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Salmonella infection is a major public health concern worldwide, has contributed to an increased economic burden on the health systems. Non-typhoidal Salmonella (NTS) is a common cause of bacterial enteritis in humans, causing 93.8 million cases of gastroenteritis globally each year, with 155,000 deaths. Guangzhou city is situated in the south of China and has a sub-tropical climate, the heat and heavy rainfall helps the spread of NTS. However, no information of NTS infection is available in humans in Conghua District, the largest administrative district of Guangzhou. To understand the prevalence, serotype distribution, risk factors and drug resistance of NTS infection in humans in the survey area, an epidemiological investigation was conducted in hospitalized patients in Conghua District in Guangzhou, China. A total of 255 fecal specimens were collected from hospitalized patients (one each), with a questionnaire for each participant, and NTS infection was identified by culture, as well as serotypes confirmed by slide agglutination tests. An average prevalence of 20.39% (52/255) was observed and three serogroups were identified—serogroup B (n = 46), serogroup C1 (n = 4) and serogroup D1 (n = 2). Among them, Salmonella Typhimurium (n = 39) was the most common serotype. Children aged <3 years were observed to have a statistically higher prevalence of NTS infection than adults (25.15% versus 4.65%, P = 0.006); children with artificial feeding had a statistically higher prevalence than those with breastfeeding (30.77% versus 8.33%, P = 0.044). Antimicrobial resistance testing revealed that the majority of strains were resistant to ampicillin (92.16%), as well as 47.06% of all strains were multi-drug resistant. Therefore, it is necessary to continuous monitoring and rational use of antibiotics, which will be helpful to reduce the prevalence of resistant strains. These data will aid in making efficient control strategies to intervene with and prevent occurrence of salmonellosis.
沙门氏菌感染是世界范围内的主要公共卫生问题，导致卫生系统的经济负担增加。非伤寒沙门氏菌 （NTS） 是人类细菌性肠炎的常见原因，全球每年导致 9380 万例胃肠炎病例，其中 155,000 人死亡。广州市位于中国南部，属亚热带气候，高温和强降雨有助于 NTS 的传播。然而，在广州市最大的行政区从化区，没有关于人类感染NTS的信息。为了解调查地区人类 NTS 感染的患病率、血清型分布、危险因素和耐药性，对中国广州从化区住院患者进行了流行病学调查。共从住院患者 （每人 1 份） 中收集了 255 份粪便标本，并为每位参与者提供了一份问卷，并通过培养鉴定了 NTS 感染，并通过玻片凝集试验确认了血清型。观察到平均患病率为 20.39% （52/255），并确定了三个血清型 — 血清型 B （n = 46）、血清型 C1 （n = 4） 和血清型 D1 （n = 2）。其中，鼠伤寒沙门氏菌 （n = 39） 是最常见的血清型。观察到 <3 岁儿童的 NTS 感染患病率高于成人 （25.15% 对 4.65%，P = 0.006）;人工喂养儿童的患病率高于母乳喂养儿童 （30.77% vs 8.33%，P = 0.044）。抗菌素耐药性检测显示，大多数菌株对氨苄西林耐药 （92.16%），47.06% 的菌株对氨苄青霉素耐药。 因此，有必要持续监测和合理使用抗生素，这将有助于降低耐药菌株的流行。这些数据将有助于制定有效的控制策略来干预和预防沙门氏菌病的发生。

Introduction 介绍

Salmonella infection is a major public health concern worldwide, in both industrialized and developing countries, has contributed to an increased economic burden on the health systems. Non-typhoidal Salmonella (NTS) is a common cause of bacterial enteritis in humans, causing 93.8 million cases of gastroenteritis globally each year, with 155,000 deaths (Ngogo et al., 2020).
沙门氏菌感染是世界范围内的主要公共卫生问题，无论是在工业化国家还是发展中国家，都导致卫生系统的经济负担增加。非伤寒沙门氏菌 （NTS） 是人类细菌性肠炎的常见原因，全球每年导致 9380 万例胃肠炎病例，其中 155,000 人死亡（Ngogo 等 人，2020 年）。

NTS causes a disease characterized mainly by gastroenteritis, a localized infection of the terminal ileum and colon characterized by diarrhea, vomiting and abdominal cramps (Lokken et al., 2016). However, clinical signs and symptoms are variable depending on the health status of infected hosts, and the genetic background and infective doses of this pathogen (Blaser and Newman, 1982; Hu et al., 2021). Usually, asymptomatic infection, diarrhea and other common symptoms of gastroenteritis occurs in immunocompetent or healthy individuals while bacteremia or focal infections at systemic sites may occur in immunodeficient or immuno-compromised individuals, such as infants, the elderly, individuals undergoing cancer chemotherapy and those with underlying diseases (Lokken et al., 2016).
NTS 导致一种主要以胃肠炎为特征的疾病，这是一种以腹泻、呕吐和腹部绞痛为特征的末端回肠和结肠的局部感染（Lokken 等 人，2016 年）。然而，临床体征和症状是可变的，具体取决于受感染宿主的健康状况，以及这种病原体的遗传背景和感染剂量（Blaser 和 Newman，1982 年;胡 et al.， 2021）。通常，无症状感染、腹泻和其他胃肠炎的常见症状发生在免疫功能正常或健康的个体中，而全身部位的菌血症或局灶性感染可能发生在免疫缺陷或免疫功能低下的个体中，例如婴儿、老年人、接受癌症化疗的个体和患有潜在疾病的人（Lokken 等 人，2016 年）。

According to the White–Kauffmann–Le Minor scheme, Salmonella composed of over 2600 serotypes, where most (approximately 1600 serotypes) of the them belong to the subspecies enterica (Elnekave et al., 2020). Though many serotypes (more than 200) have been identified as capable agents of producing pathology in humans, Salmonella Enteritidis (S. Enteritidis) and Salmonella Typhimurium (S. Typhimurium) are the two most common serotypes causing human salmonellosis (Xue et al., 2021; Xu et al., 2021).
根据 White-Kauffmann-Le Minor 方案，沙门氏菌由 2600 多种血清型组成，其中大多数（约 1600 种血清型）属于肠道亚种（Elnekave等 人，2020 年）。尽管许多血清型（超过 200 种）已被确定为能够在人类中产生病理学的病原体，但肠炎沙门氏菌 （S. Enteritidis） 和鼠伤寒沙门氏菌 （S. Typhimurium） 是导致人类沙门氏菌病的两种最常见血清型（Xue et al.， 2021;Xu et al.， 2021）。

Salmonella has been found in a variety of hosts, including human and animals (such as reptiles, rodents, birds and amphibian). Therefore, infection can be acquired through close-contact with humans or animals infected with Salmonella. (Haeusler and Curtis, 2013). However, most human infections of Salmonella are considered to result from ingesting contaminated food or water. Salmonella is one of the major cause of foodborne illness worldwide, accounts for 80.3 million foodborne cases per year (Mukherjee et al., 2019). Live poultry, eggs, meat or meat products, and dairy products are recognized as one of the major sources of human salmonellosis (Wu et al., 2015). In fact, the risk of Salmonella infection is related to a variety of factors, such as different lifestyle, dietary habits and environmental condition. For people living in low-income countries, poor hygiene and lack of access to safe water and food are major cause of high infection rate of Salmonella (Galgallo et al., 2018); for people living in developed countries, the consumption of contaminated fresh fruits and vegetables, and meat are the main reason (Carstens et al., 2019).
沙门氏菌存在于多种宿主中，包括人类和动物（如爬行动物、啮齿动物、鸟类和两栖动物）。因此，可以通过密切接触感染沙门氏菌的人或动物而获得感染。（Haeusler 和 Curtis，2013 年）。然而，大多数人类感染沙门氏菌被认为是由摄入受污染的食物或水引起的。沙门氏菌是全球食源性疾病的主要原因之一，每年占 8030 万例食源性病例（Mukherjee 等 人，2019 年）。活禽、蛋类、肉类或肉制品以及乳制品被认为是人类沙门氏菌病的主要来源之一（Wu 等 人，2015 年）。事实上，沙门氏菌感染的风险与多种因素有关，例如不同的生活方式、饮食习惯和环境条件。对于生活在低收入国家的人们来说，卫生条件差和无法获得安全的水和食物是沙门氏菌感染率高的主要原因（Galgallo 等 人，2018 年）;对于生活在发达国家的人们来说，食用受污染的新鲜水果和蔬菜以及肉类是主要原因（Carstens 等 人，2019 年）。

Currently, worldwide surveillance data has demonstrated a noticeable increase in antibiotic resistance among NTS (Haeusler and Curtis, 2013). Occurrence of antibiotic-resistant NTS are hampering the use of conventional antibiotics, and associated with an increased risk of treatment failure (Su et al., 2004). Meanwhile, the spread of these resistant strains to other parts of the world could pose a major public health challenge, causing significant morbidity and even mortality. Therefore, it is necessary to understand the situation of Salmonella infection and drug-resistance in different areas, it will be helpful to guide the clinical rational use of drugs and curb the development of antibiotic resistance.
目前，全球监测数据表明 NTS 的抗生素耐药性显着增加（Haeusler 和 Curtis，2013 年）。抗生素耐药性 NTS 的发生阻碍了传统抗生素的使用，并且与治疗失败的风险增加有关（Su 等 人，2004 年）。同时，这些耐药菌株传播到世界其他地区可能构成重大公共卫生挑战，导致严重的发病率甚至死亡率。因此，有必要了解不同地区的沙门氏菌感染和耐药情况，将有助于指导临床合理使用药物，遏制抗生素耐药性的发展。

In China, since the first report of salmonellosis caused by Salmonella in humans in Hong Kong in 1977, this pathogen has been attracting increased attention (Chau and Huang, 1977). Guangzhou city is situated in the south of China and has a sub-tropical climate, the heat and heavy rainfall helps the spread of NTS (Guentchev et al., 2016; Milazzo et al., 2016; Kraay et al., 2020). Some studies have reported occurrence of NTS in Guangzhou. However, no reports about prevalence, serotype distribution and antibiotic susceptibility of NTS infection in humans in Conghua District, the largest administrative district of Guangzhou. Conghua District is a region whose economy is relatively backward, agriculture and tourism are important to its economy. According to the clinical results in recent years, it was shown that the prevalence peak of NTS infection occurred in summer or autumn in this area. Thus, a cross-sectional epidemiological survey of NTS was carried out to understand the status of NTS infection, distribution of various NTS serotypes and drug susceptibility in hospitalized patients in Conghua District by culture, serological experiments and antimicrobial susceptibility testing. Meanwhile, possible risk factors for NTS infection were assessed in the investigated areas. The finding from the present study may assist in setting appropriate measures for the prevention and control of salmonellosis, and to provide reference basis for clinical rational drug use.
在中国，自 1977 年香港首次报告沙门氏菌在人类中引起沙门氏菌病以来，这种病原体一直受到越来越多的关注（Chau 和 Huang，1977 年）。广州市位于中国南部，属亚热带气候，高温和强降雨有助于 NTS 的传播（Guentchev 等 人，2016 年;Milazzo et al.， 2016;Kraay et al.， 2020）。一些研究报道了广州市 NTS 的发生率。然而，在广州市最大的行政区从化区，没有关于人类 NTS 感染的患病率、血清型分布和抗生素敏感性的报道。从化区是一个经济相对落后的地区，农业和旅游业对其经济很重要。根据近年来的临床结果，NTS 感染的流行高峰出现在该地区的夏季或秋季。因此，开展了 NTS 横断面流行病学调查，通过培养、血清学实验和药敏试验等方式了解从化区住院患者的 NTS 感染状况、各种 NTS 血清型的分布和药物敏感性。同时，在调查区域评估了 NTS 感染的可能危险因素。本研究结果可能有助于制定适当的防控沙门氏菌病措施，并为临床合理用药提供参考依据。

Materials and Methods 材料和方法

Ethics Statement 道德声明

The present study was reviewed and approved by the Ethics Committee of the Fifth Affiliated Hospital of Southern Medical University. All study participants were informed about the study objectives and the procedures involved in study participation at enrollment. Prior to collection of fecal specimens, signed informed consents was obtained from each adult individual. Additionally, for minors under 18 years of age, a written consent form was signed by the parent or legal guardian.
本研究由南方医科大学第五附属医院伦理委员会审查批准。所有研究参与者在入组时都被告知研究目标和参与研究所涉及的程序。在收集粪便标本之前，从每个成年人那里获得了签署的知情同意书。此外，对于 18 岁以下的未成年人，父母或法定监护人应签署书面同意书。

Study Area 研究区域

Guangzhou is the capital city of Guangdong Province in the southern part of China with 11 regions (aka Districts), and has a population of over 18 million. Guangzhou has a subtropical marine monsoon climate. The annual average temperature is 21.5°C–22.2°C, with the lowest (averaging 9°C–16°C) in January and the highest (averaging 28.7°C) in July. The annual rainfall averages nearly 1800 millimeters. Our study was carried out in Conghua District (population over 0.71 million), which is located on the north-east of Guangzhou, with a total area of 1974.5 square kilometers, as the largest administrative district of Guangzhou (geographical coordinates: 23.22° N–23.56° N latitude, 113.17° E–114.04° E longitude).
广州是中国南部广东省的省会城市，拥有 11 个地区（又名区），人口超过 1800 万。广州属亚热带海洋性季风气候。年平均气温为 21.5°C-22.2°C，1 月最低（平均 9°C-16°C），7 月最高（平均 28.7°C）。年平均降雨量接近 1800 毫米。我们的研究是在位于广州东北部的从化区（人口超过 71 万）进行的，总面积为 1974.5 平方公里，是广州最大的行政区（地理坐标：23.22° N–23.56° N 纬度，113.17° E–114.04° E 经度）。

Study Population and Collection of Fecal Specimens
粪便标本的研究人群和采集

During the period between June and October 2020, a cross-sectional investigation of NTS was carried out in the Fifth Affiliated Hospital of Southern Medical University in Conghua District. The hospital is the premier health care provider for local residents. The study population was patients who were clinically suspected with gastrointestinal disease (or “of NTS infection”). Patients or guardians were given clear sampling guidance before collecting stool or anal swab specimens from patients. All the specimens were delivered to the clinical laboratory department within one hour after collection and stored in a freezer at −4°C prior to experiments.
2020 年 6 月至 10 月期间，在从化区南方医科大学附属第五医院进行了 NTS 的横断面调查。该医院是当地居民首屈一指的医疗保健提供者。研究人群是临床怀疑患有胃肠道疾病（或“NTS 感染”）的患者。在收集患者的粪便或肛门拭子标本之前，患者或监护人接受了明确的采样指导。所有标本在采集后 1 小时内送至临床实验室部门，并在实验前储存在 -4°C 的冰箱中。

Questionnaire 问卷

A structured questionnaire was administered to each study participant or their guardians. The questionnaire contained some information on socio-demographic characteristics (gender, age and residence), personal hygiene habits (for example, washing hands before meals), and other possible risk factors (for example, source of infant supplementary food) for NTS infection as well as common clinical symptoms (diarrhea, abdominal pain, nausea, emesis, fever, cough, headache and joint pain). Meanwhile, each questionnaire was linked to one stool or anal swab specimen and used for our analysis in the present study.
向每个研究参与者或其监护人进行结构化问卷调查。问卷包含一些关于社会人口学特征 （性别、年龄和居住地）、个人卫生习惯 （例如饭前洗手） 和其他可能感染 NTS 的危险因素 （例如婴儿辅食的来源） 以及常见临床症状 （腹泻、腹痛、恶心、呕吐、发烧、咳嗽、头痛和关节痛） 的信息。同时，每份问卷都与一份粪便或肛门拭子标本相关联，并用于本研究的分析。

Isolation, Identification and Serotyping of Salmonella
沙门氏菌的分离、鉴定和血清分型

Stool or anal swab specimens from patients were transferred into 9 mL Selenite brilliant green enrichment broth (SBG) (Jiangmen Kailin Trading Co., Ltd.). The broth was incubated at 37°C for 24 h. Then, streaked onto xylose lysine deoxycholate agar (XLD) plates (Jiangmen Kailin Trading Co.,Ltd), and secondly selected on Hektoen Enteric agar (HE) plates (Jiangmen Kailin Trading Co., Ltd). These inoculated plates were incubated in 35°C, CO₂ incubator for 18–24 h. Salmonella was identified as transparent colonies with central black point. These suspected colonies were further subjected to biochemical tests by VITEK-Compact 2 automatic bacterial identification system (BioMérieux, Marcy-l’Étoile, France). The serotyping of Salmonella isolates was performed by the slide agglutination method using commercial (somatic) and H (flagellar) antigens (Ningbo Tianrun bio-pharmaceutical Co.,Ltd.) according to Kauffman-White scheme.
将患者的粪便或肛门拭子标本转移到 9 mL 亚硒酸盐亮绿富集汤 （SBG） （江门凯林贸易有限公司） 中。将肉汤在 37°C 下孵育 24 小时。然后，在木糖赖氨酸脱氧胆酸盐琼脂 （XLD） 平板（江门凯林贸易有限公司）上划线，然后在 Hektoen 肠溶琼脂 （HE） 平板（江门凯林贸易有限公司）上选择。这些接种板在 35°C、CO₂ 培养箱中孵育 18-24 小时。沙门氏菌被鉴定为具有中心黑点的透明菌落。这些可疑菌落通过 VITEK-Compact 2 自动细菌鉴定系统 （BioMérieux， Marcy-l'Étoile， France） 进一步进行生化测试。根据 Kauffman-White 方案，使用商业 （体细胞） 和 H （鞭毛） 抗原 （宁波天润生物制药有限公司） 通过玻片凝集法对沙门氏菌分离株进行血清分型。

Antimicrobial Susceptibility Testing
药敏试验

Antimicrobial susceptibility testing of culture positive bacterial isolates was performed by the standard disk-diffusion method (Kirby-Bauer) as recommended by the Clinical and Laboratory Standards Institute (CLSI). Combined with the clinical medication situation of the study hospital, the following antimicrobial agents (concentration) were used: Azithromycin (15 μg), Ampicillin (10 μg), Ciprofloxacin (5 μg), Chloramphenicol (30 µg), Ceftriaxone (30 µg) Amoxicillin-clavulanic acid (20/10 μg). In addition, the Minimum Inhibitory Concentrations (MICs) were determined using E-tests for seven antibiotics (Sulphamethoxazole/Trimethoprim, Piperacillin/Tazobactam, Cefepime, Ceftazidime, Imipenem, Levofloxacin and Cefoperazone/Sulbactam). The results of antibiotic susceptibility testing (sensitive, intermediate, and resistant) were read and interpreted with reference to the CLSI 2021 criteria. In addition, in the absence of CLSI criteria, in-vitro studies have used cefoperazone breakpoints for reporting the susceptibility results for cefoperazone-sulbactam. Thus, resistance was defined as ≥ 64 mg/L with a fixed ratio (2:1) of cefoperazone and sulbactam (the latter was used at 8 mg/L), intermediate susceptibility as 32/16 mg/L and susceptibility as < 16/8 mg/L (Jones et al., 1987).
按照临床和实验室标准研究所 （CLSI） 的建议，通过标准纸盘扩散法 （Kirby-Bauer） 对培养阳性细菌分离株进行药敏试验。结合研究医院的临床用药情况，使用以下抗菌药物（浓度）：阿奇霉素 （15 μg）、氨苄青霉素 （10 μg）、环丙沙星 （5 μg）、氯霉素 （30 μg）、头孢曲松 （30 μg） 阿莫西林-克拉维酸 （20/10 μg）。此外，使用七种抗生素（磺胺甲噁唑/甲氧苄啶、哌拉西林/他唑巴坦、头孢吡肟、头孢他啶、亚胺培南、左氧氟沙星和头孢哌酮/舒巴坦）的电子检验确定最低抑菌浓度 （MIC）。抗生素敏感性试验的结果（敏感、中度和耐药性）参考 CLSI 2021 标准进行阅读和解释。此外，在没有 CLSI 标准的情况下，体外研究使用头孢哌酮断点来报告头孢哌酮-舒巴坦的药敏结果。因此，耐药性定义为≥ 64 mg/L，头孢哌酮和舒巴坦的固定比例 （2：1）（后者以 8 mg/L 使用），中等敏感性为 32/16 mg/L，敏感性为 < 16/8 mg/L（Jones 等 人，1987 年）。

Quality Control 质量管理

Escherichia coli ATCC 25922 was used as a quality control strain in the present study.
在本研究中，大肠杆菌 ATCC 25922 用作质量控制菌株。

Statistical Analysis 统计分析

Descriptive statistics were used to determine the relationships between prevalence of NTS and the variables listed in Supplementary Table 1 in the present study. All statistical analyses were performed with Statistical Package for the Social Sciences (SPSS) 19.0. Pearson chi-square (χ 2) and Fisher’s exact tests were used to determine statistical significance, and P value of < 0.05 was considered significant.
描述性统计用于确定 NTS 患病率与本研究补充表 1 中列出的变量之间的关系。所有统计分析均使用 Statistical Package for the Social Sciences （SPSS） 19.0 进行。采用 Pearson 卡方 （χ 2） 和 Fisher 精确检验确定统计显著性，P 值为 < 0.05 被认为是显著的。

Results 结果

Prevalence of Salmonella Infection
沙门氏菌感染的患病率

A total of 255 fecal specimens were screened for the presence of Salmonella by the methods mentioned above. Fifty-two specimens (20.39%, 52/255) were positive for NTS.
通过上述方法共筛选了 255 份粪便标本是否存在沙门氏菌。52 例标本 （20.39%，52/255） NTS 阳性。

A number of possible risk factors related to NTS infection were analyzed in the present study, including gender, clinical signs, personal eating and hygiene habits and other risk factors (Supplementary Table 1). The prevalences of NTS were statistically different in two categories of possible risk factors: children (aged < 3 years) (25.15%, 43/171) versus adults (aged >18 years) (4.65%, 2/43) (P = 0.006), and artificial feeding (artificial milk) (30.77%, 40/130) versus breastfeeding (8.33%, 2/24) (P = 0.044). In other groups, no statistical significance was found although there were differences in infection rates of NTS (Supplementary Table 1).
本研究分析了许多与 NTS 感染相关的可能危险因素，包括性别、临床体征、个人饮食和卫生习惯以及其他危险因素 （补充表 1）。NTS 的患病率在两类可能的危险因素中存在统计学差异：儿童 （< 3 岁） （25.15%，43/171） 与成人 （>18 岁） （4.65%，2/43） （P = 0.006） 和人工喂养 （人工奶） （30.77%，40/130） 与母乳喂养 （8.33%，2/24） （P = 0.044）。在其他组中，尽管 NTS 感染率存在差异，但未发现统计学意义（补充表 1）。

In the present study, 151 patients had at least one of the eight clinical symptoms (diarrhea, abdominal pain, nausea, emesis, fever, cough, headache, joint pain) listed in Supplementary Table 2. Among them, the most common presenting symptom was diarrhea (72.85%, 110/151), followed by fever (52.98%, 80/151) and emesis (23.18%, 35/151) (Supplementary Table 3). However, by statistical calculation, no relationship was found between clinical symptoms and NTS infections (P > 0.05)
在本研究中，151 名患者至少患有补充表 2 中列出的 8 种临床症状（腹泻、腹痛、恶心、呕吐、发热、咳嗽、头痛、关节痛）中的一种。其中最常见的首发症状是腹泻 （72.85%， 110/151），其次是发热 （52.98%， 80/151） 和呕吐 （23.18%， 35/151） （补充表 3）。然而，通过统计计算，临床症状与 NTS 感染之间没有关系 （P > 0.05）

Serotype Distribution of NTS
NTS 的血清型分布

For the 52 NTS cases, the dominant serogroup detected in the present study was serogroup B (88.46%, 46/52), followed by serogroup C1 (7.69%, 4/53) and serogroup D1 (3.85%, 2/52). Among them, 39 isolates were further identified as S. Typhimurium. In the present study, serogroup B was dominant in all age groups. And this phenomenon was more pronounced in the children aged < 3 years (93.02%, 40/43) (Supplementary Table 4).
在 52 例 NTS 病例中，本研究检测到的优势血清型为血清型 B （88.46%，46/52），其次是血清型 C1 （7.69%，4/53） 和血清型 D1 （3.85%，2/52）。其中，39 株分离株进一步鉴定为鼠伤寒沙门氏菌。在本研究中，血清型 B 在所有年龄组中均占优势。这种现象在 < 岁的儿童中更为明显 （93.02%，40/43） （补充表 4）。

Relationship Between Clinical Symptoms and Salmonella Serotypes
临床症状与沙门菌血清型的关系

Among the 52 NTS cases, 37 had at least one of the eight clinical symptoms listed in the present study at the time of sampling, with 27, three and one being found to be infected with serogroup B, serogroup C1 and serogroup D1, respectively. For cases infected with serogroup B including S. Typhimurium, diarrhea (58.70%), fever (45.65%) and emesis (15.22%) are the three most common clinical symptoms. For cases infected with serogroup C1 or D1, both diarrhea (75% or 50%) and fever (50% or 50%) are common symptoms (Supplementary Table 5).
在 52 例 NTS 病例中，37 例在采样时至少具有本研究中列出的 8 种临床症状中的一种，其中 27 例、3 例和 1 例分别被发现感染了 B 型、C1 型和 D1 型。对于包括鼠伤寒沙门氏菌在内的 B 血清群感染病例，腹泻 （58.70%） 、发热 （45.65%） 和呕吐 （15.22%） 是最常见的 3 种临床症状。对于感染血清型 C1 或 D1 的病例，腹泻（75% 或 50%）和发烧（50% 或 50%）都是常见症状（补充表 5）。

Antimicrobial Susceptibility Pattern
药敏试验模式

Thirteen antimicrobial agents were included in this study, and antimicrobial susceptibility was performed on 51 strains (Table 1). All strains were sensitive to imipenem, levofloxacin and cefoperazone/sulbactam. The majority of strains were resistant to ampicillin (92.16%), no strains were found resistant to piperacillin/tazobactam-resistant or amoxicillin-clavulanic acid. All strains showed low prevalence of cephalosporin resistance, and the prevalence rates for resistance to cefepime, ceftriaxone and ceftazidime were 13.73%, 19.61% and 17.65%, respectively. Twenty-four (47.06%) of the 51 strains showed multidrug resistance (MDR, resistant to at least three antimicrobials) (Table 2).
本研究包括 13 种抗菌剂，对 51 种菌株进行了抗菌药敏试验（表 1）。所有菌株均对亚胺培南、左氧氟沙星和头孢哌酮/舒巴坦敏感。大多数菌株对氨苄西林耐药 （92.16%），未发现菌株对哌拉西林/他唑巴坦耐药或阿莫西林-克拉维酸耐药。所有菌株的头孢菌素耐药率均较低，对头孢吡肟、头孢曲松和头孢他啶的耐药患病率分别为 13.73% 、 19.61% 和 17.65%。51 种菌株中有 24 种 （47.06%） 显示出多药耐药性 （MDR，对至少三种抗菌剂耐药）（表 2）。

TABLE 1 表 1

Table 1 Antimicrobial susceptibility pattern of NTS strains in the present study (N = 51).
表 1本研究中 NTS 菌株的抗菌药物敏感性模式 （N = 51）。

TABLE 2 表 2

Table 2 Distribution of NTS strains resistant to antibiotics and resistant spectrum.
表 2对抗生素耐药的 NTS 菌株和耐药谱的分布。

Discussion 讨论

NTS has been reported in humans worldwide. In the present study, 20.39% (52/255) of hospitalized patients of a large hospital in the north-east of Guangzhou City were confirmed to be infected with NTS. The present prevalence was higher than that of the previous reports in patients with gastrointestinal complaints of 13.80% (41/297) in Tanzania (Ngogo et al., 2020) and 6.2% (59/957) in Ethiopia (Eguale et al., 2015), as well as in pet caregivers of 17.86% (25/140) in Thailand (Wu et al., 2020). The variation between studies on Salmonella infection could be due to multiple factors, such as differences of enrolled patient characteristics (gender, age and residence), time of sample collection (seasonal variation), and possible risk factors (Ngogo et al., 2020).
NTS 已在世界各地的人类中报道。在本研究中，广州市东北部一家大型医院 20.39% （52/255） 的住院患者确诊感染 NTS。目前的胃肠道不适患病率高于以前的报告，坦桑尼亚为 13.80% （41/297）（Ngogo 等 人，2020 年），埃塞俄比亚为 6.2% （59/957）（Eguale 等 人，2015 年），以及泰国的宠物护理人员为 17.86% （25/140）（Wu 等 人，2020 年）。沙门氏菌感染研究之间的差异可能是由于多种因素造成的，例如入组患者特征（性别、年龄和居住地）、样本采集时间（季节性变化）和可能的风险因素的差异（Ngogo 等 人，2020 年）。

In the present study, a statistical difference in the prevalence of NTS was observed between children (25.15%, 43/171) and adults (4.65%, 2/43). Children have been identified as a population group at risk for Salmonellai infection because of immature immune system and lack of good hygienic habits (Mascaro et al., 2017). There have been some studies reporting high prevalence of Salmonella in children, such as 10.3% (33/320) in Iraq (Harb et al., 2017), and 9.7% (258/2658) in China (Liu et al., 2021). In addition, this result may have been affected by selection bias (detection bias). The majority of NTS infections in humans are self-limiting, some patients can heal themselves without treatment. However, there is a greater proportion of symptomatic infections among children, who also are more likely to seek medical help and therefore to have a stool examination for the detection of Salmonella (Mascaro et al., 2017).
在本研究中，观察到儿童 （25.15%，43/171） 和成人 （4.65%，2/43） 之间 NTS 患病率存在统计学差异。由于免疫系统不成熟和缺乏良好的卫生习惯，儿童已被确定为有感染沙门氏菌i 型风险的人群（Mascaro 等 人，2017 年）。有一些研究报告称，儿童沙门氏菌的患病率很高，例如伊拉克为 10.3% （33/320）（Harb et al.， 2017），中国为 9.7% （258/2658）（Liu et al.， 2021）。此外，该结果可能受到选择偏倚 （检测偏倚） 的影响。人类的大多数 NTS 感染是自限性的，一些患者无需治疗即可自愈。然而，儿童中有症状感染的比例更大，他们也更有可能寻求医疗帮助，因此进行粪便检查以检测沙门氏菌（Mascaro 等 人，2017 年）。

The present high prevalence may also be related to the sampling period from June to October, the average temperature is above 24°C. This result was similar to that of a report conducted by the Center for Disease Control and Prevention (CDC), which found that most Salmonella infections occur between June and October in the U.S. (Centers for Disease Control and Prevention (2013)). Previous studies have shown that higher temperatures can promote the growth and reproduction of Salmonella, as well as transmission of salmonellosis (Guentchev et al., 2016). In addition, warmer weather may increase the frequency of eating out, and lead to an increased risk of Salmonella infection (Milazzo et al., 2016).
目前的高流行率也可能与 6 月至 10 月的采样期有关，平均气温在 24°C 以上。 这一结果与疾病控制和预防中心 （CDC） 的一份报告相似，该报告发现大多数沙门氏菌感染发生在美国的 6 月至 10 月之间（疾病控制和预防中心 （2013））。先前的研究表明，较高的温度可以促进沙门氏菌的生长和繁殖，以及沙门氏菌病的传播（Guentchev et al.， 2016）。此外，温暖的天气可能会增加外出就餐的频率，并导致沙门氏菌感染的风险增加（Milazzo 等 人，2016 年）。

In our analysis of multiple possible risk factors for Salmonella infection, artificial fed (non-breast-fed) infants have a higher probability of Salmonella infection than do breast-fed infants (30.77% versus 8.33%). Powdered infant formula (PIF) is not a sterile product and may be intrinsically contaminated with Salmonella. It is reported that more than ten outbreaks of salmonellosis conducted in infants and were linked to the consumption of PIF (Jones et al., 2006). Unlike artificial feeding, breastfeeding is most likely protective for babies because of passes on helpful maternal immunities. Numerous studies have shown that breastfeeding reduces the risk of a number of diseases in infants, including salmonellosis (Jones et al., 2006; Ehlayel et al., 2009).
在我们对沙门氏菌感染的多种可能危险因素的分析中，人工喂养（非母乳喂养）婴儿感染沙门氏菌的可能性高于母乳喂养婴儿（30.77% 对 8.33%）。婴儿配方奶粉 （PIF） 不是无菌产品，本质上可能受到沙门氏菌的污染。据报道，在婴儿中爆发了十多次沙门氏菌病疫情，这些疫情与食用 PIF 有关（Jones 等 人，2006 年）。与人工喂养不同，母乳喂养很可能对婴儿具有保护作用，因为它传递了有益的母体免疫力。大量研究表明，母乳喂养可降低婴儿患多种疾病的风险，包括沙门氏菌病（Jones 等 人，2006 年;Ehlayel et al.， 2009）。

In the present study, three serogroups (serogroup B, serogroup C1 and serogroup D1) were identified, and serogroup B was the most common (88.46%, 46/52) in humans in the investigated areas. And the most frequently isolated serotype is S. Typhimurium (n = 39), which was similar to findings previously reported in some studies in Guangdong Province in China (Zhang et al., 2016; Zhang, 2018; Huang, 2020). In fact, epidemiological data have revealed that the distribution of NTS serotype in humans is different among geographic areas. As reported by Li Y, S. Enteritidis is the dominant serotype in north China, in contrast, S. Typhimurium is responsible for more infections than S. Enteritidis in south China (Li et al., 2018).
在本研究中，确定了 3 个血清型 （血清型 B 、 血清型 C1 和血清型 D1），其中血清型 B 在调查地区人类中最常见 （88.46%，46/52）。最常分离的血清型是鼠伤寒沙门氏菌 （n = 39），这与之前在中国广东省的一些研究中报道的发现相似（Zhang et al.， 2016;Zhang， 2018;Huang，2020 年）。事实上，流行病学数据显示，NTS 血清型在人类中的分布因地理区域而异。据 Li Y 报道，肠炎沙门氏菌是华北地区的主要血清型，相比之下，鼠伤寒沙门氏菌比华南地区的肠炎沙门氏菌造成更多的感染（Li et al.， 2018）。

Though serogroup B was dominant in all age groups, children aged < 3 years were more likely to be infected by serogroup B, especially S. Typhimurium. This might be related to children’s mobility activities, such as crawling, touching or biting toys/food dropped and picked up from floor, increasing the opportunity of transmission of Salmonella infection from households flooring materials contaminated with Salmonella to humans. As a previous study showed that, over 99% of S. Typhimurium were transferred from tile to food after five seconds of exposure to tile (Dawson et al., 2007).
尽管血清型 B 在所有年龄组中均占优势，但 3 岁 < 儿童更容易感染血清型 B，尤其是鼠伤寒沙门氏菌。这可能与儿童的行动活动有关，例如爬行、触摸或咬从地板上掉落和捡起的玩具/食物，从而增加了沙门氏菌感染从受沙门氏菌污染的家用地板材料传播给人类的机会。正如之前的一项研究表明的那样，超过 99% 的鼠伤寒沙门氏菌在暴露于瓷砖 5 秒后从瓷砖转移到食物中（Dawson 等 人，2007 年）。

NTS has been reported to give rise to clinical symptoms, like diarrhea, abdominal pain, nausea, emesis, fever, cough, headache, joint pain. In the present study, no associations were observed between NTS infection and clinical symptoms as well as each symptom category. In fact, besides immune status of individuals, the occurrence and the severity of clinical symptoms are also observed to be related to the infection intensity and the duration of excretion of NTS, as well as the virulence of serotypes (Haeusler and Curtis, 2013). In addition, clinical symptoms might be caused by other factors, even changes in diet can affect fecal consistency (e.g., the presence or absence of diarrhea).
据报道，NTS 会引起临床症状，如腹泻、腹痛、恶心、呕吐、发烧、咳嗽、头痛、关节痛等。在本研究中，未观察到 NTS 感染与临床症状以及每个症状类别之间存在关联。事实上，除了个体的免疫状态外，观察到临床症状的发生和严重程度还与 NTS 的感染强度和排泄持续时间以及血清型的毒力有关（Haeusler 和 Curtis，2013）。此外，临床症状可能由其他因素引起，甚至饮食的改变也会影响粪便的稠度（例如，是否存在腹泻）。

With the extensive use of the antibiotic, especially abuse, bacterial resistance has been recognized as a worldwide health problem. Ampicillin, chloramphenicol, and sulphamethoxazole/trimethoprim were regarded as first-line antimicrobials used for the treatment of severe salmonellosis for a long time (Andoh et al., 2017). In the present study, resistance to ampicillin, chloramphenicol, and sulphamethoxazole/trimethoprim were 92.16%, 35.29%, and 35.29% respectively. Similarly, some studies in developing countries have found that these first-line antimicrobials have become less effective due to development of resistance (Andoh et al., 2017; Liang et al., 2019; Shen et al., 2020). In the present study, low level of resistance towards fluoroquinolones (3.92% for ciprofloxacin and 0 for levofloxacin) were observed, which was inconsistent with the findings previously reported in some studies in Uganda and Japan (Kobayashi et al., 2014; Ota et al., 2016). This may be due to the fact that 90.38% (47/52) NTS strains isolated from children aged ≤ 5 years in this study, fluoroquinolones were rarely used in children due to articular toxicity (Ke et al., 2020). Similarly, in a study conducted in China, the prevalence of resistance to ciprofloxacin among NTS isolates was 8.05% (147/1826), and children aged <5 years accounted for 73% (1329/1826) of the overall NTS infections (Liang et al., 2015).
随着抗生素的广泛使用，尤其是滥用，细菌耐药性已被认为是一个世界性的健康问题。氨苄西林、氯霉素和磺胺甲噁唑/甲氧苄啶长期以来一直被视为用于治疗严重沙门氏菌病的一线抗菌药物（Andoh et al.， 2017）。在本研究中，对氨苄西林、氯霉素和磺胺甲噁唑/甲氧苄啶的耐药率分别为 92.16%、35.29% 和 35.29%。同样，发展中国家的一些研究发现，由于耐药性的发展，这些一线抗菌剂的效果已经降低（Andoh et al.， 2017;Liang et al.， 2019;Shen et al.， 2020）。在本研究中，观察到对氟喹诺酮类药物的耐药水平较低（环丙沙星为 3.92%，左氧氟沙星为 0），这与之前在乌干达和日本的一些研究中报告的结果不一致（Kobayashi et al.， 2014;Ota等 人，2016 年）。这可能是由于在这项研究中，从 ≤ 5 岁儿童中分离出 90.38% （47/52） 的 NTS 菌株，由于关节毒性，氟喹诺酮类药物很少用于儿童（Ke et al.， 2020）。同样，在中国进行的一项研究中，NTS 分离株对环丙沙星耐药的患病率为 8.05% （147/1826），<5 岁儿童占 NTS 感染总数的 73% （1329/1826） （Liang et al.， 2015）。

Twenty-four strains were resistant to more than three antimicrobial agent, and they were regarded as MDR strains. A related study suggest that hospitalization with bloodstream infection has been reported to be more common in patients infected with antimicrobial-resistant NTS than in patients with pansusceptible infection (Varma et al., 2005). Edward Cox (director of FDA’s Office of Antimicrobial Products in the Center for Drug Evaluation and Research) said that any use of antibiotics, even appropriate therapeutic use, can promote the development of resistant bacteria (http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm378100.htm). Therefore, it is necessary to avoid overusing of antibiotics and.to reduce the emergence of antibiotic-resistant bacterial strains.
24 株菌株对 3 种以上抗菌药物耐药，被视为 MDR 菌株。一项相关研究表明，据报道，感染抗菌素耐药 NTS 的患者比泛敏感感染患者更常见血流感染住院（Varma 等 人，2005 年）。Edward Cox（FDA 药物评估和研究中心抗菌产品办公室主任）说，抗生素的任何使用，即使是适当的治疗用途，都会促进耐药细菌 （http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm378100.htm） 的发展。因此，有必要避免过度使用抗生素 and.to 以减少抗生素耐药菌株的出现。

This study provides some important insights into the epidemiological characteristics and antibiotic resistance patterns of Salmonella infections in this part (Conghua District) of Guangzhou. Bacterial isolation and culture were carried out on the specimens, and the bacteria were identified by VITEK-Compact 2 automatic bacterial identification system. This method has a high identification accuracy and low price, and is a suitable method in hospital microbiological laboratory for testing Salmonella. However, there are several limitations of the study. We did not use molecular tools (e.g., whole-genome sequencing) for the detection of Salmonella, nor did we type the antimicrobial resistance genes that conferred resistance to the studied antimicrobials. This information is considered essential to study the epidemiology, spread, source attribution of NTS as well as identify mono/polyclonal outbreaks in nosocomial settings. Further studies should focus on genotyping and phylogenetic analysis (e.g., MLST) of Salmonella, and typing the antimicrobial resistance genes. These data will be helpful to understand its biology, transmission dynamics and infection sources, as well as develop efficient control strategies to intervene with and prevent occurrence of Salmonella infection.
本研究为广州市这一地区（从化区）沙门氏菌感染的流行病学特征和抗生素耐药模式提供了一些重要的见解。对标本进行细菌分离和培养，并通过 VITEK-Compact 2 自动细菌鉴定系统对细菌进行鉴定。该方法鉴定精度高，价格低，是医院微生物实验室检测沙门氏菌的合适方法。但是，该研究存在一些局限性。我们没有使用分子工具（例如全基因组测序）来检测沙门氏菌，也没有对赋予对所研究的抗菌剂产生耐药性的抗菌素耐药基因进行分型。这些信息被认为对于研究 NTS 的流行病学、传播、来源归因以及识别院内环境中的单克隆/多克隆暴发至关重要。进一步的研究应侧重于沙门氏菌的基因分型和系统发育分析（例如 MLST）以及抗菌素耐药基因的分型。这些数据将有助于了解其生物学特性、传播动力学和感染源，以及制定有效的控制策略来干预和预防沙门氏菌感染的发生。

Conclusion 结论

The present study provided the first report on occurrence and antimicrobial susceptibility of NTS in hospitalized patients in Conghua District in Guangzhou, China. The prevalence of NTS was 20.39% (52/255) in hospitalized patients in the investigated areas, and three serogroups were identified, with serogroup B being dominant (88.46%, 46/52). Among them, S. Typhimurium was the most common serotype, representing 84.78% (39/46) of serogroup B strains. Children aged <3 years and those with artificial feeding are more likely to have NTS infection. The highest rate of resistance was recorded in relation to ampicillin (92.16%), chloramphenicol (35.29%) and sulphamethoxazole/trimethoprim (35.29%). High percentage of MDR strains (47.06%, 24/51) emphasizes the importance of the prudent use of antibiotics and antimicrobial resistance monitoring in this district. These data obtained in the present study increase our understanding of the prevalence, serotype distribution, risk factors and drug resistance of NTS infection, and will help develop efficient control strategies to intervene with and prevent the occurrence of salmonellosis in the investigated areas.
本研究首次报告了中国广州从化区住院患者 NTS 的发生率和药敏性。调查地区住院患者 NTS 患病率为 20.39% （52/255），确定了 3 个血清型，其中 B 型占优势（88.46%，46/52）。其中，鼠伤寒沙门氏菌是最常见的血清型，占 B 血清型 菌株的 84.78% （39/46）。<3 岁的儿童和人工喂养的儿童更容易感染 NTS。氨苄西林 （92.16%） 、氯霉素 （35.29%） 和磺胺甲噁唑/甲氧苄啶 （35.29%） 的耐药率最高。高比例的 MDR 菌株 （47.06%，24/51） 强调了该地区谨慎使用抗生素和抗菌素耐药性监测的重要性。本研究中获得的这些数据增加了我们对 NTS 感染的患病率、血清型分布、危险因素和耐药性的理解，并将有助于制定有效的控制策略来干预和预防沙门氏菌病在调查地区的发生。

Data Availability Statement
数据可用性声明

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.
研究中介绍的原始贡献包含在文章/补充材料中。如需进一步咨询，请直接联系通讯作者。

Ethics Statement 道德声明

The studies involving human participants were reviewed and approved by the Ethics Committee of the Fifth Affiliated Hospital of Southern Medical University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.
涉及人类参与者的研究由南方医科大学第五附属医院伦理委员会审查和批准。参与本研究的书面知情同意书由参与者的法定监护人/近亲提供。

Author Contributions 作者贡献

XL and BG conceived and designed experiments. YF and ZZ collected samples. HL and YF performed laboratory experiments. BG, SZ, and JL analyzed and interpreted data. YF, SZ, ZZ, and XC contributed reagents and materials. BG and HL wrote the manuscript. XL revised the manuscript. All authors have read and approved the final version of the manuscript.
XL 和 BG 构思并设计了实验。YF 和 ZZ 采集样本。HL 和 YF 进行实验室实验。BG、SZ 和 JL 分析和解释数据。YF、SZ、ZZ 和 XC 贡献了试剂和材料。BG 和 HL 撰写了手稿。XL 修改了手稿。所有作者均已阅读并批准了手稿的最终版本。

Funding 资金

This project was funded by the Youth Foundation of the National Natural Science Foundation of China (81902104), and the Medical Science and Technology Research Project of Foushan Science and Technology Innovation Program (1920001000717).
本项目由国家自然科学基金青年基金（81902104）和福山科技创新计划医学科技研究项目（1920001000717）资助。

Conflict of Interest 利益冲突

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
作者声明，该研究是在没有任何可能被解释为潜在利益冲突的商业或财务关系的情况下进行的。

Publisher’s Note 出版商注

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
本文中表达的所有声明仅代表作者的观点，并不一定代表其附属组织或出版商、编辑和审稿人的观点。本文中可能评估的任何商品或制造商可能提出的声明均不受出版商的保证或认可。

Acknowledgments 确认

We thank the staff at the department of the Fifth Affiliated Hospital of Southern Medical University, for their assistance with sample collection and case investigation.
我们感谢南方医科大学附属第五医院科室的工作人员在样本采集和病例调查方面的帮助。

Supplementary Material 补充材料

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fcimb.2022.805384/full#supplementary-material
本文的补充材料可在线找到：https://www.frontiersin.org/articles/10.3389/fcimb.2022.805384/full#supplementary-material

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