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

Objectives

To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases.

Methods

An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia coli expressing CTXM-15 or AmpC and Klebsiella pneumoniae expressing KPC or OXA-48 enzymes.

Results

Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 E. coli, ≥0.5 mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4 mg/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 > 0.25 mg/L were equally related to bacterial clearance (R²0.72 for both), and for K. pneumoniae (OXA-48) T > 0.25 mg/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.

Conclusions

Taniborbactam 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.