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Tytuł:
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Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae.
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Autorzy:
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Gould M; The University of Notre Dame, School of Medicine Sydney, 160 Oxford St., Darlinghurst, NSW 2010, Australia. Electronic address: .
Ginn AN; Centre for Infectious Diseases and Microbiology Laboratory Services, NSW Health Pathology, Westmead Hospital, Sydney, New South Wales, Australia; Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research, The University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia.
Marriott D; St Vincent's Hospital, Sydney, 390 Victoria St., Darlinghurst, NSW 2010, Australia.
Norris R; St Vincent's Hospital, Sydney, 390 Victoria St., Darlinghurst, NSW 2010, Australia; Discipline of Clinical Pharmacology, School of Medicine & Public Health, University of Newcastle, Newcastle, NSW 2300, Australia; Hunter Medical Research Institute, Lot 1, Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia.
Sandaradura I; Centre for Infectious Diseases and Microbiology Laboratory Services, NSW Health Pathology, Westmead Hospital, Sydney, New South Wales, Australia; St Vincent's Hospital, Sydney, 390 Victoria St., Darlinghurst, NSW 2010, Australia.
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Źródło:
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International journal of antimicrobial agents [Int J Antimicrob Agents] 2019 Aug; Vol. 54 (2), pp. 240-244. Date of Electronic Publication: 2019 May 17.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Original Publication: Amsterdam : Elsevier Science Publishers, c1991-
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MeSH Terms:
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Drug Resistance, Bacterial*
Anti-Bacterial Agents/*pharmacokinetics
Escherichia coli/*drug effects
Klebsiella pneumoniae/*drug effects
Piperacillin, Tazobactam Drug Combination/*pharmacokinetics
Urine/*chemistry
beta-Lactamase Inhibitors/*pharmacokinetics
Anti-Bacterial Agents/administration & dosage ; Microbial Sensitivity Tests ; Models, Theoretical ; Piperacillin, Tazobactam Drug Combination/administration & dosage ; beta-Lactamase Inhibitors/administration & dosage
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Contributed Indexing:
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Keywords: Enterobacteriaceae; Pharmacodynamics; Pharmacokinetics; Piperacillin; Static time–kill; Tazobactam
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Substance Nomenclature:
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0 (Anti-Bacterial Agents)
0 (beta-Lactamase Inhibitors)
157044-21-8 (Piperacillin, Tazobactam Drug Combination)
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Entry Date(s):
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Date Created: 20190521 Date Completed: 20191203 Latest Revision: 20191203
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Update Code:
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20240104
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DOI:
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10.1016/j.ijantimicag.2019.05.013
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PMID:
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31108222
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Urinary tract infections caused by multidrug-resistant Enterobacteriaceae are a growing burden worldwide. Recent studies of urinary pharmacokinetics described high piperacillin/tazobactam (TZP) concentrations in urine, but it is unknown whether this results in treatment efficacy. This study investigated the pharmacodynamics of TZP in a static in vitro model for Enterobacteriaceae to determine the concentration-effect relationship and ultimately the required free (unbound) time above the minimum inhibitory concentration (fT >MIC ) required for bacterial killing. The static simulation model investigated TZP fT >MIC between 0% and 100%. Resistant Escherichia coli and Klebsiella pneumoniae isolates with piperacillin/tazobactam MICs of 4096/512, 1024/128 and 128/16 mg/L were investigated; two of the three organisms were carbapenemase-producers. Clinical efficacy was determined as a 3-log reduction over the dosing interval by comparing interval growth with controls. TZP was observed to exhibit time dependence for all organisms. The fT >MIC was determined to be 37.5%, 37.5% and 50% for MICs of 4096/512, 1024/128 and 128/16 mg/L, respectively. Linear regression identified the overall target to be 49.85 ± 16.9% fT >MIC . In conclusion, bactericidal activity against TZP-resistant Enterobacteriaceae occurred at 49.85 ± 16.9% fT >MIC . This suggests that highly resistant urinary organisms, including carbapenemase-producers, with MICs up to 4096/512 mg/L could be treated with TZP. Further investigations are required to elucidate urinary breakpoints and to explore the impact of different resistance mechanisms.
(Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)
