Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children.
Evaluation of Ceftriaxone Plus Avibactam in an Intracellular Hollow Fiber Model of Tuberculosis: Implications for the Treatment of Disseminated and Meningeal Tuberculosis in Children.
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在细胞内空心纤维模型的结核病模型中评估头孢曲松和阿维巴坦：对儿童散布和脑膜结核的治疗的影响。
DOI：
10.1097/inf.0000000000002857
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发表时间：
2020-12
期刊：
影响因子：
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通讯作者：
Gumbo T
中科院分区：
文献类型：
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作者：
Srivastava S;van Zyl J;Cirrincione K;Martin K;Thomas T;Deshpande D;Alffenaar JW;Seddon JA;Gumbo T
头孢他啶-阿维巴坦是治疗结核病（TB）的有效药物，但由于半衰期短，需要频繁给药。由于半衰期较长，头孢曲松可允许间歇给药。首先，我们确定了头孢曲松与15 mg/L阿维巴坦在30株结核分枝杆菌临床分离株中的MIC。接下来，在模拟幼儿播散性疾病的结核细胞内中空纤维模型（HFS-TB）中进行了2项头孢曲松钠拮抗作用研究。头孢曲松每日给药一次或两次，持续28天，以探索浓度持续高于MIC（%TMIC）的时间百分比，范围为0至100%。在第三项HFS-TB实验中，使用布利斯Independence检查并分析了头孢他啶-头孢曲松-阿维巴坦的“双头孢菌素”方案。在存在15 mg/L阿维巴坦的情况下，临床菌株的MIC 99为32 mg/L。头孢曲松%TMIC <42对HFS-TB无微生物作用，%TMIC >54%显示4.1 log 10菌落形成单位/ml M。而TMIC介导的Emax为68%。“双头孢菌素”组合具有高度协同作用。对10，000名受试者进行的蒙特卡罗实验确定了最佳头孢曲松剂量为100 mg/kg，每天两次。100 mg/kg头孢曲松-阿维巴坦联合给药可在>90%的儿童中达到Emax。头孢曲松的有效活性M.结核病可能会缩短儿童播散性结核病的治疗时间。
Ceftazidime-avibactam is an effective agent for the treatment of tuberculosis (TB) but requires frequent administration because of a short half-life. Due to a longer half-life, ceftriaxone could allow intermittent dosing. First, we identified the MIC of ceftriaxone with 15 mg/L avibactam in 30 clinical Mycobacterium tuberculosis isolates. Next, 2 ceftriaxone exposure-effect studies in the intracellular hollow fiber model of TB (HFS-TB) that mimics disseminated disease in young children, were performed. Ceftriaxone was administered once or twice daily for 28 days to explore percentage of time that the concentration persisted above MIC (%TMIC) ranging from 0 to 100%. In a third HFS-TB experiment, the “double cephalosporin” regimen of ceftazidime-ceftriaxone-avibactam was examined and analyzed using Bliss Independence. The MIC99 of the clinical strains was 32 mg/L, in the presence of 15 mg/L avibactam. Ceftriaxone %TMIC <42 had no microbial effect in the HFS-TB, %TMIC >54% demonstrated a 4.1 log10 colony-forming units per milliliter M. tuberculosis kill, while %TMIC mediating Emax was 68%. The “double cephalosporin” combination was highly synergistic. Monte Carlo experiments of 10,000 subjects identified the optimal ceftriaxone dose as 100 mg/kg twice a day. The combination of ceftriaxone-avibactam at 100 mg/kg could achieve Emax in >90% of children. The ceftriaxone potent activity M. tuberculosis could potentially shorten therapy in children with disseminated TB.