Saudi Journal of Gastroenterology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 26  |  Issue : 2  |  Page : 78--83

Treatment with compound Lactobacillus acidophilus followed by a tetracycline- and furazolidone-containing quadruple regimen as a rescue therapy for Helicobacter pylori infection


Airu Liu, Yuxin Wang, Yingxiao Song, Yiqi Du 
 Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai, China

Correspondence Address:
Dr. Airu Liu
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Changhai Road 168, Shanghai - 200433
China
Dr. Yiqi Du
Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Changhai Road 168, Shanghai - 200433
China

Abstract

Background/Aim: Treatment of Helicobacter pylori infections has become more difficult because of increasing antibiotic resistance. We assessed the efficacy and safety of treatment with probiotics followed by a tetracycline- and furazolidone-containing quadruple regimen as rescue treatment for H. pylori infection. Patients and Methods: This retrospective study examined patients with at least two H. pylori eradication failures. Patients were given a two-week compound Lactobacillus acidophilus (1 g t.i.d.), followed by a quadruple antibiotic regimen (esomeprazole [20 mg b.i.d.] + bismuth potassium citrate [220 mg b.i.d.] + tetracycline [750 mg b.i.d.] + furazolidone [100 mg b.i.d.]) for 10 days as rescue therapy. Eradication was evaluated using the[13]C-urea breath test at 4 weeks after the end of therapy, and side effects were recorded. Results: The records of 50 patients were examined. Four cases experienced treatment failure, and one case received replacement with metronidazole because of allergy to furazolidone. The eradication rate was 92.0% [95% confidence interval (CI): 84.0–98.0%) in intention-to-treat (ITT) analysis and 91.8% (95% CI: 83.7–98.0%) in per protocol (PP) analysis. Side effects (mainly dizziness, dry mouth, and skin rash) occurred in 10 patients, all of which resolved after cessation of antibiotics. Conclusions: Patients who failed multiple attempts at H. pylori eradication may benefit from a treatment with probiotics followed by a tetracycline- and furazolidone-containing quadruple regimen.



How to cite this article:
Liu A, Wang Y, Song Y, Du Y. Treatment with compound Lactobacillus acidophilus followed by a tetracycline- and furazolidone-containing quadruple regimen as a rescue therapy for Helicobacter pylori infection.Saudi J Gastroenterol 2020;26:78-83


How to cite this URL:
Liu A, Wang Y, Song Y, Du Y. Treatment with compound Lactobacillus acidophilus followed by a tetracycline- and furazolidone-containing quadruple regimen as a rescue therapy for Helicobacter pylori infection. Saudi J Gastroenterol [serial online] 2020 [cited 2020 May 29 ];26:78-83
Available from: http://www.saudijgastro.com/text.asp?2020/26/2/78/282503


Full Text



 Introduction



More than 50% of the world's population currently have gastrointestinal H. pylori infections, including an estimated 40 to 60% of Chinese adults.[1] Among patients with H. pylori infections, 100% have or will develop chronic active gastritis but fewer than 10% have H. pylori- related dyspepsia. A total of 15% to 20% develop peptic ulcers, but less than 1% ultimately develop gastric malignant tumors.[2]H. pylori gastritis is defined as an infectious disease,[3] and eradication of H. pylori plays an important role in the cure, reversal, and delay of disease onset.

Consensus in China recommends bismuth-containing quadruple regimen (bismuth, PPI, and two kinds of antibiotics) for eradication, and antibiotics with high eradication rates are preferred first.[4] But due to the widespread use of antibiotics for treatment of H. pylori infections, antibiotic resistance has increased greatly.[3] In particular, epidemiological data for H. pylori in China show high resistance to clarithromycin (20–45%), levofioxacin (20–45%), and metronidazole (40–70%), although the resistance rates to tetracycline, furazolidone, and amoxicillin are all below 5%.[5],[6],[7] The increasing resistance of H. pylori to antibiotics has led to an increasing rate of failure to eradicate H. pylori. Thus, the selection of a safe and effective antibiotic regimen for patients who have failed previous regimens is a major challenge for clinicians.

 Methods



Study population

Patients were retrospectively enrolled by the Department of Gastroenterology, Changhai Hospital from June 2015 to May 2018. All included patients were 18 to 70 years old; positive for the urea breath test at least 4 weeks after last eradication treatment; and experienced at least two H. pylori eradication failures. Patients were excluded if they presented with severe comorbidity or a malignant tumor; had a known history of allergy to the drugs in the therapeutic regimen; used nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotic therapy, or bismuth salts up to 4 weeks before study inclusion; or were pregnant or breast-feeding.

All clinical data were collected. Previous eradication regimens and the dates of eradication failures were extracted from the medical records and telephone interviews. This retrospective study was approved by the ethics committee of Shanghai Changhai Hospital (No. CHEC 2017-210). Informed consent was obtained from all the patients.

Protocol

The regimen consisted of compound Lactobacillus acidophilus (1.0 g, t.i.d) for 2 weeks, followed by 10 days of esomeprazole (20 mg, b.i.d), bismuth potassium citrate (220 mg, b.i.d), tetracycline (750 mg, b.i.d), and furazolidone (100 mg, b.i.d). According to the manufacturer (Yi Jun Kang®, He Li Pharm. Co. Ltd. China), each probiotic tablet contained 5 × 10[6] cells of Lactobacillus acidophilus, 2.5 × 10[6] cells of Streptococcus faecalis, and 5 × 10[3] cells of Bacillus subtilis. Esomeprazole was taken 30 min before a meal, and all other drugs were taken after meals. All patients were asked to quit smoking and drinking alcohol during the treatment regimen.

Eradication status was evaluated using[13] C-UBT, at least 4 weeks after the end of treatment. The result was considered negative if the value was below 4. Adverse effects during treatment were also recorded.

Statistical analysis

All enrolled patients were analyzed using intention-to-treat (ITT) analysis, and all enrolled patients who completed the entire regimen were analyzed using per-protocol (PP) analysis. All the analyses were performed with IBM Statistical Package for the Social Sciences (SPSS) software version 21.0.

 Results



General information

We retrospectively examined the records of 50 patients who met the inclusion criteria (17 men and 33 women, mean age: 47.3 years, age range: 29–68 years) [Table 1]. There were five cases with atrophic gastritis, 37 cases with non-atrophic gastritis, eight cases with peptic ulcer [Table 1]. The number of previous treatment failures ranged from 2 to 10 (two times for 28 patients, three times for 12 patients, and four or more times for 10 patients).{Table 1}

Analysis of the antibiotics used in previous regimens [Table 2] indicated that clarithromycin was used in 41 cases, levofloxacin in 32 cases, amoxicillin in 42 cases (six of whom had histories of penicillin allergy), and metronidazole in 30 cases. There was no previous use of tetracycline or furazolidone.{Table 2}

The characteristics of the rescue regimens [Table 3] were also analyzed. Two cases repeated the original regimen, six cases repeated clarithromycin or levofloxacin, three cases repeated metronidazole without dose optimization, three cases used antibiotics not in the recommended guidelines (gentamicin, erythromycin, or cefaclor),[4],[8] and two cases used clarithromycin- or metronidazole-containing triple therapy without drug sensitivity testing. The 34 (68.0%) other cases met the normalization principle recommended by the Fifth Chinese National Consensus Report on the Management of Helicobacter pylori Infection (Refer to previous regimens; do not repeat the original regimen; do not repeat the application of clarithromycin or levofloxacin; optimize dosage when repeatedly using metronidazole; and perform drug sensitivity testing before using clarithromycin- or metronidazole-containing triple therapy).[4]{Table 3}

Eradication rate

Among all 50 patients, there were four failures based on the[13] C-UBT and one patient changed to another antibiotic because of an allergy to furazolidone [Table 4]. Thus, the eradication rate was 92.0% in the ITT analysis, and 91.8% in the PP analysis.{Table 4}

Adverse effects

A total of 10 patients experienced adverse effects during treatment [Table 5]. Four cases had mild dizziness, three cases complained of dry mouth, two cases experienced skin rashes, one case complained of loose stools, and one case complained of mild foot pain. All of these adverse effects were mild, did not significantly affect the quality of life, and ended after cessation of the antibiotic regimen. All patients with adverse effects completed their treatments, except for one patient who changed medications because of a skin rash. In addition, all 10 of these patients had negative results for the[13] C-UBT.{Table 5}

 Discussion



More than 50% of people worldwide are infected with H. pylori, a pathogen associated with several human diseases. Our retrospective study of patients who experienced at least two H. pylori eradication failures indicates that 10.0% had atrophic gastritis, 74.0% had non-atrophic gastritis, and 16.0% had peptic ulcers. Eradication of H. pylori is considered essential for resolving symptoms of dyspepsia,[9],[10] curing peptic ulcer,[11] delaying or reversing the progress of atrophic gastritis,[12] preventing gastric carcinoma,[13],[14] and curing or alleviating gastric mucosa-associated lymphoid tissue (MALT) lymphoma.[15] The increased use of antibiotic treatments for H. pylori has increased the rates of antibiotic resistance. In particular, H. pylori has high resistance to metronidazole, clarithromycin, and levofloxacin in certain geographic regions, but is generally not resistant to amoxicillin, tetracycline, and furazolidone.[5],[6],[7] However, metronidazole, clarithromycin, levofloxacin, and amoxicillin are the main antibiotics used to eradicate H. pylori.

Among our 50 patients, 82.0% used clarithromycin, 64.0% used levofloxacin, 60.0% used metronidazole, and 84.0% used amoxicillin. We expected that the high utilization rates of clarithromycin, metronidazole, and levofloxacin will lead to further increases in drug resistance and treatment failures. Thus, it was important to choose an effective rescue regimen after the failure of initial treatment. The latest consensus report proposed an H. pylori normalization treatment which says: do not repeat the original regimen, do not repeat the application of clarithromycin or levofloxacin, optimize dosage when repeatedly using metronidazole, and perform drug sensitivity testing before using clarithromycin- or metronidazole-containing triple therapy.[4] All of our patients had at least two eradication failures, and only 68.0% of the previous rescue regimens met this normalization principle. The improper clinical use of antibiotics may be a major reason for the repeated eradication failures.

Drug sensitivity testing is recommended for patients with multiple eradication failures,[15] although it is not widely performed in China due to the high cost and long time needed to obtain results. The European consensus recommends the use of tetracycline- and metronidazole-containing quadruple regimen for rescue treatment of H. pylori infection.[16]H. pylori in China has a relatively high resistance rate to metronidazole, but a low resistance rate to furazolidone, so multiple consensus statements recommend furazolidone.[8],[4] In addition, considering that some patients have amoxicillin allergies, tetracycline and furazolidone are used together as rescue antibiotics.

H. pylori has a low rate of resistance to tetracycline and previous studies reported that tetracycline-containing bismuth quadruple therapy can achieve a high eradication rate.[17],[18],[19] The common adverse effects of tetracycline therapy are gastrointestinal symptoms (nausea, emesis, and epigastric discomfort), allergic reactions (papules and erythema), damage to the liver and kidneys, and occasionally hemolytic anemia and certain other rare conditions. Furazolidone is a nitrofuran antibiotic that has strong antibacterial effects against many gram-positive and gram-negative bacteria, can accumulate to high levels in the gastrointestinal tract,[20] and has no cross-resistance to metronidazole.[20],[21] Furazolidone has a resistance rate below 1%, and the treatment of H. pylori infection with furazolidone generally has a high eradication rate.[22],[23] The most common adverse effects of furazolidone are nausea, vomiting, diarrhea, anorexia, skin rash, headache, dizziness, drug fever, and hypotension, although hemolytic anemia, jaundice, and polyneuritis occur occasionally. A comparison of regimens with different doses of furazolidone shows that such side effects are more common when using a 10-day-course and at high doses (200 mg b.i.d.).[24],[25],[26] The recommended dose of furazolidone is 100 mg b.i.d., and an increase to 100 mg t.i.d. improves efficacy but decreases safety.[4] The patients in the present study received a furazolidone dose of 100 mg b.i.d. for 10 days.

Relatively, few studies have examined the efficacy and safety of the tetracycline- and furazolidone-containing quadruple regimen for the treatment of refractory H. pylori, and there are limited applications in the clinic. Lu et al. reported that the eradication rate following 14 days of tetracycline (500 mg, tid)- and furazolidone (100 mg, t.i.d)-containing bismuth quadruple regimen was 96.1% when used as rescue therapy and that the side effects were mainly nausea, abdominal pain, diarrhea, and dizziness.[27] In 2014, Hu et al. showed that the eradication rate following 14 days of tetracycline (750 mg, b.i.d)- and furazolidone (100 mg, b.i.d)-containing quadruple regimen was also more than 90% in patients who had initial eradication failure, and that the incidence of side effects (mainly epigastric discomfort, dizziness, drug fever, and skin rash) was 32%.[28]

Chinese and other consensus guidelines suggest that the use of probiotics may reduce some of the adverse effects of antibiotic therapy, by modulating the gastric microenvironment, although it is still controversial whether probiotics reduce the eradication rate of H. pylori.[4],[15],[29] Several meta-analyses of randomized-controlled trials (RCTs)[20],[30],[31],[32] reported that probiotic supplements reduce the side effects associated with antibiotic-based H. pylori eradication therapies, and that there were encouraging results with Lactobacillus spp., Saccharomyces boulardii, and Bacillus clausii. Other research with different Lactobacillus strains, Bifidobacterium strains, and S. boulardii also reported that these probiotics may have beneficial effects on H. pylori eradication.[33],[34] In this study, we examined the influence of probiotics on the safety and efficacy of antibiotic therapy by giving patients a 2-week course with compound L. acidophilus before beginning the antibiotic regimen. The rate of side effects was found to be 20%, mainly dizziness, dry mouth, and skin rash. Only one patient changed treatment because of a skin rash, and all of the side effects resolved after completion of the antibiotic regimen. Compared with previous studies that did not administer probiotics,[21],[22] a significantly lower rate of gastrointestinal discomfort was found, possibly because the prior probiotic treatment regulated gastrointestinal microbiota.

The eradication rate in our patients was 92.0% based on ITT analysis and 91.8% based on PP analysis. We speculate that the high eradication rate in patients who had multiple eradication failures may be due to the addition of the 2-week course of probiotics prior to the quadruple therapy. Probiotics can improve the gastric microenvironment, and decrease H. pylori load and activity, thereby increasing the efficacy of subsequent antibiotics.[32],[35],[36] Most studies examining the use of probiotics in patients with H. pylori infections focused on the co-administration of probiotics with antibiotics, and fewer reports have examined the effect of pretreatment with probiotics. Our previous research first reported that the administration of compound L. acidophilus for 2 weeks, either before or after triple therapy, improved the eradication rates.[37] In addition, pretreatment with 2 weeks of B. infantis before standard triple therapy increased the eradication rate from 68.9% to 90.5%.[38]

Although our results showed that pretreatment with 2 weeks of probiotics prior to 10-day quadruple therapy was associated with good efficacy and safety in patients with repeated eradication failures, this study was a retrospective, single-center trial without a control group. Thus, it is necessary to develop controlled trials to confirm the benefits of probiotics in patients receiving antibiotic regimens for the treatment of H. pylori infections. However, because the eradication rate from tetracycline- and furazolidone-containing quadruple therapy is very high, large samples would be needed to identify a statistically significant difference. In addition, to further analyze the beneficial effects of probiotics on gastric microecology, it is necessary to study gene-level changes in the gastric microbiota following the use of probiotics.

 Conclusions



Patients who have failed multiple H. pylori eradication regimens may benefit from pretreatment with probiotics followed by a combined tetracycline- and furazolidone-containing quadruple regimen to achieve a high eradication rate and limited adverse effects.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Mentis A, Lehours P, Megraud F. Epidemiology and diagnosis of Helicobacter pylori infection. Helicobacter 2015;20(Suppl 1):1-7.
2Sgouras DN, Trang TT, Yamaoka Y. Pathogenesis of Helicobacter pylori infection. Helicobacter 2015;20(Suppl 1):8-16.
3Sugano K, Tack J, Kuipers EJ, Graham DY, El-Omar EM, Miura S, et al. Kyoto global consensus report on Helicobacter pylori gastritis. Gut 2015;64:1353-67.
4Liu WZ, Xie Y, Lu H, Cheng H, Zeng ZR, Zhou LY, et al. Fifth Chinese national consensus report on the management of Helicobacter pylori infection. Helicobacter 2018;23:e12475.
5Zhang YX, Zhou LY, Song ZQ, Zhang JZ, He LH, Ding Y. Primary antibiotic resistance of Helicobacter pylori strains isolated from patients with dyspeptic symptoms in Beijing: A prospective serial study. World J Gastroenterol 2015;21:2786-92.
6Bai P, Zhou LY, Xiao XM, Luo Y, Ding Y. Susceptibility of Helicobacter pylori to antibiotics in Chinese patients. J Dig Dis 2015;16:464-70.
7Thung I, Aramin H, Vavinskaya V, Gupta S, Park JY, Crowe SE, et al. Review article: The global emergence of Helicobacter pylori antibiotic resistance. Aliment Pharmacol Ther 2016;43:514-33.
8Chinese Society of Gastroenterology, Chinese Study Group on Helicobacter pylori, Liu WZ, Xie Y, Cheng H, Lu NH, Hu FL, Zhang WD, et al. Fourth Chinese national consensus report on the management of Helicobacter pylori infection. J Dig Dis 2013;14:211-21.
9Tsuda M, Kato M, Ono S, Matsuda K, Miyamoto S, Abiko S, et al. Changes of dyspeptic symptom after successful eradication in Helicobacter pylori-associated syspepsia. Digestion 2020;101:165-173.doi:10.1159/000497432.
10Kang SJ, Park B, Shin CM. Helicobacter pylori Eradication therapy for functional syspepsia: A meta-analysis by region and H. pylori prevalence. J Clin Med 2019;8. pii: E1324. doi: 10.3390/jcm8091324.
11Reshetnyak VI, Reshetnyak TM. Significance of dormant forms of Helicobacter pylori in ulcerogenesis. World J Gastroenterol 2017;23:4867-78.
12Kong YJ, Yi HG, Dai JC, Wei MX. Histological changes of gastric mucosa after Helicobacter pylori eradication: A systematic review and meta-analysis. World J Gastroenterol 2014;20:5903-11.
13Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: An open-label, randomised controlled trial. Lancet 2008;372:392-7.
14Wong BC, Lam SK, Wong WM, Chen JS, Zheng TT, Feng RE, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: A randomized controlled trial. JAMA 2004;291:187-94.
15Malfertheiner P, Megraud F, O’Morain CA, Gisbert JP. Management of Helicobacter pylori infection-the Maastricht V/Florence consensus report. Gut 2017;66:6-30.
16TMalfertheiner P, Megraud F, O’Morain CA, Atherton J, Axon AT, Bazzoli F, et al. Management of Helicobacter pylori infection--the Maastricht IV/Florence consensus report. Gut 2012;61:646-64.
17Hsu PI, Tsai FW, Kao SS, Hsu WH, Cheng JS, Peng NJ, et al. Ten-day quadruple therapy comprising proton pump inhibitor, bismuth, tetracycline, and levofloxacin is more effective than standard levofloxacin triple therapy in the second-line treatment of Helicobacter pylori infection:
18Gao W, Zheng SH, Cheng H, Wang C, Li YX, Xu Y, et al. [Tetracycline and metronidazole based quadruple regimen as first line treatment for penicillin allergic patients with Helicobacter pylori infection]. CMJ 2019;99:1536-40.
19Nyssen OP, McNicholl AG. Meta-analysis of three-in-one single capsule bismuth-containing quadruple therapy for the eradication of Helicobacter pylori. Helicobacter 2019;24:e12570.
20White AH. Absorption, distribution, metabolism, and excretion of furazolidone. A review of the literature. Scand J Gastroenterol Suppl 1989;169:4-10.
21Haas CE, Nix DE, Schentag JJ. In vitro selection of resistant Helicobacter pylori. Antimicrob Agents Chemother 1990;34:1637-41
22Cheng H, Hu FL. Furazolidone, amoxicillin, bismuth and rabeprazole quadruple rescue therapy for the eradication of Helicobacter pylori. World J Gastroenterol 2009;15:860-4.
23Song C, Qian X, Zhu Y, Shu X, Song Y, Xiong Z, et al. Effectiveness and safety of furazolidone-containing quadruple regimens in patients with Helicobacter pylori infection in real-world practice. Helicobacter 2019;24:e12591.
24Roghani HS, Massarrat S, Shirekhoda M, Butorab Z. Effect of different doses of furazolidone with amoxicillin and omeprazole on eradication of Helicobacter pylori. J Gastroenterol Hepatol 2003;18:778-82
25Felga GE, Silva FM, Barbuti RC, Navarro-Rodriguez T, Zaterka S, Eisig JN. Quadruple therapy with furazolidone for retreatment in patients with peptic ulcer disease. World J Gastroenterol 2008;14:6224-7.
26Eisig JN, Silva FM, Rodriguez TN, Hashimoto CL, Barbuti RC. A furazolidone-based quadruple therapy for Helicobacter pylori retreatment in patients with peptic ulcer disease. Clinics (Sao Paulo) 2005;60:485-8.
27Liang X, Xu X, Zheng Q, Zhang W, Sun Q, Liu W, et al. Efficacy of bismuth-containing quadruple therapies for clarithromycin-, metronidazole-, and fluoroquinolone-resistant Helicobacter pylori infections in a prospective study. Clin Gastroenterol Hepatol 2013;11:802-7.e1.
28Zhang Y, Gao W, Cheng H, Zhang X, Hu F. Tetracycline- and furazolidone-containing quadruple regimen as rescue treatment for Helicobacter pylori infection: A single center retrospective study. Helicobacter 2014;19:382-6.
29Fallone CA, Chiba N, van Zanten SV, Fischbach L, Gisbert JP, Hunt RH, et al. The Toronto consensus for the treatment of Helicobacter pylori infection in adults. Gastroenterology 2016;151:51-69.e14.
30Lu M, Yu S, Deng J, Yan Q, Yang C, Xia G, et al. Efficacy of probiotic supplementation therapy for Helicobacter pylori eradication: A meta-analysis of randomized controlled trials. PloS One 2016;11:e0163743.
31Zhou BG, Chen LX. Saccharomyces boulardii as an adjuvant therapy for Helicobacter pylori eradication: A systematic review and meta-analysis with trial sequential analysis. Helicobacter 2019;24:e12651.
32Chen L, Xu W, Lee A, He J, Huang B, Zheng W, et al. The impact of Helicobacter pylori infection, eradication therapy and probiotic supplementation on gut microenvironment homeostasis: An open-label, randomized clinical trial. EBioMedicine 2018;35:87-96.
33Dang Y, Reinhardt JD, Zhou X, Zhang G. The effect of probiotics supplementation on Helicobacter pylori eradication rates and side effects during eradication therapy: A meta-analysis. PloS One 2014;9:e111030.
34Lv Z, Wang B, Zhou X, Wang F, Xie Y, Zheng H, et al. Efficacy and safety of probiotics as adjuvant agents for Helicobacter pylori infection: A meta-analysis. Exp Ther Med 2015;9:707-16.
35Johnson-Henry KC, Mitchell DJ, Avitzur Y, Galindo-Mata E, Jones NL, Sherman PM. Probiotics reduce bacterial colonization and gastric inflammation in H. pylori-infected mice. Dig Dis Sci 2004;49:1095-102.
36Pan M, Wan C, Xie Q, Huang R, Tao X, Shah NP, et al. Changes in gastric microbiota induced by Helicobacter pylori infection and preventive effects of Lactobacillus plantarum ZDY 2013 against such infection. J Dairy Sci 2016;99:970-81.
37Du YQ, Su T, Fan JG, Lu YX, Zheng P, Li XH, et al. Adjuvant probiotics improve the eradication effect of triple therapy for Helicobacter pylori infection. World J Gastroenterol 2012;18:6302-7.
38Dajani AI, Abu Hammour AM, Yang DH, Chung PC, Nounou MA, Yuan KY, et al. Do probiotics improve eradication response to Helicobacter pylori on standard triple or sequential therapy? Saudi J Gastroenterol 2013;19:113-20.