Tags

Type your tag names separated by a space and hit enter

Urinary piperacillin/tazobactam pharmacokinetics in-vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriacae.

Abstract

BACKGROUND

Urinary tract infections caused by multi-drug resistant Enterobacteriaceae are a growing burden worldwide. Recent studies of urinary pharmacokinetics described high piperacillin/tazobactam concentrations in urine, but it is unknown whether this results in treatment efficacy.

OBJECTIVES

This study investigated the pharmacodynamics of piperacillin/tazobactam in a static in-vitro model for Enterobacteriaceae to determine the concentration-effect relationship and ultimately the required time above the Minimum Inhibitory Concentration (MIC) (fT>MIC) required for bacterial killing.

METHODS

The static simulation model investigated piperacillin/tazobactam fT>MIC between 0% and 100%. Resistant E.coli and K.pneumoniae isolates with MICs of 4096/512 mg/L, 1024/128 mg/L, and 128/16 mg/L piperacillin/tazobactam were investigated. Two of three organisms were carbapenenase resistant. Clinical efficacy was determined as a three-log-reduction over the dosing interval by comparing interval growth with controls.

RESULTS

Piperacillin/tazobactam 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 mg/L, 1024/128 mg/L and 128/16 mg/L respectively. Linear regression identified the overall target to be 49.85±16.9% fT>MIC.

CONCLUSIONS

Bactericidal activity against piperacillin/tazobactam 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 piperacillin/tazobactam. Further investigations are required to elucidate urinary breakpoints and explore the impact of different resistance mechanisms.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    The University of Notre Dame, School of Medicine Sydney, 160 Oxford St Darlinghurst, NSW 2010.

    ,

    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.

    ,

    St Vincent's Hospital, Sydney, 390 Victoria St, Darlinghurst, NSW 2010; 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.

    Source

    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 Enterobacteriacae." International Journal of Antimicrobial Agents, 2019.
    Gould M, Ginn AN, Marriott D, et al. Urinary piperacillin/tazobactam pharmacokinetics in-vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriacae. Int J Antimicrob Agents. 2019.
    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 Enterobacteriacae. International Journal of Antimicrobial Agents, 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 Enterobacteriacae. Int J Antimicrob Agents. 2019 May 17; 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 Enterobacteriacae. 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/entrez PY - 2019/5/21/pubmed PY - 2019/5/21/medline KW - pharmacodynamics KW - pharmacokinetics KW - piperacillin KW - static time-kill KW - tazobactam JF - International journal of antimicrobial agents JO - Int. J. Antimicrob. Agents N2 - BACKGROUND: Urinary tract infections caused by multi-drug resistant Enterobacteriaceae are a growing burden worldwide. Recent studies of urinary pharmacokinetics described high piperacillin/tazobactam concentrations in urine, but it is unknown whether this results in treatment efficacy. OBJECTIVES: This study investigated the pharmacodynamics of piperacillin/tazobactam in a static in-vitro model for Enterobacteriaceae to determine the concentration-effect relationship and ultimately the required time above the Minimum Inhibitory Concentration (MIC) (fT>MIC) required for bacterial killing. METHODS: The static simulation model investigated piperacillin/tazobactam fT>MIC between 0% and 100%. Resistant E.coli and K.pneumoniae isolates with MICs of 4096/512 mg/L, 1024/128 mg/L, and 128/16 mg/L piperacillin/tazobactam were investigated. Two of three organisms were carbapenenase resistant. Clinical efficacy was determined as a three-log-reduction over the dosing interval by comparing interval growth with controls. RESULTS: Piperacillin/tazobactam 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 mg/L, 1024/128 mg/L and 128/16 mg/L respectively. Linear regression identified the overall target to be 49.85±16.9% fT>MIC. CONCLUSIONS: Bactericidal activity against piperacillin/tazobactam 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 piperacillin/tazobactam. Further investigations are required to elucidate urinary breakpoints and 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 -