Exploration of a Potential DOOR Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

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 4,000 participants enrolled in six registrational trials for HABP/VABP submitted to the FDA between 2005-2022, 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. Though 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.

Predictive Modeling of Drug-Related Adverse Events with Real-World Data: A Case Study of Linezolid Hematologic Outcomes.

Electronic health records (EHRs) provide meaningful knowledge of drug-related adverse events (AEs) that are not captured in standard drug development and postmarketing surveillance. Using variables obtained from EHR data in the University of California San Francisco de-identified Clinical Data Warehouse, we aimed to evaluate the potential of machine learning to predict two hematological AEs, thrombocytopenia and anemia, in a cohort of patients treated with linezolid for 3 or more days. Features for model input were extracted at linezolid initiation (index), and outcomes were characterized from index to 14 days post-treatment. Random forest classification (RFC) was used for AE prediction, and reduced feature models were evaluated using cumulative importance (cImp) for feature selection. Grade 3+ thrombocytopenia and anemia occurred in 31% of 2,171 and 56% of 2,170 evaluable patients, respectively. Of the total 53 features, as few as 7 contributed at least 50% cImp, resulting in prediction accuracies of 70% or higher and area under the receiver operating characteristic curves of 0.886 for grade 3+ thrombocytopenia and 0.759 for grade 3+ anemia. Sensitivity analyses in strictly defined patient subgroups revealed similarly high predictive performance in full and reduced feature models. A logistic regression model with the same 50% cImp features showed similar predictive performance as RFC and good concordance with RFC probability predictions after isotonic calibration, adding interpretability. Collectively, this work demonstrates potential for machine learning prediction of AE risk in real-world patients using few variables regularly available in EHRs, which may aid in clinical decision making and/or monitoring.

A Risk Profile Using Simple Hematologic Parameters to Assess Benefits From Baricitinib in Patients Hospitalized With COVID-19: A Post Hoc Analysis of the Adaptive COVID-19 Treatment Trial-2.

BACKGROUND: The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib. OBJECTIVE: To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile. DESIGN: Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579). SETTING: Sixty-seven trial sites in 8 countries. PARTICIPANTS: Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants). INTERVENTION: Baricitinib+remdesivir versus placebo+remdesivir. MEASUREMENTS: Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories. RESULTS: In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile. LIMITATION: Secondary analysis of data collected before circulation of current SARS-CoV-2 variants. CONCLUSION: The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Moving Beyond Mortality: Development and Application of a Desirability of Outcome Ranking (DOOR) Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia.

BACKGROUND: Hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) are frequently caused by multidrug-resistant organisms. Patient-centered endpoints in clinical trials are needed to develop new antibiotics for HABP/VABP. Desirability of outcome ranking (DOOR) is a paradigm for the design, analysis, and interpretation of clinical trials based on a patient-centered, benefit-risk evaluation. METHODS: A multidisciplinary committee created an infectious diseases DOOR endpoint customized for HABP/VABP, incorporating infectious complications, serious adverse events, and mortality. We applied this to 2 previously completed, large randomized controlled trials for HABP/VABP. ZEPHyR compared vancomycin to linezolid and VITAL compared linezolid to tedizolid. For each trial, we evaluated the DOOR distribution and probability, including DOOR component and partial credit analyses. We also applied DOOR in subgroup analyses. RESULTS: In both trials, the HABP/VABP DOOR demonstrated similar overall clinical outcomes between treatment groups. In ZEPHyR, the probability that a participant treated with linezolid would have a more desirable outcome than a participant treated with vancomycin was 50.2% (95% confidence interval [CI], 45.1%--55.3%). In VITAL, the probability that a participant treated with tedizolid would have a more desirable outcome than a participant treated with linezolid was 48.7% (95% CI, 44.8%-52.6%). The DOOR component analysis revealed that participants treated with tedizolid had a less desirable outcome than those treated with linezolid when considering clinical response alone. However, participants with decreased renal function had improved overall outcomes with tedizolid. CONCLUSIONS: The HABP/VABP DOOR provided more granular information about clinical outcomes than is typically presented in clinical trials. HABP/VABP trials would benefit from prospectively using DOOR.

Contemporary Management of Staphylococcus aureus Bacteremia-Controversies in Clinical Practice.

Staphylococcus aureus bacteremia (SAB) carries a high risk for excess morbidity and mortality. Despite its prevalence, significant practice variation continues to permeate clinical management of this syndrome. Since the publication of the 2011 Infectious Diseases Society of America (IDSA) guidelines on management of methicillin-resistant Staphylococcus aureus infections, the field of SAB has evolved with the emergence of newer diagnostic strategies and therapeutic options. In this review, we seek to provide a comprehensive overview of the evaluation and management of SAB, with special focus on areas where the highest level of evidence is lacking to inform best practices.

Priorities and Progress in Gram-positive Bacterial Infection Research by the Antibacterial Resistance Leadership Group: A Narrative Review.

The Antibacterial Resistance Leadership Group (ARLG) has prioritized infections caused by gram-positive bacteria as one of its core areas of emphasis. The ARLG Gram-positive Committee has focused on studies responding to 3 main identified research priorities: (1) investigation of strategies or therapies for infections predominantly caused by gram-positive bacteria, (2) evaluation of the efficacy of novel agents for infections caused by methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci, and (3) optimization of dosing and duration of antimicrobial agents for gram-positive infections. Herein, we summarize ARLG accomplishments in gram-positive bacterial infection research, including studies aiming to (1) inform optimal vancomycin dosing, (2) determine the role of dalbavancin in MRSA bloodstream infection, (3) characterize enterococcal bloodstream infections, (4) demonstrate the benefits of short-course therapy for pediatric community-acquired pneumonia, (5) develop quality of life measures for use in clinical trials, and (6) advance understanding of the microbiome. Future studies will incorporate innovative methodologies with a focus on interventional clinical trials that have the potential to change clinical practice for difficult-to-treat infections, such as MRSA bloodstream infections.

Priorities and Progress in Diagnostic Research by the Antibacterial Resistance Leadership Group.

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.

Ceftobiprole for Treatment of Complicated Staphylococcus aureus Bacteremia.

BACKGROUND: Ceftobiprole is a cephalosporin that may be effective for treating complicated Staphylococcus aureus bacteremia, including methicillin-resistant S. aureus. METHODS: In this phase 3, double-blind, double-dummy, noninferiority trial, adults with complicated S. aureus bacteremia were randomly assigned in a 1:1 ratio to receive ceftobiprole at a dose of 500 mg intravenously every 6 hours for 8 days and every 8 hours thereafter, or daptomycin at a dose of 6 to 10 mg per kilogram of body weight intravenously every 24 hours plus optional aztreonam (at the discretion of the trial-site investigators). The primary outcome, overall treatment success 70 days after randomization (defined as survival, bacteremia clearance, symptom improvement, no new S. aureus bacteremia-related complications, and no receipt of other potentially effective antibiotics), with a noninferiority margin of 15%, was adjudicated by a data review committee whose members were unaware of the trial-group assignments. Safety was also assessed. RESULTS: Of 390 patients who underwent randomization, 387 (189 in the ceftobiprole group and 198 in the daptomycin group) had confirmed S. aureus bacteremia and received ceftobiprole or daptomycin (modified intention-to-treat population). A total of 132 of 189 patients (69.8%) in the ceftobiprole group and 136 of 198 patients (68.7%) in the daptomycin group had overall treatment success (adjusted difference, 2.0 percentage points; 95% confidence interval [CI], -7.1 to 11.1). Findings appeared to be consistent between the ceftobiprole and daptomycin groups in key subgroups and with respect to secondary outcomes, including mortality (9.0% and 9.1%, respectively; 95% CI, -6.2 to 5.2) and the percentage of patients with microbiologic eradication (82.0% and 77.3%; 95% CI, -2.9 to 13.0). Adverse events were reported in 121 of 191 patients (63.4%) who received ceftobiprole and 117 of 198 patients (59.1%) who received daptomycin; serious adverse events were reported in 36 patients (18.8%) and 45 patients (22.7%), respectively. Gastrointestinal adverse events (primarily mild nausea) were more frequent with ceftobiprole. CONCLUSIONS: Ceftobiprole was noninferior to daptomycin with respect to overall treatment success in patients with complicated S. aureus bacteremia. (Funded by Basilea Pharmaceutica International and the U.S. Department of Health and Human Services; ERADICATE ClinicalTrials.gov number, NCT03138733.).

Principles and Practice of Antimicrobial Stewardship Program Resource Allocation.

Antimicrobial Stewardship Programs (ASP) improve individual patient outcomes and clinical care processes while reducing antimicrobial-associated adverse events, optimizing operational priorities, and providing institutional cost savings. ASP composition, resources required, and priority focuses are influenced by myriad factors. Despite robust evidence and broad national support, individual ASPs still face challenges in obtaining appropriate resources. Though understanding the current landscape of ASP resource allocation, factors influencing staffing needs, and strategies required to obtain desired resources is important, acceptance of recommended staffing levels and appropriate ASP resource allocation are much needed to facilitate ASP sustainability and growth across the complex and diverse health care continuum.

A Retrospective, Observational Study of 12 Cases of Expanded-Access Customized Phage Therapy: Production, Characteristics, and Clinical Outcomes.

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. RESULTS: Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. CONCLUSIONS: Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

Risk of systemic fungal infections after exposure to wildfires: a population-based, retrospective study in California.

BACKGROUND: Large-scale wildfires in California, USA, are increasing in both size and frequency, with substantial health consequences. The capacity for wildfire smoke to displace microbes and cause clinically significant fungal infections is poorly understood. We aimed to determine whether exposure to wildfire smoke was associated with an increased risk of hospital admissions for systemic fungal infections. METHODS: In this population-based, retrospective study, we used hospital administrative data from 22 hospitals in California, USA, to analyse the association between wildfire smoke exposure and monthly hospital admissions for aspergillosis and coccidioidomycosis. We included hospitals that were members of the Vizient Clinical Data Base or Resource Manager during the study and excluded those that did not have complete reporting into Vizient during the study period. Smoke exposure was estimated using satellite-imaged smoke plumes in the hospital county. Incident rate ratios were calculated for all infection types 1 month and 3 months after smoke exposure. FINDINGS: Between Oct 1, 2014, and May 31, 2018, there were a median of 1638 annual admissions per hospital in the study sample. Individual patient demographics were not collected. We did not observe an association between smoke exposure and rate of hospital admission for aspergillosis. However, hospital admission for coccidioidomycosis increased by 20% (95% CI 5-38) in the month following any smoke exposure. Hospital admission increased by 2% (0-4) for every day that there had been smoke exposure in the previous month, after adjustment for temperature and temporal trend. Similar results were obtained with smoke exposure data from the 3 months before admission. INTERPRETATION: In the months following wildfire smoke exposure, California hospitals saw increased coccidioidomycosis infections. Given the projected increase in California wildfires and their expansion in endemic territories of soil-dwelling fungi, the ability for wildfire smoke to carry microbes and cause human disease warrants further research. FUNDING: None.

Impact of an Inpatient Allergy Guideline on ß-Lactam and Alternative Antibiotic Use.

BACKGROUND: A guideline identifying when inpatients with penicillin or cephalosporin antibiotic allergy labels (PCAAL) can receive ß-lactam antibiotics increased ß-lactam receipt at a large northeastern US health care system. OBJECTIVE: To report outcomes of implementing a similar guideline and electronic order set (OS) at an independent academic health care system. METHODS: Penicillin/cephalosporin receipt (percentage of inpatients receiving full doses) and alternative antibiotic use (days of therapy per 1000 patient-days [DOT/1000PD]) were compared over 3 periods before (February 1, 2017, to January 31, 2018) and after guideline implementation (February 1, 2018, to January 31, 2019), and after OS implementation (February 1, 2019, to January 31, 2020) among inpatients with PCAAL admitted on medical services with access to guideline/OS and education (Medical-PCAAL, n = 8721), surgical services with access to guideline/OS without education (Surgical-PCAAL, n = 5069), and obstetrics/gynecology services without interventions (Ob/Gyn-PCAAL, n = 798) and inpatients without PCAAL admitted on the same services (Medical-No-PCAAL, n = 50,840; Surgical-No-PCAAL, n = 29,845; Ob/Gyn-No-PCAAL, n = 6109). χ2 tests were used to compare categorical variables, and analysis of variance was used to compare continuous and interrupted time series analyses (ITSA) to investigate the guideline/OS implementation effect on penicillin/cephalosporin receipt. RESULTS: In the Medical-PCAAL group, penicillin/cephalosporin receipt increased (58%-68%, P < .001), specifically for cefazolin (8%-11%, P = .02) and third- to fifth-generation cephalosporins (43%-48%, P = .04), and aztreonam use decreased (12 DOT/1000PD, P = .03). In the Medical-No-PCAAL group, penicillin/cephalosporin receipt increased (88%-90%, P = .004), specifically for penicillin (40%-44%, P < .001), without changes in aztreonam use. Significant changes were not observed in these outcomes on surgical or obstetrics/gynecology services. Per ITSA, guideline/OS implementation was associated with increased penicillin/cephalosporin receipt in the Medical-PCAAL group only. CONCLUSION: Guideline and OS implementation was associated with improved antibiotic stewardship on inpatient services that also received allergy education.

Isolated Ocular Mpox without Skin Lesions, United States.

We report a case of a 53-year-old HIV-negative patient in San Francisco, California, USA, with no classic mpox prodromal symptoms or skin lesions who experienced fulminant, vision-threatening scleritis, keratitis, and uveitis. Deep sequence analysis identified monkeypox virus RNA in the aqueous humor. We confirmed the virus on the cornea and sclera by PCR.

Exploration of a Potential Desirability of Outcome Ranking Endpoint for Complicated Intra-Abdominal Infections Using 9 Registrational Trials for Antibacterial Drugs.

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.

Clinically Adjudicated Reference Standards for Evaluation of Infectious Diseases Diagnostics.

Lack of a gold standard can present a challenge for evaluation of diagnostic test accuracy of some infectious diseases tests, particularly when the test's accuracy potentially exceeds that of its predecessors. This approach may measure agreement with an imperfect reference, rather than correctness, because the right answer is unknown. Solutions consist of multitest comparators, including those that involve a test under evaluation if multiple new tests are being evaluated together, using latent class modeling, and clinically adjudicated reference standards. Clinically adjudicated reference standards may be considered as comparator methods when no predefined test or composite of tests is sufficiently accurate; they emulate clinical practice in that multiple data pieces are clinically assessed together.

Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.

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.