Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model

• Published in: Antimicrobial agents and chemotherapy Vol. 60; no. 4; pp. 2075 - 2080
• Main Authors: Nicasio, Anthony M, VanScoy, Brian D, Mendes, Rodrigo E, Castanheira, Mariana, Bulik, Catharine C, Okusanya, Olanrewaju O, Bhavnani, Sujata M, Forrest, Alan, Jones, Ronald N, Friedrich, Lawrence V, Steenbergen, Judith N, Ambrose, Paul G
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.04.2016
• Subjects: Anti-Bacterial Agents; Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; beta-Lactamase Inhibitors; beta-Lactamase Inhibitors - pharmacokinetics; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases; beta-Lactamases - genetics; beta-Lactamases - metabolism; Computer Simulation; Drug Therapy, Combination; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli - metabolism; Experimental Therapeutics; Gene Expression; Microbial Sensitivity Tests; Models, Statistical; Organisms, Genetically Modified; Penicillanic Acid; Penicillanic Acid - analogs & derivatives; Penicillanic Acid - pharmacokinetics; Penicillanic Acid - pharmacology; Piperacillin; Piperacillin - pharmacokinetics; Piperacillin - pharmacology; Plasmids - chemistry; Plasmids - metabolism; Transcription, Genetic
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02747-15

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.