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 [PublishAheadOfPrint]

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 3g q8h alone or in combination with amikacin 25 mg/kg daily or colistin 360 mg daily against four MDR P. aeruginosa isolates. C/T alone resulted in 24 hour CFU changes of -0.02±0.21, -1.81±0.55, -1.44±0.40, and +0.62±0.05 log₁₀CFU/ml against isolates with C/T MICs of 4, 4, 8 and 16 μg/ml, respectively. Amikacin and colistin monotherapy displayed varying 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) log₁₀CFU/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) log10CFU/ml reductions, respectively, against these MDR P. aeruginosa. Greater overall reductions in bacterial burden, including additive or synergistic interactions at 24 hours, with C/T plus amikacin or colistin was observed against 3 out of 4 MDR P. aeruginosa 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.

http://ift.tt/2Cp9pwQ