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ObjectiveTo evaluate the association between oral candidiasis and tuberculosis (TB) in human immunodeficiency virus (HIV) infected individuals in sub-Saharan Africa, and to investigate oral candidiasis as a potential tool for TB case finding.MethodsProtocol A5253 was a cross-sectional study designed to improve the diagnosis of pulmonary TB in HIV-infected adults in high TB prevalence countries. Participants received an oral examination to detect oral candidiasis. We estimated the association between TB disease and oral candidiasis using logistic regression, and sensitivity, specificity and predictive values.ResultsOf 454 participants with TB culture results enrolled in African sites, the median age was 33 years, 71% were female and the median CD4 count was 257 cells/mm(3). Fifty-four (12%) had TB disease; the prevalence of oral candidiasis was significantly higher among TB cases (35%) than among non-TB cases (16%, P < 0.001). The odds of having TB was 2.4 times higher among those with oral candidiasis when controlling for CD4 count and antifungals (95%CI 1.2-4.7, P = 0.01). The sensitivity of oral candidiasis as a predictor of TB was 35% (95%CI 22-48) and the specificity 85% (95%CI 81-88).ConclusionWe found a strong association between oral candidiasis and TB disease, independent of CD4 count, suggesting that in resource-limited settings, oral candidiasis may provide clinical evidence for increased risk of TB and contribute to TB case finding.

BackgroundImproved tuberculosis (TB) screening is urgently needed for human immunodeficiency virus (HIV) infected patients.MethodsAn observational, multi-country, cross-sectional study of HIV-infected patients to compare a standardized diagnostic evaluation (SDE) for TB with standard of care (SOC). SOC evaluations included TB symptom review (current cough, fever, night sweats and/or weight loss), sputum Ziehl-Neelsen staining and chest radiography. SDE screening added extended clinical signs and symptoms and fluorescent microscopy (FM). All participants underwent all evaluations. Mycobacterium tuberculosis on sputum culture was the primary outcome.ResultsA total of 801 participants were enrolled from Botswana, Malawi, South Africa, Zimbabwe, India, Peru and Brazil. The median age was 33 years; 37% were male, and median CD4 count was 275 cells/mm(3). Thirty-one participants (4%) had a positive culture on Löwenstein-Jensen media and 54 (8%) on MGIT. All but one positive culture came from sub-Saharan Africa, where the prevalence of TB was 54/445 (12%). SOC screening had 54% sensitivity (95%CI 40-67) and 76% specificity (95%CI 72-80). Positive and negative predictive values were respectively 24% and 92%. No elements of the SDE improved the predictive values of SOC.ConclusionsSymptom-based screening with smear microscopy was insufficiently sensitive. More sensitive diagnostic testing is required for HIV-infected patients.

Because both renal disease and immune activation predict progression to acquired immunodeficiency syndrome (AIDS), we evaluated the associations between proteinuria>or=1+, as determined by dipstick analysis (7 [7%] of 1012 subjects); creatinine clearance of <90 mL/min (195 [18%] of 1071 subjects); and percentages of peripheral activated CD8 cells (CD8+CD38+HLA-DR+ cells) in antiretroviral-naive, human immunodeficiency virus (HIV)-infected subjects who were enrolled in AIDS Clinical Trials Group studies 384 and A5095. Proteinuria, but not creatinine clearance, was associated with higher percentages of CD8+CD38+HLA-DR+ cells (55% vs. 50%; P=.01), with even more pronounced differences noted among men and among blacks and Hispanics. Proteinuria may be a surrogate measurement of greater immune activation in HIV-infected patients initiating antiretroviral therapy. [ABSTRACT FROM AUTHOR]

In this secondary analysis of 386 subjects with Gram-negative bacteremia enrolled in the RAPIDS GN trial, rapid antibiotic susceptibility testing had a greater benefit on the management of bacteremia caused by antibiotic-resistant compared to antibiotic-susceptible isolates, especially for Escherichia coli, Klebsiella species , and Proteus species.IMPORTANCERapid blood culture diagnostics are costly, and their use has not demonstrated clear clinical benefit for patients with Gram-negative sepsis, possibly because prior trials did not enroll sufficient numbers of patients with antibiotic-resistant infections. This analysis of patients with sepsis previously enrolled in a randomized controlled clinical trial demonstrates that rapid susceptibility testing of bacteria from blood cultures had the greatest impact for patients with antibiotic-resistant infections. Specifically, after rapid testing results were reported, patients infected with resistant bacteria received appropriate antibiotic therapy more quickly than patients with susceptible bacteria. These findings highlight the need to evaluate blood culture diagnostics in areas with high antibiotic resistance where these diagnostics are likely to have the greatest impact.

Background: Despite the global public health threat posed by carbapenem-resistant Enterobacter spp., clinical and molecular epidemiological studies on international isolates remain scarce. Historically, the taxonomy of Enterobacter has been challenging, limiting our understanding of the clinical characteristics and outcomes of carbapenemase-producing Enterobacter spp. infections., Methods: Hospitalized patients enrolled in the CRACKLE-2 study (ClinicalTrials.gov, NCT03646227) from 2016-2018 with cultures positive for carbapenemase-producing Enterobacter spp. were included. Clinical and microbiologic data were collected from health records. Whole genome sequencing was performed, and the population structures of selected predominant clones were analyzed., Results: We enrolled 136 hospitalized patients with carbapenemase-producing Enterobacter spp. from 30 hospitals in 7 countries. Among the 136 isolates, eleven Enterobacter species were identified, with most isolates belonging to E. xiangfangensis (n=81, 60%) and E. hoffmannii (n=17, 13%), and carrying blaKPC (n=106, 78%) and blaNDM (n=12, 9%). Clinical characteristics and outcomes were similar among patients with E. xiangfangensis, E. hoffmannii or the other Enterobacter spp. 30-day mortality was 20% and older age at enrollment (adjusted odds ratio 1.42, 95% confidence interval 1.08-1.87) was associated with increased mortality. Sequence type (ST)171 E. xiangfangensis, ST78 E. hoffmannii, and ST93 E. xiangfangensis were the predominant clones, and the acquisition of fluoroquinolone resistance-associated mutations and carbapenemase-encoding plasmids contributed to their formation and global dissemination., Conclusions: Our findings demonstrated that E. xiangfangensis and E. hoffmannii are common species among international carbapenemase-producing Enterobacter spp., potentially linked to the clonal spread of a few predominant clones that have acquired fluoroquinolone resistance and carbapenemase-encoding plasmids., (© 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.)

Carbapenem-resistant Enterobacterales (CRE) are an important threat to the health of solid organ transplant recipients (SOTr); data comparing outcomes of SOTr with CRE to non-SOTr with CRE are lacking. A matched cohort study was performed within 2 prospective, multicenter, cohort studies (Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales and Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacterales 2). The epidemiology, desirability of outcome rankings outcomes, and mortality of SOTr and non-SOTr hospitalized in the United States (December 2011-August 2017) with clinical isolates with Centers for Disease Control and Prevention-defined CRE were compared. In total, 121 SOTr and 242 matched non-SOTr were included. Fifty-one percent of isolates met infection criteria. SOTr were younger (P < .001), less acutely ill (P = .029), less often had a malignancy history (P = .006), and more often were admitted from home (P < .001) than non-SOTr. SOTr had more favorable adjusted desirability of outcome rankings outcomes; a randomly selected SOTr had a 58% (95% confidence interval, 53%-64%) probability of a better outcome as compared to a randomly selected non-SOTr. All-cause 30-day mortality was 14% (17/121) in SOTr vs 25% (60/242) in non-SOTr, P = .018. After stabilized inverse probability weighted adjustment, SOTr had a 7% lower 30-day mortality risk than non-SOTr (95% confidence interval, -15% to 1%). SOTr with CRE do not have worse outcomes than matched patients without transplant history., Competing Interests: Declaration of competing interest The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. All authors report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. W. Dai, E. Cober, L. Komarow, L. Chen, C. Hill, M. Grant, and G. Patel have nothing to declare other than the ARLG grant paid to their institution. A.E. Boutzoukas reports NIH grants and contracts paid to her institution, research support from the Thrasher Research Foundation, and support from the Biogen Foundation. L.M. Abbo reports honorarium for ontinuing medical education (CM lectures from Pfizer Latin America and Merck Sharp & Dohme Latin America related to the study; and in the last 3 years consulting honorarium from bioMéreiux, Shionogi, Ferring pharmaceuticals, Pfizer, La Joya, Abbvie Therapeutics; and speaker honorarium for CME lectures from Medscape and Clinical Care options. M.J. Satlin reports grants/contracts to his institution from Merck, Selux Diagnostics, SNIPRBiome, and bioMéreiux; consulting fees paid directly to him from Shionogi; and compensation for participation on a data and safety monitoring board from AbbVie paid directly to him. B.C. Fries reports support from the USVeterans Affairs Merit Review Award 5I01 BX003741 and the National Institute for Allergy Infectious Diseases R01AI181830; is an attending at the US Department of Veterans Affairs, Northport Veterans Affairs (VA) Medical Center, Northport, NY; contents of this review do not represent the views of the VA or the United States Government. T.P. McCarty reports a research contract paid to his institution from T2Biosystems. C.A. Arias reports the following grants and contracts paid to his institution NIH/NIAID 1 P01 AI152999, NIH/NIAID R01 AI148342, NIH/NIAID R01 AI134637, NIH/NIAID T32 AI141349, NIH/NIAID K24 AI121296, NIH/NIAID U19 AI144297, and NIH/NIAID R01 AI150685; payments to him for UpToDate royalties; reimbursement of meeting attendance and speaking from Infectious Diseases Society of America, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, Mérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, and Brazilian Society for Infectious Diseases; reviewer participation as part of the NIH grant Review Study Sections; travel expenses from the Infectious Disease Society of America Board of Directors; and for Editor in Chief for Antimicrobial Agents and Chemotherapy; nonpaid participation includes World Health Organization Antibacterial Pipeline Advisory Group, and participation on the Infectious Disease Society of America Board of Directors. R.A. Bonomo reports grants and contracts, paid to his institution, by VenatoRx and Merck; payments made to him by Pfizer to moderate meeting sessions; a provisional patent with Case Western Reserve University on the development of boronic acid transition state inhibitors for beta-lactamases; served on a data and safety monitoring board as a logistics associate for Division of Microbiology and Infectious Diseases-Clinical Research Operations and Management Support, Safety Oversight Committee Support; and Technical Resources International, Inc. D. van Duin reports grants and contracts from the NIH, Merck, and Shinogi, paid to his institution, outside of the published work; consultancy for Actavis, Tetraphase, Sanofi-Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, Qpex, Wellspring, Karius, and Utility, paid directly to him; honoraria from Pfizer; and an editor’s stipend from the British Society for Antimicrobial Chemotherapy., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: The CDC reported a 35% increase in hospital-onset (HO) carbapenem-resistant Enterobacterales (CRE) infections during the COVID-19 pandemic. We evaluated patient outcomes following HO and community-onset (CO) CRE bloodstream infections (BSI)., Methods: Patients prospectively enrolled in CRACKLE-2 from 56 hospitals in 10 countries between 30 April 2016 and 30 November 2019 with a CRE BSI were eligible. Infections were defined as CO or HO by CDC guidelines, and clinical characteristics and outcomes were compared. The primary outcome was desirability of outcome ranking (DOOR) 30 days after index culture. Difference in 30-day mortality was calculated with 95% CI., Results: Among 891 patients with CRE BSI, 65% were HO (582/891). Compared to those with CO CRE, patients with HO CRE were younger [median 60 (Q1 42, Q3 70) years versus 65 (52, 74); P < 0.001], had fewer comorbidities [median Charlson comorbidity index 2 (1, 4) versus 3 (1, 5); P = 0.002] and were more acutely ill (Pitt bacteraemia score ≥4: 47% versus 32%; P < 0.001). The probability of a better DOOR outcome in a randomly selected patient with CO BSI compared to a patient with HO BSI was 60.6% (95% CI: 56.8%-64.3%). Mortality at 30-days was 12% higher in HO BSI (192/582; 33%) than CO BSI [66/309 (21%); P < 0.001]., Conclusion: We found a disproportionately greater impact on patient outcomes with HO compared to CO CRE BSIs; thus, the recently reported increases in HO CRE infections by CDC requires rigorous surveillance and infection prevention methods to prevent added mortality., (© 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: Use of anti-carbapenem-resistant Enterobacterales (anti-CRE) agents such as ceftazidime/avibactam has been associated with improved clinical outcome in cohorts that primarily include patients infected with CRE that are resistant to meropenem (MCRE)., Objectives: To clarify whether patients with CRE resistant to ertapenem but susceptible to meropenem (ertapenem-only-resistant Enterobacterales; EORE) benefit from therapy with anti-CRE agents., Methods: Patients treated for CRE infection in hospitals in the USA between 2016 and 2019 and enrolled in the CRACKLE-2 study were included. The primary outcome was the desirability of outcome ranking (DOOR) assessed at 30 days after index cultures., Results: The EORE group included 213 patients and the MCRE group included 643. The demographics were similar between the groups except for the patients' race and origin before admission. The MCRE group received anti-CRE agents for definitive therapy significantly more frequently compared with the EORE group (30% versus 5% for ceftazidime/avibactam). We did not observe a significant difference between the groups in the adjusted DOOR probability of a more desirable outcome for a randomly selected patient in the EORE group compared with the MCRE group (52.5%; 95% CI, 48.3%-56.7%). The MCRE group had a similar proportion of patients who died at 30 days (26% versus 21%) and who were discharged to home (29% versus 40%), compared with the EORE group., Conclusions: Patients with clinical EORE infection rarely received anti-CRE agents, but attained similar outcomes compared with patients with MCRE infection. The findings support current IDSA treatment guidance for meropenem- or imipenem-based therapy for treatment of EORE infections., (© 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: Carbapenem-resistant Enterobacterales (CRE) are an urgent public health threat in the United States., Objective: Describe the clinical and molecular epidemiology of CRE in a multicenter pediatric cohort., Methods: CRACKLE-1 and CRACKLE-2 are prospective cohort studies with consecutive enrollment of hospitalized patients with CRE infection or colonization between 24 December 2011 and 31 August 2017. Patients younger than age 18 years and enrolled in the CRACKLE studies were included in this analysis. Clinical data were obtained from the electronic health record. Carbapenemase genes were detected using polymerase chain reaction and whole-genome sequencing., Results: Fifty-one children were identified at 18 healthcare system study sites representing all U.S. census regions. The median age was 8 months, with 67% younger than age 2 years. Median number of days from admission to culture collection was 11. Seventy-three percent of patients had required intensive care and 41% had a history of mechanical ventilation. More than half of children had no documented comorbidities (Q1, Q3 0, 2). Sixty-seven percent previously received antibiotics during their hospitalization. The most common species isolated were Enterobacter species (41%), Klebsiella pneumoniae (27%), and Escherichia coli (20%). Carbapenemase genes were detected in 29% of isolates tested, which was lower than previously described in adults from this cohort (61%). Thirty-four patients were empirically treated on the date of culture collection, but only 6 received an antibiotic to which the CRE isolate was confirmed susceptible in vitro. Thirty-day mortality was 13.7%., Conclusions: CRE infection or colonization in U.S. children was geographically widespread, predominantly affected children younger than age 2 years, associated with significant mortality, and less commonly caused by carbapenemase-producing strains than in adults., Competing Interests: Potential conflicts of interest. Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number UM1AI104681. W. C. H. is a member of an endpoint adjudication committee for Pfizer and has served as an advisory board member for ADMA Biologics. He has common stock in Pfizer, Bristol Meyers Squibb, and Zimmer Biomet. D. v. D. was supported by R01AI143910 from NIAID. B. C. F. was supported by US Veterans Affairs Merit Review Award 5I01 BX00374. She is an attending at the U.S. Department of Veterans Affairs—Northport VA Medical Center, Northport, NY. D. v. D. has received personal fees from Achaogen, Allergan, Astellas, Neumedicine, T2biosystems, Roche, Merck, Karius, Entasis, Wellspring, Qpex, Pfizer, Utility, and Union; they are all outside the submitted work. The contents is solely the responsibility of the authors and does not represent the views of the National Institute of Health, the VA, or the United States Government. All other authors report no potential conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P . aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP 8 ), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P . aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development., Competing Interests: The material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting true views of the Department of the Army, the Department of Defense, or the National Institutes of Health. R.P. reports grants from ContraFect, TenNor Therapeutics Limited, and BioFire and is a onsultant to Curetis, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, and Qvella; monies are paid to Mayo Clinic. Mayo Clinic and R.P. have a relationship with Pathogenomix. R.P. has research supported by Adaptive Phage Therapeutics (APT). Mayo Clinic has a royalty-bearing know-how agreement and equity in APT. R.P. is also a consultant to Netflix, Abbott Laboratories, Oxford Nanopore Technologies, and CARB-X. In addition, R.P. has a patent on Bordetella pertussis/Bordetella parapertussis PCR issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued. R.P. receives honoraria from the NBME, Up-to-Date, and the Infectious Diseases Board Review Course. M.N., A.F., and Walter Reed Army Institute of Research have a royalty-bearing licensing agreement with APT. J.R.F, M.L, A.N. and P.A. are employees at APT.

Developing and implementing the scientific agenda of the Antibacterial Resistance Leadership Group (ARLG) by soliciting input and proposals, transforming concepts into clinical trials, conducting those trials, and translating trial data analyses into actionable information for infectious disease clinical practice is the collective role of the Scientific Leadership Center, Clinical Operations Center, Statistical and Data Management Center, and Laboratory Center of the ARLG. These activities include shepherding concept proposal applications through peer review; identifying, qualifying, training, and overseeing clinical trials sites; recommending, developing, performing, and evaluating laboratory assays in support of clinical trials; and designing and performing data collection and statistical analyses. This article describes key components involved in realizing the ARLG scientific agenda through the activities of the ARLG centers., Competing Interests: Potential conflicts of interest. All authors report funding support to the Antibacterial Resistance Leadership Group (ARLG) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) (UM1AI104681). H. R. C., M. S., and H. S. G. report salary support from the ARLG via Duke University. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and the Japanese Journal of Cancer and Chemotherapy Publishers, Inc. H. F. C. reports royalties from the Sanford Guide to Antimicrobial Therapy, payment for expert testimony from Nexus Pharmaceuticals, participation on a Merck data safety monitoring board for molnupiravir, and stock ownership in Moderna and Merck. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Company, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer (paid to author); grants from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for service as associate editor of Clinical Infectious Diseases; travel support from ContraFect to the 2019 European Congress of Clinical Microbiology and Infectious Diseases; and a sepsis diagnostics patent pending. S. R. E. reports grants from the National Institute of Allergy and Infectious Diseases and the NIH and De Gruyter (as editor-in-chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, the International Drug Development Institute, SVB Leerink, Medtronic, Regeron, Wake Forest University, Recor, Janssen, and IDDI; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, Breast International Group, the University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis, the American Statistical Association, Society for Clinical Trials, and the Frontier Science Foundation. R. P. reports grants or contracts from ContraFect, TenNor Therapeutics, BIOFIRE, and Adaptive Phage Therapeutics; a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics through the Mayo Clinic; consulting fees from PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, HealthTrackRx, Netflix, Abbott Laboratories, Trellis Bioscience, Oxford Nanopore Technologies, and CARB-X; honoraria from the National Board of Medical Examiners, Up-to-Date, and the Infectious Diseases Board Review Course; a patent on Bordetella pertussis/parapertussis polymerase chain reaction issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued; and a financial relationship with Pathogenomix through the Mayo Clinic. 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.)

Addressing the treatment and prevention of antibacterial-resistant gram-negative bacterial infections is a priority area of the Antibacterial Resistance Leadership Group (ARLG). The ARLG has conducted a series of observational studies to define the clinical and molecular global epidemiology of carbapenem-resistant and ceftriaxone-resistant Enterobacterales, carbapenem-resistant Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter baumannii, with the goal of optimizing the design and execution of interventional studies. One ongoing ARLG study aims to better understand the impact of fluoroquinolone-resistant gram-negative gut bacteria in neutropenic patients, which threatens to undermine the effectiveness of fluoroquinolone prophylaxis in these vulnerable patients. The ARLG has conducted pharmacokinetic studies to inform the optimal dosing of antibiotics that are important in the treatment of drug-resistant gram-negative bacteria, including oral fosfomycin, intravenous minocycline, and a combination of intravenous ceftazidime-avibactam and aztreonam. In addition, randomized clinical trials have assessed the safety and efficacy of step-down oral fosfomycin for complicated urinary tract infections and single-dose intravenous phage therapy for adult patients with cystic fibrosis who are chronically colonized with P. aeruginosa in their respiratory tract. Thus, the focus of investigation in the ARLG has evolved from improving understanding of drug-resistant gram-negative bacterial infections to positively affecting clinical care for affected patients through a combination of interventional pharmacokinetic and clinical studies, a focus that will be maintained moving forward., Competing Interests: Potential conflicts of interest. All authors report funding support from the Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; grant UM1AI104681). M. J. S. reports grants or contracts from Merck, bioMérieux, SNIPRBiome, and Selux Diagnostics; consulting fees from Shionogi; and participation on a data safety monitoring board (DSMB) for AbbVie. D. v. D. reports grants or contracts from Merck; consulting fees from Utility, Shionogi, Merck, Union, Roche, and Qpex; payment or honoraria from Pfizer, Entasis, and Clinical Care Options; participation on an advisory board for Universidade Federal do Rio Grande do Sul; and leadership in the British Society of Antimicrobial Chemotherapy. K. A. R. reports royalties from Springer Nature Group (textbook royalties); consulting fees, outside the submitted work, as an advisory board member for Shionogi, Qpex Biopharma/Medicines, and Utility Therapeutics and a consultant for Pulmatrix, BugsResearch, Clinartis, Spero Therapeutics, Qpex Biopharma/Medicines, Genetech, Utility Therapeutics, Venatorx, Chimerix, and Debiopharm; payment or honoraria from Shionogi (speaker bureau) and Biri Bioscience (presentation/speaker); participation on a DSMB, outside the submitted work, for Janssen Pharmaceutical; voting membership on the National Antimicrobial Susceptibility Testing Committee for the United States; and membership in the Antimicrobial Stewardship Curriculum Workgroup of the Infectious Diseases Society of America. N. R. reports grants or contracts from Merck, Sanofi, Pfizer, Quidel, and Lilly; consulting fees from Krog; payment or honoraria from Virology Education; travel support from Sanofi; participation on a DSMB or advisory board for Moderna, Sanofi, EMMES, ICON, and Seqirus; advisory roles with the Antibacterial Resistance Leadership Group, Tropical Medicine Research Center (TMRC), Centers for Disease Control and Prevention (CDC), and Pertussis Challenge; an associate editor role with Clinical Infectious Diseases; and receipt of equipment, materials, drugs, medical writing, gifts or other services from the Georgia Research Alliance. S. R. E. reports grants from the NIAID, the NIH and De Gruyter (as editor-in-chief for Statistical Communications in Infectious Diseases), the National Cancer Institute/NIH, and the CDC; royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and IDDI; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. V. G. F. reports personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Company, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer (all paid to author); grants from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; stock options from Valanbio and ArcBio; honoraria from the Infectious Diseases Society of America for service as associate editor of Clinical Infectious Diseases; travel support from ContraFect to 2019 ECCMID; and a sepsis diagnostics patent pending. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and honoraria from Duke University and Cancer and Chemo Therapy. R. P. reports grants or contracts from ContraFect, TenNor Therapeutics Limited, BIOFIRE, and Adaptive Phage Therapeutics; a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics through the Mayo Clinic; consulting fees from PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, HealthTrackRx, Netflix, Abbott Laboratories, Trellis Bioscience, Oxford Nanopore Technologies, and CARB-X; honoraria from the NBME, Up-to-Date, and the Infectious Diseases Board Review Course; a patent on Bordetella pertussis/parapertussis polymerase chain reaction issued, a patent on a device/method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an antibiofilm substance issued; and a financial relationship with Pathogenomix through the Mayo Clinic. N. S. reports grant funding from Duke University, the NIH, and the Antibacterial Resistance Leadership Group. R. A. B. reports grants and contracts from VenatoRx, Wockhardt, and Merck; payments from Pfizer to moderate meeting sessions; a provisional patent with Case Western Reserve University on the development of boronic acid transition state inhibitors for β-lactamases; and participation on a DSMB as a logistics associate for DMID-CROMS, Safety Oversight Committee Support, and Technical Resources International. Y. D. reports grants from Entasis and Shionogi; consulting fees from GSK, Moderna, Meiji Seika Pharma, Shionogi, Gilead, FujiFilm, and bioMérieux; and speaker payments from MSD, Shionogi, and Gilead. 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.)

The advancement of infectious disease diagnostics, along with studies devoted to infections caused by gram-negative and gram-positive bacteria, is a top scientific priority of the Antibacterial Resistance Leadership Group (ARLG). Diagnostic tests for infectious diseases are rapidly evolving and improving. However, the availability of rapid tests designed to determine antibacterial resistance or susceptibility directly in clinical specimens remains limited, especially for gram-negative organisms. Additionally, the clinical impact of many new tests, including an understanding of how best to use them to inform optimal antibiotic prescribing, remains to be defined. This review summarizes the recent work of the ARLG toward addressing these unmet needs in the diagnostics field and describes future directions for clinical research aimed at curbing the threat of antibiotic-resistant bacterial infections., Competing Interests: Potential conflicts of interest. All authors report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681). K. E. H. reports holding leadership roles with ARLG as the Diagnostics Committee Chair and Study Principal Investigator (PI), the Clinical and Laboratory Standards Institute (CLSI) as an advisor, Journal of Clinical Microbiology (JCM) as a Mycology Section Editor, and Clinical Infectious Diseases as a Deputy Editor. S. B. D. reports grants or contracts from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees from Genentech and Janssen/J+J; support from the Infectious Diseases Society of America (IDSA) for travel to speak at IDWeek; patent US20100143379A1 for Mif agonists and antagonist and therapeutic uses thereof; leadership on the IDSA Antibacterial Resistance Committee, Healthcare-Associated Infection Advisory Committee for the California Department of Public Health, Antibacterial Resistance Leadership Group (ARLG) Innovations Group, ARLG Laboratory Center, ARLG Mentorship Committee, ARLG Gram-positive Committee, and ARLG Immunosuppressed Host Group; and payment to her institution from Shinogi, Basilea, and the Duke Clinical Research Institute for clinical events committee/adjudication committee participation. S. R. E. reports grants from the NIAID/NIH, National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI), Centers for Disease Control and Prevention (CDC), and Degruter (Editor-in-Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, Medtronic, Regeneron, Wake Forest University, Recor, Janssen, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organizations of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, Breast International Group, University of Pennsylvania, Washington University, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, Abbvie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, Novartis, American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. M. J. S. reports grants and contracts from Merck, Biomerieux, SNIPRBiome, and Selux Diagnostics; consulting fees from Shionogi; and participation on a Data and Safety Monitoring Board or Advisory Board for AbbVie. P. J. S. reports grants or contracts from BD Diagnostics, T2 Diagnostics, OpGen, Inc, Affinity Biosensors, and Qiagen Sciences, Inc; consulting fees from OpGen, Inc, Entasis, BD Diagnostics, Merck, Qiagen Sciences, Inc, and Shionogi; payment or honoraria from GenMark Dx, OpGen, Inc, and BD Diagnostics; leadership on the ARLG Diagnostics Committee, Clinical and Laboratory Standards Institute Antimicrobial Susceptibility Testing Subcommittee, and College of American Pathologists Microbiology Committee; and stock in GeneCapture. R. P. reports grants or contracts from ContraFect, TenNor Therapeutics Limited, BIOFIRE, and Adaptive Phage Therapeutics; a royalty-bearing know-how agreement and equity in Adaptive Phage Therapeutics through the Mayo Clinic; consulting fees from PhAST, Torus Biosystems, Day Zero Diagnostics, Mammoth Biosciences, HealthTrackRx, Netflix, Abbott Laboratories, Trellis Bioscience, Inc, Oxford Nanopore Technologies, and CARB-X; honoraria from the National Board of Medical Examiners (NBME), Up-to-Date, and the Infectious Diseases Board Review Course; a patent on Bordetella pertussis/parapertussis polymerase chain reaction (PCR) issued, a patent on a device/method for sonication with royalties paid by Samsung to Mayo Clinic, and a patent on an anti-biofilm substance issued; and a financial relationship with Pathogenomix through the Mayo Clinic. 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.)

Rapid detection of Klebsiella pneumoniae carbapenemase (KPC) in the Klebsiella species is desirable. The MALDI Biotyper ® MBT Subtyping Module (Bruker Daltonics) uses an algorithm that detects a peak at ~11,109 m/z corresponding to a protein encoded by the p019 gene to detect KPC simultaneously with organism identification by a matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-ToF MS). Here, the subtyping module was evaluated using 795 clinical Klebsiella isolates, with whole genome sequences used to assess for bla KPC and p019 . For the isolates identified as KPC positive by sequencing, the overall sensitivity of the MALDI-ToF MS subtyping module was 239/574 (42%) with 100% specificity. For the isolates harboring p019 , the subtyping module showed a sensitivity of 97% (239/246) and a specificity of 100%. The subtyping module had poor sensitivity for the detection of bla KPC -positive Klebsiella isolates, albeit exhibiting excellent specificity. The poor sensitivity was a result of p019 being present in only 43% of the bla KPC -positive Klebsiella isolates.

Background: Carbapenemase-producing (CP) Escherichia coli (CP-Ec) are a global public health threat. We aimed to describe the clinical and molecular epidemiology and outcomes of patients from several countries with CP-Ec isolates obtained from a prospective cohort., Methods: Patients with CP-Ec were enrolled from 26 hospitals in 6 countries. Clinical data were collected, and isolates underwent whole-genome sequencing. Clinical and molecular features and outcomes associated with isolates with or without metallo-β-lactamases (MBLs) were compared. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after the index culture., Results: Of the 114 CP-Ec isolates in Consortium on resistance against carbapenems in Klebsiella and other Enterobacterales-2 (CRACKLE-2), 49 harbored an MBL, most commonly blaNDM-5 (38/49, 78%). Strong regional variations were noted with MBL-Ec predominantly found among patients in China (23/49). Clinically, MBL-Ec were more often from urine sources (49% vs 29%), less often met criteria for infection (39% vs 58%, P = .04), and had lower acuity of illness when compared with non-MBL-Ec. Among patients with infection, the probability of a better DOOR outcome for a randomly selected patient with MBL-Ec as compared with non-MBL-Ec was 62% (95% CI: 48.2-74.3%). Among infected patients, non-MBL-Ec had increased 30-day (26% vs 0%; P = .02) and 90-day (39% vs 0%; P = .001) mortality compared with MBL-Ec., Conclusions: Emergence of CP-Ec was observed with important geographic variations. Bacterial characteristics, clinical presentations, and outcomes differed between MBL-Ec and non-MBL-Ec. Mortality was higher among non-MBL isolates, which were more frequently isolated from blood, but these findings may be confounded by regional variations., Competing Interests: Potential conflicts of interest. All authors report funding support from the Antibacterial Resistance Leadership Group (ARLG) of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. Additionally, during the conduct of this study, A. E. B. reports funding from the Unified Program for Therapeutics in Children (UPTiC) [1T32HD094671-01A1] from the Eunice Kennedy Shriver National institute of child health and human development. Outside of the submitted work, the authors report the following disclosures: S. S. K. reports speaker and/or advisory board payments from Pfizer, Astellas, Novartis, Merck, Menarini, and Gilead, and honoraria from UpToDate. A. E. B. reports grants or contracts from the NIH–NIAID Loan Repayment Program and Thrasher Research Foundation. B. H. reports NIH/NIAID grant K01AI148593-01 (paid to their institution). K. O. reports payments for educational events and presentations from Pfizer, MSD, and AstraZeneca; payment or honoraria from BioMerieux and Farma de Colombia; meeting support from AstraZeneca, Pfizer, MSD, and Gilead; expert testimony support from Pfizer, bioMerieux, and MSD; and payment for participation on a Data Safety and Monitoring Board (DSMB) from Pfizer. S. E. reports a Centers for Disease Control and Prevention (CDC) grant; NIH grants from the NIAID, the National Cancer Institute (NCI), and the National Heart, Lung, and Blood Institute (NHLBI); a contract with Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink, Medtronic, Regeneron, and Wake Forest University (all paid to the author); honorarium payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); honoraria from the US Food and Drug Administration, the Deming Conference on Applied Statistics, and the International Chinese Statistical Association Applied Statistics Symposium; travel support from the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, and the Antimicrobial Resistance and Stewardship Conference; and Data Safety Monitoring or Advisory Board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, and Novartis (all payments made to the author); and unpaid Board membership with the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. R. A. B. reports grants and contracts, paid to his institution, by VenatoRx, Wockhardt, and Merck; payments made to him by Pfizer to moderate meeting sessions; a patent with Case Western Reserve University on the development of boronic acid transition state inhibitors for beta-lactamases; payment for participation on a DSMB, Safety Oversight Committee Support (SOCS), and Logistics Associate for Division of Microbiology and Infectious Diseases - Clinical Research Operations And Management Support (DMID-CROMS) (Contractor), with Technical Resources International, Inc (TRI). R. P. reports grants from BIOFIRE, ContraFect, Adaptive Phage Therapeutics, and TenNor Therapeutics Limited; is a consultant to Curetis, Specific Technologies, Abbott Laboratories, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Day Zero Diagnostics, Torus Biosystems, Mammoth Biosciences, HealthTrackRx, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix and CARB-X; has a patent on Bordetella pertussis (parapertussis) polymerase chain reaction (PCR) issued, a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an anti-biofilm substance issued; receives an editor's stipend from the Infectious Diseases Society of America (IDSA); and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course; other interests paid to her institution include Adaptive Phase Therapeutics and Pathogenomix. D. L. P. serves on the Scientific Advisory Board of the Antibiotic Action Fund and a Data Safety Monitoring or Advisory Board for Symvivo; has grant funding from Shionogi, Pfizer, and Merck; reports consulting fees (paid to the author) from Merck, Shinogi, Qpex, and Spero Therapeutics; payment or honoraria (paid to the author) for speaking engagements from Sumitomo, Merck, Pfizer, and bioMerieux; travel support from Shinogi (paid to the author); and serves on advisory boards or has given lectures for Pfizer, Merck, bioMerieux, Zuellig, Entasis, QPex, and VenatoRx. C. A. A. reports the following grants and contracts paid to his institution: NIH/NIAID 1 P01 AI152999, NIH/NIAID R01 AI148342, NIH/NIAID R01 AI134637, NIH/NIAID T32 AI141349, NIH/NIAID K24 AI121296, NIH/NIAID U19 AI144297, NIH/NIAID R01 AI150685, NIH/NIAID R21 AI151536, and support from MeMed Diagnostics Ltd, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; payments to him for UpToDate royalties; reimbursement for meeting attendance for speaking engagements from IDSA, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, bioMerieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, and Brazilian Society for Infectious Diseases; reviewer participation as part of the NIH Grant Review Study Sections; travel expenses from the IDSA Board of Directors; honoraria as Editor-in-Chief for Antimicrobial Agents and Chemotherapy; and nonpaid participation in the World Health Organization Antibacterial Pipeline Advisory Group and the IDSA Board of Directors. H. F. C. reports royalties from serving as Senior Editor on the Sanford Guide to Antimicrobial Therapy; payment for expert testimony from Nexus Pharmaceuticals for patent litigation and from Eli Lilly for product liability; participation on a Merck DSMB for Molnuprivir paid directly to him, and stock ownership in Moderna and Merck. V. G. F. reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advance, Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal consulting fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from IDSA; a pending patent for a host gene expression signature diagnostic for sepsis; and stock options with Valanbio and ArcBio. D. v. D. reports grants or contracts with NIH and Merck (paid to their institution); grants or contracts with Shionogi (paid to the author); consulting fees from Actavis, Tetraphase, Sanofi-Pasteur, Medimmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, Qpex, Wellspring, Karius, Utility, and Union (all paid to the author); payment or honoraria for speaking engagements from Pfizer; and an editor's stipend from the British Society for Antimicrobial Chemotherapy., (© 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.)

Background: Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the distribution and clinical significance of carbapenemases are unclear. The aim of this study was to define characteristics and outcomes of CRPA infections and the global frequency and clinical impact of carbapenemases harboured by CRPA., Methods: We conducted an observational, prospective cohort study of CRPA isolated from bloodstream, respiratory, urine, or wound cultures of patients at 44 hospitals (10 countries) between Dec 1, 2018, and Nov 30, 2019. Clinical data were abstracted from health records and CRPA isolates were whole-genome sequenced. The primary outcome was 30-day mortality from the day the index culture was collected. We compared outcomes of patients with CRPA infections by infection type and across geographic regions and performed an inverse probability weighted analysis to assess the association between carbapenemase production and 30-day mortality., Findings: We enrolled 972 patients (USA n=527, China n=171, south and central America n=127, Middle East n=91, Australia and Singapore n=56), of whom 581 (60%) had CRPA infections. 30-day mortality differed by infection type (bloodstream 21 [30%] of 69, respiratory 69 [19%] of 358, wound nine [14%] of 66, urine six [7%] of 88; p=0·0012) and geographical region (Middle East 15 [29%] of 52, south and central America 20 [27%] of 73, USA 60 [19%] of 308, Australia and Singapore three [11%] of 28, China seven [6%] of 120; p=0·0002). Prevalence of carbapenemase genes among CRPA isolates also varied by region (south and central America 88 [69%] of 127, Australia and Singapore 32 [57%] of 56, China 54 [32%] of 171, Middle East 27 [30%] of 91, USA ten [2%] of 527; p<0·0001). KPC-2 (n=103 [49%]) and VIM-2 (n=75 [36%]) were the most common carbapenemases in 211 carbapenemase-producing isolates. After excluding USA patients, because few US isolates had carbapenemases, patients with carbapenemase-producing CRPA infections had higher 30-day mortality than those with non-carbapenemase-producing CRPA infections in both unadjusted (26 [22%] of 120 vs 19 [12%] of 153; difference 9%, 95% CI 3-16) and adjusted (difference 7%, 95% CI 1-14) analyses., Interpretation: The emergence of different carbapenemases among CRPA isolates in different geographical regions and the increased mortality associated with carbapenemase-producing CRPA infections highlight the therapeutic challenges posed by these organisms., Funding: National Institutes of Health., Competing Interests: Declaration of interests All authors report funding support from the Antibacterial Resistance Leadership Group of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. Additionally, during the conduct of this study, and outside of the submitted work, the authors report the following disclosures. KSK reports consulting fees paid directly to him by Merck, Shionogi, Qpex, and Micrux. JG-D reports grants and contracts paid to her institution from NIH, BARDA, Janssen Research & Development LLC, Pfizer, BioNTech SE, GCAR, Hoffman La-Roche, I-Mab Bioppharma, Rebiotix, Target Health, LLC OBO Lilly USA, GlaxoSmithKline, Summit Limited, Cidara Therapeutics, Merck Sharp & Dohme, Seres Therapeutics; and Infectious Diseases Society of America Research Committee participation paid to her directly. SSK reports speaker and advisory board payments from Pfizer, Astellas, Novartis, Merck, and Gilead. JMO reports speaker payments from Pfizer, MSD, and Biotoscana; and board participation on the Chair Ethics Committee. SLV-B reports personal fees from Pfizer, Biotoscana, and MSD; meeting support from MSD and Pfizer; and data safety monitoring board participation with MSD and GlaxoSmithKline. PT reports honoraria payments to his institution from Aj Biologics and bioMérieux. GW reports payment to his institution from Allergan for contracted activities. LMA reports grants and contracts paid to her institution from Rainmakers/CDC multisystem inflammatory syndrome in adults with SARS-CoV-2, and Regeneron study co-investigator; consulting and honoraria paid directly to them from Medscape for CME lectures, and Ferring Pharmaceuticals for advisory board participation; and volunteer work as the director of the IDSA Board of Directors. KO reports payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; meeting support from Pfizer, MSD, and Gilead; and expert testimony support from Pfizer, bioMérieux, and MSD. MES reports speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; consultancy for Basilea; and data safety monitoring board participation with Fulcrum Therapeutics. JMM reports grants from Pfizer, MSD, and bioMérieux, the National Fund for Scientific and Technological Development; and the Agencia Nacional de Investigation y Desarrollo Millennium Science Initiative/Millennium Initiative for Collaborative Research on Bacterial Resistance, Government of Chile. DLP reports grants and contracts paid to his institution from Merck, Pfizer, and Shionogi; consulting and honoraria payments to him by Merck, Shionogi, QPex, Spero Therapeutics, Sumitomo, Pfizer, and bioMérieux; meeting support from Shionogi; and board and committee participation with Symvivo, and AMR action fund. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. RAB reports grants and contracts, paid to his institution, by VenatoRx, Wockhardt, and Merck; payments made to him by Pfizer to moderate meeting sessions; patents with Case Western Reserve University on the development of boronic acid transition state inhibitors for β-lactamases (WO2022187362A1, US9949995B2, and US20170252326A1); and payment for participation on a data safety monitoring board, safety oversight committee support, and Logistics Associate for DMID-CROMS (contractor) with Technical Resources International. MVV reports contracts, consulting fees, and honoraria payments from Pfizer and MSD; consulting fees from West Quimica Colombia; and honoraria from bioMérieux. RP reports grants from BioFire Diagnostics, ContraFect, and TenNor Therapeutics; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Day Zero Diagnostics, Torus Biosystems, Mammoth Biosciences, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix and CARB-X; has a patent on Bordetella pertussis and parapertussis PCR issued (US8507201B2), a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic; US7076117B2), and a patent on an anti-biofilm substance issued (US8802414B2); receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course. CAA reports the grants and contracts paid to his institution from NIH and NIAID, MeMed Diagnostics, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; payments to him for UpToDate royalties, reimbursement of meeting attendance, and speaking from Infectious Diseases Society of America, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, bioMérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, Brazilian Society for Infectious Diseases, reviewer participation as part of the NIH grant Review Study Sections, travel expenses from the Infectious Disease Society of America (IDSA) Board of Directors, and for Editor in Chief for Antimicrobial Agents and Chemotherapy; non-paid participation with WHO Antibacterial Pipeline Advisory Group; and participation on the IDSA Board of Directors. HFC reports participation on a Merck data safety monitoring board for molnupiravir paid directly to him, stock ownership in Moderna and Merck, and a position as expert witness for Lilly and Nexus Pharmaceuticals. VGF reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, ContraFect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, Medicines, MedImmune, Bayer, Basilea, Affinergy, Janssen, ContraFect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from Infectious Diseases of America; pending patent for a host gene expression signature diagnostic for sepsis (US9850539B2); and stock options with Valanbio and ArcBio. YD reports grants from Entasis, Asahi Kasei Pharma, Shionogi, and Kanto Chemical paid to his institution; consulting fees paid directly to him from Meiji Seika Pharma, Shionogi, Gilead, MSD, Chugai, and bioMérieux; and speaker payments from MSD, Shionogi, AstraZeneca, Teijin Healthcare, Gilead, FujiFilm Toyama Chemical, bioMerieux, HU Frontier, and Eiken Chemical paid to him. DvD reports grants and contracts from the NIH and Merck paid to his institution outside of the published work; and consultancy for Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, and Karius. MJS reports contract payments to his institution from Merck, Allergan, BioFire Diagnostics, Affinity Biosensors, and SNIPRBiome; personal consulting fees from Shionogi; and data and safety monitoring board participation for Spero Therapeutics., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: The WHO recommended 1200mg/day of fluconazole (FCZ) in the induction phase of cryptococcal meningitis (CM) in HIV prior to 2018 in regions where amphotericin-B (AMB) was unavailable. A 2-stage AMB-controlled, dose-escalation study to determine the maximum tolerated dose and the safety/efficacy of an induction-consolidation strategy of higher doses FCZ (1200mg-2000mg/day), adjusted for weight and renal function (eGFR)in adults with CM was undertaken., Methods: In Stage-1, three induction doses of FCZ (1200mg/day, 1600mg/day and 2000mg/day) were tested in sequential cohortsand compared with AMB in a 3:1 ratio. A particular dose was not tested in Stage 2 if there were significant predetermined safety or efficacy concerns. In Stage-2, the 1200mg dose was excluded per protocol because of increased mortality, and participants were randomised to 1600mg, 2000mg FCZ or AMB in a 1:1:1 ratio., Findings: One hundred and sixty eight participants were enrolled with 48, 50, and 48 in the AMB, 1600mg and 2000mg cohorts. The Kaplan Meier proportion for mortality (90% CI) at 10 and 24 weeks for AMB was 17% (10, 29) and 24% (15, 37), compared to 20% (12, 32) and 30% (20, 43) for 1600mg, and 33% (23, 46) and 38% (27, 51) for 2000mg/day FCZ. With the exception of a higher incidence of gastrointestinal side effects in the 2000mg cohort, both induction doses of FCZ were safe and well tolerated. There were no life-threatening changes in electrocardiogram QTc which were similar across all doses of FCZ and AMB. The median (IQR) change in log10 cryptoccal colony forming units (CFU) from week 0 to week 2 was -8(-4.1,-1.9) for AMB; -2.5(-4.0, -1.4) for 1600mg FCZ and -8 (-3.2, -1.0) for 2000mg FCZ. The proportion (90% CI) CSF CM negative at 10 weeks was 81%(71,90) for AMB; 56%(45,69) for 1600mg FCZ and 60%(49,73) for 2000mg FCZ., Interpretation: Induction phase weight and renal-adjusted doses of 1600mg and 2000mg/day FCZ for CM were safe and well tolerated except for increased GI side effects in the 2000mg/day dose, and had similar times to achieve CSF sterilization, but took significantly longer than AMB. The WHO recommended 1200mg FCZ was associated with a high mortality. While not statistically significant, mortality was numerically lower in the AMB compared to 1600mg and 2000mg FCZ These data make a case for a phase 3 study of higher doses of FZC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Lalloo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKp) is the most prevalent carbapenem-resistant Enterobacterales in the United States. We evaluated CRKp clustering in patients in US hospitals., Methods: From April 2016 to August 2017, 350 patients with clonal group 258 CRKp were enrolled in the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae, a prospective, multicenter, cohort study. A maximum likelihood tree was constructed using RAxML. Static clusters shared ≤21 single-nucleotide polymorphisms (SNP) and a most recent common ancestor. Dynamic clusters incorporated SNP distance, culture timing, and rates of SNP accumulation and transmission using the R program TransCluster., Results: Most patients were admitted from home (n = 150, 43%) or long-term care facilities (n = 115, 33%). Urine (n = 149, 43%) was the most common isolation site. Overall, 55 static and 47 dynamics clusters were identified involving 210 of 350 (60%) and 194 of 350 (55%) patients, respectively. Approximately half of static clusters were identical to dynamic clusters. Static clusters consisted of 33 (60%) intrasystem and 22 (40%) intersystem clusters. Dynamic clusters consisted of 32 (68%) intrasystem and 15 (32%) intersystem clusters and had fewer SNP differences than static clusters (8 vs 9; P = .045; 95% confidence interval [CI]: -4 to 0). Dynamic intersystem clusters contained more patients than dynamic intrasystem clusters (median [interquartile range], 4 [2, 7] vs 2 [2, 2]; P = .007; 95% CI: -3 to 0)., Conclusions: Widespread intrasystem and intersystem transmission of CRKp was identified in hospitalized US patients. Use of different methods for assessing genetic similarity resulted in only minor differences in interpretation., (© 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: Bacteriophages (phages) are a promising anti-infective option for human disease. Major gaps remain in understanding their potential utility., Methods: This is a randomized, placebo-controlled, double-blind study of a single dose of intravenous phage in approximately 72 clinically stable adult cystic fibrosis volunteers recruited from up to 20 US sites with Pseudomonas aeruginosa airway colonization. The single dose of phage consists of a mixture of four anti-pseudomonal phages. Six sentinel participants will be sequentially enrolled with dose escalation of the phage mixture by one log 10 beginning with 4 × 10 7 plaque-forming units in an unblinded stage 1. If no serious adverse events related to the study product are identified, the trial will proceed to a double-blinded stage 2. In stage 2a, 32 participants will be randomly assigned to one of three phage dosages or placebo in a 1:1:1:1 allocation. An interim analysis will be performed to determine the phage dosage with the most favorable safety and microbiological activity profile to inform phage dosing in stage 2b. During stage 2b, up to 32 additional volunteers will be randomized 1:1 to the phage or placebo arm. Primary outcomes include (1) the number of grade 2 or higher treatment-emergent adverse events, (2) change in log 10 P. aeruginosa total colony counts in sputum, and (3) the probability of a randomly selected subject having a more favorable outcome ranking if assigned to receive phage therapy versus placebo. Exploratory outcomes include (1) sputum and serum phage pharmacokinetics, (2) the impact of phage on lung function, (3) the proportion of P. aeruginosa isolates susceptible to the phage mixture before and after study product administration, and (4) changes in quality of life., Discussion: This trial will investigate the activity of phages in reducing P. aeruginosa colony counts and provide insights into the safety profile of phage therapy., Trial Registration: ClinicalTrials.gov NCT05453578. Registered on 12 July 2022., (© 2022. The Author(s).)

Objectives: To describe the epidemiology of patients with nonintestinal carbapenem-resistant Enterobacterales (CRE) colonization and to compare clinical outcomes of these patients to those with CRE infection., Design: A secondary analysis of Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae 2 (CRACKLE-2), a prospective observational cohort., Setting: A total of 49 US short-term acute-care hospitals., Patients: Patients hospitalized with CRE isolated from clinical cultures, April, 30, 2016, through August 31, 2017., Methods: We described characteristics of patients in CRACKLE-2 with nonintestinal CRE colonization and assessed the impact of site of colonization on clinical outcomes. We then compared outcomes of patients defined as having nonintestinal CRE colonization to all those defined as having infection. The primary outcome was a desirability of outcome ranking (DOOR) at 30 days. Secondary outcomes were 30-day mortality and 90-day readmission., Results: Of 547 patients with nonintestinal CRE colonization, 275 (50%) were from the urinary tract, 201 (37%) were from the respiratory tract, and 71 (13%) were from a wound. Patients with urinary tract colonization were more likely to have a more desirable clinical outcome at 30 days than those with respiratory tract colonization, with a DOOR probability of better outcome of 61% (95% confidence interval [CI], 53%-71%). When compared to 255 patients with CRE infection, patients with CRE colonization had a similar overall clinical outcome, as well as 30-day mortality and 90-day readmission rates when analyzed in aggregate or by culture site. Sensitivity analyses demonstrated similar results using different definitions of infection., Conclusions: Patients with nonintestinal CRE colonization had outcomes similar to those with CRE infection. Clinical outcomes may be influenced more by culture site than classification as "colonized" or "infected."

Background: Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common., Methods: This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding., Results: Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P = .079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1-35 hours] vs 1 hour [IQR, 0-6 hours]; P < .001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%-63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%-61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (-5.3% [95% CI, -10.3% to -.4%] and -1.8 [95% CI, -6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5-13 days] vs 6 days [IQR, 4-9 days]; P < .001), and incident admission to a long-term care facility (22% vs 12%, P = .045)., Conclusions: Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders., Competing Interests: Potential conflicts of interest. J. G.-D. reports grants and contracts paid to her institution from the NIH, the Biomedical Advanced Research and Development Authority, Janssen Research & Development, Pfizer, BioNTech SE, GCAR, Hoffman La-Roche, I-Mab Biopharma, Rebiotix, Target Health, OBO Lilly USA, GlaxoSmithKline (GSK), Summit Ltd, UK, Cidara Therapeutics, Merck Sharp & Dohme (MSD), Seres Therapeutics, and Theratechnologies; and Infectious Diseases Society of America (IDSA) Research Committee participation paid to her directly. Y. D. reports grants and contracts paid to his institution from Entasis, Asahi Kasei Pharma, and Shionogi; consulting fees paid directly to him by Meiji Seika Pharma, Shionogi, Gilead, MSD, Chugai, bioMérieux, and GSK; and speaker payments from MSD, Shionogi, AstraZeneca, Teijin Healthcare, Gilead, FujiFilm Toyama Chemical, bioMérieux, H.U. Frontier, and Eiken Chemical. C. A. A. reports grants and contracts paid to his institution from NIH/NIAID (1 P01 AI152999, R01 AI148342, R01 AI134637, T32 AI141349, K24 AI121296, U19 AI144297, R01 AI150685, R21 AI151536), MeMed Diagnostics, Entasis Therapeutics, Merck Pharmaceuticals, and Harris County Public Health; payments to him for UpToDate royalties; reimbursement of meeting attendance and speaking from IDSA, American Society for Microbiology, Society of Hospital Epidemiology of America, European Society for Clinical Microbiology and Infectious Diseases, bioMérieux Foundation, Sociedad Argentina de Infectologia, Sociedad Chilena de Infectologia, Sociedad Colombiana de Infectologia, Panamerican Society for Infectious Diseases, and Brazilian Society for Infectious Diseases; reviewer participation as part of the NIH grant Review Study Sections; travel expenses from the IDSA Board of Directors; and for Editor in Chief for Antimicrobial Agents and Chemotherapy; nonpaid participation includes the World Health Organization Antibacterial Pipeline Advisory Group and participation on the IDSA Board of Directors. E. S. reports grants and contracts paid to his institution from Janssen Pharmaceuticals; speaker fees paid directly to him from Janssen Pharmaceuticals; and participation on a steering committee with no payment involved from Janssen Pharamceuticals. L. G. M. reports grants and contracts paid to his institution from Merck, Medline, Contrafect, and GSK. M. J. S. reports grants and contracts paid to his institution from Merck, Allergan, BioFire Diagnostics, Affinity Biosensors, and SNIPRBiome; consulting fees paid directly to him by Shionogi; and participation on a data and safety monitoring board paid directly to him by Spero Therapeutics. M. K. reports participating on an advisory board with payments made directly to him from Melinta, and receipt of drugs or other services paid directly to his institution by NIH. W. C. H. participates as a member of an endpoint adjudication committee for Pfizer; is a member of the advisory board for ADMA Biologics; and has stock ownership in Pfizer, Bristol-Myers Squibb, and Zimmer Biomet. R. P. reports grants from BioFire, ContraFect, and TenNor Therapeutics; is a consultant to Curetis, Abbott Laboratories, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, Day Zero Diagnostics, Torus Biosystems, Mammoth Biosciences, and Qvella; is a consultant to Netflix and CARB-X; has a patent on Bordetella pertussis (parapertussis) polymerase chain reaction issued, a patent on a device and method for sonication (with royalties paid by Samsung), and a patent on an anti-biofilm substance issued; receives an editor's stipend from the IDSA; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course. Other interests paid to her institution include Adaptive Phase Therapeutics and Pathogenomix. S. R. E. reports grants from the NIAID/NIH and De Gruyter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roviant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, the International Chinese Statistical Association Applied Statistics Symposium, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouos, Apellis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, GSK, Eli Lilly, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, Candel, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation. H. F. C. reports participation on a Merck data and safety monitoring board for molnupiravir paid directly to him, and stock ownership in Moderna and Merck. V. G. F. reports grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; royalties from UpToDate; personal fees from Novartis, Debiopharm, Genentech, Achaogen, Affinium, The Medicines Co, MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, and Roche; editorial stipend from IDSA; pending patent for a host gene expression signature diagnostic for sepsis; leadership role as associate editor for Clinical Infectious Diseases; and stock options with Valanbio and ArcBio. D. v. D. reports grants and contracts from the NIH and Merck, paid to his institution, outside the published work, and grants from Shionogi paid to him; consultancy for Actavis, Tetraphase, Sanofi Pasteur, Medimmune, Astellas, Merck, Allergan, T2 Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, Utility, and Union; payment for honoraria from Pfizer; and an editor's stipend from the British Society for Antimicrobial Chemotherapy. All other authors report no potential conflicts., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Community-acquired carbapenem-resistant Enterobacterales (CA-CRE) are an important threat., Methods: In CRACKLE-2, we defined patients with CA-CRE as admitted from home, without pre-existing conditions, and a positive culture within 48 h of admission. Healthcare-associated CRE (HA-CRE) were those with the lowest likelihood of community acquisition, not admitted from home and cultured &gt;48 h after admission. Specific genetic markers in carbapenemase-producing Klebsiella pneumoniae were evaluated through random forest modelling., Results: CA-CRE and HA-CRE were detected in 83 (10%) and 208 (26%) of 807 patients. No significant differences were observed in bacterial species or strain type distribution. K. pneumoniae (204/291, 70%) was the most common CRE species, of these 184/204 (90%) were carbapenemase producers (CPKP). The top three genetic markers in random forest models were kpi&#95;SA15, fimE, and kpfC. Of these, kpi&#95;SA15 (which encodes a chaperone/usher system) was positively associated (OR 3.14, 95% CI 1.13-8.87, P = 0.026), and kpfC negatively associated (OR 0.21, 95% CI 0.05-0.72, P = 0.015) with CA-CPKP., Conclusions: Ten percent of CDC-defined CRE were CA. The true proportion of CA-CRE in hospitalized patients is likely lower as patients may have had unrecorded prior healthcare exposure. The kpi&#95;SA15 operon was associated with the CA phenotype., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Carbapenem-resistant Acinetobacter baumannii (CR Ab ) is a major cause of health care-associated infections. CR Ab is typically multidrug resistant, and infection is difficult to treat. Despite the urgent threat that CR Ab poses, few systematic studies of CR Ab clinical and molecular epidemiology have been conducted. The Study Network of Acinetobacter as a Carbapenem-Resistant Pathogen (SNAP) is designed to investigate the clinical characteristics and contemporary population structure of CR Ab circulating in U.S. hospital systems using whole-genome sequencing (WGS). Analysis of the initial 120 SNAP patients from four U.S. centers revealed that CR Ab remains a significant threat to hospitalized patients, affecting the most vulnerable patients and resulting in 24% all-cause 30-day mortality. The majority of currently circulating isolates belonged to ST2 Pas , a part of clonal complex 2 (CC2), which is the dominant drug-resistant lineage in the United States and Europe. We identified three distinct sublineages within CC2, which differed in their antibiotic resistance phenotypes and geographic distribution. Most concerning, colistin resistance (38%) and cefiderocol resistance (10%) were common within CC2 sublineage C (CC2C), where the majority of isolates belonged to ST2 Pas /ST281 Ox . Additionally, we identified ST499 Pas as the most common non-CC2 lineage in our study. Our findings suggest a shift within the CR Ab population in the United States during the past 10 years and emphasize the importance of real-time surveillance and molecular epidemiology in studying CR Ab dissemination and clinical impact. IMPORTANCE Carbapenem-resistant Acinetobacter baumannii (CR Ab ) constitutes a major threat to public health. To elucidate the molecular and clinical epidemiology of CR Ab in the United States, clinical CR Ab isolates were collected along with data on patient characteristics and outcomes, and bacterial isolates underwent whole-genome sequencing and antibiotic susceptibility phenotyping. Key findings included emergence of new sublineages within the globally predominant clonal complex 2 (CC2), increased colistin and cefiderocol resistance within one of the CC2 sublineages, and emergence of ST499 Pas as the dominant non-CC2 CR Ab lineage in U.S. hospitals.

Carbapenem-resistant Klebsiella pneumoniae (CR Kp ) is an urgent public health threat. Worldwide dissemination of CR Kp has been largely attributed to clonal group (CG) 258. However, recent evidence indicates the global emergence of a CR Kp CG307 lineage. Houston, TX, is the first large city in the United States with detected cocirculation of both CR Kp CG307 and CG258. We sought to characterize the genomic and clinical factors contributing to the parallel endemic spread of CG258 and CG307. CR Kp isolates were collected as part of the prospective, Consortium on Resistance against Carbapenems in Klebsiella and other Enterobacterales 2 (CRACKLE-2) study. Hybrid short-read and long-read genome assemblies were generated from 119 CR Kp isolates (95 originated from Houston hospitals). A comprehensive characterization of phylogenies, gene transfer, and plasmid content with pan-genome analysis was performed on all CR Kp isolates. Plasmid mating experiments were performed with CG307 and CG258 isolates of interest. Dissection of the accessory genomes suggested independent evolution and limited horizontal gene transfer between CG307 and CG258 lineages. CG307 contained a diverse repertoire of mobile genetic elements, which were shared with other non-CG258 K. pneumoniae isolates. Three unique clades of Houston CG307 isolates clustered distinctly from other global CG307 isolates, indicating potential selective adaptation of particular CG307 lineages to their respective geographical niches. CG307 strains were often isolated from the urine of hospitalized patients, likely serving as important reservoirs for genes encoding carbapenemases and extended-spectrum β-lactamases. Our findings suggest parallel cocirculation of high-risk lineages with potentially divergent evolution. IMPORTANCE The prevalence of carbapenem-resistant Klebsiella pneumoniae (CR Kp ) infections in nosocomial settings remains a public health challenge. High-risk clones such as clonal group 258 (CG258) are particularly concerning due to their association with bla KPC carriage, which can severely complicate antimicrobial treatments. There is a recent emergence of clonal group 307 (CG307) worldwide with little understanding of how this successful clone has been able to adapt while cocirculating with CG258. We provide the first evidence of potentially divergent evolution between CG258 and CG307 with limited sharing of adaptive genes. Houston, TX, is home to the largest medical center in the world, with a large influx of domestic and international patients. Thus, our unique geographical setting, where two pandemic strains of CR Kp are circulating, provides an indication of how differential accessory genome content can drive stable, endemic populations of CR Kp . Pan-genomic analyses such as these can reveal unique signatures of successful CR Kp dissemination, such as the CG307-associated plasmid (pCG307&#95;HTX), and provide invaluable insights into the surveillance of local carbapenem-resistant Enterobacterales (CRE) epidemiology.

Importance: Bacterial and viral causes of acute respiratory illness (ARI) are difficult to clinically distinguish, resulting in the inappropriate use of antibacterial therapy. The use of a host gene expression-based test that is able to discriminate bacterial from viral infection in less than 1 hour may improve care and antimicrobial stewardship., Objective: To validate the host response bacterial/viral (HR-B/V) test and assess its ability to accurately differentiate bacterial from viral infection among patients with ARI., Design, Setting, and Participants: This prospective multicenter diagnostic study enrolled 755 children and adults with febrile ARI of 7 or fewer days' duration from 10 US emergency departments. Participants were enrolled from October 3, 2014, to September 1, 2019, followed by additional enrollment of patients with COVID-19 from March 20 to December 3, 2020. Clinical adjudication of enrolled participants identified 616 individuals as having bacterial or viral infection. The primary analysis cohort included 334 participants with high-confidence reference adjudications (based on adjudicator concordance and the presence of an identified pathogen confirmed by microbiological testing). A secondary analysis of the entire cohort of 616 participants included cases with low-confidence reference adjudications (based on adjudicator discordance or the absence of an identified pathogen in microbiological testing). Thirty-three participants with COVID-19 were included post hoc., Interventions: The HR-B/V test quantified the expression of 45 host messenger RNAs in approximately 45 minutes to derive a probability of bacterial infection., Main Outcomes and Measures: Performance characteristics for the HR-B/V test compared with clinical adjudication were reported as either bacterial or viral infection or categorized into 4 likelihood groups (viral very likely [probability score <0.19], viral likely [probability score of 0.19-0.40], bacterial likely [probability score of 0.41-0.73], and bacterial very likely [probability score >0.73]) and compared with procalcitonin measurement., Results: Among 755 enrolled participants, the median age was 26 years (IQR, 16-52 years); 360 participants (47.7%) were female, and 395 (52.3%) were male. A total of 13 participants (1.7%) were American Indian, 13 (1.7%) were Asian, 368 (48.7%) were Black, 131 (17.4%) were Hispanic, 3 (0.4%) were Native Hawaiian or Pacific Islander, 297 (39.3%) were White, and 60 (7.9%) were of unspecified race and/or ethnicity. In the primary analysis involving 334 participants, the HR-B/V test had sensitivity of 89.8% (95% CI, 77.8%-96.2%), specificity of 82.1% (95% CI, 77.4%-86.6%), and a negative predictive value (NPV) of 97.9% (95% CI, 95.3%-99.1%) for bacterial infection. In comparison, the sensitivity of procalcitonin measurement was 28.6% (95% CI, 16.2%-40.9%; P < .001), the specificity was 87.0% (95% CI, 82.7%-90.7%; P = .006), and the NPV was 87.6% (95% CI, 85.5%-89.5%; P < .001). When stratified into likelihood groups, the HR-B/V test had an NPV of 98.9% (95% CI, 96.1%-100%) for bacterial infection in the viral very likely group and a positive predictive value of 63.4% (95% CI, 47.2%-77.9%) for bacterial infection in the bacterial very likely group. The HR-B/V test correctly identified 30 of 33 participants (90.9%) with acute COVID-19 as having a viral infection., Conclusions and Relevance: In this study, the HR-B/V test accurately discriminated bacterial from viral infection among patients with febrile ARI and was superior to procalcitonin measurement. The findings suggest that an accurate point-of-need host response test with high NPV may offer an opportunity to improve antibiotic stewardship and patient outcomes.

Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries., Methods: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete., Findings: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96)., Interpretation: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions., Funding: The National Institutes of Health., Competing Interests: Declaration of interests MW, ME, LC, YY, ZL, SS, EC, LL, SSK, HG, KM, LK, SDR, SHM, CM, JR, MVV, CH, RA, KB, BCF, BNK, and RAB report funding support from the ARLG of the National Institutes of Health (NIH) and the National Institute of Allergy and Infectious Diseases (NIAID; UM1AI104681) during the conduct of this study. BMH reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), during the conduct of this study, and a grants from the NIH and the NIAID (K01AI148593–01), outside the submitted work. JMM reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and grants from Pfizer, MSD, and bioMerieux, outside the submitted work. KO reports funding support from the ALRG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; payments for educational events and presentations from Pfizer, MSD, AstraZeneca, and Farma de Colombia; and meeting support from Pfizer, MSD, and Gilead, outside the submitted work. GW reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681), and from Allergan. MJS reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; contracts payments, to his institution, from Merck, Allergan, BioFire Diagnostics, and Affinity Biosensors; personal consulting fees from Achaogen and Shionogi; and board participation for Spero Therapeutics, outside the submitted work. SLV-B reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and personal fees from MSD and Biotoscana, outside the submitted work. MES reports grants from the NIH during the conduct of the study; speaker fees from Pfizer (Argentina); advisory board participation for Wockhardt; and consultancy for Basilea, outside the submitted work. CL reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study and salary support from the National Institute of General Medical Sciences of the NIH (award number T32GM086330) outside the submitted work. DLP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants and contracts with MERCK, Pfizer, and Shionogi; consulting fees from Merck, Shionogi, and Qpex; payments and financial support from Sumitomo, Merck, Pfizer, bioMerieux, and Shionogi; and board participation for Symvivo, outside the submitted work. SE reports grants from the NIAID and the NIH and Degruter (Editor in Chief for Statistical Communications in Infectious Diseases); royalties from Taylor & Francis; consulting fees from Genentech, AstraZeneca, Cardinal Health, Microbiotix, Stryker, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, the International Drug Development Institute, and SVB Leerink; payments from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, Osaka University, and the National Cerebral and Cardiovascular Center of Japan; meeting support from the US Food and Drug Administration, the Deming Conference on Applied Statistics, the Clinical Trial Transformation Initiative, the Council for International Organizations of Medical Sciences, and the Antimicrobial Resistance and Stewardship Conference; and board member participation for the NIH, the Breast International Group, the University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Novartis, Amgen, Teva, Vir, Shire, Alexion, Gilead, Tracon, Rakuten, Abbvie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, Advantagene, the American Statistical Association, the Society for Clinical Trials, and the Frontier Science Foundation, outside the submitted work. YD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; grants from Janssen, Pfizer, MSD, Shionogi, Astellas, and Kanto Chemical, outside the submitted work; and personal fees from Janssen, MSD, Entasis, VenatoRx, AstraZeneca, Gilead, FUJIFILM Toyama Chemical, bioMerieux, and Meiji Seika Pharma, outside the submitted work. RP reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; reports grants from Merck, ContraFect, TenNor Therapeutics, and Shionogi; is a consultant to Curetis, Specific Technologies, Next Gen Diagnostics, PathoQuest, Selux Diagnostics, 1928 Diagnostics, PhAST, and Qvella, for which monies are paid to Mayo Clinic; is a consultant to Netflix; has a patent on Bordetella pertussis (parapertussis) PCR issued, a patent on a device and method for sonication (with royalties paid by Samsung to Mayo Clinic), and a patent on an anti-biofilm substance issued; receives an editor's stipend from the Infectious Diseases Society of America; and receives honoraria from the National Board of Medical Examiners, UpToDate, and the Infectious Diseases Board Review Course, outside the submitted work. HFC reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; personal fees from Merck; and stock ownership from Moderna, outside the submitted work. VGF reports personal Fees from Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, and Aridis; grants to his institution from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genentech, Regeneron, Basilea, and Janssen; educational fees from Green Cross, Cubist, Cerexa, Durata, Theravance, and Debiopharm; royalties from UpToDate; and stock options in Valanbio. CAA is employed at the University of Texas Health Science Center in Houston, TX, USA; declares money paid to the University of Texas as part of a grant from Merck, MeMed Diagnostics, Entasis Therapeutics, and the ARLG of the NIH and the NIAID (UM1AI104681); reports royalties paid as personal fees from UptoDate (Harrison Principles of Internal Medicine and Mandell Principles and Practice of Infectious Diseases); reports personal fees from the NIH and the NIAID for being a study section member and grant reviewer; reports an editor-in-chief stipend from the American Society for Microbiology for Antimicrobial Agents and Chemotherapy; reports reimbursement for travel to Infectious Disease Week and Infectious Disease programme committee meetings as Infectious Disease chair from the Infectious Disease Society of America; and reports reimbursement for traveling to the American Society for Microbiology Microbe conference from the American Society for Microbiology. DvD reports funding support from the ARLG of the NIH and the NIAID (UM1AI104681) during the conduct of this study; is a consultant for Actavis, Tetraphase, Sanofi Pasteur, MedImmune, Astellas, Merck, Allergan, T2Biosystems, Roche, Achaogen, Neumedicine, Shionogi, Pfizer, Entasis, QPex, Wellspring, Karius, and Utility; receives an editor's stipend from the British Society for Antimicrobial Chemotherapy; and reports grants from the NIH, outside the submitted work., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Rapid blood culture diagnostics are of unclear benefit for patients with gram-negative bacilli (GNB) bloodstream infections (BSIs). We conducted a multicenter, randomized, controlled trial comparing outcomes of patients with GNB BSIs who had blood culture testing with standard-of-care (SOC) culture and antimicrobial susceptibility testing (AST) vs rapid organism identification (ID) and phenotypic AST using the Accelerate Pheno System (RAPID)., Methods: Patients with positive blood cultures with Gram stains showing GNB were randomized to SOC testing with antimicrobial stewardship (AS) review or RAPID with AS. The primary outcome was time to first antibiotic modification within 72 hours of randomization., Results: Of 500 randomized patients, 448 were included (226 SOC, 222 RAPID). Mean (standard deviation) time to results was faster for RAPID than SOC for organism ID (2.7 [1.2] vs 11.7 [10.5] hours; P < .001) and AST (13.5 [56] vs 44.9 [12.1] hours; P < .001). Median (interquartile range [IQR]) time to first antibiotic modification was faster in the RAPID arm vs the SOC arm for overall antibiotics (8.6 [2.6-27.6] vs 14.9 [3.3-41.1] hours; P = .02) and gram-negative antibiotics (17.3 [4.9-72] vs 42.1 [10.1-72] hours; P < .001). Median (IQR) time to antibiotic escalation was faster in the RAPID arm vs the SOC arm for antimicrobial-resistant BSIs (18.4 [5.8-72] vs 61.7 [30.4-72] hours; P = .01). There were no differences between the arms in patient outcomes., Conclusions: Rapid organism ID and phenotypic AST led to faster changes in antibiotic therapy for gram-negative BSIs., Clinical Trials Registration: NCT03218397., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Pharyngeal and rectal Neisseria gonorrhoeae and Chlamydia trachomatis play important roles in infection and antibacterial resistance transmission, but no US Food and Drug Administration (FDA)-cleared assays for detection at these sites existed prior to this study. The objective was to estimate performance of assays to detect those infections in pharyngeal and rectal specimens to support regulatory submission., Methods: We performed a cross-sectional, single-visit study of adults seeking sexually transmitted infection testing at 9 clinics in 7 states. We collected pharyngeal and rectal swabs from participants. The primary outcome was positive and negative percent agreement for detection of N. gonorrhoeae and C. trachomatis for 3 investigational assays compared to a composite reference. Secondary outcomes included positivity as well as positive and negative predictive values and likelihood ratios. Subgroup analyses included outcomes by symptom status and sex., Results: A total of 2598 participants (79% male) underwent testing. We observed N. gonorrhoeae positivity of 8.1% in the pharynx and 7.9% in the rectum and C. trachomatis positivity of 2.0% in the pharynx and 8.7% in the rectum. Positive percent agreement ranged from 84.8% to 96.5% for different anatomic site infection combinations, whereas negative percent agreement was 98.8% to 99.6%., Conclusions: This study utilized a Master Protocol to generate diagnostic performance data for multiple assays from different manufacturers in a single study population, which ultimately supported first-in-class FDA clearance for extragenital assays. We observed very good positive percent agreement when compared to a composite reference method for the detection of both pharyngeal and rectal N. gonorrhoeae and C. trachomatis., Clinical Trials Registration: NCT02870101., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.)

Chlamydia trachomatis and Neisseria gonorrhoeae infections in the rectum and pharynx are important extragenital reservoirs of infection. Few assays approved by the US Food and Drug Administration are commercially available to diagnose pharyngeal or rectal infections. The current study reports on the analytical performance of the Abbott RealTime CT/NG assay, including the limit of detection, inclusivity, and analytical specificity for C. trachomatis and N. gonorrhoeae in rectal and pharyngeal specimens. The limit of detection was performed using known concentrations of organisms, elementary bodies per milliliter (EB/mL) for C. trachomatis and colony-forming units per milliliter (CFU/mL) for N. gonorrhoeae, in clinical rectal and pharyngeal swab matrices. Inclusivity was performed against 12 serovars of C. trachomatis and seven strains of N. gonorrhoeae. The analytical specificity was performed using 28 different bacteria and viruses. The limit of detection for C. trachomatis was 2.56 EB/mL in pharyngeal specimens and 12.8 EB/mL in rectal specimens. The limit of detection for N. gonorrhoeae was 0.0256 CFU/mL for both pharyngeal and rectal specimens. The inclusivity and analytical specificity were 100% for both rectal and pharyngeal specimens. These analytical performance data demonstrate that the Abbott CT/NG RealTime assay is an accurate, sensitive, and specific assay in rectal and pharyngeal specimens, supporting the potential of the assay for detection of rectal and pharyngeal C. trachomatis and N. gonorrhoeae infections., (Copyright © 2020 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA., Methods: CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227., Findings: 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died., Interpretation: Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales., Funding: National Institutes of Health., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Importance: The feasibility of core Infectious Diseases Society of America-recommended antimicrobial stewardship interventions in community hospitals is unknown., Objective: To determine the feasibility and results of implementing 2 core stewardship intervention strategies in community hospitals., Design, Setting, and Participants: Three-stage, multicenter, prospective nonrandomized clinical trial with crossover design. The setting was 4 community hospitals in North Carolina (median bed size, 305; range, 102-425). Participants were all patients receiving targeted study antibacterial agents or alternative, nonstudy antibacterial agents. The study dates were October 2014 through October 2015. All statistical analyses were completed as of October 2016., Interventions: Two antimicrobial stewardship strategies targeted vancomycin hydrochloride, piperacillin-tazobactam, and the antipseudomonal carbapenems on formulary at the study hospitals: (1) modified preauthorization (PA), in which the prescriber had to receive pharmacist approval for continued use of the antibiotic after the first dose, and (2) postprescription audit and review (PPR), in which the pharmacist would engage the prescriber about antibiotic appropriateness after 72 hours of therapy. Two hospitals performed modified PA for 6 months, then PPR for 6 months after a 1-month washout. The other 2 hospitals performed the reverse., Main Outcomes and Measures: The primary outcome was the feasibility of implementing the interventions, determined by (1) approval by hospital administration and committees at each study hospital; (2) completion of pharmacist training; (3) initiation and implementation as determined by number, type, and outcomes of interventions performed; and (4) time required for interventions. Secondary outcomes included antimicrobial use (days of therapy) compared with matched historical periods and length of hospitalization., Results: A total of 2692 patients (median age, 65 years; interquartile range, 53-76 years) underwent a study intervention; 1413 (52.5%) were female, 1323 (49.1%) were white, and 1047 (38.9%) were African American. Intervention approvals took a median of 95 days (range, 56-119 days); during these discussions, strict PA was deemed not feasible. Instead, the modified PA intervention was used throughout the study. Pharmacists performed 1456 modified PA interventions (median per hospital, 350 [range, 129-628]) and 1236 PPR interventions (median per hospital, 298 [range, 273-366]). Study antimicrobials were determined to be inappropriate 2 times as often during the PPR period (41.0% [435 of 1060] vs 20.4% [253 of 1243]; P < .001). Pharmacists recommended dose change more often during the modified PA intervention (15.9% [232 of 1456] vs 9.6% [119 of 1236]; P < .001) and de-escalation during PPR (29.1% [360 of 1236] vs 13.0% [190 of 1456]; P < .001). The median time dedicated to the stewardship interventions varied by hospital (range of median hours per week, 5-19). Overall antibiotic use decreased during PPR compared with historical controls (mean [SD] days of therapy per 1000 patient-days, 925.2 [109.8] vs 965.3 [109.4]; mean difference, -40.1; 95% CI, -71.7 to -8.6), but not during modified PA (mean [SD] days of therapy per 1000 patient-days, 931.0 [102.0] vs 926.6 [89.7]; mean difference, 4.4; 95% CI, -55.8 to 64.7)., Conclusions and Relevance: Strict PA was not feasible in the study hospitals. In contrast, PPR was a feasible and effective strategy for antimicrobial stewardship in settings with limited resources and expertise., Trial Registration: ClinicalTrials.gov identifier: NCT02212808.

The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Low levels of high-density lipoprotein cholesterol (HDL-C) are common in individuals with human immunodeficiency virus (HIV) infection, persist during antiretroviral therapy (ART), and are associated with increased cardiovascular disease (CVD) risk., Methods: Virologically controlled participants without CVD on stable ART with low HDL-C (men <40 mg/dL, women <50 mg/dL) and triglycerides >150 mg/dL were randomized to receive open-label extended-release niacin 1500 mg/day with aspirin 325 mg/day or fenofibrate 200 mg/day for 24 weeks. The primary endpoint was the week 24 within-arm change in brachial artery flow-mediated dilation (FMD) in participants with complete follow-up scans., Results: Of 99 participants, 74 had complete data (35 niacin, 39 fenofibrate). Median age was 45 years, 77% were male, median CD4(+) count was 561 cells/µL, and brachial FMD was 4.2%. Median HDL-C was 32 mg/dL for men and 38 mg/dL for women, low-density lipoprotein cholesterol was 103 mg/dL, and triglycerides were 232 mg/dL. In men, HDL-C increased a median of 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < .001 for both). In women, HDL-C increased a median of 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = .08 for both). After 24 weeks, there was no significant change in FMD in either arm; the median (interquartile range) change was +0.6% (-1.6 to 2.3) with niacin (P = .28) and +0.5% (-1.0 to 3.0) with fenofibrate (P = .19). Neither treatment significantly affected C-reactive protein, interleukin 6, or D-dimer levels., Conclusions: Despite improvements in lipids, niacin or fenofibrate treatment for 24 weeks did not improve endothelial function or inflammatory markers in participants with well-controlled HIV infection and low HDL-C., Clinical Trials Registration: NCT01426438., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: In the pre-antiretroviral therapy (ART) era, markers of increased disease severity during an acute opportunistic infection (OI) were associated with mortality. Even with ART, mortality remains high during the first year after an OI in persons with advanced HIV infection, but it is unclear whether previous predictors of mortality remain valid in the current era., Objective: To determine clinical and immunological predictors of death after an OI., Methods: We used clinical data and stored plasma from ACTG A5164, a multicenter study evaluating the optimal timing of ART during a nontuberculous OI. We developed Cox models evaluating associations between clinical parameters and plasma marker levels at entry and time to death over the first 48 weeks after the diagnosis of OI. We developed multivariable models incorporating only clinical parameters, only plasma marker levels, or both., Results: The median CD4+ T-cell count in study participants at baseline was 29 cells/µL. Sixty-four percent of subjects had Pneumocystis jirovecii pneumonia (PCP). Twenty-three of 282 (8.2%) subjects died. In univariate analyses, entry mycobacterial infection, OI number, hospitalization, low albumin, low hemoglobin, lower CD4, and higher IL-8 and sTNFrII levels and lower IL-17 levels were associated with mortality. In the combined model using both clinical and immunologic parameters, the presence of an entry mycobacterial infection and higher sTNFrII levels were significantly associated with death., Conclusions: In the ART era, clinical risk factors for death previously identified in the pre-ART era remain predictive. Additionally, activation of the innate immune system is associated with an increased risk of death following an acute OI.

Objective: The objective of this study was to define the test characteristics of plasma beta-glucan for diagnosis of Pneumocystis jirovecii pneumonia (PCP) in AIDS patients with respiratory symptoms., Design: Analysis of baseline blood samples in a randomized strategy study of patients with acute opportunistic infections, limited to participants with respiratory symptoms., Methods: Participants in the 282-person ACTG A5164 trial had baseline plasma samples assayed for beta-glucan testing. As part of A5164 trial, two study investigators independently adjudicated the diagnosis of PCP. Respiratory symptoms were identified by investigators from a list of all signs and symptoms with an onset or resolution in the 21 days prior to or 14 days following study entry. Beta-glucan was defined as positive if at least 80 pg/ml and negative if less than 80 pg/ml., Results: Of 252 study participants with a beta-glucan result, 159 had at least one respiratory symptom, 139 of whom had a diagnosis of PCP. The sensitivity of beta-glucan for PCP in participants with respiratory symptoms was 92.8% [95% confidence interval (CI) 87.2-96.5], and specificity 75.0% (95% CI 50.9-91.3). Among 134 individuals with positive beta-glucan and respiratory symptoms, 129 had PCP, for a positive predictive value of 96.3% (95% CI 91.5-98.8). Fifteen of 25 patients with a normal beta-glucan did not have PCP, for a negative predictive value of 60% (95% CI 38.7-78.9)., Conclusion: Elevated plasma beta-glucan has a high predictive value for diagnosis of PCP in AIDS patients with respiratory symptoms. We propose an algorithm for the use of beta-glucan as a diagnostic tool on the basis of the pretest probability of PCP in such patients.

Background and Objective: The impact of maternal antiretrovirals (ARVs) during pregnancy, labor, and postpartum on infant outcomes is unclear., Methods: Infants born to HIV-infected mothers in ARV studies were followed for 18 months., Results: Between June 2006 and December 2008, 236 infants enrolled from Africa (n = 36), India (n = 47), Thailand (n = 152), and Brazil (n = 1). Exposure to ARVs in pregnancy included ≥ 3 ARVs (10%), zidovudine/intrapartum ARV (81%), and intrapartum ARV (9%). There were 4 infant infections (1 in utero, 3 late postpartum) and 4 deaths with 1.8% mortality (95% confidence interval [CI], 0.1%-3.5%) and 96.4% HIV-1-free survival (95% CI, 94.0%-98.9%). Birth weight was ≥ 2.5 kg in 86%. In the first 6 months, Indian infants (nonbreastfed) had lowest median weights and lengths and smallest increases in growth. After 6 months, African infants had the lowest median weight and weight-for-age z scores. Infants exposed to highest maternal viral load had the lowest height and height-for-age z scores. Serious adverse events occurred in 38% of infants, did not differ by country, and correlated with less maternal ARV exposure. Clinical diagnoses were seen in 84% of Thai, 31% of African, and 9% of Indian infants. Congenital defects/inborn errors of metabolism were seen in 18 (7.6%) infants, of which 17 were Thai (11%: 95% CI, 6.7%-17.0%); none had first trimester ARV exposure., Conclusions: Infant follow-up in large international cohorts is feasible and provides important safety and HIV transmission data following maternal ARV exposure. Increased surveillance increases identification of congenital/inborn errors.

Unlabelled: (See the editorial commentary by Morris and Masur, on pages 203-204.), Background: Improved noninvasive diagnostic tests for Pneumocystis jirovecii pneumonia (PCP) are needed. We evaluated the test characteristics of plasma (1 → 3)-β-D-glucan (β-glucan) for HIV-related PCP among a large group of patients presenting with diverse opportunistic infections (OIs)., Methods: The study population included all 282 participants in AIDS Clinical Trials Group A5164, a study of early versus deferred antiretroviral therapy in conjunction with initial therapy of acute OIs. Baseline plasma samples were assayed for β-glucan, with standard assay reference values defining ≥ 80 pg/mL as positive. Before this analysis, diagnosis of PCP was independently adjudicated by 2 study investigators after reviewing reports from study sites., Results: A total of 252 persons had a β-glucan result that could be analyzed, 173 (69%) of whom had received a diagnosis of PCP. Median β-glucan with PCP was 408 pg/mL (interquartile range [IQR], 209-500 pg/mL), compared with 37 pg/mL (IQR, 31-235 pg/mL) without PCP (P < .001). The sensitivity of β-glucan dichotomized at 80 pg/mL for the diagnosis of PCP was 92% (95% confidence interval [CI], 87%-96%), and the specificity was 65% (95% CI, 53%-75%); positive and negative predictive values were 85% (95% CI, 79%-90%) and 80% (95% CI, 68%-89%) respectively, based on the study prevalence of 69% of patients with PCP. Rates of abnormal lactate dehyrogenase levels did not differ significantly between those with and without PCP., Conclusions: Blood (1 → 3)-β-D-glucan is strongly correlated with HIV-related PCP. In some clinical centers, this may be a more sensitive test than the induced sputum examination and could reduce the need for both bronchoscopy and empirical therapy of PCP.

Background: Immune reconstitution inflammatory syndrome (IRIS) is reported widely in patients initiating antiretroviral therapy (ART). However, few studies are prospective, and no study has evaluated the impact of the timing of ART when allocated randomly during an acute opportunistic infection (OI)., Methodology/principal Findings: A5164 randomized 282 subjects with AIDS-related OIs (tuberculosis excluded), to early or deferred ART. IRIS was identified prospectively using pre-defined criteria. We evaluated associations between IRIS and baseline variables in subjects with follow-up on ART using Wilcoxon and Fisher's exact tests, logistic regression, and Cox models with time-varying covariates. Twenty of 262 (7.6%) subjects developed IRIS after a median of 33 days on ART. Subjects with fungal infections (other than pneumocystis) developed IRIS somewhat more frequently (OR = 2.7; 95% CI: 1.02, 7.2; p-value = 0.06 (using Fisher's exact test)). In Cox models, lower baseline and higher on-treatment CD4+ T-cell counts and percentage were associated with IRIS. Additionally, higher baseline and lower on-treatment HIV RNA levels were associated with IRIS. Corticosteroids during OI management and the timing of ART were not associated with the development of IRIS., Implications: In patients with advanced immunosuppression and non-tuberculous OIs, the presence of a fungal infection, lower CD4+ T-cell counts and higher HIV RNA levels at baseline, and higher CD4+ T-cell counts and lower HIV RNA levels on treatment are associated with IRIS. Early initiation of ART does not increase the incidence of IRIS, and concern about IRIS should not prompt deferral of ART., Trial Registration: ClinicalTrials.gov NCT00055120.

Background: The metabolic effects of initial therapy for HIV-1 infection are important determinants of regimen selection., Methods: Open-label study in 753 subjects randomized equally to efavirenz or lopinavir/ritonavir(r) plus two nucleoside reverse-transcriptase inhibitor (NRTI) vs. the NRTI-sparing regimen of lopinavir/r plus efavirenz. Zidovudine, stavudine, or tenofovir with lamivudine was selected prior to randomization. Metabolic outcomes through 96 weeks were lipoatrophy, defined as at least 20% loss in extremity fat, and fasting serum lipids., Results: Lipoatrophy by dual-energy X-ray absorptiometry at week 96 occurred in 32% [95% confidence interval (CI) 25-39%] of subjects in the efavirenz plus two NRTIs arm, 17% (95% CI 12-24) in the lopinavir/r plus two NRTIs arm, and 9% (95% CI 5-14) in the NRTI-sparing arm (P < or = 0.023 for all comparisons). Varying the definition of lipoatrophy (> or =10 to > or =40% fat loss) and correction for baseline risk factors did not affect the significant difference in lipoatrophy between the NRTI-containing regimens. Lipoatrophy was most frequent with stavudine-containing regimens and least frequent with tenofovir-containing regimens (P < 0.001), which were not significantly different from the NRTI-sparing regimen. Total cholesterol increases at week 96 were greatest in the NRTI-sparing arm (median +57 mg/dl) compared with the other two arms (+32-33 mg/dl; P < 0.001). Use of lipid-lowering agents was more common (25 vs. 11-13%) in the NRTI-sparing arm., Conclusion: Lipoatrophy was more frequent with efavirenz than lopinavir/r when combined with stavudine or zidovudine, and less frequent when either drug was combined with tenofovir. Lipoatrophy was least frequent with the NRTI-sparing regimen, but this benefit was offset by greater cholesterol elevations and the need for lipid-lowering agents.

Background: Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined., Methods and Findings: A5164 was a randomized strategy trial of "early ART"--given within 14 days of starting acute OI treatment versus "deferred ART"--given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) >or=50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS. 282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively. THE DIFFERENCE IN THE PRIMARY ENDPOINT DID NOT REACH STATISTICAL SIGNIFICANCE: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27-0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30-0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events., Conclusions: Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications., Trial Registration: ClinicalTrials.gov NCT00055120.

BACKGROUND: Dyslipidemia is a frequent complication of antiretroviral therapy (ART) for patients with human immunodeficiency virus infection (HIV). The effects of ART on lipoproteins are less well-understood, and have not been investigated in a prospective study where assignment to ART is randomized. OBJECTIVE: To evaluate the effects of three class-sparing ART regimens on lipids and lipoproteins. METHODS: This was a substudy of a prospective, multicenter study treatment-naïve HIV-infected individuals randomly assigned to receive a regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + the non-nucleoside reverse transcriptase inhibitor efavirenz, NRTIs + the protease inhibitor lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. Lipoproteins were measured by nuclear magnetic resonance spectroscopy. RESULTS: Among the 82 participants, total and small low-density lipoprotein concentrations increased (median, interquartile range) by 152 (-49 - +407, p<0.01) and 130 (-98 - +417, p<0.01) nmol/L, respectively, especially in the arms containing lopinavir/ritonavir (p(KW)<0.04). Very low-density lipoproteins also increased (p<0.01), with a larger increase in the arms that contained lopinavir/ritonavir (p=0.022). High-density lipoproteins increased by 6.0 nmol/L (2.8 - 10.4, p<0.01), but differences between arms were not significant (p(KW)=0.069). Changes were not related to changes in markers of insulin/glucose metabolism. CONCLUSIONS: Total and small low-density lipoprotein concentrations increased, especially in the arms containing lopinavir/ritonavir, as did increases in total very low-density lipoproteins. Adverse changes were especially prominent in the arm with efavirenz + lopinavir/ritonavir.

Objectives: This study evaluated the effects of 3 class-sparing antiretroviral therapy (ART) regimens on endothelial function in human immunodeficiency virus (HIV)-infected subjects participating in a randomized trial., Background: Endothelial dysfunction has been observed in patients receiving ART for HIV infection., Methods: This was a prospective, multicenter study of treatment-naive subjects who were randomly assigned to receive a protease inhibitor-sparing regimen of nucleoside reverse transcriptase inhibitors (NRTIs) + efavirenz, a non-nucleoside reverse transcriptase inhibitor-sparing regimen of NRTIs + lopinavir/ritonavir, or a NRTI-sparing regimen of efavirenz + lopinavir/ritonavir. The NRTIs were lamivudine + stavudine, zidovudine, or tenofovir. Brachial artery flow-mediated dilation (FMD) was determined by B-mode ultrasound before starting on ART, then after 4 and 24 weeks., Results: There were 82 subjects (median age 35 years, 91% men, 54% white). Baseline CD4 cell counts and plasma HIV ribonucleic acid (RNA) values were 245 cells/mm(3) and 4.8 log(10) copies/ml, respectively. At baseline, FMD was 3.68% (interquartile range [IQR] 1.98% to 5.51%). After 4 and 24 weeks of ART, plasma HIV RNA decreased by 2.1 and 3.0 log(10) copies/ml, respectively. FMD increased by 0.74% (IQR -0.62% to +2.74%, p = 0.003) and 1.48% (IQR -0.20% to +4.30%, p < 0.001), respectively, with similar changes in each arm (Kruskal-Wallis p value >0.600). The decrease in plasma HIV RNA at 24 weeks was associated with greater FMD (r(s) = -0.30, p = 0.017)., Conclusions: Among treatment-naive individuals with HIV, 3 different ART regimens rapidly improved endothelial function. Benefits were similar for all ART regimens, appeared quickly, and persisted at 24 weeks.

Background: Long-term regional body fat outcomes have not been well described in randomized antiretroviral drug trials., Methods: Dual x-ray absorptiometry (DXA) scans were performed every 16 weeks on a subset of 157 antiretroviral-naive participants who were randomized to receive nelfinavir, efavirenz, or both, combined with zidovudine and lamivudine or stavudine and didanosine, in a multicenter trial. Participants with any available data after baseline up to week 144 contributed to this as-treated analysis., Results: Limb fat increased similarly in all groups during the first 32 weeks. After week 32, limb fat changed by - 1.7% per year for zidovudine-lamivudine and by -19.0% per year for didanosine-stavudine (mixed model analysis of variance [MMANOVA], P < 0.0001). Adjusting for nucleoside backbone, there was an additional decrease in limb fat of -8.7% per year for the combined nelfinavir and nelfinavir + efavirenz group compared with the efavirenz group (MMANOVA, P = 0.03). Among participants receiving zidovudine-lamivudine, after week 32, limb fat changed by +2.7% per year with efavirenz and by -7.9% per year for the combined nelfinavir and nelfinavir + efavirenz group (MMANOVA, P = 0.03)., Conclusions: Over 144 weeks, zidovudine-lamivudine was superior to didanosine-stavudine with regard to limb fat loss. The combination of zidovudine, lamivudine, and efavirenz showed no overall pattern suggesting limb fat loss over time and was significantly superior to the pooled zidovudine-lamivudine-nelfinavir (with and without efavirenz) arms.

Introduction: Although peripheral fat loss is a consistent feature of HIV-associated lipodystrophy, less is known about whether changes in central and peripheral fat occur in tandem or independently over time. We examined intraindividual changes in dual-energy x-ray absorptiometry (DEXA) and anthropometry data over 64 weeks after initiation of antiretroviral therapy (ART)., Methods: In ACTG 384, ART-naive subjects were randomized to receive didanosine and stavudine or zidovudine and lamivudine plus efavirenz, nelfinavir, or both. In the metabolic substudy A5005S (N= 329), waist, hip, thigh, and arm circumferences were measured in triplicate. DEXA scanning was performed in 157 subjects., Results: Individual changes in limb and trunk fat at week 64 correlated positively (R =.72, P <.001). Most subjects had directionally concordant changes in limb and trunk fat (36% gained and 32% lost in both regions). In 26%, trunk fat increased while limb fat decreased, whereas the reverse occurred in only 6% (P <.001). Changes in waist and hip circumferences also correlated positively (R =.62, P <.001). The proportion of subjects with waist/hip ratio more than .95 (men) or .90 (women) was 34% at baseline and 47% at week 64 (P =.003). In those who developed increased waist/hip ratio, 76% had increased waist circumference., Conclusions: Individual results obtained by both anthropometry and DEXA show diverse patterns of fat gain and loss over 64 weeks after initiation of ART, but changes tended to occur in the same direction. Increased waist/hip ratio was predominantly associated with increased waist circumference. There was no evidence that central fat accumulation and peripheral fat loss are linked in most subjects.