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.

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.

Risk Factors and Outcomes of Hematogenous Vertebral Osteomyelitis in Patients With Staphylococcus aureus Bacteremia.

BACKGROUND: Hematogenous vertebral osteomyelitis (HVOM) is an incompletely understood complication of Staphylococcus aureus bacteremia (SAB). METHODS: Eligible SAB patients with and without HVOM were prospectively enrolled from 1995 through 2019 at Duke University Health System. HVOM was diagnosed either radiographically or microbiologically. Multivariable logistic regression analysis was performed to identify clinical and microbial factors associated with HVOM risk. All bloodstream S. aureus isolates were genotyped using spa typing. RESULTS: Of 3165 cases of SAB, 127 (4.0%) developed HVOM. Patients who experienced HVOM were more likely to have community-acquired SAB (30.7% vs 16.7%, P < .001), have a longer time to diagnosis of SAB (median, 5 days; interquartile range [IQR], 2-10.5 vs median, 2 days; IQR, 0-4; P < .001), and to exhibit persistent bacteremia (48.8% vs 20.6%, P < .001). A significant number of HVOM patients developed infective endocarditis (26% vs 15.2%, P = .002). Overall, 26.2% (n = 33) of SAB patients with HVOM underwent surgical intervention. Methicillin resistance (46.6% vs 41.7%, P = .318) and bacterial genotype were not associated with the development of HVOM. At the 12-month follow-up, 22% of patients with HVOM had died. Of the surviving patients, 20.4% remained on antibiotic therapy, and 29.6% had recurrence of either HVOM or SAB. CONCLUSIONS: Among patients with SAB, HVOM risk was associated with clinical factors and not bacterial genotype. Despite being a rare complication of SAB, patients with HVOM had high all-cause mortality rates and healthcare resource requirements up to 1 year after their HVOM diagnosis. Close clinical monitoring is indicated in this vulnerable population.

The Future Ain't What It Used to Be Out With the Old In With the Better: Antibacterial Resistance Leadership Group Innovations.

Clinical research networks conduct important studies that would not otherwise be performed by other entities. In the case of the Antibacterial Resistance Leadership Group (ARLG), such studies include diagnostic studies using master protocols, controlled phage intervention trials, and studies that evaluate treatment strategies or dynamic interventions, such as sequences of empiric and definitive therapies. However, the value of a clinical research network lies not only in the results from these important studies but in the creation of new approaches derived from collaborative thinking, carefully examining and defining the most important research questions for clinical practice, recognizing and addressing common but suboptimal approaches, and anticipating that the standard approaches of today may be insufficient for tomorrow. This results in the development and implementation of new methodologies and tools for the design, conduct, analyses, and reporting of research studies. These new methodologies directly impact the studies conducted within the network and have a broad and long-lasting impact on the field, enhancing the scientific value and efficiency of generations of research studies. This article describes innovations from the ARLG in diagnostic studies, observational studies, and clinical trials evaluating interventions for the prevention and treatment of antibiotic-resistant bacterial infections.

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.

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.

Colonization With Methicillin-resistant Staphylococcus aureus and Risk for Infection Among Asymptomatic Athletes: A Systematic Review and Metaanalysis.

BACKGROUND: Athletes are a vulnerable population for methicillin-resistant Staphylococcus aureus (MRSA) infection. Our aim was to determine MRSA colonization in asymptomatic athletes and estimate the risk for subsequent MRSA infection. METHODS: We searched the PubMed and EMBASE (through 29 October 2015) for studies on MRSA colonization among asymptomatic athletes. RESULTS: The pooled prevalence of MRSA colonization among athletes was 6% (95% confidence interval [CI], 1,13), and it was higher in the United States (8%; 95% CI, 2,17). USA300 was the most common strain detected (22%), and 62% and 36% of isolates were resistant to clindamycin and trimethoprim/sulfamethoxazole, respectively. The prevalence of MRSA colonization among collegiate athletes reached 13% (95% CI, 4,25). Sports with the highest prevalence among collegiate athletes were wrestling (22%; 95% CI, 0,85), football (8%; 95% CI, 3,15) and basketball (8%; 95% CI, 0,28). The risk for MRSA skin and soft tissue infection within 3 months after documented colonization among MRSA-colonized athletes was significantly higher than for noncolonized athletes (relative risk = 7.37, 95% CI, [2.47,21.94]). Decolonization treatment among colonized athletes decreased significantly the risk for infection (relative risk reduction = 0.33; 95% CI, .03,4.28). CONCLUSIONS: The prevalence of MRSA colonization among asymptomatic athletes is comparable to that among individuals with chronic illness, it is higher among collegiate athletes and can be twice that for patients in intensive care units. Importantly, colonization is associated with a >7-fold increase in the incidence of subsequent MRSA infection. Infection control and decontamination protocols for this population need to be studied and implemented with urgency.

The impact of regional anesthesia on opioid demand in distal radius fracture surgery.

PURPOSE: Regional anesthesia (RA) is commonly used in distal radius fracture surgery to reduce pain and opioid consumption. The purpose of this study was to evaluate the real-world impact of RA on inpatient and outpatient opioid consumption and demand in patients undergoing distal radius fracture surgery. METHODS: All patients ages 18 and older undergoing distal radius fracture surgery between 7/2013 and 7/2018 at a single institution (n = 969) were identified. Inpatient opioid consumption and outpatient opioid prescribing in oxycodone 5-mg equivalents (OE's) up to 90-d post-operative were recorded for patients with and without RA. Adjusted models were used to evaluate the impact of RA on opioid outcomes. RESULTS: Adjusted models demonstrated decreases in inpatient opioid consumption in patients with RA (10.7 estimated OE's without RA vs. 7.6 OE's with RA from 0 to 24 h post-op, 10.2 vs. 5.3 from 24 to 48 h post-op and 7.5 vs. 5.0 from 48 to 72 h post-op, p<.05). Estimated cumulative outpatient opioid demand was significantly higher in patients with RA (65.3 OE's without RA vs. 81.0 with RA from 1-month pre-op to 2-week post-discharge, 76.1 vs. 87.7 OE's to 6-weeks, and 80.8 vs. 93.5 OE's to 90-d, all p values for RA <.05) though rates of refill were significantly lower in patients with RA from 2-week to 6-week post-op compared to patients without RA. CONCLUSIONS: Patients undergoing RA in distal radius fracture surgery had decreased inpatient opioid consumption but increased outpatient demand after adjustment for patient and operative characteristics. LEVEL OF EVIDENCE: Level III, retrospective, therapeutic cohort study.

The Attributable Burden of Clostridium difficile Infection to Long-Term Care Facilities Stay: A Clinical Study.

BACKGROUND: Advanced age, history of hospitalization, and antibiotic consumption are associated with the pathogenesis of Clostridium difficile infection (CDI). Long-term care facilities (LTCFs) represent a setting where CDI has been increasingly reported. We aimed to estimate the actual attributable burden of CDI to LTCF stay and determine the characteristics of the disease epidemiology in this setting. DESIGN: IRB-approved retrospective cohort study. SETTING: LTCF and community. PARTICIPANTS: One thousand seven hundred and sixty-one patients. MEASUREMENTS/RESULTS: The prevalence of CDI among LTCF residents was 22.4%, whereas the prevalence of CDI among community residents was 6.7% (P < .001). The prevalence of CDI among LTCF residents was significantly higher in both the 18-64 (P < .001) and the ≥65 age groups (P < .010). Measures of hospital exposure and antibiotic consumption between LTCF and community residents prior to CDI diagnosis were non-significant. A strict matching (1:2) between LTCF and community residents adjusting for age, total number of hospital admissions and antibiotic consumption showed that the odds of CDI for an LTCF resident were 6.89 times larger than the odds for a community resident (OR = 6.89, 95%, 4.67-10.17). For an LTCF resident with CDI, the odds of manifesting severe disease were 3.25 times larger than the odds for a community resident with CDI (OR = 3.25, 95%, 1.81-5.86). LTCF residents were more frequently hospitalized (P = .002) required longer hospital stays for their CDI management (P = .03) and had more recurrent CDI cases than community residents (P = .04). CONCLUSIONS: Our study highlights the increased burden of CDI among LTCF residents independently of age, antibiotic, and hospitalization background. Severe CDI disease and recurrences are more frequent in LTCFs.