Efficacy of Human-Simulated Exposures of Ceftolozane-Tazobactam Alone and in Combination with Amikacin or Colistin against Multidrug-Resistant Pseudomonas aeruginosa in an In Vitro Pharmacodynamic Model

Combination therapy is an attractive option for the treatment of multidrug-resistant (MDR) Pseudomonas aeruginosa infections; however, limited data are available on combinations with ceftolozane-tazobactam (C-T). The in vitro pharmacodynamic chemostat model was employed to compare human-simulated exposures of C-T at 3 g every 8 h alone or in combination with amikacin at 25 mg/kg of body weight daily or colistin at 360 mg daily against four MDR P. aeruginosa isolates. C-T alone resulted in 24-h changes in the number of CFU of -0.02 +/- 0.21, -1.81 +/- 0.55, -1.44 +/- 0.40, and -0.62 +/- 0.05 log(10) CFU/ml against isolates with C-T MICs of 4, 4, 8, and 16 mu g/ml, respectively. Amikacin and colistin monotherapy displayed various results. The addition of amikacin to C-T resulted in -2.00 +/- 0.23 (P < 0.001, additive)-, - 1.50 +/- 0.83 (P = 0.687, indifferent)-, - 2.84 +/- 0.08 (P = 0.079, indifferent)-, and - 2.67 +/- 0.54 (P < 0.001, synergy)-log(10) CFU/ml reductions, respectively. The addition of colistin to C-T resulted in - 3.02 +/- 0.22 (P < 0.001, additive)-, -3.21 +/- 0.24 (P > 0.05, indifferent)-, -4.6 +/- 0.11 (P = 0.002, synergy)-, and - 3.01 +/- 0.28 (P < 0.001, synergy)-log(10) CFU/ml reductions, respectively, against the MDR P. aeruginosa isolates with these MICs. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 h, with C-T plus amikacin or colistin were observed against 3 out of 4 MDR P. aeruginosa strains tested, particularly those strains that were intermediate or resistant to C-T. Further studies assessing combination regimens containing C-T against MDR P. aeruginosa are warranted.