h pylori therapy sequential vs standard therapies

I previously sent out an article finding that sequential H pylori therapy (5 days of PPI plus amoxicillin 1 g twice a day, followed by 5 days of PPI plus clarithromycin 500 twice a day plus metronidazole 500 twice a day) was superior to standard triple therapy.  This sequential therapy worked even with clarithromycin resistance, with 89% of clarithromycin-resistant strains responding vs 29% with standard therapy. they posited the mechanism for resistance being that h pylori developed efflux channels for clarithro that rapidly remove the drug from the bacteria and that amox changes the structure of the cell membrane to prevent effective clarithromycin efflux and therefore resistance. (see hpylori rx sequential annals 2007 in dropbox, or Ann Intern Med 2007; 146:555-563)

there was a recent systematic review and meta-analysis in the BMJ assessing the efficacy of sequential versus triple therapy (see hpylori rx sequential metaanal bmj 2013 in dropbox, or BMJ 2013;347:f4587 doi: 10.1136/bmj.f4587). for this review, 46 randomized control trials were assessed with 5666 patients on sequential therapy versus 7866 on standard therapies.  Results:

    --22 studies compared sequential therapy with a seven-day course of standard triple therapy (mostly PPI plus amox plus clarithro, all bid; or PPI plus amox plus metronidazole, all bid).  While in the 5000 patients randomized to each of these 2 groups, sequential therapy resulted in H. pylori eradication in 86.5% versus 71.5% for triple therapy, highly statistically significant

    --14 studies compared sequential therapy with triple therapy for 10 days.  2700 patients were divided into the 2 groups with eradication rates of 84.3% for sequential therapy and 75.3% for triple therapy of 10 days duration, a statistically significant result.  No significant differences in adverse effects.

    --7 studies compared sequential therapy will triple therapy lasting 14 days. 2500 patients were divided into the 2 groups with 81% eradication rates in each group.  No different in adverse effects

    --There was also no difference between sequential therapy and therapy that contained bismuth or with quadruple therapy.

    --in pts with clarithro resistance, efficacy of sequential therapy was 73% vs 50% in those with 7 or 10 days of standard therapy,  but no diff with 14 days of standard therapy , or with quadruple therapy or sequential therapy with levoflox instead of clarithro

    --in pts with metronidazole resistance, eradication rates for sequential therapy were 86%, vs 62% with 7 day and 59% for 10 day standard therapy, both significant, though the only one was a small study (50/group) of 14day therapy found eradication rate of an unusually low 73% with sequential therapy and 89% with 14-day standard therapy.

    --in pts with both metronid and clarithro resistance, studies too small to have generalizable conclusions

so, h pylori infection is really common, at least in boston, and global studies suggest that gastric cancer assoc with h pylori (non-cardia gastric carcinoma and MALT) in 2008 occurred in 470K people in less developed regions and 190K in more developed regions.  data of the standard therapy (per Maastriccht conference in 1997) with PPI, clarithro, and either amox or metronidazole suggest waning efficacy over time.  In Europe, resistance to clarithromycin is 17.5%, to levofloxacin is 14%, and metronidazole is 35%.  it would be very useful to use local resistance patterns as a way of choosing empiric therapy. in 2007 when the first sequential therapy article came out (above), i called several endoscopists at boston medical center and no one had data on local resistance patterns.  i called again today and this is still true. Their guess is that resistance is very common here (perhaps in the 30-50% range!!!), though they still mostly prescribe the 10 day course of standard therapy, without great results. one big issue here is that NONE of the studies have been done in the US, again clouding the picture of what we should do. I personally have been prescribing the sequential therapy since that annals article in 2007, since I suspected that antibiotic resistance was high given the commonplace use of metronidazole and clarithromycin locally for other infections. the only problem is that it is a more complex regimen and takes a while to explain the therapy, for which I made a written handout, which elineates day-to-day therapy. from the new bmj article, perhaps standard therapy for 14 days is equivalent (again, this may not be true if our resistance patterns are really different.... who knows??)