title: Pharmacological basis of β-lactamase inhibitor therapeutics: tazobactam in combination with Ceftolozane.
abstract: We recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of blaCTX-M-15. The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single β-lactamase enzyme and that clinical isolates typically produce multiple β-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r(2) values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r(2) value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized β-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r(2) value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.
authors.affiliation: Institute for Clinical Pharmacodynamics, Latham, New York, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Vanscoy
authors.forename: Rodrigo E
authors.initials: RE
authors.lastname: Mendes
authors.forename: Jennifer
authors.initials: J
authors.lastname: McCauley
authors.forename: Sujata M
authors.initials: SM
authors.lastname: Bhavnani
authors.forename: Catharine C
authors.initials: CC
authors.lastname: Bulik
authors.forename: Olanrewaju O
authors.initials: OO
authors.lastname: Okusanya
authors.forename: Alan
authors.initials: A
authors.lastname: Forrest
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Jones
authors.forename: Lawrence V
authors.initials: LV
authors.lastname: Friedrich
authors.forename: Judith N
authors.initials: JN
authors.lastname: Steenbergen
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ambrose
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D002511:Cephalosporins / Q000493:pharmacokinetics* / Q000494:pharmacology; D015169:Colony Count, Microbial; D003198:Computer Simulation; D004334:Drug Administration Schedule; D004338:Drug Combinations; D054796:Drug Dosage Calculations; D004926:Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000382:microbiology; D015870:Gene Expression; D006207:Half-Life; D006801:Humans; D007710:Klebsiella Infections / Q000188:drug therapy / Q000382:microbiology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010957:Plasmids; D000078142:Tazobactam; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004338:Drug Combinations; C519491:ceftolozane; D010397:Penicillanic Acid; D001618:beta-Lactamases; D000078142:Tazobactam
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