What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles
What we may expect from novel antibacterial agents in the pipeline with respect to resistance and pharmacodynamic principles
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DOI：
10.1007/s10928-017-9506-4
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发表时间：
2017-04-01
影响因子：
2.5
通讯作者：
Page, Malcolm G. P.
中科院分区：
文献类型：
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作者：
Bush, Karen;Page, Malcolm G. P.
从临床前晚期(7种化合物)到第一阶段(11个分子)、第二阶段(13个分子)到第三阶段(12个分子)，抗生素开发管道中大约有43个小分子。其中大多数是已确定的抗生素类别的代表，这些类别已被修改以解决耐药性问题。此外，围绕发现新类别的β-内酰胺酶抑制剂有相当大的活动，这些新类别的10种组合代表了不同发展阶段的4种抑制剂类别。这些抑制剂对丝氨酸β-内酰胺酶具有广泛的活性，甚至可能抑制一些青霉素结合蛋白，与碳青霉烯类、头孢菌素或氨曲南结合使用，可以增强对多重耐药革兰氏阴性细菌的活性。有6种代表新类别抗生素的分子，但其中只有一种，murepaadin，预计对革兰氏阴性病原菌(铜绿假单胞菌)具有活性。虽然现有类别的新类似物和新的组合是为解决特定的耐药性问题而设计的，但绝不能肯定它们不会受到一般耐药性机制的影响，特别是革兰氏阴性外膜的净通量下降。评估了耐药机制对新药物的潜在影响，并讨论了如何利用PK/PD研究来设计新药物的给药方案，特别是联合用药，以及改善现有抗生素的剂量。
There are some 43 small molecules in the antibiotic development pipeline from late preclinical stage (7 compounds) through Phase 1 (11 molecules), Phase 2 (13 molecules) to Phase 3 (12 molecules). The majority of these are representatives of established antibiotic classes that have been modified to address problems of resistance. In addition, there is considerable activity around the discovery of novel classes of beta-lactamase inhibitors with 10 combinations representing 4 inhibitor classes, at different stages of development. The combination of such inhibitors, which have broad activity against serine beta-lactamases and may even inhibit some penicillin binding proteins, with carbapenems, cephalosporins or aztreonam, provides enhanced activity against multi-drug resistant Gram-negative bacteria. There are 6 molecules representing novel classes of antibiotics but only one of these, murepavadin, is expected to have activity against a Gram-negative pathogenic bacterium (Pseudomonas aeruginosa). Although the new analogues of existing classes, and novel combinations, have been designed to address specific resistance problems, it is by no means certain than they will not be affected by the general mechanisms of resistance, particularly decreased net flux across the Gram-negative outer membrane. The potential impact of resistance mechanisms on the new agents is assessed and the ways in which PK/PD studies are used to design dosing regimens for the new agents, especially combinations, as well as to improve dosing of existing antibiotics are discussed.