Mechanism and clinical significance of metronidazole resistance in Helicobacter pylori.
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.
van der Wouden
E J
EJ
Dept. of Internal Medicine, Isala Klinieken, Zwolle, The Netherlands. ejvanderwouden@hetnet.nl
Thijs
J C
JC
Kusters
J G
JG
van Zwet
A A
AA
Kleibeuker
J H
JH
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D024881:Drug Resistance, Bacterial / Q000235:genetics; D016480:Helicobacter pylori / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008795:Metronidazole / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D008795:Metronidazole