Treatment of Helicobacter pylori Infection

Abstract

This article aims to examine current best practice in the field reference to first-line, second-line, rescue and emerging treatment regimens for Helicobater pylori eradication. The recommended first-line treatment in published guidelines in Europe and North American is proton pump inhibitor combined with amoxicillin and clarithromycin being the favoured regimen. Rates of eradication with this regimen however are falling alarmingly due to a combination of antibiotic resistance and poor compliance with therapy. Bismuth based quadruple therapies and levofloxacin based regimes have been shown to be effective second line regimens. Third-line options include regimes based on rifabutin or furazolidone, but susceptibility testing is the most rational option here, but is currently not used widely enough. Sequential therapy is promising but needs further study and validation outside of Italy. Although the success of first line treatments is falling, if compliance is good and a clear treatment paradigm adhered to, almost universal eradication rates can still be achieved. If compliance is not achievable, the problem of antibiotic resistance will continue to beset any combination of drugs used for H. pylori eradication.

The treatment of Helicobacter pylori infection has posed conundrums for clinicians since the bacterium was first discovered in the early 1980s. The challenges go beyond finding the correct combination of antibiotics and manipulation of gastric pH to ensure eradication and include avoiding the development of antimicrobial resistance and ensuring compliance with prescribed treatment. The Maastricht-III consensus stated that for an eradication treatment regime to be considered effective, it would need to achieve an intention-to-treat eradication rate in excess of 80% [1]. However, in recent times, eradication rates in practice for many of the most common regimens have fallen well below these levels, generally due to the interwoven factors of poor compliance with medication and antibiotic resistance [2].

First-Line Therapy (Standard Triple Therapy)

The combination of a proton pump inhibitor (PPI) with two antibiotics has been accepted as the first-line therapy of choice for H. pylori eradication since a randomized control trial in 1996 [3]. The recommended first-line treatment in published guidelines in Europe and North America reflect this with PPI combined with amoxicillin and clarithromycin being the favored regimen [1,4]. However, some caveats have been applied to these guidelines in recent years to take into account falling eradication rates. As recently as 2000, studies had suggested eradication rates for standard triple therapy were in excess of 90% [5]. However, more recent publications have suggested that this level has fallen alarmingly to be around 70% in many areas and even as low as 60% in some [6,7]. For instance, the most recent Maastricht guidelines recommend substituting metronidazole for clarithromycin where resistance to that antibiotic exceeds 15–20% [3]. Eradication rates with this regime are 87.8% when strains are clarithromycin sensitive and 18.3% when strains are clarithromycin resistant [8]. The rate of clarithromycin resistance is increasing, probably due to greater use of clarithromycin in the community for respiratory tract infections [9,10]. An Italian study noted that rates of clarithromycin resistance increased twofold in that country from 1990 to 2005 [11]. A similar phenomenon was noted in England with resistance rates rising by 57% between 2002 and 2006 [12]. A study in the United States estimated clarithromycin resistance at 10.1% [13]. There has also been debate as to the ideal duration of therapy. In recent years, longer regimes have supplanted the previous 7-day triple therapy. A meta-analysis in 2000 suggested a 14-day course of therapy showed 7–9% better cure regimens than 7-day regimes [14]. However, another meta-analysis differed, stating no clinical benefit from longer courses of treatment, although the quality of some of the studies included in this second meta-analysis has been questioned [15]. The published guidelines are also beginning to reflect this with the 2007 American College of Gastroenterology guidelines recommending 10-day treatment courses [4]. In addition, the most recent Maastricht consensus stated that 14 days of treatment had an advantage over 7 days in terms of eradication [1].

Second-line Therapy

As first-line therapy has been noted to fail in approximately 20% of patients, the need for effective second-line therapy is clear [16]. Many putative second-line therapies are currently in use but the most common are bismuth-based and levofloxacin-based therapies [17]. Bismuth-based quadruple therapy consisting of a PPI, bismuth, tetracycline, and metronidazole is reported to have an efficacy of 76% in patients who failed first-line therapy [18]. This is generally given for 10 days and taken four times daily, although a study of a 14-day twice daily regimen reported 95% efficacy in a mix of first-line and second-line patients which might improve compliance and tolerability [19]. Bismuth-based therapy has proved quite safe. A meta-analysis in 2008 showed no serious adverse event in 4763 patients who received it. No statistically significant increase in any side effect other than dark stools was illustrated [20]. Levofloxacin-based therapy has grown in popularity in recent years. A very recent Spanish multicenter study of 300 patients who had failed first-line eradication therapy revealed 81% per-protocol and 77% intention-to-treat analysis when a 10-day levofloxacin-based regimen was used, with good tolerability and a low side effect rate of 22% [21]. Concerns have been expressed regarding the development of fluoroquinolone resistance when levofloxacin is used for Helicobacter eradication. A rapidly increasing rate of quinolone resistance was reported in several countries: 15% in 2004 in Japan, 16.8% in 2006 in Belgium, from 11.2% in 2003 to 22.1% in 2005 in Germany, from 3% in 1999 to 15% in 2004 in France and from 2.8% to 11.8% between 1998 and 2003 in Taiwan [22–28]. The apparently rapid rate at which fluoroquinolone resistant seems to develop may limit the use of levofloxacin in H. pylori eradication to second-line therapy. Another concern exists regarding the side effects of the fluoroquinolones. Tendonitis was reported in 704 of 46,000 patients receiving levofloxacin in one study [29]. Other case reports have noted hepatotoxicity [30].

Third-line Therapy

Patients who fail both initial- and second-line therapy for H. pylori pose an interesting and challenging question [31]. Compliance must, of course, be questioned. The options are to use further empiric regimes or to employ treatments tailored to individual antibiotic sensitivities. Two of the more common empiric rescue antibiotics used are rifabutin [32] and furizoladone [33]. Rifabutin is an antituberculous agent. For the eradication of H. pylori, it can be administered as PPI, rifabutin (150 mg), amoxicillin (1 g), all twice daily for 14 days. One study on rifabutin used for treatment failures achieved 95% eradication rates as second-line therapy and 68% eradication for third- or subsequent line therapy [34]. Another study limited to patients who did not achieve eradication with standard first-line or bismuth-based second-line therapy revealed 79% eradication rates based on intention-to-treat analysis [35]. These results, however, have been contradicted somewhat by the largest study to date on rifabutin as a third-line treatment which estimated eradication rates as being 61% [36]. Rifabutin is limited as a treatment option by a number of factors. Stocks are low in Europe. Also, rifabutin is a useful tool in the treatment of the increasingly problematic multi-drug resistant tuberculosis infection. Greater use of rifabutin in the treatment of H. pylori would likely result in the development of more resistant strains of Mycobacterium tuberculosis. Also serious myelotoxicity and ocular adverse events have been reported with this treatment [37,38]. Furazolidone is also useful in treatment failures [39,40]. A study of 10 patients, in whom first-line, second-line and rifabutin-based therapy had failed revealed 60% eradication when it was used along with amoxicillin and PPI [41]. When this data was incorporated into a systematic review of furazolidone-based treatments for third- and subsequent line eradication therapy, they were shown to be effective 65% of the time [42]. The other principal strategy for salvage therapy in H. pylori involves culture and antibiotic testing. This is a very logical approach as H. pylori is a latent infection and therefore has more in common with other latent conditions such as tuberculosis and syphilis, where susceptibility testing is routinely employed, than with conditions, such as a urinary or a respiratory tract infection where empiric antibiotic regimes are used. Susceptibility testing is limited by the fact that in vivo resistance may not accurately reflect in vitro resistance, notably with respect to metronidazole [43]. Currently such an approach is mainly carried out in specialist centers with research interest and expertise in the treatment of H. pylori [44]; however, greater interest in the pathogen and its effects and the development of newer technologies in the field of susceptibility testing will encourage this practice to become more widespread. This will undoubtedly have benefits and lead to more accurate prescribing and lower rates of resistance [45].

Sequential Therapy

Sequential therapy has been proposed as an alternative to standard triple therapy for the eradication of H. pylori [46,47]. The primary goal of this regimen is to overcome clarithromycin resistance. Hypothetically, during the first part of therapy, amoxicillin weakens the bacterial cell wall, which prevents the formation of the channels that block clarithromycin from binding to the bacterium and hence causes resistance to the antibiotic. A meta-analysis published last year demonstrated that eradication rates with sequential therapy are 93.4% compared with 76.9% for standard triple therapy [48]. Sequential therapy is not affected by bacterial factors (CagA status, bacterial load) and host factors (underlying disease, smoking) which, until now, have predicted the outcome of conventional eradication treatments. Even when strains were clarithromycin resistant, the eradication rate with sequential therapy was 82.2% compared with 40.6% for triple therapy. So far, almost all of the studies analyzing sequential therapy have been performed in Italy and the sequential regimen has been given equivalent status to standard 7–14 day triple therapies as first-line treatment in the updated Italian guidelines on H. pylori management, where it has been stated that: “The Working Group advised the use of 7–14 day triple therapies or a sequential therapy as first-line treatment” [49]. The main drawback to sequential therapy may lie in its complexity and how this may affect compliance. Although the meta-analysis quoted showed that compliance was superior amongst patients receiving sequential therapy compared to standard triple therapy, it is counter-intuitive that a regimen which lasts longer and involves a change in the medications consumed in mid-course could enhance compliance [50]. The advantages of sequential treatment over triple-therapy need to be confirmed in randomized controlled trials in different countries and settings before a generalized change is recommended in first-line H. pylori treatment. Accordingly, the American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection states that “Sequential therapy may provide an alternative to clarithromycin-based triple therapy but requires validation within the United States before it can be recommended as a first-line therapy” [4], and the European Maastricht III Consensus Report points out that “Sequential treatment deserves further evaluation in different regions” [1]. The main disadvantage of the sequential therapy regime is that it is more complex for the patient, requiring a change of medication in the middle of the treatment period. Although it was not shown in the meta-analysis, it is felt that this would likely have a negative impact on compliance. Whether it is necessary to provide the drugs sequentially or whether the four constituent components of sequential therapy can be given concurrently is unclear. A meta-analysis published in 2009 on this showed a per-protocol eradication level of 92.9% and intention-to-treat eradication of 89.7% [51]. This quadruple therapy appears to be an effective, safe and well-tolerated alternative to triple therapy and is less complex than sequential therapy, emphasizing that studies comparing both alternatives are urgently needed. It must be noted that although it is designed to overcome clarithromycin resistance, clarithromycin is central to both sequential and quadruple therapy and would still be at the mercy of changes in patterns of clarithromycin resistance which are probably primarily contingent on the rates of prescription of clarithromycin in the community for nongastrointestinal infections [52]. In addition, there exists a body of opinion that clarithromycin and metronidazole ought not be used together for H. pylori eradication as those who fail to have eradication will subsequently have at least single and often double resistance [53]. Sequential therapy undoubtedly shows promise but must be further evaluated before it can supplant triple therapy in the existing guidelines.

Adjuncts

Adjunctive therapies may offer some promise in H. pylori eradication. Probiotics have been proposed as a useful adjunct [54]. In one study undertaken in 2008, prescribing probiotics with H. pylori eradication therapy had no effect on the side effect profile but did increase the rates of eradication [55]. However, another study on concurrent probiotic administration suggested the inverse with better side effect profiles but no increase in eradication or rates of compliance with therapy [56]. Vaccination has also been proposed as a means of controlling H. pylori and the morbidity associated with it. The challenge model was first established in human volunteers in 2004 [57] and subsequent to this, a vaccine is in Phase I trials and its manufacturers claim it has been shown to be safe and immunogenic in early trials [58].

Conclusion

Establishing efficacious and acceptable treatment regimens for patients infected with H. pylori continues to pose problems for physician and patient alike. The decrease in eradication rates needs to be firmly addressed with evidence-based clinical practice. It is probably the case, however, that the tools to successfully eradicate H. pylori are already present and that they simply need to be properly utilized. It has been repeatedly illustrated that, if compliance is good and a clear treatment paradigm adhered to, very high eradication rates can be achieved. For example, a study published in 2008 in a Finnish tertiary referral centre revealed 100% eradication in 644 consecutive patients where compliance was ensured and patients were treated with standard first- and second-line therapies as per the Maastricht guidelines and third-line rescue therapy was tailored to antibiotic susceptibility [59]. Another study in Greece published earlier this year found 98.1% eradication rates when the Maastricht-III guidelines were implemented with empiric therapy used for third-line patients [60]. Another 2008 study evaluated the efficacy of different ‘rescue’ therapies empirically prescribed during 10 years to 500 patients in whom at least one eradication regimen had failed to cure H. pylori infection. The authors concluded that it is possible to construct an overall treatment strategy to maximize H. pylori eradication, on the basis of administration of four consecutive empirical regimens [61]. The key factors in these studies were an awareness of the importance of compliance and the provision of structured aftercare and follow-up programs to ensure eradication. It has been proven that such measures can improve compliance [62]. It is very likely the case that empowering patients to achieve high levels of compliance is what accounts for the impressive eradication rates in centers where patient follow-up is structured and comprehensive [63]. While it is important to develop new regimes to overcome the problems of resistance, a need also exists to work as efficiently as possible with our current regimes and facilitate patient compliance. If compliance is not achievable, the problem of antibiotic resistance will continue to beset any combination of drugs used for H. pylori eradication.

Conflicts of Interest

The authors have declared no conflicts of interest.