Highly antimicrobial-resistant Nontyphoidal Salmonella from retail meats and clinical impact in children, Taiwan

Journal Pre-proof Highly Antimicrobial-Resistant Nontyphoidal Salmonella from Retail Meats and Clinical Impact in Children, Taiwan Yi-Jung Chang, Mi-Chi Chen, Ye Feng, Lin-Hui Su, Hsin-Chieh Li, Hsin-Ping Yang, Min-Jia Yu, Chyi-Liang Chen, Cheng-Hsun Chiu PII:

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https://doi.org/10.1016/j.pedneo.2020.03.017

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Pediatrics & Neonatology

Received Date: 29 November 2019 Revised Date:

4 February 2020

Accepted Date: 31 March 2020

Please cite this article as: Chang Y-J, Chen M-C, Feng Y, Su L-H, Li H-C, Yang H-P, Yu M-J, Chen C-L, Chiu C-H, Highly Antimicrobial-Resistant Nontyphoidal Salmonella from Retail Meats and Clinical Impact in Children, Taiwan, Pediatrics and Neonatology, https://doi.org/10.1016/j.pedneo.2020.03.017. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2020, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. All rights reserved.

PEDN-D-19-00226_After Eng edited_final

Highly Antimicrobial-Resistant Nontyphoidal Salmonella from Retail Meats and Clinical Impact in Children, Taiwan Yi-Jung Chang a,b,†, Mi-Chi Chen a,†, Ye Feng c,d, Lin-Hui Su b, Hsin-Chieh Li b, Hsin-Ping Yang b, Min-Jia Yu b, Chyi-Liang Chen b,*, Cheng-Hsun Chiu a,b,e,*

a

Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan

b

Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan

c

Sir Run Run Shaw Hospital, Hangzhou, China

d

Institute for Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China

e

Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan

†

These authors equally contributed to this work.

* Corresponding authors. Chyi-Liang Chen, PhD, Molecular Infectious Disease Research Center, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan 333, Taiwan; Cheng-Hsun Chiu, MD, PhD, Division of Pediatric Infectious Diseases, Department of Pediatrics, Chang Gung Children’s Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan 333, Taiwan. E-mail address: [email protected] (C.-L. Chen); Cheng-Hsun Chiu, [email protected] (C.-H. Chiu)

1

Abstract Background: The epidemiology of nontyphoidal Salmonella (NTS) resistant to ciprofloxacin or ceftriaxone and its impact on patients’ clinical course are rarely reported. Methods: Children with culture-proven salmonellosis treated in a medical center in northern Taiwan in 2017 were enrolled. To trace the source of Salmonella, Salmonella isolated from food samples were collected from markets. Antimicrobial susceptibility and serotypes were determined. Results: Among the 453 isolates, 122 (26.9%) were highly antimicrobial-resistant, as defined by resistance to ciprofloxacin or ceftriaxone or both. The most prevalent highly resistant serotype was S. Anatum (66, 54.1%). Salmonella was detected in 94.1%, 66.7%, and 8.6% of examined pork, chicken, and vegetables examined, respectively. S. Anatum (6, 21.4%) and S. Derby (6, 21.4%) were the major serotypes isolated. Majority of the S. Anatum (5, 83.3%) were highly antimicrobial-resistant. More patients infected by highly resistant Salmonella required carbapenem treatment (OR = 23.5, 95% confidence interval [CI] 2.8–192.7, P <0.001). Patients with ceftriaxone-resistant NTS infections had a significantly longer hospital stay than others (P <0.001). Totally, 34 (7.5%) presented with invasive diseases (31 bacteremia, 1 intestinal perforation, 1 toxic megacolon and 1 septic arthritis). Risk factors for invasive disease included prolonged fever for ≧5 days and infection occurring in warmer season from May to October. The rise of ambient temperature in northern Taiwan was associated with increasing Salmonella infections. Conclusions: Retail meats were the main source of highly antimicrobial-resistant NTS in northern Taiwan. Highly antimicrobial resistance significantly impacted the clinical course and treatment of children with NTS infection. Key Words: nontyphoidal Salmonella; serotype; highly antimicrobial resistance; invasive salmonellosis

2

1. Introduction Nontyphoidal Salmonella (NTS) infection is the major cause of diarrheal illness worldwide. It was estimated that there were 93.8 million cases of gastroenteritis caused by Salmonella each year.1 Generally, gastroenteritis caused by NTS is selflimiting; however, it still can cause invasive complications in children and the immunocompromised.

Antimicrobial

therapy

is

recommended

for

the

immunocompromised and those with invasive infections, such as bacteremia, septic arthritis, and meningitis. Studies have not identified clinical or laboratory characteristics unique to children with bacteremia.2,3 The difficulty in differentiating invasive infection from self-limited gastroenteritis complicates the issue of antimicrobial therapy.2,3

On the other hand, the extensive use of antimicrobials in

human and food animals has led to the increasing antimicrobial resistance of Salmonella in Southeast Asian countries, including Taiwan.4,5 Antimicrobial resistance may contribute to treatment failure, and poor clinical outcomes.6 Salmonella serotypes are the most common pathogens for pediatric bacterial gastroenteritis in Taiwan.5 Due to the high rate of resistance to conventional antimicrobials, ciprofloxacin or ceftriaxone has become the drug of choice for the treatment of invasive salmonellosis.7 Children with ceftriaxone- or ciprofloxacinresistant NTS infection were previously reported in Taiwan.5,8 However, comprehensive studies on the epidemiology and source of the highly resistant NTS and the impact of resistance on patients’ outcome are still lacking. To address this gap, we investigated the epidemiology, clinical manifestations, and laboratory characteristics of highly antimicrobial-resistant NTS infection in children in northern Taiwan.

2. Methods 2.1. Study Population and Data Collection This observational study included patients under 18 years of age with culture-proven 3

NTS infection in Chang Gung Memorial Hospital (CGMH) in 2017. CGMH is a main referral hospital for cities in northern Taiwan, mainly including Taipei, New Taipei, and Taoyuan as shown in Supplementary figure S1. The population in this region is approximately 7 million. The residences of the patients were mapped to locate hot zones of the infection. Northern Taiwan experiences a subtropical climate. The climatic data at this region of around 3,543 km2 was obtained from National Central Weather Bureau, Taiwan. We used the average values of monthly ambient temperature and relative humidity to represent historical weather conditions in northern Taiwan. We analyzed all cases and summed the highly antimicrobialresistant and invasive salmonellosis cases for each epidemiological month. We further investigated the association between average monthly values of climatic data and the occurrence of NTS infection for each epidemiological month. To ascertain the clinical characteristics and outcomes of patients with highly antimicrobial-resistant NTS infections, we classified patients into the ceftriaxone-resistant, ciprofloxacinresistant-only, and non-highly antimicrobial-resistant groups. Patients’ clinical course, antimicrobial susceptibility, and outcomes were extracted from medical records. We assessed the difference among the three groups of patients. Invasive disease was defined as patients with bacteremia, focal extraintestinal infection, toxic megacolon or intestinal perforation complicated by Salmonella infection. The study was ethically approved by the Institutional Review Board of CGMH (201601804B0). 2.2. Serotyping and Antimicrobial Susceptibility Testing All Salmonella clinical isolates from patients under 18 years of age in CGMH were analyzed. Antimicrobial susceptibility of the isolates against ampicillin, ceftriaxone, chloramphenicol,

ciprofloxacin,

imipenem,

trimethoprim-sulfamethoxazole,

ertapenem, and flomoxef was examined by a standard disk diffusion method and interpreted according to the Standards for Antimicrobial Susceptibility of the Clinical Laboratory Standards Institute.8,9 In addition, minimum inhibitory concentrations against ceftriaxone and ciprofloxacin were assessed with E-test strips (AB Biodisk, 4

Solna, Sweden). A multiplex PCR using the primers as listed in the Supplementary Table S1 was further performed to identify the serotypes of those ceftriaxone- or ciprofloxacin-resistant Salmonella isolates as described previously.10 Intermediate resistance was regarded as resistance for further statistical analysis. Highly antimicrobial resistance of Salmonella was defined by resistance to ciprofloxacin or ceftriaxone or both. Multidrug resistance (MDR) was defined as concomitant resistance to ≧3 drug classes of antimicrobials with the same selection, including ampicillin, ceftriaxone, chloramphenicol, ciprofloxacin, imipenem, trimethoprimsulfamethoxazole, ertapenem and flomoxef. 2.3. Food Investigation To trace the source of Salmonella based on the Microbiology Laboratory Guidebook of the United States Department of Agriculture,11 we went on to isolate Salmonella from food samples collected from markets at the hot zones. Salmonella isolates from food samples were further examined for their serotypes. The food investigated included vegetable (34.3%), pork (26.9%), chicken (19.4%), egg (11.9%), seafood (2.9%), fruit (2.9%), sauce (2.9%), and duck (1.4%). Most of the meats were collected from traditional markets with a cutting knife, such as pork (94.1%), chicken (83.3%), and duck (100%). Antimicrobial susceptibility to ceftriaxone and ciprofloxacin for these isolates was assessed using E-test strips. 2.4. Statistical Analysis The categorical dates were analyzed using the Chi-square. Continuous variables were compared by using the ANOVA test. Multivariate analyses were conducted using logistic regression analyses to compare invasive salmonellosis and enterocolitis.

We also

conducted a time series analysis to estimate the associations between Salmonella infections and observed regional temperature conditions at the hot zones. A time series liner regression model was used to analyze the association on a monthly scale and Salmonella infections. SPSS, version 22.0 (IBM SPSS Statistics, IBM Corporation) was used for all analyses. All statistical hypothesis tests were 2-tailed, 5

and a P-value < 0.05 was considered significant.

3. Results A total of 453 cases with NTS infection under 18 years of age were identified (Table 1). Most cases were young children aged 1–4 years (76%), followed by infants (14.3%). Among the 453 isolates, 6.8% (31/453) of the Salmonella isolates were from blood and 90.9% (412/453) from stools. Bacteremia usually occurred in children younger than 5 years old. The antimicrobial resistance rates among the isolates were: ampicillin (47.6%), chloramphenicol (34.9%), trimethoprim-sulfamethoxazole (30.7%), ceftriaxone (5.9%), ciprofloxacin (22.1%), and imipenem (0.2%). The overall rate of MDR was 34.7%. Among the 453 isolates, 122 (26.9%) were highly resistant strains, as defined by resistance to ciprofloxacin or ceftriaxone or both. Of the 122 ceftriaxone- or ciprofloxacin-resistant isolates, S. Anatum was the most common (54.1%, n = 66), followed by S. Typhimurium (15.5%, n = 19), and S. Enteritidis (9.8%, n = 12) (Table 2). Almost all S. Anatum (98.5%) also showed MDR. The clinical characteristics of the 122 patients with highly antimicrobial-resistant Salmonella infection are shown in Table 3. More patients infected by highly resistant Salmonella required carbapenem treatments than those infected by non-resistant strains (OR = 23.5, 95% confidence interval [CI] 2.8–192.7, P <0.001). Of the 453 cases, serogroup B (32.7%) was the predominant serogroup isolated, followed by D (30.7%), E (16.6%), C1 (8.8%), and C2 (7.4%). Likely due to S. Anatum, serogroup E exhibited the highest multi-drug resistance rate, being up to 90.1% (P <0.001, OR = 33.5, 95% CI: 15.5–72.6). The disease burden and the geographic location of the hot zones for NTS infection in northern Taiwan are illustrated (Supplementary figure S1). Totally, 67 food samples collected from 2 supermarkets and 5 traditional markets in the hot zones were examined for Salmonella (Supplementary Table S2). Twenty6

eight (41.8%) samples were contaminated by Salmonella. Salmonella was detected in 94.1% of examined pork, 66.7% of chicken, and 8.6 % of vegetables. S. Anatum (6, 21.4%), S. Albany (6, 21.4%), and S. Derby (5, 17.9%) were the top three isolated serotypes. Of the S. Anatum contaminations from food, 83.3% (5/6) were highly resistant; all the 5 highly resistant S. Anatum strains were concomitantly resistant to ceftriaxone and ciprofloxacin. We investigated the correlation between regional temperature and infection incidence at the hot zones (Supplementary figure S2). The increase in ambient temperature was positively correlated with the increase in salmonellosis cases. A 1 increase in mean ambient air temperature was associated with a 3.7% increase (95% CI: 2.51–4.94, P <0.001) in Salmonella infection reported in the same month. To access the outcome of patients with highly resistant NTS infection, we stratified patients into 3 groups for outcome analysis: ceftriaxone-resistant group, ciprofloxacin-resistantonly group, and non-highly resistant group. Patients who had ceftriaxone-resistant Salmonella infection showed more prolonged hospitalization, compared to the ciprofloxacin-resistant-only group and non-highly resistant group (mean ± SD: 8.8 ± 8.4 vs 6.0 ± 3.1 and 6.2 ± 3.5, P = 0.013 and P <0.001, respectively) (Fig. 1). Of the patients with Salmonella infection, 34 (7.5%) presented with invasive diseases, including 31 (6.8%) bacteremia, 1 intestinal perforation (0.2%), 1 toxic megacolon, and 1 septic arthritis. Table 4 shows the comparison of clinical characteristics between cases with invasive salmonellosis and those with gastroenteritis only. Children with fever ≧ 5 days were associated with the occurrence of invasive Salmonella infection (OR = 4.7, 95% CI: 2.2–11.2, P <0.001). Highly resistant Salmonella infections were found in both groups of invasive (23.5%) and noninvasive (27.2%) infections (P = 0.642). The odds ratio of invasive Salmonella infection was 3.6 (95% CI: 1.0–12.9, P <0.044) in warm season from May to October with a monthly average temperate >25℃.

7

4. Discussion Salmonella is among the antibiotic-resistant priority pathogens that have been posing serious threat to human health and are being monitored closely by the US CDC and ECDC surveillance system.12–14 Children usually have a higher disease burden for NTS infection. The present study explored the recent epidemiology of NTS in children in northern Taiwan and confirmed the emergence of highly antimicrobialresistant NTS. The findings are especially important owing to the identification of the recent increase in resistance to ciprofloxacin and ceftriaxone in S. Anatum in Taiwan and its impact on public health. We also identified that the rise in ambient temperature was positively correlated with the increasing incidence of salmonellosis. Taken together, caution should be taken that global warming in combination with the rising antimicrobial resistance may result in an even greater burden of the disease caused by the foodborne pathogen worldwide in the years to come. In the subgroup analysis, we found that patients with ceftriaxone-resistant NTS infection had a significantly longer hospital stay than those infected with ciprofloxacin-resistant-only and non-highly resistant Salmonella strains. Ceftriaxone has been widely used as the drug of choice for treatment of invasive or severe salmonellosis in pediatric patients in Taiwan.2 Furthermore, it was reported previously that patients with antimicrobial-resistant NTS infections were more likely to have bloodstream infections and to be hospitalized.15 Although the current study revealed that the rate of bloodstream infection was not significantly higher among patients with highly antimicrobial-resistant

NTS infection, the prolonged

hospitalization in this group of patients for more than one week still reflects the significant impact on the health care system and family from the emerging highly antimicrobial-resistant Salmonella infection. We demonstrated that 26.9% of NTS isolates in Taiwan were highly resistant strains, including 5.9% that were resistant to ceftriaxone. Resistance to thirdgeneration cephalosporins was seen in only 3% of the NTS isolates in USA and 1.4% 8

in Europe.13,14,16,17 On the other hand, approximately 23.4% of NTS isolates were resistant to ciprofloxacin in our study. This rate is also significantly higher than that reported in Europe and USA, where approximately 0.4% and 3.6% of NTS isolates were resistant to ciprofloxacin, respectively.13,14 Although ciprofloxacin is not typically used in children due to its potential adverse effects, the emergence of ciprofloxacin resistance among NTS is of concern since ciprofloxacin is the drug of choice for treating multidrug-resistant NTS infections in adults.15,18–21 Increasing antimicrobial resistance in Salmonella may be related to the increased consumption of or exposure to these antimicrobials in humans and food-producing animals. In Taiwan, salmonellosis has been caused primarily by S. Enteritidis, Typhimurium, Stanley, Newport, and Albany, which totally caused 70% of Salmonella infections from 2004– 2012.8,22 During this period, S. Anatum was not prevalent, causing only 0.4% of the infections.22 However, since 2015, S. Anatum infections have increased dramatically, and most isolates were multidrug-resistant.22 The current study identified S. Anatum as the predominant highly resistant NTS serotype causing salmonellosis in children in 2017. Also shown in this study, almost all S. Anatum isolates were MDR. The emergence and spread of MDR strains of S. Anatum was strongly associated with a plasmid carrying multiple resistance genes, including blaDHA-1, which encodes AmpC βlactamase and thereby confers resistance to β-lactam drugs, including third-generation cephalosporins.22 The study further confirmed that the MDR strains have caused enteric as well as invasive infections in humans; therefore, control measures to contain the spread of the resistance are urgently needed from public health perspectives. S. Anatum was reported from an imported Anaheim pepper in USA in 2016.23 In our study, S. Anatum was the most common serotype to be isolated from pork and chicken. Retail meats in Taiwan are often stored without adequate temperature control in traditional markets. Temperature has been identified as a key influencer on Salmonella transmission.24–27 Our study revealed that the rise of ambient temperature was associated with increasing salmonella infection in northern Taiwan. This region 9

is also a popular travel destination. Overseas travel was considered as a risk factor for spread of drug resistance.16 Taiwan is in the subtropical zone. Salmonella was reported to grow vigorously on food and express its virulence and stress genes at different temperature exposure. In Hong Kong, higher temperature was strongly associated with more hospitalizations due to salmonellosis.26 Furthermore, higher ambient temperatures may pose a challenge for safe food production.26,27 Weather has been shown to be a reason for transfer of microbial contaminants to foods.27 The study highlighted that drug resistance could make this issue even more complicated due to climate change. More attention should be paid to the association of food safety with climate change. Identification of the clinical features of invasive salmonellosis is important for infection control as well as avoiding unnecessary antibiotic use. In this study, we identified that invasive NTS infection was associated with a prolonged fever ≥5 days, especially in the warmer season. This is consistent with a previous observation that prolonged fever was closely related to the occurrence of NTS bacteremia in children.26 In this study, the most common invasive NTS infection is bacteremia, comprising 6.8% of the patients with gastroenteritis, a rate comparable to approximately 5–10% in previous reports.27 Unlike those reported in children in Africa, the course of NTS bacteremia was relatively benign in previously healthy children.28–30 Our patients with bacteremia usually recovered uneventfully. Another well-described complication of invasive salmonellosis is toxic megacolon or intestinal perforation, and there were concerns about this complication caused by antimicrobial-resistant NTS because of the difficulty in the treatment of the infection.28,29 In that case, carbapenem would be the drug of choice for the treatment of severe or complicated highly antimicrobial-resistant NTS infection. Fortunately, carbapenem resistance in NTS remains rare. Having said that, strict regulation of antibiotic use for salmonellosis is mandatory to avoid the emergence and spread of carbapenem resistance in NTS. 10

5. Conclusions The incidence of highly antimicrobial-resistant NTS in children was relatively high in northern Taiwan. S. Anatum was the most commonly identified resistant serotype. The main source of the resistant NTS was retail meats. Highly resistant NTS infection was complicated with a prolonged hospital stay. Physicians should be aware that invasive NTS infection is likely to cause prolonged fever in patients. Targeting risk individuals for timely antibiotic treatment is warranted to improve patients’ outcome and furthermore reduce unnecessary antimicrobial use. Controlling resistant Salmonella is a global issue, as climate change and global warming have contributed not only to the spread of Salmonella but also to the dissemination of resistance genes through the vector Salmonella.

Conflicts of interest The authors have no conflicts of interest relevant to this article.

Acknowledgments The study was supported by grants CMRPG3G1891, CRRPG3F0084 and CMRPG3G1451-3 from Chang Gung Memorial Hospital, Taiwan, and grants MOHW106-CDC-C-114-113702, MOHW107-CDC-C-114-123505 and MOHW108CDC-C-114-133505 from the Ministry of Health and Welfare, Taiwan.

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parenteral antimicrobial therapy for nontyphoidal Salmonella enteric infection in children. Clin Microbiol Infect 2011;17:300–5. 3.

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Su LH, Teng WS, Chen CL, Lee HY, Li HC, Wu TL, et al. Increasing ceftriaxone resistance in Salmonellae, Taiwan. Emerg Infect Dis 2011;17:1086– 90.

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Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing, 21st Informational Supplement; CLSI Document M100–S21. Wayne, PA: CLSI; 2011.

10. Kim S, Frye JG, Hu J, Fedorka-Cray PJ, Gautom R, Boyle DS. Multiplex PCRbased method for identification of common clinical serotypes of Salmonella enterica subsp. enterica. J Clin Microbiol 2006;44:3608–15. 11. USDA Microbiology Laboratory Guidebook. Isolation and Identification of Salmonella from Meat, Poultry, Pasteurized Egg, and Siluriformes (Fish) 12

Products and Carcass and Environmental Sponges. Food Safety and Inspection Service. United States Department of Agriculture. Available at External link https://www.fsis.usda.gov/wps/wcm/connect/700c05fe-06a2-492a-a6e13357f7701f52/MLG-4.pdf?MOD=AJPERES. [Accessed November 26, 2019]. 12. World Health Organization. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. Available at External

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http://ecdc.europa.eu/en/publications/Publications/antimicrobial-resistancezoonotic-bacteria-humans-animals-food-EU-summary-report-2013.pdf. [Accessed November 26, 2019]. 15. Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis 2001;32:263–9. 16. Barlow RS, Debess EE, Winthrop KL, Lapidus JA, Vega R, Cieslak PR. Travelassociated antimicrobial drug-resistant nontyphoidal Salmonellae, 2004–2009. Emerg Infect Dis 2014;20:603–11. 17. Iwamoto M, Reynolds J, Karp BE, Tate H, Fedorka-Cray PJ, Plumblee JR, et al. Ceftriaxone-resistant nontyphoidal Salmonella from humans, retail meats, and food

animals

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Dis 2017;14:74–83. 13

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18. Lee HY, Su LH, Tsai MH, Kim SW, Chang HH, Jung SI, et al. High rate of reduced susceptibility to ciprofloxacin and ceftriaxone among non-typhoid Salmonella

clinical

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Asia.

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Chemother 2009;53:2696–9. 19. Su LH, Chiu CH, Chu C, Ou JT.

Antimicrobial resistance in nontyphoid

Salmonella serotypes: a global challenge. Clin Infect Dis 2004;39:546–51. 20. Chiu CH, Wu TL, Su LH, Chu C, Chia JH, Kuo AJ, et al. The emergence in Taiwan of fluoroquinolone resistance in Salmonella enterica serotype Choleraesuis. N Engl J Med 2002;346:413–9. 21. Olsen SJ, DeBess EE, Marano N, Eby T, Mauvais S, et al. A nosocomial outbreak of fluoroquinolone-resistant salmonella infection. N Engl J Med 2001;344:1572–9. 22. Chiou CS, Hong YP, Liao YS, Wang YW, Tu YH, Chen BH, et al. New Multidrug-resistant Salmonella enterica serovar Anatum Clone, Taiwan, 2015– 2017. Emerg Infect Dis 2019;25:144–7. 23. Hassan R, Rounds J, Sorenson A, Leos G, Concepción-Acevedo J, Griswold T, et al. Multistate outbreak of Salmonella Anatum infections linked to imported hot peppers — United States, May–July 2016. MMWR Morb Mortal Wkly Rep 2017;66:663–7. 24. Yun J, Greiner M, Höller C, Messelhäusser U4, Rampp A, Klein G. Association between the ambient temperature and the occurrence of human Salmonella and Campylobacter infections. Sci Rep 2016;6:28442. 25. Williams MS, Ebel ED, Golden NJ, Schlosser WD. Temporal patterns in the occurrence of Salmonella in raw meat and poultry products and their relationship to human illnesses in the United States Food Control 2014;35:267–73. 26. Wang P, Goggins WB, Chan EYY. Associations of Salmonella hospitalizations with ambient temperature, humidity and rainfall in Hong Kong. Environ Int 2018;120:223–30. 14

27. Akil L, Ahmad HA, Reddy RS. Effects of climate change on Salmonella infections. Foodborne Pathog Dis 2014;11:974–80. 28. Gordon MA. Invasive nontyphoidal Salmonella disease: epidemiology, pathogenesis and diagnosis. Curr Opin Infect Dis 2011;24:484–9. 29. Aoki Y, Kitazawa K, Kobayashi H, Senda M, Arahata Y, Homma R, et al. Clinical features of children with nontyphoidal Salmonella bacteremia: a single institution survey in rural Japan. PLoS One 2017;12:e0176990. 30. Krueger AL, Greene SA, Barzilay EJ, Henao O, Vugia D, Hanna S, et al. Clinical outcomes of nalidixic acid, ceftriaxone, and multidrug-resistant nontyphoidal Salmonella infections compared with pansusceptible infections in FoodNet sites, 2006–2008. Foodborne Pathog Dis 2014;11:335–41.

Appendix A. Supplementary data Supplementary

data

to

this

article

can

15

be

found

online.

Figure Legends Figure 1

Comparison of the median length of hospitalization (days) among

admitted patients in the ceftriaxone-resistant, ciprofloxacin-resistant-only, and nonhighly resistant groups. *: P-value <0.05; ***: P-value <0.001; ns: no statistically significant difference.

16

Table 1 Serogroups and sources of nontyphoidal Salmonella by age of the 453 patients with culture-confirmed Salmonella infection. Sample source

Age (years) n = 453

n (%)

<1

Serogroup

Stool

Blood

Urine

Others

B

C1

C2

D

E

Others

65 (14.3)

58 (89.1)

5 (7.8)

2 (3.1)

0 (0)

29 (44.5)

8 (12.3)

5 (7.7)

8 (12.3)

12 (18.5)

3 (4.7)

1–4

344 (76.0)

314 (91.2)

25 (7.0)

3 (0.9)

2 (0.6)

108 (31.4)

30 (8.7)

27 (7.8)

112 (32.9)

58 (16.6)

9 (2.6)

5–17

44 (9.7)

40 (90.9)

1 (2.3)

3 (6.8)

0 (0)

7 (15.9)

5 (11.4)

0 (0)

19 (43.2)

13 (29.5)

0 (0)

n: number

Table 2 Serotypes and serogroups of highly antimicrobial-resistant Salmonella isolates. Serogroup

Total (n)

Serotype (n) Typhimurium (19), Agona (3), Brancaster

B

29

(2), Derby (2), Schwarzengrund (1), Stanley (2), Thompson (1), Grampian (1), Livingstone

C1

4

C2

10

Albany (5), Newport (4), Cremieu (1)

D

13

Enteritidis (12), Itami (1)

E

68

Anatum (66), Give (1), Weltevreden (1)

G

1

Idikan (1)

(1), Virchow (1)

n: number

1

Table 3 Clinical characteristics between patients with highly antimicrobial-resistant Salmonella infection and those without. Characteristics

Highly resistant infection (n = 122)

Non-highly resistant infection (n = 331)

P value

Age (years)

2.4 ± 2.4

2.3 ± 2.4

0.612

Male gender

65 (53.2)

171 (51.6)

0.788

Fever (days)

3.2 ± 2.5

3.3 ± 2.9

0.712

Hospital stay (days)

6.7 ± 5.2

6.2 ± 3.5

0.384

Admission (%)

89 (72.9)

239 (72.2)

0.875

WBC (×109/L)

11.5 ± 3.9

9.5 ± 4.3

0.052

IV antibiotics

56 (45.9)

142 (42.9)

0.594

Carbapenem

8 (14.2)

1 (0.7)

<0.001

Ceftriaxone

45 (80.3)

127 (89.4)

0.088

WBC: white blood cell; IV: intravenous

Table 4 Clinical characteristics between patients with invasive Salmonella infection and those without. Invasive Characteristics

infection (n = 34)

Gastroenteritis (n = 419)

P

Age (years)

1.7 ± 1.2

2.4 ± 2.6

0.017

Male gender

14 (43.3)

216 (52.5)

0.332

Fever (days)

5.1 ± 3.1

3.5 ± 2.2

0.019

Warm seasona

31/34

305/419

0.018

Hospital stay (average, in days)

9.3 ± 6.5

4.4 ± 4.1

<0.001

Admission (%)

30 (88.2)

289 (69.0)

0.021

WBC (×109/L)

10.9 ± 3.9

9.7 ± 4.3

0.179

Highly resistant

8 (23.5)

114 (27.2)

0.642

a

The warm season in northern Taiwan is from May to October.

WBC: white blood cell

1