Cai Yiying, Lim Tze-Peng, Teo Jocelyn Qi-Min, Sasikala Suranthran, Chan Eric Chun Yong, Hong Yan Jun, Lee Winnie, Tan Thean Yen, Tan Thuan Tong, Koh Tse Hsien, Hsu Li Yang, Kwa Andrea L
Department of Pharmacy, Singapore General Hospital, Singapore.
Department of Pharmacy, National University of Singapore, Singapore.
Antimicrob Agents Chemother. 2016 Dec 27;61(1). doi: 10.1128/AAC.01509-16. Print 2017 Jan.
Polymyxin B-based combinations have emerged as a mainstay treatment against carbapenem-resistant Escherichia coli (CREC). We investigated the activity of polymyxin B-based two-antibiotic combinations against CREC using time-kill studies (TKS) and validated the findings in a hollow-fiber infection model (HFIM). TKS were conducted using 5 clinical CREC strains at 5 log CFU/ml against 10 polymyxin B-based two-antibiotic combinations at maximum clinically achievable concentrations. HFIMs simulating dosing regimens with polymyxin B (30,000U/kg/day) and tigecycline (100 mg every 12 h) alone and in combination were conducted against two CREC strains at 5 log CFU/ml over 120 h. Emergence of resistance was quantified using antibiotic-containing media. Phenotypic characterization (growth rate and stability of resistant phenotypes) of the resistant isolates was performed. All five CREC strains harbored carbapenemases. Polymyxin B and tigecycline MICs ranged from 0.5 mg/liter to 2 mg/liter and from 0.25 mg/liter to 8 mg/liter, respectively. All antibiotics alone did not have bactericidal activity at 24 h in the TKS, except for polymyxin B against two strains. In combination TKS, only polymyxin B plus tigecycline demonstrated both bactericidal activity and synergy in two out of five strains. In the HFIM, polymyxin B alone was bactericidal against both CREC strains before regrowth was observed at 8 h. Phenotypically stable polymyxin B-resistant mutants were observed for both strains, with a reduced growth rate observed in one strain. Tigecycline alone resulted in a slow reduction in bacterial counts. Polymyxin B plus tigecycline resulted in rapid and sustained bactericidal killing up to 120 h. Polymyxin B plus tigecycline is a promising combination against CREC. The clinical relevance of our results warrants further investigations.
基于多粘菌素B的联合用药已成为治疗耐碳青霉烯类大肠杆菌（CREC）的主要手段。我们通过时间杀菌研究（TKS）调查了基于多粘菌素B的双抗生素联合用药对CREC的活性，并在中空纤维感染模型（HFIM）中验证了研究结果。使用5株临床CREC菌株，在5 log CFU/ml浓度下，针对10种基于多粘菌素B的双抗生素联合用药，在临床可达到的最大浓度下进行TKS。针对两株5 log CFU/ml的CREC菌株，进行了模拟多粘菌素B（30,000U/kg/天）和替加环素（每12小时100 mg）单独及联合给药方案的HFIM实验，持续120小时。使用含抗生素培养基对抗药性的出现进行定量分析。对耐药菌株进行了表型特征分析（生长速率和耐药表型的稳定性）。所有五株CREC菌株均携带碳青霉烯酶。多粘菌素B和替加环素的最低抑菌浓度（MIC）分别为0.5 mg/升至2 mg/升和0.25 mg/升至8 mg/升。在TKS中，除多粘菌素B对两株菌株有杀菌活性外，所有单一抗生素在24小时时均无杀菌活性。在联合TKS中，仅多粘菌素B加替加环素在五株菌株中的两株中表现出杀菌活性和协同作用。在HFIM中，单独使用多粘菌素B在8小时观察到细菌再生长之前对两株CREC菌株均有杀菌作用。两株菌株均观察到表型稳定的多粘菌素B耐药突变体，其中一株菌株的生长速率降低。单独使用替加环素导致细菌数量缓慢减少。多粘菌素B加替加环素在长达120小时内导致快速且持续的杀菌作用。多粘菌素B加替加环素是一种有前景的抗CREC联合用药方案。我们研究结果的临床相关性值得进一步研究。
