Fig. 2: Dose-fractionation and determination of PK-PD drivers of efficacy for BWC0977, either administered subcutaneously in a neutropenic P. aeruginosa infected mice thigh model (A & B) or administered via intravenous infusion in a neutropenic P. aeruginosa infected rat lung infection model (C & D).

Dose-fractionation of BWC0977 performed in P. aeruginosa infected mice (per dose n = 4 /cage, 8 thigh samples, right & left of each). A BWC0977 was administered subcutaneously at 160 mg/kg total daily dose delivered as a single, two doses or 4 doses over a 24 h period and the CFU burden monitored at various time points. Polymyxin (25 mg/kg) was used as the comparator drug. Data plotted as mean ± SD. B Aggregate plot of BWC0977 efficacy following dose-ranging studies (per dose n = 4/cage, 8 thigh samples, right & left of each) in a neutropenic mice thigh model infected with multiple isolates of P. aeruginosa, A. baumannii, K. pneumoniae and E. coli with pre-existing multidrug resistance mechanisms (Supplementary Table 6). Data plotted as mean ± SD. C Multiple isolates of P. aeruginosa, A. baumannii, K. pneumoniae and E. coli with different resistance mechanisms (Supplementary Table 7) were used for dose-ranging studies and the ΔLog₁₀CFU/gm lung from each animal (n = 2 per treatment group) is plotted as a function of fAUC₂₄/MIC for ease of comparison across isolates. D The PK-PD index that best described the in vivo efficacy of BWC0977 against P. aeruginosa in the neutropenic rat lung infection model. Dose-fractionation was carried out with BWC0977 as per the details shown in Supplementary Table 8. Log₁₀CFU/gm lung from each animal is plotted as a function of fAUC₂₄/MIC, fC_max/MIC and %T > MIC. fAUC₂₄/MIC was identified as the appropriate driver translating to BWC0977 efficacy.