- Title
- Urinary piperacillin/tazobactam pharmacokinetics in vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriaceae
- Creator
- Gould, M.; Ginn, A. N.; Marriott, D.; Norris, R.; Sandaradura, I.
- Relation
- International Journal of Antimicrobial Agents Vol. 54, Issue 2, p. 240-244
- Publisher Link
- http://dx.doi.org/10.1016/j.ijantimicag.2019.05.013
- Publisher
- Elsevier
- Resource Type
- journal article
- Date
- 2019
- Description
- 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.
- Subject
- piperacillin; tazobactam; pharmacodynamics; pharmacokinetics; static time-kill; Enterobacteriaceae
- Identifier
- http://hdl.handle.net/1959.13/1413016
- Identifier
- uon:36565
- Identifier
- ISSN:0924-8579
- Rights
- © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.
- Language
- eng
- Full Text
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