Antibiotic resistance in Helicobacter pylori: Implications for therapy

doi:10.1016/S0016-5085(98)70100-3

Gastroenterology

Volume 115, Issue 5, November 1998, Pages 1272-1277

https://doi.org/10.1016/S0016-5085(98)70100-3 Get rights and content

Abstract

Helicobacter pylori is a conventional gram-negative bacteria that causes an infection of the gastric mucosa. The organism is sensitive to most common antibiotics and theoretically should be easy to eradicate, provided that the patient takes antibiotics to which the organism is sensitive using a sufficient dose and duration of therapy. Unfortunately, the infection has proved difficult to cure. There are many other examples of bacterial infections that resist treatment with antibiotics even when the individual organisms demonstrate antibiotic sensitivity in vitro (e.g., Salmonella in the biliary tract). Failure can be due to the presence of antibiotic-resistant organisms, features of the infection may make it inaccessible to the antibiotics despite having antibiotic-sensitive organisms (a resistant infection), or both. Acquired resistance of H. pylori to clarithromycin, metronidazole, tetracycline, and amoxicillin have all been described.

GASTROENTEROLOGY 1998;115:1272-1277

Section snippets

Resistance as a statistical phenomenon

Acquired antibiotic resistance implies that the organism was originally sensitive but became resistant after exposure to an antibiotic. In reality, acquired resistance may actually represent emergence of resistant organisms that were already present in the stomach rather than actual development of resistance. Acquired antibiotic resistance can be thought of as a statistical phenomenon. Bacteria multiply rapidly, and the chance of developing resistance to an antibiotic is dependent on the

Pharmacological resistance

Pharmacological resistance describes a situation in which therapy fails because the antibiotics do not achieve the appropriate concentration or duration at the site(s) where the antibiotic-sensitive bacterium is residing and multiplying. H. pylori has many niches; it resides in the mucus that lines the gastric mucosa, it is found attached to the surface cells, and it can be seen within surface epithelial cells.⁴ H. pylori also inhabits extragastric sites such as gastric metaplasia in the

The stomach as a difficult environment for successful antimicrobial therapy

The gastric environment is very hostile for effective use of antimicrobial agents. Attempts to treat infections in the stomach have introduced parameters not usually considered when planning antimicrobial therapy for infections of other tissues. Important factors related to the physical environment of the stomach include low, but inconstant pH, active secretion, a thick mucous layer, constant emptying of contents, and regular shedding of mucous and surface mucosal cells. Many of the problems

Adjuvants to antibiotic therapy

Antimicrobial action could possibly be improved by cotherapies with mucolytics or antisecretory drugs. Although there are few data about mucolytics, there are a number of studies on antimicrobial agents and antisecretory agents. The potential advantages of coadministration of antisecretory drugs include a decrease in intragastric volume, which increases the concentration of the antibiotic, and an increase in intragastric pH, which may lower the MIC and possibly increase effectiveness. In

Methods to optimize antibiotic therapy

Factors that deserve systematic investigation to optimize therapy are shown in Table 1.

. Factors relating to resistance and outcome of therapy

Presence of resistant bacteria

Innate

Acquired

Presence of resistant infection

Biofilm phenomenon

Inoculum effect (large number of bacteria present)

Gastric environments and niches

Factors influencing effectiveness of antimicrobial therapy

Drug formulation (tablet, liquid, colloid, granule, etc.)

Administration in relation to meals

Frequency, dosage, duration of

Biofilm and inoculum effects

Successful treatment must overcome additional barriers such as the inoculum effect and the biofilm phenomenon. Attachment to a surface may be associated with an increase in the MIC of antibiotics (the biofilm phenomenon). This phenomenon has been shown with H. pylori in tissue culture²⁸ and is also likely to be present in vivo. Prevention of adhesion is another worthy goal either alone or to enhance antimicrobial therapy,29, 30, 31 but because H. pylori possess multiple different adhesins,

Effect of resistance on success of therapy

Although the effect of resistance on the effectiveness of therapy should be completely predictable, it is not largely due to the incomplete understanding of the mechanisms involved. The results of combination therapy are generally what would be expected when the other components of a combination therapy were used alone but may also be greater than expected. For example, when the combination of a PPI, clarithromycin, and metronidazole is administered to a patient whose H. pylori strain is

The future

One problem is that gastroenterologists have had to learn to think like infectious disease specialists. We have all been guilty of attempting to define the characteristics of an ideal therapy. Targets have been established for effectiveness, duration, number of tablets, etc. Clinicians accepted armchair targets as a valid method to separate good from unacceptable therapies. The best therapy is one that cures the infection in all patients, in all geographic regions, irrespective of the

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This present study aims to investigate the anti-Helicobacter pylori (H. pylori) and gastric cancer properties of Acacia nilotica (A. nilotica) aqueous leaf extract. The phytochemicals of this extract were identified by Gas chromatography-mass spectroscopy (GC–MS) analysis. The antagonistic activity of H. pylori was investigated using well diffusion assay. Cytotoxicity of crude extract studied against human gastric adenocarcinoma (AGS) cells using 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-Diphenyltetrazolium Bromide (MTT) assay. Further anti-gastric cancer properties of bioactive compounds were also validated using computational studies. The drug-likeness potential of phytochemicals was analyse based on absorption, digestion, metabolism, excretion (ADME) properties. GC–MS reveals the presence of different major phytochemicals like eicosanoic acid, oleic acid, 1-hexyl-2-nitrocyclo hexane, 9-octadecenal in the crude extract. MTT assay reveals that the maximal inhibitory concentration (IC₅₀) value of crude extract is (99.86 mg/ml). All the compounds showed good drug-likeness score; further, these compounds were selected for molecular docking studies with targeted H. pylori virulent proteins like cytotoxic associated gene A (CagA), vacuolating associated gene (VacA), urease and gastric cancer-induced signalling proteins such as epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). The validation of in vitro and in silico results proved that A. nilotica leaf extract acts as a massive anti-H. pylori and gastric cancer drug.
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Polysorbate 80, a sorbitan derivate, is a surfactant used as an emulsifier in some foods in concentrations of up to 0.5%. It was recently shown in vitro that polysorbate 80 decreases the minimum bactericidal concentrations of clarithromycin and metronidazole and may also revert antibiotic resistance. We report the case of an adult man, suffering from symptomatic Helicobacter pylori (HP) infection resistant to two courses of treatment with PPI plus amoxicillin and clarithromycin, and PPI plus clarithromycin and metronidazole. He was treated with a further antibiotic approach consisting of two-week administration of clarithromycin, metronidazole, PPI and polysorbate 80 as an add on therapy. Eradication of infection was confirmed by ¹³C-urea breath test two and five months after completion of the treatment course. Complete regression of symptoms was also achieved. To our knowledge, this is the first case of HP infection eradicated with a combination therapy based on polysorbate 80 added to antibiotics.
Geographically distinct North-East Indian Helicobacter pylori strains are highly sensitive to clarithromycin but are levofloxacin resistant
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^☆: Address requests for reprints to: David Y. Graham, M.D., Veterans Affairs Medical Center (111D), 2002 Holcombe Boulevard, Houston, Texas 77030. e-mail: [email protected]; fax: (713) 790-1040.

^☆☆: Supported by the Department of Veterans Affairs and by the generous support of Hilda Schwartz.

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Viewpoints in Digestive DiseasesAntibiotic resistance in Helicobacter pylori: Implications for therapy☆,☆☆

Abstract

Section snippets

Resistance as a statistical phenomenon

Pharmacological resistance

The stomach as a difficult environment for successful antimicrobial therapy

Adjuvants to antibiotic therapy

Methods to optimize antibiotic therapy

Biofilm and inoculum effects

Effect of resistance on success of therapy

The future

Gastroenterology

Gastroenterology

J Pharm Sci

Gastroenterol Clin North Am

Methods Enzymol

Trends Microbiol

Hum Pathol

Diagn Microbiol Infect Dis

Gastroenterology

Mutations in 23S rRNA are associated with clarithromycin resistance in Helicobacter pylori

Antimicrob Agents Chemother

Point mutations in the 23S rRNA gene of Helicobacter pylori associated with different levels of clarithromycin resistance

J Antimicrob Chemother

Is the sanctuary where Helicobacter pylori avoids antibacterial treatment intracellular?

Am J Clin Pathol

Prevention of diarrhea caused by enterotoxigenic Escherichia coli: lessons learned with volunteers

Rev Infect Dis

The who's and when's of therapy for Helicobacter pylori

Am J Gastroenterol

Trophicity of gastric epithelium and its regulation

Helicobacter pylori. Pharmacology of peptic ulcer disease

Hp and pH: implications for the eradication of Helicobacter pylori

Scand J Gastroenterol Suppl

Effect of varying pH on the susceptibility of Campylobacter pylori to antimicrobial agents

Eur J Clin Microbiol Infect Dis

Viewpoints in Digestive Diseases
Antibiotic resistance in Helicobacter pylori: Implications for therapy☆,☆☆