Antimicrob Agents Chemother. 2020 Nov 2:AAC.01764-20. doi: 10.1128/AAC.01764-20. Online ahead of print.
Combination therapy may enhance imipenem/cilastatin/relebactam's (I/R) activity against Pseudomonas aeruginosa and suppress resistance development. Human-simulated unbound plasma concentrations of I/R 1.25g every six hours (h), colistin 360 mg daily, and amikacin 25 mg/kg daily were reproduced alone and in combination against six imipenem-non-susceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 hours. For I/R alone, reductions in colony forming units (CFU) by 24h were -2.52±0.49, -1.49±0.49, -1.15±0.67, and -0.61±0.10 log10CFU/mL against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/mL, respectively. Amikacin alone also resulted in 24h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant sub-populations were observed after 24h in 1, 4, and 3 I/R, colistin, and amikacin exposed isolates, respectively. The combination of I/R and colistin resulted in synergistic (n = 1) or additive (n = 2) interactions against three isolates with 24h CFU reductions ranging from -2.62 to -4.67 log10CFU/mL. The combination of I/R and amikacin exhibited indifferent interactions against all isolates with combined drugs achieving -0.51 to -3.33 log10CFU/mL reductions. No resistant sub-populations were observed during I/R and colistin combination studies, and when added to amikacin, I/R prevented the emergence of amikacin resistance. Against these six multidrug resistant P. aeruginosa, I/R alone achieved significant CFU reductions against I/R susceptible isolates. Combinations of I/R plus colistin resulted in additivity or synergy against some P. aeruginosa, while the addition of amikacin did not provide further antibacterial efficacy against these isolates.