Browsing by Author "Hill, Carol"

Filter results by typing the first few letters
Now showing 1 - 3 of 3
  • Thumbnail Image
    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.
  • Thumbnail Image
    ItemOpen Access
    Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.
    (The Lancet. Infectious diseases, 2021-11-09) Wang, Minggui; Earley, Michelle; Chen, Liang; Hanson, Blake M; Yu, Yunsong; Liu, Zhengyin; Salcedo, Soraya; Cober, Eric; Li, Lanjuan; Kanj, Souha S; Gao, Hainv; Munita, Jose M; Ordoñez, Karen; Weston, Greg; Satlin, Michael J; Valderrama-Beltrán, Sandra L; Marimuthu, Kalisvar; Stryjewski, Martin E; Komarow, Lauren; Luterbach, Courtney; Marshall, Steve H; Rudin, Susan D; Manca, Claudia; Paterson, David L; Reyes, Jinnethe; Villegas, Maria V; Evans, Scott; Hill, Carol; Arias, Rebekka; Baum, Keri; Fries, Bettina C; Doi, Yohei; Patel, Robin; Kreiswirth, Barry N; Bonomo, Robert A; Chambers, Henry F; Fowler, Vance G; Arias, Cesar A; van Duin, David; Multi-Drug Resistant Organism Network Investigators

    Background

    Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries.

    Methods

    In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete.

    Findings

    Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96).

    Interpretation

    Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions.

    Funding

    The National Institutes of Health.
  • Thumbnail Image
    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.