Therapy failure may depend on several factors, of both bacterial and host origin. Not infrequently, different factors act simultaneously in reducing antibiotic therapy efficacy in the same patient.
The “ecological niche”: Due to its urease production and presence of flagella, H. pylori is able to survive in the gastric environment over a wide pH spectrum, to penetrate the gastric mucous layer, and to reach the gastric epithelium where it can be found attached to cells and even within cells. In this “gastric niche”, H. pylori could be protected against both antibiotic action and immune response. Indeed, the high efficacy of several antibiotics in vitro appears to be strongly reduced in vivo because of both difficult diffusion into mucous layer and inactivation at low pH values. It is been also suggested that H. pylori may persist in a limited region of the stomach, the gastric cardia, even following successful eradication from the antrum and gastric body. Such a phenomenon has been attributed to an insufficient antibiotic concentration in this gastric area. Similarly, immunoglobulins produced in all infected patients exert a reduced activity or are inactivated at low pH values. Moreover, H. pylori is able to camouflage its surface, reducing the exposure of antigens by masking flagella with lipopolysaccarides which mimic the host carbohydrates. Finally, due its motility, H. pylori the bacterium is skilled at escaping direct contact with the immune cells, slowly migrating across gastric mucosa.
Coccoid form: As for other bacterial species, the existence of viable but not culturable bacterial forms has been reported for H. pylori. These coccoid forms have being identified as a natural evolutionary stage of spiral H. pylori. Although are unable to grow in culture, these bacterial forms have been shown to be able to infect mice and pigs. Of note, these dormant forms of H. pylori are not susceptible to antibiotic action, which requires active bacterial proliferation. The presence of coccoid forms in the stomach may have a clinical relevance, due to the potential reactivation of H. pylori in its spiral form following therapy.
Bacterial load: Several studies have reported that the high bacterial load is a significant risk factor in therapeutic failure when using current triple therapies[14-16]. It was suggested that delta values greater than 35% over baseline (DOB) values could be considered to point to high risk of the therapeutic failure. Nevertheless, our recent data failed to confirm this observation.
Virulence factors: There is evidence that some H. pylori virulence factors significantly affect bacterial susceptibility towards different antibiotics. Some studies reported that CagA-positive H. pylori strains seem to be more susceptible to antibiotics when compared to CagA-negative. Similarly, presence of the VacA s1m1 allele increases bacterial susceptibility, compared to the VacAs2m2 allele. From a biological point of view, the relationship between the outcome of eradication therapy and CagA status has been attributed to the severity of gastritis due to the cytotoxin. In this event, the increased mucosal blood flow may favour antibiotic diffusion through the gastric mucosa. Another possible mechanism is the increased antibiotic activity on actively replicating bacterial cells. Indeed, the presence of CagA and VacA s1m1 confer rapid growth to H. pylori strains a.
Primary antibiotic resistance: Undeniably, primary antibiotic resistance is recognized as the main factor affecting the efficacy of current H. pylori eradicating regimens. Bacterial resistance appears to be increasing worldwide, most likely due the large use of antibiotics such as macrolides, quinolones, amoxicillin, and nitroimidazoles in clinical practice. A recent, systematic review updated knowledge of the level of primary H. pylori resistance towards different antibiotics worldwide.
Clarithromycin remains the most powerful antibiotic against H. pylori currently available, and primary resistance towards this drug has been found to be the main factor hampering the efficacy of standard therapies. Various polymerase chain reaction-based studies have demonstrated that point mutations in the peptidyltransferase region, encoded in domain V of 23S rRNA, are responsible of H. pylori resistance towards clarithromycin. The more frequent mutations associated with clarithromycin resistance are the adenine to transitions at positions 2142 and 2143 of rRNA (A2143G and A2143C), whilst the substitution of adenine by cytosine at position 2142 (A2142C) is less frequent. These mutations are able to prevent the binding between clarithromycin and the ribosomal subunit and are responsible of more than 90% of clarithromycin resistance in developed countries. Of note, we found that presence of the A2143G point mutation, rather than the A2142G or A2142C mutation, markedly reduces H. pylori eradication rate.
Very high resistance rates towards metronidazole have been reported, particularly in developing countries and in female patients. Complex and multiple mechanisms are implicated in the development of imidazole resistance, including point mutations, deletion in rdxA gene, and pump efflux system. Primary metronidazole resistance seems to exert only a minor impact on therapeutic outcome.
Primary H. pylori resistance towards levofloxacin is significantly increasing worldwide. Point mutations in the Quinolones Resistance-Determining Region of gyrA prevent binding between the antibiotic and the enzyme, conferring antibiotic bacterial resistance to quinolones. This observation is clinically relevant as levofloxacin-based therapy is generally used as second-line regimen. Finally, primary resistance towards either tetracycline or amoxicillin remain particularly low, most likely due to the requirement to develop simultaneous mutations in the respective genes.
Patient compliance: It would appear counterintuitive that an antibiotic therapy cannot exert its whole action when it is not taken for the well-established period and dose. Poor compliance to H. pylori eradication regimen is inversely associated with the probability of therapeutic success. It has been reported that 12% of patients prematurely stopped the eradication therapy, as a result of side-effects. Unfortunately, the approved eradication regimens require the combination of 3-4 different drugs in multiple daily doses. Therapy regimen complexity and side-effects incidence are associated with a reduced patient compliance. In this context, the persuasive ability of the physician, together with elucidation of the possible, generally mild, side-effects, is of fundamental importance for therapeutic success.
Gastric acid secretion: The in vitro activity of various antibiotics is greatly reduced or eliminated in vivo by the very low pH values encountered in the gastric juice. This explains the need to include a proton pump inhibitor (PPI) in H. pylori eradication regimens. However, a significant variability in gastric acid secretion among different subjects has been reported. A small proportion of subjects show a higher basal acid output in association with normal values of the gastrin. In these hypersecretor subjects, who probably have a larger parietal cell mass, lower eradication rates have been reported. Besides this phenomenon, eradication therapy success depends on metabolism and bio-availability of PPIs, which is genetically determined. Indeed, PPIs are to a large extent metabolized in the liver by the cytocrome P450, isozyme CYP2C19. Based on gene polymorphism, subjects are sub-grouped in poor, intermediate and extensive metabolizers. Although some controversial data do exist, standard PPI doses seem to be insufficient in extensive metabolizer patients to achieve sufficient pH inhibition to allow antibiotic activity in gastric mucosa, with consequent lower eradication rates.
Gastroduodenal diseases: Several studies have reported lower H. pylori cure rates in patients with non-ulcer dyspepsia, compared to those with peptic ulcer disease. Such a difference has been attributed, at least in part, to infection with different H. pylori strains. Indeed, dyspeptic patients are more frequently infected with less virulent (cagA negative; vacA s2 or m2 genotype) and slow proliferating strains than are peptic ulcer patients. These bacterial strains would appear less susceptible towards antibiotics, and cause a less marked inflammation, as discussed above[18,19]. In addition, some studies have found a higher prevalence of primary clarithromycin resistance in non-ulcer dyspepsia than in peptic ulcer patients, although conflicting data have been reported[21,30,31].
Smoking habit: Consistent data have indicated that ongoing smoking negatively affects the therapeutic success rate following standard therapies[32,33]. It has been hypothesized that smoking may induce a decrease in gastric blood flow and mucus secretion, and therefore reduce the efficacy of treatment by reducing the delivery of antibiotics into gastric mucosa. A further possible explanation may be that the smoking habit can induce gastric acid hypersecretion which, in turn, reduces antibiotic activity.