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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.)

Background: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI)., Methods: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator., Results: Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator., Conclusions: We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. H. C. reports grant funding from the NIH; participation in a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. D. C. reports grant funding from Apellis Pharmaceuticals, CRUK Cancer Grand Challenges, Kinnate Biopharma, and Incyte; consulting fees from Health Literacy Media and MaxisIT Clinical Science; payment for expert panel session from Pfizer; participation on a patient advisory council and travel support for meetings from M2GEN; and participation in the American Society of Clinical Oncology TAPUR Study DSMB and Parexel patient advisory council. S. B. D. reports grant funding from NIH; grant funding for COVID-19–related clinical trials from Gilead and Regeneron; payments for clinical event adjudication committees from Basilea and Shinogi; and consulting fees from Genentech. S. E. reports grant funding from NIH, Degruyter, and Aceragen; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Dickinson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION); support for attending meetings from FDA, Deming Conference on Applied Statistics, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association Applied Statistics Symposium, and Antimicrobial Resistance and Stewardship Conference; participation on DSMB for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Candel; and board membership for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. V. G. F. reports grant funding or contracts from NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck, Medical Biosurfaces, Locus, Affinergy, Contrafect, Karius, Genetech, Regeneron, Deep Blue, Basilea, and Janssen; royalties from UpToDate; consulting fees from Novartis, Debiopharm, Genetech, Achaogen, Affinium, The Medicines Co., MedImmune, Bayer, Basilea, Affinergy, Janssen, Contrafect, Regeneron, Destiny, Amphliphi Biosciences, Integrated Biotherapeutics, C3J, Armata, Valanbio, Akagera, Aridis, Roche, and Pfizer; support from Contrafect to present phase 2 data at 2019 European Congress of Clinical Microbiology and Infectious Diseases; a patent for sepsis diagnostics; serving as Associate Editor of Clinical Infectious Diseases in 2017–2022; and stock options from ArcBio and Valanbio. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma K.K; a contract from Aceragen; payment for lectures from Duke University and Johnson & Johnson K.K.; and payment for manuscript preparation from Cancer and Chemotherapy K.K. (Japanese Journal of Cancer and Chemotherapy). T. L. H. reports grant funding from NIH; royalties from UpToDate; consulting fees from Lysovant and Affinivax; and participation on DSMB for SNAP Trial Platform. J. H.-A. reports grant funding from NIH. S. N. is an employee of Johnson & Johnson. U. W. reports support from the American Society for Microbiology to attend ASM Microbe 2022 as a speaker. 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.)

Background: Traditional end points used in registrational randomized, controlled trials (RCTs) often do not allow for complete interpretation of the full range of potential clinical outcomes. Desirability of outcome ranking (DOOR) is an approach to the design and analysis of clinical trials that incorporates benefits and risks of novel treatment strategies and provides a global assessment of patient experience., Methods: Through a multidisciplinary committee of experts in infectious diseases, clinical trial design, drug regulation, and patient experience, we developed a DOOR end point for infectious disease syndromes and demonstrated how this could be applied to 3 registrational drug trials (ZEUS, APEKS-cUTI, and DORI-05) for complicated urinary tract infections (cUTIs). ZEUS compared fosfomycin to piperacillin/tazobactam, APEKS-cUTI compared cefiderocol to imipenem, and DORI-05 compared doripenem to levofloxacin. Using DOOR, we estimated the probability of a more desirable outcome with each investigational antibacterial drug., Results: In each RCT, the DOOR distribution was similar and the probability that a patient in the investigational arm would have a more desirable outcome than a patient in the control arm had a 95% confidence interval containing 50%, indicating no significant difference between treatment arms. DOOR facilitated improved understanding of potential trade-offs between clinical efficacy and safety. Partial credit and subgroup analyses also highlight unique attributes of DOOR., Conclusions: DOOR can effectively be used in registrational cUTI trials. The DOOR end point presented here can be adapted for other infectious disease syndromes and prospectively incorporated into future clinical trials., Competing Interests: Potential conflicts of interest. H. W. B. declares consulting fees from Antimicrobial Agents and Chemotherapy, Sanford Guide, and ID Clinics of North America. T. B. is an employee of and holds stock in Shionogi & Co and reports a nondisclosure agreement between Duke University and Shionogi (to share the analysis conducted by Shionogi with the Antibacterial Resistance Leadership Group [ARLG]). H. F. C. reports grant funding from NIH; consulting fees from Johnson & Johnson; participation on a data and safety monitoring board (DSMB) for Merck; and stock in Merck and Moderna. S. B. D. reports research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. S. R. E. reports grant funding from NIH and Degruyter; royalties from Taylor & Francis; consulting fees from Genetech, AstraZeneca, Takeda, Microbiotix, Johnson & Johnson, Endologix, ChemoCentryx, Becton Bickenson, Atricure, Roivant, Neovasc, Nobel Pharma, Horizon, International Drug Development Institute, and SVB Leerink; payments for lectures from the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; support for attending meetings from FDA, Clinical Trial Transformation Initiative, Council for International Organization of Medical Sciences, International Chinese Statistical Association, participation on DSMBs for NIH, Breast International Group, University of Pennsylvania, Duke University, Roche, Pfizer, Takeda, Akouous, Appelis, Teva, Vir, DayOneBio, Alexion, Tracon, Rakuten, AbbVie, Nuvelution, Clover, FHI Clinical, Lung Biotech, SAB Biopharm, and Advantagene; and being a board member for the American Statistical Association, Society for Clinical Trials, and Frontier Science Foundation. 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 the Infectious Diseases of America for service as associate editor of Clinical Infectious Diseases; and a patent for sepsis diagnostics is pending. S. P. G. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. T. H. reports consulting fees from Tanabe-Mitsubishi Pharma and payment for lectures from Johnson & Johnson and Duke University. T. L. H. declares royalties from UpToDate and consulting fees from Basilea Pharmaceutica, MotifBio, Genentech, and Lysovant. D. M. is an employee of Nabriva Therapeutics and holds stock in Nabriva Therapeutics. S. N. is an employee of Johnson & Johnson and holds stock in Johnson & Johnson. J. H.-A. report grants from NIH (funding to ARLG, payments made to institution). S. B. D. reports grants or contracts from NIH funding to the ARLG; research funding from Gilead, Regeneron, and NIH; payments for clinical event adjudication committees from Basilea and Shionogi (pending); and consulting fees from Genentech. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Infections remain a leading cause of death in neonates. The sparse antibiotic development pipeline and challenges in conducting neonatal research have resulted in few effective antibiotics being adequately studied to treat multidrug-resistant (MDR) infections in neonates, despite the increasing global mortality burden caused by antimicrobial resistance. Of 40 antibiotics approved for use in adults since 2000, only four have included dosing information for neonates in their labelling. Currently, 43 adult antibiotic clinical trials are recruiting patients, compared with only six trials recruiting neonates. We review the World Health Organization (WHO) priority pathogens list relevant to neonatal sepsis and propose a WHO multiexpert stakeholder meeting to promote the development of a neonatal priority antibiotic development list. The goal is to develop international, interdisciplinary consensus for an accelerated neonatal antibiotic development programme. This programme would enable focused research on identified priority antibiotics for neonates to reduce the excess morbidity and mortality caused by MDR infections in this vulnerable population., ((c) 2022 The authors; licensee World Health Organization.)

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.)

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.)

A decline in antibacterial drug development coupled with emerging bacterial resistance has resulted in limited treatment options. One of the challenges facing antibacterial drug development is appropriate clinical trial designs. Noninferiority trials are appropriate to study new antibacterial drugs for the treatment of serious diseases; superiority trials can be challenging and cannot be the only acceptable trial design to study antibacterial drugs. Our efforts must continue to make new therapies available to meet patient needs.

We report hypersensitivity reactions associated with fidaxomicin, an antibacterial drug approved for the treatment of Clostridium difficile-associated diarrhea. These reactions are viewed as significant because of severity and unexpected because fidaxomicin is minimally absorbed. The fidaxomicin labeling was revised to include information about the possibility of hypersensitivity reactions.

Background: Addition of antibacterial drugs to interim antibacterial cement spacers (ACSs) is considered to be standard of care for surgical revision in prosthetic joint infections (PJIs). We reviewed published studies evaluating the choice and doses of antibacterials in spacers., Methods: We conducted a PubMed search of all clinical study reports evaluating the use of ACSS in a 2-stage hip or knee arthroplasty for treatment of PJI (1988 through August 2011). The trial design, antibacterials used, and end points studied were analyzed., Results: No randomized trials were found comparing either ACSs with different concentrations of antibacterials or ACSs with or without antibacterials. Most of the studies were uncontrolled and used various time points to evaluate the outcome. Twenty publications that reported doses of antibacterials in spacers and had a follow-up of ≥ 24 months after the second stage were selected for review. Most ACSs included vancomycin and aminoglycosides. The doses of aminoglycosides and vancomycin ranged from 0.25 to 4.8 g and from 1 to 4 g, respectively, per 4 g of cement. No association between reported eradication of the infection and antibacterial load was found., Conclusions: Published data do not allow evaluation of whether antibacterials in temporary cement spacers provide additional benefits in the treatment of PJI, compared with systemic antibacterials, and are not sufficient to support recommendations on dosages. Complications of ACSs have not been consistently analyzed. Prospective randomized trials comparing spacers with and without antibacterials or spacers with different loads of antibacterials are needed to evaluate the safety and efficacy of ACSs.

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.

Background: On the basis of meta-analyses, concern has been raised regarding a possible signal of increased mortality associated with the use of cefepime versus other beta-lactam antibiotics. To further investigate this possible signal, we accessed findings and data from published and unpublished cefepime clinical trials., Methods: We performed meta-analyses using trial- and patient-level data from comparative trials. Trial-level analyses were performed using summary data from all patients in the trials, and patient-level analyses were performed on trials for which patient-level data were available. Thirty-day, all-cause mortality was analyzed using the Mantel-Haenszel adjusted risk difference (ARD) method., Results: The trial-level meta-analysis was based on 88 trials (9467 cefepime patients and 8288 comparator patients). The 30-day, all-cause mortality rates were 6.21% (588/9467) for the cefepime patients and 6.00% (497/8288) for comparator patients (ARD per 1000 population, 5.38; 95% confidence interval [CI], -1.53 to 12.28). In the patient-level analysis (35 trials, 5058 cefepime patients, and 3976 comparator patients), 30-day, all-cause mortality rates were 5.63% (285/5058) for cefepime patients and 5.68% (226/3976) for comparator patients (ARD per 1000 population, 4.83; 95% CI, -4.72 to 14.38). A sensitivity analysis based solely on the 24 febrile neutropenia trials did not show a statistically significant increase in mortality with cefepime use (ARD per 1000 population, 9.67; 95% CI, -2.87 to 22.21)., Conclusions: In both trial-level and patient-level meta-analyses, we did not identify a statistically significant increase in mortality among cefepime-treated patients, compared with those treated with other antibacterials.

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.

Objectives: Unsolicited reports regarding potentially serious adverse drug reactions in neonates and young infants were reported to the Food and Drug Administration, leading to changes in the package label for ceftriaxone. This report describes and summarizes the reported cases that led to safety concerns regarding the concurrent administration of intravenous ceftriaxone and calcium in this age group., Methods: Nine reported cases were assessed. The Food and Drug Administration Adverse Event Reporting System database was searched for potential drug interactions in patients who were receiving concomitant ceftriaxone and calcium therapy., Results: Eight of the reported 9 cases (7 were < or =2 months of age) represented possible or probable adverse drug events. There were 7 deaths. None of the cases were reported from the United States. The dosage of ceftriaxone that was administered to 4 of 6 infants for whom this information was available was between 150 and 200 mg/kg per day. The rate of occurrence of these serious adverse drug reactions cannot be accurately determined from available data., Conclusions: The concurrent use of intravenous ceftriaxone and calcium-containing solutions in the newborn and young infant may result in a life-threatening adverse drug reaction. Contributing factors for infants in this report may include the use of ceftriaxone at dosages higher than those approved by the Food and Drug Administration, intravenous "push" administration, and administration of the total daily dosage as a single infusion.

All recent studies of antibacterial drugs for the indication of community-acquired pneumonia submitted to the US Food and Drug Administration have been designed as noninferiority studies. We provide a summary of results of 7 recent clinical studies of oral antibacterial drugs for treatment of community-acquired pneumonia. In these 7 studies, the majority of patients enrolled had Pneumonia Patient Outcomes Research Team scores of I or II. The percentage of randomized subjects with pathogens identified at baseline ranged from 47% to 76%, and the percentage of subjects with Streptoccocus pneumoniae isolated at baseline ranged from approximately 6% to 20%. The primary end point in these studies was clinical cure, assessed 7-21 days after completion of therapy. Clinical cure rates were >80% in the intent-to-treat populations and >90% in the per-protocol populations. We also briefly summarize the results from several recently submitted clinical studies of intravenously administered antibacterial drugs for treatment of community-acquired pneumonia, in which we found similar results.

A noninferiority margin based on the treatment effect of antibacterial drugs is required for noninferiority studies of community-acquired pneumonia. A quantitative estimate of treatment effect is generally determined from placebo-controlled trials, but, since the mid-to-late 1930s, no studies have compared outcomes for patients who received placebo (or no specific therapy) with those for patients who received an antibacterial drug for treatment of community-acquired pneumonia. In this article, early controlled studies, as well as observational data, are reviewed, and the beneficial effect of antibacterial drugs on mortality rates among patients with pneumococcal pneumonia is demonstrated. However, because these data were obtained in the early 20th century, several important factors have changed, including patient populations, the etiological agents of pneumonia, and medical standards of care. Thus, the applicability of these studies to the determination of a noninferiority margin for contemporary trials for community-acquired pneumonia remains in question.

Background: In 1997, the Centers for Disease Control and Prevention (CDC), in collaboration with other professional organizations, released principles for judicious use of antibiotics in pediatric upper respiratory illnesses (URI). This study compared use of antibiotics for URI in children before (1995) and after (1998) publication of the principles and compared survey responses with practice habits., Methods: A questionnaire was mailed to a sample of pediatricians in northern Virginia. Office records of a randomly selected subset of pediatricians were reviewed., Results: Seventy-five percent of pediatricians completed the questionnaire; 51/149 (34%) chose to prescribe antibiotics for purulent rhinorrhea of less than 10 days' duration. This was significantly lower than that reported in the 1995 survey. However, review of office records of a random sample of these pediatricians revealed no significant difference in antibiotic use in children with uncomplicated URI in the 2 years studied., Conclusions: Injudicious antibiotic use for URI is prevalent among pediatricians in northern Virginia. Actual practice habits are at variance with response to case vignettes.