Fluoroquinolone-based protocols for eradication of Helicobacter pylori

Abstract

Helicobacter pylori (H. pylori) is a widespread pathogen infecting about 40% of people living in urban areas and over 90% of people living in the developing regions of the world. H. pylori is well-documented as the main factor in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric malignancies such as cancer and mucosa-associated lymphoid tissue-lymphoma; hence, its eradication is strongly recommended. The Maastricht IV consensus, which focused on the management of H. pylori infection, set important new strategies in terms of treatment approaches, particularly with regards to first- and second-line treatment protocols and led to improved knowledge and understanding of H. pylori resistance to antibiotics. In recent years, various fluoroquinolone-based protocols, mainly including levofloxacin, have been proposed and effectively tested at all therapeutic lines for H. pylori eradication. The aim of the present paper is to review the scientific literature focused on the use of fluoroquinolones in eradicating H. pylori.

Key Words: Helicobacter pylori, Eradication, Fluoroquinolone, Therapy

Core tip: The Maastricht IV consensus, which focused on the management of Helicobacter pylori (H. pylori) infection, set important new strategies in terms of treatment approaches, particularly with regards to first- and second-line treatment protocols and led to improved knowledge and understanding of H. pylori resistance to antibiotics. In recent years, various fluoroquinolone-based protocols, mainly including levofloxacin, have been proposed and effectively tested at all therapeutic lines for H. pylori eradication. The aim of the present invited paper is to review the scientific literature focused on the use of fluoroquinolones in eradicating H. pylori.

INTRODUCTION

Nalidixic acid, the precursor of all fluoroquinolones, was developed and marketed during the 1960s for the oral treatment of urinary tract infections and is still prescribed with this indication. Several fluoroquinolones were developed since; however, the role of new molecules only became significant when it was demonstrated that substitutions at the Carbon atoms in C-6 and C-7 positions improved both antibacterial activity and pharmacological features. From that point onwards, fluoroquinolones were tested and used in the treatment of urinary, respiratory, gastrointestinal, urogenital, and intra-abdominal infections in the context of several pathological conditions[1-5].

Helicobacter pylori (H. pylori) is a widespread pathogen infecting about 40% of people living in urban areas and over 90% of people living in the developing regions of the world[6,7]. H. pylori is well-documented as the main factor in the pathogenesis of peptic ulcer disease, chronic gastritis, and gastric malignancies such as cancer and mucosa-associated lymphoid tissue-lymphoma. Hence, its eradication is strongly recommended[8-13]. The Maastricht III consensus proposed that triple therapy protocols containing clarithromycin and metronidazole should be used as first-line treatment for H. pylori infection, in view of their high efficacy and safety[14]. However, more recent data show that these antibiotics have lost some efficacy because of increased primary/secondary drug resistance, so that they permit H. pylori eradication in only a maximum of 70% of the affected patients (a percentage significantly lower than the one that can be expected for the treatment of an infectious disease - about 90% at per-protocol analysis). Thus, antibiotics different from clarithromycin and metronidazole have been proposed for eradicating H. pylori [15,16]. The Maastricht IV consensus generated important new information with regard to the treatment of H. pylori infection. In particular, it proposed the prescription of three antibiotics together with a proton pump inhibitor (PPI; non-bismuth sequential or quadruple therapy) as first-line treatment for H. pylori infection in areas of high clarithromycin resistance[17-21].

In recent years, various fluoroquinolone-based protocols, mainly including levofloxacin, have been proposed and tested at all therapeutic lines for H. pylori eradication. The aim of this paper is to review the scientific literature focused on the use of fluoroquinolones in eradicating H. pylori.

Studies providing information on the use of levofloxacin-based anti-H. pylori protocols were identified through systematic searches in the MEDLINE and EMBASE databases. Various combinations of the terms “H. pylori”, “fluoroquinolone”, “levofloxacin”, “ciprofloxacin”, “eradication”, “first-line”, “second-line” and “rescue” were used for the searches. Additionally, references of retrieved articles were screened to identify additional relevant studies (cross-referencing). We also performed a manual search of all review articles, recently published editorials, and retrieved original studies presented at the Digestive Disease Week, United European Gastroenterology Week, and European Helicobacter Study Group conferences. In addition, reference lists from relevant identified papers were manually searched. All original research articles and abstracts published up to August 1, 2013 were included. Searches were limited to randomized controlled trials and studies comparing fluoroquinolone-based protocols to other treatment regimens. Two investigators (Dr Capone and Dr Rea) independently extracted data from the included studies by using a structured form. Only data from patients undergoing fluoroquinolone-based eradication protocols were included in the analysis. There was a > 95% agreement in data extraction between the two investigators.

CURRENT RECOMMENDATIONS FOR ERADICATING H. PYLORI

As mentioned above, the Maastricht IV consensus introduced important changes to the treatment of H. pylori infection (Table 1)[17].

Table 1 Current recommendations for Helicobacter pylori eradication.

Treatment	Region with low clarithromycin prevalence	Region with high clarithromycin prevalence
First line	PPI - clarithromycin - amoxicillin/metronidazole or bismuth quadruple	Bismuth quadruple1. If not available: non-bismuth quadruple (either sequential or concomitant)
Second line	Bismuth quadruple1 or PPI - levofloxacin/amoxicillin	PPI - levofloxacin/amoxicillin
Third line	Based on susceptibility testing only. Besides clarithromycin and levofloxacin, rifabutin is another candidate that may be used

¹PPI + tetracyclines + bismuth + metronidazole. PPI: Proton pump inhibitors.

The consensus led to abandoning the use of clarithromycin-containing triple therapy in regions where clarithromycin resistance rate is over 15%-20% - for example, many areas of Europe and North America - if susceptibility testing cannot be carried out[16,22]. However, in areas of known low clarithromycin resistance, clarithromycin-containing protocols are still recommended for the first-line empirical treatment of H. pylori infection. In these areas of low clarithromycin resistance bismuth-containing quadruple treatment protocols are considered an effective alternative, whilst in regions with high clarithromycin resistance, they are the recommended protocols for first-line empirical treatment of H. pylori infection[23-25]. In countries where a bismuth-based regimen is not easily available, sequential treatment or a non-bismuth quadruple treatment is recommended as first-line eradication protocol[26-29].

With regard to the role of fluoroquinolones for H. pylori eradication, current recommendations stress their efficacy as a second-line treatment option. In particular, either bismuth-containing quadruple therapy or levofloxacin-containing triple therapy is recommended after failure of a regimen containing PPI-clarithromycin. In areas of low fluoroquinolone resistance, a levofloxacin-containing regimen (together with a PPI and clarithromycin) can prove an effective second-line alternative in the presence of penicillin allergy[30-35]. However, when considering a treatment approach including fluoroquinolones, clinicians should be aware of the rising rates of levofloxacin resistance, particularly in Europe and North America.

DRUG RESISTANCE IN THE TREATMENT OF H. PYLORI INFECTION

The success of treatment protocols for the eradication of H. pylori is currently being compromised by the increase in antimicrobial resistance[36,37].

Clarithromycin resistance in particular has a major negative impact on the efficacy of the recommended first-line triple therapy and a progressive increase in its prevalence may limit its use. The almost two-fold increase (from 9.8% to 17.5%) of the prevalence of clarithromycin resistance over the past 10 years (in specific areas of Southern Europe it is higher than 30%) could have been anticipated on the grounds of the genetic basis of this resistance. By contrast, metronidazole resistance, although highly prevalent (particularly in Mediterranean Africa), can be partly overcome and is therefore of secondary importance. As for amoxicillin, all the surveys performed so far have reported a resistance rate lower than 1%, indicating that resistance to this drug is not yet a clinical concern[38-42].

At present, it is well known that fluoroquinolones are the only class of antibiotics for clinical use that directly inhibit bacterial DNA synthesis. Fluoroquinolones inhibit DNA gyrase and topoisomerase IV, two bacterial enzymes which have essential and distinct roles in DNA replication. Resistance to fluoroquinolones occurs mainly by means of a mutation in the chromosomal genes for gyrase and topoisomerase IV. Miyachi et al[43] showed that primary levofloxacin resistance, found in approximately 15% of H. pylori strains, was related to point mutations in gyrA at Asn-87 or Asp-91 in 84% of cases; only 14% of the susceptible strains had gyrA mutations. The difference in occurrence of gyrA mutations between levofloxacin-resistant and -susceptible strains was significant. Other mechanisms that can determine bacterial resistance to fluoroquinolones could be microbial SOS response, auto-induction of resistance and plasmid-mediated resistance, with the latter being more frequent for other kind of urinary, pulmonary and intestinal infections. In contrast to other bacteria, resistant H. pylori strains show no spread of resistance through horizontal transfer of mobile genetic elements (e.g. plasmids)[44]. As a consequence, the low transmission rate of H. pylori and the lack of expansion of specific clones in the community imply that antibiotic resistance in H. pylori is caused by previous and direct exposure to antibiotics in infected patients. H. pylori infection is an example of long-lasting infection and it should be highlighted that the exposure to antibiotics for this microbe may be much longer than that for most other pathogens.

A recent paper by Mégraud et al[37] focused on the antibiotic resistance of H. pylori. The study by these authors included more than 2000 patients with H. pylori infection and showed resistance rates of 14.1% for levofloxacin, 17.5% for clarithromycin, and 34.9% for metronidazole, with significantly higher fluoroquinolone resistance in Western/Central and Southern Europe (> 20%) than in Northern European countries (< 10%). The results of this paper correlate well with those reported by O’Connor et al[45] in Ireland. These authors encountered a rate of levofloxacin resistance of 2.6 % in the under-45 age group, compared to 19.1% in patients above 45 years of age. In keeping with the suggested mechanisms of H. pylori resistance to fluoroquinolones, a significant association was found between fluoroquinolone use among outpatients and the proportion of levofloxacin resistance.

Carothers et al[46] have already shown how H. pylori resistance to fluoroquinolones and its impact on treatment outcomes are influenced by previous use of this class of antibiotics. In their study, resistance rates appeared to be significantly associated with any prior fluoroquinolone assumption over the previous 10 years and with the total number of courses prescribed. For patients who have previously undergone treatment with fluoroquinolones, a treatment protocol not comprising levofloxacin should be suggested.

However, previous use of fluoroquinolones for therapeutic purposes is not the only mechanism through which resistance to the drug occurs. A recent paper from Germany demonstrated that about 85% of all antibiotics used in general practice is administered in food animals; animal manure waste is spread onto agricultural land and will influence ecosystem compartments. Antibiotics such as fluoroquinolones and tetracyclines are not biodegradable; they can persist in soil for long periods and/or in high concentrations and can be detected in soil and water[47]. Antibiotic resistance pre-dates the use of antibiotics because resistance determinants have been circulating within the microbial genome for millennia[48]. Ongoing non-therapeutic use of antibiotics in food animals will increase the pool and occurrence rate of resistance genes in many bacterial species, thus having dramatic public health consequences. The Maastricht IV consensus recommendations relating to the rising rate of levofloxacin resistance are therefore extremely relevant for every-day clinical practice[17,5,49].

FLUOROQUINOLONE-BASED PROTOCOLS IN THE FIRST-LINE TREATMENT OF H. PYLORI INFECTION

Fluoroquinolones - levofloxacin being the main representative of this class of molecules - are antibacterial agents with a wide spectrum of activity against Gram-positive and -negative bacteria, including in vitro activity against H. pylori and atypical pathogens. Levofloxacin is widely used for the rescue treatment of resistant H. pylori infections. Recent meta-analyses have underlined its better efficacy and tolerability profile in the second-line treatment of H. pylori infection when compared with the quadruple protocol comprising bismuth (which we discuss shortly).

Since 2006, several clinical trials have tested the efficacy of levofloxacin in the first-line treatment of H. pylori. The majority of authors utilised levofloxacin as part of a triple drug regimen including a PPI and another antibiotic agent (frequently amoxicillin). The first experience by Cammarota et al[50] in a trial including 100 patients with H. pylori infection treated with levofloxacin (500 mg/d), clarithromycin and rabeprazole showed an eradication rate of 84%. An analogous rate of H. pylori eradication (87%) was reported by Nista et al[51], who treated 300 infected patients with levofloxacin, clarithromycin and esomeprazole. Drawing upon this existing research, our team carried out a study to evaluate the efficacy of a triple therapy including levofloxacin in the first-line treatment of H. pylori infection when compared to the conventional protocol containing clarithromycin. We prospectively randomized 130 consecutive outpatients with histological first diagnosis of H. pylori infection in two treatment groups: the LAE group (65 patients) was treated with levofloxacin 250 mg bid, amoxicillin 1 g bid, esomeprazole 20 mg bid; and the CAE group (65 patients) with clarithromycin 500 mg bid, amoxicillin 1 g bid, and esomeprazole 20 mg bid. The success rate was assessed by means of ¹³C urea breath test, which showed H. pylori eradication in 90.8% of patients in the LAE group, compared to 76.9% of those in the CAE group (P < 0.01; NNT = 7). In our experience the eradication rate was unrelated to the baseline characteristics of the patients and their underlying gastro-duodenal disease[52].

However, subsequent trials, mainly conducted in Spain and Asia, did not confirm our remarkable results. In effect, almost all recent papers coming from Spain, Northern Africa, and Asia highlighted that the rate of H. pylori eradication achieved by means of levofloxacin-based triple protocols is less noteworthy than expected (about 85%), probably as a result of the increased rate of H. pylori resistance to fluoroquinolones (Table 2). Indeed, these quite rather inadequate eradication rates are likely to be related to a higher prevalence of levofloxacin resistant H. pylori strains in that particular geographical areas in which the studies were carried out. Furthermore, not only has fluoroquinolone resistance readily increased over the last decade, but regional differences within the same country can be significant; this appears clearly and particularly true for Spain and China[53-66].

Table 2 Randomized controlled trials containing levofloxacin in first-line triple therapy of Helicobacter pylori.

Ref.	Year	Nation	Patients	Therapy	Posology	Duration	Comparator	ITT
Shah et al[53]	2013	India	131	LTE	500	7		85.0%
Qian et al[54]	2012	China	345	LAE	500	7	SEQ-L	78.1%
Cuadrado-Lavín et al[61]	2012	Spain	250	LAO	500	10	CAO	82.8%
Pan et al[62]	2010	China	199	LAE	500	7	NAR	87.1%
Chen et al[63]	2010	Taiwan	189	LCE	500	7	CAE	78.9%
Assem et al[64]	2010	Egypt	450	LAE	500	7	CLE/CAE	84.7%
Erçin et al[65]	2010	Turkey	91	LAL	500	14	LAL (7)	72.0%
Liou et al[66]	2010	Taiwan	432	LAL	500	7	CAL	74.0%
Chen et al[63]	2010	China	300	LAL	500	7	CAL	74.0%
Molina-Infante et al[69]	2010	Spain	460	LAO	500	10	SEQ-L	82.6%
Castro-Fernández et al[59]	2009	Spain	135	LAO	500	10		71.8%
Gisbert et al[55]	2007	Spain	64	LARBIS	500	10		84.4%
Rispo et al[52]	2007	Italy	130	LAE	500	7	CAE	90.8%
Nista et al[51]	2006	Italy	300	CLE	500	7	CME/CAE	87.0%
Lee et al[56]	2006	South Korea	267	LAE	500	7	CAE	69.8%
Cammarota[50]	2004	Italy	100	CLR	500	7	CLR (250)	84.0%

LTE: Levofloxacin + tinidazole + esomeprazole; LAE: Levofloxacin + amoxicillin + esomeprazole; SEQ-L: Standard sequential therapy or levofloxacin-containing sequential therapy; LAO: Levofloxacin + amoxicillin + omeprazole; CAO: Clarithromycin + amoxicillin + omeprazole; LCE: Levofloxacin + clarithromycin + esomeprazole; CAE: Clarithromycin + amoxicillin + esomeprazole; CLE: Clarithromycin + levofloxacin + esomeprazole; LAL: Levofloxacin + amoxicillin + lansoprazole; CAL: Clarithromycin + amoxicillin + lansoprazole; LARBIS: Levofloxacin + amoxicillin + ranitidine bismuth citrate; CLR: Clarithromycin + levofloxacin + rifabutin; ITT: Intention-to-treat.

More recently, levofloxacin has been effectively used in first-line sequential and quadruple protocols. Romano et al[67] carried out a randomised trial aimed at evaluating the efficacy of a levofloxacin-containing sequential regimen compared to a clarithromycin containing sequential therapy in the eradication of H. pylori infection in patients from Southern Italy, a geographical area with > 15% prevalence of clarithromycin resistance. Eradication rates in these authors’ intention-to-treat analyses were: 80.8% with clarithromycin sequential treatment; 96.0% with levofloxacin-250 sequential treatment; and 96.8% with levofloxacin-500 sequential treatment. The levofloxacin-250 sequential treatment appeared to be cost-saving compared to the clarithromycin sequential therapy. Two years after this study, the same authors performed a non-inferiority randomized trial to determine whether a 5-d treatment course of levofloxacin-containing quadruple concomitant regimen was as safe and effective as the 10-d course of sequential regimen in eradicating H. pylori in previously untreated patients. The intention-to-treat analysis showed similar eradication rates for concomitant (92.2%) and sequential regimens (93.3%). In addition, the authors showed that the concomitant regimen cost $9 less than the sequential one[67,68]. However, once again the remarkable results of using levofloxacin as the first-line eradication drug were not similarly satisfying in different geographical areas. The trials by Molina-Infante et al[69] (Spain) and by Qian et al[54] (China), using a modified levofloxacin-based quadruple sequential protocol, showed an eradication rate of 80%-85%, highlighting once again the importance of geographical differences in terms of H. pylori resistance to antibiotics[70].

We agree with all the experts who emphasise that susceptibility testing may help to identify the most suitable treatment protocol and to therefore use only the antibiotic agent that works well locally.

FLUOROQUINOLONE-BASED PROTOCOLS IN THE SECOND-LINE TREATMENT OF H. PYLORI INFECTION

With regard to the role of fluoroquinolones in H. pylori eradication, current recommendations underline their efficacy as a second-line option, in particular as levofloxacin containing triple therapy. Levofloxacin has been widely used for the rescue treatment of resistant infection, and a meta-analysis by Gisbert et al[34] has highlighted its better efficacy and tolerability profile in the second-line treatment of H. pylori infection compared to the quadruple protocol comprising bismuth. More specifically, this meta-analysis - which included 14 trials with a total of 977 patients - showed that the mean eradication rate with levofloxacin-based regimens was 80%, with 10-d regimens appearing to be more effective than 7-d combinations (81% vs 73%; P < 0.01). The meta-analysis also showed better results with levofloxacin than with the quadruple combination (81% vs 70%; OR = 1.80), and a better safety profile for levofloxacin than for the quadruple regimen, both overall (19% vs 44%) and in terms of severe adverse effects (0.8% vs 8.4%).

More recently, Di Caro et al[71] updated Gisbert et al[72], s meta-analysis by comparing the effectiveness of levofloxacin/amoxicillin-based schemes to that of quadruple regimens for the eradication of H. pylori in second-line treatment. In total, 10 articles and four abstracts were identified; the analysis, including 14 trials with a total of 677 patients, showed an overall eradication rate of 76.5% in the group treated with levofloxacin-amoxicillin and of 67.4% in that treated with quadruple regimen, with a cure rate of 70.6% for 7-d regimens and 88.7% for 10-d combinations. Interestingly, even though the 7-d levofloxacin-amoxicillin and quadruple protocols showed comparable efficacy, the 10-d fluoroquinolone-based regimen was significantly more effective than the quadruple regimen (OR = 0.5). No differences were reported in quadruple protocol-based eradication rates among Asian and European studies, whereas levofloxacin-amoxicillin regimens were more effective in European populations (78.3% vs 67.7%; P = 0.05). The incidence of side effects was lower in the levofloxacin-amoxicillin treatment group than in the quadruple regiment group (OR = 0.39; 95%CI: 0.18-0.85; P = 0.02). Consequently, the meta-analysis supported the use of 10-d levofloxacin-amoxicillin regimens as a second-line treatment for the eradication of H. pylori with excellent tolerability and eradication rates[71].

More recently, Gisbert et al[72] have re-assessed this issue in 100 consecutive patients in whom a non-bismuth quadruple regimen, administered either sequentially (PPI + amoxicillin for 5 d followed by PPI plus clarithromycin plus metronidazole for 5 more days) or concomitantly (PPI plus amoxicillin plus clarithromycin plus metronidazole for 10 d) had previously failed. At the end of the study the per-protocol and intention-to-treat H. pylori eradication rates were 75.5% and 74%. Intention-to-treat eradication rates achieved with levofloxacin in the “sequential” and “concomitant” failed regimen groups were 74.4% and 71.4%, respectively. A rate of H. pylori eradication of approximately 75% obtained using levofloxacin-based triple protocol as a second-line regimen was confirmed also by Manfredi et al[73] in Italy. Furthermore, the efficacy of levofloxacin-based protocols and their value over time were explored by a Spanish multicenter study. The study sample comprised 1000 consecutive patients who had not responded to previous treatment with the standard clarithromycin-based triple protocol. It showed per-protocol and intention-to-treat eradication rates of 75.1% and 73.8%, respectively. The treatment (intention-to-treat) efficacy was 76% in year 2006; 68% in year 2007; 70% in year 2008; 76% in year 2009; 74% in year 2010; and 81% in year 2011, underlying the fact that the efficacy of levofloxacin-based protocols tends to remain stable over time[74].

However, once again, different results in terms of efficacy were reported from Eastern countries. Moon et al[75] evaluated the efficacy and safety of triple therapy with levofloxacin, metronidazole, and lansoprazole as a second-line treatment, compared to those of quadruple therapy. According to the intention-to-treat analysis, the infection was eradicated in 38 of the 56 patients (67.9%) treated with triple therapy and in 48 of the 57 (84.2%) treated with quadruple therapy (P = 0.042). Per-protocol analysis showed successful eradication in 38 of 52 patients (73.1%) from the triple protocol group and 48 of 52 patients (92.3%) from the quadruple protocol group (P = 0.01). Even though the choice of metronidazole instead of amoxicillin could partially explain the results of this study, geographical differences in terms of H. pylori resistance to fluoroquinolones should not be ignored.

More recently, levofloxacin has been used in a non-bismuth quadruple second-line protocol. Calhan et al[76] designed a study aiming to investigate the efficacy of two levofloxacin-containing second-line treatment protocols for H. pylori infection. The patients were randomized consecutively to two treatment groups: 73 patients were assigned to the levofloxacin-containing sequential regimen and 75 to the levofloxacin-containing quadruple regimen group. The first group received pantoprazole 40 mg and amoxicillin 1000 mg twice daily for 5 d followed by pantoprazole 40 mg twice daily and metronidazole 500 mg three times daily and levofloxacin 500 mg once daily for 7 d. The second group received pantoprazole 40 mg twice daily, tetracycline 500 mg four times daily, bismuth subcitrate 300 mg four times daily and levofloxacin 500 mg once daily for 10 d. The intention-to-treat analysis showed eradication rates of 82.2% and 90.6%, respectively, for the two treatment groups, with no statistically significant difference.

On the basis of these studies and findings, the role of levofloxacin (and the modalities of its use) in the second-line treatment of H. pylori infection is well defined by Statement 14 of the Maastricht IV Consensus. According to these recommendations, after failure of a PPI- and clarithromycin-containing treatment, either a bismuth-containing quadruple protocol or a levofloxacin-containing triple protocol is recommended, although the rising rates of levofloxacin resistance should be taken into account.

FLUOROQUINOLONE-BASED PROTOCOLS IN THE THIRD-LINE TREATMENT OF H. PYLORI INFECTION

The Maastricht IV consensus clearly states that after failure of second-line treatment, the therapeutic approach should be guided by antimicrobial susceptibility testing whenever possible. The work by Cammarota et al[77] assessed the efficacy of a third-line, culture-guided treatment approach for the eradication of H. pylori infection. Patterns of resistance to antibiotics were analysed in H. pylori isolates from 94 consecutive patients in whom the infection had persisted after two eradication protocols. Using the E-test, susceptibility analysis was performed for amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin. Patients were then treated with a culture-guided, third-line regimen: 89 patients with a 1-wk quadruple regimen including omeprazole, bismuth, doxycycline and amoxicillin, and 5 patients with a 1-wk triple regimen containing omeprazole, amoxicillin and levofloxacin or clarithromycin. The study showed that 94 patients (100%) were resistant to metronidazole, 89 (95%) to clarithromycin, 29 (31%) to levofloxacin and 5 (5%) to tetracycline. No resistance to amoxicillin was found. The overall eradication rate was 90%. The quadruple regimen was effective in 91% of patients (ITT). Four patients (80%, both per protocol and intention-to-treat analyses) were H. pylori negative after the triple regimen.

Regrettably, antimicrobial susceptibility testing is not widely and promptly available, being performed almost exclusively at third-level centres. In view of these limitations, a number of studies have assessed the effectiveness of empirical third-line H. pylori eradicating protocols, which frequently included levofloxacin. Gisbert et al[78] reported on a prospective multicentre study which focused on this type of treatment. The authors included in their study 100 patients for whom a first treatment with omeprazole-clarithromycin-amoxicillin and a second with omeprazole-bismuth-tetracycline-metronidazole (or ranitidine bismuth citrate with these antibiotics) had failed in eradicating the H. pylori infection. These patients were treated with a 10-d third-line eradication protocol comprising levofloxacin (500 mg bid), amoxicillin (1 g bid), and omeprazole (20 mg bid). Per-protocol and intention-to-treat eradication rates were 66% and 60%, respectively. A prospective study carried out in Spain evaluated the efficacy of different “rescue” treatments empirically prescribed over the course of 10 years to 500 (consecutive) patients for whom at least one eradication regimen had failed to cure the H. pylori infection. The ‘rescue’ regimens included: quadruple therapy with omeprazole-bismuth-tetracycline-metronidazole; ranitidine bismuth citrate-tetracycline-metronidazole; omeprazole-amoxicillin-levofloxacin; and omeprazole-amoxicillin-rifabutin. Antibiotic susceptibility was unknown (rescue regimens were chosen empirically). Overall, H. pylori eradication rates with the second-, third- (mostly levofloxacin-based), and fourth-line rescue regimens were 70%, 74%, and 76%, respectively. Cumulative H. pylori eradication rate with four successive treatments was 99.5%[32].

A levofloxacin-based third-line H. pylori eradicating protocol was also compared to the rescue treatment based on rifabutin. Forty patients were randomised to receive a 10-d treatment course with either rifabutin (150 mg b.d.) or levofloxacin (500 mg b.d.), plus amoxicillin (1 g b.d.) and omeprazole (20 mg b.d.). At the end of the study, per-protocol eradication rates were 45% in the rifabutin group and 81% in the levofloxacin group (P < 0.05). Intention-to-treat eradication rates were 45% and 85%, respectively (P < 0.01)[79]. However, bearing in mind the efficacy of levofloxacin compared to rifabutin, regional differences in H. pylori resistance to antibiotics should be carefully considered. A study by Jeong et al[80] from South Korea compared rifabutin and levofloxacin rescue regimens in patients with first- and second-line H. pylori eradication failures. These patients received treatment with either rifabutin or levofloxacin, plus amoxicillin (1 g b.d) and standard dose PPI. Eradication rates were 71.4% in the rifabutin group, and 57.1% in the levofloxacin group. Although there was no significant difference in H. pylori eradication rates between the two groups (P = 0.656), the rifabutin based regimen showed a relatively higher eradication rate in that geographical region. Once again the choice of antibiotics should be based on available data on regional H. pylori antibiotic resistance and susceptibility.

CONCLUSION

Even the most effective regimens for the treatment of H. pylori infection are likely to fail to eradicate H. pylori in more than 20% of affected patients. At present, clinicians need to have solid up-to-date knowledge of the first-line eradication regimens - including the more recent quadruple and sequential (bismuth-including or not) protocols - and to be prepared to face treatment failures.

The treatment strategies for the eradication of H. pylori have been enriched by the use and diffusion of fluoroquinolones, an effective and safe option in eradicating H. pylori infection. However, as highlighted in the current review and in accordance with the Maastricht IV consensus, the choice of a first or “rescue” treatment based on fluoroquinolones should be based on regional H. pylori antibiotic resistance. It follows that clinicians should be aware of the prevalence of H. pylori drug resistance in the geographical area in which they operate. As for second and third line protocols, another crucial variable for the selection of the right drugs is the accurate assessment of the treatment/s that was/were previously used.

In summary, current H. pylori eradication guidelines recommend the prescription of levofloxacin (a fluoroquinolone) as part of a sequential treatment or a non-bismuth quadruple treatment in first-line eradication protocols in counties where bismuth-based regimens are not easily available. With regard to second-line treatment regimens, levofloxacin-based protocols constitute an encouraging strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure and offering the advantages of efficacy, simplicity, and safety. Finally, with regards to third-line and “rescue” protocols, the antibiotic choice should be guided by antimicrobial susceptibility testing irrespective of the efficacy of levofloxacin in the empirical eradication strategies. This appears to be the most sensible and effective treatment option[81-83].

ACKNOWLEDGMENTS

Many thanks to Giovanna Affinito, our endoscopy nurse, for her precious help and contribution.