Aaron James Heffernan1, Fekade Bruck Sime2, Jing Sun1, Jeffrey Lipman3, Anand Kumar4, Katherine Andrews5, David Ellwood6, Keith Grimwood7, Jason Roberts8. 1. School of Medicine, Griffith University, Gold Coast, Queensland, Australia. 2. Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Woolloongabba, Queensland, Australia; Faculty of Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. 3. Faculty of Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. 4. Sections of Critical Care Medicine and Infectious Diseases, University of Manitoba, Winnipeg, Manitoba, Canada. 5. Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia. 6. School of Medicine and Menzies Health Institute Queensland, Gold Coast campus, Griffith University, Gold Coast, Queensland, Australia; Department of Maternal-Foetal Medicine, Gold Coast Health, Gold Coast, Queensland, Australia. 7. School of Medicine and Menzies Health Institute Queensland, Gold Coast campus, Griffith University, Gold Coast, Queensland, Australia; Departments of Paediatrics and Infectious Diseases, Gold Coast Health, Gold Coast, Queensland, Australia. 8. Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, University of Queensland, Woolloongabba, Queensland, Australia; Faculty of Medicine, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. Electronic address: j.roberts2@uq.edu.au.
Abstract
BACKGROUND: Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. OBJECTIVE: To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy. METHODS: A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. RESULTS: Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63-1.08, P = 0.10, I2 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64-0.99, P = 0.04, I2 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83-2.09, P = 0.40, I2 0%). CONCLUSIONS: The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.
BACKGROUND: Combining aminoglycosides with β-lactam antibiotics for treating serious infections has not been associated with reduced mortality in previous meta-analyses. However, the multiple daily aminoglycoside dosing regimen principally used in most of the included studies is inconsistent with current practice. OBJECTIVE: To determine if a combination of an aminoglycoside administered as a single daily dose and a β-lactam antibiotic reduces all-cause mortality in patients compared with β-lactam antibiotic monotherapy. METHODS: A systematic review and meta-analysis of clinical studies was performed (Prospero registration number #68506). Studies were included if they compared β-lactam antibiotic monotherapy with combined β-lactam and single daily dose aminoglycoside therapy for treating serious infections. Studies investigating multiple daily dosing aminoglycoside regimens, infective endocarditis and febrile neutropaenia were excluded. Study quality was assessed using the PEDro and Newcastle-Ottawa scoring systems. The end points for outcome analyses were 30-day all-cause mortality, clinical cure and nephrotoxicity. RESULTS: Four randomised controlled trials and five retrospective cohort studies were analysed. Compared with β-lactam antibiotic monotherapy, single daily aminoglycoside dosing in combination with β-lactam antibiotics was not associated with reduced mortality compared with β-lactam antibiotic monotherapy (n = 3686, OR 0.82, 95% CI 0.63-1.08, P = 0.10, I2 42%). A subgroup analysis of cohort studies suggested reduced mortality with combination therapy (n = 3563, OR 0.79, 95% CI 0.64-0.99, P = 0.04, I2 32%). No increased risk of nephrotoxicity was identified (n = 1110, OR 1.31, 95% CI 0.83-2.09, P = 0.40, I2 0%). CONCLUSIONS: The existing evidence suggests no added survival benefit from a single daily dosing regimen of an aminoglycoside when combined with β-lactam antibiotics.
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