Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis

Amy Legg; Matthew A Roberts; Jane Davies; Alan Cass; Niamh Meagher; Archana Sud; Vered Daitch; Yael Dishon Benattar; Dafna Yahav; Mical Paul; Chen Xinxin; Yeo He Ping; David Lye; Russel Lee; J Owen Robinson; Hong Foo; Adrian R Tramontana; Narin Bak; Adelaide Grenfell; Benjamin Rogers; Ying Li; Neela Joshi; Matthew O'Sullivan; Genevieve McKew; Niladri Ghosh; Kellie Schneider; Natasha E Holmes; Ravindra Dotel; Timothy Chia; Sophia Archuleta; Simon Smith; Morgyn S Warner; Christina Titin; Shirin Kalimuddin; Jason A Roberts; Steven Y C Tong; Joshua S Davis; Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Study Group

doi:10.1093/ofid/ofad337

Longer-term Mortality and Kidney Outcomes of Participants in the Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Trial: A Post Hoc Analysis

Open Forum Infect Dis. 2023 Jul 3;10(7):ofad337. doi: 10.1093/ofid/ofad337. eCollection 2023 Jul.

Authors

Amy Legg^{1

2}, Matthew A Roberts³, Jane Davies^{1

4}, Alan Cass¹, Niamh Meagher^{5

6}, Archana Sud⁷, Vered Daitch^{8

9}, Yael Dishon Benattar¹⁰, Dafna Yahav¹¹, Mical Paul^{11

12}, Chen Xinxin¹³, Yeo He Ping¹³, David Lye^{13

14

15

16}, Russel Lee¹³, J Owen Robinson^{17

18}, Hong Foo¹⁹, Adrian R Tramontana^{20

21}, Narin Bak²², Adelaide Grenfell²³, Benjamin Rogers²⁴, Ying Li²⁵, Neela Joshi²⁵, Matthew O'Sullivan^{26

27

28}, Genevieve McKew^{29

30}, Niladri Ghosh³¹, Kellie Schneider³², Natasha E Holmes^{33

34}, Ravindra Dotel³⁵, Timothy Chia³⁶, Sophia Archuleta^{16

36}, Simon Smith³⁷, Morgyn S Warner^{38

39}, Christina Titin⁴⁰, Shirin Kalimuddin^{40

41}, Jason A Roberts^{42

43

44}, Steven Y C Tong^{45

46}, Joshua S Davis^{1

47}; Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Study Group

Collaborators

Combination Antibiotics for Methicillin-Resistant Staphylococcus aureus (CAMERA2) Study Group:
Steven Y C Tong, David C Lye, Dafna Yahav, Archana Sud, J Owen Robinson, Jane Nelson, Sophia Archuleta, Matthew A Roberts, Alan Cass, David L Paterson, Hong Foo, Mical Paul, Stephen D Guy, Adrian R Tramontana, Genevieve B Walls, Stephen McBride, Narin Bak, Niladri Ghosh, Benjamin A Rogers, Anna P Ralph, Jane Davies, Patricia E Ferguson, Ravindra Dotel, Genevieve L McKew, Timothy J Gray, Natasha E Holmes, Simon Smith, Morgyn S Warner, Shirin Kalimuddin, Barnaby E Young, Naomi Runnegar, David N Andresen, Nicholas A Anagnostou, Sandra A Johnson, Mark D Chatfield, Allen C Cheng, Vance G Fowler Jr, Benjamin P Howden, Niamh Meagher, David J Price, Sebastiaan J van Hal, Satinder Gill, Alexander Rofe, Matthew O'Sullivan, Joshua S Davis

Affiliations

¹ Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
² Herston Infectious Diseases Institute, Brisbane, Queensland, Australia.
³ Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.
⁴ Department of Infectious Diseases, Royal Darwin Hospital, Darwin, Northern Territory, Australia.
⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
⁶ Department of Infectious Diseases, Doherty Institute for Infection and Immunity, University of Melbourne and Royal Melbourne Hospital, Melbourne, Victoria, Australia.
⁷ Department of Infectious Diseases, Nepean Hospital and Nepean Clinical School, University of Sydney, Sydney, New South Wales, Australia.
⁸ Department of Medicine E, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
⁹ Sackler Faculty of Medicine, Tel Aviv University, Ramat-Aviv, Israel.
¹⁰ Infectious Diseases Institute, Rambam Health Care Campus, Haifa, Israel.
¹¹ Infectious Diseases Unit, Sheba Medical Centre, Ramat-Gan, Israel.
¹² Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
¹³ National Centre for Infectious Diseases, Singapore.
¹⁴ Department of Infectious Diseases, Tan Tock Seng Hospital, Singapore.
¹⁵ Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
¹⁶ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
¹⁷ Infectious Disease Department, Royal Perth Hospital and Fiona Stanley Hospital, PathWest Laboratory Medicine, Perth, Western Australia, Australia.
¹⁸ College of Science, Health, Engineering and Education, Discipline of Health, Murdoch University, Perth, Western Australia, Australia.
¹⁹ Department of Microbiology and Infectious Diseases, NSW Health Pathology, Liverpool, New South Wales, Australia.
²⁰ Infectious Diseases Department, Western Health, Footscray, Victoria, Australia.
²¹ Western Clinical School, University of Melbourne, St Albans, Victoria, Australia.
²² Infectious Diseases Department, The Royal Adelaide Hospital, Adelaide, South Australia, Australia.
²³ Monash Health, Department of Medicine, Clayton, Victoria, Australia.
²⁴ Monash Infectious Diseases, Monash Health, Monash University School of Clinical Sciences at Monash Health, Clayton, Victoria, Australia.
²⁵ Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁶ Department of Infectious Diseases and Microbiology, Westmead Hospital, Sydney, New South Wales, Australia.
²⁷ New South Wales Health Pathology, Department of Microbiology, Sydney, New South Wales, Australia.
²⁸ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
²⁹ Department of Microbiology and Infectious Diseases, Concord Repatriation and General Hospital, New South Wales Health Pathology, Sydney, NSW, Australia.
³⁰ Concord Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
³¹ Department of Infectious Diseases, Wollongong Public Hospital, Wollongong, New South Wales, Australia.
³² Immunology and Infectious Diseases Unit, John Hunter Hospital, Newcastle, New South Wales, Australia.
³³ Department of Infectious Diseases, Austin Health, Heidelberg, Victoria, Australia.
³⁴ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
³⁵ Department of Infectious Diseases, Blacktown Hospital, Sydney, New South Wales, Australia.
³⁶ Division of Infectious Diseases, Department of Medicine, National University Hospital, National University Health System, Singapore.
³⁷ Department of Medicine, Cairns Hospital, Cairns, Queensland, Australia.
³⁸ Microbiology and Infectious Diseases Directorate, South Australia Pathology, Infectious Diseases Unit, Central Adelaide Local Health Network, Adelaide, South Australia, Australia.
³⁹ Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.
⁴⁰ Department of Infectious Diseases, Singapore General Hospital, Singapore.
⁴¹ Duke-National University of Singapore Medical School, Programme in Emerging Infectious Diseases, Singapore.
⁴² Faculty of Medicine, University of Queensland Centre for Clinical Research, Brisbane, Queensland, Australia.
⁴³ Departments of Intensive Care Medicine and Pharmacy, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.
⁴⁴ Division of Anaesthesiology, Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.
⁴⁵ Victorian Infectious Diseases Service, Royal Melbourne Hospital, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁴⁶ Department of Infectious Diseases, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
⁴⁷ School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

Abstract

Background: The Combination Antibiotic Therapy for Methicillin-Resistant Staphylococcus aureus (CAMERA2) trial ceased recruitment in July 2018, noting that a higher proportion of patients in the intervention arm (combination therapy) developed acute kidney injury (AKI) compared to the standard therapy (monotherapy) arm. We analyzed the long-term outcomes of participants in CAMERA2 to understand the impact of combination antibiotic therapy and AKI.

Methods: Trial sites obtained additional follow-up data. The primary outcome was all-cause mortality, censored at death or the date of last known follow-up. Secondary outcomes included kidney failure or a reduction in kidney function (a 40% reduction in estimated glomerular filtration rate to <60 mL/minute/1.73 m²). To determine independent predictors of mortality in this cohort, adjusted hazard ratios were calculated using a Cox proportional hazards regression model.

Results: This post hoc analysis included extended follow-up data for 260 patients. Overall, 123 of 260 (47%) of participants died, with a median population survival estimate of 3.4 years (235 deaths per 1000 person-years). Fifty-five patients died within 90 days after CAMERA2 trial randomization; another 68 deaths occurred after day 90. Using univariable Cox proportional hazards regression, mortality was not associated with either the assigned treatment arm in CAMERA2 (hazard ratio [HR], 0.84 [95% confidence interval [CI], .59-1.19]; P = .33) or experiencing an AKI (HR at 1 year, 1.04 [95% CI, .64-1.68]; P = .88).

Conclusions: In this cohort of patients hospitalized with methicillin-resistant S aureus bacteremia, we found no association between either treatment arm of the CAMERA2 trial or AKI (using CAMERA2 trial definition) and longer-term mortality.

Keywords: Staphylococcus aureus bacteremia; acute kidney injury; nephrotoxicity.