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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Aliment Pharmacol Ther 2012; 35: 209–221

Summary

Background  Even with the current most effective treatment regimens, a relevant proportion of patients will fail to eradicate Helicobacter pylori infection.

Aim  To evaluate the role of rifabutin in the treatment of H. pylori infection.

Methods  Bibliographical searches were performed in MEDLINE. Data on the efficacy of rifabutin-containing regimens on H. pylori eradication were combined and meta-analysed using the generic inverse variance method.

Results  Rifabutin shows good in vitro activity against H. pylori. Mean H. pylori rifabutin resistance rate (calculated from 11 studies including 2982 patients) was 1.3% (95% confidence interval = 0.9–1.7%). When only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%). On the other hand, higher values of rifabutin resistance were calculated (1.59%) when only post-treatment patients were considered. Overall, mean H. pylori eradication rate (intention-to-treat analysis) with rifabutin-containing regimens (1008 patients) was 73% (67–79%). Respective cure rates for second-line (223 patients), third-line (342 patients) and fourth/fifth-line (95 patients) rifabutin therapies were 79% (67–92%), 66% (55–77%) and 70% (60–79%) respectively. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment remains unclear, but 10- to 12-day regimens are generally recommended. The mean rate of adverse effects was 22% (19–25%). Myelotoxicity is the most significant, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in a few days, and there have been no reports of infection or other adverse outcomes related to it.

Conclusion  Rifabutin-containing rescue therapy constitutes an encouraging strategy after multiple (usually three) previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

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. The most widely recommended approach for the eradication of H. pylori is the so-called standard, or proton pump inhibitor (PPI)–based, triple therapy.2–5 Even with the current standard triple treatment regimens, >20% of patients will fail to eradicate the infection and remain H. pylori positive.6, 7

Antibiotic resistance is probably the primary cause of therapeutic failure in patients with infectious diseases, particularly H. pylori infection.8–11 During the last two decades, widespread use of certain antibiotics (e.g. clarithromycin for respiratory infections) in the general population has led to an increase in primary H. pylori resistance. Consequently, the efficacy of standard triple therapy has progressively declined to unacceptable levels.12 For example, two recent large double-blind, multicentre studies performed in the United States both found disappointingly low eradication rates (77%) with standard triple therapy,13, 14 and two meta-analyses including more than 53 000 patients revealed the cure rate to be below 80%.15, 16

Bismuth-containing quadruple therapy (a PPI, bismuth, tetracycline and metronidazole) has been generally used as the optimal second-line therapy after standard triple therapy failure, and has been the recommended rescue regimen in most guidelines.2–5 Nevertheless, this rescue regimen still fails to eradicate H. pylori infection in approximately 20–30% of the cases, and these patients constitute a therapeutic dilemma.6, 7 Thus, patients who are not cured with these consecutive treatments including clarithromycin and nitroimidazoles will have at least single, and usually double, antibiotic resistance, and no logical empirical (third) treatment remains thereafter.11, 17

In designing a treatment strategy, we should not focus on the results of primary therapy alone; an adequate strategy for treating this infection should use several therapies which, if used consecutively, come as close to the 100% cure rate as possible.18 Therefore, the evaluation of drugs without cross-resistance to nitroimidazole or macrolides as components of re-treatment combination therapies seems to be worthwhile.11, 17, 19, 20

Rifabutin is a rifamycin-S derivative, which is commonly used to treat Mycobacterium avium and Mycobacterium intracellulare, also referred to as Mycobacterium avium-intracellulare complex (MAC) in human immunodeficiency virus (HIV)-infected patients.21 This antibiotic has potential utility against H. pylori because the in vitro sensitivity is high and it does not share resistance to clarithromycin.11, 17 Furthermore, the selection of resistant H. pylori strains has been low in experimental conditions. Consequently, rifabutin-based rescue therapies represent a potential strategy for eradication failures.

The aim of this study was to evaluate the role of rifabutin in the treatment of H. pylori infection. We will review the following aspects: (i) Rifabutin’s general antimicrobial activity. (ii) Pharmacokinetics and pharmacodynamics of rifabutin. (iii) Mechanisms of action of rifabutin against H. pylori. (iv) In vitro antimicrobial activity of rifabutin against H. pylori. (v) Resistance of H. pylori to rifabutin. (vi) Efficacy of rifabutin for H. pylori eradication. (vii) Dosage of rifabutin in H. pylori eradication regimens. (viii) Duration of rifabutin treatment for H. pylori infection. (ix) The necessity of H. pylori culture before administering rifabutin. (x) Tolerability of rifabutin. (xi) Concerns and limitations of rifabutin treatment for H. pylori infection and (xii) Indications of rifabutin treatment for H. pylori infection in clinical practice.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Bibliographical searches were performed in MEDLINE up to May 2011 using the following keywords (all fields): (‘Helicobacter pylori’ or ‘H. pylori’) and rifabutin. Articles published in any language were included. Reference lists from the trials selected in the electronic search were hand-searched to identify further relevant trials. Abstracts of the articles selected in each of these multiple searches were reviewed, and those meeting the inclusion criteria were selected. References from reviews on H. pylori treatment and from the works selected for the study were also examined to identify articles meeting the inclusion criteria, that is, dealing with the effect of rifabutin on H. pylori infection.

The variables extracted for each study evaluating the efficacy of rifabutin-containing treatment were as follows: author, year of publication, country, therapy regimen (drugs and doses), duration of treatment, number of patients included, number of previous failed treatments, and type of previous treatments, eradication rate and rate of adverse events.

The outcome of interest was the successful eradication of H. pylori at least four weeks after completion of treatment, as assessed by at least one reliable method (that is, histology or urea breath test); studies that used only serology testing for the detection of H. pylori were excluded.

Analysis of H. pylori eradication efficacy was considered 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).

Subanalyses of the data were performed by duration of therapy (7, 10 or 14 days), rifabutin dose (150 mg or 300 mg/day) and number of previous failed treatments (1, 2, 3 or ≥4).

Data on the efficacy of rifabutin-containing regimens on H. pylori eradication were combined using the generic inverse variance method, which involves a weighted average of the effect estimates from the individual studies. The weight for each study is taken to be the inverse of the variance (one divided by the square of the standard error) of the effect estimate. The meta-analysis was performed using Review Manager, developed by the Cochrane Collaboration. If the results were homogeneous, a fixed-effect model was used, and if the results were heterogeneous (I2 > 50%), a random-effect model (DerSimonian and Laird) was applied.

Rifabutin’s general antimicrobial activity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Rifabutin is structurally related to and shares many of the properties of rifampin (rifampicin).22 Rifabutin has a broad spectrum of antimicrobial activity; this includes activity against mycobacteria, a variety of gram-positive and gram-negative bacteria, Chlamydia trachomatis and Toxoplasma gondii. It is active against Mycobacterium tuberculosis, Mycobacterium leprae, and atypical mycobacteria, including the MAC.22

Rifabutin is generally more active in vitro than rifampicin against rifampicin-susceptible isolates of M. tuberculosis. It is also active against some rifampicin-resistant isolates, although there is substantial cross-resistance in vitro between the two drugs.23 Rifabutin and rifampicin exhibit similar activity against Staphylococcus aureus, Haemophilus ducreyi and Chlamydia trachomatis.23

Pharmacokinetics and pharmacodynamics of rifabutin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Rifabutin is a highly lipid-soluble compound with a pKa of 6.9, is well absorbed when given orally, and exhibits high tissue to plasma ratios.22 High concentrations of the drug are attained in all tissues, particularly those of the liver and lung.22 Furthermore, rifabutin has high penetrance into neutrophils, lymphocytes, macrophages and the central nervous system.22, 24

Rifabutin is chemically stable at a wide pH range and its antibacterial activity is likely not to be hampered by the acidic environment of the stomach.22, 24, 25 In one in vivo study performed in rats, the concentrations of rifabutin in gastric juice were 10–17 times higher than in blood, indicating extensive secretion into the stomach.26

Oral administration of single doses of rifabutin 300–900 mg to patients with HIV infection resulted in mean maximum plasma concentrations of 0.37–0.9 mg/L.23 Mean absolute bioavailability is about 20% after a single dose.23 When rifabutin is administered with food, its absorption is delayed, but not decreased.23 The apparent volume of distribution is about 8–9 L/kg, and the extent of binding to plasma proteins varies between 71% and 94%.23

Rifabutin is extensively metabolised.23, 27 The two major metabolites of rifabutin contribute to its antimicrobial activity.27 The reported mean plasma elimination half-life varies between individuals and studies, ranging from 32 h to 67 h.23 Although the pharmacokinetic properties of rifabutin are influenced by hepatic and renal impairment, dosage alteration is probably required only in patients with severe renal or hepatic dysfunction.23 Rifabutin metabolism in liver microsomes may be inhibited by clarithromycin.28 Thus, the coadministration of clarithromycin and rifabutin results in increased plasma concentrations of rifabutin.27

Mechanism of action of rifabutin against H. pylori

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The mechanism of action of rifabutin against H. pylori has recently been recognised. As occurring in strains of Escherichia coli and Bacillus subtilis, rifabutin inhibits the β-subunit of H. pylori DNA-dependent RNA polymerase encoded by the rpoB gene.29 Laboratory mutants of H. pylori, which are obtained after multiple serial passages in vitro and exhibit amino acid exchanges in codons 524–545 or in codon 585 of the rpoB gene, are resistant to rifabutin.29, 30

Some studies clearly showed that past rifampicin usage is strongly linked to high minimal inhibitory concentrations (MICs) of rifabutin and the prevalence of point mutations in rpoB gene, suggesting a cross-resistance between both antibiotics.31 Therefore, although rifabutin is a potent candidate antibiotic for H. pylori eradication as a rescue option, careful consideration must be given to rifampicin treatment history prior to H. pylori eradication with rifabutin.31

Resistance of H. pylori to rifabutin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The high clinical effectiveness of rifabutin in eradicating H. pylori is likely to be related to the restricted use of this drug in the clinical practice.34 This antimycobacterial drug is generally used to cure or prevent MAC disease in patients with advanced HIV infection, and for this reason, the secondary resistance of H. pylori to rifabutin is likely to be absent in the general healthy population.34

The emergence of the rifabutin resistance occurs very rarely in laboratory H. pylori strains, and only after multiple serial passages in vitro.29 The majority of the rifampicin-resistant strains were isolated from patients after treatment failures, suggesting that previous, unsuccessful attempts of eradication seem to be an important risk factor for the development of rifabutin resistance and/or multiresistance.35, 36 In particular, some reports have documented the (exceptional) possibility of resistance to rifabutin, which was largely explained by previous exposure to this antibiotic.31 However, the efficacy of rifabutin-containing regimens to treat MAC infection appeared to be uninfluenced by prior prophylactic administration of the drug to patients with acquired immune deficiency syndrome (AIDS).23

Recently, Glocker et al.36 assessed the rate of rifampicin resistance in H. pylori, and detected rifampicin resistance-associated mutations. Susceptibility to rifampicin was tested by disc diffusion and/or by the Etest method. The rpoB genes of a selection of both resistant and susceptible clinical isolates were sequenced. From 1585 clinical isolates examined, 1.4% showed phenotypic resistance to rifampicin. The majority of the resistant strains harboured point mutations in their rpoB genes at codons 530, 540 and 545 and showed cross-resistance to rifabutin.

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.37 Several other studies, summarised in Table S1 in the Supporting Information, have evaluated the H. pylori rifabutin resistance rate.29, 36, 38–46 From these studies, including a total of 2982 patients, an overall rate of rifabutin resistance of 1.3% was calculated [95% confidence interval (95% CI) from 0.9% to 1.7%]. However, when only studies including pre-treatment patients (that is, naïve to H. pylori eradication treatment) were considered, this figure was even lower (0.6%, 95% CI from 0.2% to 1.4%). The higher rates of rifabutin resistance reported in some countries may be due to the fact that tuberculosis is still common in some geographical areas and rifampicin is frequently used in anti-tuberculosis treatment regimens.40

On the other hand, higher values of rifabutin resistance were calculated when only post-treatment patients (after receiving H. pylori eradication therapy) were included (1.59%, 95% CI from 1% to 2.1%). The highest (and outlier) result was reported in the study by Miehlke et al.,44 where H. pylori eradication treatment was previously prescribed and a rifabutin resistance rate as high as 31% was confirmed in five of the 16 patients remaining H. pylori-positive after this treatment.

As suggested by Toracchio et al.,46 by analogy with clarithromycin resistance, it may be hypothesised that the presence of multiple strains of H. pylori, resistant and/or susceptible to the same antibiotic, in the same patient is possible. Various studies have reported the coexistence of the strains of H. pylori that determine the mixed pattern in the same patient.47 In addition, the presence of H. pylori hetero-resistance between two biopsy sites (antrum and fundus) has been recently shown in 34% of patients with secondary resistance, suggesting the necessity, in these cases, to perform an antimicrobial susceptibility test from both sites of the stomach.48 In particular, some authors have performed culture and susceptibility tests from antrum and fundus in all patients with secondary resistance, and H. pylori sensitive to rifabutin in the antrum and resistant in the fundus has been found in two of the 10 cases examined (20%).48

Other authors have assessed the relationship between the presence of mixed infection of H. pylori and both antimicrobial susceptibility and virulence markers.49 When different bacteria were isolated in the host, they showed a resistance to rifabutin (10%) that was higher than that of bacteria in single infection (4%).49 In other words, when mixed or single colonisation was compared with antimicrobial susceptibility, the presence of more resistant strains was consistent with the coinfection.49

Efficacy of rifabutin for H. pylori eradication

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The studies which have evaluated rifabutin-containing regimens for the treatment of H. pylori infection are summarised in Table S2 in the Supporting Information.34, 38, 43, 44, 46, 50–65 The first study was published in 1998, but most of them were published during the last 10 years. Most of the experience comes from European studies (mainly from Germany, Italy and Spain). In most of the cases, rifabutin was prescribed at doses of 300 mg each day (either as 150 mg twice a day or as 300 mg once a day). Duration of treatment was 7 or 10 days in most of the protocols. The number of patients included in each study was lower than 100 in all cases, an even lower than 50 in most of them. All the studies included patients with at least one previous eradication treatment (that is, no study included patients naïve to H. pylori eradication treatment). Type of previous H. pylori eradication treatment varied depending on the study, but in most of the cases, it included a first-line regimen with a PPI, clarithromycin and either amoxicillin or nitroimidazole.

Overall, from the 1008 patients treated with rifabutin-containing regimens included in Table S2 in the Supporting Information, a mean H. pylori eradication rate (intention-to-treat analysis) of 73% was calculated (95% CI from 67% to 79%) (Figure 1). Results were heterogeneous (I2 = 79%), so a random-effect model was applied and planned subanalyses were performed.

image

Figure 1.  Efficacy (intention-to-treat analysis) of rifabutin-containing therapies for the eradication of Helicobacter pylori.

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When only second-line rifabutin-containing therapies administered to the 223 patients with one previous eradication failure were considered, a mean 79% eradication rate was calculated (95% CI from 67% to 92%) (Figure 2). Results were still heterogeneous (I2 = 87%). When subanalysis was performed depending on the duration of the rifabutin regimen, better results were observed with 10–12 days (92%; homogeneous results, with I2 = 0%) than with 7 days (69%).

image

Figure 2.  Efficacy (intention-to-treat analysis) of second-line rifabutin-containing therapies for the eradication of Helicobacter pylori in patients with one previous eradication failure.

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Figure 3 summarises the experience of rifabutin regimens as third-line treatment (in 342 patients with two previous eradication failures). Mean H. pylori eradication rate was 66% (95% CI from 55% to 77%), results being heterogeneous (I2 = 87%). When only studies combining rifabutin with a PPI and amoxicillin were considered (and the single study prescribing moxifloxacin instead of amoxicillin was excluded), mean eradication rate was slightly lower (63%) and the heterogeneity decreased (I2 = 62%).

image

Figure 3.  Efficacy (intention-to-treat analysis) of third-line rifabutin-containing therapies for the eradication of Helicobacter pylori in patients with two previous eradication failures.

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It has been suggested that rifabutin efficacy decreases with increasing number of failed previous therapies, perhaps due to patients who had failed at least two courses of eradication therapy and may have harboured H. pylori strains that were more difficult to eradicate62. However, as shown in Figure 4, where studies assessing the efficacy of rifabutin in fourth- or fifth-line regimens are summarised, encouraging results may be obtained even after three or four previous eradication failures. Thus, the mean eradication rate in this scenario was 70% (95% CI from 60% to 79%), the results being homogeneous (I2 = 2%). Accordingly, a recent study found that the efficacy of rifabutin treatment was not significantly influenced by the number of previous treatment failures: eradication rates in patients with one, two, three, and four or more previous failures were 78.3, 89.6, 68.6 and 88.9% respectively (nonstatistically significant differences).44

image

Figure 4.  Efficacy (intention-to-treat analysis) of fourth- or fifth-line rifabutin-containing therapies for the eradication of Helicobacter pylori in patients with at least three previous eradication failures.

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Only few studies have directly compared – in the same protocol – rifabutin vs. other antibiotics in H. pylori eradication regimens. First, three studies have compared a triple combination of a PPI, amoxicillin and rifabutin with the widely used ‘classic’ bismuth-containing quadruple regimen.34, 43, 57, 64 Perri et al.34 were the first authors to perform a randomised study in which patients were treated for 10 days with pantoprazole, amoxicillin, and rifabutin (300 mg/24 h) and quadruple therapy on patients who had failed eradication after standard triple therapy. On intention-to-treat analysis, eradication rates were 87% for rifabutin-containing therapy and 67% for quadruple therapy (these differences being statistically significant). Furthermore, side effects were less frequent in rifabutin-treated patients than in those on quadruple therapy. Thus, approximately 15% of patients on quadruple therapy experienced moderate-to-severe side effects, and 6% had to discontinue treatment. In contrast, in the rifabutin-treated groups, no moderate or severe side effects were observed and no patients discontinued treatment because of side effects. The second study, performed by Wong et al.,64 compared the efficacy of rabeprazole, levofloxacin and rifabutin triple therapy vs. quadruple therapy for the second-line treatment of H. pylori infection, and reported similar high intention-to-treat eradication rates (91%) and similar good compliance (>95%) with both regimens. These two studies concluded that in patients who failed standard eradicating treatments, a 10-day course of rifabutin with a PPI and amoxicillin is similarly effective or even more effective and well tolerated than the bismuth-containing quadruple therapy. However, more recently, Navarro-Jarabo et al.57 compared these two regimens in patients for whom first-line H. pylori eradication treatment had failed. The eradication achieved, analysed by intention-to-treat, was 70% for quadruple therapy and only 44% for rifabutin regimen (these differences being statistically significant). The reason for this remarkably low eradication rate with the rifabutin regimen remains unclear, but it may be suggested that the 7-day course prescribed in this study was probably insufficient.

Other studies have compared the rifabutin treatment with other regimens different from the quadruple therapy. Miehlke et al.43 investigated the efficacy of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of H. pylori. Patients infected with H. pylori resistant to both metronidazole and clarithromycin were randomised to esomeprazole, rifabutin and amoxicillin for 7 days, or to omeprazole 40 mg and amoxicillin 1000 mg, each given three times daily for 14 days. Intention-to-treat eradication rates were 74% and 70%. Premature discontinuation of treatment occurred in 2% and 5% of patients respectively. Therefore, the authors concluded that rifabutin triple therapy and high-dose omeprazole/amoxicillin dual regimen are comparable, effective, and safe for rescue therapy of H. pylori.

Finally, one study has directly compared levofloxacin with rifabutin as third-line therapy for H. pylori.54 Adverse events in the rifabutin and levofloxacin groups were reported in 60% and 50% of the cases respectively. While this study showed a statistical superiority for the levofloxacin regimen (intention-to-treat cure rate of 85%), it should be noted that the quoted eradication rate of 45% for rifabutin triple therapy was surprisingly low.

Dosage of rifabutin in H. pylori eradication regimens

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The recommended prophylactic regimen for patients with HIV infection and a CD4 + T lymphocyte count of <100 cells/μL is rifabutin 300 mg once daily orally.23 Rifabutin 300–600 mg once daily has also been used in combination with at least two other antimycobacterial drugs for the treatment of MAC infection.23 In the treatment of pulmonary tuberculosis caused by mycobacteria susceptible to rifampicin, rifabutin 300–600 mg once daily has been administered in combination with two or more antimycobacterial drugs.23

For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day. The H. pylori cure rate in the only two studies prescribing rifabutin 150 mg/day was approximately 65%. There is only one study directly comparing both doses. Perri et al.34 performed a randomised study in which two groups of patients were treated for 10 days with pantoprazole, amoxicillin and rifabutin 150 mg once daily or 300 mg once daily. On intention-to-treat analysis, eradication rates were 67% in the rifabutin 150 mg group and significantly higher (87%) in the rifabutin 300 mg group.

Borody et al.51 showed that 12 days of half the dose of rifabutin (150 mg daily) in combination with increasing frequency of dosing with amoxicillin (1 g three times daily) and pantoprazole (80 mg three times daily) achieved an intention-to-treat eradication rate of 91%. By increasing the dosage of amoxicillin to 1.5 g three times daily for 12 days, an excellent overall eradication rate of 97% was achieved. These data suggest that frequent dosing of a high-dose amoxicillin and a double-dose PPI in the presence of low-dose rifabutin (150 mg daily) are critical in driving the efficacy of rifabutin-based triple therapy.51

There is some evidence that the incidence of adverse events is related to dose, with events reported more frequently in patients treated with doses of ≥450 mg daily than in those receiving 300 mg daily, and in those receiving 300 mg compared with 150 mg daily.23

Duration of rifabutin treatment for H. pylori infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The ideal length of treatment for the rifabutin regimen remains unclear, as does the influence this has on the treatment outcome. In some reports, a 7-day course has been equally efficacious as 10- to 14-day regimens, whereas others have found that this shorter duration dramatically reduced the efficacy with eradication rates at only 44%.57 From studies included in Table S1 in the Supporting Information and Figure 1, a mean H. pylori eradication rate of 75% (95% CI from 68% to 83%) for the 7-day regimen was calculated, while the corresponding figure for the 10- to 14-day regimen was similar or even slightly lower (71%; 95% CI, 63% to 79%). However, as previously reviewed, when a subanalysis was performed depending on the duration of the second-line rifabutin therapy, better results were observed with 10–12 days (92%) than with 7 days (69%). Finally, therapy between 12 and 14 days have yielded results similar to the 10-day course and are likely to increase the incidence of adverse events.62

Is an H. pylori culture necessary before administering rifabutin?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

The utility of the culture (with consequent antibiotic susceptibility testing) and the moment when it must be performed after eradication failure are both controversial.66 It is evident that the knowledge of the organism’s antibiotic susceptibility represents a great aid in selecting the therapy regimen,8–11 and that therapy may be based on pre-treatment antibiotic-susceptibility testing, but this strategy is currently not practical.66 However, an H. pylori culture is expensive, time consuming, not available on a routine basis, and implies the performance of endoscopic exploration. Moreover, the sensitivity of a bacterial culture is not 100% and therefore the antimicrobial susceptibility cannot be obtained in all cases. Furthermore, even knowing the susceptibility of H. pylori, eradication rates do not achieve 100%, as the results observed in vivo by following in vitro susceptibility to anti-H. pylori antibiotics are often disappointing.67, 68 On the other hand, when a repeat therapy must be selected, we have several data that will aid in suspecting resistance to a particular antibiotic, without the necessity of a culture. Thus, when a therapy with clarithromycin fails, resistance to this antibiotic will appear in most cases, and the same is true when a nitroimidazole is the antibiotic first used.8–11 Therefore, the position in the case of first-line therapy failure would be clear: do not prescribe any of the antibiotics against which H. pylori has probably become resistant.69–71

Moreover, it seems that performing a culture even after a second (or third) eradication failure may not be necessary, as it is possible to construct an overall strategy to maximise H. pylori eradication, based on the different possibilities of empirical treatment (when antibiotic susceptibilities are unknown).18 Thus, if one does not want to or cannot perform a culture before the administration of the third/fourth treatment after failure of the first two/three trials, different possibilities of empirical treatment exist, and among them stand up the rifabutin-containing regimens.

Given the low frequency of rifabutin use in the general population, the likelihood of H. pylori resistance is low. As previously reviewed, the mean rate of rifabutin resistance was calculated to be only of about 1% that is exceptional. 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).38, 43, 45, 46, 50, 51, 64 Finally, H. pylori resistance to amoxicillin is extremely rare.17 Therefore, rifabutin (together with a PPI and amoxicillin) can be administered as a rescue treatment without the need for a prior antibiogram.

Furthermore, the results with the empirical administration of rifabutin are encouraging (see Figures 1 and 4), especially when it is emphasised that this rescue regimen was prescribed after eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin.

Some authors have evaluated, in the same study, different regimens after failure of two or more eradication treatments and have achieved a final (overall) eradication rate of almost 100%,50, 55, 68, 72–76 which emphasises the recommendation that in designing a treatment strategy, we should use two or more therapies which, if used consecutively, come as close to the 100% cure rate as possible.77 In this respect, the aforementioned studies underline 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.

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.78

Tolerability of rifabutin

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

In patients with AIDS treated prophylactically with rifabutin 300 mg daily or placebo, the overall incidence rate for the occurrence of at least one adverse event was comparable in patients receiving rifabutin (51%) and placebo (50%).23 Myalgias, eructation and taste perversion were, however, significantly more common with rifabutin than placebo.23 Like other rifamycin derivatives, rifabutin causes discoloration of the urine, and may cause an orange/tan discoloration of the skin in patients with AIDS receiving prolonged treatment.23 Other reported adverse events include rash (3%), nausea/vomiting (0.4%), neutropenia (0.4%), anaemia (0.4%) and, rarely, clinically important impairment of liver function.23, 79 In studies in which rifabutin was administered to treat non-H. pylori infections, the rate of adverse effects was approximately of 30%.80 On the other hand, mean rate of adverse effects to rifabutin treatment calculated from H. pylori studies (Table S1 in the Supporting Information) was of 22% (95% CI from 19% to 25%).

Uveitis has recently been reported in patients treated with a combination of rifabutin, clarithromycin and ethambutol or fluconazole.23 This serious complication is more common in the immunocompromised or those on prolonged anti-tuberculous therapy81 and has not as yet been reported during H. pylori therapy.

Myelotoxicity is the most significant adverse event of rifabutin.82, 83 Overall, this complication is rare and is far more likely when high dose (600 mg/day) and prolonged duration therapy is used.82, 83 Several cases of myelotoxicity have been reported during H. pylori therapy.46, 52, 54, 59, 60, 62, 64 However, myelotoxicity was not reported in most of the studies evaluating rifabutin for H. pylori infection. In those studies reporting this complication, myelotoxicity was observed in 1.5–3% of the patients,46, 60, 62, 64 although, in some studies, the incidence has been higher: 10%52 or even 25%.54

All patients recovered uneventfully in few days, with spontaneous recovery of leucopenia, although it took 15 days to normalise white cell count after rifabutin discontinuation in one case.52 In some cases, the leucopenia was clinically apparent with fever.52, 62 There have been no reports of infection or other adverse outcome related to reduced white cell count in the setting of H. pylori treatment.46, 52, 54, 59, 60, 62, 64 Thus, it has been suggested that the clinical significance of minor reductions in leukocyte count such as reported by others may be overestimated.62

Although myelotoxicity is a rare event, it indicates that during short-term rifabutin treatment, blood cell count should be checked at any suspicious symptom. It has been recommended to perform systematic blood controls in all patients receiving rifabutin, despite being asymptomatic.53, 54 However, a practical approach may be to check the full blood count, only if fever or other signs of systemic toxicity occur.

Concerns and limitations of rifabutin treatment for H. pylori infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Despite its relatively high efficacy, several concerns still remain regarding rifabutin treatment for H. pylori infection. Firstly, this drug is extremely expensive. Secondly, as reviewed, severe leucopenia and thrombocytopenia have been reported in some patients treated with rifabutin. Finally, 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.38

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.62 Acquired rifabutin resistance has been noted in these cohorts, but only when associated with CD4 counts <100 cells/mm3 and when intermittent dosing is used.84 Even in the setting of prolonged tuberculosis treatment, continuous daily rifabutin has led to negligible rates of resistance.84, 85 Moreover, no reports as yet have definitively linked rifabutin resistance with short course treatment of rifabutin for H. pylori or other nonmycobacterial indications.29, 62

Indications of rifabutin treatment for H. pylori infection in clinical practice

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

At present, rifabutin should be restricted to patients where previous (multiple) eradication regimens with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin have failed.17, 67, 86 In this respect, the following algorithm for the treatment of H. pylori infection may be suggested: First-line treatment may include a standard triple therapy (mainly PPI plus clarithromycin and amoxicillin) in areas of low clarithromycin resistance, while alternative regimens (such as sequential87 or nonbismuth quadruple combinations88) may be prescribed in areas with high clarithromycin resistance. In case of treatment failure, as a second-line regimen, a levofloxacin-containing regimen may be recommended.89–91 If this last treatment fails, a third-line rescue regimen with a bismuth-containing quadruple treatment may then be prescribed.55 Finally, if H. pylori eradication is still not achieved after three consecutive attempts, and the benefit of H. pylori eradication is definitively established, a PPI-rifabutin-amoxicillin regimen may be considered as a fourth-line rescue regimen.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information

Even with the current most effective treatment regimens, a relevant proportion of patients will fail to eradicate H. pylori infection. This issue seems important at the present time, as therapy for H. pylori infection is becoming more and more frequently prescribed. Nowadays, apart from having to know well first-line eradication regimens, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy, we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate.

Rifabutin shows good in vitro activity against H. pylori, and the prevalence rate of rifabutin resistance is very low, only about 1% in the reviewed studies. Furthermore, when only studies including patients naïve to H. pylori eradication treatment were considered, this figure was even lower (0.6%).

Overall, mean H. pylori eradication rate (intention-to-treat analysis) with rifabutin-containing regimens was 73%. Respective cure rates for second-line, third-line and fourth/fifth-line rifabutin therapies were 79, 66 and 70%. For treating H. pylori infection, almost all studies have administered rifabutin 300 mg/day; this dose seems to be more effective than 150 mg/day. The ideal length of treatment for rifabutin regimen remains unclear, but 10- to 12 day-regimens are generally recommended.

Based on that the resistance to rifabutin is practically inexistent, and that rifabutin therapy is highly effective even in patients with primary resistance to both clarithromycin and metronidazole, its use in an empirical manner, as ‘rescue’ therapy without culture in those patients in whom clarithromycin and nitroimidazoles or other antibiotics have failed, may be suggested. However, most of the currently available studies regarding the resistance rates of H. pylori to rifabutin and the eradication rates of rifabutin-containing regimens were conducted in Western countries. Therefore, more studies from other parts of the world are warranted on this issue.

The mean rate of adverse effects to rifabutin treatment in H. pylori studies was 22%. Uveitis has recently been reported in patients treated with a combination of rifabutin and other antimycobacterial drugs, but this complication has not yet been reported during H. pylori therapy. Myelotoxicity is the most significant adverse event of rifabutin during H. pylori therapy, although this complication was rare. Until now, all patients have recovered of leucopenia uneventfully in few days, and there have been no reports of infection or other adverse outcome related to it in the setting of H. pylori treatment.

Despite its relatively high efficacy, several concerns remain regarding the use of rifabutin for treating H. pylori infection: the drug is very expensive, relevant adverse effects (mainly myelotoxicity) have been reported and finally, a broader use of this drug in populations with a high prevalence of tuberculosis might lead to the development of resistance in M. tuberculosis.

At present, therefore, rifabutin should be restricted to patients where previous (multiple) eradication regimens with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin 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, that is, only after previous failure of three eradication regimens.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Rifabutin’s general antimicrobial activity
  6. Pharmacokinetics and pharmacodynamics of rifabutin
  7. Mechanism of action of rifabutin against H. pylori
  8. In vitro antimicrobial activity of rifabutin against H. pylori
  9. Resistance of H. pylori to rifabutin
  10. Efficacy of rifabutin for H. pylori eradication
  11. Dosage of rifabutin in H. pylori eradication regimens
  12. Duration of rifabutin treatment for H. pylori infection
  13. Is an H. pylori culture necessary before administering rifabutin?
  14. Tolerability of rifabutin
  15. Concerns and limitations of rifabutin treatment for H. pylori infection
  16. Indications of rifabutin treatment for H. pylori infection in clinical practice
  17. Conclusions
  18. Acknowledgement
  19. References
  20. Supporting Information