van der Wouden E J, Thijs J C, Kusters J G, van Zwet A A, Kleibeuker J H
Dept. of Internal Medicine, Isala Klinieken, Zwolle, The Netherlands.
Scand J Gastroenterol Suppl. 2001(234):10-4. doi: 10.1080/003655201753265055.
Metronidazole was introduced in 1959 for the treatment of Trichomonas vaginalis, but was subsequently shown to be active against anaerobic and some micro-aerophilic bacteria as well. In anaerobic microorganisms with their low redox potential, metronidazole is reduced to its active metabolite by a one-electron transfer step. Metronidazole is often used in treatment regimens for Helicobacter pylori, a microaerophilic bacterium, but resistance to this drug is frequently encountered. The metabolism of metronidazole in H. pylori must differ from that in anaerobic bacteria as metabolites formed by a one-electron transfer are readily re-oxidized in the micro-aerophilic environment of H. pylori. This process is called 'futile cycling' and is accompanied by the formation of toxic oxygen radicals that are neutralized by an active scavenger system. Recently, it has been shown that in H. pylori, in contrast to the situation in anaerobes, an oxygen-insensitive nitroreductase. encoded by the rdxA gene, is responsible for the activation of metronidazole. Activation by this enzyme is by a two-electron transfer step, preventing futile cycling' and thereby enabling the activation of metronidazole in a micro-aerophilic environment. Metronidazole resistance has been shown to be associated with null mutations in the rdxA gene in most clinical isolates. However, there may be some 'background metronidazole susceptibility' in metronidazole-resistant strains caused by other (oxygen-sensitive) nitroreductases. Recently, three meta-analyses of the impact of metronidazole resistance on treatment efficacy have all shown a significant reduction in efficacy of metronidazole containing regimens in patients infected with a resistant strain. The impact of resistance proved to be dependent on the other components of the regimen and on treatment duration.
甲硝唑于1959年被用于治疗阴道毛滴虫，但随后发现它对厌氧菌和一些微需氧菌也有活性。在氧化还原电位低的厌氧微生物中，甲硝唑通过单电子转移步骤还原为其活性代谢产物。甲硝唑常用于幽门螺杆菌（一种微需氧菌）的治疗方案中，但对这种药物的耐药性经常出现。幽门螺杆菌中甲硝唑的代谢一定与厌氧菌不同，因为单电子转移形成的代谢产物在幽门螺杆菌的微需氧环境中很容易被重新氧化。这个过程被称为“无效循环”，并伴随着有毒氧自由基的形成，这些自由基被一个活跃的清除系统中和。最近发现，与厌氧菌的情况相反，在幽门螺杆菌中，由rdxA基因编码的一种对氧不敏感的硝基还原酶负责甲硝唑的激活。这种酶的激活是通过双电子转移步骤，防止“无效循环”，从而使甲硝唑在微需氧环境中得以激活。在大多数临床分离株中，甲硝唑耐药性已被证明与rdxA基因的无效突变有关。然而，在耐药菌株中可能存在一些由其他（对氧敏感的）硝基还原酶引起的“背景甲硝唑敏感性”。最近，三项关于甲硝唑耐药性对治疗效果影响的荟萃分析均显示，感染耐药菌株的患者使用含甲硝唑方案的疗效显著降低。耐药性的影响被证明取决于方案的其他成分和治疗持续时间。
