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Sung, Kim, Park, Hwang, Kwon, Na, Choi, Kang, Kim, Kim, and Lee: Rifabutin-based Fourth and Fifth-line Rescue Therapy in Patients with for Helicobacter pylori Eradication Failure
Original Article

Korean J Gastroenterol 2017;69(2):109-118.

Published online: 4 October 2017

DOI: https://doi.org/10.4166/kjg.2017.69.2.109

Rifabutin-based Fourth and Fifth-line Rescue Therapy in Patients with for Helicobacter pylori Eradication Failure

Jihee Sung1, Nayoung Kim1, 2, Yo Han Park1, Young Jae Hwang1, Soohoon Kwon1, Gyeongjae Na1, Joon Young Choi1, Jae Bin Kang1, Hye Rang Kim3, Jin-Wook Kim1, Dong Ho Lee1, 2

1Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea

2Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea

3Hospital Health Promotion Center, Seoul St. Mary's Hospital, The Catholic University of Korea, College of Medicine, Seoul, Korea

Correspondence to: Nayoung Kim, Department of Internal Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea. Tel: +82-31-787-7008, Fax: +82-31-787-4051, E-mail: nayoungkim49@empas.com

Received 16 August 2016       Revised 9 December 2016       Accepted 15 December 2016

Copyright © 2017 Korean Ophthalmological Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background/Aims

Optimized regimen has not yet been established for failures of multiple Helicobacter pylori (H. pylori) eradication. Hence, we aimed to evaluate the efficacy of rifabutin-based rescue therapy, at least after three eradication failures.

Methods

Twelve patients, who failed in the treatment for H. pylori eradication at least three times, were consecutively enrolled between 2007 and 2015 at Seoul National University Bundang Hospital. The rifabutin-based rescue regimen was consisted of proton pump inhibitor (PPI), rifabutin (150 mg b.i.d.), and amoxicillin (1 g b.i.d.), given for 7 or 14 days. MIC concentration test by the agar dilution method was performed on six patients prior to rifabutin-based rescue therapy.

Results

One patient did not take this regimen, and per-protocol (PP) analysis was performed in 11 patients. The overall eradication rate by intention-to-treat and PP analysis with rifabutin-based rescue therapy was 50.0% (6/12 patients) and 54.5% (6/11 patients), respectively. There was no difference of the eradication rate depending on the underlying disease, smoking, alcohol, number of previous eradication failures, and CYP2C19 genotype. All of the six patients were susceptible to rifabutin, but only three of them suc-ceeded in eradicating with H. pylori. Side effe cts occurred in two patients (18.2%), and compliance was 90.9%.

Conclusions

Even the eradication rate of rifabutin-based rescue therapy was not very good. Rifabutin-based rescue therapy could be considered as a rescue therapy, perhaps as the fourth or the fifth-line treatment option. No correlation of rifabutin sensitivity with eradication success rate of H. pylori suggests that frequent administration of high dose PPI and amoxicillin might be important.

Keywords: Helicobacter pylori, Eradication, Salvage therapy, Rifabutin

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Fig. 1.
Flow chart of the study and eradication rate by rifabutin-based rescue therapy. ITT, intention-to-treat; PP, per-protocol.
kjg-69-109f1.tif
Table 1.
Comparison of Eradication Group and Non-eradication Group
Variable Total (n=11) Eradication group (n=6) Non-eradication group (n=5) p-value
Age (yr) 53.9±8.53 53.8±10.09 54.0±7.4 0.976 a
Male/female 10/1 6/0 4/1 0.251 b
 Underlying disease 　 　 　 0.325 b
 Benign gastric ulcer 3 (27.3) 1 (16.7) 2 (40) 　
 Duodenal ulcer 2 (18.2) 2 (33.3) 0 　
 Post ESD d/t EGC 1 (9.1) 1 (16.7) 0 　
 Non-ulcer dyspepsia 5 (45.5) 2 (33.3) 3 (60) 　
Smoking 　 　 　 0.535 b
 Never 4 (36.4) 2 (33.3) 2 (40.0) 　
 Ex-smoker 3 (27.3) 1 (16.7) 2 (40.0) 　
 Current 4 (36.4) 3 (50.0) 1 (20.0) 　
Alcohol 　 　 　 0.323 b
 None 3 (27.3) 1 (16.7) 2 (40.0) 　
 Past 2 (18.2) 2 (33.3) 0 　
 Current 6 (54.5) 3 (50.0) 3 (60.0) 　
Eradication failure number 　 　 　 0.497 b
 3 7 (63.6) 3 (50.0) 4 (80.0) 　
 4 3 (27.3) 2 (33.3) 1 (20.0) 　
 5 1 (9.1) 1 (16.7) 0 　
Test of confirm H. pylori infection before rifabutin 　 　 　 0.064 b
 13C-urea breath test 8 (72.7) 3 (50.0) 5 (100.0) 　
 Culture, Histology and CLOtest 3 (27.3) 3 (50.0) 0 　
Duration of treatment (day) 　 　 　 0.122 b
 7 5 (45.5) 4 (66.7) 1 (20.0) 　
 14 6 (54.5) 2 (33.3) 4 (80.0) 　
Proton pump inhibitor dose 　 　 　 0.371 b
 Lansoprazole 15 mg b.i.d. 5 (45.5) 3 (50.0) 2 (40.0) 　
 Lansoprazole 30 mg q.d. 1 (9.1) 0 1 (20.0) 　
 Lansoprazole 30 mg b.i.d. 4 (36.4) 3 (50.0) 1 (20.0) 　
 Esomeprazole 40 mg b.i.d. 1 (9.1) 0 1 (20.0) 　
CYP2C19 genotype(n=8) 　 　 　 0.465 b
 HomEM 4 (50.0) 1 (33.3) 3 (60.0) 　
 HetEM 4 (50.0) 2 (66.7) 2 (40.0) 　
Test for eradication confirmation 　 　 　 0.887 b
 13 C-urea breath test 9 (81.8) 5 (83.3) 4 (80.0) 　
 Culture, Histology and CLOtest 2 (18.2) 1 (16.7) 1 (20.0) 　

Values are presented as mean±standard deviation or number (%).

ESD, endoscopic submucosal dissection; EGC, early gastric cancer; H. pylori, Helicobacter pylori; CLOtest, Campylobacter-Like Organism test

HomEM, homozygous extensive metabolizer; HetEM, heterogygous extensive metabolizer.

a t-test

b chi-squared test.

Table 2.
Baseline Characteristics of 11 Patients
Patient number Sex/ Age Underlying disease Smoking Drinking CYP2C19 genotype N t Number of previous treatment failure Test of H. pylori infection confirmation before rifabutin Duration o treatment (day) PPI dose
1 M/45 Non ulcer dyspepsia Never None HetEM 5 13 C-UBT 7 Lansoprazole 30 mg b.i.d.
2 M/46 Duodenal ulcer Current smoker Current drinker   3 Culture, Histology, CLOtest 7 Lansoprazole 15 mg b.i.d.
3 M/47 Duodenal ulcer Never Current drinker   4 13 C-UBT 14 Lansoprazole 30 mg b.i.d.
4 M/55 Post ESD d/t EGC Current smoker Past drinker HomEM 3 Culture, Histology, CLOtest 7 Lansoprazole 15 mg b.i.d.
5 M/59 Benign gastric ulcer Current smoker Current drinker   3 13 C-UBT 7 Lansoprazole 15 mg b.i.d.
6 M/71 Non ulcer dyspepsia Ex-smoker Past drinker HetEM 4 Culture, Histology, CLOtest 14 Lansoprazole 30 mg b.i.d.
7 M/45 Non ulcer dyspepsia Never Current drinker HetEM 3 13 C-UBT 14 Lansoprazole 15 mg b.i.d.
8 F/48 Non ulcer dyspepsia Never None HomEM 4 13 C-UBT 14 Lansoprazole 30 mg b.i.d.
9 M/56 Benign gastric ulcer Current smoker None HetEM 3 13 C-UBT 14 Lansoprazole 30 mg q.d.
10 M/58 Non ulcer dyspepsia Ex-smoker Current drinker HomEM 3 13 C-UBT 14 Esomeprazole 40 mg b.i.d.
11 M/63 Benign gastric ulcer Ex-smoker Current drinker HomEM 3 13 C-UBT 7 Lansoprazole 15 mg b.i.d.

H. pylori, Helicobacter pylori; PPI, proton pump inhibitor; CLOtest, Campylobacter-Like Organism test; 13 C-UBT, 13 C-urea breath test; ESD, endoscopic submucosal dissection; EGC, early gastric cancer; HomEM, homozygous extensive metabolizer; HetEM, heterogygous extensive

Table 3.
Minimal Inhibitory Concentration of Helicobacter pylori
Patient number Sex/Age Antibiotics (μ g/mL)
AMO (R: ≥0.5) CLA (R: >1) MTZ (R: >8) TC (R: >4) CPR (R: >1) Rifa (R: ≥0.25) LEVO (R: >1) MOXI (R: >1)
1 M/45 ≤0.125 2–4 a 16–32 a ≤1 ≤0.015 ≤0.015 4–8 a 8–16 a
3 M/47 1–2 a 4–8 a ≥32 a ≤1 2–4 a ≤0.015 4–8 a 4–8 a
6 M/71 ≤0.125 2–4 a 16–32 a ≤1 2–4 a ≤0.015 ≥2 a ≥2 a
7 M/45 ≤0.125 2–4 a ≤2 ≤1 ≤0.25 ≤0.015 ≤0.125 ≤0.125
8 F/48 0.125–0.25 ≥32 a 16–32 a 8∼16 a 0.06–0.125 0.06–0.125 4–8 a 8–16 a
9 M/56 ≤0.125 ≥32 a ≥32 a ≤1 ≤0.06 ≤0.015 8–16 a 8–16 a

Resistant cut-off values were defined as >0.5 μ g/mL for AMO, >1 μ g/mL for CLA, >8 μ g/mL for MTZ, >4 μ g/mL for TC, >1 μ g/mL for CPR, LEVO and MOXI, ≥0.25 μ g/m for Rifa.

AMO, amoxicillin; CLA, clarithromycin; MTZ, metronidazole; TC, tetracycline; CPR, ciprofloxacin; Rifa, rifabutin; LEVO, levofloxacin; MOXI, moxifloxacin.

a Indicates the resistance of each antibiotic.

Table 4.
Adverse Events and Compliance of the Subjects
Variable Eradication group (n=6) Non-eradication group (n=5) p-value
Bloating 0 0  
Epigastric soreness 1 0  
Anorexia 0 0  
Taste distortions 0 1  
Nausea 0 0  
Vomiting 0 0  
Abdominal pain 0 1  
Headache 0 0  
Dyspepsia 0 1  
Diarrhea 0 1  
Constipation 0 0  
Reflux 0 1 　
Total patient 1 (16.7) 1 (20) a 1.00 b
 Major c 1 0 0.368 b
 Minor 0 1 　
Total event 1 5a 　
Compliance 5 (83.3) 5 (100) 0.389 b

Values are presented as number (%).

a Adverse events were occurred in only one person in non-eradication group.

b Chi-squared test.

c When the adverse events were so serious that patients discontinued the drug or when patients' daily life was disturbed by these events then it was classified as major.

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