Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study

A Henderson^{1

2}, D L Paterson¹, M D Chatfield¹, P A Tambyah³, D C Lye^{4

5

6}, P P De⁷, R T P Lin⁷, K L Chew⁸, M Yin³, T H Lee^{4

5

6}, M Yilmaz⁹, R Cakmak⁹, T H Alenazi¹⁰, Y M Arabi¹⁰, M Falcone¹¹, M Bassetti¹², E Righi^{13

14}, B A Rogers^{15

16}, S S Kanj¹⁷, H Bhally¹⁸, J Iredell^{19

20}, M Mendelson²¹, T H Boyles²¹, D F M Looke^{2

22}, N J Runnegar^{2

22}, S Miyakis^{23

24

25}, G Walls²⁶, M A I Khamis²⁷, A Zikri²⁷, A Crowe^{28

29}, P R Ingram^{30

31

32}, N Daneman³³, P Griffin^{22

34

35}, E Athan³⁶, L Roberts³⁷, S A Beatson³⁷, A Y Peleg^{38

39}, K Cottrell¹, M J Bauer¹, E Tan¹, K Chaw^{40

41

42}, G R Nimmo⁴³, T Harris-Brown¹, P N A Harris^{1

43}; 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):
Peter Newton, Heather Wren, Maryza Graham, Tony Korman, Sameera M Aljohani, Bassam Alalwan, Khizra Sultana, Assunta Sartor, Darren Welch, Gunnar Kahlmeter

Affiliations

¹ University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.
² Infection Management Services, Princess Alexandra Hospital, Brisbane, Australia.
³ Department of Infectious Diseases, National University Hospital, Singapore.
⁴ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵ Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
⁶ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁷ Department of Laboratory Medicine, Tan Tock Seng Hospital, Singapore.
⁸ Division of Microbiology, National University Hospital, Singapore.
⁹ Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
¹⁰ King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹¹ Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
¹² Infectious Diseases Clinic, Department of Health Sciences, University of Genoa and Ospedale Policlinico San Martino Genoa, Italy.
¹³ Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy.
¹⁴ Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
¹⁵ Monash University, Centre for Inflammatory Diseases, Victoria, Australia.
¹⁶ Monash Infectious Diseases, Monash Health, Victoria, Australia.
¹⁷ Department of Internal Medicine, Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon.
¹⁸ Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand.
¹⁹ Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, Australia.
²⁰ Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, Australia.
²¹ Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
²² University of Queensland, Brisbane, Australia.
²³ School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.
²⁴ Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
²⁵ Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia.
²⁶ Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.
²⁷ King Fahad Specialist Hospital, Dammam, Saudi Arabia.
²⁸ Department of Infectious Diseases, St Vincent's Hospital, Melbourne, Australia.
²⁹ Department of Microbiology, St Vincent's Hospital, Melbourne, Australia.
³⁰ School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia.
³¹ Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia.
³² Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia.
³³ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
³⁴ Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Australia.
³⁵ QIMR Berghofer, Brisbane, Queensland, Australia.
³⁶ Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia.
³⁷ Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, University of Queensland, Queensland, Australia.
³⁸ Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
³⁹ Department of Microbiology, Monash University, Clayton, Australia.
⁴⁰ Department of Microbiology, Pathology Queensland, Toowoomba Laboratory, Australia.
⁴¹ Department of Microbiology, Mater Pathology, Australia.
⁴² Infectious Diseases Department, Redcliffe Hospital, Australia.
⁴³ Department of Microbiology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.

PMID: 33106863
DOI: 10.1093/cid/ciaa1479

Clinical Trial

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study

A Henderson et al. Clin Infect Dis. 2021.

. 2021 Dec 6;73(11):e3842-e3850.

doi: 10.1093/cid/ciaa1479.

Authors

Collaborators

MERINO Trial Investigators and the Australasian Society for Infectious Disease Clinical Research Network (ASID-CRN):
Peter Newton, Heather Wren, Maryza Graham, Tony Korman, Sameera M Aljohani, Bassam Alalwan, Khizra Sultana, Assunta Sartor, Darren Welch, Gunnar Kahlmeter

Affiliations

¹ University of Queensland, UQ Centre for Clinical Research, Brisbane, Australia.
² Infection Management Services, Princess Alexandra Hospital, Brisbane, Australia.
³ Department of Infectious Diseases, National University Hospital, Singapore.
⁴ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁵ Department of Infectious Diseases, Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
⁶ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
⁷ Department of Laboratory Medicine, Tan Tock Seng Hospital, Singapore.
⁸ Division of Microbiology, National University Hospital, Singapore.
⁹ Department of Infectious Diseases and Clinical Microbiology, School of Medicine, Istanbul Medipol University, Istanbul, Turkey.
¹⁰ King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹¹ Division of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Pisa, Italy.
¹² Infectious Diseases Clinic, Department of Health Sciences, University of Genoa and Ospedale Policlinico San Martino Genoa, Italy.
¹³ Infectious Diseases Clinic, Department of Medicine University of Udine and Santa Maria Misericordia Hospital, Udine, Italy.
¹⁴ Infectious Diseases, Department of Diagnostics and Public Health, University of Verona, Verona, Italy.
¹⁵ Monash University, Centre for Inflammatory Diseases, Victoria, Australia.
¹⁶ Monash Infectious Diseases, Monash Health, Victoria, Australia.
¹⁷ Department of Internal Medicine, Division of Infectious Diseases, American University of Beirut Medical Center, Beirut, Lebanon.
¹⁸ Department of Medicine and Infectious Diseases, North Shore Hospital, Auckland, New Zealand.
¹⁹ Marie Bashir Institute for Infectious Disease and Biosecurity, University of Sydney, Sydney, Australia.
²⁰ Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, Australia.
²¹ Division of Infectious Diseases & HIV Medicine, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
²² University of Queensland, Brisbane, Australia.
²³ School of Medicine, University of Wollongong, Wollongong, New South Wales, Australia.
²⁴ Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia.
²⁵ Department of Infectious Diseases, Wollongong Hospital, Wollongong, New South Wales, Australia.
²⁶ Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.
²⁷ King Fahad Specialist Hospital, Dammam, Saudi Arabia.
²⁸ Department of Infectious Diseases, St Vincent's Hospital, Melbourne, Australia.
²⁹ Department of Microbiology, St Vincent's Hospital, Melbourne, Australia.
³⁰ School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, Australia.
³¹ Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Australia.
³² Department of Microbiology, PathWest Laboratory Medicine, Perth, Western Australia.
³³ Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.
³⁴ Department of Medicine and Infectious Diseases, Mater Hospital and Mater Medical Research Institute, Brisbane, Australia.
³⁵ QIMR Berghofer, Brisbane, Queensland, Australia.
³⁶ Department of Infectious Diseases, Barwon Health and Deakin University, Geelong, Victoria, Australia.
³⁷ Australian Centre for Ecogenomics, School of Chemistry and Molecular Biosciences, University of Queensland, Queensland, Australia.
³⁸ Infection & Immunity Program, Biomedicine Discovery Institute, Monash University, Clayton, Australia.
³⁹ Department of Microbiology, Monash University, Clayton, Australia.
⁴⁰ Department of Microbiology, Pathology Queensland, Toowoomba Laboratory, Australia.
⁴¹ Department of Microbiology, Mater Pathology, Australia.
⁴² Infectious Diseases Department, Redcliffe Hospital, Australia.
⁴³ Department of Microbiology, Pathology Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia.

PMID: 33106863
DOI: 10.1093/cid/ciaa1479

Abstract

Introduction: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial.

Methods: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations.

Results: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum β-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%).

Conclusions: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Keywords: bloodstream infection; extended spectrum beta-lactamase; meropenem; piperacillin-tazobactam.

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Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study

Collaborators

Affiliations

Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study

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