Fig. 2 Exposure effect screening study of CAV against Mtb.

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Fig. 2 Exposure effect screening study of CAV against Mtb. Exposure effect screening study of CAV against Mtb. Each concentration was examined in triplicate, and results shown are for mean and SD (error bar). For each study, concentration versus log10 CFU/ml was examined using the inhibitory sigmoid Emax model. (A) Pyrazinamide failed to kill intracellular Mtb in 7 days. We acidified broth, which enabled pyrazinamide to kill Mtb but had poor fit of the model to the data (r2 = 0.718), associated with maximal kill (Emax) of 1.43 ± 1.07 log10 CFU/ml. (B) Isoniazid Emax was 3.56 ± 0.10 log10 CFU/ml against intracellular Mtb (r2 = 0.988), similar to the Emax of 3.32 ± 0.33 log10 CFU/ml (r2 = 0.845) for extracellular Mtb. (C) Rifampin Emax for intracellular Mtb was 5.68 ± 0.30 log10 CFU/ml (r2 = 0.976), and that for extracellular bacteria was 5.30 ± 0.09 log10 CFU/ml (r2 = 0.996). (D) Ceftazidime alone did not kill Mtb. (E) There was also poor fit of the model to the data for avibactam because of minimal to no microbial kill by the avibactam (r2 = 0.357). (F) CAV achieved an Emax of 7.05 ± 0.00 log10 CFU/ml and an EC50 (median effective concentration) of 104.50 ± 13.44 mg/liter (r2 = 0.910) against extracellular Mtb. This EC50 is easily achieved with standard doses. (G) CAV achieved an Emax of 4.19 ± 0.29 log10 CFU/ml and an EC50 of 74.92 ± 9.03 mg/liter (r2 = 0.960) against intracellular Mtb. (H) CAV MICs for five laboratory isolates are shown by arrows. The modal MIC in clinical isolates was 32 mg/liter. Devyani Deshpande et al. Sci Adv 2017;3:e1701102 Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).