The effectiveness of rifabutin triple therapy for patients with difficult-to-eradicate helicobacter pylori in clinical practice

Alimentary Pharmacology & Therapeutics The effectiveness of rifabutin triple therapy for patients withdifficult-to-eradicate Helicobacter pylori in clinical practice D . V A N D E R P O O R T E N & P . H . K A T E L A R I S BackgroundFailure of first line and subsequent Helicobacter pylori eradication ther- apy is a significant problem and alternative treatments are few.
To evaluate the efficacy of a rifabutin-based triple therapy in clinical practice and determine the optimal strategy for its use.
Patients referred after first or subsequent treatment failure were pre- scribed rifabutin triple therapy consisting of standard dose proton pump inhibitor, amoxicillin 1 g and rifabutin 150 mg each b.d. for 10 days.
ResultsIn 67 patients, the main indications for treatment were dyspepsia (55%),peptic ulcer disease (24%) and increased gastric cancer risk (18%). Themedian number of previous treatments was 2 (range: 1–9). Eradicationof Helicobacter pylori was achieved in 76% (48 ⁄ 63) per protocol and72% (48 ⁄ 67) on an intention-to-treat basis. When used as second linetherapy, 95% (18 ⁄ 19) achieved eradication compared with 68% (30 ⁄ 44)when two or more previous treatments had been used (P = 0.03). Out-come was independent of age, ethnicity, gender or indication for treat-ment. Adverse events were reported in 10%.
ConclusionRifabutin triple therapy is a well tolerated and effective second linetherapy in the treatment of persistent Helicobacter pylori; however, itsefficacy decreases with increasing number of failed previous therapies.
Journal compilation ª 2007 Blackwell Publishing Ltddoi:10.1111/j.1365-2036.2007.03531.x 1538 D . V A N D E R P O O R T E N A N D P . H . K A T E L A R I S Later, rifabutin was used frequently as a second line therapy because of difficulties in accessing the qua- The optimal management of Helicobacter pylori after druple therapy and familiarity with the rifabutin regi- failed eradication therapy remains to be defined. After men. Adverse events and compliance were determined first line failure, current guidelines recommend a bis- in an interview following completion of treatment.
muth-based quadruple therapy1 for 7–10 days, whichhas reported eradication rates of 59–95%.2–4 The accessibility of this regimen is limited in some parts ofthe world and compliance and tolerability are issues All patients were treated with a proton pump inhibitor related to frequent dosing and gastrointestinal adverse (pantoprazole 40 mg, esomeprazole 40 mg, rabeprazole effects. A rifabutin-based triple therapy was first 20 mg or omeprazole 20 mg), amoxycillin 1 g and described by Perri et al. in 19985 and has subsequently rifabutin 150 mg each twice daily for 10 days. Written been reported to be efficacious as salvage therapy and verbal instructions were provided stressing the although reported eradication rates vary between 40% and 95%.6–9 For reasons of limited treatment data and adverse events. Outcome assessment was performed concerns regarding drug toxicity and antibiotic resis- with a 100-mg 13C-urea breath test not <1 month after tance, the precise place of this regimen in H. pylori We undertook an audit of patients with difficult-to- eradicate H. pylori who were treated with a rifabutintriple therapy at a tertiary referral centre. The aim of Data were analysed using SPSS 13.0 (SPSS Inc., Chicago, the study was to characterize better the efficacy, toler- IL, USA) software. Categorical variables were assessed ability and place of this treatment in salvage therapy.
using the chi-squared equation and t-tests were appliedto continuous parametric variables. P-values of <0.05were considered significant.
A prospective clinical practice evaluation was con- Baseline characteristics of 67 patients included in the ducted on all patients treated with a rifabutin-based study are shown in Table 1. The cohort was ethnically triple therapy in a 2-year period at a tertiary referral diverse, 62% were female and the mean age was clinical practice. Patients included were referred after 51 years. The most common indication for treatment first or subsequent H. pylori treatment failure. Patients was dyspepsia, peptic ulcer disease and risk reduction.
with a known definite history of penicillin allergy The median number of previous treatments was 2 were excluded. All patients were managed by a single (range: 1–9), with 46% of patients having undergone gastroenterologist and their details, including indica- three or more treatments prior to the rifabutin triple tion and prior treatments were recorded prospectively.
therapy. All patients had had prior clarithromycin- Pharmacy records were accessed to ensure that no based triple therapy. A bismuth-based treatment had patients were missed from the audit. All patients been previously used in 42%. Three patients were lost included had H. pylori eradication failure, documented to follow-up and one patient did not take any of the with either a positive13 C-urea breath test or positive histology and ⁄ or urease test on gastric biopsy at least1 month after completion of treatment. Demographic data including country of birth were noted, as priorstudies at our institution revealed that antibiotic resis- The overall eradication rate was 76% (48 ⁄ 63) on a per tance by H. pylori varied according to country of protocol basis and 72% (48 ⁄ 67) on an intention- birth.10 Initially, patients who did not previously have to-treat basis. A number of previous treatments signif- a bismuth containing quadruple therapy were pre- icantly affected the outcome (see Figure 1). When scribed this as second line treatment and rifabutin was rifabutin triple therapy was used second line, the per reserved for third line or subsequent treatment failures.
protocol eradication rate was 95%, compared with ª 2007 The Authors, Aliment Pharmacol Ther 26, 1537–1542Journal compilation ª 2007 Blackwell Publishing Ltd R I F A B U T I N T R I P L E T H E R A P Y H. PYLORI 1539 appeared to reduce the eradication rates. When con- Table 1. Baseline patient characteristics trolled for the number of prior treatments, this was not significant. Patients’ gender, country of birth andindication for treatment did not affect the outcome (Table 2). The choice of proton pump inhibitor (PPI) Overall, the treatment was well tolerated and no adverse events (11%). Of these, six were considered minor, (nausea two, headache two and mild diarrhoea two). One patient had presumed drug-related fever and mild myelosuppression. The patient, a 54-year-old female, was admitted to hospital on day 10 of therapy having had 2 days of fever and back pain. She was found to have mild leucopenia with a white cell count (WCC) of 2.0 · 109 ⁄ L; neutrophils 1.2 · 109 ⁄ L, but Prior failure with bismuth containing therapy Prior failure with clarithromycin triple therapy with normal haemoglobin and platelet counts. Sherecovered uneventfully in 48 h with negative blood Figure 1. Eradication rate related to number of previous 68% when used as third line or subsequent therapy(P < 0.05). When used as second or third line therapy, the eradication rate was 88%, while it was 62%, when Eradication results are analysed on a per protocol basis.
given as fourth or more therapy (P < 0.05). By univar- *Not significant on multivariate analysis.
iate analysis, prior use of bismuth-based therapy ª 2007 The Authors, Aliment Pharmacol Ther 26, 1537–1542Journal compilation ª 2007 Blackwell Publishing Ltd 1540 D . V A N D E R P O O R T E N A N D P . H . K A T E L A R I S cultures, normal CT scan of her spine and repeat WCC Currently, bismuth-based quadruple therapy remains of 3.5 · 109 ⁄ L. This was considered to be related to the standard second line treatment for H. pylori, but there is an argument that rifabutin triple therapy maybe more effective and better tolerated. As we andothers6 have reported, eradication rates of above 90% are possible for rifabutin triple therapy in this setting, This clinical audit confirms the usefulness of rifabu- whereas the overall success of bismuth quadruple ther- tin-based triple therapy for patients with difficult-to- apy, when studies are pooled, is between 60% and eradicate H. pylori. The per protocol eradication rate 65%.20, 21Adverse events occur in over 50% of patients of 76% for a 10-day course is comparable with most in many studies of quadruple therapy22–24 and compli- of the published reports.11–14 The ideal length of ance is consistently a problem with this complex regi- treatment for this regimen remains unclear, as does men. Moreover, as the recent Maastricht III consensus the influence this has on treatment outcome. In statement notes1, bismuth compounds are no longer some reports, a 7-day course has been equally effi- available in many countries and tetracycline may also cacious8, 14, while others have found that this shorter become increasingly difficult to access. Certainly in duration dramatically reduced the efficacy with erad- these areas, of which Australia is one, rifabutin triple ication rates of only 44%.15 Longer durations of therapy may be considered as a second line treatment therapy between 126 and 147 days have yielded and bismuth quadruple therapy reserved for subse- results similar to our 10-day course and are likely quent treatment failure. While the relative place of to increase the incidence of adverse events. All our rifabutin compared with levofloxacin triple therapy is patients were given the rifabutin regimen empirically yet to be defined, there are data supporting levofloxa- in the absence of antibiotic susceptibility testing.
cin as an effective salvage therapy. Two recent meta- analysis have shown overall salvage eradication rates H. pylori resistance to either rifabutin16 or amoxicil- of between 80% and 87%20, 21for levofloxacin triple lin17–19 is extremely rare. Moreover, treatment failure therapy and demonstrated its superiority to bismuth- does not reduce the option for other salvage ther- based quadruple therapy. Only one study has directly apy, such as bismuth quadruple therapy, if not compared levofloxacin to rifabutin as third line ther- apy for H. pylori.25 While it showed a statistical supe- This rifabutin therapy appears to be far more effec- riority for the levofloxacin regimen, it should be noted tive when used as second line therapy, with eradica- that the quoted eradication rate of 44% for rifabutin tion rates of 95% compared to 68% when two or more triple therapy was surprisingly low.
An argument raised consistently against the wider (P < 0.05). Similar results have been noted in other use of rifabutin is the concern regarding propagation recent reports where the majority of patients had only of resistance, especially in mycobacterial species. The one previous eradication attempt.6 As with all salvage major use of rifabutin is for treatment of tuberculosis therapies, there appears to be diminishing efficacy and other mycobacteria especially in the setting of from therapy as the number of previous failed treat- immunodeficiency or HIV infection.26, 27 Acquired ments increases. The reason for this is not clear. It is rifabutin resistance has been noted in these cohorts, possible that in a sub-group of these patients, unrec- ognized non-compliance is the issue. Drug resistance <100 cells ⁄ mm3 and when intermittent dosing is may play a role, but this is unproven, given the pau- used.27 Even in the setting of prolonged tuberculosis city of data reporting either amoxycillin or rifabutin treatment, continuous daily rifabutin has led to negli- resistant H. pylori isolates. In our analysis, prior failed gible rates of resistance.27, 28 Moreover, no reports as therapy with a bismuth-based regimen appeared to be yet have definitively linked rifabutin resistance with a significant factor for subsequent rifabutin failure.
short course treatment of rifabutin for H. pylori or However, when this was controlled for total number of treatments in a multivariate model, it lost its signifi- Another concern relates to side-effects and the risk cance, suggesting the prior use of bismuth-based ther- drug was very well tolerated with only 10% of patients ª 2007 The Authors, Aliment Pharmacol Ther 26, 1537–1542Journal compilation ª 2007 Blackwell Publishing Ltd R I F A B U T I N T R I P L E T H E R A P Y H. PYLORI 1541 gastrointestinal symptoms. This rate is similar to find- potentiality to cause anterior uveitis. This serious com- ings in our studies of similar patients undergoing first plication is more common in the immunocompromised line clarithromycin triple or bismuth quadruple thera- or those on prolonged anti-tuberculous therapy32 pies.24 The one patient with transient leucopenia and has not as yet been reported during H. pylori recovered within 48 h with no adverse outcome. Other studies have reported adverse events between 40% and In conclusion, this rifabutin-based triple therapy is 50%6, 25 of patients, although most of these have been an effective regimen for patients with difficult-to- mild. Myelotoxicity, which has now been reported on eradicate H. pylori. When used as second or third line at least two occasions during H. pylori therapy,13, 29 is the most significant adverse event. Overall, this com- although its efficacy decreases with increasing number plication is rare and is far more likely when high dose of failed previous therapies. Concerns do exist relating (600 mg ⁄ day) and prolonged duration therapy is to toxicity and resistance, but neither issue appears to used.30, 31 There have been no reports of infection or preclude its use. Especially in regions where bismuth other adverse outcome related to reduced WCC in the and levofloxacin are less readily available, it is a setting of H. pylori treatment. Thus, the clinical signif- rational and safe choice for second line and subse- icance of minor reductions in leucocyte count such as quent attempts at salvage eradication therapy.
reported by others may be overestimated25. A practicalapproach may be to check the full blood count, only if fever or other signs of systemic toxicity occur. Clini-cians using rifabutin should also be aware of its Declaration of personal and funding interests: None.
6 Borody TJ, Pang G, Wettstein AR, et al.
11 Qasim A, Sebastian S, Thornton O, et al.
Efficacy and safety of rifabutin-contain- 1 Malfertheiner P, Megraud F, O’Morain C, ing ‘rescue therapy’ for resistant Heli- after failure of standard first- and sec- ment of Helicobacter pylori infection – 7 Gisbert JP, Gisbert JL, Marcos S, Pajares JM. Empirical Helicobacter pylori ‘res- cue’ therapy after failure of two eradi- 12 Perri F, Festa V, Clemente R, et al. Ran- domized study of two ‘rescue’ therapies failure of Helicobacter pylori eradication for Helicobacter pylori-infected patients after failure of standard triple therapies.
hert W, et al. Randomized trial of rifab- Am J Gastroenterol 2001; 96: 58–62.
13 Canducci F, Ojetti V, Pola P, Gasbarrini 3 Gisbert JP, Gisbert JL, Marcos S, Grava- cobacter pylori eradication ‘rescue ther- ‘rescue’ therapy after Helicobacter pylori 9 Perri F, Festa V, Clemente R, Quitadamo M, Andriulli A. Rifabutin-based ‘rescue therapy’ for Helicobacter pylori infected tion treatment: preliminary experience.
J Clin Gastroenterol 2000; 31: 222–5.
et al. Quadruple therapy is effective for FL, et al. Efficacy of rifabutin-based tri- 10 Katelaris PH, Nguyen TV, Robertson GJ, eradicate Helicobacter pylori infection.
16 Heep M, Beck D, Bayerdorffer E, Lehn N.
5 Perri F, Festa V, Andriulli A. Treatment Agents Chemother 1999; 43: 1497–9.
ª 2007 The Authors, Aliment Pharmacol Ther 26, 1537–1542Journal compilation ª 2007 Blackwell Publishing Ltd 1542 D . V A N D E R P O O R T E N A N D P . H . K A T E L A R I S 17 Branca G, Spanu T, Cammarota G, et al.
triple ‘rescue therapy’ vs. quadruple 28 Li J, Munsiff SS, Driver CR, Sackoff J.
‘rescue therapy’ for the eradication of Helicobacter pylori resistant to metroni- in vitro activity of levofloxacin against 23 Georgopoulos SD, Ladas SD, Karatapanis Antimicrob Agents 2004; 24: 433–8.
S, et al. Effectiveness of two quadruple, 19 Duck WM, Sobel J, Pruckler JM, et al.
25 Gisbert JP, Gisbert JL, Marcos S, Moren- 20 Gisbert JP, Morena F. Systematic review 32 Skolik S, Willermain F, Caspers LE.
for persistent Helicobacter pylori infec- 27 Burman W, Benator D, Vernon A, et al.
Rifabutin-associated panuveitis with ret- 22 Isakov V, Domareva I, Koudryavtseva L, ª 2007 The Authors, Aliment Pharmacol Ther 26, 1537–1542Journal compilation ª 2007 Blackwell Publishing Ltd


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