Mechanism and clinical significance of metronidazole resistance in Helicobacter pylori

Metronidazole was introduced in 1959 for the treatment of Trichomonas vagin alis, but was subsequently shown to be active against anaerobic and some mi cro-aerophilic bacteria as well. In anaerobic microorganisms with their low redox potential, metronidazole is reduced to its active metabolite by a on e-electron transfer step, Metronidazole is often used in treatment regimens for Helicobacter pylori, a microaerophilic bacterium, but resistance to th is drug is frequently encountered. The metabolism of metronidazole in H, py lori must differ from that in anaerobic bacteria as metabolites formed by a one-electron transfer are readily re-oxidized in the micro-aerophilic envi ronment of H. pylori. This process is called 'futile cycling' and is accomp anied 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 nitroreductas e. encoded by the rdxA gene, is responsible for the activation of metronida zole. Activation by this enzyme is by a two-electron transfer step. prevent ing 'futile cycling' and thereby enabling the activation of metronidazole i n a micro-aerophilic environment. Metronidazole resistance has been shown t o be associated with Mill Mutations in the rdxA gene in most clinical isola tes. However. there may be some 'background metronidazole susceptibility' i n strains caused by other (oxygen-sensitive) nitroreductases. Recently, thr ee meta-analyses of the impact of metronidazole resistance on treatment eff icacy have all shown a significant reduction in efficacy of metronidazole c ontaining regimens in patients infected with a resistant strain, The impact of resistance proved to be dependent on the other components of the regime n and on treatment duration.