Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis.
Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis.
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DOI：
10.3389/fphar.2021.677005
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发表时间：
2021
影响因子：
5.6
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Srivastava S;Thomas T;Howe D;Malinga L;Raj P;Alffenaar JW;Gumbo T
背景：人们对重新利用β-内酰胺抗生素治疗结核病（TB）重新产生了兴趣。我们研究了头孢地尼对药物敏感和多药耐药（MDR）结核分枝杆菌（Mtb）的疗效，头孢地尼可耐受许多细菌中存在的β-内酰胺酶。 研究方法：使用Mtb H37 Ra、8株药物敏感性和12株MDR-TB临床分离株（含和不含最终浓度为15 mg/L的β-内酰胺酶抑制剂阿维巴坦）进行最小抑菌浓度（MIC）实验。接下来，我们在试管中用Mtb H37 Ra进行剂量反应研究，然后在使用MDR-TB临床菌株的结核病临床前中空纤维模型（HFS-TB）研究中进行杀菌活性研究。采用抑制S型Emax模型描述药物暴露与细菌负荷的关系。 结果：头孢地尼对Mtb H37 Ra的MIC分别为4和2 mg/L，伴或不伴阿维巴坦。临床菌株的MIC范围为0.5 ~ 16 mg/L。在试管实验中，头孢地尼在7天内杀死4.93 ± 0.07 log 10 CFU/ml Mtb H37 Ra。在HFS-TB研究中，头孢地尼对MDR-TB显示出剂量依赖性杀灭作用，不与阿维巴坦联合。与Mtb灭菌效果相关的头孢地尼PK/PD指数被确定为浓度-时间曲线下面积与MIC的比值（AUC 0 -24/MIC），最佳暴露量计算为AUC 0 -24/MIC 578.86。HFS-TB对头孢地尼未出现耐药性。 结论：头孢地尼在不联合β-内酰胺酶抑制剂的情况下，对耐药结核病和耐多药结核病均有效。然而，这些发现的临床验证仍有待确定。
Background: There is renewed interest in repurposing β-lactam antibiotics for treatment of tuberculosis (TB). We investigated efficacy of cefdinir, that withstand the β-lactamase enzyme present in many bacteria, against drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Methods: Minimum inhibitory concentration (MIC) experiments were performed with Mtb H37Ra, eight drug-susceptible, and 12 MDR-TB clinical isolates with and without the β-lactamase inhibitor, avibactam at 15 mg/L final concentration. Next, we performed dose-response study with Mtb H37Ra in test-tubes followed by a sterilizing activity study in the pre-clinical hollow fiber model of tuberculosis (HFS-TB) study using an MDR-TB clinical strain. Inhibitory sigmoid Emax model was used to describe the relationship between the drug exposure and bacterial burden. Results: Cefdinir MIC for Mtb H37Ra was 4 and 2 mg/L with or without avibactam, respectively. The MIC of the clinical strains ranged between 0.5 and 16 mg/L. In the test-tube experiments, cefdinir killed 4.93 + 0.07 log10 CFU/ml Mtb H37Ra in 7 days. In the HFS-TB studies, cefdinir showed dose-dependent killing of MDR-TB, without combination of avibactam. The cefdinir PK/PD index linked to the Mtb sterilizing efficacy was identified as the ratio of area under the concentration-time curve to MIC (AUC0–24/MIC) and optimal exposure was calculated as AUC0–24/MIC of 578.86. There was no resistance emergence to cefdinir in the HFS-TB. Conclusion: In the HFS-TB model, cefdinir showed efficacy against both drug susceptible and MDR-TB without combination of β-lactamase inhibitor. However, clinical validation of these findings remains to be determined.
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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
影响因子：
5.2
作者：
Deshpande, Devyani;Srivastava, Shashikant;Gumbo, Tawanda
通讯作者：
Gumbo, Tawanda
影响因子：
9.6
作者：
MITCHISON, DA
通讯作者：
MITCHISON, DA
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
DOI：
10.1016/j.ijid.2021.01.062
发表时间：
2021-03
期刊：
International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases
影响因子：
--
作者：
Gumbo T;Sherman CM;Deshpande D;Alffenaar JW;Srivastava S
通讯作者：
Srivastava S