Urinary piperacillin/tazobactam pharmacokinetics in-vitro to determine the pharmacodynamic breakpoint for resistant Enterobacteriacae.
BACKGROUNDUrinary 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.
OBJECTIVESThis 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.
METHODSThe 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.
RESULTSPiperacillin/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.
CONCLUSIONSBactericidal 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.
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.
Pub Type(s)Journal Article