ABSTRACT
Carbapenem-resistant Enterobacteriaceae (CRE) infection is highly endemic in China, but estimates of the infection burden are lacking. We established the incidence of CRE infection from a multicenter study that covered 25 tertiary hospitals in 14 provinces. CRE cases defined as carbapenem-nonsusceptible Citrobacter freundii, Escherichia coli, Enterobacter cloacae, or Klebsiella pneumoniae infections during January to December 2015 were collected and reviewed from medical records. Antimicrobial susceptibility testing and carbapenemase gene identification were performed. Among 664 CRE cases, most were caused by K. pneumoniae (73.9%), followed by E. coli (16.6%) and E. cloacae (7.1%). The overall CRE infection incidence per 10,000 discharges was 4.0 and differed significantly by region, with the highest in Jiangsu (14.97) and the lowest in Qinghai (0.34). Underlying comorbidities were found in 83.8% of patients; the median patient age was 62 years (range, 45 to 74 years), and 450 (67.8%) patients were male. Lower respiratory tract infections (65.4%) were the most common, followed by urinary tract infection (16.6%), intra-abdominal infection (7.7%), and bacteremia (7.7%). The overall hospital mortality rate was 33.5%. All isolates showed nonsusceptibility to carbapenems and cephalosporins. The susceptibility rate of polymyxin B was >90%. Tigecycline demonstrated a higher susceptibility rate against E. coli than against K. pneumoniae (90.9% versus 40.2%). Of 155 clinical isolates analyzed, 89% produced carbapenemases, with a majority of isolates producing KPC (50%) or NDM (33.5%)-type beta-lactamases among K. pneumoniae and E. coli. The incidence of CRE infection in China was 4.0 per 10,000 discharges. The patient-based disease burden in tertiary hospitals in China is severe, suggesting an urgent need to enhance infection control.
KEYWORDS: carbapenem-resistant Enterobacteriaceae, incidence, clinical characteristics, microbiological characteristics, disease burden
INTRODUCTION
Carbapenem-resistant Enterobacteriaceae (CRE) is an urgent public health problem worldwide. These multidrug-resistant organisms exhibit resistance to most, if not all, available antibiotics today and are associated with considerable mortality (1). In one study, approximately 32% of patients with bloodstream infections caused by carbapenemase-producing CRE died within 14 days (2). In recent years, significant increases in the prevalence of CRE have been reported in the world (3–5). Since the first report of carbapenemase-producing K. pneumoniae isolate in Zhejiang Province, China, in 2007, carbapenem resistance rates in E. coli and K. pneumoniae have increased from 0% and 0.7% in 2004 to 1.0% and 13.4% in 2014 (6, 7), and CRE has been identified in almost every province in China (8, 9). The rapid spread of CRE is due to the clonal and plasmid-mediated dissemination of clinical carbapenem-resistant strains (5).
Most of previous studies were laboratory based and focused on the molecular characteristics and distribution of CRE in China (7, 9, 10). None of the published studies examined the patient-based disease burden. This dearth of data is notable, because CRE infections are increasingly identified in China with high mortality, but the patient-based CRE burden remains unknown. The epidemiology should be fully understood to inform national prevention and control efforts.
To better understand CRE epidemiology and provide the latest baseline data for the development of infection control protocols for CRE in China, we initiated a surveillance study to assess the burden of CRE infection in a large geographically widespread network of tertiary hospitals in China.
RESULTS
Incidence of CRE cases among inpatients in tertiary hospitals.
Table 1 demonstrates the patient-based incidences among different tertiary hospitals and regions. Between 1 January and 31 December 2015, 767 patients with CRE infection were eligible for screening in this study. After application of the exclusion criteria, a total of 664 patients were included. The overall annual CRE infection incidence across the 25 hospitals during 2015 was 4.0 per 10,000 hospital discharges and 4.05 per 100,000 patient-days. The site-specific infection incidence rates varied significantly between different regions, with the highest rate in Jiangsu (14.97 per 10,000 discharges and 14.38 per 100,000 patient-days) and the lowest rate in Qinghai (0.34 per 10,000 discharges and 0.32 per 100,000 patient-days).
TABLE 1.
Basic information of 25 participating tertiary hospitals, CRE cases, and incidence estimates by site in 2015
| Region | Hospital | No. of beds | Annual no. of discharges | Bed occupancy | Patient-daysa | No. of CRE casesb | Incidence rate/10,000 dischargesc | Incidence rate/100,000 patient-days |
|---|---|---|---|---|---|---|---|---|
| Beijing | BJ-1 | 1,857 | 71,875 | 0.92 | 623,580.6 | 24 | 3.34 | 3.86 |
| BJ-2 | 1,415 | 62,401 | 0.96 | 495,816 | 25 | 4.00 | 5.03 | |
| BJ-3 | 1,770 | 63,335 | 0.95 | 613,747.5 | 20 | 3.16 | 3.25 | |
| Beijing total | 5,042 | 197,611 | 0.94d | 1,729,910.2 | 69 | 3.49 | 3.97 | |
| Chongqing | CQ-1 | 924 | 24,146 | 0.8 | 269,808 | 3 | 1.24 | 1.12 |
| CQ-2 | 1,346 | 59,635 | 1.17 | 574,809.3 | 7 | 1.17 | 1.22 | |
| Chongqing total | 2,270 | 83,781 | 0.98d | 811,979 | 10 | 1.19 | 1.23 | |
| Fujian | FJ-1 | 1,445 | 54,696 | 1.04 | 548,522 | 1 | 0.18 | 0.18 |
| FJ-2 | 1,900 | 74,165 | 0.99 | 686,565 | 49 | 6.61 | 7.10 | |
| Fujian total | 3,345 | 128,861 | 1.02d | 1,245,343.5 | 50 | 3.88 | 4.02 | |
| Guangdong | GD-1 | 2,458 | 88,582 | 0.89 | 798,481.3 | 15 | 1.69 | 1.88 |
| GD-2 | 1,329 | 46,558 | 0.89 | 431,725.7 | 4 | 0.86 | 0.93 | |
| GD-3 | 1,200 | 53,776 | 1.06 | 464,280 | 1 | 0.19 | 0.22 | |
| Guangdong total | 4,987 | 188,916 | 0.95d | 1,729,242.25 | 20 | 1.06 | 1.16 | |
| Henan | HN-1 | 939 | 26,582 | 0.83 | 284,470.1 | 1 | 0.38 | 0.35 |
| HN-2 | 2,012 | 43,340 | 1.32 | 969,381.6 | 38 | 8.77 | 3.91 | |
| Henan total | 2,951 | 69,922 | 1.08d | 1,163,284.2 | 39 | 5.58 | 3.36 | |
| Hebei | HB-1 | 1,693 | 50,915 | 0.98 | 605,586.1 | 21 | 4.12 | 3.46 |
| Heilongjiang | HLJ-1 | 2,000 | 85,036 | 1.22 | 890,600 | 11 | 1.29 | 1.24 |
| Hunan | HUN-1 | 2,625 | 80,388 | 0.86 | 823,987.5 | 40 | 4.98 | 4.85 |
| Inner Mongolia | NMG-1 | 1,455 | 47,078 | 0.90 | 477,967.5 | 2 | 0.42 | 0.42 |
| Jiangsu | JS-1 | 4,378 | 176,968 | 1.15 | 1,837,665.5 | 265 | 14.97 | 14.38 |
| Ningxia | NX-1 | 1,012 | 26,476 | 0.88 | 325,054.4 | 3 | 1.13 | 0.93 |
| Qinghai | QH-1 | 1,800 | 59,598 | 0.96 | 630,720 | 2 | 0.34 | 0.32 |
| Shanghai | SH-1 | 2,077 | 98,784 | 1.02 | 773,267.1 | 54 | 5.47 | 7.00 |
| Shandong | SD-1 | 1,628 | 44,874 | 0.84 | 499,144.8 | 4 | 0.89 | 0.80 |
| SD-2 | 1,200 | 64,833 | 1.10 | 481,800 | 7 | 1.08 | 1.45 | |
| SD-3 | 726 | 28,082 | 1.05 | 278,239.5 | 19 | 6.77 | 6.81 | |
| SD-4 | 3,555 | 136,190 | 1.02 | 1,323,526.5 | 29 | 2.13 | 2.19 | |
| SD-5 | 2,381 | 93,255 | 1.00 | 869,065 | 19 | 2.04 | 2.20 | |
| Shandong total | 9,490 | 367,234 | 1.00d | 3,463,850 | 78 | 2.12 | 2.25 | |
| Total | 45,125 | 1,661,568 | 0.99 | 16,305,918.8 | 664 | 4.00 | 4.05 |
The total number of patient days was calculated as average bed occupancy × number of beds × 365.
CRE cases were defined as the first CRE isolate from a patient during hospitalization that met the surveillance definition.
The number of discharges per hospital for the year 2015, including the number who died.
Average bed occupancy.
Clinical data analysis.
Of these 664 individual patients, 214 patients were female (32.2%) and 450 patients were male (67.8%), and the median age was 62 years (interquartile range, 45 to 74 years; Table 2). Regardless of gender, the largest proportion was 65 years or older (304/664 [45.8%]). Of the patients, 37.1% (246/663) had acute care hospitalization in the prior year, and 83.8% (554/661) had more than one underlying disease, with a median Charlson comorbidity index of 1 (interquartile range, 0 to 3). Comorbidities include hypertension (281/664 [42.3%]), followed by pulmonary diseases (237/662 [35.8%]), neurological diseases (194/662 [29.3%]), and heart diseases (167/664 [25.2%]). The majority of patients had a urinary catheter (428/661 [64.8%]), and 90.9% had antimicrobial use 30 days prior to culture. Of 592 patients with available detailed antimicrobial use data, most of the patients had the use of multiple antibiotics (355/592 [60%]) prior to culture.
TABLE 2.
Demographic characteristics of patients infected with carbapenem-resistant Enterobacteriaceae
| Characteristica | Datab |
|---|---|
| Female | 214/664 (32.2) |
| Age (median [IQR]) (yr) | 62 (45–74) |
| 0–4 | 57/664 (8.6) |
| 5–17 | 13/664 (2.0) |
| 18–49 | 131/664 (19.7) |
| 50–64 | 159/664 (23.9) |
| 65–79 | 192/664 (28.9) |
| ≥80 | 112/664 (16.9) |
| Travel history to Southeast Asia | 5/656 (0.8) |
| Health care exposure during prior yr | |
| Acute care hospitalization | 246/663 (37.1) |
| Dialysis | 44/661 (6.7) |
| Long-term acute care facility | 47/663 (7.1) |
| Resident of a long-term-care facility | 74/663 (11.2) |
| Underlying conditions | |
| Charlson comorbidity index (median [IQR]) | 1 (0–3) |
| None | 107/661 (16.2) |
| Cancerc | 106/661 (16.0) |
| Diabetes mellitus | 140/664 (21.1) |
| Heart diseasesd | 167/664 (25.2) |
| Hypertension | 281/664 (42.3) |
| Immunodeficiencye | 44/663 (6.6) |
| ICU stay | 137/660 (20.8) |
| Liver diseasesf | 60/663 (9.0) |
| Neurological diseasesg | 194/662 (29.3) |
| Pulmonary diseasesh | 237/662 (35.8) |
| Renal diseasesi | 98/662 (14.8) |
| Receipt of corticosteroids | 99/660 (15) |
| Receipt of immunosuppressor | 8/661 (1.2) |
| Smoking history | 110/664 (16.6) |
| Indwelling devices prior to culture | |
| Arterial cannula | 38/663 (5.7) |
| Central venous catheter | 265/661 (40.1) |
| Gastric tube | 195/660 (29.5) |
| Tracheal cannula | 260/663 (39.2) |
| Tracheotomy | 161/662 (24.3) |
| Urinary catheter | 428/661 (64.8) |
| Antimicrobial use prior to culture within 30 days | |
| None | 60/660 (9.1) |
| Single antimicrobial use | 237/592 (40.0) |
| Multiple antimicrobial use | 355/592 (60.0) |
| Third- or fourth-generation cephalosporin use | 214/592 (36.1) |
| Carbapenem use | 191/592 (32.3) |
IQR, interquartile range; ICU, intensive care unit.
Data are presented as the number/total number (%), unless otherwise indicated.
Cancer includes malignancy in lung, digestive tract, gynecology, hematological system, and neurological system.
Heart diseases include congestive heart failure, coronary heart disease, valve replacement, and congenital heart disease.
Immunodeficiency includes splenectomy, agranulocytosis, and chemotherapy.
Liver diseases include cirrhosis, hepatitis, liver abscess, hepar adiposum, and hepatic injury.
Neurological diseases include stroke, transient ischemic attack, cerebral palsy, and meningitis.
Pulmonary diseases include chronic obstructive pulmonary disease (COPD), asthma, interstitial lung disease, history of pneumonia and tuberculosis, emphysema, respiratory failure, and infection.
Renal diseases include azotemia and chronic kidney disease.
The clinical characteristics and outcomes of the cases are summarized in Table 3. Of the patients, 65.4% (434/664) presented with a lower respiratory tract infection. The majority of the patients demonstrated increased white blood cell count (332/567 [58.6%]) and elevated levels of C-reactive protein (252/320 [78.8%]) and procalcitonin (93/312 [29.8%]). A total of 363 (363/662 [54.8%]) patients were discharged to home, and others were discharged to either a long-term acute facility (7/662 [1.1%]), follow-up outpatient facility (41/662 [6.2%]), or other hospitals (29/662 [4.4%]). The all-cause hospital mortality rate was 33.5% (222/662).
TABLE 3.
Clinical characteristics and outcomes of patients infected with carbapenem-resistant Enterobacteriaceae
| Characteristic | Dataa |
|---|---|
| Infection typesb | |
| Bacteremia | 51/664 (7.7) |
| Intra-abdominal infection | 51/664 (7.7) |
| Lower respiratory tract infection | 434/664 (65.4) |
| Meningitis | 10/664 (1.5) |
| Urinary tract infection | 110/664 (16.6) |
| Wound infectionc | 9/664 (1.4) |
| Other infectionsd | 12/664 (1.8) |
| APACHE II score (median [IQR])e | 17 (12–23) |
| Septic shock | 58/664 (8.7) |
| Laboratory findings | |
| White blood cells/mm3 | |
| Median (IQR) | 10,000 (5,925–14,165) |
| Subgroup | |
| <4,000 | 26/567 (4.6) |
| >10,000 | 332/567 (58.6) |
| C-reactive protein >10 mg/liter | 252/320 (78.8) |
| Procalcitonin | |
| 0.5 to 2 ng/ml | 73/312 (23.4) |
| >2 ng/ml | 93/312 (29.8) |
| Clinical outcomes | |
| Length of stay (median [IQR]) (days) | 29 (16–48) |
| ICU admission | 378/664 (56.9) |
| Length of ICU stay (median [IQR]) (days) | 5 (0–15) |
| Discharge disposition | |
| Home | 363/662 (54.8) |
| Long-term acute facility | 7/662 (1.1) |
| Follow-up outpatient | 41/662 (6.2) |
| Transfer to other hospitals | 29/662 (4.4) |
| Mortality | |
| In-hospital mortality | 222/662 (33.5) |
| Bacteremia-associated mortality | 22/51 (43.1) |
| Intra-abdominal infection-associated mortality | 13/50 (26) |
| Lower respiratory tract infection-associated mortality | 148/425 (34.8) |
| Urinary tract infection-associated mortality | 30/99 (30.3) |
Data are presented as the number/total number (%), unless otherwise indicated.
Patients with multiple diagnoses were listed under more than one category, so total numbers may be larger than the number of patients.
Wound infection includes wound infection and surgical site infection.
Other infections include skin and soft tissue infection and other infections.
APACHE II, Acute Physiology and Chronic Health Evaluation II.
Antimicrobial susceptibility testing and microbiological characteristics.
Most of the infections were caused by K. pneumoniae (491/664 [73.9%]), followed by E. coli (110/664 [16.6%]), E. cloacae (47/664 [7.1%]), and C. freundii (16/664 [2.4%]). Available antimicrobial susceptibility testing results were collected from local clinical laboratories. Antimicrobial susceptibility results for CRE of various species from sterile or nonsterile sites are listed in Table 4. All isolates showed nonsusceptibility to carbapenems and cephalosporins. For the antimicrobial agents that served as candidates for the treatment of CRE, aminoglycosides displayed better activity than fluoroquinolones, with susceptibility rates of >60% and <11% for sterile isolates, respectively. Polymyxin B retained excellent activity, with a susceptibility rate of >90%, regardless of species. However, tigecycline demonstrated relatively higher performance against E. coli than with K. pneumoniae isolates (susceptibility rate of 90.9% versus 40.2%, respectively).
TABLE 4.
Antimicrobial susceptibility testing results of CRE isolates based on local clinical laboratories
| Antimicrobial agent | % (no. of susceptible isolates/no. of isolates tested) |
||||
|---|---|---|---|---|---|
| By site |
By organism |
||||
| Isolated from sterile site (n = 242) | Isolated from nonsterile site (n = 422) | Klebsiella pneumoniae (n = 491) | Escherichia coli (n = 110) | Enterobacter cloacae (n = 47) | |
| Ertapenem | 0 (0/57) | 0 (0/29) | 0 (0/54) | 4.2 (1/24) | 0 (0/7) |
| Meropenem | 4.4 (11/249) | 7.9 (14/177) | 4.7 (14/301) | 9.2 (7/76) | 5.4 (2/37) |
| Imipenem | 0.5 (2/419) | 2.1 (5/237) | 0.6 (3/487) | 2.8 (3/106) | 0 (0/47) |
| Ceftazidime | 2.5 (7/280) | 2.4 (5/205) | 1.2 (4/335) | 2.2 (2/91) | 13.6 (6/44) |
| Ceftriaxone | 0.9 (3/347) | 1.1 (2/186) | 1.0 (4/399) | 0 (0/81) | 5 (2/40) |
| Cefotaxime | 0 (0/114) | 1.4 (1/70) | 1.7 (2/119) | 0 (0/41) | 0 (0/20) |
| Aztreonam | 3 (11/364) | 8.1 (17/210) | 2.3 (10/429) | 12.4 (12/97) | 21.2 (7/33) |
| Cefepime | 1.7 (7/416) | 3.9 (9/233) | 1.6 (8/485) | 2.8 (3/108) | 12.5 (5/40) |
| Piperacillin-tazobactam | 2.9 (12/414) | 9 (21/233) | 3.1 (15/485) | 4.7 (5/107) | 25.6 (10/39) |
| Ciprofloxacin | 6.4 (26/409) | 11.4 (25/219) | 7.8 (37/477) | 5 (5/101) | 22.2 (8/36) |
| Levofloxacin | 10.4 (42/404) | 15.1 (32/212) | 10.3 (48/467) | 9.3 (9/97) | 42.1 (16/38) |
| Gentamicin | 14.1 (54/384) | 26 (57/219) | 15.2 (67/441) | 22.5 (23/102) | 40.9 (18/44) |
| Tobramycin | 11.4 (34/298) | 21.3 (34/160) | 11 (38/344) | 26 (19/73) | 25 (7/28) |
| Amikacin | 63 (266/422) | 61.2 (145/237) | 58.2 (284/488) | 75.9 (82/108) | 72.3 (34/47) |
| Trimethoprim-sulfamethoxazole | 26.3 (110/419) | 39.3 (92/234) | 32.6 (158/484) | 26.4 (28/106) | 46.8 (22/47) |
Of the 155 CRE isolates submitted for an investigation of resistance mechanisms, KPC-type enzymes were the most common carbapenemase and were identified in 78 isolates (78/155 [50.3%]). In E. coli, the most frequently detected carbapenemase was the NDM-type enzymes (29/39 [74.4%]), with NDM-5 being identified in 51.3% of isolates (Table 5). In K. pneumoniae isolates, the most prevalent enzyme was KPC-2, with 77.0% of isolates being PCR positive (Table 6). No KPC-3 was found in this study. IMP-4, IMP-26, NDM-1, and NDM-6 were detected in C. freundii and E. cloacae. IMP-type enzymes were found in only a small proportion (8/155 [5.2%]) of isolates, but interestingly, not in E. coli. Multilocus sequence typing (MLST) results showed that the most prevalent sequence type (ST) among K. pneumoniae and E. coli was ST11 (75/100 [75%]) and ST167 (10/39 [25.6%]), respectively (Table 5 and 6). Furthermore, most CRE isolates (more than 90%) were susceptible to colistin and tigecycline. However, colistin and tigecycline nonsusceptibility was identified in three and nine isolates, respectively. For these three colistin-resistant isolates, only one had the mcr-1 gene. One isolate that co-carried blaNDM-5 and mcr-1 was identified in this study. Fig. S1 shows the MIC distributions of meropenem, tigecycline, and polymyxin based on KPC-2 and NDM.
TABLE 5.
Molecular characteristics of E. coli isolates submitted for testing
| Regiona | No. of carbapenemase-producing isolates/no. of isolates submitted for testing | Carbapenemase-producing isolates (no. [%]) |
Sequence type (no. [%]) |
||||||
|---|---|---|---|---|---|---|---|---|---|
| KPC-2 | NDM-1 | NDM-5 | NDM-6 | ST167 | ST405 | ST410 | Others | ||
| Beijing | 4/7 | 0 | 0 | 4 (57.1) | 0 | 2 (28.6) | 0 | 0 | 5 (71.4) |
| Fujian | 1/1 | 0 | 0 | 1 (100) | 0 | 0 | 0 | 0 | 1 (100) |
| Guangdong | 5/6 | 0 | 0 | 4 (66.7) | 1 (16.7) | 1 (16.7) | 0 | 0 | 5 (83.3) |
| Henan | 2/3 | 1 (33.3) | 0 | 1 (33.3) | 0 | 1 (33.3) | 1 (33.3) | 0 | 1 (33.3) |
| Hunan | 5/7 | 0 | 4 (57.1) | 1 (14.3) | 0 | 0 | 1 (14.3) | 1 (14.3) | 5 (71.4) |
| Jiangsu | 2/2 | 0 | 2 (100) | 0 | 0 | 1 (50) | 0 | 0 | 1 (50) |
| Ningxia | 1/1 | 0 | 0 | 1 (100) | 0 | 1 (100) | 0 | 0 | 0 |
| Shandong | 10/12 | 0 | 0 | 8 (66.7) | 2 (16.7) | 4 (33.3) | 0 | 2 (16.7) | 6 (50) |
| Total | 30/39 | 1 (2.6) | 6 (15.4) | 20 (51.3) | 3 (7.7) | 10 (25.6) | 2 (5.1) | 3 (7.7) | 24 (61.5) |
Chongqing, Hebei, Heilongjiang, Hubei, Inner Mongolia, Qinghai, and Shanghai did not submit any E. coli isolates for molecular characterization.
TABLE 6.
Molecular characteristics of K. pneumoniae isolates submitted for testing
| Regiona | No. of carbapenemase-producing isolates/no. of isolates submitted for testing | Carbapenemase-producing isolates (no. [%]) |
Sequence type (no. [%]) |
|||||
|---|---|---|---|---|---|---|---|---|
| IMP | KPC-2 | NDM-1 | NDM-5 | NDM-6 | ST11 | Others | ||
| Beijing | 32/37 | 1 (2.7)b | 29 (78.4) | 0 | 0 | 2 (5.4) | 31 (83.8) | 6 (16.2) |
| Fujian | 9/9 | 0 | 9 (100) | 0 | 0 | 0 | 9 (100) | 0 |
| Guangdong | 9/10 | 0 | 7 (70) | 0 | 0 | 2 (20) | 6 (60) | 4 (40) |
| Henan | 9/9 | 0 | 9 (100) | 0 | 0 | 0 | 9 (100) | 0 |
| Hebei | 1/1 | 0 | 1 (100) | 0 | 0 | 0 | 1 (100) | 0 |
| Hunan | 5/5 | 1 (20)b | 0 | 4 (80) | 0 | 0 | 0 | 5 (100) |
| Inner Mongolia | 2/2 | 0 | 2 (100) | 0 | 0 | 0 | 1 (50) | 1 (50) |
| Shandong | 27/27 | 0 | 20 (74.1) | 0 | 1 (3.7) | 6 (22.2) | 18 (66.7) | 9 (33.3) |
| Total | 94/100 | 2 (2) | 77 (77) | 4 (4) | 1 (1) | 10 (10) | 75 (75) | 25 (25) |
Heilongjiang, Jiangsu, Ningxia, Qinghai, and Shanghai did not submit any K. pneumoniae isolates for molecular characterization.
The types of IMP in Beijing and Hunan were IMP-1 and IMP-4, respectively.
DISCUSSION
Carbapenem-resistant Enterobacteriaceae presents a particularly critical problem worldwide due to rapidly rising resistance rates and subsequent high mortality. Prior to this study, only the percentage of CRE strains among clinical isolates was reported in China. In this multicenter retrospective research, we first demonstrated an overall CRE infection incidence rate of 4.0 per 10,000 discharges. Previous studies reported the CRE incidences in the United States and the European countries, which were 2.93 per 100,000 population and 1.3 per 10,000 hospital admissions, respectively (11, 12).
Variation by site for the incidence of CRE per 10,000 hospital discharges was observed, ranging from 14.97 in Jiangsu to 0.34 in Qinghai. The percentage of CRE in Jiangsu was considerably higher in 2015 than the other hospitals. However, this is likely due to a CRE outbreak in the hospital at the time of data collection. Furthermore, the incidence of CRE infection per 100,000 patient-days ranged from 14.38 in Jiangsu to 0.32 in Qinghai, with an average of 4.05 across all Chinese participating sites.
Previous studies showed that hospitalization and cumulative antibiotic exposure history, especially for previous use of beta-lactams and carbapenems, were considered as risk factors associated with CRE infections (13, 14). In this study, 90.9% of patients had antimicrobial therapy prior to culture, with a total of 214/592 (36.1%) and 191/592 (32.3%) of patients being exposed to third- or fourth-generation cephalosporins or carbapenems.
The mortality rates from CRE bacteremia have ranged from approximately 20% to 70% (15–18); however, fewer studies have reported the hospital mortality rates of CRE nonbloodstream infections. Carbapenem-resistant K. pneumoniae nonbacteremic infections were associated with 24.3% mortality, and 40% of patients with lower respiratory tract infections eventually died (19). Urinary tract infections were reported to have limited mortality (19–21). For carbapenem-resistant K. pneumoniae infections, pneumonia and bloodstream infections were related to high mortality risks, while urinary tract infections showed no excess mortality (21). Bacteremia presented a high death rate in this study, with an overall mortality of 43.1%. However, contrary to previous studies, urinary tract infection had a relatively high mortality rate (30.3%); the potential reason for this is that we assessed the all-cause mortality, and since most patients (83.8%) had underlying diseases in this study, they likely died of their comorbidities.
Carbapenem resistance as a result of carbapenemase production is the most prevalent mechanism in CRE globally. This is supported by epidemiological data that highlight the changes in resistance mechanisms (10, 22). In this study, at least one KPC-producing CRE isolate has been reported from all participating sites. As previously reported, the majority of the KPC-producing K. pneumoniae isolates in China belong to a common sequence type, ST11 (23), which was different from that in the United States (with a predominance of ST258) (24). While KPC remains the predominant carbapenemase in most regions in China, NDM was detected in 71.4% of CRE isolates in Hunan. Most of the KPC-2- and NDM-producing isolates demonstrated a moderate MIC level of meropenem resistance (see Fig. S1 in the supplemental material).
To the best of our knowledge, this study was the first of its kind in China; however, several limitations exist. First, information on clinical characteristics and outcomes could not be completely acquired because of the limitations of a retrospective study. Second, although hospitals in a broad geographic distribution of China were recruited in this study, not all hospitals in China participated in this study. Third, for the strains submitted to the Center Laboratory, the antimicrobial susceptibility profiles of carbapenems had a high accordance with those tested by participating hospitals. However, variations in detection platforms and technique skills may exist between hospitals, although they have good external quality control. Therefore, there might be an overestimation of CRE incidence due to the lack of confirmation of CRE through centralized testing of all isolates. Fourth, given the lack of available medical data for ascertainment of all infections, our data likely overestimated the proportion of lower respiratory and urinary tract infections.
In conclusion, the overall incidence of CRE infection was 4.0 per 10,000 discharges among 25 tertiary hospitals in China, which indicated high patient-based disease burden in tertiary hospitals in China, suggesting an urgent need to enhance infection control measures and clinical awareness. Our study also highlights the importance of conducting a prospective study with more participating hospitals and isolates to further understand the CRE burden in China.
MATERIALS AND METHODS
Setting.
A retrospective epidemiologic surveillance study of CRE infection was conducted within the network of tertiary hospitals from January to December 2015. A total of 25 hospitals in 14 provinces contributed data to this study. All sites were tertiary hospitals with more than 700 beds, equivalent quality control, skilled facilities, and qualified specialties. All the participating hospitals pass the regional or national external quality assessment for bacterial identification and antimicrobial susceptibility testing, which is carried out and analyzed by the Local or National Center for Clinical Laboratories external quality assessment service annually. Geographic locations and basic information, including the number of beds, annual number of discharges, and average bed occupancy of the participating hospitals are shown in Fig. 1 and Table 1, respectively. The study was reviewed and approved by the research ethics board of Peking University People's Hospital and was also in accordance with institutional policies of the participating hospitals. Informed consent was not required, as all data in this study were anonymized.
FIG 1.
Distribution of participating hospitals (red dots) in this study.
Study population.
Inpatients with CRE from clinical culture were selected at each site by a review of microbiology reports. Patients with clinical symptoms and positive culture from either respiratory tract secretions, urine, or surgical wounds were evaluated for CRE infection according to the Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network (NHSN) criteria (25). Hospital-acquired CRE infection is defined as an infection that occurred after more than 48 h of hospitalization. If a patient has the following health care-associated risk factors, such as surgery, residence in a long-term-care facility, or hospitalization during the previous year, a positive culture within 48 h is defined as a health care-associated infection. For this study, patients with clinically significant hospital-acquired infection and health care-associated infection due to CRE were eligible. Exclusion criteria were community-acquired infection, missing key data, isolates with colonization only, screening samples, and subsequent episodes in the same patient.
A CRE case was defined as the first clinical culture with carbapenem-nonsusceptible (imipenem, meropenem, or ertapenem) organism of the Enterobacteriaceae family, which includes Citrobacter freundii, Enterobacter cloacae, Escherichia coli, or Klebsiella pneumoniae for each individual patient. CRE isolates were identified by local diagnostic laboratories in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines (26). Notably, all participating hospitals are tertiary hospitals and have standardized protocols for CRE identification and antimicrobial susceptibility testing, with strict quality control and high external detection quality.
Data collection.
Medical records of all cases were reviewed to collect clinical and epidemiologic data, including sample date, location of culture collection, specimen source, patient demographics, nosocomial or community acquisition, location in the hospital, travel history to Southeast Asia, health care exposures during the prior year, underlying medical conditions, indwelling devices and antimicrobial therapy exposures 30 days prior to culture, infection types, clinical manifestations, treatment, and outcomes. Identification of organisms and susceptibility testing were done at each participating center. The results of antimicrobial susceptibility testing for all isolates were also obtained.
Isolate collection and microbiological investigation.
All participating hospitals were required to submit CRE isolates to the Center Laboratory in Peking University People's Hospital for further microbiological investigation involving the detection of resistance mechanisms. Each center submitted all the strains they kept, but only a minority of isolates were submitted to the Center Laboratory for resistance gene screening, because not all CRE isolates were routinely stored in every site.
The MICs of the following antimicrobials, including ceftriaxone (Roche, Shanghai, China), ceftazidime, cefoxitin, cefepime, and amikacin (National Institutes for Food and Drug Control, Beijing, China), piperacillin-tazobactam and tigecycline (Pfizer, NY, USA), imipenem (MSD, Hangzhou, China), meropenem (Sumitomo Pharmaceuticals, Suzhou, China), ciprofloxacin (Bayer, Leverkusen, Germany), and colistin (Amresco, Solon, OH, USA), were determined by agar and broth dilution methods, according to CLSI guidelines (27). The results were interpreted based on CLSI breakpoints (26). The interpretive criteria for tigecycline were based on the breakpoints of the Food and Drug Administration (FDA).
PCR was used to detect the presence of carbapenemase genes (blaNDM, blaKPC, blaIMP, and blaVIM), other β-lactamase genes (blaCTX-M, blaTEM, blaSHV, blaDHA, and blaCMY), and the mobilized colistin resistance gene (mcr-1), as previously described (28, 29). Multilocus sequence typing (MLST) was performed according to the protocol described on the Pasteur Institute MLST website (http://bigsdb.pasteur.fr/klebsiella/klebsiella.html) for K. pneumoniae and the MLST websites for E. coli (http://mlst.warwick.ac.uk/mlst/dbs/Ecoli), E. cloacae (https://pubmlst.org/ecloacae/), and C. freundii (https://pubmlst.org/cfreundii/).
Statistical analyses.
Annual incidence rates for CRE infections were calculated as the number of CRE cases divided by the number of discharges in the participating hospitals in 2015. CRE infection incidence was also reported as the number of CRE cases per 100,000 hospital patient-days.
Descriptive statistics were used to summarize the clinical and epidemiologic characteristics of CRE infections. The Charlson comorbidity index score was calculated. Continuous variables were presented as medians with the interquartile range. For categorical variables, the percentage of patients or isolates in each category was calculated. All analyses were performed using Whonet (version 5.6), GraphPad Prism (version 5), and the SPSS software (version 18.0).
Supplementary Material
ACKNOWLEDGMENTS
This study was partly supported by the National Natural Science Foundation of China (grant no. 81625014 and 81661138006).
We thank Thamarai Schneiders in the University of Edinburgh for her suggestions on our manuscript.
We declare no conflicts of interest.
Footnotes
Supplemental material for this article may be found at https://doi.org/10.1128/AAC.01882-17.
REFERENCES
- 1.Centers for Disease Control and Prevention (CDC). 2013. Vital signs: carbapenem-resistant Enterobacteriaceae. MMWR Morb Mortal Wkly Rep 62:165–170. [PMC free article] [PubMed] [Google Scholar]
- 2.Tamma PD, Goodman KE, Harris AD, Tekle T, Roberts A, Taiwo A, Simner PJ. 2017. Comparing the outcomes of patients with carbapenemase-producing and non-carbapenemase-producing carbapenem-resistant Enterobacteriaceae bacteremia. Clin Infect Dis 64:257–264. doi: 10.1093/cid/ciw741. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Cantón R, Akóva M, Carmeli Y, Giske CG, Glupczynski Y, Gniadkowski M, Livermore DM, Miriagou V, Naas T, Rossolini GM, Samuelsen Ø, Seifert H, Woodford N, Nordmann P, European Network on Carbapenemases. 2012. Rapid evolution and spread of carbapenemases among Enterobacteriaceae in Europe. Clin Microbiol Infect 18:413–431. doi: 10.1111/j.1469-0691.2012.03821.x. [DOI] [PubMed] [Google Scholar]
- 4.Gupta N, Limbago BM, Patel JB, Kallen AJ. 2011. Carbapenem-resistant Enterobacteriaceae: epidemiology and prevention. Clin Infect Dis 53:60–67. doi: 10.1093/cid/cir202. [DOI] [PubMed] [Google Scholar]
- 5.Nordmann P, Naas T, Poirel L. 2011. Global spread of carbapenemase-producing Enterobacteriaceae. Emerg Infect Dis 17:1791–1798. doi: 10.3201/eid1710.110655. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Xiao YH, Wang J, Li Y, MOH National Antimicrobial Resistance Investigation Net. 2008. Bacterial resistance surveillance in China: a report from Mohnarin 2004–2005. Eur J Clin Microbiol Infect Dis 27:697–708. doi: 10.1007/s10096-008-0494-6. [DOI] [PubMed] [Google Scholar]
- 7.Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC, Zhang XJ, Zhang CX, Ji P, Xie Y, Kang M, Wang CQ, Wang AM, Xu YH, Shen JL, Sun ZY, Chen ZJ, Ni YX, Sun JY, Chu YZ, Tian SF, Hu ZD, Li J, Yu YS, Lin J, Shan B, Du Y, Han Y, Guo S, Wei LH, Wu L, Zhang H, Kong J, Hu YJ, Ai XM, Zhuo C, Su DH, Yang Q, Jia B, Huang W. 2016. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005–2014. Clin Microbiol Infect 22(Suppl 1):S9–S14. doi: 10.1016/j.cmi.2016.01.001. [DOI] [PubMed] [Google Scholar]
- 8.Wei ZQ, Du XX, Yu YS, Shen P, Chen YG, Li LJ. 2007. Plasmid-mediated KPC-2 in a Klebsiella pneumoniae isolate from China. Antimicrob Agents Chemother 51:763–765. doi: 10.1128/AAC.01053-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhang R, Chan EW, Zhou H, Chen S. 2017. Prevalence and genetic characteristics of carbapenem-resistant Enterobacteriaceae strains in China. Lancet Infect Dis 17:256–257. doi: 10.1016/S1473-3099(17)30072-5. [DOI] [PubMed] [Google Scholar]
- 10.Xu A, Zheng B, Xu YC, Huang ZG, Zhong NS, Zhuo C. 2016. National epidemiology of carbapenem-resistant and extensively drug-resistant Gram-negative bacteria isolated from blood samples in China in 2013. Clin Microbiol Infect 22(Suppl 1):S1–S8. doi: 10.1016/j.cmi.2015.09.015. [DOI] [PubMed] [Google Scholar]
- 11.Guh AY, Bulens SN, Mu Y, Jacob JT, Reno J, Scott J, Wilson LE, Vaeth E, Lynfield R, Shaw KM, Vagnone PM, Bamberg WM, Janelle SJ, Dumyati G, Concannon C, Beldavs Z, Cunningham M, Cassidy PM, Phipps EC, Kenslow N, Travis T, Lonsway D, Rasheed JK, Limbago BM, Kallen AJ. 2015. Epidemiology of carbapenem-resistant Enterobacteriaceae in 7 US communities, 2012–2013. JAMA 314:1479–1487. doi: 10.1001/jama.2015.12480. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Grundmann H, Glasner C, Albiger B, Aanensen DM, Tomlinson CT, Andrasević AT, Cantón R, Carmeli Y, Friedrich AW, Giske CG, Glupczynski Y, Gniadkowski M, Livermore DM, Nordmann P, Poirel L, Rossolini GM, Seifert H, Vatopoulos A, Walsh T, Woodford N, Monnet DL, European Survey of Carbapenemase-Producing Enterobacteriaceae (EuSCAPE) Working Group. 2017. Occurrence of carbapenemase-producing Klebsiella pneumoniae and Escherichia coli in the European survey of carbapenemase-producing Enterobacteriaceae (EuSCAPE): a prospective, multinational study. Lancet Infect Dis 17:153–163. doi: 10.1016/S1473-3099(16)30257-2. [DOI] [PubMed] [Google Scholar]
- 13.Patel N, Harrington S, Dihmess A, Woo B, Masoud R, Martis P, Fiorenza M, Graffunder E, Evans A, McNutt LA, Lodise TP. 2011. Clinical epidemiology of carbapenem-intermediate or -resistant Enterobacteriaceae. J Antimicrob Chemother 66:1600–1608. doi: 10.1093/jac/dkr156. [DOI] [PubMed] [Google Scholar]
- 14.Wang Q, Zhang Y, Yao X, Xian H, Liu Y, Li H, Chen H, Wang X, Wang R, Zhao C, Cao B, Wang H. 2016. Risk factors and clinical outcomes for carbapenem-resistant Enterobacteriaceae nosocomial infections. Eur J Clin Microbiol Infect Dis 35:1679–1689. doi: 10.1007/s10096-016-2710-0. [DOI] [PubMed] [Google Scholar]
- 15.Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. 2014. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis 20:1170–1175. doi: 10.3201/eid2007.121004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Fraenkel-Wandel Y, Raveh-Brawer D, Wiener-Well Y, Yinnon AM, Assous MV. 2016. Mortality due to blaKPC Klebsiella pneumoniae bacteraemia. J Antimicrob Chemother 71:1083–1087. doi: 10.1093/jac/dkv414. [DOI] [PubMed] [Google Scholar]
- 17.Tumbarello M, Viale P, Viscoli C, Trecarichi EM, Tumietto F, Marchese A, Spanu T, Ambretti S, Ginocchio F, Cristini F, Losito AR, Tedeschi S, Cauda R, Bassetti M. 2012. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 55:943–950. doi: 10.1093/cid/cis588. [DOI] [PubMed] [Google Scholar]
- 18.Daikos GL, Tsaousi S, Tzouvelekis LS, Anyfantis I, Psichogiou M, Argyropoulou A, Stefanou I, Sypsa V, Miriagou V, Nepka M, Georgiadou S, Markogiannakis A, Goukos D, Skoutelis A. 2014. Carbapenemase-producing Klebsiella pneumoniae bloodstream infections: lowering mortality by antibiotic combination schemes and the role of carbapenems. Antimicrob Agents Chemother 58:2322–2328. doi: 10.1128/AAC.02166-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Tumbarello M, Trecarichi EM, De Rosa FG, Giannella M, Giacobbe DR, Bassetti M, Losito AR, Bartoletti M, Del Bono V, Corcione S, Maiuro G, Tedeschi S, Celani L, Cardellino CS, Spanu T, Marchese A, Ambretti S, Cauda R, Viscoli C, Viale P, ISGRI-SITA (Italian Study Group on Resistant Infections of the Società Italiana Terapia Antinfettiva). 2015. Infections caused by KPC-producing Klebsiella pneumoniae: differences in therapy and mortality in a multicentre study. J Antimicrob Chemother 70:2133–2143. doi: 10.1093/jac/dkv086. [DOI] [PubMed] [Google Scholar]
- 20.Qureshi ZA, Syed A, Clarke LG, Doi Y, Shields RK. 2014. Epidemiology and clinical outcomes of patients with carbapenem-resistant Klebsiella pneumoniae bacteriuria. Antimicrob Agents Chemother 58:3100–3104. doi: 10.1128/AAC.02445-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Hauck C, Cober E, Richter SS, Perez F, Salata RA, Kalayjian RC, Watkins RR, Scalera NM, Doi Y, Kaye KS, Evans S, Fowler VG Jr, Bonomo RA, van Duin D, Antibacterial Resistance Leadership Group. 2016. Spectrum of excess mortality due to carbapenem-resistant Klebsiella pneumoniae infections. Clin Microbiol Infect 22:513–519. doi: 10.1016/j.cmi.2016.01.023. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Yang Q, Wang H, Sun H, Chen H, Xu Y, Chen M. 2010. Phenotypic and genotypic characterization of Enterobacteriaceae with decreased susceptibility to carbapenems: results from large hospital-based surveillance studies in China. Antimicrob Agents Chemother 54:573–577. doi: 10.1128/AAC.01099-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Qi Y, Wei Z, Ji S, Du X, Shen P, Yu Y. 2011. ST11, the dominant clone of KPC-producing Klebsiella pneumoniae in China. J Antimicrob Chemother 66:307–312. doi: 10.1093/jac/dkq431. [DOI] [PubMed] [Google Scholar]
- 24.Giani T, Pini B, Arena F, Conte V, Bracco S, Migliavacca R; AMCLI-CRE Survey Participants, Pantosti A, Pagani L, Luzzaro F, Rossolini GM. 2013. Epidemic diffusion of KPC carbapenemase-producing Klebsiella pneumoniae in Italy: results of the first countrywide survey, 15 May to 30 June 2011. Euro Surveill 18:pii=20489 http://www.eurosurveillance.org/docserver/fulltext/eurosurveillance/18/22/art20489-en.pdf?expires=1512179861&id=id&accname=guest&checksum=54EF2E779EA3823E1746DC3A7AFB18D2. [PubMed] [Google Scholar]
- 25.Horan TC, Andrus M, Dudeck MA. 2008. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control 36:309–332. doi: 10.1016/j.ajic.2008.03.002. [DOI] [PubMed] [Google Scholar]
- 26.Clinical and Laboratory Standards Institute. 2015. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 10th ed CLSI document M07-A10. Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 27.Clinical and Laboratory Standards Institute. 2016. Performance standards for antimicrobial susceptibility testing, 26th ed; approved standard M100S Clinical and Laboratory Standards Institute, Wayne, PA. [Google Scholar]
- 28.Wang X, Xu X, Li Z, Chen H, Wang Q, Yang P, Zhao C, Ni M, Wang H. 2014. An outbreak of a nosocomial NDM-1-producing Klebsiella pneumoniae ST147 at a teaching hospital in mainland China. Microb Drug Resist 20:144–149. doi: 10.1089/mdr.2013.0100. [DOI] [PubMed] [Google Scholar]
- 29.Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J. 2016. Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16:161–168. doi: 10.1016/S1473-3099(15)00424-7. [DOI] [PubMed] [Google Scholar]
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