Pharmacological Basis of β-lactamase Inhibitor Therapeutics: Tazobactam in Combination with Ceftolozane.
Antimicrob Agents Chemother. 2013 Sep 16;
Authors: Vanscoy B, Mendes RE, McCauley J, Bhavnani SM, Bulik CC, Okusanya OO, Forrest A, Jones RN, Friedrich LV, Steenbergen JN, Ambrose PG
Abstract
We recently investigated the 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 percent 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 varying transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between 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 co-modeling across clinical isolates. The initial challenge panel included four well-characterized β-lactamase-producing E. coli 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 tazobactam %Time>threshold and change in log10 CFU from baseline; however, the data from the four isolates did not co-model well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/L. We identified an enabling translational relationship for the tazobactam threshold that allowed co-modeling of all four clinical isolates, which was the product of the individual isolates 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 K. pneumoniae with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the co-modeling of the four E. coli isolates performed well for the expanded dataset (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.
PMID: 24041895 [PubMed - as supplied by publisher]