Methods: Previously-described ceftolozane dose-fractionation data from a study using a neutropenic murine thigh-infection model were evaluated [AAC 2013; 57(4):1577-82]. In this prior study, mice were infected with E. coli ATCC 25922 (MIC = 0.5 mg/L) or K. pneumoniae ATCC 43816 (MIC = 1.4 mg/L). Ceftolozane doses ranged from 1.56 to 1600 mg/kg/24h given q3h, q6h, q12h, or q24h. Relationships between log10 colony forming units (CFU) at 24 h and AUC:MIC ratio, Cmax:MIC ratio, %T>MIC, and AUC/τ:MIC ratio were evaluated by pathogen and pooled using Hill-type models and non-linear least squares regression.
Results: For evaluations of data by pathogen, AUC/τ:MIC ratio best described changes in log10 CFU at 24 h. The coefficients of determination (r2) for these pathogens were improved by 0.20 and 0.11, respectively, relative to the highest r2 achieved using any of the traditional PK-PD indices. Similar results were observed when the data were evaluated using a pooled approach (Figure 1).
Conclusion: AUC/τ:MIC ratio may be useful to evaluate drugs demonstrating the extremes of PK. Accordingly, this PK-PD index best described ceftolozane PK-PD, an agent with a very short murine plasma half-life (<15 minutes). Use of the PK-PD index that allows for the best fit of the data to the Hill function and reduced variability about the fitted function will not only improve the characterization of PK-PD but will also improve the accuracy of future dose selection analyses.
E. A. Lakota,
S. M. Bhavnani, None
D. R. Andes, None
P. G. Ambrose, None
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