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 at 1.25 g every 6 h (h), colistin at 360 mg daily, and amikacin at 25 mg/kg daily were reproduced alone and in combination against six imipenem-nonsusceptible P. aeruginosa isolates in an in vitro pharmacodynamic model over 24 h. For I/R alone, the mean reductions in CFU ± the standard errors by 24 h were −2.52 ± 0.49, −1.49 ± 0.49, −1.15 ± 0.67, and −0.61 ± 0.10 log₁₀ CFU/ml against isolates with MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. Amikacin alone also resulted in 24 h CFU reductions consistent with its MIC, while colistin CFU reductions did not differ. Resistant subpopulations were observed after 24 h 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 24-h CFU reductions ranging from −2.62 to −4.67 log₁₀ CFU/ml. The combination of I/R and amikacin exhibited indifferent interactions against all isolates, with combined drugs achieving −0.51- to −3.33-log₁₀ CFU/ml reductions. No resistant subpopulations 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, whereas the addition of amikacin did not provide further antibacterial efficacy against these isolates.

中文翻译：

---

单独使用亚胺培南/西拉他汀/雷巴坦及其在体外药效学模型中对铜绿假单胞菌的组合

联合疗法可增强亚胺培南/西司他丁/雷巴坦（I / R）对铜绿假单胞菌的活性，并抑制耐药性的发展。人体模拟的未结合血浆I / R的I / R浓度为每6 h（h）1.25 g，每天360 mg的粘菌素和每天25 mg / kg的丁胺卡那霉素，分别针对6种亚胺培南不敏感的铜绿假单胞菌分离株进行组合。的体外24小时以上药效学模型。仅对于I / R，到24 h时CFU的平均减少量±标准误差为-2.52±0.49，-1.49±0.49，-1.15±0.67和-0.61±0.10 log ₁₀CFU / ml分别针对MIC分别为1 / 4、2 / 4、4 / 4和8/4μg/ ml的分离株。单独使用丁胺卡那霉素也会导致24小时CFU降低，与其MIC一致，而粘菌素CFU的降低没有差异。在分别暴露于1、4、3 I / R，粘菌素和丁胺卡那霉素的分离物中，分别在24小时后观察到了抗药性亚群。I / R和粘菌素的组合导致针对三种分离株的协同（n = 1）或加性（n = 2）相互作用，其24 h CFU降低范围为-2.62至-4.67 log ₁₀ CFU / ml。I / R和丁胺卡那霉素的组合对所有分离物均表现出微弱的相互作用，且组合药物的−0.51至−3.33 log ₁₀CFU / ml减少。在I / R和粘菌素联合研究中未观察到耐药亚群，将I / R添加到丁胺卡那霉素中可阻止丁胺卡那霉素抗性的出现。针对这六种具有多重耐药性的铜绿假单胞菌，单独的I / R对易受I / R感染的分离株实现了显着的CFU降低。I / R和粘菌素的组合导致对某些铜绿假单胞菌的加和作用或协同作用，而添加丁胺卡那霉素并未对这些分离物提供进一步的抗菌作用。