Eradication of Helicobacter pylori: A Clinical Update

Marco Romano, MD; Antonio Cuomo, MD

Disclosures
In This Article

Drugs Used to Eradicate H pylori Infection

PPI-based triple therapies have shown efficacy in various clinical trials from different geographic areas.[9] PPIs have direct antimicrobial effects in vitro on H pylori. However, the direct antimicrobial effect of PPIs does not seem to play a major role in the eradication of the infection. In fact, in terms of better eradication rates, consistent advantage has not been demonstrated for any particular PPI.[10]

The mechanism(s) mediating the synergy of PPIs combined with antimicrobials to increase the clinical efficacy of antimicrobial therapy against H pylori has (have) not been fully elucidated. Antisecretory drugs, such as PPIs, can interfere with the indirect delivery of antibiotics (as has already been suggested for metronidazole and clarithromycin),[11] may decrease gastric juice volume, and may reduce the washout of antibiotics, hence increasing luminal antibiotic concentration.[12,13,14] In addition, the increased absorption and tissue penetration of antimicrobial agents that occur with elevated gastric mucosal levels caused by omeprazole may contribute to the observed synergy.[12,13,14] Furthermore, acid suppression may reduce the chemical degradation or increase the drug (antimicrobial) stability at a higher gastric pH.[12]

Bismuth was one of the first agents used against H pylori infection. There is evidence that bismuth is directly bactericidal, although its minimum inhibitory concentration (MIC) is relatively high for H pylori. Like other heavy metals such as zinc and nickel, bismuth compounds interfere with the activity of urease enzyme, the high activity of which is a characteristic feature of H pylori. Also, bismuth compounds exert their topical antimicrobial activity, acting directly on bacterial cell walls to disrupt their integrity by accumulating in the periplasmic space and along membranes.

H pylori is generally highly sensitive to metronidazole, which is actively secreted into gastric juice and saliva, with activity independent of pH. Metronidazole is a prodrug that must undergo activation by bacterial nitroreductases. There are a number of H pylori enzymes with the potential to reduce metronidazole, and it is possible that increased drug dosage and resulting very high concentrations in the stomach allow sufficient drug to become activated to kill the organism. Reduced nitroimidazoles (eg, metronidazole) cause loss of the helical structure of bacterial DNA, strand breakage, and thus, impairment of bacterial function.

Clarithromycin, a 14-membered ring macrolide antibiotic, is a derivative of erythromycin, with a similar spectrum of activity and clinical application. However, clarithromycin is more acid-resistant, has more consistent absorption, and has a longer elimination half-time compared with erythromycin. Results of studies showing approximately 90% H pylori eradication with triple-therapy regimens using clarithromycin have led to widespread use of this antibiotic. However, the increasing prevalence of clarithromycin-resistant H pylori strains must be kept in mind before using this antimicrobial agent. In this setting, unlike the situation with metronidazole, there is no evidence that increasing the dosage of drug will overcome the problem of bacterial resistance.

Amoxicillin is a close chemical and pharmacologic relative of ampicillin. This agent is stable in acid and inhibits the synthesis of the bacterial cell wall, acting both topically and systemically after absorption into the bloodstream and subsequent delivery into the gastric lumen. H pylori demonstrates good sensitivity to this antibiotic in vitro, but gastric antisecretory cotherapy is required for any significant efficacy.

The tetracyclines are close derivatives of the polycyclic naphtacenecarboxamides. The site of action of tetracyclines is the bacterial ribosome, which results in the interruption of protein biosynthesis -- but at least 2 processes appear to be required for these antibiotics to gain access to the ribosomes of gram-negative bacteria. The first of these is their passive diffusion through hydrophilic pores in the outer cell membrane. The second process involves an energy-dependent active transport system that pumps all tetracyclines through the inner cytoplasmic membrane. Once the tetracyclines gain access to the bacterial cell, they inhibit protein synthesis and bind specifically to the 30-S ribosomal subunit. The latter thereby prevents aminoacyl tRNA access to the acceptor site on the mRNA-ribosome complex, and thus precludes the addition of amino acids to the growing peptide chain. Tetracycline has demonstrated in vitro efficacy against H pylori and is active at low pH.

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