Treatment for H. pylori Infection. New Challenges With Antimicrobial Resistance

CLINICAL REVIEW Treatment for H. pylori Infection New Challenges With Antimicrobial Resistance Nimish Vakil, MD, FACP, FACG, AGAF, FASGE* and Dino Vaira, MDw Abstract: The treatment of Helicobacter pylori infection is in a state of flux as traditional therapies fail and new therapies do not achieve the 90% eradication rates desired by clinicians. Triple, which has been the mainstay of treatment in many countries over the last decade, now has suboptimal results in many parts of the world. A number of new treatments have been described with variable success in different parts of the world. In this article, the fundamentals of treatment for H. pylori treatment are reviewed and new treatment algorithms are proposed for regions of the world where triple is failing. Sequential and quadruple (either bismuth-based or non bismuth-based) are the best current options to replace initial treatment with triple. When initial treatment fails, salvage treatments using rifabutin and levofloxacin are the best options. With knowledge of local resistance patterns and with meticulous confirmation of eradication with retreatment, most H. pylori infections can be successfully eradicated. Key Word: H. pylori treatment, sequential, quadruple, triple (J Clin Gastroenterol 2013;47:383 388) Helicobacter pylori is an important pathogen worldwide. It has been associated with chronic gastritis, peptic ulcer disease, gastric cancer, gastric mucosa associated lymphoid tumor lymphoma, some patients with unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. Eradication of H. pylori is an important challenge in clinical practice because of the increasing prevalence of resistant strains of H. pylori worldwide. A rational strategy for the management of H. pylori depends on knowledge of the role of individual agents in the therapeutic regimen, appropriate durations of treatment, and local resistance patterns. PRINCIPLES OF ANTIMICROBIAL THERAPY FOR H. PYLORI Gastric ph and Volume The gastric mucus layer limits the delivery of antimicrobials to H. pylori and penetration of antimicrobials into the mucus is important for treatment success. Drugs that dissolve mucus (eg, pronase) increase drug delivery through the gastric mucus but are not used clinically. 1 Instead, proton pump inhibitors (PPIs) are used as an From the *University of Wisconsin School of Medicine and Public Health, Madison, WI; and wdepartment of Clinical Medicine, S. Orsola Hospital, University of Bologna, Bologna, Italy. N.V.: Consultant at Astra-Zeneca, Takeda, Axcan, Otsuka. The remaining author declares that he has nothing to disclose. Reprints: Nimish Vakil, MD, FACP, FACG, AGAF, FASGE, Aurora Summit Hospital, 56500 Aurora Drive, Summit WI 53066 (e-mail: nvakil@wisc.edu). Copyright r 2013 by Lippincott Williams & Wilkins integral part of the treatment regimen to enhance drug delivery through the gastric mucus. PPIs decrease the volume of gastric juice and raise antimicrobial concentrations in the gastric juice. PPIs also decrease the viscosity of the gastric mucus layer and therefore improve its permeability. Antibiotics can be unstable at the low ph found in the stomach. Clarithromycin is very sensitive to degradation by gastric acid and has a half-life of <1 hour at a ph of 2. 2,3 Metronidazole is very stable in gastric juice regardless of ph with a half-life of over 800 hours. Amoxicillin is less stable at low ph but its half-life is 15 hours at a ph of 2. 2,3 Antimicrobial agents used for H. pylori infections were not specifically designed for this application. Drug Substitutions The antimicrobial effect of agents used to treat H. pylori is primarily local, within the gastric lumen, but the formulation of the drugs is designed to enhance blood levels for the treatment of systemic infections. As a result, some drug substitutions are not effective in H. pylori treatment regimens, for example, ampicillin cannot be substituted for amoxicillin, clarithromycin cannot be replaced by azithromycin, and ciprofloxacin cannot replace levofloxacin. Adherence With Treatment Regimens As antimicrobial resistance rates increase and the success of decreases, adherence with treatment is a very important consideration. There are a number of challenges with H. pylori treatment: (1) side effects are reported by approximately 50% of patients; (2) the treatment regimens are complicated and require careful attention to detail. Quadruple therapies, which require ingestion of multiple medications 4 times a day, can cause problems with adherence. 4 Sequential can cause confusion because the first 5 days of require 2 agents and the subsequent 5 days need 3 agents. (3) Patients taking <80% of their treatment regimen has a high rate of treatment failure; and (4) failed treatment is associated with the emergence of antimicrobial resistance. Measures to enhance compliance improve success with eradication and are meaningful in areas with a high prevalence of H. pylori infection where large numbers of patients are treated. At a minimum, patients should receive counseling regarding the anticipated side effects, the importance of completing the treatment regimen, and the risk of antimicrobial resistance with failed. Some drugs have been specifically developed for delivery to H. pylori, but there has been little progress in this area in the last few years. Ranitidine bismuth citrate is an example of such an agent. It disintegrates rapidly in the stomach allowing bismuth to be delivered to H. pylori but is no longer available in the United States. 5 J Clin Gastroenterol Volume 47, Number 5, May/June 2013 www.jcge.com 383

Vakil and Vaira J Clin Gastroenterol Volume 47, Number 5, May/June 2013 TABLE 1. Antimicrobial Resistance Rates for Helicobacter pylori Around the World Country/Region Year Clarithromycin Metronidazole Amoxicillin Flouroquniolones Tetracycine United States 2004 12.9 25.1 0.9 Northern Europe 2012 7.7 28.6 7.7 Central Western 2012 18.7 43.8 18.6 Europe Rifabutin Eastern Europe 2012 21.5 29.7 13.1 Korea 2012 10.8 30.3 2.2 15.7 0.5 Japan 0.24 China 2011 84.9 61.6 13.7 Antimicrobial Resistance There are 3 key antimicrobial agents that are used in treatment regimens for H. pylori. Key agents in eradication regimens for H. pylori are amoxicillin, clarithromycin, and metronidazole (or tinidazole). In salvage regimens, TABLE 2. Treatment Regimens for Helicobacter pylori Treatment Drugs + Dose Duration Triple Triple for the penicillin allergic patient Bismuth quadruple Nonbismuth quadruple Sequential Levofloxacin triple Rifabutin triple bid + clarithromycin 500 mg bid bid + metronidazole 500 mg bid PPI twice a day, bismuth 3 times a day (dose depends on preparation) + metronidazole 500 mg 3 times a day + tetracycline 500 mg 3 times a day Single-capsule preparation: (140 mg of bismuth subcitrate potassium + 125 mg metronidazole + 125 mg of tetracycline hydrochloride) 3 capsules 4 times a day + PPI twice a day PPI twice a day, amoxicillin 1 g twice a day + metronidazole 500 mg 3 times a day + tetracycline 500 mg 3 times a day twice a day for 5 d followed by PPI twice a day + clarithromycin 500 mg twice a day + tinidazole 500 mg twice a day twice a day + levofloxacin 1 g twice a day twice a day + rifabutin 150 mg twice a day PPI indicates proton pump inhibitor. 7-14 d preferred in the United States 7-14 d preferred in the United States 10-14 d 14 d preferred in the United States 10-14 d levofloxacin and rifabutin are also key agents. All successful treatment regimens for H. pylori contain Z1 of these agents. Combinations of drugs that contain none of these agents have limited efficacy. Of the 3 key drugs, amoxicillin is used in many different combinations of drugs because resistance to this agent rarely develops in clinical practice. Metronidazole and clarithromycin resistance are important in clinical practice and resistance to one of these agents is often the cause of failed. Antimicrobial resistance is a major cause of treatment failure and is responsible for the declining rates of H. pylori eradication seen in many countries. Clarithromycin works by interruption of bacterial protein synthesis and resistance is caused by a mutation in the organism that prevents binding of the antibiotic to the ribosome of H. pylori. A rapid efflux pathway may also develop in H. pylori. These efflux channels develop in the organism when exposed to clarithromycin. The drug is rapidly pumped out of the organism preventing the antimicrobial effect. It has been suggested that sequential may be more effective than triple because the initial treatment with a PPI and amoxicillin poisons the cell wall of the organism preventing the development of efflux channels. There is cross-reactivity between macrolides, and therefore, resistance to clarithromycin may develop with exposure to any macrolides. A nitroimidazole such as metronidazole is a prodrug, which needs to be reduced in the cell to have an adverse effect on bacterial DNA. Frame-shift mutations in a gene called rdxa have been associated with metronidazole resistance, but mutations in other genes may also be responsible. 6 In 1999, a systematic review of H. pylori found that when clarithromycin was the key drug in a regimen, eradication rates fell by 56% when clarithromycin resistant strains were present. 7 A more recent analysis of published studies found a 70% decline in eradication rates if clarithromycin resistance was present and a clarithromycin-containing regimen was used. 8 Nitroimidazole resistance causes a 50% reduction in eradication with triple and quadruple therapies. 7 Resistance rates in Europe have recently been reported and are summarized in Table 1. 9 Recent data from Asia are also summarized in Table 1. 10 12 TREATMENT FOR H. PYLORI INFECTION PPI Triple Therapy Triple is the most widely used treatment in much of the United States (Table 2). 13,14 The most recent studies performed in the United States are now several years old and have demonstrated very low eradication 384 www.jcge.com r 2013 Lippincott Williams & Wilkins

J Clin Gastroenterol Volume 47, Number 5, May/June 2013 H. pylori Treatment rates. 15 20 In 1 study, the intent-to-treat eradication rate was 65% with confidence interval (CI) ranging from 57% to 73%. 19 In another, the intent-to-treat eradication rate was 78% with CI ranging from 72% to 84%. 20 It is likely that eradication rates have declined further. The recent Maastricht guidelines recommend that triple should be abandoned as a primary form of when the prevalence of clarithromycin resistance rises to 15% to 20%. Unfortunately, there is no active monitoring for resistance rates in the United States and the prevalence of resistance is unclear. However, as the pattern of antibiotic use in the United States resembles practices in western Europe, high resistance rates are very likely at least in some parts of the United States. Therefore, most practitioners in the United States should be considering using sequential or quadruple as the initial treatment regimen. The results of triple in Latin America remain surprisingly robust. 21 In a recent study performed in multiple Latin American countries, eradication success with triple was 82 2%, which was higher than with quadruple (73 6%) and sequential (76 5%). Some studies have suggested that triple can still be used in clinical practice by testing for cure and selectively using second-line and third-line treatments in the event of failure. In an Irish study, 3280 patients received PPI triple, which was effective in 2530 (77%) patients. Bismuth-based quadruple or an alternative triple was successful in 56% of 270 treatment failures with the initial. Subsequent eradication attempts using rifabutin-based and furazolidone-based regimens were successful in 38% and 60% patients, respectively. 22 This trial suggested that it is possible to achieve successful eradication in the majority of patients using traditional treatments. In another trial performed in Greece, patients were initially treated with PPI triple, failures were given quadruple and patients failing both treatments were given levofloxacin triple. 23 Using this strategy, of the 540 patients receiving treatment, 484 had successful eradication (intent-to-treat eradication rate: 89.6%). A study from Spain with a total of 500 patients reported a high success rate of 99.5% when traditional triple was used initially and salvage therapies were administered to those who failed triple. 24 A practical strategy in areas where the results of antimicrobial sensitivity testing are not available is to monitor success with whatever treatment is being used as the initial. If all patients return for confirmation of eradication, the failure rate for the initial treatment regimen can be determined. The initial treatment regimen should be changed if the failure rate is Z20%. The major points to be taken away from recent data on triple are: (a) Initial treatment may fail in as many as 30% of patients; (b) test all patients after treatment to confirm eradication and use the results as a guide to success with triple in your area; (c) establish a salvage plan for treatment failures; and (d) consider switching to sequential or quadruple as the first line of treatment. Quadruple Therapy Quadruple (bismuth + metronidazole + tetracycline + PPI administered for 7 to ) is a particularly useful treatment in areas where metronidazole resistance is low and clarithromycin resistance is high. As it is an inexpensive regimen, it is often preferred in situations where the cost of is the main concern. In 2002, a large, randomized, controlled trial (RCT) compared 7-day quadruple (bismuth + metronidazole + tetracycline + PPI) with 7-day triple. Eradication rates were similar with PPI triple (78%) and quadruple (82%). 25 In another RCT in Spain, a 7-day PPI triple was similar to quadruple in the eradication of H. pylori. 26 A recent meta-analysis found 9 studies of sufficient quality to allow comparisons between quadruple and triple and concluded that there was no statistically significant difference between PPI triple and quadruple. 27 Many of these comparative studies predate the emergence of high rates of clarithromycin resistance. Recent studies performed with a single-capsule preparation of bismuth biskalcitrate with metronidazole and tetracycline provides insights into current success with quadruple and triple. 16 Initial results were promising with an eradication rate of 93% by intent-to-treat analysis in Europe and 87.7% in the United States for 10-day. 16,28 A recent RCT in Europe showed that quadruple using this single-capsule preparation was superior to triple and with an eradication rate of 93% compared with 68% with triple. 29 In the United States, the single capsule contains (40 mg of bismuth subcitrate potassium, 125 mg of metronidazole, and 125 mg of tetracycline hydrochloride). Quadruple using bismuth has a long track record and is an attractive alternative to triple as an initial treatment. Bismuth is concentrated in H. pylori and as the organism does not seem to develop resistance to bismuth, the use of a bismuth quadruple may offer advantages over nonbismuth quadruple. The main take-away points with bismuth-based quadruple are: (a) this treatment is a good alternative to triple in areas with high prevalence rates of clarithromycin resistance and (b) when clarithromycin fails, bismuth quadruple is the best choice for empirical treatment in the United States (Table 2). Nonbismuth Quadruple Therapies The combination of PPI-clarithromycin-amoxicillinnitroimidazole is referred to as nonbismuth quadruple and was developed because bismuth is not available in some countries. This treatment has also been referred to as concomitant, a term that implies that all the antibiotics are administered together. This is a misnomer as all treatments for H. pylori, with the exception of sequential are in fact concomitant therapies. A meta-analysis of randomized trials comparing nonbismuth quadruple was recently reported and showed that the eradication rate with quadruple was 90% compared with 78% with triple. 30 A recent open-label study using a novel quadruple comprising levofloxacin, omeprazole, nitazoxanide, and doxycycline with a PPI had a high eradication rate in a single open-label study. 31 It needs further validation. The main take-away points with non bismuth-based quadruple are: (a) this treatment is a good alternative to triple in areas with high prevalence rates of clarithromycin resistance where bismuth is not available; (b) if this fails, empirical becomes difficult as the patient has been exposed to both metronidazole and clarithromycin and a levofloxacin-containing or rifabutincontaining regimen may be necessary; (c) we recommend bismuth-based quadruple in the United States. r 2013 Lippincott Williams & Wilkins www.jcge.com 385

Vakil and Vaira J Clin Gastroenterol Volume 47, Number 5, May/June 2013 Triple Bismuth Quadruple Quadruple Sequential Therapy Levofloxacin or Rifabutin triple FIGURE 1. Traditional treatment paradigm for Helicobacter pylori. Sequential Therapy Sequential is a novel treatment method. Instead of administering the antimicrobials all at once, they are administered in sequence. 32 The best-characterized sequential regimen that has been best described is a 10-day treatment consisting of a PPI and amoxicillin 1 g (both twice daily) administered for the first 5 days followed by triple consisting of a PPI, clarithromycin 500 mg, and tinidazole 500 mg (all twice daily) for the remaining 5 days. 33 A large RCT compared sequential and standard triple. A total of 300 patients with H. pylori infection were randomized to sequential or triple. Sequential was significantly more effective in patients with clarithromycin resistant strains (89% vs. 29%; P = 0.0034). A recent meta-analysis evaluated 10 RCTs included 1400 patients treated with sequential were compared with 1611 patients treated with triple of 7 to ays duration. 34 The eradication rate was 91.0% (95% CI, 89.6-92.1) for sequential and 75.7% (95% CI, 73.6-77.7) for triple, with a difference in the eradication rate of 15.3% (95% CI, 13.1-17.4). The odds ratio (OR) for eradication of H. pylori with sequential compared with triple was 2.99 (95% CI, 2.47-3.62). In patients with clarithromycin resistance, the OR for eradication with sequential was 10.21 (95% CI, 3.01-34.58) Sequential Bismuth quadruple Levofloxacin or Rifabutin triple FIGURE 2. Proposed new treatment paradigm based on initial sequential. Levofloxacin or Rifabutin triple FIGURE 3. Proposed alternative treatment paradigm based on initial quadruple. compared with triple, but the numbers studied are small. The available data suggest that sequential treatment seems to maintain a high level of efficacy in patients with clarithromycin resistance. In Korea, where a high prevalence of clarithromycin resistant H. pylori is seen, the results of sequential (79% eradication) were significantly better than triple (62%). 35 An RCT that compared sequential and nonbismuth quadruple in Taiwan found that the both treatments were similar and had high efficacy. 36 The rate of clarithromycin resistance in the population studied was low and therefore the potential advantage of sequential in patients with resistant strains may not have been realized. The major take-away points about sequential are: (a) the results vary depending on the prevalence of clarithromycin resistance; (b) despite the variable results, eradication rates are consistently 15% better than with triple ; (c) sequential should be considered as a potential replacement treatment for triple in areas with moderate rates of resistance to H. pylori, for example, United States; (d) in areas with extremely high levels of clarithromycin resistance (Table 1), quadruple is preferable. Salvage Therapies Levofloxacin and rifabutin are treatments for patients in whom standard treatments fail. There are important differences between these 2 agents. The first is that levofloxacin resistance develops rapidly in populations where this agent is used frequently (Table 1). Rifabutin resistance is generally low (Table 1). A recent meta-analysis performed a comparison of bismuth quadruple (bismuth + tetracycline + metronidazole + PPI) with triple using levofloxacin (levofloxacin 500 mg/d + amoxicillin 1 g twice a day + a PPI twice a day) in patients who failed eradication with standard triple. 37 Levofloxacin triple was better tolerated than quadruple and had better eradication rates (81% vs. 70%; OR,1.80; 95% CI, 0.94-3.46). Ten-day levofloxacin triple was superior to 7-day and the lower dose of levofloxacin (250 mg twice a day) was as effective as the higher dose (500 mg twice a day). In Korea, which has a high prevalence of levofloxacin resistance, an 386 www.jcge.com r 2013 Lippincott Williams & Wilkins

J Clin Gastroenterol Volume 47, Number 5, May/June 2013 H. pylori Treatment RCT in patients who had failed 2 initial treatments, rifabutin triple was more effective (71% eradication) and was more effective than levofloxacin triple (57%). 38 In an older randomized comparison of levofloxacin triple and rifabutin triple in patients who had failed 2 other treatment trials, levofloxacin triple was significantly better than rifabutin triple (85% vs. 45%). 39 Side effects occurred frequently with both regimens: leukopenia with rifabutin in 25% and myalgia with levofloxacin in 30%. The leukopenia with rifabutin resolves with observation. Rifabutin has been reported to cure approximately 50% of patients with H. pylori infection who have failed 3 regimens (a clarithromycin-based regimen, a metronidazole-tetracycline regimen, and a levofloxacin-based regimen). 40 CONCLUSIONS Triple is failing in many countries worldwide. Although monitoring of resistance is no longer being performed in the United States, there is no reason to believe that clarithromycin resistance is very different from western Europe. Standard triple is unlikely to be an effective in many areas of the United States. We have previously suggested that sequential or quadruple should replace triple as the first-line treatment for H. pylori. 41 Figure 1 shows the traditional paradigm for the treatment of H. pylori. We suggest that practitioners consider 2 alternate treatment paradigms (Figs. 2, 3). The paradigm shown in Figure 2 should result in a roughly 15% increase in eradication success compared with triple. The paradigm shown in Figure 3 avoids the use of a clarithromycin-containing regimen as the first step making this the preferred strategy where clarithromycin-based treatment regimens fail. REFERENCES 1. Sherwood P, Wibawa J, Atherton J, et al. 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Vakil and Vaira J Clin Gastroenterol Volume 47, Number 5, May/June 2013 infection: Systematic review and meta-analysis of efficacy and tolerability. Am J Gastroenterol. 2010;105:65 73. 28. O Morain C, Borody T, Farley A, et al. Efficacy and safety of single-triple capsules of bismuth biskalcitrate, metronidazole and tetracycline, given with omeprazole, for the eradication of Helicobacter pylori: an international multicentre study. Aliment Pharmacol Ther. 2003;17:415 420. 29. Malfertheiner P, Bazzoli F, Delchier JC, et al. Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple : a randomised, openlabel, non-inferiority, phase 3 trial. Lancet. 2011;377:905 913. 30. Gisbert JP, Calvet X. Update on non-bismuth quadruple (concomitant) for eradication of Helicobacter pylori. Clin Exp Gastroenterol. 2012;5:23 34. 31. Basu PP, Rayapudi K, Pacana T, et al. A randomized study comparing levofloxacin, omeprazole, nitazoxanide, and doxycycline versus triple for the eradication of Helicobacter pylori. Am J Gastroenterol. 2011;106:1970 1975. 32. Rinaldi V, Zullo A, Pugliano F, et al. The management of failed dual or triple for Helicobacter pylori eradication. Aliment Pharmacol Ther. 1997;11:929 933. 33. Vaira D, Zullo A, Vakil N, et al. Sequential versus standard triple-drug for Helicobacter pylori eradication: a randomized trial. Ann Intern Med. 2007;146:556 563. 34. Gatta L, Vakil N, Leandro G, et al. Sequential or triple for Helicobacter pylori infection: systematic review and meta-analysis of randomized controlled trials in adults and children. Am J Gastroenterol. 2009;104:3069 3079. 35. Park HG, Jung MK, Jung JT, et al. Randomised clinical trial: a comparative study of 10-day sequential with 7-day standard triple for Helicobacter pylori infection in naive patients. Aliment Pharmacol Ther. 2012;35:56 65. 36. Wu DC, Hsu PI, Wu JY, et al. Sequential and concomitant with four drugs is equally effective for eradication of H. pylori infection. Clin Gastroenterol Hepatol. 2010;8:36 41. 37. Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple versus bismuth-based quadruple for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol. 2006;101:488 496. 38. Jeong MH, Chung JW, Lee SJ, et al. Comparison of rifabutinand levofloxacin-based third-line rescue therapies for Helicobacter pylori Korean. J Gastroenterol. 2012;59:401 406. 39. Gisbert JP, Gisbert JL, Marcos S, et al. Third-line rescue with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther. 2006;24:1469 1474. 40. Gisbert JP, Castro-Fernandez M, Perez-Aisa A, et al. Fourthline rescue with rifabutin in patients with three Helicobacter pylori eradication failures. Aliment Pharmacol Ther. 2012;35:941 947. 41. Vakil N, Vaira D. Sequential for Helicobacter pylori: time to consider making the switch? JAMA. 2008;300: 1346 1347. 388 www.jcge.com r 2013 Lippincott Williams & Wilkins