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Trends in Antimicrobial Resistance against Enterobacteriaceae Strains Isolated from Blood: A 10-year Epidemiological Study in Mainland China (2004–2014).

Byline: Xiang-Jun. Liu, Yuan. Lyu, Yun. Li, Feng. Xue, Jian. Liu

Background: Antimicrobial resistance is a serious problem that compromises the empirical treatment of infections, resulting in a lack of effective antibiotics and high medical expenses. Here, we aimed to monitor the trends in antimicrobial resistance among Enterobacteriaceae isolated from blood samples in mainland China. Methods: A total of 2240 Enterobacteriaceae isolates from blood were collected from hospitalized patients at 19 tertiary hospitals between October 2004 and June 2014. The minimum inhibitory concentrations of all isolates were determined using the agar dilution method according to the Clinical and Laboratory Standards Institute 2016 guidelines. Results: The most commonly isolated bacteria were Escherichia coli, compromising 47.0% (1053/2240) of the total isolates, followed by Klebsiella spp. (26.3%), Salmonella spp. (10.4%), and Enterobacter spp. (9.2%). The detection rates of extended-spectrum [sz]-lactamases (ESBLs) among E. coli were 68.9% (2004–2005), 73.2% (2007–2008), 67.9% (2009–2010), 72.6% (2011–2012), and 58.4% (2013–2014), whereas those in ESBL-producing Klebsiella pneumoniae were slightly decreased (75.9%, 50.0%, 41.4%, 40.2%, and 43.0%, respectively). Carbapenems were the most potent agents against the Enterobacteriaceae isolates, followed by moxalactam, tigecycline, and amikacin. However, there was a decrease in the susceptibility rates for carbapenems in all species, particularly K. pneumoniae(decreased by 10.6% for imipenem) and Enterobacter aerogenes (decreased by 21.1% for imipenem). Reviving antibiotics (tigecycline and polymyxins) showed good in vitro activity against Enterobacteriaceae. Conclusions: The activity of antibiotics against Enterobacteriaceae isolated from blood was decreased overall. Large proportions of ESBL-producing isolates were identified among E. coli and Klebsiella spp. Carbapenem-resistant isolates have become a major challenge in the treatment of infections.


Enterobacteriaceae pathogens are the most commonly isolated Gram-negative bacteria identified in human blood samples. Once bloodstream infection occurs, these pathogens often result in major health problems, requiring a lengthy hospital stay, multiple antibiotic use, high medical expenses, and even death. A previous study [sup][1] showed that patients with Gram-negative bloodstream infections have more severe inflammatory reactions and clinical symptoms than patients with Gram-positive bloodstream infections. Due to poor regulations and inappropriate use of antibiotics, antimicrobial resistance (AMR) has become a major challenge, particularly within the last decade.

In this study, we evaluated the antimicrobial susceptibility profiles ofEnterobacteriaceae from blood samples with the goal of controlling AMR and improving the efficient utilization of antibiotics.


Ethical approval

Ethics committee approval was not required because we did not collect patient identifying information.

Clinical isolates

All isolates obtained from blood samples were collected biennially from a cumulative total of 19 tertiary hospitals in mainland China over five consecutive 1-year periods between October 2004 and June 2014 (2004–2005, 2007–2008, 2009–2010, 2011–2012, and 2013–2014) and were then sent to the Institute of Clinical Pharmacology, Peking University First Hospital. These participating tertiary hospitals are located in 15 different provinces in China, and only one isolate per species per patient was collected to avoid repetitive counts in this study. Every strain to be tested was recovered and purified before the experiment to ensure the viability and purity of the bacteria. Bacterial suspensions were obtained by inoculation with 10[sup]4 CFU of each bacterium via a multipoint inoculator. All isolates were identified by standard methods used in clinical microbiology laboratories. All organisms were deemed clinically significant by local participant criteria.

Susceptibility testing

In vitro susceptibilities to antimicrobial agents were identified by the agar dilution method, and susceptibility profiles were identified by the minimum inhibitory concentration (MIC) interpretative breakpoint criteria according to Clinical and Laboratory Standards Institute 2016 guidelines (CLSI 2016)[sup][2] or EUCAST 2016[sup][3] if CLSI 2016 did not provide the specific breakpoint. The double-disk synergy test was performed to identify ESBL-producing isolates among Escherichia coli and Klebsiella pneumoniae , as recommended by CLSI 2016.

Quality control

Quality control was performed using the reference strains E. coli ATCC 25922 and E. coli ATCC 35218 according to CLSI 2016. The following antibiotics were included: amoxicillin, amoxicillin-clavulanic acid (AMC), piperacillin, piperacillin-tazobactam (TZP), mezlocillin, mezlocillin-sulbactam (MSU), cefazolin, cefuroxime, ceftriaxone, cefotaxime, ceftazidime, cefoperazone, cefoperazone-sulbactam (CSL), cefepime, aztreonam, moxalactam, imipenem, meropenem, panipenem, ertapenem, gentamycin, amikacin, tetracycline, minocycline, tigecycline, ciprofloxacin, levofloxacin, nitrofurantoin, fosfomycin, polymyxin B, and colistin.

Statistical analysis

Statistical tests were analyzed by Statistical Package for the Social Sciences 20.0 software (SPSS, Inc., Chicago, IL, USA). Enumeration data were presented as percentage values. Differences in susceptibility to antibiotics between groups were analyzed by Fisher's exact tests and Chi-square tests. Results with P < 0.05 were considered statistically significant using two-tailed tests.


Distribution of Enterobacteriaceae pathogens

Over five consecutive 1-year studies, a total of 2240 Enterobacteriaceae pathogens isolated from blood samples from 19 participating hospitals nationwide were collected. There were no significant changes in the ratio of targeted species among all studied isolates. E. coli (47%, n = 1053), K. pneumoniae (23.4%, n = 524), Salmonella spp. (10.4%, n = 233), and Enterobacter cloacae (6.8%, n = 152) were the most commonly detected species in blood samples. Notably, the average prevalence rate of Salmonella spp. was higher than that of E. cloacae , in contrast to other reports.[sup][4],[5],[6],[7] However, over the entire study period, the number of Salmonella spp. declined gradually, whereas that of E. cloacae increased continually, accounting for a much larger proportion of the yearly total isolates [Table 1].{Table 1}

Escherichia coli

The nonsusceptibility rates of third- and fourth-generation cephalosporins (except for ceftazidime, CSL, and cefepime) and fluoroquinolones remained high among E. coli isolates, although some fluctuations were observed for some antibiotics, with the yearly resistance rates ranging from 53.3% to 81.4%. However, the susceptibility rates of cefazolin, ceftazidime, CSL, and cefepime decreased dramatically>10% over the 10-year study. Beta-lactamase inhibitor-based combination therapy (including AMC, TZP, MSU, and CSL) showed significantly greater in vitro activity than monotherapy ( P < 0.01). The same activity was observed for K. pneumoniae , albeit to a lesser degree. Carbapenems, moxalactam, tigecycline, and fosfomycin maintained excellent in vitro activity against the E. coli isolates, with susceptibility rates ranging from 95% to 100% over the 10-year study. Moreover, the nonsusceptibility rate of carbapenems only increased by 0.7–1.3% [Figure 1].{Figure 1}

The detection rates of ESBL-positive E. coli isolates were extremely high and reached a plateau at 58.4–76.3% of all E. coli isolates. Compared with cefotaxime and ceftriaxone, ceftazidime maintained better activity against ESBL-positive isolates. However, there was a sharp decrease in the susceptibility rate for ceftazidime from 48.4% to 25.7% over the 10-year study. Moreover, CSL showed decreased efficacy against ESBL-positive E. coli isolates, with fluctuations during 2011–2012, and the susceptibility rate dropped from 83.9% to 62.6% over 10 years. Carbapenems, moxalactam, amikacin, and tigecycline maintained excellent in vitro efficacy against ESBL-positive E. coli isolates [Figure 1] and [Figure 2].{Figure 2}

Klebsiella spp.

The antimicrobial profiles of Klebsiella spp. were similar to those of E. coli ; however, Klebsiella spp. isolates displayed higher susceptibility rates to [sz]-lactam agents than E. coli isolates. Notably, over the 10-year period, susceptibility rates to ceftazidime, TZP, and CSL decreased dramatically by 12.8%, 16.2%, and 22.7%, respectively, among K. pneumoniae isolates. Among all tested agents,>90% of K. pneumoniae isolates were susceptible to moxalactam, carbapenems (except ertapenem 88.3% susceptible during 2013–2014), tigecycline, fosfomycin, and polymyxin. Importantly, the frequency of occurrence of carbapenem-resistant K. pneumoniae increases significantly from 0% in 2004 to 8.9% in 2014, which is higher than the nationwide level for the same period [6.4% in 2014;[sup][8] [Figure 1].

The detection rates of ESBL-producing K. pneumoniae isolates were lower than those of E. coli isolates, with a yearly average rate of 44.1% [Figure 1]. There was a pronounced decrease in the in vitro activity of CSL over the study period, with susceptibility rates decreasing from 90.9% in 2004 to 51.9% in 2014. Over the 10-year study period, carbapenems showed good activity against ESBL-producing K. pneumoniae (>90.9% susceptible). Amikacin showed increased in vitro activity against these isolates, with susceptibility rates increasing from 77.3% in 2004 to 90.9% in 2014. Compared with E. coli , imipenem, amikacin, and tigecycline showed relatively lower in vitro activity against K. pneumoniae , whereas fluoroquinolones displayed much better efficacy against K. pneumoniae than E. coli . Moxalactam and polymyxins maintained good potency against K. pneumoniae , inhibiting>90% of ESBL-producing isolates. The antimicrobial patterns of Klebsiella oxytoca were similar to those of K. pneumoniae [data not shown and [Figure 3].{Figure 3}

Enterobacter spp.

During the study period, the total isolation rate of E. cloacae was much higher than that of Enterobacter aerogenes (6.8% versus 2.4%). Due to the low number (<10 strains) of tested isolates, the antimicrobial profiles were not determined for both 2004–2005 and 2007–2008. Annual susceptibility rates to tested antimicrobial agents for E. cloacae were generally lower than those for E. aerogenes during 2009–2010 and 2011–2012, similar to other previous studies in China.[sup][9] Over the three 1-year consecutive periods (2009–2010, 2011–2012, and 2013–2014), high resistance rates for [sz]-lactam agents (except for carbapenems) were uniformly observed in E. cloacae and E. aerogenes . Carbapenems, moxalactam, amikacin, tigecycline, and fosfomycin displayed acceptable in vitro activity against E. cloacae and E. aerogenes , with the susceptibility rates of>75%. Notably, resistance to carbapenems tended to increase in E. aerogenes , particularly for ertapenem (from 0% in 2009–2010 to 15.8% in 2013–2014), with MIC[sub]90 increased from 0.25 to 4 mg/L. The same trend was observed for E. cloacae , but to a lesser degree. During 2013–2014, polymyxins (including polymyxin B and colistin) exhibited prominent in vitro activity against E. aerogenes isolates, with susceptibility rates of>90%. In contrast, polymyxins showed much lower in vitro activity against E. cloacae (<68.3% susceptible).

Salmonella spp.

Salmonella spp. were the third most commonly isolated organisms. Unlike other species within the Enterobacteriaceae family, most tested antimicrobial agents exhibited strong in vitro activity against Salmonella spp. Among [sz]-lactam agents,>90% of the isolates were susceptible to TZP, CSL, ceftazidime, cefepime, moxalactam, and carbapenems. Amikacin, tigecycline, and fosfomycin showed strong in vitro activity against Salmonella spp. Over the 10-year study, only one strain was found to be resistant to carbapenems, and no tigecycline-resistant Salmonella spp. were found. Interestingly, there were no significant changes in the resistance rates for fluoroquinolones (<10% throughout the collection period); however, a large proportion of Salmonella spp. (48.7–83.3%) showed intermediate resistance to fluoroquinolones.

Citrobacter spp., Serratia spp., Morganella spp., and Proteus spp.

There were low isolation rates of Citrobacter spp., Serratia spp., Morganella spp., and Proteus spp. in this study. The antimicrobial profiles of these species to tested antibiotics are shown in [Supplementary Table 1] [SUPPORTING:1], [Supplementary Table 2] [SUPPORTING:2], [Supplementary Table 3] [SUPPORTING:3], [Supplementary Table 4] [SUPPORTING:4], [Supplementary Table 5] [SUPPORTING:5], [Supplementary Table 6] [SUPPORTING:6]. The third- and fourth-generation cephalosporins showed good in vitro activity against Serratia spp. and Morganella spp., acceptable in vitro activity against Proteus spp., and low in vitro activity against Citrobacter spp. The differences in susceptibility to other antibiotics were typically large. Moxalactam and carbapenems showed relatively superior in vitro potency compared with other tested antibiotics.


Over the collection periods (2004–2005, 2007–2008, 2009–2010, 2011–2012, 2013–2014), Enterobacteriaceae isolates exhibited distinctively different antimicrobial susceptibilities to tested antibiotics. In this study, [sz]-lactam antibiotics (except for carbapenems) displayed extremely poor in vitro activity against the Enterobacteriaceae family with the exception of Salmonella spp. Third-generation cephalosporin-resistant isolates were often found to be resistant to fluoroquinolones and aminoglycosides (gentamycin and amikacin) simultaneously. In this 10-year study, 2.1–6.3% of the 2240 Enterobacteriaceae isolates were resistant to these three types of antibiotics (data not shown), corresponding to the results of a European survey over the same period (1.4–19.7%).[sup][10]

The detection rates of ESBL-producing E. coli and K. pneumoniae isolates were almost unchanged and remained consistently high over the 10-year study, with yearly total rates of 66.7% (702/1053) and 44.1% (231/524), respectively; these rates were much higher than those of other countries.[sup][10],[11] ESBL production is the main reason for treatment failure of [sz]-lactam antibiotics. According to a previous survey, the CTX-M genotype, associated with the hydrolysis of cefotaxime and ceftriaxone, is the main genotype of ESBLs.[sup][12],[13] This could explain why cefotaxime and ceftriaxone showed much lower in vitro efficacy than ceftazidime against ESBLs.

Throughout the study,[sup][7] a trend toward increased nonsusceptibility rates for carbapenems was observed, especially for K. pneumoniae and E. aerogenes . During 2013–2014, the nonsusceptibility rates of K. pneumoniae and E. aerogenes to ertapenem reached up to 11.7% and 21.1%, respectively. Furthermore, carbapenem resistance was generally caused by the production of carbapenemases carried by plasmids, which could be transmitted within species or even from species to species. However, the genes encoding carbapenemases often carry some other resistance factors at the same time, leading to extensively drug-resistant bacteria.[sup][14] Thus, the problem of carbapenem-resistant Enterobacteriaceae (CRE) has become a major challenge to public health worldwide, resulting in higher mortality rates caused by infections and a lack of reliable treatment.[sup][15],[16],[17],[18]

In this study, some reviving antibiotics, including fosfomycin and polymyxins, were found to be effective alternative treatments against CRE. Polymyxins displayed strong activity against Enterobacteriaceae, with susceptibility rates of>90%, except for E. cloacae (66.7% susceptible). However, colistin-resistant isolates have emerged globally within the last few years.[sup][19],[20] Recently, a mobile colistin-resistance gene, called mcr-1 , has been reported in Enterobacteriaceae isolated both from livestock and humans; this gene may compromise treatment with last resort antimicrobial agents (colistin), thereby posing a major threat to public health.[sup][21],[22] According to a survey in Europe, the resistance rate for polymyxins among carbapenem-resistant K. pneumoniae isolates is as high as 43%.[sup][23] In this study, only 6.25% (1/16) of carbapenem-resistant K. pneumoniae isolates were found to be resistant to polymyxin B, whereas no isolates were resistant to colistin. This finding may be associated with the rare clinical use of polymyxins in China.

Given the severe condition of AMR among Enterobacteriaceae isolated from blood, precautions must be taken to control the presence of drug-resistance bacteria. A previous study [sup][24] showed that [sz]-lactamase-producing Gram-negative bacteria are associated with antibiotic use in healthcare settings, antibiotic use in animals, hand hygiene, environmental contamination with antibiotic-resistant bacteria, and travel. Thus, only interdisciplinary collaboration will be able to overcome the latent threat of AMR.

Several approaches could be helpful in this regard. First, professional training and public education should be strengthened. For example, leaflets, posters, and educational courses are needed to emphasize the urgency and seriousness of reducing AMR. Second, antimicrobial prescriptions must be optimized;[sup][25] the use, misuse, and overuse of antibiotics are major determinants of AMR,[sup][24] and promoting rational prescribing and proper use of existing antibiotics will be important. Third, governments should implement regulations to contain AMR, such as bans on the use of antibiotic growth promoters in livestock and agriculture. Fourth, better use of surveillance data, including development of comprehensive nationwide surveillance networks and monitoring of trends in AMR, is essential. Finally, the development of new drugs as powerful antimicrobial agents, particularly those that are active against ESBL producers and multidrug-resistant bacteria, is urgently needed to replace ineffective drugs; however, antibiotics show little opportunity compared with other therapeutic categories owing to the development bottleneck in new scientific breakthroughs and lack of economic incentives.[sup][26]

In conclusion, the control of AMR requires interdisciplinary cooperation of medical microbiologists, veterinarians, hospital doctors, microbiology laboratories, and government officials. The increasing AMR in Enterobacteriaceae strains isolated from the blood is still a major problem that should be monitored closely worldwide.

Supplementary information is linked to the online version of the paper on the Chinese Medical Journal website.


The authors would like to thank all the participating hospitals: Institute of Clinical Pharmacology, Peking University First Hospital (Beijing), Beijing Hospital (Beijing), Ji Lin University Second Hospital (Changchun), Tianjin Medical University General Hospital (Tianjin), The Second Hospital of Hebei Medical University (Shijiazhuang), The First Affiliated Hospital with Nanjing Medical University (Nanjing), Zhongshan Hospital Fudan University (Shanghai), Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University (Hangzhou), Guangzhou Women and Children's Medical Center (Guangzhou), Renmin Hospital of Wuhan University (Wuhan), Xiangya Hospital of Central South University (Changsha), Kunming First People's Hospital (Kunming), Affiliated Hospital of Guiyang Medical College (Guiyang), Southwest Hospital, Third Military Medical University (Chongqing), Xijing Hospital, Forth Military Medical University (Xi'an), Jinan Central Hospital Affiliated to Shandong University (Jinan), Lanzhou University Second Hospital (Lanzhou), The First Teaching Hospital of Xinjiang Medical University (Urumchi), Hanzhong Center Hospital (Hanzhong).

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.


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Title Annotation:Original Article
Author:Liu, Xiang-Jun; Lyu, Yuan; Li, Yun; Xue, Feng; Liu, Jian
Publication:Chinese Medical Journal
Article Type:Report
Geographic Code:9CHIN
Date:Sep 1, 2017
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