Which Therapy for Helicobacter pylori Infection?

Abstract

Clarithromycin-containing triple, sequential, concomitant, and hybrid therapies, bismuth-containing 4 drug therapies, and now a levofloxacin-containing concomitant therapy - what is the clinician to do? This issue of Gastroenterology contains a non-inferiority comparison of two newer approaches to 4 drug fluoroquinolone-containing therapies and report good to excellent results 1. The trial is a model of how such studies should be done. Bravo! H. pylori is an infectious disease and clinicians should expect, and in fact, demand that recommended treatments provide cure rates of at least 90%, preferably ≥95%. The current report provides essentially all the details one might wish including those regarding patient selection, follow-up, therapy for treatment failures, susceptibility testing, outcome with different patterns of resistance, etc (i.e., the data clinicians need to use in their practices). There are few mysteries with regard to treatment success with H. pylori therapy: one only need know the success rates with susceptible and resistant strains 2. The calculations are slightly more complicated with multiple antibiotic containing regimens because as the number of antibiotics increases, the combinations of antibiotics still remaining effective when resistance is present to one or more also increases (see below). Where a study is done (e.g., Italy or the U.S.) is not important. What is important is the local pattern of resistance (i.e., if their bugs are like your bugs one should expect the same results). If such data were available for each new therapy, acceptance or rejection for local use could be based on rational grounds. Until recently, most comparative trials and meta-analyses of anti-H. pylori therapies consisted of comparisons of regimens with unacceptably low success (e.g., bismuth 60.9% vs. clari triple 46.5%) 3 or a good regimen vs. one with unacceptable results (i.e., a good vs. a bad) (e.g., sequential 91% vs. triple 75.5%)4. Randomization to regimens known to be inferior is now generally recognized as unethical and should neither be done, published, nor subject to meta-analysis 5, 6. Hopefully, in the future few such trials will be done and fewer will be published. What should you expect in your practice? Here, we will focus on the levofloxacin concomitant regimen as it combined success, simplicity and cost savings compared to the same drugs used as a sequential therapy. Treatment success with levofloxacin susceptible strains (and no other resistances) was about 97% vs. 67% for levofloxacin resistant but metronidazole susceptible strains and 90% for metronidazole resistance but levofloxacin susceptible strains. In the Fredrico et al. trial1 the number of resistant strains was low, resulting in wide 95% confidence intervals for the results with resistant strains; more clinical experience is required to fully understand and quantify the limitations of this new therapy. In the presence of fluoroquinolone resistance, the fluoroquinolone effectively drops out leaving a 5 day metronidazole-amoxicillin-PPI triple therapy. Metronidazole resistance alone leaves a 5 day levofloxacin triple therapy. Both triple regimens still have a relatively high dose of PPI. Dual levofloxacin and metronidazole resistance produces a 5 day dual PPI-amoxicillin therapy which should yield a treatment success of around 25% 7, 8. The formula for treatment outcome based on these study data would be [Outcome = (% with no resistances X 0.97) + (% metronidazole resistant X 0.9) + (% levofloxacin resistant X 0.67) + (% dual resistant X 0.25)]. Figure 1 shows that one would expect the regimen to maintain its effectiveness as long as fluoroquinolone resistance remained below 20% to 25%. Using the formula one would expect a high prevalence of metronidazole resistance alone (e.g., 50%) to be well tolerated (success ≥90%), however dual levofloxacin and metronidazole resistance alone would compromise success if resistance exceeded approximately 10%. Figure 1 Effect of fluoroquinolone resistance on treatment success with levofloxacin concomitant therapy. The ability to extrapolate outcome based on trial data is only possible if the susceptibility data and outcome for each subgroup are presented. Studies without such data should be strongly discouraged and hopefully fewer journals will be willing to accept them. The lack of such data is largely responsible for the ongoing controversy regarding the place of sequential therapy 9.