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Epidemiology and risk factors of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci infections in Zhejiang China from 2015 to 2017

Epidemiology and risk factors of methicillin-resistant Staphylococcus aureus and... Background: Gram-positive bacteria are dangerous and challenging agents of infection due to their increasing resistance to antibiotics. We aim to analyse the epidemiology and risk factors of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) in Zhejiang China. Methods: Gram-positive bacteria (including S. aureus, Enterococcus faecalis and Enterococcus faecium) were collected from eighty-six hospitals of eleven cities in Zhejiang China from 2015 to 2017. The detection rates of MRSA and VRE infection were calculated for the non-duplicated isolate according to year, region, hospital level, patient age, specimen type and patient category. Meanwhile, the detected resistances of MRSA, E. faecalis and E. faecium to different antibiotics from 2015 to 2017 were compared. The risk factors and the differences in MRSA and VRE detection rates were compared using odds ratio (OR) with 95% confidence interval (95% CI) and Chi-square test respectively. Results: From 2015 to 2017, the detection rates of MRSA and VRE decreased gradually. The cities with the highest MRSA and VRE detection rates tended to be adjacent; for example, the neighbouring cities Hangzhou and Quzhou had simultaneously high rates of MRSA and VRE infection. Patients from IIIA hospital who were older than 75 years and in the intensive care unit (ICU) were most at risk. No vancomycin-resistant isolate was found in MRSA. Resistance of E. faecalis and E. faecium to vancomycin and linezolid decreased slightly and then maintained a low level. Conclusions: The detection rates of MRSA and VRE stayed at moderate and low levels during the three year period of this study, while local dissemination was found in MRSA and VRE isolates. Sustained surveillance is necessary to prevent the spread or clonal dissemination of drug-resistant strains in Zhejiang China. Keywords: Epidemiology, Risk factor, Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant enterococci * Correspondence: chengongxiang@zju.edu.cn Department of Clinical Microbiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 2 of 9 Background automated system (the Vitek 2 compact, BD Phoenix-100, Gram-positive bacteria, such as Staphylococcus aureus, MicroScan WalkAway-96) or Matrix-Assisted Laser De- Enterococcus faecalis, and Enterococcus faecium are dan- sorption/Ionization Time of Flight Mass Spectrometry gerous and challenging agents of infection due to their (MALDI-TOF-MS). increasing resistance to antibiotics [1]. Among these, S. aureus are the most frequently isolated, making up Antimicrobial susceptibility testing 29.1% of the isolated Gram-positive bacterial popula- Standard operation procedures were established accord- tions, and infections caused by S. aureus (both ing to the Clinical and Laboratory Standards Institute’s community-associated or nosocomial-associated) are re- (CLSI) criteria, M100-S24 [14]. Every participating la- ported all over the world [2, 3]. Enterococci (including E. boratory conducted the antibiotic susceptibility testing faecalis and E. faecium) are the second frequently iso- for the clinical isolates using the Kirby-Bauer disk diffu- lated Gram-positive bacteria at 19.5%. Past generations sion method or the commercialized automated system of enterococci were mainly associated to urinary-tract in- following the instrument specifications. S. aureus (ATCC fection, but recently more and more enterococci are iso- 25923, ATCC 43300) and E. faecalis (ATCC 29212, lated from other infections [4], and an outbreak of ATCC 51299) were used as quality control strains for vancomycin resistant enterococci (VRE) in a solid organ the testing. transplant unit was reported in 2018 [5]. The epidemiology of resistance in Gram-positive bac- Statistical analysis teria has undergone major changes in recent decades, We analysed the risk factors for MRSA and VRE propor- with methicillin-resistant S. aureus (MRSA) and VRE tions, and for the multivariable model, year, region, hos- now being of international concern [6]. Antimicrobial pital level, patient age, specimen type and patient resistances of Gram-positive bacteria have been reported category were considered. The lowest detection rates of in many countries [7–9]; however, it was only in recent MRSA and VRE were set as contrasts. The risk factors years that vanM-carrying E. faecalis strains were isolated and the differences in MRSA and VRE detection rates from patients and the clinical environment in the Sec- were compared using odds ratio (OR) with 95% confi- ond Affiliated Hospital of Zhejiang University School of dence interval (95% CI) and Chi-square test. Chi-square Medicine [10], we speculate that if vanM infection has values were corrected when the quantities of VRE iso- been spreading in the Zhejiang province, it may lead to lates were less than forty. Results with P-value < 0.05 an increase of VRE overall. In China, although several were considered statistically significant. SPSS 19.0 (IBM local studies have examined the prevalence of resistance Company, Chicago, IL) and WHONET 5.5 (WHO) soft- in Gram-positive bacteria [11, 12], the studies usually ware were used for all statistical analyses. only cover the tertiary hospitals. Therefore, the present study is a retrospective surveillance covering a wider Results range of hospitals, including tertiary and secondary hos- Distribution of MRSA, Enterococci and VRE isolates pitals. Our aim is to seek trends in antimicrobial resist- During the years 2015–2017, the total number of MRSA ance among clinical isolates of important Gram-positive isolates increased from 9292 to 10,237 cases; in contrast, bacteria in the Zhejiang province of China. VRE isolates decreased from 173 to 137 cases (data not shown). Among the 11 cities that participated in the sur- Materials and methods vey, Hangzhou contributed 37.6% of all MRSA isolates Bacterial isolates (29,866 cases); and 41.0% of all Enterococci isolates We extracted data of S. aureus, E. faecalis and E. fae- (58,329 cases), although the population of Hangzhou is cium infections from the Zhejiang surveillance system’s only about 9.5 millon (16.5% of the Zhejiang province outpatient and inpatient records from January 1, 2015 to population). This high number of isolates may be due to December 31, 2017. The number of surveyed hospitals Hangzhou having more IIIA hospitals, which were the for each city was as follows: Hangzhou (n = 24), Huzhou contributors of 67% of all MRSA and enterococci isolates. (n = 4), Jiaxing (n = 11), Jinhua (n = 9), Lishui (n = 6), However, Hangzhou also contributed 245 VRE isolates, Ningbo (n = 10), Quzhou (n = 5), Shaoxing (n = 6), Tai- which was 54.2% of all of the VRE isolates in the study, zhou (n = 5), Wenzhou (n = 5), and Zhoushan (n = 1). and a much higher percentage than the province’s Sample collection was in accordance with the clinical MRSA and enterococci contributions. MRSA were most microbiology manual [13]. To avoid duplicate isolates, frequently isolated from respiratory samples (14,339 or only one isolate from the same species was included per 48.0% of all samples); VRE were dominantly isolated patient, as determined by the personal identifying code from urine samples (313 or 69.2% of all samples) (data and hospital name. Species identification of the isolates not shown). The number of samples based on age of pa- was performed by standard biochemical methods, tient and inpatient vs. out-patient were also categorized. Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 3 of 9 Patients older than 75 and patients who were hospital- against E. faecalis and E. faecium. The resistance rates of E. ized (especially those in the ICU) had dominantly higher faecium to ampicillin, nitrofurantoin, ciprofloxacin, MRSA, enterococci and VRE isolation rates compared to gentamicin-high level, levofloxacin, teicoplanin and vanco- other patient groups (data not shown). mycinwerehigherthanthatof E. faecalis, while lower re- sistance rates to tetracycline and linezolid were seen in E. Resistance rates of MRSA, E. faecalis and E. faecium to faecium in comparison to E. faecalis. antimicrobial agents from 2015 to 2017 During the period of 2015 to 2017, the resistance rates of Resistance rates of S. aureus and Enterococci to MRSA to trimethoprim-sulfamethoxazole and nitrofuran- antimicrobial agents among different patients toin increased from 9.66 to 14.94% (P < 0.001) and from For isolates collected from the outpatients, non-ICU inpa- 0.51 to 0.95% (P < 0.001) respectively. The resistance rates tients and ICU inpatients, resistance rates of S. aureus to of MRSA to erythromycin, tetracycline, tigecycline and all the antimicrobial agents increased gradually except for levofloxacin decreased from 90.32 to 88.24% (P = 0.003), clindamycin and trimethoprim-sulfamethoxazole (Fig. 2). from 35.58 to 29.05% (P < 0.001), from 0.14% to 0, and from Among which, the resistance rates to oxacillin, gentamicin 53.01 to 40.77% (P < 0.001) respectively (Fig. 1). MRSA and levofloxacin increased more dramatically. Resistance showed 100% susceptibility to vancomycin and teicoplanin, rates of enterococcus (including E. faecalis and E. faecium) however, a few linezolid-resistant strains were found in to all the antimicrobial agents increased gradually except 2016. The resistance rates of E. faecium to nitrofurantoin for linezolid and tetracycline (Fig. 3). and gentamicin-high level increased from 51.90 to 55.47% (P < 0.001) and from 34.15 to 41.67% (P <0.001) increased Analysis of risk factors associated with MRSA and VRE respectively. The resistance rates of E. faecium to linezolid, strains tetracycline, teicoplanin and vancomycin decreased from In multivariable analysis for risk factors associated with 1.15 to 0.67% (p = 0.168), from 38.33 to 30.77% (p = 0.243), MRSA and VRE (Table 2), we observed that the 2015 from 0.51 to 0.16% (P < 0.001), and from 1.69 to 0.90% (p = isolation rates of MRSA (OR = 1.022, 95% CI 1.010– 0.006) respectively (Table 1). Theresistancerateof E. faeca- 1.035, p < 0.001) and of VRE (OR = 1.005, 95% CI 1.003– lis to gentamicin-high level increased from 7.32 to 41.67% 1.006, p < 0.001) were higher than those in 2017. Com- (P < 0.001). The resistance rates of E. faecalis to ampicillin, pared to Huzhou, Zhoushan was the most likely city to nitrofurantoin, linezolid, tetracycline, and levofloxacin de- have MRSA isolates (OR = 1.775, 95% CI 1.676–1.880, creased from 5.72 to 3.04% (p = 0.021), from 3.95 to 2.56% p < 0.001). Compared to Lishui, Huzhou was the most (P < 0.001), from 3.17 to 2.73% (p = 0.002), from 77.29 to likely city to have VRE isolates (OR = 1.025, 95% CI 76.32% (P < 0.001), and from 20.78 to 19.79% (p = 0.009) re- 1.017–1.033, p < 0.001). The cities with high detection spectively (Table 1). Tigecycline showed 100% susceptibility rates of MRSA were distributed in the east and west of Fig. 1 Resistance rates of MRSA to antimicrobial agents during 2015 to 2017. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin were only from urine isolates. Abbreviations: F nitrofurantoin, SXT trimethoprim-sulfamethoxazole, E erythromycin, DA clindamycin, RD rifampicin, LZD linezolid, CN gentamicin, TE tetracycline, TGC tigecycline, TEC teicoplanin, VA vancomycin, LEV levofloxacin Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 4 of 9 Table 1 Resistance rates (%) of E. faecalis (E.fa) and E. faecium (E.fm) to antimicrobial agents during 2015 to 2017 Antimicrobial 2015 2016 2017 P value agent E.fa(n = 9109) E.fm (n = 7106) E.fa(n = 10,740) E.fm(n = 9135) E.fa (n = 11,860) E.fm (n = 10,379) E.fa E.fm Ampicillin 5.72 88.22 4.66 89.58 3.04 89.13 0.021 < 0.001 Nitrofurantoin 3.95 51.90 3.19 54.96 2.56 55.47 < 0.001 < 0.001 Gentamicin-High 7.32 34.15 18.06 41.57 41.67 41.67 < 0.001 < 0.001 Ciprofloxacin 22.54 89.13 23.14 90.47 22.05 90.32 0.009 0.147 Linezolid 3.17 1.15 2.97 1.00 2.73 0.67 0.002 0.168 Tetracycline 77.29 38.33 76.90 33.75 76.32 30.77 < 0.001 0.243 Tigecycline 0 0 0 0 0 0 / / Teicoplanin 0 0.51 0 0.45 0 0.16 / < 0.001 Vancomycin 0.67 1.69 0.37 1.22 0.42 0.90 < 0.001 0.006 Levofloxacin 20.78 87.49 20.43 89.04 19.79 88.47 0.009 0.195 / No comparison when appearing resistance rate was 0% the Zhejiang province, and the cities with high detection Discussion rates of VRE were distributed in the west of the Zhejiang It is a global trend that the drug resistance of province (Fig. 4). Isolates from tertiary hospitals were Gram-positive bacteria decreases gradually. In our study, more likely to be MRSA and VRE than isolates from sec- there is a slight decline in the isolation rates of MRSA ondary hospitals. Analysis based on age groups revealed (from 34.98 to 33.53%). The downward trend is also ob- that isolates derived from patients older than 75 years served in France, Germany and the UK [15, 16], but it is had the highest proportion of MRSA (OR = 1.443, 95% not seen in Saudi Arabia, where MRSA is maintaining its CI 1.409–1.478, p < 0.001) and VRE (OR = 1.011, 95% CI high level [17]. The use of alcohol-based hand-rub and 1.009–1.013, p < 0.001). Isolates from bile had the high- decolonization with antimicrobial agents may have helped est proportion of MRSA (OR = 1.385, 95% CI 1.151– to reduce MRSA transmission. As with other studies, linez- 1.665, p < 0.001) and isolates from blood had the highest olid, tigecycline and vancomycin are the most active agents proportion of VRE (OR = 1.007, 95% CI 1.003–1.010, against MRSA [18]. TherewerenoMRSA isolatesthat p < 0.001). Patients who were in ICU had the highest were resistant to vancomycin and teicoplanin. Unlike other proportion of MRSA (OR = 1.439, 95% CI 1.407–1.473, reports, the minimum inhibitory concentration (MIC) of p < 0.001) and VRE (OR = 1.019, 95% CI 1.013–1.025, MRSA to vancomycin was distributed around 0.5 and 1 p < 0.001). mg/L,and wasstableduringthe threeyears study[19]. Fig. 2 Resistance rates of S. aureus to antimicrobial agents among different patients. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin were only from urine isolates. Abbreviations: OX oxacillin, F nitrofurantoin, SXT trimethoprim-sulfamethoxazole, E erythromycin, DA clindamycin, RD rifampicin, LZD linezolid, P penicillin, CN gentamicin, TE tetracycline, TGC tigecycline, TEC teicoplanin, VA vancomycin, LEV levofloxacin Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 5 of 9 Fig. 3 Resistance rates of enterococci (E. faecalis and E. faecium) to antimicrobial agents among different patients. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin, tetracycline, ciprofloxacin and levofloxacin were only from urine isolates. Abbreviations: AMP ampicillin, F nitrofurantoin, CN gentamicin-high level, CIP ciprofloxacin, LZD linezolid, TE tetracycline, TGC tigecycline, TEC teicoplanin, LEV levofloxacin, VA vancomycin These results may be attributed to vancomycin being an gene vanB may have the highest resistance to vanco- unlikely empirical therapy due to its narrow-spectrum and mycin [27]. These may have a different resistance than its injection-only administration, thus resistances may not strains with the vanM gene, seen in China [28]or in have had a chance to form. Meanwhile, vancomycin be- strains with vanA dominance, seen in Poland [29]. In longs to the highest limit level in the classification manage- our study, resistance rate of E. faecalis to linezolid in- ment system of antibiotics. Linezolid resistances in creased from 1.6% in 2008 to 2.97% in 2016 [21] and li- coagulase negative staphylococci are greater than resistance nezolid resistance was higher in E. faecalis than in E. in S. aureus [20, 21]. Staphylococcus capitis isolates were faecium. In the past, mutations in the central loop of do- the highest in Zhejiang province, and the resistance rates main V of the 23S rRNA represented the most common to linezolid increased from 1.8% in 2014 [20]to3.5%in mechanism of oxazolidinone resistance in enterococci, 2016 [21]. This is duetoanoutbreakoflinezolid-resistant with G2576 T (Escherichia coli numbering) as the pre- S. capitis infection in Zhejiang. Since the first report of li- dominant mutation [30]. Increasingly, transferable oxa- nezolid resistance in methicillin-resistant coagulase nega- zolidinone resistance from the multi-resistance genes cfr tive staphylococci in the Second Affiliated Hospital of and optrA are being reported all over the world [31–33]. Zhejiang University School of Medicine in 2011, linezolid Furthermore, it was reported that the optrA gene was resistance in human clinical isolates has become an in- detected more frequently from food-producing animals creasing problem in China [22, 23], and the cfr-carrying than from humans [34]. plasmid has appeared in S. aureus [24]. We isolated several In the multivariable analysis for risk factors associated linezolid-resistant S. aureus strains in 2016, but not in with MRSA and VRE, we found that Hangzhou and Quz- 2015 and 2017. No outbreaks of linezolid resistance were hou simultaneously had high MRSA and VRE detection seen in S. aureus isolates. rates. As the provincial capital of Zhejiang, Hangzhou has The results of the present study show that the resist- more tertiary hospitals and receives a greater number of crit- ance rates of E. faecium are greater than the resistance ically ill patients from other cities. As a relatively rates of E. faecalis, and the resistance rates of E. faecium under-developedcity, Quzhou mayhaveapoorer sanitary to ampicillin and quinolones are more than 80%. There- arrangement, and the compliance with antibiotics may be fore infections caused by E. faecium present a serious worse. Meanwhile, we found that the cities of relatively high clinical challenge for physicians [25], and treatment op- MRSA and VRE detection rates tend to neighbour one an- tions for these infections are limited. Vancomycin is one other. This phenomenon may be caused by the increased treatment option that could be considered. In the last likelihood of interaction between the populations and pa- ten years, a weak downward trend for VRE cases was tients of these adjacent cities, allowing greater dissemination found worldwide and may be seen in the Zhejiang prov- of MRSA and VRE isolates. To be a patient in a IIIA hos- ince. We also confirmed that the resistance rate of en- pital (the highest classified and possibly largest hospital type terococcus to vancomycin remains at a low level, and in China) and a patient in the ICU ward are the greatest risk showed downward trends, similar to other reports in factors associated with MRSA and VRE infection. These China and lower than that in Ireland [26]. We found findings are in accordance with the literature [35, 36]and that the resistance rates of E. faecalis and E. faecium to can be attributed to patients with severe co-morbidities. vancomycin are higher than the resistance rates to teico- Stratifying the data by patient age, it is observed that the planin. We speculate that strains with the dominant proportion of MRSA and VRE was the highest in isolates Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 6 of 9 Table 2 Analysis of risk factors associated with MRSA and VRE strains MRSA VRE OR (95%CI) P value OR (95%CI) P value Year 2015 1.022 (1.010–1.035) < 0.001 1.005 (1.003–1.006) < 0.001 2016 1.018 (1.006–1.030) 0.002 1.001 (0.999–1.003) 0.214 2017 1 – 1 – Region Hangzhou 1.329 (1.295–1.363) < 0.001 1.010 (1.008–1.012) < 0.001 Huzhou 1 – 1.025 (1.017–1.033) < 0.001 Jiaxing 1.109 (1.080–1.139) < 0.001 1.006 (1.003–1.009) < 0.001 Jinhua 1.229 (1.195–1.265) < 0.001 1.005 (1.002–1.008) 0.001 Lishui 1.030 (1.002–1.059) 0.045 1 (0.997–1.003) 1 Ningbo 1.406 (1.365–1.447) < 0.001 1.002 (1–1.004) 0.054 Quzhou 1.453 (1.398–1.511) < 0.001 1.017 (1.011–1.024) < 0.001 Shaoxing 1.189 (1.156–1.224) < 0.001 1.003 (1.001–1.006) 0.015 Taizhou 1.197 (1.163–1.231) < 0.001 1.005 (1.002–1.009) 0.001 Wenzhou 1.282 (1.245–1.319) < 0.001 1 – Zhoushan 1.775 (1.676–1.880) < 0.001 1.004 (0.999–1.010) 0.079 Hospital Level IIIA (n = 46) 1.267 (1.213–1.322) < 0.001 1.016 (1.009–1.024) 0.031 IIIB (n = 24) 1.189 (1.138–1.242) < 0.001 1.010 (1.002–1.019) 0.143 IIA (n = 15) 1.139 (1.089–1.190) < 0.001 1.016 (1.006–1.025) 0.045 IIB (n =1) 1 – 1 – Age < =7d 1.130 (1.063–1.201) < 0.001 * * 8d-28d 1.085 (1.043–1.129) < 0.001 * * 1 m-1y 1.054 (1.030–1.079) < 0.001 * * 2y-3y 1 – 1.008 (0.998–1.019) 0.015 4y-19y 1.015 (0.992–1.037) 0.203 1 – 20y-43y 1.057 (1.035–1.080) < 0.001 1.004 (1.002–1.005) 0.044 44y-59y 1.104 (1.080–1.128) < 0.001 1.007 (1.005–1.009) 0.002 60y-74y 1.190 (1.164–1.217) < 0.001 1.006 (1.004–1.008) 0.004 75 + y 1.443 (1.409–1.478) < 0.001 1.011 (1.009–1.013) < 0.001 Specimen type Blood 1.142 (1.101–1.185) < 0.001 1.007 (1.003–1.010) < 0.001 Bile 1.385 (1.151–1.665) < 0.001 1.001 (0.999–1.004) 0.403 Respiratory 1.318 (1.278–1.360) < 0.001 1.003 (0.995–1.011) 0.515 Urine 1.186 (1.139–1.235) < 0.001 1.006 (1.004–1.008) < 0.001 Secretion 1.115 (1.081–1.150) < 0.001 1 – Puncture fluid 1 – 1.004 (1–1.009) 0.012 stool 1.342 (1.262–1.426) < 0.001 1.001 (0.997–1.005) 0.839 Other 1.137 (1.102–1.173) 0.002 1 (0.998–1.002) 1 Patient category Outpatient 1 – 1.004 (0.995–1.014) 0.4 Inpatient-non ICU 1.132 (1.118–1.147) < 0.001 1 – Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 7 of 9 Table 2 Analysis of risk factors associated with MRSA and VRE strains (Continued) MRSA VRE OR (95%CI) P value OR (95%CI) P value Inpatient-ICU 1.439 (1.407–1.473) < 0.001 1.019 (1.013–1.025) < 0.001 OR odds ratio, CI confidence interval IIIA number of bed more than 500, comprehensive examination score more than 900 points IIIB number of bed more than 500, comprehensive examination score between 750 and 899 points IIA number of bed between 100 and 499, comprehensive examination score more than 900 points IIB number of bed between 100 and 499, comprehensive examination score between 750 and 899 points Comprehensive examination including departments, staffing, management level, technical level, work quality and technical facilities d day old, m month old, y year old Respiratory containing sputum and bronchoalveolar lavage fluid Secretion containing pus and wound swab Puncture fluid containing hydrothorax, ascites, articular cavity fluid, pericardial fluid and Cerebrospinal fluid * No VRE isolate from elderly patients older than 75 years, but was the low- our study, a wider range of scenarios were seen where est from children aged 2 years - 3 years and infants youn- resistant strains could occur, indicating the importance ger than 1 year. The high numbers of MRSA and VRE of performing regional antibiotic resistance surveillance. isolates from elderly patients may be due to these patients The current study had some limitations: we had a rela- having more underlying diseases and a greater history of tively short span of time (3 years) for the data collection, antibiotic use than the child and the infant group. As well, we had a limited number of IIB hospitals to contribute decreased nutrition and immune function, often seen in data to the study, and because ours was a retrospective the elderly, may also be contributing elements. Other analysis, we had an inability to obtain the original identified risk factors associated with MRSA and VRE in- strains. In the future, we would like to expand this sur- clude having a source of isolates. We found that puncture veillance to cover more IIB and rural area clinics and fluid (containing hydrothorax, ascites, articular cavity also collect the original strains for intensive study. fluid, pericardial fluid and cerebrospinal fluid) has the lowest proportion (21.32%) of MRSA, though the under- lying reason for this phenomenon needs to be further Conclusion studied. In terms of treatment, we should be wary of The detection rates of MRSA stayed at moderate levels, methicillin-sensitive S. aureus when S. aureus is isolated and VRE stayed at low levels during the last three years, from puncture fluid in Zhejiang province. With the noted and local dissemination was found in MRSA and VRE exception of blood and urine, there is no difference in the isolates. The highest risk factors for MRSA and VRE in- specimen types in proportions of VRE isolates. fection were patient status in a IIIA hospital, age older These findings will provide valuable information for than 75 years and hospitalization in the ICU ward. As a infection control practices. Although many surveillance result of our findings, we suggest that sustained surveil- projects of antibiotic resistance have been carried out in lance is necessary to prevent the spread or clonal dis- China, they always cover only the tertiary hospitals. In semination of drug-resistant strains in Zhejiang China. Fig. 4 Distribution of MRSA (a) and VRE (b) by geographic area Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 8 of 9 Abbreviations Staphylococcus aureus and Vancomycin-resistant Enterococci. Infect Control CI: Confidence interval; ICU: Intensive care unit; MALDI-TOF-MS: Matrix- Hosp Epidemiol. 2017;38(8):1–3. Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry; 7. Ramirez MJY, Nick D, Elias MN, Amuah JE, Kathryn B, Couris CM, Kira L. A MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant comparison of administrative data versus surveillance data for hospital- Staphylococcus aureus; OR: Odds ratio; VRE: Vancomycin-resistant enterococci associated methicillin-resistant Staphylococcus aureus infections in Canadian hospitals. Infect Control Hosp Epidemiol. 2017;38(4):436–43. Acknowledgements 8. Watson S, Cabrera‐Aguas M, Khoo P, Pratama R, Gatus BJ, Gulholm T, We want to thank the participating hospitals for their work and cooperation. El‐Nasser J, Lahra MM. Keratitis antimicrobial resistance surveillance We also want to thank the drug resistance monitoring group of the Zhejiang program, Sydney, Australia: 2016 Annual Report. Clin Exp Ophthalmol. Province. 2019;47(1):20-5. 9. Seas C, Garcia C, Salles MJ, Labarca J, Luna C, Alvarez-Moreno C, Mejía- Funding Villatoro C, Zurita J, Guzmán-Blanco M, Rodríguez-Noriega E, et al. This study was supported by grants from the National Natural Science Staphylococcus aureus bloodstream infections in Latin America: results of a Foundation of China (No. 81871705 from Gongxiang Chen). multinational prospective cohort study. J Antimicrob Chemother. 2018;73(1). 10. Zhang GS, Lin XH, Cai JC, Zhang R, Xiu HQ, Tian BP, Cui W. Characteristics of Availability of data and materials clinical and environmental, vanM-carrying vancomycin-resistant enterococci All data generated or analysed during this study are included in this isolates from an infected patient. Int J Antimicrob Agents. 2018: manuscript. S0924857918300062. 11. Zhao C, Sun H, Wang H, Liu Y, Hu B, Yu Y, Sun ZY, Chu YZ, Cao B, Liao K, et Authors’ contributions al. 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Performance standards for antimicrobial susceptibility testing; twenty-fourth InformationalSupplement. Clinical and Consent for publication laboratory standards institute antimicrobial susceptibility testing M100-S24, Not applicable vol. 34; 2014. p. 1–230. 15. Decousser JW, Woerther PL, Soussy CJ, Marguerite FG, Dowzicky MJ. The Competing interests tigecycline evaluation and surveillance trial; assessment of the activity of The authors declare that they have no competing interests. tigecycline and other selected antibiotics against gram-positive and gram- negative pathogens from France collected between 2004 and 2016. Antimicrob Resist Infect Control. 2018;7(1):68. Publisher’sNote 16. European Centre for Disease Prevention and Control. Surveillance of Springer Nature remains neutral with regard to jurisdictional claims in antimicrobial resistance in Europe 2016. Annual report of the European published maps and institutional affiliations. antimicrobial resistance network (EARS-net). 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Epidemiology and risk factors of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci infections in Zhejiang China from 2015 to 2017

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Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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10.1186/s13756-019-0539-x
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Abstract

Background: Gram-positive bacteria are dangerous and challenging agents of infection due to their increasing resistance to antibiotics. We aim to analyse the epidemiology and risk factors of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) in Zhejiang China. Methods: Gram-positive bacteria (including S. aureus, Enterococcus faecalis and Enterococcus faecium) were collected from eighty-six hospitals of eleven cities in Zhejiang China from 2015 to 2017. The detection rates of MRSA and VRE infection were calculated for the non-duplicated isolate according to year, region, hospital level, patient age, specimen type and patient category. Meanwhile, the detected resistances of MRSA, E. faecalis and E. faecium to different antibiotics from 2015 to 2017 were compared. The risk factors and the differences in MRSA and VRE detection rates were compared using odds ratio (OR) with 95% confidence interval (95% CI) and Chi-square test respectively. Results: From 2015 to 2017, the detection rates of MRSA and VRE decreased gradually. The cities with the highest MRSA and VRE detection rates tended to be adjacent; for example, the neighbouring cities Hangzhou and Quzhou had simultaneously high rates of MRSA and VRE infection. Patients from IIIA hospital who were older than 75 years and in the intensive care unit (ICU) were most at risk. No vancomycin-resistant isolate was found in MRSA. Resistance of E. faecalis and E. faecium to vancomycin and linezolid decreased slightly and then maintained a low level. Conclusions: The detection rates of MRSA and VRE stayed at moderate and low levels during the three year period of this study, while local dissemination was found in MRSA and VRE isolates. Sustained surveillance is necessary to prevent the spread or clonal dissemination of drug-resistant strains in Zhejiang China. Keywords: Epidemiology, Risk factor, Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant enterococci * Correspondence: chengongxiang@zju.edu.cn Department of Clinical Microbiology, The Second Affiliated Hospital of Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, Zhejiang 310009, People’s Republic of China Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 2 of 9 Background automated system (the Vitek 2 compact, BD Phoenix-100, Gram-positive bacteria, such as Staphylococcus aureus, MicroScan WalkAway-96) or Matrix-Assisted Laser De- Enterococcus faecalis, and Enterococcus faecium are dan- sorption/Ionization Time of Flight Mass Spectrometry gerous and challenging agents of infection due to their (MALDI-TOF-MS). increasing resistance to antibiotics [1]. Among these, S. aureus are the most frequently isolated, making up Antimicrobial susceptibility testing 29.1% of the isolated Gram-positive bacterial popula- Standard operation procedures were established accord- tions, and infections caused by S. aureus (both ing to the Clinical and Laboratory Standards Institute’s community-associated or nosocomial-associated) are re- (CLSI) criteria, M100-S24 [14]. Every participating la- ported all over the world [2, 3]. Enterococci (including E. boratory conducted the antibiotic susceptibility testing faecalis and E. faecium) are the second frequently iso- for the clinical isolates using the Kirby-Bauer disk diffu- lated Gram-positive bacteria at 19.5%. Past generations sion method or the commercialized automated system of enterococci were mainly associated to urinary-tract in- following the instrument specifications. S. aureus (ATCC fection, but recently more and more enterococci are iso- 25923, ATCC 43300) and E. faecalis (ATCC 29212, lated from other infections [4], and an outbreak of ATCC 51299) were used as quality control strains for vancomycin resistant enterococci (VRE) in a solid organ the testing. transplant unit was reported in 2018 [5]. The epidemiology of resistance in Gram-positive bac- Statistical analysis teria has undergone major changes in recent decades, We analysed the risk factors for MRSA and VRE propor- with methicillin-resistant S. aureus (MRSA) and VRE tions, and for the multivariable model, year, region, hos- now being of international concern [6]. Antimicrobial pital level, patient age, specimen type and patient resistances of Gram-positive bacteria have been reported category were considered. The lowest detection rates of in many countries [7–9]; however, it was only in recent MRSA and VRE were set as contrasts. The risk factors years that vanM-carrying E. faecalis strains were isolated and the differences in MRSA and VRE detection rates from patients and the clinical environment in the Sec- were compared using odds ratio (OR) with 95% confi- ond Affiliated Hospital of Zhejiang University School of dence interval (95% CI) and Chi-square test. Chi-square Medicine [10], we speculate that if vanM infection has values were corrected when the quantities of VRE iso- been spreading in the Zhejiang province, it may lead to lates were less than forty. Results with P-value < 0.05 an increase of VRE overall. In China, although several were considered statistically significant. SPSS 19.0 (IBM local studies have examined the prevalence of resistance Company, Chicago, IL) and WHONET 5.5 (WHO) soft- in Gram-positive bacteria [11, 12], the studies usually ware were used for all statistical analyses. only cover the tertiary hospitals. Therefore, the present study is a retrospective surveillance covering a wider Results range of hospitals, including tertiary and secondary hos- Distribution of MRSA, Enterococci and VRE isolates pitals. Our aim is to seek trends in antimicrobial resist- During the years 2015–2017, the total number of MRSA ance among clinical isolates of important Gram-positive isolates increased from 9292 to 10,237 cases; in contrast, bacteria in the Zhejiang province of China. VRE isolates decreased from 173 to 137 cases (data not shown). Among the 11 cities that participated in the sur- Materials and methods vey, Hangzhou contributed 37.6% of all MRSA isolates Bacterial isolates (29,866 cases); and 41.0% of all Enterococci isolates We extracted data of S. aureus, E. faecalis and E. fae- (58,329 cases), although the population of Hangzhou is cium infections from the Zhejiang surveillance system’s only about 9.5 millon (16.5% of the Zhejiang province outpatient and inpatient records from January 1, 2015 to population). This high number of isolates may be due to December 31, 2017. The number of surveyed hospitals Hangzhou having more IIIA hospitals, which were the for each city was as follows: Hangzhou (n = 24), Huzhou contributors of 67% of all MRSA and enterococci isolates. (n = 4), Jiaxing (n = 11), Jinhua (n = 9), Lishui (n = 6), However, Hangzhou also contributed 245 VRE isolates, Ningbo (n = 10), Quzhou (n = 5), Shaoxing (n = 6), Tai- which was 54.2% of all of the VRE isolates in the study, zhou (n = 5), Wenzhou (n = 5), and Zhoushan (n = 1). and a much higher percentage than the province’s Sample collection was in accordance with the clinical MRSA and enterococci contributions. MRSA were most microbiology manual [13]. To avoid duplicate isolates, frequently isolated from respiratory samples (14,339 or only one isolate from the same species was included per 48.0% of all samples); VRE were dominantly isolated patient, as determined by the personal identifying code from urine samples (313 or 69.2% of all samples) (data and hospital name. Species identification of the isolates not shown). The number of samples based on age of pa- was performed by standard biochemical methods, tient and inpatient vs. out-patient were also categorized. Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 3 of 9 Patients older than 75 and patients who were hospital- against E. faecalis and E. faecium. The resistance rates of E. ized (especially those in the ICU) had dominantly higher faecium to ampicillin, nitrofurantoin, ciprofloxacin, MRSA, enterococci and VRE isolation rates compared to gentamicin-high level, levofloxacin, teicoplanin and vanco- other patient groups (data not shown). mycinwerehigherthanthatof E. faecalis, while lower re- sistance rates to tetracycline and linezolid were seen in E. Resistance rates of MRSA, E. faecalis and E. faecium to faecium in comparison to E. faecalis. antimicrobial agents from 2015 to 2017 During the period of 2015 to 2017, the resistance rates of Resistance rates of S. aureus and Enterococci to MRSA to trimethoprim-sulfamethoxazole and nitrofuran- antimicrobial agents among different patients toin increased from 9.66 to 14.94% (P < 0.001) and from For isolates collected from the outpatients, non-ICU inpa- 0.51 to 0.95% (P < 0.001) respectively. The resistance rates tients and ICU inpatients, resistance rates of S. aureus to of MRSA to erythromycin, tetracycline, tigecycline and all the antimicrobial agents increased gradually except for levofloxacin decreased from 90.32 to 88.24% (P = 0.003), clindamycin and trimethoprim-sulfamethoxazole (Fig. 2). from 35.58 to 29.05% (P < 0.001), from 0.14% to 0, and from Among which, the resistance rates to oxacillin, gentamicin 53.01 to 40.77% (P < 0.001) respectively (Fig. 1). MRSA and levofloxacin increased more dramatically. Resistance showed 100% susceptibility to vancomycin and teicoplanin, rates of enterococcus (including E. faecalis and E. faecium) however, a few linezolid-resistant strains were found in to all the antimicrobial agents increased gradually except 2016. The resistance rates of E. faecium to nitrofurantoin for linezolid and tetracycline (Fig. 3). and gentamicin-high level increased from 51.90 to 55.47% (P < 0.001) and from 34.15 to 41.67% (P <0.001) increased Analysis of risk factors associated with MRSA and VRE respectively. The resistance rates of E. faecium to linezolid, strains tetracycline, teicoplanin and vancomycin decreased from In multivariable analysis for risk factors associated with 1.15 to 0.67% (p = 0.168), from 38.33 to 30.77% (p = 0.243), MRSA and VRE (Table 2), we observed that the 2015 from 0.51 to 0.16% (P < 0.001), and from 1.69 to 0.90% (p = isolation rates of MRSA (OR = 1.022, 95% CI 1.010– 0.006) respectively (Table 1). Theresistancerateof E. faeca- 1.035, p < 0.001) and of VRE (OR = 1.005, 95% CI 1.003– lis to gentamicin-high level increased from 7.32 to 41.67% 1.006, p < 0.001) were higher than those in 2017. Com- (P < 0.001). The resistance rates of E. faecalis to ampicillin, pared to Huzhou, Zhoushan was the most likely city to nitrofurantoin, linezolid, tetracycline, and levofloxacin de- have MRSA isolates (OR = 1.775, 95% CI 1.676–1.880, creased from 5.72 to 3.04% (p = 0.021), from 3.95 to 2.56% p < 0.001). Compared to Lishui, Huzhou was the most (P < 0.001), from 3.17 to 2.73% (p = 0.002), from 77.29 to likely city to have VRE isolates (OR = 1.025, 95% CI 76.32% (P < 0.001), and from 20.78 to 19.79% (p = 0.009) re- 1.017–1.033, p < 0.001). The cities with high detection spectively (Table 1). Tigecycline showed 100% susceptibility rates of MRSA were distributed in the east and west of Fig. 1 Resistance rates of MRSA to antimicrobial agents during 2015 to 2017. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin were only from urine isolates. Abbreviations: F nitrofurantoin, SXT trimethoprim-sulfamethoxazole, E erythromycin, DA clindamycin, RD rifampicin, LZD linezolid, CN gentamicin, TE tetracycline, TGC tigecycline, TEC teicoplanin, VA vancomycin, LEV levofloxacin Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 4 of 9 Table 1 Resistance rates (%) of E. faecalis (E.fa) and E. faecium (E.fm) to antimicrobial agents during 2015 to 2017 Antimicrobial 2015 2016 2017 P value agent E.fa(n = 9109) E.fm (n = 7106) E.fa(n = 10,740) E.fm(n = 9135) E.fa (n = 11,860) E.fm (n = 10,379) E.fa E.fm Ampicillin 5.72 88.22 4.66 89.58 3.04 89.13 0.021 < 0.001 Nitrofurantoin 3.95 51.90 3.19 54.96 2.56 55.47 < 0.001 < 0.001 Gentamicin-High 7.32 34.15 18.06 41.57 41.67 41.67 < 0.001 < 0.001 Ciprofloxacin 22.54 89.13 23.14 90.47 22.05 90.32 0.009 0.147 Linezolid 3.17 1.15 2.97 1.00 2.73 0.67 0.002 0.168 Tetracycline 77.29 38.33 76.90 33.75 76.32 30.77 < 0.001 0.243 Tigecycline 0 0 0 0 0 0 / / Teicoplanin 0 0.51 0 0.45 0 0.16 / < 0.001 Vancomycin 0.67 1.69 0.37 1.22 0.42 0.90 < 0.001 0.006 Levofloxacin 20.78 87.49 20.43 89.04 19.79 88.47 0.009 0.195 / No comparison when appearing resistance rate was 0% the Zhejiang province, and the cities with high detection Discussion rates of VRE were distributed in the west of the Zhejiang It is a global trend that the drug resistance of province (Fig. 4). Isolates from tertiary hospitals were Gram-positive bacteria decreases gradually. In our study, more likely to be MRSA and VRE than isolates from sec- there is a slight decline in the isolation rates of MRSA ondary hospitals. Analysis based on age groups revealed (from 34.98 to 33.53%). The downward trend is also ob- that isolates derived from patients older than 75 years served in France, Germany and the UK [15, 16], but it is had the highest proportion of MRSA (OR = 1.443, 95% not seen in Saudi Arabia, where MRSA is maintaining its CI 1.409–1.478, p < 0.001) and VRE (OR = 1.011, 95% CI high level [17]. The use of alcohol-based hand-rub and 1.009–1.013, p < 0.001). Isolates from bile had the high- decolonization with antimicrobial agents may have helped est proportion of MRSA (OR = 1.385, 95% CI 1.151– to reduce MRSA transmission. As with other studies, linez- 1.665, p < 0.001) and isolates from blood had the highest olid, tigecycline and vancomycin are the most active agents proportion of VRE (OR = 1.007, 95% CI 1.003–1.010, against MRSA [18]. TherewerenoMRSA isolatesthat p < 0.001). Patients who were in ICU had the highest were resistant to vancomycin and teicoplanin. Unlike other proportion of MRSA (OR = 1.439, 95% CI 1.407–1.473, reports, the minimum inhibitory concentration (MIC) of p < 0.001) and VRE (OR = 1.019, 95% CI 1.013–1.025, MRSA to vancomycin was distributed around 0.5 and 1 p < 0.001). mg/L,and wasstableduringthe threeyears study[19]. Fig. 2 Resistance rates of S. aureus to antimicrobial agents among different patients. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin were only from urine isolates. Abbreviations: OX oxacillin, F nitrofurantoin, SXT trimethoprim-sulfamethoxazole, E erythromycin, DA clindamycin, RD rifampicin, LZD linezolid, P penicillin, CN gentamicin, TE tetracycline, TGC tigecycline, TEC teicoplanin, VA vancomycin, LEV levofloxacin Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 5 of 9 Fig. 3 Resistance rates of enterococci (E. faecalis and E. faecium) to antimicrobial agents among different patients. / No comparison when appearing resistance rate was 0%. Results of nitrofurantoin, tetracycline, ciprofloxacin and levofloxacin were only from urine isolates. Abbreviations: AMP ampicillin, F nitrofurantoin, CN gentamicin-high level, CIP ciprofloxacin, LZD linezolid, TE tetracycline, TGC tigecycline, TEC teicoplanin, LEV levofloxacin, VA vancomycin These results may be attributed to vancomycin being an gene vanB may have the highest resistance to vanco- unlikely empirical therapy due to its narrow-spectrum and mycin [27]. These may have a different resistance than its injection-only administration, thus resistances may not strains with the vanM gene, seen in China [28]or in have had a chance to form. Meanwhile, vancomycin be- strains with vanA dominance, seen in Poland [29]. In longs to the highest limit level in the classification manage- our study, resistance rate of E. faecalis to linezolid in- ment system of antibiotics. Linezolid resistances in creased from 1.6% in 2008 to 2.97% in 2016 [21] and li- coagulase negative staphylococci are greater than resistance nezolid resistance was higher in E. faecalis than in E. in S. aureus [20, 21]. Staphylococcus capitis isolates were faecium. In the past, mutations in the central loop of do- the highest in Zhejiang province, and the resistance rates main V of the 23S rRNA represented the most common to linezolid increased from 1.8% in 2014 [20]to3.5%in mechanism of oxazolidinone resistance in enterococci, 2016 [21]. This is duetoanoutbreakoflinezolid-resistant with G2576 T (Escherichia coli numbering) as the pre- S. capitis infection in Zhejiang. Since the first report of li- dominant mutation [30]. Increasingly, transferable oxa- nezolid resistance in methicillin-resistant coagulase nega- zolidinone resistance from the multi-resistance genes cfr tive staphylococci in the Second Affiliated Hospital of and optrA are being reported all over the world [31–33]. Zhejiang University School of Medicine in 2011, linezolid Furthermore, it was reported that the optrA gene was resistance in human clinical isolates has become an in- detected more frequently from food-producing animals creasing problem in China [22, 23], and the cfr-carrying than from humans [34]. plasmid has appeared in S. aureus [24]. We isolated several In the multivariable analysis for risk factors associated linezolid-resistant S. aureus strains in 2016, but not in with MRSA and VRE, we found that Hangzhou and Quz- 2015 and 2017. No outbreaks of linezolid resistance were hou simultaneously had high MRSA and VRE detection seen in S. aureus isolates. rates. As the provincial capital of Zhejiang, Hangzhou has The results of the present study show that the resist- more tertiary hospitals and receives a greater number of crit- ance rates of E. faecium are greater than the resistance ically ill patients from other cities. As a relatively rates of E. faecalis, and the resistance rates of E. faecium under-developedcity, Quzhou mayhaveapoorer sanitary to ampicillin and quinolones are more than 80%. There- arrangement, and the compliance with antibiotics may be fore infections caused by E. faecium present a serious worse. Meanwhile, we found that the cities of relatively high clinical challenge for physicians [25], and treatment op- MRSA and VRE detection rates tend to neighbour one an- tions for these infections are limited. Vancomycin is one other. This phenomenon may be caused by the increased treatment option that could be considered. In the last likelihood of interaction between the populations and pa- ten years, a weak downward trend for VRE cases was tients of these adjacent cities, allowing greater dissemination found worldwide and may be seen in the Zhejiang prov- of MRSA and VRE isolates. To be a patient in a IIIA hos- ince. We also confirmed that the resistance rate of en- pital (the highest classified and possibly largest hospital type terococcus to vancomycin remains at a low level, and in China) and a patient in the ICU ward are the greatest risk showed downward trends, similar to other reports in factors associated with MRSA and VRE infection. These China and lower than that in Ireland [26]. We found findings are in accordance with the literature [35, 36]and that the resistance rates of E. faecalis and E. faecium to can be attributed to patients with severe co-morbidities. vancomycin are higher than the resistance rates to teico- Stratifying the data by patient age, it is observed that the planin. We speculate that strains with the dominant proportion of MRSA and VRE was the highest in isolates Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 6 of 9 Table 2 Analysis of risk factors associated with MRSA and VRE strains MRSA VRE OR (95%CI) P value OR (95%CI) P value Year 2015 1.022 (1.010–1.035) < 0.001 1.005 (1.003–1.006) < 0.001 2016 1.018 (1.006–1.030) 0.002 1.001 (0.999–1.003) 0.214 2017 1 – 1 – Region Hangzhou 1.329 (1.295–1.363) < 0.001 1.010 (1.008–1.012) < 0.001 Huzhou 1 – 1.025 (1.017–1.033) < 0.001 Jiaxing 1.109 (1.080–1.139) < 0.001 1.006 (1.003–1.009) < 0.001 Jinhua 1.229 (1.195–1.265) < 0.001 1.005 (1.002–1.008) 0.001 Lishui 1.030 (1.002–1.059) 0.045 1 (0.997–1.003) 1 Ningbo 1.406 (1.365–1.447) < 0.001 1.002 (1–1.004) 0.054 Quzhou 1.453 (1.398–1.511) < 0.001 1.017 (1.011–1.024) < 0.001 Shaoxing 1.189 (1.156–1.224) < 0.001 1.003 (1.001–1.006) 0.015 Taizhou 1.197 (1.163–1.231) < 0.001 1.005 (1.002–1.009) 0.001 Wenzhou 1.282 (1.245–1.319) < 0.001 1 – Zhoushan 1.775 (1.676–1.880) < 0.001 1.004 (0.999–1.010) 0.079 Hospital Level IIIA (n = 46) 1.267 (1.213–1.322) < 0.001 1.016 (1.009–1.024) 0.031 IIIB (n = 24) 1.189 (1.138–1.242) < 0.001 1.010 (1.002–1.019) 0.143 IIA (n = 15) 1.139 (1.089–1.190) < 0.001 1.016 (1.006–1.025) 0.045 IIB (n =1) 1 – 1 – Age < =7d 1.130 (1.063–1.201) < 0.001 * * 8d-28d 1.085 (1.043–1.129) < 0.001 * * 1 m-1y 1.054 (1.030–1.079) < 0.001 * * 2y-3y 1 – 1.008 (0.998–1.019) 0.015 4y-19y 1.015 (0.992–1.037) 0.203 1 – 20y-43y 1.057 (1.035–1.080) < 0.001 1.004 (1.002–1.005) 0.044 44y-59y 1.104 (1.080–1.128) < 0.001 1.007 (1.005–1.009) 0.002 60y-74y 1.190 (1.164–1.217) < 0.001 1.006 (1.004–1.008) 0.004 75 + y 1.443 (1.409–1.478) < 0.001 1.011 (1.009–1.013) < 0.001 Specimen type Blood 1.142 (1.101–1.185) < 0.001 1.007 (1.003–1.010) < 0.001 Bile 1.385 (1.151–1.665) < 0.001 1.001 (0.999–1.004) 0.403 Respiratory 1.318 (1.278–1.360) < 0.001 1.003 (0.995–1.011) 0.515 Urine 1.186 (1.139–1.235) < 0.001 1.006 (1.004–1.008) < 0.001 Secretion 1.115 (1.081–1.150) < 0.001 1 – Puncture fluid 1 – 1.004 (1–1.009) 0.012 stool 1.342 (1.262–1.426) < 0.001 1.001 (0.997–1.005) 0.839 Other 1.137 (1.102–1.173) 0.002 1 (0.998–1.002) 1 Patient category Outpatient 1 – 1.004 (0.995–1.014) 0.4 Inpatient-non ICU 1.132 (1.118–1.147) < 0.001 1 – Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 7 of 9 Table 2 Analysis of risk factors associated with MRSA and VRE strains (Continued) MRSA VRE OR (95%CI) P value OR (95%CI) P value Inpatient-ICU 1.439 (1.407–1.473) < 0.001 1.019 (1.013–1.025) < 0.001 OR odds ratio, CI confidence interval IIIA number of bed more than 500, comprehensive examination score more than 900 points IIIB number of bed more than 500, comprehensive examination score between 750 and 899 points IIA number of bed between 100 and 499, comprehensive examination score more than 900 points IIB number of bed between 100 and 499, comprehensive examination score between 750 and 899 points Comprehensive examination including departments, staffing, management level, technical level, work quality and technical facilities d day old, m month old, y year old Respiratory containing sputum and bronchoalveolar lavage fluid Secretion containing pus and wound swab Puncture fluid containing hydrothorax, ascites, articular cavity fluid, pericardial fluid and Cerebrospinal fluid * No VRE isolate from elderly patients older than 75 years, but was the low- our study, a wider range of scenarios were seen where est from children aged 2 years - 3 years and infants youn- resistant strains could occur, indicating the importance ger than 1 year. The high numbers of MRSA and VRE of performing regional antibiotic resistance surveillance. isolates from elderly patients may be due to these patients The current study had some limitations: we had a rela- having more underlying diseases and a greater history of tively short span of time (3 years) for the data collection, antibiotic use than the child and the infant group. As well, we had a limited number of IIB hospitals to contribute decreased nutrition and immune function, often seen in data to the study, and because ours was a retrospective the elderly, may also be contributing elements. Other analysis, we had an inability to obtain the original identified risk factors associated with MRSA and VRE in- strains. In the future, we would like to expand this sur- clude having a source of isolates. We found that puncture veillance to cover more IIB and rural area clinics and fluid (containing hydrothorax, ascites, articular cavity also collect the original strains for intensive study. fluid, pericardial fluid and cerebrospinal fluid) has the lowest proportion (21.32%) of MRSA, though the under- lying reason for this phenomenon needs to be further Conclusion studied. In terms of treatment, we should be wary of The detection rates of MRSA stayed at moderate levels, methicillin-sensitive S. aureus when S. aureus is isolated and VRE stayed at low levels during the last three years, from puncture fluid in Zhejiang province. With the noted and local dissemination was found in MRSA and VRE exception of blood and urine, there is no difference in the isolates. The highest risk factors for MRSA and VRE in- specimen types in proportions of VRE isolates. fection were patient status in a IIIA hospital, age older These findings will provide valuable information for than 75 years and hospitalization in the ICU ward. As a infection control practices. Although many surveillance result of our findings, we suggest that sustained surveil- projects of antibiotic resistance have been carried out in lance is necessary to prevent the spread or clonal dis- China, they always cover only the tertiary hospitals. In semination of drug-resistant strains in Zhejiang China. Fig. 4 Distribution of MRSA (a) and VRE (b) by geographic area Huang et al. Antimicrobial Resistance and Infection Control (2019) 8:90 Page 8 of 9 Abbreviations Staphylococcus aureus and Vancomycin-resistant Enterococci. Infect Control CI: Confidence interval; ICU: Intensive care unit; MALDI-TOF-MS: Matrix- Hosp Epidemiol. 2017;38(8):1–3. Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry; 7. Ramirez MJY, Nick D, Elias MN, Amuah JE, Kathryn B, Couris CM, Kira L. A MIC: Minimum inhibitory concentration; MRSA: Methicillin-resistant comparison of administrative data versus surveillance data for hospital- Staphylococcus aureus; OR: Odds ratio; VRE: Vancomycin-resistant enterococci associated methicillin-resistant Staphylococcus aureus infections in Canadian hospitals. Infect Control Hosp Epidemiol. 2017;38(4):436–43. Acknowledgements 8. Watson S, Cabrera‐Aguas M, Khoo P, Pratama R, Gatus BJ, Gulholm T, We want to thank the participating hospitals for their work and cooperation. El‐Nasser J, Lahra MM. Keratitis antimicrobial resistance surveillance We also want to thank the drug resistance monitoring group of the Zhejiang program, Sydney, Australia: 2016 Annual Report. Clin Exp Ophthalmol. Province. 2019;47(1):20-5. 9. 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