Browsing by Author "Paterson, David L"

Now showing 1 - 4 of 4
  • Thumbnail Image
    ItemOpen Access
    CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: study protocol for a randomised controlled trial.
    (Trials, 2016-03-31) Tong, Steven YC; Nelson, Jane; Paterson, David L; Fowler, Vance G; Howden, Benjamin P; Cheng, Allen C; Chatfield, Mark; Lipman, Jeffrey; Van Hal, Sebastian; O'Sullivan, Matthew; Robinson, James O; Yahav, Dafna; Lye, David; Davis, Joshua S; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network
    BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. METHODS/DESIGN: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. DISCUSSION: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.
  • Thumbnail Image
    ItemOpen Access
    Can ceftazidime/avibactam and aztreonam overcome β-lactam resistance conferred by metallo-β-lactamases in Enterobacteriaceae?
    (Antimicrob Agents Chemother, 2017-02-06) Marshall, Steven; Hujer, Andrea M; Rojas, Laura J; Papp-Wallace, Krisztina M; Humphries, Romney M; Spellberg, Brad; Hujer, Kristine M; Marshall, Emma K; Rudin, Susan D; Perez, Federico; Wilson, Brigid M; Wasserman, Ronald B; Chikowski, Linda; Paterson, David L; Vila, Alejandro J; van Duin, David; Kreiswirth, Barry N; Chambers, Henry F; Fowler, Vance G; Jacobs, Michael R; Pulse, Mark E; Weiss, William J; Bonomo, Robert A
    Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram negative bacteria, we tested the effectiveness of the combination of ceftazidime/avibactam (CAZ/AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk-diffusion and agar based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ/AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ/AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ/AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥ 21 mm. All isolates demonstrated a reduction in CAZ/AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥ 4 log10 CFU decrease for all groups that had CAZ/AVI plus ATM (8 μg/ml) added, compared to the CAZ/AVI alone group. In the murine neutropenic thigh infection model, an almost 4 log10 reduction in CFUs was noted at 24 h for CAZ/AVI (32 mg/kg q8h) plus ATM (32 mg/kg q8h) vs. CAZ/AVI (32 mg/kg q8h) alone. The data presented herein, requires us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.
  • 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
    COVID-19-Lessons Learned and Questions Remaining.
    (Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021-06) Fang, Ferric C; Benson, Constance A; Del Rio, Carlos; Edwards, Kathryn M; Fowler, Vance G; Fredricks, David N; Limaye, Ajit P; Murray, Barbara E; Naggie, Susanna; Pappas, Peter G; Patel, Robin; Paterson, David L; Pegues, David A; Petri, William A; Schooley, Robert T
    In this article, the editors of Clinical Infectious Diseases review some of the most important lessons they have learned about the epidemiology, clinical features, diagnosis, treatment and prevention of SARS-CoV-2 infection and identify essential questions about COVID-19 that remain to be answered.