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Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae.
Int J Antimicrob Agents 2019; 54(2):240-244IJ

Abstract

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.

Authors+Show Affiliations

The University of Notre Dame, School of Medicine Sydney, 160 Oxford St., Darlinghurst, NSW 2010, Australia. Electronic address: 20150927@my.nd.edu.au.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.St Vincent's Hospital, Sydney, 390 Victoria St., Darlinghurst, NSW 2010, Australia.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31108222

Citation

Gould, M, et al. "Urinary Piperacillin/tazobactam Pharmacokinetics in Vitro to Determine the Pharmacodynamic Breakpoint for Resistant Enterobacteriaceae." International Journal of Antimicrobial Agents, vol. 54, no. 2, 2019, pp. 240-244.
Gould M, Ginn AN, Marriott D, et al. Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae. Int J Antimicrob Agents. 2019;54(2):240-244.
Gould, M., Ginn, A. N., Marriott, D., Norris, R., & Sandaradura, I. (2019). Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae. International Journal of Antimicrobial Agents, 54(2), pp. 240-244. doi:10.1016/j.ijantimicag.2019.05.013.
Gould M, et al. Urinary Piperacillin/tazobactam Pharmacokinetics in Vitro to Determine the Pharmacodynamic Breakpoint for Resistant Enterobacteriaceae. Int J Antimicrob Agents. 2019;54(2):240-244. PubMed PMID: 31108222.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae. AU - Gould,M, AU - Ginn,A N, AU - Marriott,D, AU - Norris,R, AU - Sandaradura,I, Y1 - 2019/05/17/ PY - 2019/01/11/received PY - 2019/05/08/revised PY - 2019/05/08/accepted PY - 2019/5/21/pubmed PY - 2019/5/21/medline PY - 2019/5/21/entrez KW - Enterobacteriaceae KW - Pharmacodynamics KW - Pharmacokinetics KW - Piperacillin KW - Static time–kill KW - Tazobactam SP - 240 EP - 244 JF - International journal of antimicrobial agents JO - Int. J. Antimicrob. Agents VL - 54 IS - 2 N2 - 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. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/31108222/Urinary_piperacillin/tazobactam_pharmacokinetics_in-vitro_to_determine_the_pharmacodynamic_breakpoint_for_resistant_Enterobacteriacae L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(19)30120-7 DB - PRIME DP - Unbound Medicine ER -