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Background: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)., Methods: Through comprehensive examination of data from nearly 4000 participants enrolled in six registrational trials for HABP/VABP submitted to the Food and Drug Administration (FDA) between 2005 and 2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator., Results: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Although infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar., Conclusions: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design., Competing Interests: Potential conflicts of interest. V. G. F. reports personal 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, Roche, grants from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Deep Blue, Basilea, Janssen; Royalties from UpToDate, stock options from Valanbio and ArcBio, Honoraria from Infectious Diseases of America for his service as Associate Editor of Clinical Infectious Diseases, and a patent sepsis diagnostics pending. H. W. B. reports royalties to author from Sanford Guide; editorial consulting fees from Sanford Guide, Antimicrobial Agents and Chemotherapy/ASM, ID Clinics of North America/Elsevier; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Grand Rounds at Temple; IDWeek lecture travel support from Finland Award; role as PACCARB Voting Member (travel reimbursed) and on Board of Trustees, College of the Holy Cross (travel reimbursed). T. H. reports grants or contracts from Aceragen; consulting fees from Astellas Pharma US and Mitsubishi Tanabe Pharma; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Cancer and Chemotherapy KK. S. R. E. reports NCI/NIH grant, NHLBI/NIH grant, CDC grant, and grants or contracts from Degruyter (Editor-in-Chief: Statistical Communications in Infectious Diseases); book 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, Wake Forest University, Recor, Janssen, IDDI; honorarium from Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION), and payment or honorarium for travel from Liver Forum and Paris NASH Meeting; support for attending meetings and/or travel from FDA (honorarium); paid participation on a Data Safety Monitoring Board or Advisory Board for NIH, BARDA, 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; unpaid Board member for American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. J. H. A. reports grant funding to institution for work unrelated to this from the Centers for Disease Control and Prevention (CDC); support for speaking at SHEA Spring Conference from SHEA. S. N. reports support for travel to meetings is supported by my employer, Johnson and Johnson; stocks in J&J, author's employer. T. H. reports grant from NIH to Antibacterial Resistance Leadership Group and grants or contracts from Karius for Adjudication committee; royalties or licenses from UpToDate; consulting fees from Aridis, Pfizer, Lysovant, Affinivax, Basilea, Concert Genetics; participation on Data and Safety Monitoring Board (DSMB) for Staphylococcus aureus Network Adaptive Platform (SNAP) trial and Spero and on Advisory Board for Basilea and Paul Scherrer Institut (PSI). S. B. D. reports grants or contracts to University of California San Francisco (UCSF) from Gilead, Pfizer, F2G, Regeneron, Chan Zuckerberg Biohub, and NIAID/NIH; consulting fees to author from Genentech and Janssen/J + J; support for travel to speak at IDWeek from Infectious Diseases Society of America (IDSA); patent US20100143379A1 for Mif agonists and antagonist and therapeutic uses thereof; leadership or fiduciary roles on IDSA Antibacterial Resistance Committee, CADPH HAI Advisory Committee, Antibacterial Resistance Leadership Group Innovations Group, Laboratory Center, Mentorship Committee, Gram Positive Committee, Immunosuppressed Host Group; payment for clinical events committee/adjudication committee participation from Shinogi, Basilea, Duke Clinical Research Institute. H. C. reports stock or stock options from Merck and Moderna; membership of DSMB for COVID antiviral RCT for Merck. D. C. reports grants or contracts from Duke University for COMET study (cancer) Patient Leadership Group, from UCSF for STORMing Cancer Patient Advocate Team, and from MD Anderson for PRECISION Patient Advisory Involvement Panel; consulting fees for ongoing projects from SimBioSys and MaxisHealth, from Health Literacy Media (HLM) for Patient Advisor for ongoing projects, and from Appelis Pharmaceuticals, Inc., for consulting/project ended in 12/2022 and from Kinnate Biopharma for consulting/project ended in 06/2022; honoraria and travel support from HMP Education; support for travel from Agile Falcon Strategic Group, DGE Events, and Informa; participation on DSMB for American Society for Clinical Oncology and on Patient Partner Council for Evidera; a role on Executive Group for Metastatic Breast Cancer Alliance and a role as committee member for Alliance for Clinical Trials in Oncology; receitp of manuscript writing support from IQVIA through Regeneron. 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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Allergic bronchopulmonary aspergillosis and invasive fungal diseases represent distinct infectious entities that cause significant morbidity and mortality. Currently, administered inhaled antifungal therapies are unapproved, have suboptimal efficacy, and are associated with considerable adverse reactions. The emergence of resistant pathogens is also a growing concern. Inhaled antifungal development programs are challenged by inadequate nonclinical infection models, highly heterogenous patient populations, low prevalence rates of fungal diseases, difficulties defining clinical trial enrollment criteria, and lack of robust clinical trial endpoints. On 25 September 2020, the US Food and Drug Administration (FDA) convened a workshop with experts in pulmonary medicine and infectious diseases from academia, industry, and other governmental agencies. Key discussion topics included regulatory incentives to facilitate development of inhaled antifungal drugs and combination inhalational devices, limitations of existing nonclinical models and clinical trial designs, patient perspectives, and industry insights., Competing Interests: Potential conflicts of interest. L. B. is a full-time employee of Pulmocide. As an employee, he receives reimbursements for conference- and travel-related costs to attend scientific conferences. He also owns Pulmocide stock options. D. J. C. serves as a consultant to TFF Pharmaceuticals, which covers his travel to conferences/meetings. He also owns TFF Pharmaceuticals stock options. R. G. C. is an interim executive and consultant for companies developing and commercializing pharmaceutical, biologic, and medical device products. He is currently working with Pulmatrix (has antifungal product in development), Larimar Therapeutics (not in antifungal space), and Respira, Inc (not in antifungal space). D. W. D. and family hold Founder shares in F2G Ltd, a University of Manchester spin-out antifungal discovery company, and share options in TFF Pharmaceuticals. He acts or has recently acted as a consultant to Pulmatrix, Pulmocide, Biosergen, TFF Pharmaceuticals, Pfizer, Omega, Novacyt, Rostra Therapeutics, MucPharm, Mundipharma, and Cipla, and reports grants from Pfizer. He chairs a Data Review Committee for Pulmocide and as Phase 1 Medical Monitor for Biosergen. In the last 3 years, he has been paid for talks on behalf of BioRad, Basilea, and Pfizer. He is a longstanding member of the Infectious Diseases Society of America Aspergillosis Guidelines group, the European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines group, and recently joined the One World Guideline for Aspergillosis. He also reports issued and licensed patents for assays for fungal infection. S. H. has received grants from Pulmocide, Synerxis, Takeda, Merck, Avir Pharma, Inc, and Astellas. He also reports receiving consulting fees from Takeda. K. A. M. is the founder and chief executive officer of MycoMed Technologies. She is a consultant for Cidara Therapeutics and receives license revenue from Pearl Diagnostics. She also reports leadership or fiduciary roles at Pearl Diagnostics and Sfunga Therapeutics, and ownership of stocks or stock options of Pearl Diagnostics, Sfunga Therapeutics, and Cidara Therapeutics. R. B. M. is currently a consultant to 4D Molecular Therapeutics, Aridis Pharmaceuticals, Zambon Company SpA, and Nob Hill Therapeutics. He receives authorship and editorial royalties from UpToDate. He is on the Board of Directors of Cystic Fibrosis Research Institute. S.N.’s contributions occurred entirely while she worked at the Food and Drug Administration. She is currently employed by Johnson & Johnson and, as an employee, her travel to conferences/meetings is covered; she also owns Johnson & Johnson stock or stock options. S. N. is an unpaid member of the Scientific Advisory Committee for Global Antibiotic Research and Development Partnership. T. J. W. reports support for the workshop from the Henry Schueler Foundation. He has received grants for experimental and clinical antimicrobial pharmacology and therapeutics to his institution from Amplyx, Astellas, Leadiant, Gilead, Merck, and Shionogi. He reports payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing, or educational events from Astellas, Leadiant, Scynexis, Shionogi, Statera, and T2 Biosystems. T. J. W. also reports a leadership or fiduciary role in the Medical Mycological Society of the Americas. J. F. reports being a US government employee. 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. 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.)

Pressing challenges in the treatment of invasive fungal infections (IFIs) include emerging and rare pathogens, resistant/refractory infections, and antifungal armamentarium limited by toxicity, drug-drug interactions, and lack of oral formulations. Development of new antifungal drugs is hampered by the limitations of the available diagnostics, clinical trial endpoints, prolonged trial duration, difficulties in patient recruitment, including subpopulations (eg, pediatrics), and heterogeneity of the IFIs. On 4 August 2020, the US Food and Drug Administration convened a workshop that included IFI experts from academia, industry, and other government agencies to discuss the IFI landscape, unmet need, and potential strategies to facilitate the development of antifungal drugs for treatment and prophylaxis. This article summarizes the key topics presented and discussed during the workshop, such as incentives and research support for drug developers, nonclinical development, clinical trial design challenges, lessons learned from industry, and potential collaborations to facilitate antifungal drug development., Competing Interests: Potential conflicts of interest. P. C. was employed at the Food and Drug Administration until 31 December 2020. S. N.'s contributions occurred entirely while she worked at the Food and Drug Administration. She is currently employed by Johnson & Johnson, and as an employee her travel to conferences/meetings is covered; she also owns Johnson & Johnson stock or stock options. D. A. is an employee and own shares of Scynexis. A. D. of DaneStat Consulting is a statistical consultant for the Pharmaceutical and Biotechnology Industry; he has acted as a consultant for Adaigo, AN2, Achaogen, Allecra, Amicrobe, Amplyx, Artizan, Bioscript, Bugworks, CARBX, Cidara, Closed Loop Medicine, Correvio, ContraFect, DaVolterra, Destiny, F2G, Entasis, Gates, Geom, GSK, Gyroscope, Humanigen, Kymab, Liverpool University, Melinta, Mironid, Modis, Nabriva, Orca, Pfizer, Phico, Pled, Quince, Roche, SFunga, Scynexis, Spero, Sinovent, SNIPR Biome, TenNor, Transcrip, VenatoRx, and Zavante (payments to DaneStat Consulting). He also reports as the independent statistician on data safety monitoring boards for a number of companies, including Aridis, ContraFect Midatech, Pfizer, Pled, Rare Thyroid, Sanofi, and Transcrip. M. R. H. reports support as a full-time employee of Amplyx Pharmaceuticals, a biotech company that was developing fosmanogepix, and received stock potions and a salary. T. S. is a full-time employee of and owns stock or stock options in Cidara Therapeutics. W. H. reports grants or contracts from F2G and Pfizer; personal consulting fees from F2G, Amplyx, Pfizer, Mundipharma, and Gilead (payments to DaneStat Consulting); participation on F2G's advisory board; a role as National Institutes of Health Research Specialty Co-lead for Infection; and a data sharing agreement with Astellas without any financial commitment. T. J. W. has received grants for experimental and clinical antimicrobial pharmacology and therapeutics to his institution from Allergan, Amplyx, Astellas, Lediant, Medicines Company, Merck, Scynexis, and Tetraphase; has served as consultant to Amplyx, Astellas, Allergan, ContraFect, Gilead, Leadiant, Medicines Company, Merck, Methylgene, Pfizer, and Scynexis; reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astellas, Leadiant, Scynexis, Shinogi, Statera, and T2 Biosystems; and reports a leadership or fiduciary role in the Medical Mycological Society of the Americas. P. P. reports grants from Merck, Astellas, Scynexis, Cidara, and F2G and consulting fees from F2G and Cidara. L. K. reports support as a full-time employee of Astellas Pharma Global Development. J. H. R. is chief medical officer and director of F2G, operating partner and consultant for Advent Life Sciences, and expert in residence for Wellcome Trust. He sits on the scientific advisory boards of Bugworks Research, Basilea Pharmaceutica, Forge Therapeutics, Novo Holdings, and Roche Pharma Research & Early Development and is a shareholder in AstraZeneca Pharmaceuticals, F2G, Advent Life Sciences, Macrolide Pharmaceuticals, and Bugworks Research. He has also received consulting fees from Phico Therapeutics, ABAC Therapeutics, Polyphor, Heptares Therapeutics, Gangagen, Meiji Seika Pharma, Basilea Pharmaceutica International, Allecra Therapeutics, Forge Therapeutics, SinSa Labs, AtoxBio, Peptilogics, F. Hoffmann-LaRoche, Novo Holdings, Innocoll, Vedanta, Progenity, Nosopharm, Roivant Sciences, and Shionogi. K. A. M. is founder and chief executive officer of MycoMed Technologies and a consultant and advisory board member for Cidara Therapeutics and Sfunga Therapeutics. She has consulted for Amplyx Pharmaceuticals, Astellas Pharma, Advaxis, Chimerix, F2G, Genentech, Incyte, Merck & Co, OncoSec, RTI Surgical, Scynexis. and Vical. She receives authorship and editorial royalties from UpToDate and a grant from Merck, owns shares in Pearl Diagnostics and Sfunga Therapeutics, and is an employee of Sfunga Therapeutics. L. O. Z. has received research funding and/or personal honoraria for consulting or speaking from Pulmocide, Pfizer, Merck, Astellas, Cidara, Scynexis, F2G, Amplyx, Gilead, Therapeutics, Viracor, Octapharma, Biotoscana, Stendhal, Mayne, Takeda, RealTime Labs, and Viracor. L. O. Z. also reports honoraria from F2G, Pfizer, and Gilead; participation on a data safety monitoring board or advisory board for Octapharma, Cidara, F2G, and Pfizer; and leadership roles as president for the Mycoses Study Group and Education Consortium, president-elect for the Immunocompromised Host Society, senior editor for Journal of Antimicrobial Chemotherapy, and an associate editor for Clinical Infectious Diseases. J. F. reports being a US government employee. 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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Healthy People 2020 and the National Colorectal Cancer Roundtable established colorectal cancer (CRC) screening targets of 70.5% and 80%, respectively. While evidence-based interventions (EBIs) have increased CRC screening, the ability to achieve these targets at the population level remains uncertain. We simulated the impact of multicomponent interventions in North Carolina over 5 years to assess the potential for meeting national screening targets. Each intervention scenario is described as a core EBI with additional components indicated by the "+" symbol: patient navigation for screening colonoscopy (PN-for-Col+), mailed fecal immunochemical testing (MailedFIT+), MailedFIT+ targeted to Medicaid enrollees (MailedFIT + forMd), and provider assessment and feedback (PAF+). Each intervention was simulated with and without Medicaid expansion and at different levels of exposure (i.e., reach) for targeted populations. Outcomes included the percent up-to-date overall and by sociodemographic subgroups and number of CRC cases and deaths averted. Each multicomponent intervention was associated with increased CRC screening and averted both CRC cases and deaths; three had the potential to reach screening targets. PN-for-Col + achieved the 70.5% target with 97% reach after 1 year, and the 80% target with 78% reach after 5 years. MailedFIT+ achieved the 70.5% target with 74% reach after 1 year and 5 years. In the Medicaid population, assuming Medicaid expansion, MailedFIT + forMd reached the 70.5% target after 5 years with 97% reach. This study clarifies the potential for states to reach national CRC screening targets using multicomponent EBIs, but decision-makers also should consider tradeoffs in cost, reach, and ability to reduce disparities when selecting interventions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Coccidioidomycosis is a fungal disease endemic to the southwestern United States, Mexico, and Central and South America. Prevalence rates are increasing steadily, and new endemic areas of Coccidioides are emerging. Standard treatment is often administered for months to decades, and intolerance to medications and treatment failures are common. No new treatments for coccidioidomycosis have been approved in the United States in nearly 40 years. On 5 August 2020, the US Food and Drug Administration convened experts in coccidioidomycosis from academia, industry, patient groups, and other government agencies to discuss the disease landscape and strategies to facilitate product development for treatment of coccidioidomycosis. This article summarizes the key topics concerning drug development for coccidioidomycosis presented by speakers and panelists during the workshop, such as unmet need, trial designs, endpoints, incentives, research and development support, and collaborations to facilitate antifungal drug development., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

Parental feeding practices and styles influence child diet quality and growth. The extent to which these factors have been assessed in the context of disadvantage, particularly household food insecurity (HFI), is unknown. This is important, as interventions designed to increase responsive practices and styles may not consider the unique needs of families with HFI. To address this gap, a scoping review of studies published from 1990 to July 2021 in three electronic databases was conducted. A priori inclusion criteria were, population: families with children aged 0-5 years experiencing food insecurity and/or disadvantage; concept: parental feeding practices/behaviours/style; and context: high income countries. The search identified 12,950 unique papers, 504 full-text articles were screened and 131 met the inclusion criteria. Almost all the studies (91%) were conducted in the United States with recruitment via existing programs for families on low incomes. Only 27 papers assessed feeding practices or styles in the context of HFI. Of the eleven interventions identified, two assessed the proportion of participants who were food insecure. More research is required in families outside of the United States, with an emphasis on comprehensive and valid measures of HFI and feeding practices. Intervention design should be sensitive to factors associated with poverty, including food insecurity.

In November 2019, the Food and Drug Administration (FDA) approved cefiderocol for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by susceptible gram-negative bacteria in adults with limited to no alternative treatment options based on a randomized, double-blind, noninferiority cUTI trial (APEKS-cUTI). In a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria, an increase in all-cause mortality was observed in patients treated with cefiderocol as compared to best available therapy. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure. Preliminary data from a randomized, double-blind trial (APEKS-NP) in patients with nosocomial pneumonia due to carbapenem-susceptible gram-negative bacteria showed a similar rate of mortality as compared to meropenem. We describe the uncertainties and challenges in the interpretation of the CREDIBLE-CR trial and some benefit-risk considerations for the use of cefiderocol in clinical practice. Clinical Trials Registration: NCT02321800., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

Although screening is effective in reducing incidence, mortality, and costs of treating colorectal cancer (CRC), it remains underutilized, in part due to limited insurance access. We used microsimulation to estimate the health and financial effects of insurance expansion and reduction scenarios in North Carolina (NC). We simulated the full lifetime of a simulated population of 3,298,265 residents age-eligible for CRC screening (ages 50-75) during a 5-year period starting January 1, 2018, including polyp incidence and progression and CRC screening, diagnosis, treatment, and mortality. Insurance scenarios included: status quo, which in NC includes access to the Health Insurance Exchange (HIE) under the Affordable Care Act (ACA); no ACA; NC Medicaid expansion, and Medicare-for-all. The insurance expansion scenarios would increase percent up-to-date with screening by 0.3 and 7.1 percentage points for Medicaid expansion and Medicare-for-all, respectively, while insurance reduction would reduce percent up-to-date by 1.1 percentage points, compared to the status quo (51.7% up-to-date), at the end of the 5-year period. Throughout these individuals' lifetimes, this change in CRC screening/testing results in an estimated 498 CRC cases averted with Medicaid expansion and 6031 averted with Medicare-for-all, and an additional 1782 cases if health insurance gains associated with ACA are lost. Estimated cost savings - balancing increased CRC screening/testing costs against decreased cancer treatment costs - are approximately $30 M and $970 M for Medicaid expansion and Medicare-for-all scenarios, respectively, compared to status quo. Insurance expansion is likely to improve CRC screening both overall and in underserved populations while saving money, with the largest savings realized by Medicare., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) can be effectively prevented or detected with guideline concordant screening, yet Medicaid enrollees experience disparities. We used microsimulation to project CRC screening patterns, CRC cases averted, and life-years gained in the population of 68,077 Oregon Medicaid enrollees 50-64 over a five year period starting in January 2019. The simulation estimated the cost-effectiveness of five intervention scenarios - academic detailing plus provider audit and feedback (Detailing+), patient reminders (Reminders), mailing a Fecal Immunochemical Test (FIT) directly to the patient's home (Mailed FIT), patient navigation (Navigation), and mailed FIT with Navigation (Mailed FIT + Navigation) - compared to usual care. Each intervention scenario raised CRC screening rates compared to usual care, with improvements as high as 11.6 percentage points (Mailed FIT + Navigation) and as low as 2.5 percentage points (Reminders) after one year. Compared to usual care, Mailed FIT + Navigation would raise CRC screening rates 20.2 percentage points after five years - averting nearly 77 cancer cases (a reduction of 113 per 100,000) and exceeding national screening targets. Over a five year period, Reminders, Mailed FIT and Mailed FIT + Navigation were expected to be cost effective if stakeholders were willing to pay $230 or less per additional year up-to-date (at a cost of $22, $59, and $227 respectively), whereas Detailing+ and Navigation were more costly for the same benefits. To approach national CRC screening targets, health system stakeholders are encouraged to implement Mailed FIT with or without Navigation and Reminders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The Clinical Trials Transformation Initiative convened with several groups in the pediatric antibacterial drug development community with the goal of identifying challenges and recommending ways to improve current practice. Attention to 5 major areas hold the promise of making new antibiotics available for use in children as soon as possible after they are approved for use in adults., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society.)

Background and Objectives: The impact of the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) on pediatric antibacterial or antifungal drug trials is unknown. Our objective was to identify and characterize trials conducted under the BPCA and/or the PREA., Methods: Pediatric antibacterial and antifungal drug trials with industry or US federal funding registered in clinicaltrials.gov from 2007 to 2017 were identified. Those conducted under BPCA and/or PREA were identified through US Food and Drug Administration and National Institute of Child Health and Human Development databases., Results: Of 17 495 pediatric trials registered on clinicaltrials.gov between October 2007 and September 2017, 122 systemic antibacterial or antifungal drug trials with industry or US federal funding were identified. Of these 122 trials, 98 (80%) involved antibacterials only, 23 (19%) antifungals only, and 1 (1%) both antibacterials and antifungals. These represented <1% (122 of 17 495) of pediatric trials. Neither pediatric antibacterial nor antifungal drug trials commonly enrolled neonates 0 to 30 days old (30% [30 of 99] vs 42% [10 of 24], respectively). Pediatric antibacterial and antifungal trials were commonly industry funded (79% [78 of 99] and 83% [20 of 24], respectively). In total, 65% (79 of 122) of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA. Researchers in trials conducted under BPCA and/or PREA, relative to non-BPCA and/or PREA trials, more often collected pharmacokinetic data (70% [55 of 79] vs 26% [11 of 43])., Conclusions: Although the majority of pediatric antibacterial and/or antifungal drug trials were conducted under BPCA and/or PREA, the overall number was low. Greater effort is needed to stimulate such trials., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Benjamin has received grants and revenue from AstraZeneca, Cempra Pharmaceuticals, Shionogi Inc, The Medicines Company, and Cidara Therapeutics, which are unrelated to the current study. Dr Smith has consulted on antifungal trials for Astellas Pharma Inc; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Hypoglycemia was not previously known to be a linezolid-associated adverse reaction. A case report describing symptomatic hypoglycemia in a linezolid recipient prompted a review of the US Food and Drug Administration Adverse Event Reporting System, which demonstrated a relationship between linezolid and hypoglycemia. A warning with this information was added to the linezolid package insert., (© The Author 2014. 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.)

Purpose: In 2005, the Food and Drug Administration approved Qualaquin (quinine) for treatment of malaria and later ordered unapproved quinine formulations off the market. In 2009, labeling for Qualaquin added a warning for use for leg cramps, as serious hematologic reactions could occur. We examined quinine use trends among Medicare beneficiaries focusing on indications for use and associations with adverse hematologic outcomes., Methods: Medicare beneficiaries, aged 65 years and older, in 2006-2012, were included in incident quinine or comparator, diltiazem, cohorts if 183 days prior to dispensing, they were enrolled in Medicare, had no dispensing of quinine, diltiazem, ticlodipine, clopidogrel, and sulfonamide drugs, and had no diagnoses of thrombocytopenia, immune thrombocytopenic purpura (ITP), thrombotic microangiopathy (TMA), or hemolytic-uremic syndrome (HUS). Diagnoses of malaria or leg cramps were observed during 183 days prior to index dispensing. Outcomes of ITP, TMA, or HUS in inpatient or emergency room settings were then observed during drug use., Results: Prevalent use of quinine decreased by 99%, from 419 675 to 6036 users during 2006-2012. Of 88 066 quinine users, 9 had diagnoses of malaria and 36 218 had leg cramps. Incidence rates (per 1000 person-years) for ITP were quinine 1.67 and diltiazem 0.40 [incidence rate ratio 4.2 (95% confidence interval 2.5, 6.5)], for TMA were quinine 0.23 and diltiazem 0.03 [incidence rate ratio 6.9 (95% confidence interval 1.3, 24.0)], and for HUS were quinine 0 and diltiazem 0.01., Conclusions: Use of quinine decreased substantially, although diagnoses of leg cramps persist. To our knowledge, this is the first demonstration of an association for quinine and ITP and TMA in claims data., (Copyright © 2014 John Wiley & Sons, Ltd.)

In response to concerns raised about the quality of parenteral vancomycin products, the U.S. Food and Drug Administration (FDA) is investigating the product quality of all FDA-approved parenteral vancomycin products available in the United States. Product quality was evaluated independently at two FDA Office of Testing and Research (FDA-OTR) sites. In the next phase of the investigation, being done in collaboration with the National Institute of Allergy and Infectious Diseases, the in vivo activity of these products will be evaluated in an appropriate animal model. This paper summarizes results of the FDA investigation completed thus far. One site used a validated ultrahigh-pressure liquid chromatography method (OTR-UPLC), and the second site used the high-performance liquid chromatography (HPLC) method for related substances provided in the British Pharmacopeia (BP) monograph for vancomycin intravenous infusion. Similar results were obtained by the two FDA-OTR laboratories using two different analytical methods. The products tested had 90 to 95% vancomycin B (active component of vancomycin) by the BP-HPLC method and 89 to 94% vancomycin by OTR-UPLC methods. Total impurities were 5 to 10% by BP-HPLC and 6 to 11% by OTR-UPLC methods. No single impurity was >2.0%, and the CDP-1 level was ≤ 2.0% across all products. Some variability in impurity profiles of the various products was observed. No adverse product quality issues were identified with the six U.S. vancomycin parenteral products. The quality parameters of all parenteral vancomycin products tested surpassed the United States Pharmacopeia acceptance criteria. Additional testing will characterize in vivo performance characteristics of these products.

Background: Eosinophilic pneumonia (EP) has been noted in association with daptomycin use. The product labelling was recently updated to include EP in the Warnings and Precautions and Post-Marketing Experience sections., Objective: The objective of this study was to analyse adverse event (AE) reports submitted to the US FDA as well as published cases to characterize the clinical features and course of EP in daptomycin-treated patients., Methods: We searched for EP cases associated with daptomycin administration in the FDA Adverse Event Reporting System (AERS) submitted from 2004 to 2010, and the published literature. Cases were defined as definite, probable, possible and unlikely in terms of the diagnosis of EP and the potential association with daptomycin exposure. Definite cases had concurrent exposure to daptomycin, fever, dyspnoea with increased oxygen requirement or required mechanical ventilation, new infiltrates on chest imaging, bronchoalveolar lavage with >25% eosinophils and clinical improvement following daptomycin withdrawal. Additionally, we assessed inpatient daptomycin utilization., Results: We identified 7 definite, 13 probable, 38 possible cases of daptomycin-induced EP, and 23 unlikely cases. The seven definite EP cases had resolution after daptomycin was stopped, including two with EP recurrence following daptomycin rechallenge. Regarding the definite cases: (i) ages ranged from 60 to 87 years; (ii) dosing ranged from 4.4 to 8.0 mg/kg/day; and (iii) EP developed 10 days to 4 weeks after starting daptomycin. There was a gradual increase in the number of patients with an inpatient hospital discharge billing for daptomycin from the year 2004 to 2010., Conclusions: We report 7 definite, 13 probable and 38 possible EP cases associated with daptomycin administration. As AERS is based on voluntary reporting, the incidence of EP cannot be assessed. Healthcare providers should have heightened awareness of this serious AE associated with daptomycin use.

Since 1989, 12 registration trials have been submitted to the US Food and Drug Administration to support the clinical efficacy of 8 antibacterial drugs for the treatment of nosocomial pneumonia. Six trials used noninferiority designs, whereas the others were equivalence trials or lacked a prespecified hypothesis. Patients with nosocomial pneumonia and ventilator-associated pneumonia were frequently enrolled in the same clinical trials. Enrolled patients were predominantly male and had mean Acute Physiology and Chronic Health Evaluation II scores of 12-18. The investigator's assessment of clinical response was the primary end point, which was usually measured 7-14 days after study drug completion. Clinical cure rates among the intent-to-treat population for nosocomial pneumonia and ventilator-associated pneumonia ranged from 37% to 69% and 25% to 58%, respectively. All-cause mortality ranged from 8% to 28%. Pseudomonas aeruginosa, Acinetobacter species, and methicillin-resistant Staphylococcus aureus were common bacterial pathogens. The design, implementation, and limitations of the clinical trials and implications for future clinical research are discussed.

Background: Gram-negative rods (GNR) and species are important causes of health care-associated infections in neonatal intensive care units (NICUs). In prior reports, Gram-positive cocci (GPC) have been identified as the most common pathogens causing nosocomial infections in NICUs., Objective: To describe the epidemiology of health care-associated infections in a Level III NICU at a free-standing children's hospital., Methods: All health care-associated infections in neonates from August 1996 to July 2001 were analyzed. Data were collected prospectively by standard surveillance protocols and nosocomial infection site definitions from the National Nosocomial Infection Surveillance system of the Centers for Disease Control and Prevention., Results: During the 5-year study period, 665 pathogens caused 640 infections in the NICU. GNR were the most common pathogens isolated. Of the 665 pathogens 284 (43%) were GNR, followed by 223 (33.5%) GPC, 106 (16%) fungi and 52 (8%) others. spp. were the most common GNR isolated. Ceftazidime resistance was present in 56 of 81 (69%) isolates. Bloodstream and lower respiratory tract infections were the most common sites of infection. More than one-half of the pathogens (388 of 665) were isolated from neonates weighing < or =1000 g., Conclusions: There is a change in the epidemiology of health care-associated infections in our NICU with a predominance of GNR. This change can impact choice of antimicrobials for the empiric treatment of health care-associated infections in high risk neonates.