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 nitroreductase enzyme encoded by the rdxA gene of Helicobacter pylori was responsible for reductive activation of nitrofurantoin and whether a triple-therapy regimen with nitrofurantoin was able to eradicate metronidazole-sensitive and -resistant H. pylori infections from mice. The susceptibilities to nitrofurantoin of parent and isogenic rdxA mutant strains (three pairs), as well as a series of matched metronidazole-sensitive and -resistant strains isolated from mice (30) and patients (20), were assessed by agar dilution determination of the MIC. Groups of mice colonized with the metronidazole-sensitive H. pylori SS1 strain or a metronidazole-resistant rdxA SS1 mutant were treated with either metronidazole or nitrofurantoin as part of a triple-therapy regimen. One month after the completion of treatment the mice were sacrificed and their stomachs were cultured for H. pylori. The nitrofurantoin MICs for all strains tested were between 0.5 and 4.0 microg/ml. There was no significant difference between the susceptibility to nitrofurantoin of the parental strains and those of respective rdxA mutants or between those of matched metronidazole-sensitive and -resistant H. pylori isolates. The regimen with metronidazole eradicated infection from all eight SS1-infected mice and from one of eight mice inoculated with the rdxA mutant (P < or =0.001). The regimen with nitrofurantoin failed to eradicate infection from any of the six SS1-infected mice (P < or =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 nitrofurantoin against H. pylori and the lack of cross-resistance between metronidazole and nitrofurantoin, eradication regimens involving nitrofurantoin are unable to eradicate either metronidazole-sensitive or -resistant H. pylori infections from mice.
Jenks
P J
PJ
Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur, 75724 Paris Cedex 15, France. pjenks2@hotmail.com
Ferrero
R L
RL
Tankovic
J
J
Thiberge
J M
JM
Labigne
A
A
D000818:Animals; D000892:Anti-Infective Agents, Urinary / Q000627:therapeutic use*; D000994:Antitrichomonal Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D003001:Cloning, Molecular; D017931:DNA Primers; D004352:Drug Resistance, Microbial; D016481:Helicobacter Infections / Q000188:drug therapy* / Q000382:microbiology; D016480:Helicobacter pylori / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008795:Metronidazole / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009154:Mutation / Q000235:genetics; D009582:Nitrofurantoin / Q000627:therapeutic use*; D010084:Oxidation-Reduction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000892:Anti-Infective Agents, Urinary; D000994:Antitrichomonal Agents; D001426:Bacterial Proteins; D017931:DNA Primers; D008565:Membrane Proteins; D008795:Metronidazole; C077236:RdxA protein, Rhodobacter sphaeroides; D009582:Nitrofurantoin