Intrapulmonary pharmacokinetics of antibiotics used to treat nosocomial pneumonia caused by Gram-negative bacilli: A systematic review |
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Authors: | Aaron J Heffernan Fekade B Sime Jeffrey Lipman Jayesh Dhanani Katherine Andrews David Ellwood Keith Grimwood Jason A Roberts |
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Institution: | 1. School of Medicine, Griffith University, Gold Coast, Queensland 4222, Australia;2. Centre for Translational Anti-Infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Woolloongabba, Queensland, Australia;3. Faculty of Medicine, The University of Queensland, Brisbane, Queensland 4006, Australia;4. Griffith Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111, Australia;5. Gold Coast Health, Southport, Queensland 4215, Australia |
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Abstract: | BackgroundKnowledge of antibiotic concentrations achievable in the epithelial lining fluid (ELF) will help guide antibiotic dosing for treating patients with Gram-negative bacillary ventilator-associated pneumonia (VAP).ObjectiveTo compare: (1) the ELF:serum penetration ratio of antibiotics in patients with pneumonia, including VAP, with that in healthy study participants; and (2) the ELF and/or tracheal aspirate antibiotic concentrations following intravenous and nebuliser delivery.MethodsWeb of Science, EMBASE and PubMed databases were searched and a systematic review undertaken.ResultsFifty-two studies were identified. ELF penetration ratios for aminoglycosides and most β-lactam antibiotics administered intravenously were between 0.12 and 0.57, whereas intravenous colistin may be undetectable in the ELF. In contrast, estimated mean fluoroquinolone ELF penetration ratios of up to 1.31 were achieved. Importantly, ELF penetration ratios appear reduced in critically ill patients with pneumonia compared with in healthy volunteers receiving intravenous ceftazidime, levofloxacin and fosfomycin; thus, dose adjustment is likely to be required in critically ill patients. In contrast to the systemic administration route, nebulisation of antibiotics achieves high ELF concentrations. Nebulised 400 mg twice-daily amikacin resulted in a median peak ELF steady-state concentration of 976.01 mg/L (interquartile range 410.3–2563.1 mg/L). Similarly, nebulised 1 million international units of colistin resulted in a peak ELF concentration of 6.73 mg/L (interquartile range 4.80–10.10 mg/L).ConclusionFurther pharmacokinetic studies investigating the mechanisms for ELF penetration in infected patients and healthy controls are needed to guide antibiotic dosing in VAP and to determine the potential benefits of nebulised therapy. |
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Keywords: | Epithelial lining fluid pharmacokinetics Gram-negative bacilli ventilator-associated pneumonia |
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