Song et al.

BMC Gastroenterology (2019) 19:132

https://doi.org/10.1186/s12876-019-1056-3

RESEARCH ARTICLE Open Access

Cefuroxime, levofloxacin, esomeprazole,

and bismuth as first-line therapy for
eradicating Helicobacter pylori in patients
allergic to penicillin
Zhiqiang Song, Wei Fu and Liya Zhou*

Abstract
Background: Eradicating Helicobacter pylori infection is clinically challenging, notably in cases with penicillin allergy.
Cephalosporin could be used in lieu of amoxicillin to eradicate Helicobacter pylori. The current work aimed to assess
therapeutic efficacy and safety of a cefuroxime-based quadruple regimen in treatment-naïve individuals with penicillin
allergy, as well as patient compliance.
Methods: In the present prospective single-center cohort study, 152 Helicobacter pylori infected individuals with penicillin
allergy received eradication therapy with cefuroxime (500 mg twice/day), levofloxacin (500 mg once/day), esomeprazole
(20 mg twice/day) and bismuth potassium citrate (220 mg twice/day; 14 days). Safety and compliance were evaluated 1
to 3 days upon eradication. The urea breath test was carried out 8 to 12 weeks upon eradication for efficacy assessment.
Results: This quadruple antimicrobial regimen eradicated the pathogen at 85.5% (95% confidence interval (CI) 79.6–
90.8%), 88.4% (95% CI 83.0–93.2%) and 90.1% (95% CI 85.2–94.4%) in intention-to-treat, modified intention-to-treat and
per-protocol analyses, respectively, with resistance rates of 4.6 and 40.0% in the background of cefuroxime and
levofloxacin, respectively. Meanwhile, 21.3% of patients had adverse reactions, but none was serious. A total of 95.3% of
patients showed good compliance. Poor compliance and cefuroxime resistance were detected by uni- or multivariate
analyses as independent factors predicting therapeutic failure. Eradication rates in patients with dual levofloxacin and
cefuroxime susceptibility, isolated levofloxacin resistance, isolated cefuroxime resistance and dual resistance were 97.2,
84.0, 50.0, and 0%, respectively (P = 0.002).
Conclusions: Cefuroxime, levofloxacin, esomeprazole, and bismuth achieved decent efficacy, safety and compliance as
first-line antimicrobial regimen in patients with Helicobacter pylori and penicillin allergy.
Keywords: Helicobacter pylori, Penicillin allergy, Cefuroxime, Levofloxacin, Eradication, Safety, Compliance

Background clinical practice [1–4]. Amoxicillin (semi-synthetic peni-

Helicobacter pylori (H. pylori) infection and associated cillin) is the core medicine used for H. pylori eradication
diseases are important global health problems. Eradica- due to its long-term low resistance rate [2–5]. However,
tion therapy is important in treating and preventing H. approximately 5–10% of patients cannot take amoxicillin
pylori infection-related diseases [1]. In recent years, H. because of penicillin allergy, leading to more difficult H.
pylori eradication has been increasingly difficult, mostly pylori eradication in such cases [6–8]. According to the
due to increased antibiotic resistance (e.g., to clarithro- guidelines of Maastricht V Consensus Report, for pa-
mycin and metronidazole) and the limited availability of tients allergic to penicillin, the proton pump inhibitor
some antibiotics (e.g., tetracycline and furazolidone) in (PPI)-clarithromycin-metronidazole triple therapy is rec-
ommended as first-line eradication regimen in regions
* Correspondence: [email protected] with low resistance to clarithromycin; in geographical
Department of Gastroenterology, Peking University Third Hospital, Beijing areas with elevated resistance to clarithromycin, bismuth
100191, China

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Song et al. BMC Gastroenterology (2019) 19:132 Page 2 of 9

quadruple antimicrobial regimen is recommended [1]. further improvement of the eradication efficacy [14, 26].
Because of generally increased resistance to clarithromy- Moreover, our previous study showed that 14-day cefur-
cin and metronidazole, PPI-clarithromycin-metronida- oxime-levofloxacin-PPI-bismuth treatment results in a
zole therapy achieves unsatisfactory cure rates in most relatively good eradication rate (89.8% in the per-proto-
regions of the world [9–12]. In addition, due to a num- col analysis) in patients without penicillin allergy [20].
ber of shortcomings (e.g., complicated administration, Currently, clinical studies assessing levofloxacin-contain-
common adverse reactions, and tetracycline unavailabil- ing regimens for first-line H. pylori eradication in pa-
ity in many regions), the clinical application of bismuth tients with penicillin allergy are unavailable.
quadruple therapy has been restricted [13–15]. There- Therefore, this work primarily aimed to assess the eradi-
fore, for penicillin-allergic patients, safe, effective and cation efficacy of cefuroxime, levofloxacin, esomeprazole,
accessible regimens for H. pylori eradication are still and bismuth (CLEB) regimen in patients infected by H.
lacking. pylori with penicillin allergy. We also evaluated safety and
Cephalosporin and penicillin are β-lactam antibiotics, compliance for the above regimen, and analyzed risk fac-
which share the same bactericidal mechanism (competi- tors that affect its efficacy in eradicating H. pylori.
tive inhibition of trans-peptidase, hindering peptidoglycan
synthesis to suppress the biological functions or cause cell Methods
wall destruction in H. pylori) [16–18]. Antimicrobial sensi- Patients and setting
tivity testing in vitro revealed a low resistance rate for The current prospective cohort study was performed at
cephalosporin in H. pylori (similar to that of amoxicillin) the Gastroenterology clinic in a tertiary hospital of
[19–21]. The limited data from a few clinical studies dem- Beijing, China, from January 2015 to March 2017. Adult
onstrated that cephalosporin-containing regimens achieve patients with dyspepsia and penicillin allergy were en-
relatively satisfactory eradication rates [20, 22, 23]. .These rolled with clinically diagnosed H. pylori infection and
findings suggested that cephalosporin has a high potential no prior eradication treatment.
for H. pylori treatment. On the other hand, early observa- Exclusion criteria were: age < 18 years; medicines with
tional studies have shown that approximately 10% of peni- potential to affect results, including PPIs, H2-receptor
cillin-allergic patients are also allergic to cephalosporin blockers, bismuth salts, and antibiotics within 4 weeks;
(cross-allergic phenomena) [24, 25]. However, with the ac- gastrointestinal cancer; a history of gastric or esophageal
cumulation of treatment experiences and further related operation; severe concomitant disease; known allergy to
researches, it is currently considered that the actual inci- any study drug; pregnancy or lactation in women.
dence of cross-allergy phenomena is very low [6, 8].
Meanwhile, cross-allergy phenomena appear only in first- Ethical consideration
generation and some second-generation cephalosporins Each patient provided signed informed consent. This
with the similar side-chain structure of penicillin; other trial had approval from the Ethics Committee of Peking
cephalosporins could be safely applied in penicillin-allergic University Third Hospital, Beijing, China, and con-
patients [6, 8, 16, 18]. Moreover, cephalosporins are formed to the Declaration of Helsinki following Good
generally characterized by good safety and tolerance, Clinical Practice. All authors evaluated study results and
as well as convenience and wide clinical application approved the final manuscript.
[6, 8, 22, 23]. In view of these characteristics and
advantages, it is reasonable to hypothesize that for Study procedures
penicillin-allergic patients, second or third generation Health care professionals at the Gastroenterology Unit
cephalosporins without the penicillin-like side-chain provided a comprehensive explanation regarding the
structure could be potential effective alternatives to regimen and possible deleterious effects to the included
amoxicillin in eradicating H. pylori. To date, no re- patients. In addition, the patients were instructed orally
lated clinical study in this field has been reported. and in writing regarding the importance of regular medi-
Levofloxacin is usually used for rescue eradication of ation intake, with recommendation to continue treat-
H. pylori infection [1, 3]. However, recently published ment even in case of mild or moderate adverse reactions
studies indicated that 14-day first-line treatment with and to call physicians for severe secondary effects. They
amoxicillin-levofloxacin-PPI-bismuth still achieves satis- were required to return within 3 days of eradication for
factory eradication rates in regions with high levofloxa- the assessment of treatment compliance and adverse
cin resistance [20, 26]. This finding suggested that events. H. pylori eradication was evaluated 8–12 weeks
bismuth and levofloxacin have synergistic bactericidal upon treatment by the urea breath test (UBT; UCBT Kit,
effects. Bismuth increases the sensitivity of H. pylori to Atom High Tech, China). This was an open label trial.
levofloxacin and, to a certain extent, facilitates the over- Adverse events were determined by asking open-ended
coming of resistance to the latter, which results in questions using patient self-reports and physical
Song et al. BMC Gastroenterology (2019) 19:132 Page 3 of 9

examinations, and grouped into the mild (no interfer- H. pylori culture and antibacterial sensitivity test
ence with daily routine), moderate (limited effects on H. pylori was cultured or obtained from the gastric mu-
daily routine), severe (marked effects on daily routine cosa, and in vitro antibiotic resistance was evaluated by
and medication discontinuation), and serious (death, the Epsilometer test (AB Biodisk, Sweden) [2, 19]. H.
hospitalization, disability, or required intervention for pylori strains with minimal inhibitory concentrations
permanent damage prevention) types. (μg/ml) of > 0.5, > 0.5, > 1, > 8, > 2, and > 1 were deemed
Compliance assessed by pill count was considered good to show resistance to amoxicillin, cefuroxime, clarithro-
(≥ 80% of pills taken) or poor (< 80% of drugs taken). Indi- mycin, metronidazole, levofloxacin, and tetracycline, re-
viduals poorly complying were not taken into account in spectively [2, 5, 19, 27–30].
the per-protocol (PP) analysis.
Statistical analysis
Intervention The sample size of 138 cases administered the CLEB
The CLEB regimen consisted of cefuroxime (500 mg regimen produced a 95% confidence interval (CI) reflect-
twice/day after breakfast and supper), levofloxacin (500 ing the sample proportion ± 5% with an estimated H.
mg once/day after breakfast), esomeprazole (20 mg pylori first-line eradication rate of 90% (in a pilot trial
twice/day before breakfast and supper) and bismuth po- conducted prior to the present investigation, successful
tassium citrate (220 mg twice/day before breakfast and eradication was achieved in 27/30 patients). Therefore,
supper) for 14 days. ≥152 cased had to be enrolled to compensate for a 10%
withdrawal rate.
H. pylori detection The primary outcome was eradication rates in the
Before enrolment, H. pylori infection was assessed as fol- intention-to-treat (ITT; all patients administered at least
lows: (1) positive rapid urease test (RUT; HPUT-H102, one drug dose), modified intention-to-treat (mITT; cases
San Qiang Bio & Che, China) and histological Warthin- administered at least one drug dose and submitted to
Starry staining, and (2) positive UBT. Post-therapeutic UBT), and PP (cases with complete adhesion to the trial
H. pylori detection was by UBT 8 to 12 weeks upon protocol, except for poorly compliant individuals) ana-
eradication treatment. H. pylori infection was deemed lyses. Secondary outcomes included adverse event and
eradicated with a single negative UBT. compliance rates.
In the patients who underwent upper endoscopy, gas- SPSS v18 (SPSS Inc., USA) was employed for all statis-
tric tissue biopsies obtained from the antrum were tical analyses. P < 0.05 indicated statistical significance.
assessed by the RUT. In case of positive RUT, 2 biopsy Categorical variables were presented as percentages or
samples from the antrum and corpus, respectively, were frequencies, and continuous ones as mean ± SD. Eradica-
submitted to Warthin-Starry staining and H. pylori dens- tion rates and 95%CIs were determined. Pearson’s chi-
ity evaluation. Two other samples from the antrum and square or Fisher’s exact test was employed to compare
corpus, respectively, were cultured for H. pylori and categorical variables. Univariate analysis was carried out
assessed for antibacterial sensitivity. Histological index to determine factors predicting H. pylori eradication
grading was based on the updated Sydney system [27]. after ≥1 drug dose with the patient showing an endpoint.
H. pylori density assessment was as + (sparse and spor- Multivariate logistic regression analysis (backward mod-
adic), ++ (dense) and +++ (aggregated) distributions. eling and likelihood ratio) was performed for variables
The information about antibiotic resistance was statistically significant in univariate analysis.
employed for the analysis of parameters affecting eradi- Penicillin allergy definition included any of the follow-
cation efficacy, but not for selecting first-line therapeu- ing criteria: (1) a history of allergic reactions, such as
tics. In case of CLEB therapy failure, the information fever, rash, skin itching, and anaphylactic shock after
was used to guide drug selection for second-line eradica- penicillin received by oral administration, muscular in-
tion therapy. jection, and intravenous injection; (2) positive skin test.
UBT was carried out following overnight fasting. Base- A total of 20 min after intradermal injection of 0.1 ml of
line breath samples were collected by blowing through the penicillin skin reagent, the penicillin skin test was
plastic straws into 20-ml containers, and capsules with considered to be positive with any of the following signs:
75 mg of 13C-urea were provided to the patients with local skin uplift with red halos, subcutaneous induration
100 ml water. Then, breath samples were obtained 30 with a diameter of more than 1 cm, pseudopodia and
min later. A difference between baseline and 30-min itching around the red halos, skin rash all over the body,
samples exceeding 4.0 parts/1,000 of 13CO2 as assessed and anaphylactic shock.
on a gas isotope ratio mass spectrometer (GIRMS ZC- Cigarette smoking was reflected by > 1 cigarette pack/
202, Wan Yi Sci& Tech, China) indicated positive week consumed in the past 6 months. Alcohol drinking
results. was reflected by > 50 g of alcohol/day consumed in the
Song et al. BMC Gastroenterology (2019) 19:132 Page 4 of 9

past 6 months. After upper endoscopy, patients showing 85.2–94.4%; 128 of 142) in ITT, mITT and PP analyses,
duodenal and/or gastric ulcers were considered to have with resistance rates of 4.6 and 40.0% in the background
peptic ulcer disease, whereas those with no ulcers were of cefuroxime and levofloxacin, respectively.
regarded as non-ulcer dyspepsia cases. In addition, the
cases with dyspepsia not examined by upper endoscopy
Adverse effects and compliance
were considered as having uninvestigated dyspepsia.
A total of 32 (21.3%) patients showed adverse reactions,
with 20, 9 and 3 mild, moderate and severe types, re-
Results
spectively. Nevertheless, serious adverse reactions were
The study flowchart is displayed in Fig. 1. One hundred
not observed. Adverse reactions are summarized in
fifty-two cases were included and administered eradica-
Table 2. Good compliance was achieved in 143 (95.3%)
tion treatment. Ten cases were excluded from the PP
cases.
analysis due to loss to follow-up (n = 2), intolerance to
study drugs (n = 3), protocol violation (n = 1), and poor
compliance (n = 4). The baseline properties of all en- Parameters affecting eradication efficacy
rolled patients are listed in Table 1. H. pylori was de- In univariable analysis, eradication rate was markedly
tected in 77 patients by upper endoscopy using the RUT elevated in cases with good compliance compared with
and Warthin-Starry staining (these cases underwent H. the non-compliance group (90.1% vs. 40.0%, P < 0.001).
pylori culture, antibacterial sensitivity test, and H. pylori Eradication rate was equally affected by cefuroxime re-
density assessment) and 75 patients by the UBT (H. pyl- sistance (91.8% vs. 33.3%, P = 0.002). Age, gender, body
ori culture and antimicrobial sensitivity test were suc- mass index, cigarette smoking, alcohol drinking, diagno-
cessfully performed in 65 patients or 84.4%). ses, H. pylori density, and levofloxacin resistance did not
significantly affect the eradication rate (Table 3). Multi-
Eradication rates variable analysis further revealed that poor compliance
CLEB treatment yielded eradication rates of 85.5% (95% (odds ratio (OR) = 18.000, 95% CI 1.843–175.775, P =
CI 79.6–90.8%; 130 of 152 patients), 88.4% (95% CI 0.013) and cefuroxime resistance (36.000, 2.500–518.371,
83.0–93.2%; 130 of 147 patients) and 90.1% (95% CI P = 0.008) independently predicted therapy failure.

Fig. 1 Study flowchart ITT, intention-to-treat; mITT, modified intention-to-treat; PP, per-protocol; UBT, urea breath test
Song et al. BMC Gastroenterology (2019) 19:132 Page 5 of 9

Table 1 Patient baseline features resistance, and dual cefuroxime and levofloxacin resist-
Variable Patients enrolled ance were 97.2, 84.0, 50.0, and 0%, respectively (P = 0.002).
(n = 152)
Age, mean ± SD (years) 42.8 ± 13.7 Discussion
Gender (female/male) 70/82 H. pylori represents one of the major human pathogens.
Body mass index, mean ± SD (kg/m2) 23.1 ± 2.8 About 50% of all humans currently have H. pylori infec-
tion, with 5–10% of cases combined with penicillin al-
Cigarette smoking (yes/no) 24/128
lergy [1, 6–8]. Therefore, cases of H. pylori infection and
Alcohol drinking (yes/no) 28/124
penicillin allergy are relatively common and constitutes
Allergy to penicillin (skin 112/40 an important subgroup in H. pylori eradication strat-
test positive/past allergy history)
egies. Eradicating H. pylori in individuals allergic to
Diagnosis (PUD/NUD/UID) 14/63/75 penicillin is an important medical challenge. According
H. pylori density (+/++/+++) a
30/28/19 to the recommendations of Maastricht V Consensus
Amoxicillin resistance (%) b 3.1 Report, PPI-clarithromycin-metronidazole and bismuth
Cefuroxime resistance (%) b
4.6 quadruple therapies are considered first-line eradication
Clarithromycin resistance (%) b 38.5
regimens in areas with low and high clarithromycin
b resistance, respectively [1]. Due to the small number of
Metronidazole resistance (%) 63.1
relevant studies and relatively low quality (Table 5)
Levofloxacin resistance (%) b 40.0 [9–12, 31–33], the degree of evidence is extremely low
b
Tetracycline resistance (%) 6.2 and the grade of recommendation is weak in the above
NUD Non-ulcer dyspepsia, PUD Peptic ulcer disease, UID guidelines. In addition, due to significantly increased
Uninvestigated dyspepsia
a
Data for H. pylori density were available in 77 patients
resistance, PPI-clarithromycin-metronidazole therapy could
b
Data for H. pylori antibacterial sensitivity were available in 65 patients not achieve satisfactory eradication efficacies in most
regions of the world [9–12]. The clinical application of
Effects of antibiotic resistance on eradication success bismuth quadruple therapy has also been restricted due to
The impacts of cefuroxime and levofloxacin resistance complicated administration, frequent adverse reactions, and
on the success rate based on various probable resistance tetracycline unavailability in many regions [13–15]. There-
combinations are shown in Table 4. Eradication rates of fore, more related studies are required to establish a new
cases showing dual cefuroxime and levofloxacin suscep- safe, effective, and widely applied regimen for eradicating
tibility, single levofloxacin resistance, isolated cefuroxime H. pylori.
In the present study, the CLEB regimen achieved satis-
Table 2 Adverse events and compliance factory eradication efficacy (85.5, 88.4, and 90.1% in ITT,
Variable, n (%) Eradication therapy mITT, and PP analyses, respectively) even in an area
(n = 150) with high resistance (38.5% to clarithromycin, 63.1% to
Fatigue 18 (12.0) metronidazole, and 40.0% to levofloxacin). Moreover,
Anorexia 15 (10.0) both safety (incidence of side effects of only about 20%)
and compliance (good compliance beyond 95%) data
Abdominal pain/discomfort 14 (9.3)
were good. The majority of adverse events were transi-
Nausea 12 (8.0)
ent and mild or moderate, and no overt cross-allergic
Diarrhea 12 (8.0) reactions occurred. These findings provide a very prom-
Headache 5 (3.3) ising new eradication regimen for H. pylori infected
Vomiting 3 (2.0) cases with penicillin allergy.
Skin rash 2 (1.3) As mentioned above, cephalosporin could be a good
alternative to amoxicillin for H. pylori eradication in pa-
Taste distortion 2 (1.3)
tients with penicillin allergy. In this study, we used
Dizziness 2 (1.3)
cefuroxime, mainly for the following reasons. (1) Cefur-
Patients with adverse reactions 32 (21.3) oxime and amoxicillin have an identical bactericidal
Mild adverse reactions 20 (13.3) mechanism through inhibition of cell wall synthesis [16–
Moderate adverse reactions 9 (6.0) 18]. (2) Cefuroxime is active against H. pylori [19, 20]. .The
Severe adverse reactions 3 (2.0) resistance rate in this study was only 4.6%, similar to that of
(Medication discontinuation) amoxicillin (3.1%). (3) It is widely available in clinical prac-
Good compliance 143 (95.3) tice. (4) Its safety and tolerance are exceedingly good. (5)
Among the enrolled patients, two (one each for lost to follow-up and protocol
Our previous study indicated that the CLEB regimen
violation) were not included in adverse effect and compliance assessments achieves relatively good eradication efficacy in patients
Song et al. BMC Gastroenterology (2019) 19:132 Page 6 of 9

Table 3 Variable analysis of factors affecting eradication efficacy

Variable, n/N (%) Univariable analysis Multivariable analysis
Eradication efficacy (n = 147) P value OR (95% CI) P value
Age
< 35 years 40/45 (88.9) 0.991
35–55 years 59/67 (88.1)
> 55 years 31/35 (88.6)
Gender:
female 61/68 (89.7) 0.655
male 69/79 (87.3)
Body mass index:
< 22.0 kg/m2 38/42 (90.5) 0.856
2
22.0–25.0 kg/m 60/68 (88.2)
> 25.0 kg/m2 32/37 (86.5)
Cigarette smoking:
yes 19/22 (86.4) 0.742
no 111/125 (88.8)
Alcohol drinking:
yes 21/25 (84.0) 0.447
no 109/122 (89.3)
Diagnosis:
PUD 14/14 (100.0) 0.361
NUD 53/61 (86.9)
UID 63/72 (87.5)
H. pylori density :
a

+ 25/29 (86.2) 0.929

++ 24/27 (88.9)
+++ 17/19 (89.4)
Compliance:
good 128/142 (90.1) < 0.001 18.000 0.013
poor 2/5 (40.0) (1.843–175.775)
Cefuroxime resistance b:
susceptible 56/61 (91.8) 0.002 36.000
resistant 1/3 (33.3) (2.500–518.371) 0.008
Levofloxacin resistance b:
susceptible 36/38 (94.7) 0.079
resistant 21/26 (80.8)
CI Confidence interval, NUD Non-ulcer dyspepsia, OR Odds ratio, PUD Peptic ulcer disease, UID Uninvestigated dyspepsia
a
Data for H. pylori density were available in 75 patients
b
Data for H. pylori antimicrobial sensitivity were available in 64 patients

Table 4 Effects of cefuroxime and levofloxacin resistance on Helicobacter pylori eradication

Variable, n/N (%) Eradication efficacy (n = 64)
Cefuroxime susceptible and levofloxacin susceptible 35/36 (97.2)
Cefuroxime susceptible and levofloxacin resistant 21/25 (84.0)
Cefuroxime resistant and levofloxacin susceptible 1/2 (50.0)
Cefuroxime resistant and levofloxacin resistant 0/1 (0)
P = 0.002
Song et al. BMC Gastroenterology (2019) 19:132 Page 7 of 9

Table 5 Clinical studies of first-line Helicobacter pylori eradication in patients allergic to penicillin
Publication year Country Center Number Regimen ITT cure rate PP cure rate Adverse reaction rate
2005 [10] Spain single 12 PPI + CLA + MET 7 days 58% 64% 17%
2005 [31] Puerto Rico single 17 PPI + TET + MET 10 days 84% 84% unavailable
2006 [32] Japan single 5 PPI + TET + MET 7–14 days 80% 100% unavailable
2010 [11] Spain multiple 50 PPI + CLA + MET 7 days 54% 55% 10%
2014 [33] Japan single 11 PPI + MET+SIT 7–14 days 100% 100% 64%
2015 [9] Spain multiple 112 PPI + CLA + MET 7 days 57% 59% 14%
50 PPI + TET + MET+BIS 10 days 74% 75% 14%
2017 [12] Japan single 10 PPI + CLA + MET 7 days 50% 56% unavailable
13 VPZ + CLA + MET 7 days 92% 92% unavailable
20 PPI + MET+SIT 7 days 100% 100% unavailable
14 VPZ + MET+SIT 7 days 93% 100% unavailable
BIS Bismuth, CLA Clarithromycin, MET Metronidazole, ITT Intention-to-treat, PP Per-protocol, PPI Proton pump inhibitor, SIT Sitafloxacin, TET Tetracycline,
VPZ Vonoprazan

without penicillin allergy, with good safety and compliance factors for failed eradication of H. pylori related disease,
[20]; (6) As a second-generation cephalosporin, cefuroxime confirming that antibiotic sensitivity and treatment com-
does not have a side chain structure similar to amoxicillin, pliance represent the two top parameters determining
showing no overt cross-allergy phenomenon [6, 8, 16, 18]. successful H. pylori treatment [1, 36].
The present study further confirmed that no obvious cross- At present, tetracycline is difficult to obtain clinically
allergic effects were observed. in the mainland of China, so bismuth-containing quad-
In the present study, another crucial antibiotic was levo- ruple therapy (bismuth, metronidazole, tetracycline and
floxacin, and the main reasons for its selection are PPI) is rarely used. In the case of penicillin allergy, most
described below. (1) Levofloxacin is broadly available in patients were received two antibiotics from clarithromy-
clinic. (2) Its overall safety and tolerability are good. (3) cin, levofloxacin and metronidazole for eradication.
Recently published clinical studies have shown that 14-day These three antibiotics have high resistance rates in the
amoxicillin-levofloxacin-PPI-bismuth quadruple antimicro- mainland of China, and the cure rate is poor and unsat-
bial treatment as a first-line regimen achieves satisfactory isfactory. According to the relevant expert experiences
eradication rates even in areas showing elevated levofloxa- and past study reports, the eradication rates were esti-
cin resistance [20, 26]. A study further by our group mated only about 50–60% [9–12]. This study provides
showed that 14-day cefuroxime-levofloxacin-PPI-bismuth us a promising regimen for the patients allergic to peni-
quadruple antimicrobial treatment also yields relatively cillin. If the CLEB regimen fails, it will be very difficult.
good eradication rates in patients without penicillin allergy Tetracycline, furazolidone and rifabutin are difficult to
[20]. Previous studies revealed that at levofloxacin re- obtain clinically, and the resistance rates of clarithromy-
sistance rates reaching 15–20%, levofloxacin-containing cin and metronidazole are very high. For the patients
triple regimens do not yield acceptable eradication ef- with penicillin allergy in the mainland of China, maybe
ficacy [5, 26]. In the current work, however, levofloxacin other options could be chosen for the next eradication,
resistance rate reached 40%, but the CLEB regimen still such as minocycline/metronidazole containing quadru-
showed relatively good efficacy, which may be closely re- ple regimen [37] or eradication therapy based on culture
lated to the inclusion of bismuth. On one hand, bismuth and susceptibility.
possesses antimicrobial properties itself [14, 34]. On the The present work had limitations: (1) All patients were
other hand, bismuth helped overcome H. pylori resistance from the same hospital, and multi-center trials in various
to levofloxacin, further improving eradication efficacy. world areas are required to confirm the present results.
This might be explained by that bismuth suppresses pro- (2) The previous antibiotic use experience would affect
ton translocation to the bacterial cytoplasm and maintains the eradication rate, probably related to secondary anti-
intracellular pH at a level beneficial for metabolism and biotic resistance from previous treatment [1, 17]. Unfor-
division in bacteria, enhancing the antibacterial efficacies tunately, in this study we did not ask about the history
of antimicrobials [34, 35]. of antibiotic use for other infectious diseases. In the
As shown above, uni- and multi-variable analyses re- future research, we can do an in-depth and accurate
vealed antibiotic resistance and poor compliance as risk evaluation and discussion on this topic. (3) In addition,
Song et al. BMC Gastroenterology (2019) 19:132 Page 8 of 9

no control group was set. Therefore, it remains unknown 5. Graham DY. Hp-normogram (normo-graham) for assessing the outcome of
whether any actual differences exist in eradication efficacy, H. pylori therapy: effect of resistance, duration, and CYP2C19 genotype.
Helicobacter. 2016;21(2):85–90.
safety, and compliance between this regimen and other 6. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr
recommended regimens for patents with penicillin allergy. Allergy Asthma Rep. 2014;14(11):476.
Nevertheless, the present study provides an important ref- 7. Mirakian R, Leech SC, Krishna MT, Richter AG, Huber PA, Farooque S, et al.
Management of allergy to penicillins and other beta-lactams. Clin Exp
erence for carrying out further related studies. Allergy. 2015;45(2):300–27.
8. Pichichero ME, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy
Conclusions Asthma Immunol. 2014;112(5):404–12.
9. Gisbert JP, Barrio J, Modolell I, Molina-Infante J, Aisa AP, Castro-Fernandez
Overall, quadruple therapy with cefuroxime, levofloxa- M, et al. Helicobacter pylori first-line and rescue treatments in the presence
cin, esomeprazole and bismuth achieves satisfactory of penicillin allergy. Dig Dis Sci. 2015;60(2):458–64.
eradication effectiveness, safety and compliance as first- 10. Gisbert JP, Gisbert JL, Marcos S, Olivares D, Pajares JM. Helicobacter pylori
first-line treatment and rescue options in patients allergic to penicillin.
line treatment in H. pylori infected cases with penicillin Aliment Pharmacol Ther. 2005;22(10):1041–6.
allergy. 11. Gisbert JP, Perez-Aisa A, Castro-Fernandez M, Barrio J, Rodrigo L, Cosme A,
et al. Helicobacter pylori first-line treatment and rescue option containing
Abbreviations levofloxacin in patients allergic to penicillin. Dig Liver Dis. 2010;42(4):287–90.
H. pylori: Helicobacter pylori; PP: Per-protocol; PPI: Proton pump inhibitor 12. Ono S, Kato M, Nakagawa S, Mabe K, Sakamoto N. Vonoprazan improves
the efficacy of Helicobacter pylori eradication therapy with a regimen
Acknowledgements consisting of clarithromycin and metronidazole in patients allergic to
None. penicillin. Helicobacter. 2017;22(3):e12374.
13. Graham DY, Lee SY. How to effectively use bismuth quadruple therapy: the
Authors’ contributions good, the bad, and the ugly. Gastroenterol Clin N Am. 2015;44(3):537–63.
ZS contributed to study design, the clinical study, and manuscript 14. Lu H, Zhang W, Graham DY. Bismuth-containing quadruple therapy for
preparation. WF contributed to the clinical study and experimental testing. helicobacter pylori: lessons from China. Eur J Gastroenterol Hepatol. 2013;
LZ contributed to study design and manuscript editing. All authors have 25(10):1134–40.
read and approved the final manuscript. 15. Zhang W, Chen Q, Liang X, Liu W, Xiao S, Graham DY, et al. Bismuth,
lansoprazole, amoxicillin and metronidazole or clarithromycin as first-line
Funding helicobacter pylori therapy. Gut. 2015;64(11):1715–20.
The current work was funded by the National Science & Technology Pillar 16. Campagna JD, Bond MC, Schabelman E, Hayes BD. The use of
Program of the twelfth Five-Year Plan in China (2012BAI06B02), the National cephalosporins in penicillin-allergic patients: a literature review. J Emerg
Natural Science Foundation of China (Grant No. 81670605), the Clinical key Med. 2012;42(5):612–20.
projects of Peking University Third Hospital (Y76493–03) and the Key labora- 17. Furuta T, Graham DY. Pharmacologic aspects of eradication therapy for
tory for Helicobacter pylori infection and upper gastrointestinal diseases in helicobacter pylori infection. Gastroenterol Clin N Am. 2010;39(3):465–80.
Beijing (No. BZ0371). The funding body had no role in the design of the 18. Pichichero ME, Casey JR. Safe use of selected cephalosporins in penicillin-allergic
study and collection, analysis, and interpretation of data and in writing the patients: a meta-analysis. Otolaryngol Head Neck Surg. 2007;136(3):340–7.
manuscript. 19. Bai P, Zhou LY, Xiao XM, Luo Y, Ding Y. Susceptibility of helicobacter pylori
to antibiotics in Chinese patients. J Dig Dis. 2015;16(8):464–70.
Availability of data and materials 20. Fu W, Song Z, Zhou L, Xue Y, Ding Y, Suo B, et al. Randomized clinical trial:
The datasets employed and/or analyzed in this study are available from the esomeprazole, bismuth, levofloxacin, and amoxicillin or cefuroxime as first-
corresponding author upon reasonable request. line eradication regimens for helicobacter pylori infection. Dig Dis Sci. 2017;
62(6):1580–9.
Ethics approval and consent to participate 21. Samra Z, Shmuely H, Niv Y, Dinari G, Passaro DJ, Geler A, et al. Resistance of
Each patient provided signed informed consent. This trial had approval from helicobacter pylori isolated in Israel to metronidazole, clarithromycin, tetracycline,
the Ethics Committee of Peking University Third Hospital, Beijing, China, and amoxicillin and cefixime. J Antimicrob Chemother. 2002;49(6):1023–6.
conformed to the Declaration of Helsinki following Good Clinical Practice. All 22. Fagoonee S, Astegiano M, Smedile A, Pellicano R. Efficacy of cefixime-based
authors evaluated study results and approved the final manuscript. triple therapy for helicobacter pylori eradication: a retrospective study.
Panminerva Med. 2013;55(3):309–10.
Consent for publication 23. Tatsuta M, Ishikawa H, Iishi H, Okuda S, Yokota Y. Reduction of gastric ulcer
Not applicable. recurrence after suppression of helicobacter pylori by cefixime. Gut. 1990;
31(9):973–6.
Competing interests 24. Miranda A, Blanca M, Vega JM, Moreno F, Carmona MJ, Garcia JJ, et al.
The authors declare that they have no competing interests. Cross-reactivity between a penicillin and a cephalosporin with the same
side chain. J Allergy Clin Immunol. 1996;98(3):671–7.
Received: 14 December 2018 Accepted: 21 July 2019 25. Pichichero ME. Use of selected cephalosporins in penicillin-allergic patients:
a paradigm shift. Diagn Microbiol Infect Dis. 2007;57(3 Suppl):13s–8s.
26. Liao J, Zheng Q, Liang X, Zhang W, Sun Q, Liu W, et al. Effect of
References fluoroquinolone resistance on 14-day levofloxacin triple and triple plus
1. Malfertheiner P, Megraud F, O'Morain CA, Gisbert JP, Kuipers EJ, Axon AT, et bismuth quadruple therapy. Helicobacter. 2013;18(5):373–7.
al. Management of Helicobacter pylori infection-the Maastricht V/Florence 27. Liou JM, Chen CC, Chen MJ, Chen CC, Chang CY, Fang YJ, et al. Sequential
consensus report. Gut. 2017;66(1):6–30. versus triple therapy for the first-line treatment of helicobacter pylori: a
2. Song Z, Zhang J, He L, Chen M, Hou X, Li Z, et al. Prospective multi-region multicentre, open-label, randomised trial. Lancet. 2013;381(9862):205–13.
study on primary antibiotic resistance of helicobacter pylori strains isolated 28. Molina-Infante J, Romano M, Fernandez-Bermejo M, Federico A, Gravina AG,
from Chinese patients. Dig Liver Dis. 2014;46(12):1077–81. Pozzati L, et al. Optimized nonbismuth quadruple therapies cure most
3. Graham DY, Fischbach L. Helicobacter pylori treatment in the era of patients with Helicobacter pylori infection in populations with high rates of
increasing antibiotic resistance. Gut. 2010;59(8):1143–53. antibiotic resistance. Gastroenterology. 2013;145(1):121–128.e121.
4. Megraud F, Coenen S, Versporten A, Kist M, Lopez-Brea M, Hirschl AM, et al. 29. Su P, Li Y, Li H, Zhang J, Lin L, Wang Q, et al. Antibiotic resistance of
Helicobacter pylori resistance to antibiotics in Europe and its relationship to helicobacter pylori isolated in the southeast coastal region of China.
antibiotic consumption. Gut. 2013;62(1):34–42. Helicobacter. 2013;18(4):274–9.
Song et al. BMC Gastroenterology (2019) 19:132 Page 9 of 9

30. Zhou L, Zhang J, Song Z, He L, Li Y, Qian J, et al. Tailored versus triple plus
bismuth or concomitant therapy as initial helicobacter pylori treatment: a
randomized trial. Helicobacter. 2016;21(2):91–9.
31. Rodriguez-Torres M, Salgado-Mercado R, Rios-Bedoya CF, Aponte-Rivera E,
Marxuach-Cuetara AM, Rodriguez-Orengo JF, et al. High eradication rates of
helicobacter pylori infection with first- and second-line combination of
esomeprazole, tetracycline, and metronidazole in patients allergic to
penicillin. Dig Dis Sci. 2005;50(4):634–9.
32. Matsushima M, Suzuki T, Kurumada T, Watanabe S, Watanabe K, Kobayashi
K, et al. Tetracycline, metronidazole and amoxicillin-metronidazole
combinations in proton pump inhibitor-based triple therapies are equally
effective as alternative therapies against helicobacter pylori infection. J
Gastroenterol Hepatol. 2006;21(1 Pt 2):232–6.
33. Furuta T, Sugimoto M, Yamade M, Uotani T, Sahara S, Ichikawa H, et al.
Eradication of H. pylori infection in patients allergic to penicillin using triple
therapy with a PPI, metronidazole and sitafloxacin. Intern Med. 2014;53(6):571–5.
34. Dore MP, Lu H, Graham DY. Role of bismuth in improving helicobacter
pylori eradication with triple therapy. Gut. 2016;65(5):870–8.
35. Marcus EA, Sachs G, Scott DR. Colloidal bismuth subcitrate impedes proton
entry into helicobacter pylori and increases the efficacy of growth-
dependent antibiotics. Aliment Pharmacol Ther. 2015;42(7):922–33.
36. Graham DY, Lee YC, Wu MS. Rational Helicobacter pylori therapy: evidence-
based medicine rather than medicine-based evidence. Clin Gastroenterol
Hepatol. 2014;12(2):177–186.e173 Discussion e112–173.
37. Song ZQ, Zhou LY. Esomeprazole minocycline metronidazole and bismuth
as first-line and second-line regimens for helicobacter pylori eradication. J
Dig Dis. 2016;17(4):260–7.

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