TREATMENT FAILURE
The success rate for primary therapy ranges from 60% to 85%.1 Antibiotic resistance, particularly to clarithromycin, is a major cause of treatment failure.3
Metronidazole and tinidazole are the two imidazole antibiotics most often used to treat H pylori infection.18 Unfortunately, resistance to imidazoles is common; it approaches 35% in developed countries and is almost universal in developing countries because imidazoles are used to treat many parasitic infections. In addition, substantial cross-resistance occurs between these two medications. Therefore, imidazoles are given as a prodrug and activates in target cells. Resistance is mediated by mutations in any one of several proteins that are necessary to convert a prodrug to its active form.
Macrolide resistance is seen less often—10% of cases of H pylori isolates in western countries and up to 50% of cases in developing countries. Cross-resistance between macrolides can also occur. Macrolide resistance is caused by point mutations in one of two target ribosomal nucleotides.
The incidence of resistance to amoxicillin and tetracycline is increasing, though not to the levels seen with imidazoles and macrolides.18 Higher levels of resistance are generally seen in areas where access to amoxicillin and tetracycline without a prescription is common. In general, penicillin resistance is usually caused by beta-lactamase produced by gram-negative organisms or mutations in the penicillin-binding proteins in gram-positive organisms. However, alterations in the penicillin-binding proteins, not beta-lactamase, are the mechanism in H pylori resistance to amoxicillin.
Tetracycline is bacteriostatic and exerts its effect on 16S ribosomal RNA and interferes with protein synthesis. H pylori resistance to tetracycline seems to be mediated by alterations in the target molecule as well as changes in the ribosomal binding site.18 Resistance rates for other antibiotics used to treat H pylori infection are difficult to calculate because of the small number of studies that examine this phenomenon.
Antibiotic susceptibility testing is an important part of selecting the appropriate salvage therapy when initial treatment fails. Antibiotic resistance is measured with culture-based or nucleic acid-based assays.18 The US National Committee for Clinical Laboratory Standards recommends using the agar dilution test to detect resistance to the antibiotics commonly used for H pylori eradication. Initially, the test involved serial dilutions of antibiotics in tubes of agar. This has been simplified, and the current test uses medium containing the critical concentration that defines bacterial resistance (the break-point method). Disc diffusion methods are also available. But agar dilution
and disc diffusion are slow and take up to 10 days to produce results. Nucleic acid-based assays are faster and do not require live or growing bacteria. Nucleic acid tests are available for clarithromycin, tetracycline, and ciprofloxacin. However, these tests are expensive and require special equipment and technician expertise.
SALVAGE THERAPY
When first-line treatment fails to eradicate H pylori, a number of other regimens are available. A triple-drug regimen of pantoprazole, amoxicillin, and levofloxacin was proven effective in 70% of patients in whom standard triple therapy failed.8 Second-line therapy with omeprazole, amoxicillin, and rifabutin is also suggested. A 2007 study showed that a quadruple therapy with omeprazole, bismuth, levofloxacin, and amoxicillin for 7 days was not as efficacious as the standard quadruple therapy (omeprazole, bismuth, metronidazole, and tetracycline) for the same duration.19 Furthermore, another 2007 study demonstrated that the recommended quadruple therapy was more efficacious than triple therapy with omeprazole, amoxicillin, and rifabutin.20 However, these authors noted that treatment duration in their study was only 7 days, and other researchers showed success rates for a similar triple therapy administered for 10 days that were as good as those that followed standard quadruple therapy.
Attempts to reduce issues with adherence to H pylori treatment led to the development of sequential treatment regimens. Sequential therapy consists of a PPI and a single antibiotic, typically amoxicillin, for 5 days, followed by triple therapy with a PPI, clarithromycin, and an imidazole for 5 days.20 Sequential therapy was proven to be superior to standard regimens in treatment-naïve patients. Theories about why this approach may be more successful include a similarity to quadruple therapy, a longer duration of therapy (10 days), and a possible synergistic effect between amoxicillin and clarithromycin. Amoxicillin during the initial 5 days likely weakens the bacterial cell membrane, thereby reducing the number of drug efflux transporters in the cell membrane that diminish the effectiveness of drugs such as clarithromycin. Sequential treatment was also beneficial for patients with risk factors for treatment failure, such as smoking and antimicrobial resistance.16
Lactoferrin is a bovine glycoprotein that has demonstrated in vitro activity against H pylori.21 Lactoferrin binds iron with high affinity, reducing the availability of iron to microorganisms. In a prospective randomized controlled trial, lactoferrin was added to a quadruple therapy of esomeprazole, amoxicillin, ranitidine bismuth citrate,* and tinidazole. The eradication rate was insignificantly increased in patients who were given lactoferrin;22 however, they experienced significantly fewer side effects. Therefore, the addition of lactoferrin to quadruple therapy may reduce side effects, which would enhance adherence and improve the effectiveness of treatment.
CONCLUSION
Standard triple-drug regimens are relatively effective; however, higher rates of antibiotic resistance are increasing the failure rate of initial treatment. Antibiotic susceptibility testing is an important part of follow-up therapy to ensure that the appropriate salvage therapy is selected. Sequential therapy with a PPI and amoxicillin followed by a triple-drug regimen (a PPI and two other antibiotics) may be more effective than the standard triple therapy, given current resistance patterns. Quadruple therapy with a PPI, bismuth, metronidazole, and tetracycline is the recommended initial salvage therapy.
Levofloxacin and rifabutin may be important adjuncts to salvage therapy. But recent trials demonstrated that these drugs offered no significant improvement in treatment efficacy over standard regimens. However, these trials were limited because they examined the effectiveness of 7-day treatment regimens, and the standard duration of treatment
in the United States is 10 to 14 days. Adding lactoferrin to quadruple therapies may increase adherence because lactoferrin can reduce side effects. JAAPA
John Lopes is an assistant professor in the PA program, School of Rehabilitation and Medical Sciences, The Herbert H. and Grace A. Dow College of Health Professions, Central Michigan University, Mount Pleasant, Michigan. The author has indicated no relationships to disclose relating to the content of this article.
RUGS MENTIONED
Amoxicillin Metronidazole (Flagyl, generics)
Bismuth subsalicylate (Kaopectate, Maalox Total Relief, Pepto-Bismol)
Ciprofloxacin (Cipro, Proquin XR, generics)
Clarithromycin (Biaxin, generics)
Esomeprazole (Nexium)
Levofloxacin (Levaquin)
Omeprazole (Prilosec, generics)
Pantoprazole (Protonix, generics)
Rifabutin (Mycobutin)
Tetracycline (Sumycin, generics)
Tinidazole (Tindamax)
IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read
Hyperphosphatemia: Understanding the role of phosphate metabolism; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to
www.aapa.org and searching for keyword
JAAPA post-tests. All others may complete and submit the post-test online at no charge at
www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.
REFERENCES
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3. Napolitano L. Refractory peptic ulcer disease. Gastroenterol Clin North Am. 2009;38(2):267-288.
4. Bartnik W. Clinical aspects of Helicobacter pylori infection. Pol Arch Med Wewn. 2008;118(7-8):
426-430.
5. Lauwers GY, Srivastava A. Gastric preneoplastic lesions and epithelial dysplasia. Gastroenterol Clin North Am. 2007;36(4):813-829, vi.
6. Collins J, Ali-Ibrahim A, Smoot DT. Antibiotic therapy for Helicobacter pylori. Med Clin North Am. 2006;90(6):1125-1140.
7. Conroy RT, Siddiqi B. Dyspepsia. Prim Care. 2007;34(1):99-108.
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9. Ramakrishnan K, Salinas RC. Peptic ulcer disease. Am Fam Physician. 2007;76(7):1005-1012.
10. Granstrom M, Lehours P, Bengtsson C, Mégraud F. Diagnosis of Helicobacter pylori. Helicobacter. 2008;13(suppl 1):7-12.
11. Tahara T, Shibata T, Nakamura M, et al. Gastric mucosal pattern by using magnifying narrow-band imaging endoscopy clearly distinguishes histological and serological severity of chronic gastritis. Gastrointest Endosc. 2009;70(2):246-253.
12. Goh KL, Cheah PL, Navaratnam P, et al. HUITAI rapid urease test: a new ultra-rapid biopsy urease test for the diagnosis of Helicobacter pylori infection. J Dig Dis. 2007;8(3):139-142.
13. Dondi E, Rapa A, Boldorini R, et al. High accuracy of noninvasive tests to diagnose Helicobacter pylori infection in very young children. J Pediatr. 2006;149(6):817-821.
14. McNulty CA, Whiting JW. Patients' attitudes to Helicobacter pylori breath and stool antigen tests compared to blood serology. J Infect. 2007;55(1):19-22.
15. Uygun A, Kadayifci A, Yesilova Z, et al. Comparison of sequential and standard triple-drug regimen for Helicobacter pylori eradication: a 14 day, open-label, randomized, prospective parallel-arm study in adult patients with nonulcer dyspepsia. Clin Ther. 2008;30(3):528-534.
16. Suzuki T, Matsuo K, Ito H, et al. Smoking increases the treatment failure for Helicobacter pylori eradication. Am J Med. 2006;119(3):217-224.
17. Gerrits MM, van Vliet AH, Kuipers EJ, Kusters JG. Helicobacter pylori and antimicrobial resistance: molecular mechanisms and clinical implications. Lancet Infect Dis. 2006;6(11):699-709.
18. Robles-Jara C, Robles-Medranda C, Moncayo M, et al. Is a 7-day Helicobacter pylori treatment enough for eradication and inactivation of gastric inflammatory activity? World J Gastroenterol. 2008;14(18):2838-2843.
19. Yee YK, Cheung TK, Chu KM, et al. Clinical trial: levofloxacin-based quadruple therapy was inferior to traditional quadruple therapy in the treatment of resistant Helicobacter pylori infection. Aliment Pharmacol Ther. 2007;26(7):1063-1067.
20. Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007;146(8):556-563.
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IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read
Hyperphosphatemia: Understanding the role of phosphate metabolism; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to
www.aapa.org and searching for keyword
JAAPA post-tests. All others may complete and submit the post-test online at no charge at
www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.