Evaluation of nitrofurantoin combination therapy of metronidazole-sensitive and -resistant Helicobacter pylori infections in mice

The main objectives of this study were to determine whether the nitroreduct ase enzyme encoded by the rdxA gene of Helicobacter pylori was responsible for reductive activation of nitrofurantoin and whether a triple-therapy reg imen with nitrofurantoin was able to eradicate metronidazole-sensitive and -resistant H. pylori infections from mice. The susceptibilities to nitrofur antoin of parent and isogenic rdxA mutant strains (three pairs), as well as a series of matched metronidazole-sensitive and -resistant strains isolate d from mice (30) and patients (20), were assessed by agar dilution determin ation of the MIC. Groups of mice colonized with the metronidazole-sensitive H. pylori SS1 strain:or a metronidazole-resistant rdxA SS1 mutant were tre ated with either metronidazole or nitrofurantoin as part of a triple-therap y regimen. One month after the completion of treatment the mice were sacrif iced and their stomachs were cultured for H. pylori. The nitrofurantoin MIC s for all strains tested were between 0.5 and 4.0 mu g/ml. There was no sig nificant difference between the susceptibility to nitrofurantoin of the par ental strains and those of respective rdxA mutants or between those of matc hed metronidazole-sensitive and -resistant H. pylori isolates. The regimen with metronidazole eradicated infection from all eight SS1-infected mice an d from one of eight mice inoculated with the rdxA mutant (P less than or eq ual to 0.001). The regimen with nitrofurantoin failed to eradicate infectio n from any of the six SS1-infected mice (P less than or equal to 0.001) and cleared infection from one of seven mice inoculated with the rdxA mutant. These results demonstrate that, despite the good in vitro activity of nitro furantoin against H. pylori and the lack of cross-resistance between metron idazole and nitrofurantoin, eradication regimens involving nitrofurantoin a re unable to eradicate either metronidazole-sensitive or -resistant H. pylo ri infections from mice.