Browsing by Author "Boucher, Helen W"

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    ItemOpen Access
    A Desirability of Outcome Ranking Analysis of a Randomized Clinical Trial Comparing Seven Versus Fourteen Days of Antibiotics for Uncomplicated Gram-Negative Bloodstream Infection.
    (Open forum infectious diseases, 2022-06) Howard-Anderson, Jessica; Dai, Weixiao; Yahav, Dafna; Hamasaki, Toshimitsu; Turjeman, Adi; Koppel, Fidi; Franceschini, Erica; Hill, Carol; Sund, Zoë; Chambers, Henry F; Fowler, Vance G; Boucher, Helen W; Evans, Scott R; Paul, Mical; Holland, Thomas L; Doernberg, Sarah B

    Background

    Although a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome.

    Methods

    We applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy.

    Results

    For the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy.

    Conclusions

    Both short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB.
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    ItemOpen Access
    Antibacterial Resistance Leadership Group 2.0: Back to Business.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-08) Chambers, Henry F; Evans, Scott R; Patel, Robin; Cross, Heather R; Harris, Anthony D; Doi, Yohei; Boucher, Helen W; van Duin, David; Tsalik, Ephraim L; Holland, Thomas L; Pettigrew, Melinda M; Tamma, Pranita D; Hodges, Kathryn R; Souli, Maria; Fowler, Vance G
    In December 2019, the Antibacterial Resistance Leadership Group (ARLG) was awarded funding for another 7-year cycle to support a clinical research network on antibacterial resistance. ARLG 2.0 has 3 overarching research priorities: infections caused by antibiotic-resistant (AR) gram-negative bacteria, infections caused by AR gram-positive bacteria, and diagnostic tests to optimize use of antibiotics. To support the next generation of AR researchers, the ARLG offers 3 mentoring opportunities: the ARLG Fellowship, Early Stage Investigator seed grants, and the Trialists in Training Program. The purpose of this article is to update the scientific community on the progress made in the original funding period and to encourage submission of clinical research that addresses 1 or more of the research priority areas of ARLG 2.0.
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    ItemOpen Access
    Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial.
    (JAMA, 2018-09) Holland, Thomas L; Raad, Issam; Boucher, Helen W; Anderson, Deverick J; Cosgrove, Sara E; Aycock, P Suzanne; Baddley, John W; Chaftari, Anne-Marie; Chow, Shein-Chung; Chu, Vivian H; Carugati, Manuela; Cook, Paul; Corey, G Ralph; Crowley, Anna Lisa; Daly, Jennifer; Gu, Jiezhun; Hachem, Ray; Horton, James; Jenkins, Timothy C; Levine, Donald; Miro, Jose M; Pericas, Juan M; Riska, Paul; Rubin, Zachary; Rupp, Mark E; Schrank, John; Sims, Matthew; Wray, Dannah; Zervos, Marcus; Fowler, Vance G; Staphylococcal Bacteremia Investigators

    Importance

    The appropriate duration of antibiotics for staphylococcal bacteremia is unknown.

    Objective

    To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events.

    Design, setting, and participants

    A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization.

    Interventions

    Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care.

    Main outcomes and measures

    Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia.

    Results

    Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]).

    Conclusions and relevance

    Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm.

    Trial registration

    ClinicalTrials.gov Identifier: NCT01191840.
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    ItemOpen Access
    Exploration of a Potential Desirability of Outcome Ranking Endpoint for Complicated Intra-Abdominal Infections Using 9 Registrational Trials for Antibacterial Drugs.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023-08) Kinamon, Tori; Gopinath, Ramya; Waack, Ursula; Needles, Mark; Rubin, Daniel; Collyar, Deborah; Doernberg, Sarah B; Evans, Scott; Hamasaki, Toshimitsu; Holland, Thomas L; Howard-Anderson, Jessica; Chambers, Henry; Fowler, Vance G; Nambiar, Sumati; Kim, Peter; Boucher, Helen W

    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.
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    ItemOpen Access
    Improving Traditional Registrational Trial End Points: Development and Application of a Desirability of Outcome Ranking End Point for Complicated Urinary Tract Infection Clinical Trials.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2023-02) Howard-Anderson, Jessica; Hamasaki, Toshimitsu; Dai, Weixiao; Collyar, Deborah; Rubin, Daniel; Nambiar, Sumathi; Kinamon, Tori; Hill, Carol; Gelone, Steven P; Mariano, David; Baba, Takamichi; Holland, Thomas L; Doernberg, Sarah B; Chambers, Henry F; Fowler, Vance G; Evans, Scott R; Boucher, Helen W

    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.