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    Ceftizoxime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefsulodin, and cefpiramide
    (CRC Press, 2017) Yılmaz, Mesut; Paterson, David L.
    Extended-spectrum, or third-generation cephalosporins, were developed after the first- and second-generation drugs. Due to their prominence, ceftriaxone (see Chapter 27, Ceftriaxone), cefotaxime (see Chapter 26, Cefotaxime), and ceftazidime (see Chapter 30, Ceftazidime and ceftazidime-avibactam) are discussed in detail in their own chapters. However, other thirdgeneration cephalosporins, such as ceftizoxime, cefdinir, cefditoren, cefpodoxime, ceftibuten, cefsulodin, and cefpiramide, are available in only certain countries or are seldom if ever used in contemporary practice. Description of these antibiotics is therefore limited, with the exception of ceftizoxime (as a representative of a parenterally administered third-generation cephalosporin) and cefpodoxime (as a representative of an orally administered third-generation cephalosporin).
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    Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with e coli or klebsiella pneumoniae bloodstream infection and ceftriaxone resistance a randomized clinical trial
    (American Medical Association, 2018) Harris, Patrick N. A.; Tambyah, Paul Anatharajah; Lye, David Chien; Mo Yinli; Lee, Tau Hong; Yılmaz, Mesut; Alenazi, Tamer H.; Arabi, Yaseen; Falcone, Marco; Bassetti, Matteo; Righi, Elda; Rogers, Benjamin A.; Kanj, Souha; Bhally, Hasan; Iredell, Jon; Mendelson, Marc; Boyles, Tom H.; Looke, David; Miyakis, Spiros; Walls, Genevieve; Al Khamis, Mohammed; Zikri, Ahmed; Crowe, Amy; Ingram, Paul; Daneman, Nick; Griffin, Paul; Athan, Eugene; Lorenc, Penelope; Baker, Peter; Roberts, Leah; Beatson, Scott A.; Peleg, Anton Y.; Harris-Brown, Tiffany; Paterson, David L.
    IMPORTANCE Extended-spectrum beta-lactamases mediate resistance to third-generation cephalosporins (eg, ceftriaxone) in Escherichia coli and Klebsiella pneumoniae. Significant infections caused by these strains are usually treated with carbapenems, potentially selecting for carbapenem resistance. Piperacillin-tazobactam may be an effective "carbapenem-sparing" option to treat extended-spectrum beta-lactamase producers. OBJECTIVES To determine whether definitive therapy with piperacillin-tazobactam is noninferior to meropenem (a carbapenem) in patients with bloodstream infection caused by ceftriaxone-nonsusceptible E coli or K pneumoniae. DESIGN, SETTING, AND PARTICIPANTS Noninferiority, parallel group, randomized clinical trial included hospitalized patients enrolled from 26 sites in 9 countries from February 2014 to July 2017. Adult patients were eligible if they had at least 1 positive blood culture with E coli or Klebsiella spp testing nonsusceptible to ceftriaxone but susceptible to piperacillin-tazobactam. Of 1646 patients screened, 391 were included in the study. INTERVENTIONS Patients were randomly assigned 1: 1 to intravenous piperacillin-tazobactam, 4.5 g, every 6 hours (n = 188 participants) or meropenem, 1 g, every 8 hours (n = 191 participants) for a minimum of 4 days, up to a maximum of 14 days, with the total duration determined by the treating clinician. MAIN OUTCOMES AND MEASURES The primary outcome was all-cause mortality at 30 days after randomization. A noninferiority margin of 5% was used. RESULTS Among 379 patients (mean age, 66.5 years; 47.8% women) who were randomized appropriately, received at least 1 dose of study drug, and were included in the primary analysis population, 378 (99.7%) completed the trial and were assessed for the primary outcome. A total of 23 of 187 patients (12.3%) randomized to piperacillin-tazobactam met the primary outcome of mortality at 30 days compared with 7 of 191 (3.7%) randomized to meropenem (risk difference, 8.6%[1-sided 97.5% CI, -infinity to 14.5%]; P = .90 for noninferiority). Effects were consistent in an analysis of the per-protocol population. Nonfatal serious adverse events occurred in 5 of 188 patients (2.7%) in the piperacillin-tazobactam group and 3 of 191 (1.6%) in the meropenem group. CONCLUSIONS AND RELEVANCE Among patients with E coli or K pneumoniae bloodstream infection and ceftriaxone resistance, definitive treatment with piperacillin-tazobactam compared with meropenem did not result in a noninferior 30-day mortality. These findings do not support use of piperacillin-tazobactam in this setting.
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    Meropenem versus piperacillin-tazobactam for definitive treatment of bloodstream infections caused by AmpC beta-lactamase-producing enterobacter spp, citrobacter freundii, morganella morganii, providencia spp, or serratia marcescens: A pilot multicenter randomized controlled trial (MERINO-2)
    (Oxford University Press, 2021) Stewart, Adam G.; Paterson, David L.; Young, Barnaby; Lye, David C.; Davis, Joshua S.; Schneider, Kellie; Yılmaz, Mesut; Dinleyici, Rümeysa; Runnegar, Naomi; Henderson, Andrew; Archuleta, Sophia; Kalimuddin, Shirin; Forde, Brian M.; Chatfield, Mark D.; Bauer, Michelle J.; Lipman, Jeffrey; Harris-Brown, Tiffany; Harris, Patrick N. A.
    Background: Carbapenems are recommended treatment for serious infections caused by AmpC-producing gram-negative bacteria but can select for carbapenem resistance. Piperacillin-tazobactam may be a suitable alternative. Methods: We enrolled adult patients with bloodstream infection due to chromosomal AmpC producers in a multicenter randomized controlled trial. Patients were assigned 1:1 to receive piperacillin-tazobactam 4.5 g every 6 hours or meropenem 1 g every 8 hours. The primary efficacy outcome was a composite of death, clinical failure, microbiological failure, and microbiological relapse at 30 days. Results: Seventy-two patients underwent randomization and were included in the primary analysis population. Eleven of 38 patients (29%) randomized to piperacillin-tazobactam met the primary outcome compared with 7 of 34 patients (21%) in the meropenem group (risk difference, 8% [95% confidence interval {CI},-12% to 28%]). Effects were consistent in an analysis of the per-protocol population. Within the subcomponents of the primary outcome, 5 of 38 (13%) experienced microbiological failure in the piperacillin-tazobactam group compared to 0 of 34 patients (0%) in the meropenem group (risk difference, 13% [95% CI, 2% to 24%]). In contrast, 0% vs 9% of microbiological relapses were seen in the piperacillin-tazobactam and meropenem arms, respectively. Susceptibility to piperacillin-tazobactam and meropenem using broth microdilution was found in 96.5% and 100% of isolates, respectively. The most common AmpC ?-lactamase genes identified were blaCMY-2, blaDHA-17, blaCMH-3, and blaACT-17. No ESBL, OXA, or other carbapenemase genes were identified. Conclusions: Among patients with bloodstream infection due to AmpC producers, piperacillin-tazobactam may lead to more microbiological failures, although fewer microbiological relapses were seen. Clinical Trials Registration: NCT02437045.