Fig 1: Pharmacokinetic profile and efficacy of the tebipenem prodrug TBP-PI combined with the avibactam prodrug AVI-ARX in mice. (A) Plasma concentration-time profile of TBP, the active component of TBP-PI, and AVI, the active component of AVI-ARX, following a single oral dose of 400 mg/kg TBP-PI (EC/13222; GlaxoSmithKline, Tres Cantos, Madrid, Spain) and 200 mg/kg AVI-AXR (catalog number HY-132987; MedChemExpress) in CD1 mice. The red dotted line shows the MIC of TBP (4 μM; 1.5 μg/mL) in the presence of 4 μg/mL AVI (indicated by the black dotted line) against M. abscessus K21 (16). (B) Efficacy of TBP-PI plus AVI-ARX (TPB/AVI) and clarithromycin (CLR) control in an NOD SCID mouse model. Mouse lung (left) and spleen (right) CFU are shown 1 day after intranasal infection with M. abscessus K21 (D1), following daily oral vehicle 0.5% carboxymethyl cellulose with 0.2% Tween 80 (TBP-PI plus AVI-AXR vehicle) for 10 days (D11), 6 times twice-daily oral administration followed by 4 days of once-daily oral administration of 400 mg/kg TBP-PI plus 200 mg/kg AVI-AXR (TBP/AVI), or daily oral administration of clarithromycin (250 mg/kg formulated in 0.5% carboxymethyl cellulose) for 10 days. The mean and standard deviation are shown for each treatment group (n = 6). Statistical significance of the results was analyzed by one-way analysis of variance (ANOVA) multicomparison and Dunnett’s posttest; *, P < 0.05. (C) Plasma concentration monitoring of TBP and AVI in infected NOD SCID mice 30 min and 24 h after the last dose in the efficacy experiment shown in panel B.