Infectious Diseases Service, Laboratory of Experimental Infection, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, Barcelona, Spain.
Department of Microbiology, Hospital Universitari de Bellvitge, IDIBELL, Universitat de Barcelona, Barcelona, Spain.
Int J Antimicrob Agents. 2019 May;53(5):612-619. doi: 10.1016/j.ijantimicag.2019.01.010. Epub 2019 Jan 23.
Ceftolozane/tazobactam is a potential tool for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa), but its efficacy against some difficult-to-treat infections has not been well defined.
Using an in vitro pharmacodynamic biofilm model, this study evaluated the comparative efficacy of ceftolozane/tazobactam against MDR/extensively drug-resistant (XDR) P. aeruginosa strains, alone and in combination with colistin. Simulated regimens of ceftolozane/tazobactam (2 g/1 g every 8 h), meropenem (2 g every 8 h) and ceftazidime (2 g every 8 h), alone and in combination with colistin (continuous infusion) were evaluated against three colistin-susceptible and ceftazidime-resistant strains: MDR-HUB1, ceftolozane/tazobactam-susceptible and meropenem-susceptible; XDR-HUB2, ceftolozane/tazobactam-susceptible and meropenem-resistant; MDR-HUB3, ceftolozane/tazobactam-resistant and meropenem-susceptible. Antibiotic efficacy was evaluated by decreases in bacterial counts (Δlog CFU/mL) from biofilm-embedded bacteria over 54 h. Resistance emergence was screened.
Among monotherapies, ceftolozane/tazobactam had low killing but no resistance appeared, ceftazidime was ineffective, colistin was initially effective but regrowth and resistance occurred, and meropenem was bactericidal against carbapenem-susceptible strains. Ceftolozane/tazobactam plus colistin was the most effective combination against the meropenem-resistant XDR-HUB2 strain (Δlog CFU/mL 54-0 h = -4.42 vs. -3.54 for meropenem-colistin; P = 0.002), whereas this combination against MDR-HUB1 (-4.36) was less effective than meropenem-colistin (-6.25; P < 0.001). Ceftolozane/tazobactam plus colistin was ineffective against the ceftolozane/tazobactam-resistant strain; meropenem plus colistin was the most bactericidal therapy (-6.37; P < 0.001 vs. others). Combinations of active beta-lactams plus colistin prevented the emergence of colistin-resistant strains.
Combinations of colistin plus ceftolozane/tazobactam and meropenem were the most appropriate treatments for biofilm-related infections caused by XDR and MDR P. aeruginosa strains, respectively. These combinations could be considered as potential treatment options for these difficult to treat infections.
头孢他洛滨/他唑巴坦是一种治疗多重耐药（MDR）铜绿假单胞菌（P. aeruginosa）感染的潜在药物，但对某些治疗困难的感染的疗效尚未明确。
本研究采用体外药效学生物膜模型，评估了头孢他洛滨/他唑巴坦单独和联合黏菌素治疗 MDR/XDR 铜绿假单胞菌的疗效。评估了头孢他洛滨/他唑巴坦（2 g/1 g，每 8 小时）、美罗培南（2 g，每 8 小时）和头孢他啶（2 g，每 8 小时）单独和联合黏菌素（连续输注）的模拟方案对三种黏菌素敏感和头孢他啶耐药的菌株的疗效：MDR-HUB1，头孢他洛滨/他唑巴坦敏感和美罗培南敏感；XDR-HUB2，头孢他洛滨/他唑巴坦敏感和美罗培南耐药；MDR-HUB3，头孢他洛滨/他唑巴坦耐药和美罗培南敏感。通过生物膜内细菌 54 小时内的细菌计数减少（Δlog CFU/mL）评估抗生素疗效。筛选了耐药性的出现。
在单药治疗中，头孢他洛滨/他唑巴坦的杀菌效果较低，但没有出现耐药性，头孢他啶无效，黏菌素最初有效，但出现了细菌再生和耐药性，美罗培南对碳青霉烯类敏感株具有杀菌作用。头孢他洛滨/他唑巴坦联合黏菌素对美罗培南耐药的 XDR-HUB2 菌株最有效（54-0 h 的 Δlog CFU/mL 为-4.42 比美罗培南-黏菌素为-3.54；P=0.002），而对 MDR-HUB1 的联合治疗（-4.36）不如美罗培南-黏菌素有效（-6.25；P<0.001）。头孢他洛滨/他唑巴坦联合黏菌素对头孢他洛滨/他唑巴坦耐药株无效；美罗培南联合黏菌素是最具杀菌作用的治疗方法（-6.37；P<0.001 比其他方法）。β-内酰胺类联合黏菌素可防止黏菌素耐药菌株的出现。
黏菌素联合头孢他洛滨/他唑巴坦和美罗培南分别是治疗 XDR 和 MDR 铜绿假单胞菌引起的生物膜相关感染的最佳治疗方法。这些联合治疗方法可作为这些治疗困难的感染的潜在治疗选择。
