H Pylori treatment antibiotic-guided therapy

In many areas, there is increasing H Pylori resistance to several antibiotics, including clarithromycin, with decreasing H Pylori eradication rates over time. A recent Korean study assessed the utility of selecting antimicrobial therapy based on antibiotic susceptibility vs standard clarithromycin-based triple therapy (see hpylori rx resistance guided AJG 2014 in dropbox, or doi: 10.1038/ajg.2014.222). This issue is important because H pylori is so common, affecting about 50% of the global population (and in our experience, 80-90% of people from high risk countries), is an important risk factor for noncardiac gastric cancer, and there are significant data that H  Pylori elimination reduces the incidence of stomach cancers. in this study 112 patients with H Pylori and gastric epithelial neoplasia (adenoma and adenocarcinoma)  were randomized to a 7 day course of a proton pump inhibitor (PPI) such as pantoprazole 40mg bid, amoxacillin 1 g bid,  and clarithromycin 500mg bid (PAC) or, if randomized to the pretreatment antimicrobial susceptibility wing, to that regimen if sensitive to clarithromycin but substituting methronidazole 500 mg bid if resistant (PAM) or substituting levofloxacin 400mg daily (PAL) if resistant to both clarithromycin and metronidazole. results:

--mean age 62, 70% male, 50% with early gastric cancer
--medication adherence was 98% in both the clarithromycin-based triple therapy (PAC) and the antimicrobial susceptibility-guided therapy  
--resistance pattern: 25% to clarithromycin, 46% to metronidazole, 37% to levofloxacin, 10% to amoxacillin, 3% to tetracycline
--in the antimicrobial susceptibility-guided therapy wing, 78.9% received PAC, 10.5% PAM, and 10.5% PAL therapies (ie most still got PAC)
--intention-to-treat analysis found 94.7% eradication rate in antimicrobial susceptibility-guided therapy and 71.9% in clarithromycin-based triple therapy (PAC) -- this 71.9% is not so different from other studies i've seen recently
--in patients with clarithromycin resistance, the eradication rate with antimicrobial susceptibility-guided therapy was 12/12 (100%), but was only 20% in those on PAC
--in those who failed therapy (10 patients involved), they were given antimicrobial susceptibility-guided therapy, 4 of whom got PAL and 6 got PPI bid, metronidazole 500mg tid, tetracycline 500mg qid and bismuth subcitrate 125mg qid for 7 days, with almost 100% success rates
--adverse events: 8% in each group, esp abdominal pain, nausea, vomiting, bitter taste, and diarrhea, with one patient dropping out of each group because of adverse events

so, this study, done in an area where there was high levels of antibiotic resistance, confirmed pretty clearly that antibiotic resistance matters in terms of eradication of H Pylori and that with appropriate antibiotics (even for only a 7-day course), there was nearly 100% success. Unfortunately, susceptibility testing is not available here in Boston. My guess is that the pattern of resistance is pretty different here from Korea where this study was done. I would not be surprised if there were even higher rates of metronidazole and levofloxacin resistance here (both being used a lot as monotherapy for, for example, bacterial vaginosis or urinary tract infections/pneumonia respectively, potentially leading to H Pylori resistance) as well as to clarithromycin (with azithromycin used so often for upper respiratory tract infections). i spoke with a couple of gastroenterologists here whose approach was just to try regular PAC therapy, then choose one of the alternatives if no response, specifically a quadruple therapy with bismuth. however, it seems to me that the Maastricht IV/Florence Consensus report in 2012 makes more sense -- that clarithromycin based triple therapy should not be used if clarithromycin resistance rates are higher than 15-20%. This Consensus report does suggest empiric bismuth-containing quadruple therapy as first-line empirical treatment in that case, with levofloxacin-containing triple therapy as second-line, then antimicrobial resistance testing to determine third-line, if failure of second-line. (although this Korean study questions that approach some, given the high rates of levofloxacin resistance there). I have been using sequential therapy with great success for many years now. this involves a more complex regimen with the first 5 days being PPI plus amoxacillin 1 gm (both bid), then followed by PPI plus clarithromycin 500mg plus metronidazole 500mg (all bid) for another 5 days. i got this from a study comparing PAC with this therapy (though i used metronidazole instead of tinidazole, since insurance would not cover tinidazole, though that is likely better -- less resistance). this study found pretty remarkably that there was a 90% H Pylori clearance rate in those with documented clarithromycin-resistance, positing that since clarithromycin-resistance is from cells developing efflux channels to clarithromycin and transporting the antibiotic out of bacterial cells, but that the pretreatment with amoxacillin disturbs the bacterial cell wall and prevents this from happening, rendering the bacteria clarithromycin-sensitive (see hpylori rx sequential annals 2007​ in dropbox, or  Ann Intern Med. 2007;146:556-563.). subsequent studies have confirmed 90%+ cure rates with sequential therapy.

what does this all mean?  it seems to me that when an H Pylori organism is isolated (eg, with a biopsy during endoscopy), therapy should be guided by antibiotic resistance, which should be done routinely in the microbiology lab. but, in primary care, we mostly treat empirically. given that, it would be really useful to know the general antibiotic susceptibility patterns of H Pylori to devise the optimal empirical therapy.  sort of like treating a urinary tract infection. so, i'm not sure why, in boston, the mecca of the high-concentration, high-cost, high-tech medical-industrial complex, that we don't have this really useful information.....  in its absence i will continue on my merry way with sequential therapy.