title: Pharmacokinetics-pharmacodynamics of tazobactam in combination with ceftolozane in an in vitro infection model.
abstract: Despite β-lactamase inhibitors being available for clinical use for nearly 30 years, a paucity of data exists describing the pharmacokinetic-pharmacodynamic (PK-PD) determinants of efficacy for these agents. Herein, we describe dose fractionation studies designed to determine the exposure measure most predictive of tazobactam efficacy in combination with ceftolozane and the magnitude of this measure necessary for efficacy in a PK-PD in vitro infection model. The challenge organism panel was comprised of an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla(CTX-M-15). These recombinant strains exhibited ceftolozane MIC values of 4, 16, and 64 μg/ml representing low, moderate, and high levels of CTX-M-15, respectively. Different bla(CTX-M-15) transcription levels were confirmed by relative quantitative real-time PCR (qRT-PCR) and β-lactamase hydrolytic assays. The exposure measure associated with efficacy was the percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold), regardless of enzyme expression (r(2) = 0.938). The threshold concentrations identified were 0.05 μg/ml for low and moderate and 0.25 μg/ml for the high-β-lactamase expression strain constructs. The magnitudes of %Time>threshold for tazobactam associated with net bacterial stasis and a 1- and 2-log10 CFU reduction in bacteria at 24 h were approximately 35, 50, and 70%, respectively. These data provide an initial target tazobactam concentration-time profile and a paradigm to optimize tazobactam dosing when combined with ceftolozane.
authors: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors: Brian
authors: B
authors: VanScoy
authors: Rodrigo E
authors: RE
authors: Mendes
authors: Anthony M
authors: AM
authors: Nicasio
authors: Mariana
authors: M
authors: Castanheira
authors: Catharine C
authors: CC
authors: Bulik
authors: Olanrewaju O
authors: OO
authors: Okusanya
authors: Sujata M
authors: SM
authors: Bhavnani
authors: Alan
authors: A
authors: Forrest
authors: Ronald N
authors: RN
authors: Jones
authors: Lawrence V
authors: LV
authors: Friedrich
authors: Judith N
authors: JN
authors: Steenbergen
authors: Paul G
authors: PG
authors: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D002511:Cephalosporins / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy* / Q000382:microbiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008969:Molecular Sequence Data; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D000078142:Tazobactam; D001618:beta-Lactamases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D010397:Penicillanic Acid; C473109:beta-lactamase CTX-M-15; D001618:beta-Lactamases; D000078142:Tazobactam
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