Watson I D, Stewart M J, Platt D J
Department of Biochemistry, Glasgow Royal Infirmary, Scotland.
Clin Pharmacokinet. 1988 Sep;15(3):133-64. doi: 10.2165/00003088-198815030-00001.
The effectiveness of some antimicrobial agents can be enhanced by using them in combination; such combinations are termed synergistic. Where one compound potentiates the effect of a second drug they may be coformulated. Inhibition of the bacterial degradation of an active antimicrobial is the basis of clavulanate and sulbactam-potentiated penicillin combinations, and inhibition of degradative pathways in the host is the rationale behind imipenem/cilastatin therapy. Trimethoprim/sulphonamide combinations depend on the maintenance of an effective ratio for synergistic action. In order to achieve potentiation the coformulated drugs should have similar pharmacokinetics. Trimethoprim was originally matched with sulphamethoxazole, since these two drugs have similar elimination half-lives, but the significantly poorer penetration of sulphonamides, their greater non-renal clearance, the emergence of resistance, and the adverse reactions attributable to them argue against the rationale that underlies their coformulation. Time-dependent inhibition of bacterial beta-lactamases by clavulanic acid and sulbactam has extended the use of penicillins which are highly susceptible to beta-lactamase inactivation. The beta-lactamase inhibitors must penetrate to the same extent as the penicillin used with them, and be present long enough to effect inhibition; thus, rapid penetration, similar or slower elimination and equivalent volume of distribution are necessary. These requirements are met for amoxycillin/clavulanic acid, ticarcillin/clavulanic acid and ampicillin/sulbactam combinations. Clavulanic acid is absorbed orally and is given with amoxycillin. However, since sulbactam is labile by this route, the combination of sulbactam with ampicillin to form the prodrug sultamicillin has been necessary to enable an oral form to be developed. Imipenem is metabolised by renal brush-border dehydropeptidases, and may cause proximal tubular necrosis. Cilastatin was designed to inhibit this metabolism, which it effectively does, thereby both potentiating the effect of imipenem and avoiding toxicity. Appropriate matching of the kinetics of coformulated drugs is intended to maximise potentiation and minimise the risk of emergent resistance. The kinetics of the above combinations are discussed in the light of these requirements and the effects of age and disease.
某些抗菌药物联合使用时疗效可增强，这种联合被称为协同作用。如果一种化合物能增强另一种药物的效果，它们可以制成复方制剂。抑制活性抗菌药物的细菌降解是克拉维酸和舒巴坦增强青霉素联合使用的基础，而抑制宿主中的降解途径是亚胺培南/西司他丁治疗的原理。甲氧苄啶/磺胺类药物的联合依赖于维持协同作用的有效比例。为了实现增效，复方制剂中的药物应具有相似的药代动力学。甲氧苄啶最初与磺胺甲恶唑匹配，因为这两种药物具有相似的消除半衰期，但磺胺类药物的穿透性明显较差、非肾清除率更高、耐药性的出现以及与之相关的不良反应，都与它们制成复方制剂的原理相悖。克拉维酸和舒巴坦对细菌β-内酰胺酶的时间依赖性抑制作用，扩大了对极易被β-内酰胺酶灭活的青霉素的使用范围。β-内酰胺酶抑制剂的穿透程度必须与与之联用的青霉素相同，且存在时间要足够长以实现抑制作用；因此，快速穿透、相似或较慢的消除以及相同的分布容积是必要的。阿莫西林/克拉维酸、替卡西林/克拉维酸和氨苄西林/舒巴坦组合满足这些要求。克拉维酸口服吸收，并与阿莫西林一起给药。然而，由于舒巴坦通过该途径不稳定，所以必须将舒巴坦与氨苄西林组合形成前体药物舒他西林，以便开发出口服剂型。亚胺培南被肾刷状缘脱氢肽酶代谢，可能导致近端肾小管坏死。西司他丁旨在抑制这种代谢，它有效地做到了这一点，从而既增强了亚胺培南的效果又避免了毒性。复方制剂中药物动力学的适当匹配旨在最大程度地增强疗效并最小化出现耐药性的风险。根据这些要求以及年龄和疾病的影响，讨论了上述组合的动力学。
