Fourth-line rescue therapy with rifabutin in patients with three Helicobacter pylori eradication failures

Authors

  • J. P. Gisbert,

    Corresponding author
    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
    • Gastroenterology Department, Hospital de La Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • M. Castro-Fernandez,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
    2. Gastroenterology Department, Hospital de Valme, Sevilla, Spain
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  • A. Perez-Aisa,

    1. Gastroenterology Department, Agencia Sanitaria Costa del Sol, Málaga, Spain
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  • A. Cosme,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
    2. Gastroenterology Department, Hospital de Donostia, San Sebastián, Spain
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  • J. Molina-Infante,

    1. Gastroenterology Department, Hospital de San Pedro de Alcántara, Cáceres, Spain
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  • L. Rodrigo,

    1. Gastroenterology Department, Hospital Central de Asturias, Oviedo, Spain
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  • I. Modolell,

    1. Gastroenterology Department, Consorci Sanitari de Terassa, Barcelona, Spain
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  • J. L. Cabriada,

    1. Gastroenterology Department, Hospital de Galdakao, Vizcaya, Spain
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  • J. L. Gisbert,

    1. Gastroenterology Department, Hospital de La Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • E. Lamas,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
    2. Gastroenterology Department, Hospital de Valme, Sevilla, Spain
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  • E. Marcos,

    1. Gastroenterology Department, Hospital de La Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain
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  • X. Calvet,

    1. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain
    2. Gastroenterology Department, Hospital de Sabadell, Barcelona, Spain
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  • on behalf of the H. pylori Study Group of the Asociación Española de Gastroenterología (Spanish Gastroenterology Association)


Correspondence to:

Prof. J. P. Gisbert, Playa de Mojácar 29, Urb. Bonanza, 28669 Boadilla del Monte, Madrid, Spain.

E-mail: gisbert@meditex.es

Summary

Background

In some cases, Helicobacter pylori infection persists even after three eradication treatments.

Aim

To evaluate the efficacy of an empirical fourth-line rescue regimen with rifabutin in patients with three eradication failures.

Methods

Design: Multicentre, prospective study. Patients: In whom the following three treatments had consecutively failed: first (PPI + clarithromycin + amoxicillin); second (PPI + bismuth + tetracycline + metronidazole); third (PPI + amoxicillin + levofloxacin). Intervention: A fourth regimen with rifabutin (150 mg b.d.), amoxicillin (1 g b.d.) and a PPI (standard dose b.d.) was prescribed for 10 days. Outcome: Eradication was confirmed by 13C-urea breath test 4–8 weeks after therapy. Compliance and tolerance: Compliance was determined through questioning and recovery of empty medication envelopes. Adverse effects were evaluated using a questionnaire.

Results

One-hundred patients (mean age 50 years, 39% men, 31% peptic ulcer/69% functional dyspepsia) were included. Eight patients did not take the medication correctly (in six cases due to adverse effects). Per-protocol and intention-to-treat eradication rates were 52% (95% CI = 41–63%) and 50% (40–60%). Adverse effects were reported in 30 (30%) patients: nausea/vomiting (13 patients), asthenia/anorexia (8), abdominal pain (7), diarrhoea (5), fever (4), metallic taste (4), myalgia (4), hypertransaminasemia (2), leucopenia (<1,500 neutrophils) (2), thrombopenia (<150 000 platelets) (2), headache (1) and aphthous stomatitis (1). Myelotoxicity resolved spontaneously in all cases.

Conclusions

Even after three previous H. pylori eradication failures, an empirical fourth-line rescue treatment with rifabutin may be effective in approximately 50% of the cases. Therefore, rifabutin-based rescue therapy constitutes a valid strategy after multiple previous eradication failures with key antibiotics, such as clarithromycin, metronidazole, tetracycline and levofloxacin.

Introduction

Helicobacter pylori infects approximately 50% of the adult population and is associated with a wide range of upper gastrointestinal diseases including gastritis, peptic ulcer disease and gastric cancer.[1] After almost 30 years of experience in H. pylori treatment, however, the ideal regimen to treat this infection has yet to be found. Thus, even with the currently recommended first-line treatment regimens, including a proton pump inhibitor (PPI) plus two antibiotics, ≥20% of patients will fail to eradicate the infection.[2] A ‘rescue’ therapy with a bismuth-containing quadruple combination has been recommended.[3] However, it still fails to eradicate H. pylori in approximately 20–30% of the patients.[2]

Currently, a standard third-line therapy is lacking, and European guidelines recommend performing culture in these patients to select a third-line treatment according to a microbial sensitivity to antibiotics,[3] but this strategy is currently not practical.[4, 5] Therefore, the evaluation of drugs without cross-resistance to nitroimidazole or macrolides as components of re-treatment combination therapies seems to be worthwhile. Recently, some studies have evaluated the efficacy of new fluoroquinolones, such as levofloxacin, which could prove to be a valid alternative to standard antibiotics.[6] In few cases, however, H. pylori infection persists even after three eradication treatments and these patients constitute a therapeutic dilemma.[7]

Rifabutin is a rifamycin-S derivative, which is commonly used to treat Mycobacterium avium-intracellulare complex in human immunodeficiency virus (HIV)-infected patients.[8] This antibiotic has potential utility against H. pylori because the in vitro sensitivity is high.[9-12] The in vitro MIC of rifabutin against H. pylori was 0.004–0.008 μg/mL,[10, 13, 14] a value that was four, six and 50 times lower than that found for amoxicillin, clarithromycin and metronidazole respectively.[13, 14] Furthermore, rifabutin does not share resistance to clarithromycin, and the selection of resistant H. pylori strains has been low in experimental conditions.[15] Consequently, rifabutin-based rescue therapies represent a potential strategy for eradication failures.[8] However, the experience with this drug in H. pylori treatment is still very limited.

Therefore, the aim of the present study was to evaluate the efficacy of an empirical fourth-line rescue regimen with rifabutin in patients with three eradication failures.

Patients and Methods

Patients

This was a prospective multicentre study involving nine Spanish hospitals, including consecutive patients for whom the following three treatments had consecutively failed to eradicate H. pylori infection: first treatment with a PPI, clarithromycin and amoxicillin; second treatment with a quadruple regimen with a PPI, bismuth, tetracycline and metronidazole; and third treatment with a PPI, amoxicillin and levofloxacin. H. pylori eradication failure with first-, second-, and third-line regimens was defined by a positive 13C-urea breath test 4–8 weeks after completion of treatment. The exclusion criteria were as follows: (i) age under 18 years, (ii) presence of clinically significant associated conditions (neoplastic diseases, coagulation disorders, and hepatic, cardiorespiratory, or renal diseases), (iii) previous gastric surgery and (iv) allergy to any of drugs used in the study. The protocol was approved by the local ethics committee, and informed consent was obtained from all the patients.

Therapy

A fourth eradication regimen with rifabutin (150 mg b.d.), amoxicillin (1 g b.d.) and a PPI (standard dose b.d.) was prescribed for 10 days. All drugs were administered together after breakfast and dinner. Patients were informed of potential side effects (mainly metallic taste, nausea, and diarrhoea) during the treatment period. Compliance with therapy was defined as intake of 100% of the medication prescribed and was determined by a questionnaire and recovery of empty medication envelopes (both performed by the same gastroenterology responsible for treating the patient). The incidence of adverse effects was evaluated using a specific questionnaire. Adverse effects were classified as mild, moderate, or severe depending on the intensity.

Diagnostic methods to confirm eradication

Eradication of H. pylori was defined by a negative 13C-urea breath test result (with citric acid and 100 mg of urea, using a previously reported protocol[16]) performed 4–8 weeks after completion of re-treatment. The test was carried out by nurses who were unaware of the therapy administered and the patients’ H. pylori status. As endoscopy – and consequent culture – was not performed after therapy, antibiotic susceptibility was unknown and, as such, the eradication regimen was chosen empirically.

Analytical control

As leucopenia and trombocytopenia have been reported after treatment with rifabutin, serum samples were obtained in all patients before and after completing treatment to exclude myelotoxicity.

Statistical analysis

The 95% CI was calculated for categorical variables and the mean ± standard deviation for quantitative variables. Analysis of the efficacy of H. pylori eradication was performed on an intention-to-treat basis (including all eligible patients enrolled in the study regardless of compliance with the study protocol; patients with unevaluable data were assumed to have been unsuccessfully treated) and on a per-protocol basis (excluding patients whose compliance with therapy was poor and patients with unevaluable data after therapy). Sample size was predetermined taking the following parameters into consideration: epsilon = ±10%; p1 (initial estimate) of efficacy of H. pylori treatment = 50%; confidence level = 0.95%. A sample size of 97 patients was necessary. As the probability of loss to follow-up was estimated at around 5%, the final size of the sample was approximately 100 patients.

Results

Demographic variables

One-hundred patients were included in the study, 31 with peptic ulcer disease and 69 with uninvestigated or functional dyspepsia. Mean age ± standard deviation was 50 ± 13 years, 39% were men, and 31% were smokers.

Compliance with the protocol and loss to follow-up

All patients returned for their follow-up visit (no patient was lost to follow-up). All but eight (8%) patients complied with the protocol (that is, reported that they took 100% of the prescribed medication). Of those who did not comply, six were due to adverse effects. A CONSORT flow diagram of subjects’ progress through the phases of the study is shown in Figure 1.

Figure 1.

CONSORT flow diagram of subjects’ progress through the phases of the study.

Tolerance to eradication therapy

Adverse effects were reported in 30/100 (30%) patients: nausea/vomiting (13%), asthenia/anorexia (8%), abdominal pain (7%), diarrhoea (5%), fever (4%), metallic taste (4%), myalgia (4%), hypertransaminasemia (2%), leucopenia (<1500 neutrophils) (2%), thrombopenia (<150 000 platelets) (2%), headache (1%) and aphthous stomatitis (1%). In most cases, symptoms were only present while the patient was taking medication. Myelotoxicity resolved spontaneously, in few days, in all cases. In 5% (5/100) of the cases, adverse effects were classified as severe (based on the intensity), and included nausea (2%), vomiting (2%) and myalgia (1%).

Efficacy of eradication therapy

Per-protocol eradication was achieved in 52% (48/92; 95% CI, 41–63%) of the patients, while intention-to-treat eradication rate was 50% (50/100; 95% CI, 40–60%). Cure rates were similar in patients with peptic ulcer disease and in those with uninvestigated or functional dyspepsia [intention-to-treat eradication rate of 52% (16/31) and 49% (34/69) respectively].

Discussion

Nowadays, apart from having a good understanding of the first-line eradication regimens, we must also be prepared to face H. pylori treatment failures. Bismuth-containing quadruple therapy has generally been used as the optimal second-line therapy after PPI-clarithromycin-amoxicillin failure.[2] A levofloxacin-containing triple regimen is an encouraging third-line alternative after two previous H. pylori eradication failures.[17] In few cases, however, H. pylori infection persists even after three eradication treatments, and these patients constitute a therapeutic dilemma.[7]

Our results with the combination of rifabutin, amoxicillin and a PPI for 10 days, with a cure rate of ≥50%, are relatively encouraging, especially when it is taken into account that this rescue regimen was prescribed after three eradication failures with key antibiotics such as clarithromycin, metronidazole, tetracycline and levofloxacin.

Other authors have also reported encouraging experience with rifabutin. In a recent systematic review, data on the efficacy of rifabutin-containing regimens on H. pylori eradication were combined and meta-analysed.[8] Overall, mean H. pylori eradication rate (intention-to-treat analysis) was 73%. Until now, only seven studies have evaluated the rifabutin regimen in patients in whom three (or more) eradication regimens have previously failed, with a mean cure rate of 70% (Table 1).[18-24]

Table 1. Rifabutin-containing therapies for the eradication of H. pylori in patients in whom three (or more) eradication treatments have failed
AuthorYearCountryDrugs and dosesDuration of treatment (days)Number of patientsNumber of previously failed treatmentsType of previous treatmentsEradication ratea (%)
  1. PPI, proton pump inhibitor; Type of previous treatments: (1) indicates first-line treatment, (2) indicates second-line treatment and (3) indicates third-line treatment; Tx, treatments; C, clarithromycin; A, amoxicillin; Q, quadruple therapy (PPI, bismuth, tetracycline and nitroimidazole); RBC, ranitidine bismuth citrate; T, tetracycline; M, metronidazole; L, levofloxacin.

  2. a

    Intention-to-treat analysis.

  3. b

    Patients infected with H. pylori resistant to both clarithromycin and metronidazole/tinidazole, and susceptible to rifabutin.

Bock et al.[18]2000GermanyRifabutin 150 mg/12 h723PPI + A- and C- containing tx100
Amoxicillin 1 g/12 h     
Lansoprazole 30 mg/12 h     
Canducci et al.[19]2001ItalyRifabutin 300 mg/24 h1010≥370
Amoxicillin 1 g/12 h     
Omeprazole 20 mg/12 h     
Gisbert et al.[20]2008SpainRifabutin 150 mg/12 h 10–1473(1) PPI + C + A71
Amoxicillin 1 g/12 h   (2) Q, RBC + T + M 
Omeprazole 20 mg/12 h   (3) O + A + L 
Miehlke et al.[21]b2008GermanyRifabutin 300 mg/24 h 7173PPI + A, PPI + C, 69
Moxifloxacin 400 mg/24 h    PPI + C + A, PPI + C + M, Q, 
Esomeprazole 40 mg/24 h   PPI + A + L 
Miehlke et al.[21]b2008GermanyRifabutin 300 mg/24 h710≥4PPI + A, PPI + C, 89
Moxifloxacin 400 mg/24 h   PPI + C + A, PPI + C + M, Q, 
Esomeprazole 40 mg/24 h   PPI + A + L 
Perri et al.[22]2000ItalyRifabutin 300 mg/24 h716≥3(1) PPI + C + A56
Amoxicillin 1 g/12 h   (2) PPI + C + A, PPI + C + M, PPI + C + T 
Pantoprazole 40 mg/12 h   (3/4) PPI + A, PPI + C + M, PPI + A + T, PPI + C + T, RBC + A + T, RBC + C, Q 
Van der Poorten et al.[23]2007AustraliaRifabutin 150 mg/12 h1031≥3(1) C-containing tx62
Amoxicillin 1 g/12 h   (2) Q (42% of the cases) 
PPI/12 h   (3) Others 
Van Zanten et al.[24]2010CanadaRifabutin 300 mg/24 h723(1) PPI + C + A, Q50
Amoxicillin 1 g/12 h   (2) PPI + A, PPI + C + M 
PPI/12 h   (3) PPI + C + A 

However, the sample size of the individual studies included in Table 1 was remarkably low, with only 95 in total when all studies were considered (the study with the highest number of patients included 31 patients). Thus, to the best of our knowledge, our study, with 100 patients, is the largest to evaluate a rifabutin-containing regimen, not only overall but also specifically in patients with three or more previous eradication failures. Moreover, with an estimated efficacy of 80% with our first-line regimen (PPI, clarithromycin, amoxicillin), 75% with our second-line treatment (PPI, bismuth, tetracycline, and metronidazole) and 70% with our third-line treatment (PPI, levofloxacin, amoxicillin), it was necessary to initially include and treat almost 7000 patients to obtain the final sample size of 100 patients that constitutes our fourth-line study population.

Given the low frequency of rifabutin use in the general population, the likelihood of H. pylori resistance is low. A recent systematic review of studies on primary H. pylori antibiotic resistance published from 2006 to 2009 demonstrated that the prevalence rate of rifabutin resistance was as low as 1.4%, but only two studies were included in the analysis.[25] Another systematic review published in 2011 calculated a mean H. pylori rifabutin resistance rate of only 1.3%.[8] Furthermore, when only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%).[8] On the other hand, rifabutin therapy is highly effective when applied in H. pylori infection with primary resistance to clarithromycin or metronidazole (and even in patients with double resistance).[18, 26-31] Finally, H. pylori resistance to amoxicillin is extremely rare.[15] Therefore, we believe that rifabutin (together with a PPI and amoxicillin) can be administered as a rescue treatment without the need for a prior antibiogram. In this respect, our study underlines the fact that a wider perspective of the benefits of re-treating H. pylori infection can be obtained if cumulative eradication rates and not only absolute figures with successive re-treatments are taken into account. For example, with an estimated efficacy of 80%, 75%, 70% and 50% (the figure reported in our study), respectively with first-, second-, third- and fourth-line regimens, H. pylori eradication can finally be achieved in more than 99% of the patients. Nevertheless, it would be desirable to have regularly updated, reliable information on the prevalence of antibiotic H. pylori resistance from several countries, regions, or healthcare areas, so that the potentially most effective eradicating regimen could be assessed on an individual basis.[32]

For treating H. pylori infection, almost all studies, including ours, have administered rifabutin 300 mg/day. There is only one study directly comparing 300 mg/day vs. 150 mg/day, demonstrating that the highest dose is the most effective.[33] The ideal length of treatment for the rifabutin regimen remains unclear. In some reports, a 7-day course has been equally efficacious than 10 to 14 day regimens, while others have found that this shorter duration dramatically reduced the efficacy with eradication rates.[34] In the previously mentioned systematic review, better results were observed with 10–12 days than with 7 days.[8] Finally, therapy between 12 and 14 days has yielded results similar to the 10-day course and is likely to increase the incidence of adverse events.[23] In summary, the ideal length of treatment for rifabutin regimen remains unclear, but 10- to 12-day regimens are generally recommended.

The mean rate of adverse effects to rifabutin treatment in H. pylori studies has been approximately 20%.[8] In our study, this incidence was reported to be somewhat higher (30%), but in most cases, symptoms were mild and only present while the patient was taking medication. Myelotoxicity is the most significant adverse event of rifabutin, and several cases of this complication have been reported during H. pylori therapy.[19, 22, 23, 28, 29, 35, 36] In those studies reporting this complication, myelotoxicity was observed in 1.5–3% of the patients,[23, 28, 29, 35] which coincides with the 2% complication rate reported in our study. Nevertheless, in some (exceptional) studies, the incidence of myelotoxicity has been higher: 10%[19] or even 25%.[36] This complication is far more likely when high dose (600 mg⁄day) and prolonged duration therapy is used,[37, 38] which is not the case for H. pylori eradication regimens. Until now, all patients have recovered uneventfully in a few days, with spontaneous recovery of leucopenia, although it took 15 days to normalise white cell count after rifabutin discontinuation in one case.[19] Accordingly, myelotoxicity resolved spontaneously, in a few days, in our two cases. There have been no reports of infection or other adverse outcome related to reduced white cell count in the setting of H. pylori treatment.[19, 22, 23, 28, 29, 35, 36] Thus, it has been suggested that the clinical significance of minor reductions in leucocyte count such as reported by others may be overestimated.[23] Nevertheless, it has been recommended to perform systematic blood controls in all patients receiving rifabutin, despite they being asymptomatic,[39] as we have done in our study.

Despite its relatively high efficacy, several concerns still remain regarding rifabutin treatment for H. pylori infection. First, this drug is extremely expensive. Secondly, there is some concern about a widespread use of rifabutin, a member of a class of established antimycobacterial drugs, in patients with H. pylori infection. As multiresistant strains of Mycobacterium tuberculosis increase in numbers, indications for these drugs should be chosen very carefully to avoid further acceleration of development of resistance.[18] At present, therefore, rifabutin should be restricted to patients where previous (multiple) eradication regimens have failed. Thus, it may be suggested that the position of rifabutin in the algorithm of H. pylori treatment may be at a fourth-line rescue regimen.[8] Using this strategy, the drug will be administered to a very small group of selected patients, thus minimising the likelihood of increasing the resistances to this antibiotic.

In addition, although an argument raised consistently against the wider use of rifabutin is the concern regarding propagation of resistance, especially in mycobacterial species, it should be taken into account that the major use of rifabutin is for treatment of tuberculosis and other mycobacteria, especially in the setting of immunodeficiency or HIV infection.[23] Acquired rifabutin resistance has been noted in these cohorts, but only when associated with CD4 counts <100 cells/mm[3] and when intermittent dosing is used.[40] Even in the setting of prolonged tuberculosis treatment, continuous daily rifabutin has led to negligible rates of resistance.[40, 41] Moreover, no reports as yet have definitively linked rifabutin resistance with short-course treatment of rifabutin for H. pylori or other nonmycobacterial indications.[11, 23]

In summary, this study shows that even after three previous H. pylori eradication failures – a very complicated setting – an empirical rescue treatment with rifabutin may be effective in approximately 50% of the cases. Therefore, rifabutin-based rescue therapy constitutes a valid strategy after multiple previous eradication failures with major key antibiotics such as clarithromycin, metronidazole, tetracycline and levofloxacin.

Acknowledgement

Declaration of personal and funding interests: None.

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