error rate of 0.05., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Observational data published over the past decade have suggested that concomitant receipt of piperacillin-tazobactam with vancomycin significantly increases the risk for vancomycin-associated acute kidney injury. Importantly, however, there is significant controversy surrounding this association, and debate continues about the veracity of the risk. Given this ongoing debate, the recently published "Cefepime vs Piperacillin-Tazobactam in Adults Hospitalized With Acute Infection: The ACORN Randomized Clinical Trial" is of tremendous interest to the infectious diseases community. In ACORN, the authors conclude that there was no association between receipt of cefepime or piperacillin-tazobactam and the primary outcome of acute kidney injury or death by day 14, despite the fact that >75% of the population received concomitant vancomycin. In this perspective, we provide a brief history on the controversy, provide a critical analysis of the ACORN findings, and ultimately discuss how these data help inform the ongoing debate., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

In the past decade, the prevalence of multidrug-resistant gram-negative (MDR-GN) bacterial infections has increased significantly, leading to higher rates of morbidity and mortality. Treating these infections poses numerous challenges, particularly when selecting appropriate empiric therapy for critically ill patients for whom the margin for error is low. Fortunately, the availability of new therapies has improved the treatment landscape, offering safer and more effective options. However, there remains a need to establish and implement optimal clinical and therapeutic approaches for managing these infections. Here, we review strategies for identifying patients at risk for MDR-GN infections, propose a framework for the choice of empiric and definitive treatment, and explore effective multidisciplinary approaches to managing patients in the hospital while ensuring a safe transition to outpatient settings., Competing Interests: Potential conflicts of interest. J. M. P. reports a grant from Merck and consulting fees from Merck, Shionogi, AbbVie, Entasis, Qpex, Melinta, La Jolla, and VenatoRx. R. G. S. reports consulting fees from AbbVie and MoInIycke and serving as a board member of the Surgical Infection Society Foundation. K. S. K. reports a grant from the National Institutes of Health (NIH) and Agency for Healthcare Research and Quality; consulting fees from Shionogi, Allecra, Spero, Qpex, Merck, GSK, VenatoRx, MicuRx, and Entasis; participation on advisory boards for VenatoRx, Entasis, the Division of Microbiology and Infectious Diseases of the NIH, and Meji Seika Pharma; and having stock in Merck.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. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Competing interests: TCL reports receiving research salary support from Fonds de Recherche du Québec–Santé and peer-reviewed operating grants for COVID-19-related research from the Canadian Institutes of Health Research and being an investigator for several investigator-initiated trials involving outpatients with Covid-19. JMP discloses serving as a consultant to Merck, Shionogi and Roche. EKM discloses serving as a consultant to Shionogi and is the Director of infectious diseases improvement and clinical research innovation at UPMC. In this role, EKM oversaw clinical trials involving use of sotrovimab (donated by GSK) and evaluation of tixagevimab–cilgavimab in outpatients (funded by AstraZeneca). She does not receive salary support or funding for her involvement in these trials. AMM has no competing interest to declare.

Objectives: To develop a population pharmacokinetic (PK) model with data from the largest polymyxin B-treated patient population studied to date to optimize its dosing in hospitalized patients., Methods: Hospitalized patients receiving intravenous polymyxin B for ≥48 hours were enrolled. Blood samples were collected at steady state and drug concentrations were analysed by liquid chromotography tandem mass spectrometry (LC-MS/MS). Population PK analysis and Monte Carlo simulations were performed to determine the probability of target attainment (PTA)., Results: One hundred and forty-two patients received intravenous polymyxin B (1.33-6 mg/kg/day), providing 681 plasma samples. Twenty-four patients were on renal replacement therapy, including 13 on continuous veno-venous hemodiafiltration (CVVHDF). A 2-compartment model adequately described the PK with body weight as a covariate on the volume of distribution that affected C max , but it did not impact clearance or exposure. Creatinine clearance was a statistically significant covariate on clearance, although clinically relevant variations of dose-normalized drug exposure were not observed across a wide creatinine clearance range. The model described higher clearance in CVVHDF patients than in non-CVVHDF patients. Maintenance doses of ≥2.5 mg/kg/day or ≥150 mg/day had a PTA ≥90% (for non-pulmonary infections target) at a steady state for minimum inhibitory concentrations ≤2 mg/L. The PTA at a steady state for CVVHDF patients was lower., Discussion: Fixed loading and maintenance doses of polymyxin B seemed to be more appropriate than weight-based dosing regimens in patients weighing 45-90 kg. Higher doses may be needed in patients on CVVHDF. Substantial variability in polymyxin B clearance and volume of distribution was found, suggesting that therapeutic drug monitoring may be indicated., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Infections caused by extensively drug-resistant Pseudomonas aeruginosa are difficult to treat due to limited effective treatment options. In this issue, a patient with a corneal infection caused by a Verona integron-encoded metallo-β-lactamase (VIM)- and Guiana extended-spectrum β-lactamase (GES)-coproducing P. aeruginosa strain associated with the recent artificial tears-related outbreak in the United States is described. This resistance genotype/phenotype further compromises therapeutic options, and this report provides insights into diagnostic and treatment approaches for clinicians dealing with infections due to this highly resistant P. aeruginosa.

Acinetobacter baumannii-Acinetobacter calcoaceticus complex (referred to herein as A. baumannii) treatment guidelines contain numerous older antimicrobial agents with susceptibility test interpretive criteria (STIC, also known as susceptibility breakpoints) set using only epidemiological data. We utilized a combination of in vitro surveillance data, preclinical murine thigh and lung infection models, population pharmacokinetics, simulation, and pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses to evaluate A. baumannii STIC for four commonly recommended antimicrobials from different classes (amikacin, ceftazidime, ciprofloxacin, and minocycline). Antimicrobial in vitro surveillance data were based on 1,647 clinical A. baumannii isolates obtained from 109 centers in the United States and Europe. Among these isolates, 5 were selected for evaluation in murine infection models based on fitness and MIC variability. PK and dose-ranging studies were conducted using neutropenic murine thigh and lung infection models The MIC ranges for the 5 isolates evaluated were as follows: amikacin, 2 to 32 μg/mL; ceftazidime, 4 to 16 μg/mL; ciprofloxacin, 0.12 to 2 μg/mL; minocycline, 0.25 to 4 μg/mL. All organisms grew ≥1.5 log 10 CFU in both models in untreated controls. Plasma and epithelial lining fluid (ELF) pharmacokinetics for all drugs were determined in mice using liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods. For each isolate, 5 dose levels of each drug were tested individually in the thigh and lung infection model. The inoculum ranged from 7.9 to 8.4 and 6.8 to 7.7 log 10 CFU/mL for the lung and thigh models, respectively. PK/PD targets associated with net bacterial stasis and 1- and 2-log 10 CFU reductions from baseline were identified for each organism/infection model using Hill-type models. Population pharmacokinetic models for each agent were identified from the literature. Using demographic variables for simulated patients with hospital-acquired or ventilator-associated bacterial pneumonia or urinary tract infections (including acute pyelonephritis) who were administered maximal dosing regimens of each agent, estimates of protein binding, and ELF penetration ratios based on data from the literature, free-drug plasma and total-drug concentration-time profiles were generated, and PK/PD indices by MIC were calculated. Percent probabilities of attaining median and randomly assigned PK/PD targets associated with the above-described endpoints were determined. Recommended susceptible breakpoints for each agent were those representing the highest MIC at which the percent probabilities of achieving PK/PD targets associated with a 1-log 10 CFU reduction from baseline approached or were ≥90%. The following susceptible breakpoints for A. baumannii were identified: amikacin, ≤8 μg/mL for pneumonia; ceftazidime, ≤32 and ≤8 μg/mL for pneumonia; ciprofloxacin, ≤1 μg/mL; and minocycline, ≤0.5/≤1 μg/mL which correspond to the standard and high minocycline dosing regimens of 200 mg per day and 200 mg every 12 h, respectively. Implementation of appropriate STIC will help clinicians optimally use the above-described agents and improve the likelihood of successful patient outcomes.

Background: Administration of doses via an extended infusion (EI) is an important strategy to optimize beta-lactams. Available data on the impact of EI on outcomes largely focus on clinical cure or mortality in critically ill patients or those with resistant pathogens. The potential benefits of EI extend beyond these populations and outcomes, and further study is warranted., Methods: This was a retrospective cohort study of adult patients who received cefepime, piperacillin/tazobactam, or meropenem for Gram-negative bacteremia via EI or intermittent infusion. Patients were matched 1:1 based on study drug, sepsis severity, intensive care unit (ICU) status, bacteremia source, and pathogen. Outcomes assessed included time to clinical stabilization, rates of treatment failure, mortality, recurrence, and length of stay (LOS)., Results: Two hundred sixty-eight patients were included. Baseline characteristics were similar between groups. Forty-two percent of patients were in the ICU at infection onset and the most common pathogen was Escherichia coli (41%). After adjusting for residual differences between groups, receipt of EI was independently associated with shorter time to clinical stability (adjusted odds ratio, 0.32; 95% confidence interval, .22-.47), time to defervescence, and time to white blood cell count normalization. Furthermore, EI was associated with a lower incidence of treatment failure, decreased recurrence of bacteremia, and shorter LOS. There was no difference in mortality. These findings were consistent regardless of patient location (ICU vs ward), baseline renal function, source of bacteremia, or study drug received., Conclusions: These findings suggest that EI beta-lactams are an important stewardship strategy to improve clinical outcomes in patients with Gram-negative bacteremia., Competing Interests: Potential conflicts of interest. The authors declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Carbapenem-resistant Enterobacterales (CRE) remain a significant public health threat, and, despite recent approvals, new antibiotics are needed. Severe infections caused by CRE, such as nosocomial pneumonia and bloodstream infections, are associated with a relatively high risk of morbidity and mortality. The recent approval of ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, plazomicin, eravacycline and cefiderocol has broadened the armamentarium for the treatment of patients with CRE infections. Cefiderocol is a siderophore cephalosporin with overall potent in vitro activity against CRE. It is taken up via iron transport channels through active transport, with some entry into bacteria through traditional porin channels. Cefiderocol is relatively stable against hydrolysis by most serine- and metallo-beta-lactamases, including KPC, NDM, VIM, IMP and OXA carbapenemases-the most frequent carbapenemases detected in CRE. The efficacy and safety of cefiderocol has been demonstrated in three randomised, prospective, parallel group or controlled clinical studies in patients at risk of being infected by multidrug-resistant or carbapenem-resistant Gram-negative bacteria. This paper reviews the in vitro activity, emergence of resistance, preclinical effectiveness, and clinical experience for cefiderocol, and its role in the management of patients with CRE infections., (© 2023. The Author(s).)

Recommended antimicrobial treatment durations for ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa have evolved over the past few decades. In this Viewpoint, we provide a narrative review of landmark trials investigating antimicrobial treatment durations for VAP caused by P. aeruginosa, and appraise iterations of expert consensus guidelines based on these data. We highlight strengths and weaknesses of existing data on this topic and provide recommendations for future avenues of study., Competing Interests: Potential conflicts of interest. O. R. A. reports grants or contracts from Charles River Laboratories; consulting fees from Shionogi, Charles River Laboratories. K. S. K. reports consulting fees from Merck, Qpex, Allecra, Utility Pharmaceuticals, Melinta, GSK, CARB-X, ARLG; stock or stock options from Merck. E. K. M. reports consulting fees for Advisory Boards from AbbVie, Merck, Shionogi, Cidara, Ferring, Summit, La Jolla, Venatorx, Entasis; participation on DMBD for A Phase I, Randomized, Double-blind, Placebo-controlled, Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Intravenous Ertapenem in Combination with Zidebactam (WCK 6777) in Healthy Adult Subjects; role as Treasurer of Society of Infectious Diseases Pharmacists. J. M. P. reports grants or contracts from Merck; consulting fees from Merck, Shionogi, GlaxoSmithKline, Qpex, Abbive, Melinta. 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.)

Background: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii , XDR Pseudomonas aeruginosa , and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections., Methods: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii , XDR P. aeruginosa , or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure., Results: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively., Conclusions: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Competing Interests: JMP discloses serving as a consultant to Merck, Shionogi, and Roche. EKM discloses serving as a consultant to Shionogi and is the Director of infectious diseases improvement and clinical research innovation at UPMC. In this role, EKM oversaw clinical trials involving use of sotrovimab (donated by GSK) and evaluation of tixagevimab–cilgavimab in outpatients (funded by AstraZeneca). She does not receive salary support or funding for her involvement in these trials.

Importance: Some experts have cautioned that national and health system emphasis on rapid administration of antimicrobials for sepsis may increase overall antimicrobial use even among patients without sepsis., Objective: To assess whether temporal changes in antimicrobial timing for sepsis are associated with increasing antimicrobial use, days of therapy, or broadness of antimicrobial coverage among all hospitalized patients at risk for sepsis., Design, Setting, and Participants: This is an observational cohort study of hospitalized patients at 152 hospitals in 2 health care systems during 2013 to 2018, admitted via the emergency department with 2 or more systemic inflammatory response syndrome (SIRS) criteria. Data analysis was performed from June 10, 2021, to March 22, 2022., Exposures: Hospital-level temporal trends in time to first antimicrobial administration., Outcomes: Antimicrobial outcomes included antimicrobial use, days of therapy, and broadness of antibacterial coverage. Clinical outcomes included in-hospital mortality, 30-day mortality, length of hospitalization, and new multidrug-resistant (MDR) organism culture positivity., Results: Among 1 559 523 patients admitted to the hospital via the emergency department with 2 or more SIRS criteria (1 269 998 male patients [81.4%]; median [IQR] age, 67 [59-77] years), 273 255 (17.5%) met objective criteria for sepsis. In multivariable models adjusted for patient characteristics, the adjusted median (IQR) time to first antimicrobial administration to patients with sepsis decreased by 37 minutes, from 4.7 (4.1-5.3) hours in 2013 to 3.9 (3.6-4.4) hours in 2018, although the slope of decrease varied across hospitals. During the same period, antimicrobial use within 48 hours, days of antimicrobial therapy, and receipt of broad-spectrum coverage decreased among the broader cohort of patients with SIRS. In-hospital mortality, 30-day mortality, length of hospitalization, new MDR culture positivity, and new MDR blood culture positivity decreased over the study period among both patients with sepsis and those with SIRS. When examining hospital-specific trends, decreases in antimicrobial use, days of therapy, and broadness of antibacterial coverage for patients with SIRS did not differ by hospital antimicrobial timing trend for sepsis. Overall, there was no evidence that accelerating antimicrobial timing for sepsis was associated with increasing antimicrobial use or impaired antimicrobial stewardship., Conclusions and Relevance: In this multihospital cohort study, the time to first antimicrobial for sepsis decreased over time, but this trend was not associated with increasing antimicrobial use, days of therapy, or broadness of antimicrobial coverage among the broader population at-risk for sepsis, which suggests that shortening the time to antibiotics for sepsis is feasible without leading to indiscriminate antimicrobial use.

Adoption of revised antimicrobial susceptibility breakpoints is often slow, potentially leading to underreporting of antimicrobial resistance. We compared facility-reported rates of carbapenem nonsusceptibility (NS; intermediate or resistant) with NS rates based on current Clinical and Laboratory Standards Institute (CLSI) breakpoints for Enterobacterales or Pseudomonas aeruginosa isolates in ambulatory and inpatient adults in the BD Insights Research Database (US) from 2016 to 2020. Overall, 77.4% (937,926/1,211,845) and 90.6% (2,157,785/2,381,824) of nonduplicate Enterobacterales isolates with facility-reported susceptibility results had MIC data for ertapenem (ETP) and imipenem/meropenem/doripenem (IPM/MEM/DOR), respectively; 86.9% (255,844/294,426) of P. aeruginosa isolates had MIC data for IPM/MEM/DOR. Facility-reported susceptibility and susceptibility based on CLSI criteria resulted in comparable carbapenem susceptibility rates (99.3% versus 99.1% for ETP-susceptible Enterobacterales, 98.9% versus 98.4% for IPM/MEM/DOR-susceptible Enterobacterales, and 84.9% versus 83.3% for IPM/MEM/DOR-susceptible P. aeruginosa). However, compared with CLSI criteria, facilities underreported Enterobacterales- and IPM/MEM/DOR-NS isolates by 18.8% and 26.5%, respectively, and P. aeruginosa IPM/MEM/DOR-NS isolates by 9.8%. Underreporting was observed for both intermediate and resistant isolates. Our data suggest that delayed adoption of revised breakpoints has a small but potentially important impact on reported rates of antimicrobial resistance. Facilities should be aware of local epidemiology, evaluate potential underreporting of resistance, and assess the related clinical impact. IMPORTANCE Clinicians often base antimicrobial therapeutic decisions on laboratory determinations of pathogen susceptibility to an antibiotic based on MIC breakpoints. MIC breakpoints evolve over time based on new information; between 2010 and 2012 the CLSI lowered carbapenem breakpoints for Enterobacterales and Pseudomonas aeruginosa, and these were subsequently adopted by the US Food and Drug Administration. Carbapenems are important therapeutic options for these difficult-to-treat pathogens, so understanding resistance rates is critically important. However, laboratories can be slow to adopt updated breakpoints. We used MIC data to evaluate whether reports received by hospitals for carbapenem susceptibility were consistent with updated CLSI breakpoints. Although overall susceptibility rates were similar between hospital reports and susceptibility based on updated CLSI criteria, the percentages of carbapenem-resistant isolates were significantly underreported by hospital reports. Delayed adoption of MIC breakpoints may impact epidemiological understanding of resistance and contribute to the spread of resistant pathogens.

Background: Carbapenem-resistant (CR) Acinetobacter baumannii is a concerning pathogen in the USA and worldwide., Methods: To assess the comparative burden of CR vs carbapenem-susceptible (CS) A. baumannii, this retrospective cohort study analyzed data from adult patients in 250 US hospitals from the Premier HealthCare Database (2014-2019). The outcomes analyzed included hospital length of stay (LOS), intensive care unit (ICU) utilization, discharge status, in-hospital mortality, readmission rates and hospital charges. Logistic regression was used for univariate and multivariable assessment of the independent relationship between relevant covariates, with a focus on CR status, and in-hospital mortality., Results: 2047 Patients with CR and 3476 patients with CS A. baumannii infections were included. CR A. baumannii was more commonly isolated in respiratory tract infections (CR 40.7% and CS 27.0%, P < 0.01), whereas CS A. baumannii was more frequently associated with bloodstream infections (CS 16.7% and CR 8.6%, P < 0.01). Patients with CR A. baumannii infections had higher in-hospital (CR 16.4% vs CS 10.0%; P < 0.01) and 30-day (CR 32.2% vs CS 21.6%; P < 0.01) mortality compared to those with CS infections. After adjusting for age, sex, admission source, infection site, comorbidities, and treatment with in vitro active antibiotics within 72 h, carbapenem resistance was independently associated with increased mortality (adjusted odds ratio 1.42 [95% confidence interval 1.15; 1.75], P < 0.01). CR infections were also associated with increases in hospital length of stay (CR 11 days vs CS 9 days; P < 0.01), rate of intensive care unit utilization (CR 62.3% vs CS 45.1%; P < 0.01), rate of readmission with A. baumannii infections (CR 17.8% vs CS 4.0%; P < 0.01) and hospital charges., Conclusions: These data suggest that the burden of illness is significantly greater for patients with CR A. baumannii infections and are at higher risk of mortality compared with CS infections in US hospitals., (© 2022. The Author(s).)

Background: Antibiotics are commonly prescribed to patients as they leave the hospital. We aimed to create a comprehensive metric to characterize antibiotic overuse after discharge among hospitalized patients treated for pneumonia or urinary tract infection (UTI), and to determine whether overuse varied across hospitals and conditions., Methods: In a retrospective cohort study of hospitalized patients treated for pneumonia or UTI in 46 hospitals between 1 July 2017-30 July 2019, we quantified the proportion of patients discharged with antibiotic overuse, defined as unnecessary antibiotic use, excess antibiotic duration, or suboptimal fluoroquinolone use. Using linear regression, we assessed hospital-level associations between antibiotic overuse after discharge in patients treated for pneumonia versus a UTI., Results: Of 21 825 patients treated for infection (12 445 with pneumonia; 9380 with a UTI), nearly half (49.1%) had antibiotic overuse after discharge (56.9% with pneumonia; 38.7% with a UTI). For pneumonia, 63.1% of overuse days after discharge were due to excess duration; for UTIs, 43.9% were due to treatment of asymptomatic bacteriuria. The percentage of patients discharged with antibiotic overuse varied 5-fold among hospitals (from 15.9% [95% confidence interval, 8.7%-24.6%] to 80.6% [95% confidence interval, 69.4%-88.1%]) and was strongly correlated between conditions (regression coefficient = 0.85; P < .001)., Conclusions: Antibiotic overuse after discharge was common and varied widely between hospitals. Antibiotic overuse after discharge was associated between conditions, suggesting that the prescribing culture, physician behavior, or organizational processes contribute to overprescribing at discharge. Multifaceted efforts focusing on all 3 types of overuse and multiple conditions should be considered to improve antibiotic prescribing at discharge., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Guidance on the recommended durations of antibiotic therapy, the use of oral antibiotic therapy, and the need for repeat blood cultures remain incomplete for gram-negative bloodstream infections. We convened a panel of infectious diseases specialists to develop a consensus definition of uncomplicated gram-negative bloodstream infections to assist clinicians with management decisions., Methods: Panelists, who were all blinded to the identity of other members of the panel, used a modified Delphi technique to develop a list of statements describing preferred management approaches for uncomplicated gram-negative bloodstream infections. Panelists provided level of agreement and feedback on consensus statements generated and refined them from the first round of open-ended questions through 3 subsequent rounds., Results: Thirteen infectious diseases specialists (7 physicians and 6 pharmacists) from across the United States participated in the consensus process. A definition of uncomplicated gram-negative bloodstream infection was developed. Considerations cited by panelists in determining if a bloodstream infection was uncomplicated included host immune status, response to therapy, organism identified, source of the bacteremia, and source control measures. For patients meeting this definition, panelists largely agreed that a duration of therapy of ~7 days, transitioning to oral antibiotic therapy, and forgoing repeat blood cultures, was reasonable., Conclusions: In the absence of professional guidelines for the management of uncomplicated gram-negative bloodstream infections, the consensus statements developed by a panel of infectious diseases specialists can provide guidance to practitioners for a common clinical scenario., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales are a global threat to public health due to their antimicrobial resistance profile and, consequently, their limited available treatment options. Tazobactam is a sulfone β-lactamase inhibitor with in vitro inhibitory activity against common ESBLs in Enterobacterales, including CTX-M. However, the role of tazobactam-based combinations in treating infections caused by ESBL-producing Enterobacterales remains unclear. In the United States, two tazobactam-based combinations are available, piperacillin-tazobactam and ceftolozane-tazobactam. We evaluated and compared the roles of tazobactam-based combinations against ESBL-producing organisms with emphasis on pharmacokinetic/pharmacodynamic exposures in relation to MIC distributions and established breakpoints, clinical outcomes data specific to infection site, and considerations for downstream effects with these agents regarding antimicrobial resistance development. While limited data with ceftolozane-tazobactam are encouraging for its potential role in infections due to ESBL-producing Enterobacterales, further evidence is needed to determine its place in therapy. Conversely, currently available microbiologic, pharmacokinetic, pharmacodynamic, and clinical data do not suggest a role for piperacillin-tazobactam, and we caution clinicians against its usage for these infections., (© 2021 Pharmacotherapy Publications, Inc.)

Objective: To compare the detection of gaps in jejunal continuous anastomoses by probing (PT) versus leak testing (LT)., Study Design: Experimental study., Animals: Normal jejunal segments (n = 24) from two fresh canine cadavers., Methods: Intestinal segments were randomly selected by four volunteers who created six simple continuous anastomoses: two constructs using standard technique with 2-3 mm suture spacing (ST, 8 total), and four constructs with one 4-mm gap (IG, 16 total). All 24 anastomoses were examined with PT (1 volunteer) prior to LT (3 volunteers). LT was performed within a maximal peristaltic pressure range (34-54 cmH 2 O). The presence and location of anastomotic leaks (L A ) detected with LT were compared with gaps detected with PT., Results: Nineteen out of twenty-four (79.2%) samples had at least one probe drop, and four out of twenty-three (17.4%) samples leaked. LT results from one sample were excluded due to iatrogenic suture failure. PT was 100% sensitive (95% CI: 51.01, 100%) with a 100% negative predictive value (95% CI: 56.55, 100%) at detecting gaps compared with LT. The location of all L A was accurately identified with PT and confirmed during LT., Conclusion: PT was highly sensitive at detecting gaps compared with LT. All L A were accurately detected by PT. None of the segments negative during PT leaked., Clinical Significance: The diagnostic value of PT appears adequate to recognize gaps in cadaveric small intestinal anastomoses. PT offers surgeons an alternative to detect suture gaps that may contribute to postoperative dehiscence of intestinal anastomoses., (© 2021 American College of Veterinary Surgeons.)

Antibiotic overuse and misuse has contributed to rising rates of multidrug-resistant organisms and Clostridioides difficile. Decreasing antibiotic misuse has become a national public health priority. This review outlines the goals of antimicrobial stewardship, essential members of the program, implementation strategies, approaches to measuring the program's impact, and steps needed to build a program. Highlighted is the alliance between antimicrobial stewardship programs and infection prevention programs in their efforts to improve antibiotic use, improve diagnostic stewardship for C difficile and asymptomatic bacteriuria, and decrease health care-associated infections and the spread of multidrug-resistant organisms., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Severe coronavirus disease 2019 (COVID-19) can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers, consistent with cytokine release syndrome for which IL-6 blockade is an approved treatment., Methods: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability postintubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared with tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability of treatment weighting (IPTW)., Results: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range, 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean: 55 vs 60 years), less likely to have chronic pulmonary disease (10% vs 28%), and had lower D-dimer values at time of intubation (median: 2.4 vs 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death (HR, .55; 95% CI, .33-.90) and improved status on the ordinal outcome scale [OR per 1-level increase, .58; .36-.94). Although tocilizumab was associated with an increased proportion of patients with superinfections (54% vs 26%; P < .001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection (22% vs 15%; P = .42). Staphylococcus aureus accounted for ~50% of bacterial pneumonia., Conclusions: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with lower mortality despite higher superinfection occurrence., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infection (BSI) management remains challenging for clinicians. Numerous in vitro studies report synergy when vancomycin (VAN) and daptomycin (DAP) are combined with beta-lactams (BLs), which has led to clinical implementation of these combinations. While shorter durations of bacteremia have often been reported, there has been no significant impact on mortality., Methods: The Detroit Medical Center (DMC) developed and implemented a clinical pathway algorithm for MRSA BSI treatment in 2016 that included the early use of BL combination therapy with standard of care (VAN or DAP) and a mandatory Infectious Diseases consultation. This was a retrospective, quasi-experimental study at the DMC between 2013 and 2020. Multivariable logistic regression was used to assess the independent association between pathway implementation and 30-day mortality while adjusting for confounding variables., Results: Overall, 813 adult patients treated for MRSA BSI were evaluated. Compared with prepathway (PRE) patients (n = 379), those treated postpathway (POST; n = 434) had a significant reduction in 30-day and 90-day mortality: 9.7% in POST vs 15.6% in PRE ( P = .011) and 12.2% in POST vs 19.0% in PRE ( P = .007), respectively.The incidence of acute kidney injury (AKI) was higher in the PRE compared with the POST group: 9.6% vs 7.2% ( P = .282), respectively. After adjusting for confounding variables including Infectious Diseases consult, POST was independently associated with a reduction in 30-day mortality (adjusted odds ratio [aOR], 0.608; 95% CI, 0.375-0.986)., Conclusions: Implementation of an MRSA BSI treatment pathway with early use of BL reduced mortality with no increased rate of AKI. Further prospective evaluation of this pathway approach is warranted., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Monoclonal antibodies targeting the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 spike protein are important outpatient treatment options in coronavirus disease 2019 to mitigate progression of disease and prevent hospitalization. The impact of different RBD mutations on the efficacy of the available monoclonal antibodies and processes for incorporating this impact into treatment algorithms are ill defined. Herein, we synthesize the data surrounding the impact of key RBD mutations on the efficacy of US Food and Drug Administration Emergency Use Authorized monoclonal antibodies and describe our approach at Michigan Medicine at monitoring mutation frequency in circulating virus and developing an algorithm that incorporates these data into outpatient treatment pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Nosocomial pneumonia due to multidrug-resistant Gram-negative pathogens poses an increasing challenge. We compared the efficacy and safety of cefiderocol versus high-dose, extended-infusion meropenem for adults with nosocomial pneumonia., Methods: We did a randomised, double-blind, parallel-group, phase 3, non-inferiority trial in 76 centres in 17 countries in Asia, Europe, and the USA (APEKS-NP). We enrolled adults aged 18 years and older with hospital-acquired, ventilator-associated, or health-care-associated Gram-negative pneumonia, and randomly assigned them (1:1 by interactive response technology) to 3-h intravenous infusions of either cefiderocol 2 g or meropenem 2 g every 8 h for 7-14 days. All patients also received open-label intravenous linezolid (600 mg every 12 h) for at least 5 days. An unmasked pharmacist prepared the assigned treatments; investigators and patients were masked to treatment assignment. Only the unmasked pharmacist was aware of the study drug assignment for the infusion bags, which were administered in generic infusion bags labelled with patient and study site identification numbers. Participants were stratified at randomisation by infection type and Acute Physiology and Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16). The primary endpoint was all-cause mortality at day 14 in the modified intention-to-treat (ITT) population (ie, all patients receiving at least one dose of study drug, excluding patients with Gram-positive monomicrobial infections). The analysis was done for all patients with known vital status. Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference between cefiderocol and meropenem groups was less than 12·5%. Safety was investigated to the end of the study in the safety population, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03032380, and EudraCT, 2016-003020-23., Findings: Between Oct 23, 2017, and April 14, 2019, we randomly assigned 148 participants to cefiderocol and 152 to meropenem. Of 292 patients in the modified ITT population, 251 (86%) had a qualifying baseline Gram-negative pathogen, including Klebsiella pneumoniae (92 [32%]), Pseudomonas aeruginosa (48 [16%]), Acinetobacter baumannii (47 [16%]), and Escherichia coli (41 [14%]). 142 (49%) patients had an APACHE II score of 16 or more, 175 (60%) were mechanically ventilated, and 199 (68%) were in intensive care units at the time of randomisation. All-cause mortality at day 14 was 12·4% with cefiderocol (18 patients of 145) and 11·6% with meropenem (17 patients of 146; adjusted treatment difference 0·8%, 95% CI -6·6 to 8·2; p=0·002 for non-inferiority hypothesis). Treatment-emergent adverse events were reported in 130 (88%) of 148 participants in the cefiderocol group and 129 (86%) of 150 in the meropenem group. The most common treatment-emergent adverse event was urinary tract infection in the cefiderocol group (23 patients [16%] of 148) and hypokalaemia in the meropenem group (23 patients [15%] of 150). Two participants (1%) of 148 in the cefiderocol group and two (1%) of 150 in the meropenem group discontinued the study because of drug-related adverse events., Interpretation: Cefiderocol was non-inferior to high-dose, extended-infusion meropenem in terms of all-cause mortality on day 14 in patients with Gram-negative nosocomial pneumonia, with similar tolerability. The results suggest that cefiderocol is a potential option for the treatment of patients with nosocomial pneumonia, including those caused by multidrug-resistant Gram-negative bacteria., Funding: Shionogi., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Nephrotoxicity and neurotoxicity are commonly associated with polymyxin treatment; however, the emergence of multidrug-resistant Gram-negative bacteria with limited therapeutic options has resulted in increased use of polymyxins., Objectives: To determine the rates of nephrotoxicity and neurotoxicity during polymyxin treatment and whether any factors influence these., Data Sources: Medline, Embase and Cochrane Library databases were searched on 2 January 2020., Study Eligibility Criteria: Studies reporting nephrotoxicity and/or neurotoxicity rates in patients with infections treated with polymyxins were included. Reviews, meta-analyses and reports not in English were excluded., Participants: Patients hospitalized with infections treated with systemic or inhaled polymyxins were included. For comparative analyses, patients treated with non-polymyxin-based regimens were also included., Methods: Meta-analyses were performed using a random-effects model; subgroup meta-analyses were conducted where data permitted using a mixed-effects model., Results: In total, 237 reports of randomized controlled trials, cohort and case-control studies were eligible for inclusion; most were single-arm observational studies. Nephrotoxic events in 35,569 patients receiving polymyxins were analysed. Overall nephrotoxicity rate was 0.282 (95% confidence interval (CI) 0.259-0.307). When excluding studies where >50% of patients received inhaled-only polymyxin treatment or nephrotoxicity assessment was by methods other than internationally recognized criteria (RIFLE, KDIGO or AKIN), the nephrotoxicity rate was 0.391 (95% CI 0.364-0.419). The odds of nephrotoxicity were greater with polymyxin therapies compared to non-polymyxin-based regimens (odds ratio 2.23 (95% CI 1.58-3.15); p < 0.001). Meta-analyses showed a significant effect of polymyxin type, dose, patient age, number of concomitant nephrotoxins and use of diuretics, glycopeptides or vasopressors on the rate of nephrotoxicity. Polymyxin therapies were not associated with a significantly different rate of neurotoxicity than non-polymyxin-based regimens (p 0.051). The overall rate of neurotoxicity during polymyxin therapy was 0.030 (95% CI 0.020-0.043)., Conclusions: Polymyxins are associated with a higher risk of nephrotoxicity than non-polymyxin-based regimens., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Determining a suitable dose of intravenous colistimethate is challenging because of complicated pharmacokinetics, confusing terminology, and the potential for renal toxicity. Only recently have reliable pharmacokinetic/pharmacodynamic data and dosing recommendations for intravenous colistimethate become available., Objective: The aim of this work was to develop a clinician-friendly, easy-to-use mobile app incorporating up-to-date dosing recommendations for intravenous colistimethate in critically ill adult patients., Methods: Swift programming language and common libraries were used for the development of an app, ColistinDose, on the iPhone operating system (iOS; Apple Inc). The compatibility among different iOS versions and mobile devices was validated. Dosing calculations were based on equations developed in our recent population pharmacokinetic study. Recommended doses generated by the app were validated by comparison against doses calculated manually using the appropriate equations., Results: ColistinDose provides 3 major functionalities, namely (1) calculation of a loading dose, (2) calculation of a daily dose based on the renal function of the patient (including differing types of renal replacement therapies), and (3) retrieval of historical calculation results. It is freely available at the Apple App Store for iOS (version 9 and above). Calculated doses accurately reflected doses recommended in patients with varying degrees of renal function based on the published equations. ColistinDose performs calculations on a local mobile device (iPhone or iPad) without the need for an internet connection., Conclusions: With its user-friendly interface, ColistinDose provides an accurate and easy-to-use tool for clinicians to calculate dosage regimens of intravenous colistimethate in critically ill patients with varying degrees of renal function. It has significant potential to avoid the prescribing errors and patient safety issues that currently confound the clinical use of colistimethate, thereby optimizing patient treatment., (©Xueliang Hua, Chen Li, Jason M Pogue, Varun S Sharma, Ilias Karaiskos, Keith S Kaye, Brian T Tsuji, Phillip J Bergen, Yan Zhu, Jiangning Song, Jian Li. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 16.12.2020.)

Background: Microbiologic cure is a common outcome in pneumonia clinical trials, but its clinical significance is incompletely understood., Methods: We conducted a retrospective cohort study of adult patients hospitalized with bacterial pneumonia who achieved clinical cure. Rates of recurrent pneumonia and death were compared between patients with persistent growth of the index pathogen at the time of clinical cure (microbiologic failure) and those with pathogen eradication (microbiologic cure)., Results: Among 441 patients, 237 experienced microbiologic cure and 204 experienced microbiologic failure. Prevalences of comorbidities, ventilator dependence, and severity of acute illness were similar between groups. Patients with microbiologic failure experienced significantly higher rates of recurrent pneumonia or death following clinical cure than patients with microbiologic cure, controlling for comorbid conditions, severity of acute illness, appropriateness of empiric antibiotics, intensive care unit placement, tracheostomy dependence, and immunocompromised status (90-day multivariable adjusted odds ratio [OR], 1.56; 95% confidence interval [CI], 1.04-2.35). This association was observed among patients with pneumonias caused by Staphylococcus aureus (90-day multivariable adjusted OR, 3.69; 95% CI, 1.73-7.90). A trend was observed among pneumonias caused by nonfermenting gram-negative bacilli, but not Enterobacteriaceae or other pathogens., Conclusions: Microbiologic treatment failure was independently associated with recurrent pneumonia or death among patients with bacterial pneumonia following clinical cure. Microbiologic cure merits further study as a metric to guide therapeutic interventions for patients with bacterial pneumonia., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Polymyxin resistance is a major public health threat, because the polymyxins represent last-line therapeutics for gram-negative pathogens resistant to essentially all other antibiotics. Minimizing any potential emergence and dissemination of polymyxin resistance relies on an improved understanding of mechanisms of and risk factors for polymyxin resistance, infection prevention and stewardship strategies, together with optimization of dosing of polymyxins (eg, combination regimens)., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Reducing antibiotic use in patients with asymptomatic bacteriuria (ASB) has been inpatient focused. However, testing and treatment is often started in the emergency department (ED). Thus, for hospitalized patients with ASB, we sought to identify patterns of testing and treatment initiated by emergency medicine (EM) clinicians and the association of treatment with outcomes., Methods: We conducted a 43-hospital, cohort study of adults admitted through the ED with ASB (February 2018-February 2020). Using generalized estimating equation models, we assessed for (1) factors associated with antibiotic treatment by EM clinicians and, after inverse probability of treatment weighting, (2) the effect of treatment on outcomes., Results: Of 2461 patients with ASB, 74.4% (N = 1830) received antibiotics. The EM clinicians ordered urine cultures in 80.0% (N = 1970) of patients and initiated treatment in 68.5% (1253 of 1830). Predictors of EM clinician treatment of ASB versus no treatment included dementia, spinal cord injury, incontinence, urinary catheter, altered mental status, leukocytosis, and abnormal urinalysis. Once initiated by EM clinicians, 79% (993 of 1253) of patients remained on antibiotics for at least 3 days. Antibiotic treatment was associated with a longer length of hospitalization (mean 5.1 vs 4.2 days; relative risk = 1.16; 95% confidence interval, 1.08-1.23) and Clostridioides difficile infection (CDI) (0.9% [N = 11] vs 0% [N = 0]; P  = .02)., Conclusions: Among hospitalized patients ultimately diagnosed with ASB, EM clinicians commonly initiated testing and treatment; most antibiotics were continued by inpatient clinicians. Antibiotic treatment was not associated with improved outcomes, whereas it was associated with prolonged hospitalization and CDI. For best impact, stewardship interventions must expand to the ED., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Remdesivir is a nucleoside antiviral recently studied in several randomized trials for treatment of COVID-19. The available observational and prospective data are conflicting, requiring clinicians to critically evaluate and reconcile results to determine patient populations that may optimally benefit from remdesivir therapy, especially while drug supply is scarce. In this review, we analyze pertinent clinical remdesivir data for patients with COVID-19 from January 1, 2020, through May 31, 2020.

Coronavirus disease 2019 (COVID-19), caused by the 2019 novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently responsible for a global pandemic. To date, only remdesivir and dexamethasone have demonstrated a positive response in a prospective, randomized trial for the treatment of patients with COVID-19. Hydroxychloroquine (HCQ) is an agent available in an oral formulation with in vitro activity against SARS-CoV-2 that has been suggested as a potential agent. Unfortunately, results of randomized trials evaluating HCQ as treatment against a control group are lacking, and little is known about its pharmacokinetic/pharmacodynamic (PK/PD) profile against SARS-CoV-2. The objective of this review was to describe the current understanding of the PK/PD and dose selection of HCQ against SARS-CoV-2, discuss knowledge gaps, and identify future studies that are needed to optimize the efficacy and safety of treatments against COVID-19.

Background: Ceftolozane/tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination that often retains activity against resistant Pseudomonas aeruginosa. The comparative safety and efficacy vs polymyxins or aminoglycosides in this setting remains unknown., Methods: A retrospective, multicenter, observational cohort study was performed. Patients who received ceftolozane/tazobactam were compared with those treated with either polymyxin or aminoglycoside-based regimens for infections due to drug-resistant P. aeruginosa. Multivariate logistic regression was performed controlling for factors associated with treatment to assess the independent impact of ceftolozane/tazobactam on clinical cure, acute kidney injury (AKI), and in-hospital mortality., Results: A total of 200 patients were included (100 in each treatment arm). The cohort represented an ill population with 69% in the intensive care unit, 63% mechanically ventilated, and 42% in severe sepsis or septic shock at infection onset. The most common infection type was ventilator-associated pneumonia (52%); 7% of patients were bacteremic. Combination therapy was more commonly used in polymyxin/aminoglycoside patients than those who received ceftolozane/tazobactam (72% vs 15%, P < .001). After adjusting for differences between groups, receipt of ceftolozane/tazobactam was independently associated with clinical cure (adjusted odds ratio [aOR], 2.63; 95% confidence interval [CI], 1.31-5.30) and protective against AKI (aOR, 0.08; 95% CI, 0.03-0.22). There was no difference in in-hospital mortality. The number needed to treat for a clinical cure with ceftolozane/tazobactam was 5, and the number needed to harm with AKI with a polymyxin/aminoglycoside was 4., Conclusions: These data support the preferential use of ceftolozane/tazobactam over polymyxins or aminoglycosides for drug-resistant P. aeruginosa infections., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Bloodstream infections (BSIs) due to ceftriaxone (CRO)-resistant Enterobacteriaceae are associated with delays in time to appropriate therapy and worse outcomes compared with infections due to susceptible isolates. However, treating all at-risk patients with empiric carbapenem therapy risks overexposure. Strategies are needed to appropriately balance these competing interests. The purpose of this study was to compare 4 methods for achieving this balance., Methods: This was a retrospective hypothetical observational study of patients at the Detroit Medical Center with monomicrobial BSIs due to E. coli, K. oxytoca, K. pneumoniae, or P. mirabilis . This study compared the effectiveness of 4 methods to predict CRO resistance at the time of organism isolation. Three methods were based on applying published extended-spectrum beta-lactamase (ESBL) scoring tools. The fourth method was based on the presence or absence of the CTX-M marker from Verigene., Results: Four hundred fifty-one Enterobacteriaceae BSIs were included, 73 (16%) of which were CRO-resistant. Verigene accurately predicted ceftriaxone susceptibility for 97% of isolates, compared with 70%-81% using the scoring tools ( P  < .001). Verigene was associated with fewer cases of treatment with CRO when the isolate was CRO-resistant (15% vs 63%-71% with scoring tools) and fewer cases of overtreatment with a carbapenem for CRO-susceptible strains (0.3% vs 10%-12%)., Conclusions: Verigene significantly outperformed published ESBL scoring tools for identifying CRO-resistant Enterobacteriaceae BSI. Institutions should validate scoring tools before implementation. Stewardship programs should consider adoption of rapid diagnostic tests to optimize early therapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Severe COVID-19 can manifest in rapid decompensation and respiratory failure with elevated inflammatory markers. This presentation is consistent with cytokine release syndrome in chimeric antigen receptor T cell therapy, for which IL-6 blockade is approved treatment., Methods: We assessed effectiveness and safety of IL-6 blockade with tocilizumab in a single-center cohort of patients with COVID-19 requiring mechanical ventilation. The primary endpoint was survival probability post-intubation; secondary analyses included an ordinal illness severity scale integrating superinfections. Outcomes in patients who received tocilizumab compared to tocilizumab-untreated controls were evaluated using multivariable Cox regression with propensity score inverse probability weighting (IPTW)., Findings: 154 patients were included, of whom 78 received tocilizumab and 76 did not. Median follow-up was 47 days (range 28-67). Baseline characteristics were similar between groups, although tocilizumab-treated patients were younger (mean 55 vs. 60 years), less likely to have chronic pulmonary disease (10% vs. 28%), and had lower D-dimer values at time of intubation (median 2.4 vs. 6.5 mg/dL). In IPTW-adjusted models, tocilizumab was associated with a 45% reduction in hazard of death [hazard ratio 0.55 (95% CI 0.33, 0.90)] and improved status on the ordinal outcome scale [odds ratio per 1-level increase: 0.59 (0.36, 0.95)]. Though tocilizumab was associated with an increased proportion of patients with superinfections (54% vs. 26%; p<0.001), there was no difference in 28-day case fatality rate among tocilizumab-treated patients with versus without superinfection [22% vs. 15%; p=0.42]., Interpretation: In this cohort of mechanically ventilated COVID-19 patients, tocilizumab was associated with a decreased likelihood of death despite higher superinfection occurrence. Randomized controlled trials are urgently needed to confirm these findings.