此外,临床中还可见到一些其它酶抑制剂,如:亚胺培南易被人体近端肾小管细胞刷状缘中的去氢肽酶破坏,与酶抑制剂西司他丁联合应用后,可因药物灭活量减少而取得良好效果。
3.4 两种β?内酰胺类联用
β?内酰胺类抗生素主要作用于细菌细胞膜上的特殊蛋白即青霉素结合蛋白(penicillin binding proteins,PBPs)发挥杀菌作用。同一种细菌中可存在多种PBPs,因此,当联用的两种药物分别作用于不同的青霉素结合蛋白或其中一种可发挥β?内酰胺酶抑制剂作用时,可能会产生协同作用。Mainardi等[29]研究了针对肠球菌的两种β?内酰胺类抗生素的协同作用。在50株临床分离粪肠球菌中,阿莫西林与头孢噻肟对大多数肠球菌表现出协同作用。作者推测协同作用的产生与低浓度阿莫西林使PBPs4及PBPs5部分饱和,4μg/ml的头孢噻肟使PBPs2及PBPs3完全饱和有关。阿莫西林与头孢曲松也在粪肠球菌感染的实验性心内膜炎中表现出协同作用[29]。转贴于 中国论文下载中心 http://www.studa.net
相对于β?内酰胺类与氨基糖苷类之间的协同作用,两种β?内酰胺类之间的协同作用很少见到,体外多显示无关或相加作用,拮抗作用有时也会看到[30]。为避免作用机制相同的药物联用互相竞争作用靶位产生耐药,联合应用两种β?内酰胺类抗生素时仍需慎重。
4 联合用药的适应证
不恰当的联合用药不仅不会起到期望的疗效,还会加重医疗负担和不良反应,引起二重感染,甚至因为拮抗作用减弱疗效,因此临床在选择联合用药时需要慎重考虑,掌握适应证[2,14],在以下几种情况下可考虑联合应用抗菌药物:
(1)病因未明确的严重感染 对于危及生命的严重感染,常常不能等待相应的病原学检查结果,可通过联合用药扩大抗菌谱,之后根据病原学诊断调整用药。
(2)单一抗菌药物不能控制的严重混合感染 感染性心内膜炎应用单一抗菌药物常不能有效控制,此时应联合用药。
(3)长期用药易产生耐药者 如长期单独应用抗结核药物易产生耐药性,联合用药后耐药菌出现机会明显减少。
(4)联合用药后可使毒性较大的药物使用剂量减少 两性霉素B和氟胞嘧啶合用后抗菌活性增强,且因为减少了两性霉素B的剂量减轻了毒副反应。
5 结论
抗菌药物的联合用药在临床上应用越来越广,主要是为了治疗严重混合感染、扩大抗菌谱、减少耐药发生和减轻毒副反应。临床检验联合用药疗效绝大多数是回顾性研究,缺乏理想的随机、对照、双盲试验,体外检测联合药敏试验方法虽然种类较多,但目前仍缺乏统一的结果判定标准,这些因素都导致了临床与体外及动物试验结果不一致。尤其是β?内酰胺类联合大环内酯类抗生素理论上不应联合使用,但临床上仍被作为经验性治疗社区获得性肺炎的一线用药,相关的研究仍然需要继续完善以更好地指导临床用药。
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