Repurposing Cefazolin-Avibactam for the Treatment of Drug Resistant Mycobacterium tuberculosis.
Repurposing Cefazolin-Avibactam for the Treatment of Drug Resistant Mycobacterium tuberculosis.
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DOI：
10.3389/fphar.2021.776969
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发表时间：
2021
影响因子：
5.6
通讯作者：
Thomas T
中科院分区：
文献类型：
--
作者：
Srivastava S;Gumbo T;Thomas T
背景：虽然结核病(TB)是可以治愈和预防的，但最有效的一线抗生素无法杀死耐多药(MDR)的结核分枝杆菌(Mtb)。因此，需要有效的药物来抗击耐多药结核病，特别是在儿童中。我们的目标是利用药代动力学/药效学原理(PK/PD)调整头孢唑林治疗儿童耐多药结核病的用途。方法：测定17株临床分离结核分枝杆菌在联合应用β-内酰胺酶抑制剂阿维巴坦前后的头孢唑林最低抑菌浓度。接下来，使用结核的细胞内中空纤维模型(HFS-TB)进行剂量范围研究，以确定头孢唑林的最佳暴露剂量。然后，在10,000名儿童中进行了蒙特卡罗实验，以根据三个年龄组的累积应答分数(CFR)和结核分枝杆菌敏感性断点确定最佳剂量。结果：阿维巴坦对头孢唑林的最低抑菌浓度为5倍。28天内，头孢唑林-阿维巴坦对HFS-TB细胞的最大杀伤率为4.85log10CFU/mL。最大效应(EC80)的MIC以上时间为给药间隔的46.76%(95%可信区间：43.04~50.49%)。100 mg/kg每日1~2次，对3岁以下播散性肺结核儿童的CFR值分别为8.46和61.39%，3~5岁儿童的CFR值分别为9.70和84.07%，12~15岁儿童的CFR值分别为17.20和76.13%。结论：头孢唑林-阿维巴坦联合应用对HFS-TB中的药物敏感株和耐多药结核临床株均有效，可用于儿童结核病的治疗。临床研究是有根据的，以证实我们的发现。
Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD). Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups. Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children <3 years with disseminated TB, 9.70 and 84.07% for 3–5 years-old children, and 17.20 and 76.13% for 12–15 years-old children. The PK/PD-derived susceptibility breakpoint was dose dependent at 1–2 mg/L. Conclusion: Cefazolin-avibactam combination demonstrates efficacy against both drug susceptible and MDR-TB clinical strains in the HFS-TB and could potentially be used to treat children with tuberculosis. Clinical studies are warranted to validate our findings.
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Ceftazidime-avibactam对高度耐药性结核病具有有效的消毒活性。
影响因子：
13.6
作者：
Deshpande D;Srivastava S;Chapagain M;Magombedze G;Martin KR;Cirrincione KN;Lee PS;Koeuth T;Dheda K;Gumbo T
通讯作者：
Gumbo T
DOI：
10.1093/cid/ciw473
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
DOI：
10.1093/cid/ciw474
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
影响因子：
11.8
作者：
Alffenaar, Jan-Willem C.;Gumbo, Tawanda;Migliori, Giovanni Battista
通讯作者：
Migliori, Giovanni Battista
影响因子：
4.1
作者：
Hall RG;Leff RD;Gumbo T
通讯作者：
Gumbo T