Srivastava Shashikant, Gumbo Tawanda, Thomas Tania
Department of Pulmonary Immunology, University of Texas Health Science Centre, Tyler, TX, United States.
Department of Immunology, UT Southwestern Medical Center, Dallas, TX, United States.
Front Pharmacol. 2021 Oct 22;12:776969. doi: 10.3389/fphar.2021.776969. eCollection 2021.
While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) (). 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). Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical 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 susceptibility breakpoint in three age-groups. Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC) 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. 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.
虽然结核病是可治愈和可预防的，但最有效的一线抗生素无法杀死耐多药（MDR）结核分枝杆菌。因此，需要有效的药物来对抗耐多药结核病，尤其是在儿童中。我们的目标是利用药代动力学/药效学（PK/PD）原理，将头孢唑林重新用于儿童耐多药结核病的治疗。在17株临床菌株中确定了头孢唑林的最低抑菌浓度（MIC），这些菌株添加或未添加β-内酰胺酶抑制剂阿维巴坦。接下来，使用结核细胞内中空纤维模型（HFS-TB）进行剂量范围研究，以确定最佳的头孢唑林暴露量。然后在10000名儿童中进行蒙特卡洛实验，根据三个年龄组的反应累积分数（CFR）和药敏折点确定最佳剂量。阿维巴坦使头孢唑林的MIC降低了五个倍比稀释度。在28天内，头孢唑林-阿维巴坦在细胞内HFS-TB中显示出最大杀菌效果为4.85 log CFU/mL。与最大效应（EC）相关的高于MIC的时间百分比为给药间隔的46.76%（95%置信区间：43.04-50.49%）。对于每日一次或两次100mg/kg的剂量，3岁以下播散性结核病儿童的CFR分别为8.46%和61.39%，3至5岁儿童为9.70%和84.07%，12至15岁儿童为17.20%和76.13%。PK/PD推导的药敏折点在1-2mg/L时呈剂量依赖性。头孢唑林-阿维巴坦组合在HFS-TB中对药物敏感和耐多药结核临床菌株均显示出疗效，有可能用于治疗儿童结核病。有必要进行临床研究来验证我们的发现。
