title: Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model.
abstract: We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (%time>threshold). Using anin vitroinfection model and the same isogenic CTX-M-15-producingEscherichia colitriplet set genetically engineered to transcribe different levels ofblaCTX-M-15, herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different β-lactam agent, or differentblaCTX-M-15transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128, >256, and >256 μg/ml for the low-, moderate-, and high-level CTX-M-15-producingE. colistrains, respectively. The MIC value for piperacillin in the presence of 4 μg/ml of tazobactam was 2 μg/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be %time>threshold, regardless of β-lactamase transcription (r(2)= 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 μg/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2)= 0.921, 0.773, and 0.875, respectively). The %time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log10-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a β-lactam-β-lactamase inhibitor combination is dependent on the amount of β-lactamase produced. These data provide important information for the development of β-lactam-β-lactamase inhibitor combination agents.
authors.affiliation: Albany College of Pharmacy and Health Sciences, Albany, New York, USA.
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Nicasio
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: VanScoy
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Mendes
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Mariana
authors.initials: M
authors.lastname: Castanheira
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Catharine C
authors.initials: CC
authors.lastname: Bulik
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Olanrewaju O
authors.initials: OO
authors.lastname: Okusanya
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.affiliation: Merck & Co, Inc., Kenilworth, New Jersey, USA.
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Friedrich
authors.affiliation: Merck & Co, Inc., Kenilworth, New Jersey, USA.
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA University of Oxford, Oxford, United Kingdom pambrose@ICPD.com.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D003198:Computer Simulation; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D030781:Organisms, Genetically Modified; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010878:Piperacillin / Q000493:pharmacokinetics / Q000494:pharmacology*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D000078142:Tazobactam; D014158:Transcription, Genetic; D065093:beta-Lactamase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; C473109:beta-lactamase CTX-M-15; D001618:beta-Lactamases; D000078142:Tazobactam; D010878:Piperacillin