pathogens

Article
A Comparison of Doxycycline and Amoxicillin Containing
Quadruple Eradication Therapy for Treating Helicobacter
pylori-Infected Duodenal Ulcers: A Multicenter, Opened,
Randomized Controlled Trial in China
Jingshu Chi 1 , Canxia Xu 1, *, Xiaoming Liu 1, * , Hao Wu 1 , Xiaoran Xie 1 , Peng Liu 1 , Huan Li 1 , Guiying Zhang 2 ,
Meihua Xu 3 , Chaomin Li 4 , Chunlian Wang 5 , Fengqian Song 6 , Ming Yang 7 and Jie Wu 1

1 Department of Gastroenterology, Third Xiangya Hospital of Central South University, Changsha 410013, China
2 Xiangya Changde Hospital, Changde 415000, China
3 Department of Gastroenterology, Xiangya Hospital of Central South University, Changsha 410008, China
4 Shaoyang Central Hospital, Shaoyang 422000, China
5 Department of Gastroenterology, Second Xiangya Hospital of Central South University, Changsha 410011, China
6 Loudi Central Hospital, Loudi 417000, China
7 The Affiliated Hospital of Yongzhou Vocational Technical College, Yongzhou 425006, China
* Correspondence: xucanxia@csu.edu.cn (C.X.); liuxiaoming26@csu.edu.cn (X.L.)

Abstract: Background: Increased antibiotic resistance is one of the major factors contributing to the
failure of H. pylori eradication. This study aimed to compare the efficacy and safety of doxycycline
and amoxicillin, both critical components for bismuth-based quadruple therapy, for the first-line
Citation: Chi, J.; Xu, C.; Liu, X.; Wu, treatment of H. pylori-infected duodenal ulcers. Methods: An open, randomized case-controlled,
H.; Xie, X.; Liu, P.; Li, H.; Zhang, G.; multicenter trial was conducted in seven hospitals in China. A total of 184 eligible participants
Xu, M.; Li, C.; et al. A Comparison of
were divided into an IDFB (ilaprazole 5 mg, doxycycline 100 mg, furazolidone 100 mg, and bismuth
Doxycycline and Amoxicillin
220 mg bid) or IAFB (ilaprazole 5 mg, amoxicillin 1000 mg, furazolidone 100 mg, and bismuth
Containing Quadruple Eradication
220 mg bid) group for 14 days. Both groups were administrated with ilaprazole 5 mg qd for another
Therapy for Treating Helicobacter
14 days. The main outcome was an H. pylori eradication rate; secondary outcomes were ulcer healing,
pylori-Infected Duodenal Ulcers: A
Multicenter, Opened, Randomized
relief of symptoms, and incidence of adverse effects. Results: The H. pylori eradication rates were
Controlled Trial in China. Pathogens 85.9% (95% CI 78.6–93.9) in the IDFB vs. 84.8% (95% CI 77.3–92.3) in the IAFB group in ITT analysis
2022, 11, 1549. https://doi.org/ (p > 0.05), and 92.9% (95% CI 87.4–98.5) vs. and 91.8% (95% CI 85.8–97.7) in PP analysis (p > 0.05).
10.3390/pathogens11121549 The overall ulcer healing rates of IDFB and IAFB were 79.1% and 84.7% (p > 0.05), both effective in
relieving symptoms. Only nine participants had adverse reactions in this trial (4/92 in IDFB and
Academic Editors: Emad M. El-Omar
and Lawrence S. Young
5/92 in IAFB). Conclusion: A bismuth quadruple regimen containing doxycycline or amoxicillin
could be an effective and safe treatment for H. pylori eradication, while doxycycline replacement is an
Received: 31 October 2022 alternative for participants with penicillin allergy.
Accepted: 14 December 2022
Published: 16 December 2022
Keywords: Helicobacter pylori; antibiotic resistance; doxycycline; eradication; safety; penicillin allergy
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in
published maps and institutional affil-
iations. 1. Introduction
Although the detection and treatment of Helicobacter pylori (H. pylori) are more accessi-
ble, H. pylori infection is highly prevalent worldwide, especially in developing countries [1].
Peptic ulcers, such as duodenal ulcers, are one of the most common diseases caused by
Copyright: © 2022 by the authors.
H. pylori infection [2]. It is likely to cause delayed healing and complications such as
Licensee MDPI, Basel, Switzerland.
This article is an open access article
bleeding and perforation and may even endanger the patient’s life once not well treated [3].
distributed under the terms and
The treatment of H. pylori is low-cost and highly effective. Authors of consensus guidelines
conditions of the Creative Commons
strongly recommend that timely eradication therapy is necessary for H. pylori-infected ulcer
Attribution (CC BY) license (https:// participants [4–7].
creativecommons.org/licenses/by/ Increased antimicrobial resistance with high resistance rates to clarithromycin, lev-
4.0/). ofloxacin, and metronidazole has been found [8], which is the most common reason the

Pathogens 2022, 11, 1549. https://doi.org/10.3390/pathogens11121549 https://www.mdpi.com/journal/pathogens

Pathogens 2022, 11, 1549 2 of 10

bismuth-based quadruple therapy (BQT) approach fails [4,6]. In contact, antibiotics such
as furazolidone, amoxicillin, and tetracycline have comparatively low resistance and can
achieve effective eradication, especially when used in BQT [9]. As the most used semi-
synthetic penicillin broad-spectrum-lactam antibiotic, amoxicillin consistently demon-
strates good efficacy and compliance both in the initial and remedial eradication treatment
of H. pylori. However, penicillin is one of the most common drugs to cause an allergic
reaction with an allergy rate of 5–10% of the population [10,11], patients treated with
amoxicillin are prone to erythema as well as severe adverse events such as hemorrhagic
enteritis [12]. The selection of a suitable therapeutic regimen is thus difficult for H. pylori-
infected participants with penicillin allergies.
A series of previous studies have tended to recommend proton pump inhibitor (PPI)-
clarithromycin-metronidazole and/or bismuth-containing regimens for first-line eradica-
tion of H. pylori infection with penicillin allergy, but such eradication regimens are less
effective due to the high drug resistance of clarithromycin and metronidazole in most
regions, achieving only 50–70% eradication rates [13,14]. The use of tetracycline instead
of clarithromycin was slightly more effective [15]. While tetracycline is the recommended
drug of conventional guidelines for eradicating H. pylori [16,17], others have shown that
the use of tetracycline increases the risk of side reactions [18], limiting its clinical use.
Doxycycline is a second-generation semi-synthetic tetracycline antibiotic that is less com-
monly used in H. pylori eradication therapies [19]. Interestingly, its range of medications
is similar to that of amoxicillin, which could theoretically replace amoxicillin for H. pylori
eradication treatment.
In this parallel opened, randomized controlled, multicenter study, the efficacy and
safety of bismuth-based quadruple therapy containing doxycycline or amoxicillin for
initially treating participants with H. pylori infection-associated duodenal ulcer were com-
pared. The overall aim was to provide a safe, effective new treatment for the eradication of
H. pylori in penicillin-allergic patients.

2. Methods
2.1. Study Design and Patients
A parallel opened, randomized controlled, multicenter trial was conducted in seven
tertiary class hospitals in five cities of Hunan Province, China, between November 2017 and
September 2019. A random sequence was constructed in 1:1, which was divided into two
groups. Outpatients were randomly assigned to one of the groups in sequence. The study
terminated at the last expiration date of the same batch of drugs. This study was approved
by the committee of central research institution (Third Xiangya Hospital of Central South
University), then other hospitals recorded and followed this approval. The study also has
been registered on ClinicalTrials.gov (number NCT03342456). All participants gave their
informed consent.
Participants all had a gastroscopic diagnosis of an active duodenal ulcer (Sakita and
Miwa ulcer stage A1/A2) with a diameter of 0.3–2.0 cm and counts of less than two,
accompanied by gastrointestinal symptoms. Further, participants ranged in age from
18 to 65, and H. pylori infection was initially found through 13C/14C-urea breath test or
histopathological examination. Potential participants who had taken PPI in the past two
weeks, antibiotics and/or bismuth in the past four weeks, or had been taking non-steroidal
anti-inflammatory drugs and adrenocortical hormones, or were allergic to the tested drugs
were excluded. Patients who were suspected to have cancerous ulcers or who had tumor
alarm symptoms, other severe diseases of the digestive and other systems, or surgical
history were also excluded. Potential participants who were pregnant, breastfeeding, or
planning a family, who had severe heart and lung diseases, or who abused drugs and/or
alcohol were unsuitable for this clinical drug trial.
Pathogens 2022, 11, 1549 3 of 10

2.2. Interventions
Participants were randomly assigned to one of two groups by computer-generated
random sequences. Those in the IDFB group received 5 mg of ilaprazole (Livzon Phar-
maceutical Group Inc., Zhuhai, China, 100 mg of doxycycline (Yung Shin Pharm, Ind.,
Kunshan Co., Ltd., Kunshan, China), 100 mg of furazolidone (Yunpeng Shanxi Pharmaceu-
tical Co., Ltd., Linfen, China), and 220 mg of bismuth potassium bismuth citrate (Livzon
Pharmaceutical Group Inc., Zhuhai, China) twice a day for 14 days. The IAFB group was
treated with 1000 mg of amoxicillin (Zhuhai United Laboratories (Zhongshan) Co., Ltd.,
Zhongshan, China) instead of the doxycycline. After 14 days, 5 mg of ilaprazole was given
to both groups, once a day, for an additional 14 days.

2.3. CurativeEffects Evaluation

H. pylori eradication: A negative 13C/14C-urea breath test four weeks after discontin-
uation of all drugs indicated successful eradication of H. pylori. The H. pylori eradication
rate = number of cases eradicated/total number of cases ×100%.
Therapeutic effects of duodenal ulcer: Four weeks after eradication drugs were
taken, the gastroscopic manifestations were compared with those during screening gas-
troscopy. The degree of ulcer healing was assessed using the classification of Sakita and
Miwa [20]. The criterion for cure efficiency was whether the ulcer disappeared or was in
Stage S1/S2 [21]. Overall cure rate = number of cured cases/total number of cases ×100%.
Evaluation of symptomatic remissions: All symptoms including epigastric pain, heart-
burn, acid regurgitation, nausea and vomiting, belching, and abdominal distension were
recorded before and on days 14 and 28 after taking medicine. Severity was graded as
0 (none), 1 (mild: easy to tolerate), 2 (moderate: affecting normal life), or 3 (severe: unable
to live a normal life) [22]. The method has been verified and used to assess gastrointestinal
symptoms in Chinese patients [23,24].

2.4. Outcome Evaluation

The primary outcome was the H. pylori eradication rate, while the therapeutic effects
on the duodenal ulcer and symptomatic remissions were the secondary outcomes.

2.5. Side Effects Evaluation

Side effects including abdominal pain, diarrhea, erythema, nausea, and dizziness were
recorded on days 14 and 28, as well as 28 days after withdrawal of the drugs. Any necessary
treatment was given.

2.6. Sample Size Estimation and Statistical Analysis

A non-inferiority design was used in this study. Based on previous studies, we
assumed that the eradication rate of the amoxicillin-containing quadruple eradication
program was 90% [25,26] and 92% for the doxycycline regimen [27]. According to PASS12,
the non-inferiority margin should be set to −10%, α = 0.025 and β = 0.20, and each group
should include at least 80 individuals. In this trial, 200 participants were initially included
during screening.
H. pylori eradication rates and gastroscopic cure rates for ulcers were expressed as
percentages and evaluated with 95% confidence intervals. The H. pylori eradication rate
was analyzed by per-protocol (PP) and intention-to-treat (ITT), while symptom relief and
ulcer effectiveness were analyzed by PP analysis alone. p < 0.05 represents statistical
significance. All data were analyzed using SPSS18. A chi-square test or Fisher’s exact
test was used to assess the significance of the categorical data, while a t-test was used for
continuous variables.

3. Results
A total of 200 outpatients diagnosed with duodenal ulcers and H. pylori infection were
screened in different hospitals. Sixteen patients were excluded for the following reasons:
 nificance. All data were analyzed using SPSS18. A chi-square test or Fisher’s exact tes
used to assess the significance of the categorical data, while a t-test was used for con
ous variables.

Pathogens 2022, 11, 1549 3. Results 4 of 10

A total of 200 outpatients diagnosed with duodenal ulcers and H. pylori infe
were screened in different hospitals. Sixteen patients were excluded for the followin
sons:
history of taking PPIhistory of taking
and other PPIinand
drugs theother
past drugs in the (n
two weeks past twoulcer
= 5); weeksnot (nin
= 5); ulcer not in a
active
phase (n = 4); ulcer with active bleeding (n = 3); and the refusal
phase (n = 4); ulcer with active bleeding (n = 3); and the refusal of the treatment regimen of the treatment reg
(n = 4). Following this, 184 eligible participants were randomly
(n = 4). Following this, 184 eligible participants were randomly assigned to two groups: assigned to two gr
the IDFB group (92 participants) and the IAFB group (92
the IDFB group (92 participants) and the IAFB group (92 participants). Throughout the participants). Throughou
study, 14
study, 14 participants participants
(7.6%) dropped(7.6%) dropped
out, of which 12 out, of which
were lost to12 were lostastothey
follow-up follow-up
could as they
notor
not be contacted berefused
contacted or refused
to recheck, andtotwo
recheck, and two because
discontinued discontinued because
of giving of giving up t
up taking
medication by themselves
medication by themselves (Figure 1). (Figure 1).

Figure 1. StudyFigure
flow chart. Baseline
1. Study data concerning
flow chart. age,concerning
Baseline data sex, vital signs, andvital
age, sex, history of the
signs, andstudy
history of the
population werepopulation
analyzed. No statistical
were difference
analyzed. was founddifference
No statistical between thewastwo groups
found (p > 0.05,
between theTable
two1).
groups (p
Table 1).
Table 1. Demographic analysis of the study population.

Variable IDFB (n = 92) IAFB (n = 92) p Value

Age (y) 41.84 ± 11.48 43.09 ± 11.31 0.46 a
Gender (n,%)
Male 56 (60.9%) 61 (66.3%)
0.44 b
Female 36 (39.1%) 31 (33.7%)
BMI 22.53 ± 2.61 22.29 ± 3.00 0.56 a
Vital Signs
ortho-arteriotomy (n,%) 87 (94.6%) 86 (93.5%) 0.76 b
respiratory rate (t) 16.52 ± 2.08 16.73 ± 2.31 0.53 a
pulse rate (b/min) 75.48 ± 8.30 73.96 ± 7.21 0.19 a
temperature (°C) 36.79 ± 1.04 36.67 ± 0.30 0.31 a
Course (d) 51.77 ± 130.55 39.49 ± 84.36 0.45 a
Past-history
none (n,%) 78 (84.8%) 83 (90.2%) 0.27 b
a t-test; b Chi-square test; BMI, body mass index.
Pathogens 2022, 11, 1549 5 of 10

The eradication rates in the ITT analysis were 85.9% (95% CI 78.6–93.9) for the IDFB
group and 84.8% (95% CI 77.3–92.3) for the IAFB group, p = 0.84. The use of PP analysis
showed that eradication rates for the two groups were 92.9% (95% CI 87.4–98.5) and 91.8%
(95% CI 85.8–97.7), respectively, p = 0.77. No statistical difference in the eradication rate
between the two groups was found for either analysis (Table 2).

Table 2. Eradication of H. pylori infection in different treatment groups.

Efficacy IDFB (n = 92) IAFB (n = 92) χ2 p Value b

Eradication success 79 78
Eradication failure 6 7
Cases dropped 7 7
Eradication rate
TT (95%CI) 85.9% (78.6–93.9) 84.8% (77.3–92.3) 0.04 0.84
PP (95%CI) 92.9% (87.4–98.5) 91.8% (85.8–97.7) 0.08 0.77
b Chi-square test; ITT, intention-to-treat; PP, per-protocol; CI, confidence interval.

Ulcer healing was determined by comparing endoscopic features of participants who

had re-examined gastroscopy before and after taking medicine. The ulcer cure rate for the
two groups was 79.1% (95% CI 69.1–89.1) and 84.7% (95% CI 76.2–93.2) by PP analysis,
with no significant difference found between the two groups (p = 0.39, Table 3).

Table 3. Therapeutic effects of duodenal ulcer in different treatment groups.

Efficacy IDFB (n = 67) IAFB (n = 72) χ2 p Value b

Obvious effect 53 61
No effect 14 11
Effective rate
79.1% (69.1–89.1) 84.7% (76.2–93.2) 0.74 0.39
P (95%CI)
b Chi-square test; PP, per-protocol; CI, confidence interval.

Subjective symptoms were quantified by a rating scale. Two groups presented similar
scores of the baseline symptoms (Table 4). Both groups achieved good overall symptom
remission after participating in the study. The decreased total scores were 4.65 ± 0.32 in IDFB
and 5.09 ± 0.34 in IAFB after 14 days and 5.25 ± 0.37 and 5.73 ± 0.33 after 28 days of therapies,
respectively. Two groups reduced more than 96% of the initial symptom scores (Table 5).

Table 4. Baseline of clinical symptom scores of two groups.

Variable IDFB (n = 85) IAFB (n = 85) p Value a

Epigastric pain
day 1.13 ± 0.07 1.27 ± 0.07 0.17
night 1.08 ± 0.09 1.28 ± 0.09 0.13
Heartburn
day 0.35 ± 0.06 0.45 ± 0.07 0.32
night 0.28 ± 0.06 0.35 ± 0.07 0.42
Acid regurgitation
day 0.53 ± 0.08 0.51 ± 0.08 0.84
night 0.33 ± 0.07 0.29 ± 0.06 0.71
Nausea and vomiting 0.33 ± 0.06 0.33 ± 0.07 1
Belching 0.65 ± 0.08 0.65 ± 0.07 1
Abdominal distension 0.75 ± 0.08 0.82 ± 0.08 0.53
Total 5.44 ± 0.37 5.95 ± 0.33 0.29
a t-test.
Pathogens 2022, 11, 1549 6 of 10

Table 5. Changes of clinical symptom scores after 14 and 28 days of therapy in different groups.

14 Days 28 Days
Variable IDFB IAFB IDFB IAFB
p Value a p Value a
(n = 85) (n = 85) (n = 85) (n = 85)
Epigastric pain
day 1.00 ± 0.07 1.05 ± 0.08 0.67 1.11 ± 0.07 1.24 ± 0.08 0.25
night 0.93 ± 0.09 1.12 ± 0.10 0.16 1.05 ± 0.09 1.26 ± 0.09 0.14
Heartburn
day 0.27 ± 0.06 0.41 ± 0.07 0.12 0.32 ± 0.06 0.45 ± 0.07 0.18
night 0.22 ± 0.05 0.33 ± 0.07 0.2 0.25 ± 0.06 0.35 ± 0.07 0.31
Acid
regurgitation
day 0.47 ± 0.08 0.46 ± 0.08 0.92 0.52 ± 0.08 0.51 ± 0.08 0.91
night 0.31 ± 0.06 0.26 ± 0.07 0.61 0.32 ± 0.07 0.28 ± 0.06 0.64
Nausea and
0.28 ± 0.06 0.29 ± 0.07 0.9 0.33 ± 0.06 0.32 ± 0.07 0.96
vomiting
Belching 0.55 ± 0.07 0.44 ± 0.06 0.22 0.62 ± 0.08 0.51 ± 0.07 0.37
Abdominal
0.61 ± 0.07 0.74 ± 0.08 0.30 0.74 ± 0.08 0.82 ± 0.08 0.43
distension
Total 4.65 ± 0.32 5.09 ± 0.34 0.34 5.25 ± 0.37 5.73 ± 0.33 0.33
a t-test.

A total of nine participants had adverse reactions during the trial. These included
abdominal pain, diarrhea, erythema, nausea, and dizziness, all of which were mild with
spontaneous remission. The incidence of both side effects was low, with four (4.3%) in the
IDFB group and five (5.4%) in the IAFB group. Similarly, no statistical significance was
found between the two groups (Table 6).

Table 6. Side effects associated with the two groups (n, %).

Side Effects IDFB (n = 92) IAFB (n = 92) p Value c

Abdominal pain 1
Diarrhea 1 2
Dizziness 1 1
Nausea 1 1
Erythema 1
Total 4 (4.3%) 5 (5.4%) 1
c Fisher’s exact test.

4. Discussion
In this study, participants with H. pylori infections complicated with duodenal ulcer
were treated for the first-time using doxycycline or amoxicillin combined with furazolidone
and Ilaprazole as a 14-day bismuth agent quadruple therapy with significant, remarkable re-
sults. Both therapeutic schemes achieved good eradication efficacy, a clearly deceased ulcer
area, effectively alleviated gastric symptoms, and had few side effects. Additionally, these
results did not differ significantly between the two groups, suggesting that doxycycline
could replace amoxicillin as a new option for H. pylori eradication.
Due to widespread, inappropriate antibiotic use, antimicrobial resistance is a common
factor affecting treatment to eradicate H. pylori [28]. Raising eradication efficiency can be
achieved by selecting better and large doses of PPI, and adding bismuth, an antibiotic
combination, or personalized medication following a drug susceptibility test [29]. Unfor-
tunately, susceptibility testing for patients is rarely performed and unrealistic in China,
because of our large H. pylori infected population and the limitation of testing technology in
primary hospitals. Compared with antimicrobial susceptibility testing, an empiric 14-day
bismuth-containing quadruple therapy is an option that can improve the eradication effect
distinctly with a higher cost–benefit ratio [6]. Our research is further evidence of the superi-
Pathogens 2022, 11, 1549 7 of 10

ority of such a scheme; both types of eradication therapy had high cure rates of H. pylori
infection in PP analyzed. Moreover, Ilaprazole was selected as PPI in the current study.
It is the third generation of PPI and not metabolized by CYP2C19 enzymes, which has a
prolonged plasma half-life hence small individual differences [30]. Ilaprazole can effectively
inhibit gastric acid secretion with a low dose and fewer times of administration [31,32]. As
well as amoxicillin and doxycycline, furazolidone is another antibiotic used in this study,
which is a nitrofuran antibiotic with low resistance rates [33]. These drugs also helped
the trial run smoothly, and effectively alleviate the symptoms of ulcer participants and
promote ulcer healing
Authors of previous studies have shown that the total eradication rate of H. pylori can
reach approximately 90.0% with a combination of two antibiotics containing amoxicillin [9].
As well as amoxicillin and doxycycline, furazolidone is another antibiotic used in this study,
which is a nitrofuran antibiotic with low resistance rates [33]. Quadruple therapies based
on a combination of furazolidone and amoxicillin were effective in eradicating H. pylori,
with a rate of more than 90% at seven days treatment to 10 days [34]. In this trial, the
eradication rate of the control group (IAFB) was as high as 91.8%, which is similar to the
efficacy found in previous studies. However, amoxicillin was quite effective in traditional
therapies, including the IAFB scheme in this study. The allergic phenomenon of penicillin is
still a challenge for H. pylori eradication. Thus, many authors have focused on anti-H. pylori
therapy for participants who have an amoxicillin allergy [35]. In addition to conventional
alternatives for clarithromycin and metronidazole, previous retrospective research has
demonstrated that a first-line bismuth-based quadruple therapy (tetracycline and metron-
idazole or furazolidone) received an eradication rate of over 91%, while about 30% were
adverse events [36,37]. Recent first-line studies showed non-inferiority in the eradication
efficiency between tetracycline and amoxicillin bismuth-based quadruple therapies, but the
tetracycline-containing regimens showed a higher risk of adverse reactions [17,38]. These
data indicated that traditional tetracycline was effective in H. pylori eradication treatments
and, particularly, could be used instead of amoxicillin. However, at the same time, it was
associated with a greater risk of side effects that led to its limited clinical application.
As a second-generation, semi-synthetic tetracycline antibiotic, doxycycline has approx-
imately the same antibacterial spectrum as tetracycline, but a higher bioavailability [39]. A
study between doxycycline and tetracycline for a 10-day regimen found that the doxycy-
cline group not only had a higher eradication rate but also far fewer side effects (11.6%)
than the tetracycline group (31.0%) [40]. Thus, doxycycline appears to show better safety
by comparison. In the current study, only 4.6% of the participants in the IDFB group
experienced mild adverse reactions that disappeared with the cessation of the drug, further
verifying the safety of doxycycline. In addition, a meta-analysis found that treatment with
doxycycline was more effective for eradicating H. pylori than those without semisynthetic
tetracycline [41]. Researchers have found that a 14-day doxycycline-containing (100 mg bid)
bismuth-basted quadruple regimen could gain approximately 93.8% eradication in the
first-line treatment [42] but was not as satisfactory in a 5-day regimen [43]. Therefore,
doxycycline seems more effective when used in an entire course with a bismuth-containing
quadruple regimen. From our results, the therapeutic effect in the doxycycline and furazoli-
done group (IDFB) was up to 92.9%, slightly higher than the amoxicillin therapy, suggesting
a potential application value of doxycycline for the treatment of H. pylori eradication. In
addition, this trial has reflected the superior performance of doxycycline in symptom relief
for patients with duodenal ulcers, which other researchers rarely demonstrate.
Doxycycline has not been widely used for eradicating H. pylori, meaning there are
limited studies in this area so far [44,45]. There is controversy about the application of
its course of treatment, dosage, and other details. In this prospective study, doxycycline
showed significant efficacy and safety, possibly due to the dose, the 14-day full course,
the low resistance of antibiotic combination, and the use of bismuth. It is suggested that
the use of doxycycline in the first-line treatment for H. pylori infection could be expanded,
especially in antibacterial treatment for patients allergic to penicillin. However, there are
Pathogens 2022, 11, 1549 8 of 10

some limitations to this study. We did not test patients’ sensitivity to each medicine nor did
we explore whether a shorter duration of antibiotic treatment (such as 7 or 10 days) could
achieve similar efficacy. This can be clarified in future in-depth studies.

5. Conclusions
To conclude, doxycycline-containing bismuth-based quadruple therapy is safe and
effective for the eradication treatment of H. pylori infection, providing a good alternative
for amoxicillin-allergic patients.

Author Contributions: J.C.: Data curation, Formal analysis, Investigation, Methodology, and
Writing—original draft; C.X.: Conceptualization, Funding acquisition, Investigation, Project adminis-
tration, and Writing—review and editing; X.L.: Investigation, Methodology, Project administration,
Supervision, and Writing—review and editing; H.W. and X.X.: Data curation, Investigation, Project
administration, and Supervision; H.L. and P.L.: Data curation, Investigation, and Supervision; G.Z.:
Investigation, Methodology, and Project administration; M.X., C.W., C.L., F.S. and M.Y.: Data curation
and Investigation; J.W.: Data curation. All authors have read and agreed to the published version of
the manuscript.
Funding: This study was supported by the National Natural Science Foundation of China,
NO. 81570509; the Changsha Municipal Natural Science Foundation, NO. kq2014257, and the Scien-
tific Research Project of Hunan Provincial Health Commission, NO. 202103031034.
Institutional Review Board Statement: The study was conducted in accordance with the guidelines
of China and was approved by the Institutional Review Board of Third Xiangya Hospital of Central
South University (NO.17147, 10/17/2017).
Informed Consent Statement: Informed consent was obtained from all participants involved in
the study.
Data Availability Statement: Not applicable.
Acknowledgments: The authors would like to thank Livzon Pharmaceutical Group Inc. for providing
free ilaprazole and bismuth potassium bismuth citrate for this study. Furthermore, we thank Yung
Shin Pharm. Ind., Kunshan Co., Ltd. for providing doxycycline, amoxicillin, and other drugs needed.
Conflicts of Interest: All authors declare no conflict of interest.

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