Heman-Ackah S M
J Pharm Sci. 1975 Oct;64(10):1621-6. doi: 10.1002/jps.2600641006.
The functional dependencies of apparent first-order generation rate constants kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. Clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However, clindamycin possesses only one of the two mechanisms of lincomycin action, which is bacteriostatic, against Escherichia coli. The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show "equivalence" or "indifference" of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism.
受药物影响的培养物中表观一级生成速率常数kapp对药物浓度的功能依赖性表明，林可霉素和克林霉素对金黄色葡萄球菌具有相同的作用机制，即抑菌作用。在高浓度水平时，克林霉素还具有另一种作用机制，即杀菌作用。然而，克林霉素对大肠杆菌仅具有林可霉素两种作用机制中的一种，即抑菌作用。克林霉素 - 林可霉素组合对金黄色葡萄球菌的相对效价作用是可变的，有效比率在5:1至9:1之间；在很宽的浓度范围内，对大肠杆菌的有效比率固定为6:1。这种差异归因于药物分子结构修饰导致的生物利用度和/或药物与生物受体结合特性的差异，以及各生物体中作用方式的差异。含有等效分数的克林霉素和林可霉素的混合物对金黄色葡萄球菌显示出“等效”或“无差异”的作用。混合物的联合作用可以从单独一种组分药物的剂量 - 反应曲线进行定量预测。因此，可以得出结论，克林霉素和林可霉素可能与参与微生物蛋白质合成的相同受体位点结合，以抑制金黄色葡萄球菌的生成。然而，克林霉素和林可霉素的组合在对大肠杆菌的作用中比单独使用任何一种药物的先验等效浓度活性更低，明确显示出作用的拮抗作用。此外，拮抗程度取决于药物添加的顺序，这归因于克林霉素和林可霉素可能在大肠杆菌中参与蛋白质合成的同一受体位点的活性位点和变构位点上有不同的结合方式。因此，一种合理的抗生素联合作用定量和预测方法不仅必须基于单独抗生素在宽浓度范围内作用的动力学、作用机制以及剂量 - 反应关系，还必须基于受试生物体的菌株和种类。
