Combinatorial pharmacodynamics of ceftolozane-tazobactam against genotypically defined β-lactamase-producing Escherichia coli: Insights into the pharmacokinetics/pharmacodynamics of β-lactam-P-lactamase inhibitor combinations

Despite a dearth of new agents currently being developed to combat multidrug-resistant Gram-negative pathogens, the combination of ceftolozane and tazobactam was recently approved by the Food and Drug Administration to treat complicated intraabdominal and urinary tract infections. To characterize the activity of the combination product, time-kill studies were conducted against 4 strains of Escherichia coli that differed in the type of P-lactamase they expressed. The four investigational strains included 2805 (no P-lactamase), 2890 (AmpC P-lactamase), 2842 (CMY-10 P-lactamase), and 2807 (CTX-M-15 P-lactamase), with MICs to ceftolozane of 0.25, 4,8, and > 128 mg/liter with no tazobactam, and MICs of 0.25,1,4, and 8 mg/liter with 4 mg/liter tazobactam, respectively. All four strains were exposed to a 6 by 5 array of ceftolozane (0,1,4,16,64, and 256 mg/liter) and tazobactam (0,1,4,16, and 64 mg/liter) over 48 h using starting inocula of 10⁶and 10⁸CFU/ml. While ceftolozane-tazobactam achieved bactericidal activity against all 4 strains, the concentrations of ceftolozane and tazobactam required for a ≥3-log reduction varied between the two starting inocula and the 4 strains. At both inocula, the Hill plots (R²> 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC₅₀s) at tazobactam concentrations of:≤4 mg/liter than those at concentrations of ≥16 mg/liter (P < 0.01). Moreover, the EC₅₀s at 10⁸CFU/ml were 2.81 to 66.5 times greater than the EC₅₀s at 10⁶CFU/ml (median, 10.7-fold increase; P = 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of P-lactamase-producing E. coli strains.