In Vivo Pharmacodynamic Profile of EVER206, a Novel Polymyxin Antimicrobial, against Gram-Negative Bacteria in the Murine Thigh Infection Model.

Abstract

The objective was to determine the magnitude of the EVER206 free-plasma area under the concentration time curve (fAUC)/MIC target associated with bacteriostasis and 1-log10 kill against clinically relevant Gram-negative bacteria in the murine thigh model. Twenty-seven clinical isolates (Pseudomonas aeruginosa, n = 10; Escherichia coli, n = 9; Klebsiella pneumoniae, n = 5; Enterobacter cloacae, n = 2; and Klebsiella aerogenes, n = 1) were tested. Mice were pretreated with cyclophosphamide (induce neutropenia) and uranyl nitrate (increase the exposure of test compound through predictable renal dysfunction). Two hours postinoculation, five doses of EVER206 were administered subcutaneously. EVER206 pharmacokinetics were determined in infected mice. Data were fit using maximum effect (Emax) models to elucidate the fAUC/MIC targets for stasis and 1-log10 bacterial kill (reported as mean [range] by species). EVER206 MICs (mg/L) ranged from 0.25 to 2 mg/L (P. aeruginosa), 0.06 to 2 mg/L (E. coli), 0.06 to 0.125 mg/L (E. cloacae), 0.06 mg/L (K. aerogenes), and 0.06 to 2 mg/L (K. pneumoniae). In vivo, the mean 0-h baseline bacterial burden was 5.57 ± 0.39 log10 CFU/thigh. Stasis was achieved in 9/10 P. aeruginosa (fAUC/MIC, 88.13 [50.33 to 129.74]), 9/9 E. coli (fAUC/MIC, 112.84 [19.19 to 279.38]), 2/2 E. cloacae (fAUC/MIC, 259.28 [124.08 to 394.47]), 0/1 K. aerogenes, and 4/5 K. pneumoniae (fAUC/MIC, 99.26 [62.3 to 144.43]) isolates tested. 1-log10 kill was achieved in 9/10 for P. aeruginosa (fAUC/MIC, 106.43 [55.22 to 152.08]), 3/9 for E. coli (fAUC/MIC, 258.96 [74.08 to 559.4]), and 1/2 for E. cloacae (fAUC/MIC, 255.33). Using the murine thigh model, the fAUC/MIC targets of EVER206 were assessed across a broad MIC distribution. Integrating these data with microbiologic and clinical exposure data will aid in determining the clinical dose of EVER206.