Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection

Abstract

ObjectivesTo define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases. MethodsAn in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1hr infusion 8hrly. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24h (Δ 24) was the primary end point and four strains were used: E. coli expressing CTXM-15 or AmpC and K. pneumoniae expressing KPC or OXA-48 enzymes. ResultsTaniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01mg/L against CTXM-15 E. coli, ≥0.5mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli(AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R20.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T>0.25mg/L were equally related to bacterial clearance (R20.72 for both), and for K. pneumoniae (OXA-48) T>0.25mg/L was the best predictor (R20.94). The taniborbactam AUC range to produce a 1-log10 reduction in viable count was 4.4-11.2 mg∙h/L. Analysis of data from all strains indicated T>MIC divided by 4 was best related to change in viable count; however, curve fit was poor R2<0.49. ConclusionsTaniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time>threshold, both being closely related to antibacterial effect.