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

doi:10.1001/jama.2018.12163

Randomized Controlled Trial

. 2018 Sep 11;320(10):984-994.

doi: 10.1001/jama.2018.12163.

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

Patrick N A Harris^{1

2

3}, Paul A Tambyah⁴, David C Lye^{5

6

7}, Yin Mo⁴, Tau H Lee^{5

6

7}, Mesut Yilmaz⁸, Thamer H Alenazi⁹, Yaseen Arabi⁹, Marco Falcone¹⁰, Matteo Bassetti¹¹, Elda Righi¹¹, Benjamin A Rogers^{12

13}, Souha Kanj¹⁴, Hasan Bhally¹⁵, Jon Iredell^{16

17}, Marc Mendelson¹⁸, Tom H Boyles¹⁸, David Looke^{3

19}, Spiros Miyakis^{20

21

22}, Genevieve Walls²³, Mohammed Al Khamis²⁴, Ahmed Zikri²⁴, Amy Crowe^{25

26}, Paul Ingram^{27

28

29}, Nick Daneman³⁰, Paul Griffin^{19

31

32}, Eugene Athan³³, Penelope Lorenc¹, Peter Baker³⁴, Leah Roberts³⁵, Scott A Beatson³⁵, Anton Y Peleg^{36

37

38}, Tiffany Harris-Brown¹, David L Paterson^{1

39}; MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN)

Collaborators, Affiliations

Collaborators

MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN):
John McNamara, Rachel Sieler, Jill Garlick, Jess Costa, Janine Roney, Nigel Pratt, Houssam Tabaja, Joumana Kmeid, Ralph Tayyar, Saeed El Zein, Stephanie Jones, Raquel Cowan, Alex Tai, Belinda Lin, Babak Rad, Eleanor MacMorran, James Pollard, Rumeysa Dinleyici, Ayse Istanbullu, Bahadir Ceylan, Ali Mert, Mai Hashhoush, Taleb Dalwi, Tony Korman, Rula Azzam, Michael Birrell, Carly Hughes, Sadid Khan, Jillian Lau, Layyang Lee, Karen Lim, Yi Dani Lin, David Lister, David New, Nastaran Rafiei, James Stewart, Alex Tai, Mohamad Ali Trad, Victor Aye Yeung, Stephen McBride, David Holland, Christopher Hopkins, Christopher Luey, Susan Taylor, Susan Morpeth, Melissa Finney, Megan Martin, Umit Holland, Jaminah Ali, Roland Jureen, Neil Underwood, Andrew Henderson, Naomi Runnegar, Monica Slavin, Owen Robinson, Asgar Rishu, Samia Shawkat, Janaye Fish, Kwee Chin Liew, Peter Newton, Maria Merelli, Alessia Carnelutti, Silvia Ussai, Davide Pecori, Ezlyn Izharuddin, Barnaby Young, Ying Ding, Ristila Ram, June Kelly, Neela Joshi, Guy Richards, Oliver Smith, Ahmad Alli, Inge Vermeulen, Brenda Wright, Chedwin Grey, Annemie Stewart, Denasha Reddy, Sean Wasserman, Hanie Richi, Khizra Sultana, Nouf Alanazi, Eman Bin Awad, Fabio Franzetti, Anton Stolz, Elsabe De Kock, Tebogo Magongoa, Marizane Dutoit, Alessandro Russo, Chiara Dentone, Damon Eisen, Liz Heyer

Affiliations

¹ University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia.
² Department of Microbiology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
³ Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁴ Department of Infectious Diseases, National University Hospital, Singapore.
⁵ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶ Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁸ Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
⁹ King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹⁰ Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Italy.
¹¹ Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy.
¹² Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
¹³ Monash Infectious Diseases, Monash Health, Melbourne, Victoria, Australia.
¹⁴ Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
¹⁵ Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand.
¹⁶ Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia.
¹⁸ Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹⁹ University of Queensland, Brisbane, Queensland, Australia.
²⁰ School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.
²¹ Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
²² Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia.
²³ Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.
²⁴ King Fahad Specialist Hospital, Dammam, Saudi Arabia.
²⁵ Department of Infectious Diseases, St Vincent's Hospital, Melbourne, Victoria, Australia.
²⁶ Department of Microbiology, St Vincent's Hospital, Melbourne, Victoria, Australia.
²⁷ School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia.
²⁸ Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia.
²⁹ Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia.
³⁰ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
³¹ Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Queensland, Australia.
³² QIMR Berghofer, Brisbane, Queensland, Australia.
³³ Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia.
³⁴ School of Public Health, University of Queensland, Brisbane, Queensland, Australia.
³⁵ Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Australia.
³⁶ Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
³⁷ Department of Microbiology, Monash University, Clayton, Australia.
³⁸ Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
³⁹ Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

PMID: 30208454
PMCID: PMC6143100
DOI: 10.1001/jama.2018.12163

Randomized Controlled Trial

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

Patrick N A Harris et al. JAMA. 2018.

. 2018 Sep 11;320(10):984-994.

doi: 10.1001/jama.2018.12163.

Authors

Collaborators

MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN):
John McNamara, Rachel Sieler, Jill Garlick, Jess Costa, Janine Roney, Nigel Pratt, Houssam Tabaja, Joumana Kmeid, Ralph Tayyar, Saeed El Zein, Stephanie Jones, Raquel Cowan, Alex Tai, Belinda Lin, Babak Rad, Eleanor MacMorran, James Pollard, Rumeysa Dinleyici, Ayse Istanbullu, Bahadir Ceylan, Ali Mert, Mai Hashhoush, Taleb Dalwi, Tony Korman, Rula Azzam, Michael Birrell, Carly Hughes, Sadid Khan, Jillian Lau, Layyang Lee, Karen Lim, Yi Dani Lin, David Lister, David New, Nastaran Rafiei, James Stewart, Alex Tai, Mohamad Ali Trad, Victor Aye Yeung, Stephen McBride, David Holland, Christopher Hopkins, Christopher Luey, Susan Taylor, Susan Morpeth, Melissa Finney, Megan Martin, Umit Holland, Jaminah Ali, Roland Jureen, Neil Underwood, Andrew Henderson, Naomi Runnegar, Monica Slavin, Owen Robinson, Asgar Rishu, Samia Shawkat, Janaye Fish, Kwee Chin Liew, Peter Newton, Maria Merelli, Alessia Carnelutti, Silvia Ussai, Davide Pecori, Ezlyn Izharuddin, Barnaby Young, Ying Ding, Ristila Ram, June Kelly, Neela Joshi, Guy Richards, Oliver Smith, Ahmad Alli, Inge Vermeulen, Brenda Wright, Chedwin Grey, Annemie Stewart, Denasha Reddy, Sean Wasserman, Hanie Richi, Khizra Sultana, Nouf Alanazi, Eman Bin Awad, Fabio Franzetti, Anton Stolz, Elsabe De Kock, Tebogo Magongoa, Marizane Dutoit, Alessandro Russo, Chiara Dentone, Damon Eisen, Liz Heyer

Affiliations

¹ University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, Australia.
² Department of Microbiology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
³ Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.
⁴ Department of Infectious Diseases, National University Hospital, Singapore.
⁵ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁶ Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
⁷ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁸ Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
⁹ King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹⁰ Department of Public Health and Infectious Diseases, "Sapienza" University of Rome, Italy.
¹¹ Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy.
¹² Monash University, Centre for Inflammatory Diseases, Melbourne, Victoria, Australia.
¹³ Monash Infectious Diseases, Monash Health, Melbourne, Victoria, Australia.
¹⁴ Division of Infectious Diseases, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon.
¹⁵ Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand.
¹⁶ Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, New South Wales, Australia.
¹⁷ Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia.
¹⁸ Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
¹⁹ University of Queensland, Brisbane, Queensland, Australia.
²⁰ School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.
²¹ Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
²² Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia.
²³ Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.
²⁴ King Fahad Specialist Hospital, Dammam, Saudi Arabia.
²⁵ Department of Infectious Diseases, St Vincent's Hospital, Melbourne, Victoria, Australia.
²⁶ Department of Microbiology, St Vincent's Hospital, Melbourne, Victoria, Australia.
²⁷ School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia.
²⁸ Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia.
²⁹ Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia.
³⁰ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
³¹ Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Queensland, Australia.
³² QIMR Berghofer, Brisbane, Queensland, Australia.
³³ Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia.
³⁴ School of Public Health, University of Queensland, Brisbane, Queensland, Australia.
³⁵ Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, The University of Queensland, Queensland, Australia.
³⁶ Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
³⁷ Department of Microbiology, Monash University, Clayton, Australia.
³⁸ Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia.
³⁹ Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.

PMID: 30208454
PMCID: PMC6143100
DOI: 10.1001/jama.2018.12163

Erratum in

Missing Information on Sample Size.
[No authors listed] [No authors listed] JAMA. 2019 Jun 18;321(23):2370. doi: 10.1001/jama.2019.6706. JAMA. 2019. PMID: 31211326 Free PMC article. No abstract available.

Abstract

Importance: Extended-spectrum β-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 β-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, -∞ 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.

Trial registration: anzctr.org.au Identifiers: ACTRN12613000532707 and ACTRN12615000403538 and ClinicalTrials.gov Identifier: NCT02176122.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Harris reported receiving grants from the Australian Society for Antimicrobials; the International Society for Chemotherapy; the National University Hospital Singapore; the Study, Education, and Research Committee of Pathology; and the Royal College of Pathologists of Australasia Foundation. Dr Harris also reported receiving support to speak at an educational event sponsored by Pfizer. Dr Tambyah reported receiving grants from the National University Health System, GlaxoSmithKline, Janssen, Shionogi, Sanofi-Pasteur, Visterra, Baxter, ADAMAS, Merlion Pharmaceuticals, Fabentech, and Inviragen. He has also received honoraria from Novartis and AstraZeneca. Dr Falcone reported receiving personal fees from MSD, Angelini, and Astellas and grants from Gilead. Dr Bassetti reported receiving grants and/or personal fees from Pfizer, MSD, Astellas, Menarini, Roche, Tetraphase, Achaogen, Angelini, AstraZeneca, Bayer, Basilea, Cidara, Gilead, MSD, Paratek, Pfizer, The Medicines Company, and Vifor. Dr Rogers reported receiving grants and personal fees from MSD Australia for attending advisory boards and research and personal fees from Mayne Pharma for consulting. Dr Kanj reported receiving honoraria for speaking and serving on advisory boards for Pfizer, Merck, Bayer, Gilead, Hikma, and Aventis. Ms Lorenc reported receiving grants from the Australian Society for Antimicrobials, the International Society for Chemotherapy, and the National University Hospital Singapore. Dr Beatson reported receiving support for speaking at an educational event sponsored by Pfizer. Dr Peleg reported receiving grants from MSD. Dr Paterson reported receiving grants and/or personal fees from Merck, Pfizer, Shionogi, Achaogen, AstraZeneca, Leo Pharmaceuticals, Bayer, GlaxoSmithKline, and Cubist. No other disclosures were reported.

Figures

**Figure 1.. Patient Recruitment, Randomization, and Flow Through Study**
^aPatients could meet more than 1 exclusion criteria. A total of 376 patients were excluded because more than 72 hours had elapsed since initial blood culture; 317, based on microbiology criteria; 110, allergy to trial drug; 94, polymicrobial infection; 78, not expected to survive more than 96 hours; 44, pregnant or breastfeeding; 28, no intent to cure; 20, younger than 18 years old (<21 years old in Singapore); and 20, previously enrolled. For 317 patients, microbiological exclusions based on susceptibility testing were as follows: 13.3% were susceptible to ceftriaxone, 10.7% were nonsusceptible to meropenem, and 78.9% were nonsusceptible to piperacillin-tazobactam. Other microbiological exclusions included organism not being *E coli* or *Klebsiella* spp (<1%). One patient was excluded from both the primary analysis and the per-protocol population following self-discharge and loss to follow-up.

**Figure 2.. Secondary Outcomes**
^aClinical and microbiological success defined as survival, negative blood cultures, temperature of 38°C or less, and peripheral white blood cell count of less than or equal to 12 000/μL (to convert to ×10⁹/L, multiply by 0.001). ^bTwelve patients with meropenem- or piperacillin-tazobactam–resistant organism and 3 with *Clostridium difficile* infection. ^cSix patients with meropenem- or piperacillin-tazobactam–resistant organism and 2 with *Clostridium difficile* infection.

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Comment in

Carbapenem-Sparing Therapy for Extended-Spectrum β-Lactamase-Producing E coli and Klebsiella pneumoniae Bloodstream Infection: The Search Continues.
Hayden MK, Won SY. Hayden MK, et al. JAMA. 2018 Sep 11;320(10):979-981. doi: 10.1001/jama.2018.12565. JAMA. 2018. PMID: 30208439 No abstract available.
Antibiotics for Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections.
Rodríguez-Baño J, Gutiérrez-Gutiérrez B, Kahlmeter G. Rodríguez-Baño J, et al. JAMA. 2019 Feb 12;321(6):612-613. doi: 10.1001/jama.2018.19345. JAMA. 2019. PMID: 30747960 No abstract available.
Antibiotics for Ceftriaxone-Resistant Gram-Negative Bacterial Bloodstream Infections.
Prevel R, Berdaï D, Boyer A. Prevel R, et al. JAMA. 2019 Feb 12;321(6):613. doi: 10.1001/jama.2018.19349. JAMA. 2019. PMID: 30747961 No abstract available.

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References

1. Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8(3):159-166. doi:10.1016/S1473-3099(08)70041-0 - DOI - PubMed
1. Centers for Disease Control and Prevention Antibiotic Resistance Threats in the United States. Washington, DC: US Department of Health and Human Services; 2013.
1. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657-686. doi:10.1128/CMR.18.4.657-686.2005 - DOI - PMC - PubMed
1. Doi Y, Park YS, Rivera JI, et al. . Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis. 2013;56(5):641-648. doi:10.1093/cid/cis942 - DOI - PMC - PubMed
1. Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med. 2010;362(19):1804-1813. doi:10.1056/NEJMra0904124 - DOI - PMC - PubMed

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[1] Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8(3):159-166. doi:10.1016/S1473-3099(08)70041-0 - DOI - PubMed

[2] Pitout JD, Laupland KB. Extended-spectrum beta-lactamase-producing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8(3):159-166. doi:10.1016/S1473-3099(08)70041-0 - DOI - PubMed

[3] Centers for Disease Control and Prevention Antibiotic Resistance Threats in the United States. Washington, DC: US Department of Health and Human Services; 2013.

[4] Centers for Disease Control and Prevention Antibiotic Resistance Threats in the United States. Washington, DC: US Department of Health and Human Services; 2013.

[5] Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657-686. doi:10.1128/CMR.18.4.657-686.2005 - DOI - PMC - PubMed

[6] Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev. 2005;18(4):657-686. doi:10.1128/CMR.18.4.657-686.2005 - DOI - PMC - PubMed

[7] Doi Y, Park YS, Rivera JI, et al. . Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis. 2013;56(5):641-648. doi:10.1093/cid/cis942 - DOI - PMC - PubMed

[8] Doi Y, Park YS, Rivera JI, et al. . Community-associated extended-spectrum β-lactamase-producing Escherichia coli infection in the United States. Clin Infect Dis. 2013;56(5):641-648. doi:10.1093/cid/cis942 - DOI - PMC - PubMed

[9] Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med. 2010;362(19):1804-1813. doi:10.1056/NEJMra0904124 - DOI - PMC - PubMed

[10] Peleg AY, Hooper DC. Hospital-acquired infections due to gram-negative bacteria. N Engl J Med. 2010;362(19):1804-1813. doi:10.1056/NEJMra0904124 - DOI - PMC - PubMed

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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

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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

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