Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined β-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of β-Lactam-β-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 intra-abdominal 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 beta-lactamase they expressed. The four investigational strains included 2805 (no beta-lactamase), 2890 (AmpC beta-lactamase), 2842 (CMY-10 beta-lactamase), and 2807 (CTX-M-15 beta-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 10(6) and 10(8) CFU/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 (R-2 > 0.882) of ceftolozane revealed significantly higher 50% effective concentrations (EC(50)s) at tazobactam concentrations of <4 mg/liter than those at concentrations of >= 16 mg/liter (P < 0.01). Moreover, the EC(50)s at 10(8) CFU/ml were 2.81 to 66.5 times greater than the EC(50)s at 10(6) CFU/ml (median, 10.7-fold increase; P = 0.002). These promising results indicate that ceftolozane-tazobactam achieves bactericidal activity against a wide range of beta-lactamase-producing E. coli strains.