Combinatorial Pharmacodynamics of Ceftolozane-Tazobactam against Genotypically Defined ?-Lactamase-Producing Escherichia coli: Insights into the Pharmacokinetics/Pharmacodynamics of ?-Lactam-?-Lactamase Inhibitor Combinations.

ABSTRACT: 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 ofEscherichia colithat differed in the type of ?-lactamase they expressed. The four investigational strains included 2805 (no ?-lactamase), 2890 (AmpC ?-lactamase), 2842 (CMY-10 ?-lactamase), and 2807 (CTX-M-15 ?-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 (EC50s) at tazobactam concentrations of ?4 mg/liter than those at concentrations of ?16 mg/liter (P< 0.01). Moreover, the EC50s at 10(8)CFU/ml were 2.81 to 66.5 times greater than the EC50s 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 ?-lactamase-producingE. colistrains.

SUBMITTER: Soon RL 

PROVIDER: S-EPMC4808171 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature