协同口服β-内酰胺类药物治疗结核病。
Synergistic oral beta-lactam combinations for treating tuberculosis.
机构信息
Tuberculosis Research Program, Centenary Institute, The University of Sydney, 2006 NSW, Australia.
Centre for Infectious Diseases and Microbiology, The Westmead Institute, 2145 NSW, Australia.
出版信息
J Appl Microbiol. 2024 Oct 3;135(10). doi: 10.1093/jambio/lxae255.
BACKGROUND
The enormous burden of tuberculosis (TB) worldwide is a major challenge to human health, but the costs and risks associated with novel drug discovery have limited treatment options for patients. Repurposing existing antimicrobial drugs offers a promising avenue to expand TB treatment possibilities. This study aimed to explore the activity and synergy of beta-lactams in combination with a beta-lactamase inhibitor, which have been underutilized in TB treatment to date.
METHODS
Based on inhibitory concentration, oral bioavailability, and commercial availability, seven beta-lactams (cefadroxil, tebipenem, cephradine, cephalexin, cefdinir, penicillin V, and flucloxacillin), two beta-lactamase inhibitors (avibactam and clavulanate), and three second-line TB drugs (moxifloxacin, levofloxacin, and linezolid) were selected for combination in vitro testing against Mycobacterium tuberculosis H37Rv. Resazurin assays and colony forming unit enumeration were used to quantify drug efficacy, Chou-Talalay calculations were performed to identify drug synergy and Chou-Martin calculations were performed to quantify drug dose reduction index.
RESULTS
The order of activity of beta-lactams was cefadroxil > tebipenem > cephradine > cephalexin > cefdinir > penicillin V > flucloxacillin. The addition of clavulanate improved beta-lactam activity to a greater degree than the addition of avibactam. As a result, avibactam was excluded from further investigations, which focused on clavulanate. Synergy was demonstrated for cefdinir/cephradine, cefadroxil/tebipenem, cefadroxil/penicillin V, cefadroxil/cefdinir, cephalexin/tebipenem, cephalexin/penicillin V, cephalexin/cefdinir, cephalexin/cephradine, and cefadroxil/cephalexin, all with clavulanate. However, combining beta-lactams with moxifloxacin, levofloxacin, or linezolid resulted in antagonistic effects, except for the combinations of penicillin V/levofloxacin, penicillin V/moxifloxacin, and cefdinir/moxifloxacin.
CONCLUSIONS
Beta-lactam synergy may provide viable combination therapies for the treatment of TB.
背景
结核病（TB）在全球造成了巨大的负担，对人类健康构成了重大挑战，但新型药物发现的成本和风险限制了患者的治疗选择。重新利用现有的抗菌药物为扩大结核病治疗的可能性提供了一个有希望的途径。本研究旨在探索β-内酰胺类药物与β-内酰胺酶抑制剂联合使用的活性和协同作用，迄今为止，这些药物在结核病治疗中尚未得到充分利用。
方法
根据抑制浓度、口服生物利用度和商业可用性，选择了七种β-内酰胺类药物（头孢羟氨苄、替比培南、头孢拉定、头孢氨苄、头孢地尼、青霉素 V 和氟氯西林）、两种β-内酰胺酶抑制剂（阿维巴坦和克拉维酸）以及三种二线结核病药物（莫西沙星、左氧氟沙星和利奈唑胺）进行体外测试，以评估它们对结核分枝杆菌 H37Rv 的活性。使用 Resazurin 测定法和菌落形成单位计数法来量化药物疗效，通过 Chou-Talalay 计算来确定药物协同作用，通过 Chou-Martin 计算来量化药物剂量减少指数。
结果
β-内酰胺类药物的活性顺序为头孢羟氨苄>替比培南>头孢拉定>头孢氨苄>头孢地尼>青霉素 V>氟氯西林。克拉维酸的加入比阿维巴坦更能提高β-内酰胺类药物的活性。因此，阿维巴坦被排除在进一步的研究之外，研究重点是克拉维酸。头孢地尼/头孢拉定、头孢羟氨苄/替比培南、头孢羟氨苄/青霉素 V、头孢羟氨苄/头孢地尼、头孢氨苄/替比培南、头孢氨苄/青霉素 V、头孢氨苄/头孢地尼、头孢氨苄/头孢拉定和头孢羟氨苄/头孢氨苄均表现出协同作用，所有这些药物均与克拉维酸联合使用。然而，除了青霉素 V/左氧氟沙星、青霉素 V/莫西沙星和头孢地尼/莫西沙星的组合外，β-内酰胺类药物与莫西沙星、左氧氟沙星或利奈唑胺联合使用均产生拮抗作用。
结论
β-内酰胺类药物的协同作用可能为结核病的治疗提供可行的联合治疗方案。
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