Antibiotic Resistance and Clinical Presentation of Health Care-Associated Hypervirulent Klebsiella pneumoniae Infection in Korea

Abstract

Hypervirulent Klebsiella pneumoniae typically presents as a community-acquired infection causing a liver abscess. It is often associated with rmpA and magA genes and confers a mucoid phenotype. Our aim was to evaluate the clinical presentation and antibiotic resistance of hypervirulent K. pneumoniae (hvKP) of health care-associated origin. The study was performed on 414 K. pneumoniae isolates recovered from patients that visited our hospital from December 2013 through November 2015. Hypervirulence was determined by the presence of a hypermucoviscous phenotype, in 155 isolates (37.4%). We compared health care-associated hvKP infections with community-acquired infections. The hypermucoviscous phenotype was 60 isolates (24.2%) in health care-associated infection and 90 isolates (53.8%) in community-acquired infection. Respiratory infection was the most common source of health care-associated K. pneumoniae. Antibiotic resistance was higher in health care-associated hvKP infections, which were more frequently associated with non-K1/K2 serotypes and less frequently associated with rmpA gene. In our study, 38% of hvKP was health care associated. Pneumonia is the most common infection, besides intraabdominal infection, in community-originating strains. These results suggest that health care-associated hvKP may have different microbiological characteristics from classical community-associated infections. Further investigation is needed for other virulent factors associated with health care-associated hvKP.

Introduction

Klebsiella pneumoniae causes a wide range of infections, including urinary tract, intraabdominal, pneumonia, and bacteremia. Typically, these infections are hospital acquired and resistant to antimicrobials, including carbapenem-resistant K. pneumoniae.¹ Recently, antimicrobial resistance of K. pneumoniae has become a serious public health concern. Among carbapenem-resistant Enterobacteriaceae, carbapenem-resistant K. pneumoniae is the most commonly reported organism and a primary cause of hospital-acquired infections.²

In the past three decades, quite different from classical K. pneumoniae, a new group of hypervirulent K. pneumoniae (hvKP) has become the leading cause of community-acquired infections leading to pyogenic liver abscess in Asian countries.³ This group includes mostly the K1 and K2 serotype with magA and rmpA genes.⁴ In Korea, K1 serotype K. pneumoniae is now the most common cause of pyogenic liver abscess.⁵ This is not a concern only in Asia, however. There have been recent reports of hvKP infections on all continents with the exception of Antartica.^6–10

HvKP has distinctive features compared with classical K. pneumoniae. Clinically, infections arising from hypervirulent strains are characterized by community origin and primary liver abscess, sometimes resulting in metastatic endophthalmitis and meningitis.^11,12 The patients are usually immunocompetent healthy young adults although diabetes is a risk factor for this infection.¹³ Microbiologically, hypermucoviscosity is a typical phenotypic feature of hvKP, which is confirmed by string test. HvKP is associated with the virulence factor magA, rmpA, and aerobactin.¹⁴

After the first cases of hvKP were published, the following studies revealed that hvKP is usually susceptible to most antibiotics, except ampicillin.³ Recently, additional reports followed antibiotic resistance and health care-associated infections.¹⁵ It is not clear whether the global dissemination of antibiotic-resistant genes, which can be transferred to other bacteria, such as K. pneumoniae carbapenemase, New Delhi metallo-β-lactams, and oxacillinase-48(OXA-48) type, is affected by the antibiotic-resistant, hvKP.² Both the increase of antibiotic resistance in hvKP and instances of carbapenemase-producing hvKP have been reported in several studies.¹⁶ Given this, we suspected that the K. pneumoniae strains in Korea are changing and that their well-known characteristics, such as being community acquired (rather than health care-associated) and susceptibility to antimicrobials will give way to traits more commonly associated with hypervirulence. The aim of the present study was to evaluate antibiotic resistance and clinical presentation of hvKP infections.

Materials and Methods

Subjects and K. pneumoniae identification

The study was performed retrospectively and reviewed on 414 K. pneumoniae isolates recovered from different specimens collected from Keimyung University of Dongsan Medical Center from December 2013 through November 2015. The specimen sources included: blood (n = 129), sputum (n = 141), urine (n = 65), pus (n = 67), and others (n = 12). Asymptomatic colonizers and patients lost to follow-up owing to transfers to other hospitals were excluded. Each isolate came from a different patient during the first diagnosis of K. pneumoniae. Any subsequent infections from the same patient were not used in this study. The medical records of identified patients were reviewed manually. Demographic data and information related to the underlying disease, place of infection acquisition, clinical manifestations, and clinical outcome were collected. These isolates were identified by the automated microbial identification and susceptibility test system (VITEK 2 system; bioMerieux, Lyon, France). All isolates were subcultured in Luria-Bertani (LB) broth and frozen at −70°C until used in the study. This study was approved by the Institutional Review Board (IRB) of Keimyung University Dongsan Medical Center (IRB NO. 2014-09-027).

Detection of hvKP

Strains with the hypermucoviscous phenotype were defined as hvKP. To determine the hypermucoviscous phenotype, a string test was performed. The string test was positive when a bacteriologic inoculation loop was able to generate a viscous string >5 mm in length by stretching bacterial colonies on an agar plate (Fig. 1).

FIG. 1.

Colony morphology and String test of hypermucoviscous Klebsiella pneumoniae. (A) Colonies are circular, convex with entire margin, and mucoid. (B) Stretching of the K. pneumoniae colonies resulted in the formation of a string ≥ 5 mm in length, demonstrating the hypermucoviscous type. Color images are available online.

Polymerase chain reaction

Capsular serotypes, rmpA, magA, and aerobactin(iucA) were identified by polymerase chain reaction (PCR). Strains were serotyped as one of the following: K1, K2, K5, K20, K54, and K57, or as nondetermining when no specific serotype could be identified. Primers for bla_SHV-1a were included as a positive control. The amplification was performed using a thermal cycler (C1000 Thermal Cycler; Bio-Rad, Pleasanton, CA). The specific primers used to detect the alleles of the target gene sequences are listed in Table 1. Crude DNA was prepared by lysis of colonies at 100°C for 10 min in 500 μL of sterile distilled water, followed by centrifugation. The lysis supernatant was used for PCR. The PCR conditions comprised an initial activation at 95°C for 15 min, followed by 40 cycles at 94°C for 30 sec, 60°C for 90 sec, and 72°C for 60 sec, and a final extension period at 72°C for 10 min. The amplicons were separated at 100 V for 2 hr in a 2% agarose gel containing ethidium bromide.

Table 1.

Primers Used in This Study

Primer	Sequence
K1
Forward	5′-GTAGGTATTGCAAGCCATGC-3′
Reverse	5′-GCCCAGGTTAATGAATCCGT-3′
K2
Forward	5′-GGAGCCATTTGAATTCGGTG-3′
Reverse	5′-TCCCTAGCACTGGCTTAAGT-3′
K5
Forward	5′-GCCACCTCTAAGCATATAGC-3′
Reverse	5′-CGCACCAGTAATTCCAACAG-3′
K20
Forward	5′-CCGATTCGGTCAACTAGCTT-3′
Reverse	5′-GCACCTCTATGAACTTTCAG-3′
K54
Forward	5′-CATTAGCTCAGTGGTTGGCT-3′
Reverse	5′-GCTTGACAAACACCATAGCAG-3′
K57
Forward	5′-CGACAAATCTCTCCTGACGA-3′
Reverse	5′-CGCGACAAACATAACACTCG-3′
rmpA
Forward	5′-ACTGGGCTACCTCTGCTTCA-3'
Reverse	5′-CTTGCATGAGCCATCTTTCA-3′
magA
Forward	5′-GGTGCTCTTTACATCATTGC-3′
Reverse	5′-GCAATGGCCATTTGCGTTAG-3′
aerobactin
Forward	5′-GCATAGGCGGATACGAACAT-3′
Reverse	5′-CACAGGGCAATTGCTTACCT-3′
bla _SHV-1a (positive control)
Forward	5′-ATCTGGTGGACTACTCGC-3′
Reverse	5′-GCCTCATTCAGTTCCGTT-3′

Statistical analyses

Data management and statistical analyses were performed using SPSS software version 23.0 (SPSS; IBM Corp, Armonk, NY). The nominal variables were expressed as numbers and percentages. To compare the nominal variables without a normal distribution, a Wilcoxon signed-rank test was used. The level of statistical significance was set at p < 0.05.

Results

Incidence of hvKP infection according to origin

This study consisted of both male patients, 248 (59.9%), and female patients, 166 (40%). The mean age was 67.8 ± 13 years. Health care-associated infections comprised 247 (59.7%) patients, and there were 167 (40.3%) patients with community-acquired infections. The category of infection was as follows: pneumonia 163 (39.4%), intraabdominal infection 114 (27.5%), urinary tract infection 88 (21.3%), skin and soft tissue infection 14 (3.4%), catheter-related bloodstream infection 12 (2.9%), bacteremia of unknown origin 7 (1.7%), and infection of central nervous system 2 (0.5%).

Of the 414 isolates, 155 (37.4%) were hvKP, as determined by their hypermucoviscous phenotype. Compared with classic K. pneumoniae, the hvKP were highly community-associated infection than classic KP [95 (61.3%) vs. 72 (27.8%), p = 0.001].

Among the hvKP, 38% (60 of 155 isolates) were health care-associated infections. Community-acquired infections were significantly more likely to be hvKP compared with health care-associated infections [60 (38.7%) vs. 95 (61.2%), p = 0.0001].

Serotype of K. pneumoniae according to origin

Serotypes of isolates are shown in Table 2. Both K1 and K2 serotypes were more commonly associated with community-acquired infections than with health care-associated infections. Results showed K1 serotype 53 (31.7%) versus 24 (9.7%), p = 0.001 and K2 serotype 34 (20.4%) versus 25 (10.1%), p = 0.003 for community-acquired and health care-associated infections, respectively. Nondetermined isolates were more significantly common in health care-associated infections [175 (70.9%) vs. 61 (36.5%), p = 0.001].

Table 2.

Specimen Origin and Prevalence of Serotypes in All Klebsiella pneumoniae Isolates, According to Community- and Health Care-Associated Infection

Serotype	Community acquired infection						Health care-associated infection
Serotype	Blood n = 67	Sputum n = 40	Urine n = 20	Pus n = 37	Wound n = 3	Total n = 167	Blood n = 62	Sputum n = 102	Urine n = 45	Pus n = 29	Wound n = 9	Total n = 247
K1	19	9	1	22	2	53	4	11	1	6	2	24
K2	15	10	0	9	0	34	7	10	4	3	1	25
K5	0	1	0	0	0	1	1	0	1	0	0	2
K20	1	7	2	0	0	10	1	5	2	1	0	9
K54	2	0	0	0	0	2	1	0	0	0	1	2
K57	1	5	0	0	0	6	3	5	0	2	0	10
ND	29	8	17	6	1	61	45	71	37	17	5	175

Characteristics of health care-associated hvKP

To determine clinical characteristics of health care-associated hvKP, we compared underlying disease and clinical presentation of hvKP with community origin. Solid tumor and neurological disease were presented as higher in the health care group. We used the McCabe classification to determine comorbidity; ultimately fatal disease was more presented in health care-associated origin (Table 3).

Table 3.

Clinical Characteristics of Hypervirulent Klebsiella pneumoniae Isolates, According to Community and Health Care-Associated Infection

	Community origin Hv K. pneumoniae n = 95	Health care origin Hv K. pneumoniae n = 60	p-value
Underlying disease
Solid tumor	10 (10.5%)	21 (35%)	0.001
Chronic liver disease	13 (13.7%)	10 (16.7%)	0.064
Cardiovascular disease	14 (46.3%)	37 (61.3%)	0.071
Neurologic disease	20 (21.1%)	35 (58.3%)	0.001
Chronic renal disease	5 (5.3%)	5 (8.3%)	0.511
Chronic lung disease	8 (8.4%)	7 (11.7%)	0.581
Diabetes mellitus	34 (35.8%)	18 (30%)	0.489
Antibiotic use within 1 month	13 (13.7%)	28 (46.7%)	0.001
McCabe classification
Nonfatal underlying disease	86 (90.5%)	42 (70%)
Ultimately fatal disease	9 (9.5%)	18 (30%)	0.002
Infection source
Urinary tract infection	14 (14.7%)	2 (3.3%)	0.029
Intraabdominal infection	37 (38.9%)	20 (33.3%)	0.499
Respiratory infection	31 (32.6%)	32 (53.3%)	0.012
Clinical presentation
Metastatic infection	2 (2.1%)	2 (3.3%)	0.641
Acute kidney injury	11 (11.6%)	9 (15%)	0.422
Mechanical ventilation	15 (15.8%)	15 (25%)	0.210
Intensive care unit admission	20 (21.2%)	24 (40%)	0.017
Mortality	8 (8.4%)	13 (21.7%)	0.029

HvKP isolated from sputum was more common in health care-associated infections. Similar to the origin of specimen, respiratory infection was the most common type in health care-associated infection, whereas urinary tract infections were less commonly associated with these isolates. Analogous to the results of all strains, hypervirulent isolates designated as K1 and K2 serotypes occurred more frequently in community-acquired infections compared with those originating in a health care setting [73 (76.8%) vs. 32 (53.4%), p = 0.003]. Almost all hvKP of community origin belonged to one of the six distinct serotypes we examined, but a high proportion of health care-associated hvKP was unable to be serotyped and labeled as nondetermined. The virulence genes, rmpA, magA, and aerobactin, were strongly associated with community origin hvKP. Mortality rate was higher in health care-associated hvKP (Table 4).

Table 4.

Microbiological Characteristics of Hypervirulent Klebsiella pneumoniae Isolates, According to Community and Health Care-Associated Infection

	Community origin Hv K. pneumoniae n = 95	Health care origin Hv K. pneumoniae n = 60	p-value
Specimen origin
Blood	35 (36.8%)	17 (28.3%)	0.299
Sputum	26 (27.4%)	25 (41.7%)	0.048
Urine	6 (6.3%)	0	0.082
Pus	26 (27.4%)	15 (25%)	0.852
Serotype
K1	42 (44.2%)	19 (31.7%)	0.132
K2	31 (32.6%)	13 (21.7%)	0.149
K5	0	1 (1.7%)	0.387
K20	5 (5.3%)	3 (5%)	1
K54	2 (2.1%)	0	0.522
K57	6 (6.3%)	7 (11.7%)	0.251
ND	9 (9.5%)	17 (29.3%)	0.004
Virulence gene
rmpA	36 (76.6%)	8 (14.3%)	0.001
magA	24 (51.5%)	7 (12.5%)	0.001
aerobactin	67 (70.5%)	33 (55%)	0.037

Antibiotic resistance in health care-associated hvKP was higher in most usable antibiotics. But all isolates were susceptible to carbapenem antibiotics, and there was no statistical difference on tigecycline resistance. Extended-spectrum β-Lactamase (ESBL) positivity showed higher resistance in health care-originating strains (Table 5).

Table 5.

Antibiotic Resistance of Hypervirulent Klebsiella pneumoniae According to the Community and Health Care-Associated Infection

	Community origin Hv K. pneumoniae n = 95	Health care origin Hv K. pneumoniae n = 60	p-value
Amikacin	0	10 (16.7%)	0.021
Amoxicillin/Clavulanic acid	4 (4.2%)	10 (16.7%)	0.018
Aztreonam	3 (3.2%)	12 (20%)	0.001
Cefazolin	3 (3.2%)	13 (21.7%)	0.001
Cefoxitin	4 (4.2%)	10 (16.7%)	0.018
Cefepime	3 (3.2%)	12 (20%)	0.001
Cefotaxime	3 (3.2%)	13 (21.7%)	0.001
Ceftazidime	3 (3.2%)	13 (21.7%)	0.001
Ciprofloxacin	2 (2.1%)	11 (18.3%)	0.001
Piperacillin/tazobactam	3 (3.2%)	7 (11.7%)	0.047
Tigecycline	4 (4.2%)	7 (11.7%)	0.108
TMP/SMX	3 (3.2%)	6 (10%)	0.09
ESBL positivity	3 (3.2%)	12 (20%)	0.001

TMP/SMX, trimethoprim/sulfamethoxazole; ESBL, extended-spectrum β-lactamase.

Discussion

The epidemiological studies of hvKP focused on report epidemics typically occurring in Asian countries, including Taiwan, China, and South Korea.^4,5,17 These epidemics are usually community acquired and often result in liver abscess with metastatic infection.

There is little known about the exact portion of health care-associated hvKP infections, although some data do exist. In China, there are reports that among the 49 patients of ventilator-associated pneumonia, 13 (28.6%) had hvKP, and that of the 35 patients with hypervirulent septic K. pneumoniae, 13 (37.1%) were acquired in the intensive care unit.¹⁸ Another study in China reported that among 29 isolates of the hvKP, 37.9% (11/29) were health care-associated infections.¹⁵

We found that 38% (60/155) of total hvKP infections were health care-associated infections and that pneumonia is the most common infection of hvKP acquired in these settings. These results fail to correspond with the notion that liver abscess is the most common infection by hvKP. In community-acquired hvKP, intraabdominal infection is the most common source of infection like other studies have already reported.

K1 and K2 are well-recognized serotypes, which are associated with community-acquired liver abscess in hvKP infections.¹⁹ Non-K1/K2 serotypes are not well studied. However, some studies report liver abscesses caused from non-K1/K2 serotypes. Non-K1/K2 serotypes made up 32.9% (24/73) of liver abscesses resulting from K. pneumoniae infections and showed a low prevalence of hypermucoviscosity and virulence factor expression.^20,21 We categorized the isolates as one of six serotypes or as nondetermined when a serotype could not be identified: K1, K2, K5, K20, K54, and K57. We successfully serotyped many K. pneumoniae isolates, with the exception of most of the health care-associated isolates. Of those, 70% were labeled as a nondetermined serotype. In health care-associated hvKP, non-K1/K2 serotypes were 46.6% and nondetermined serotype was 28.3%. We found that health care-associated hvKP have diverse spectrum of serotypes and are not restricted to K1/K2.

In our study, sixty isolates of health care-associated hvKP had 55% aerobactin, 14.3% rmpA, and 12.5% magA. These results are also quite different from those of the community-originating strains. Community-origin hvKP showed 70.5% aerobactin, 76.6% rmpA, and 51.5% magA. Health care-associated hvKP showed a very low prevalence of magA and rmpA genes, which are well-known virulence genes in community-acquired infections that result in liver abscess.⁴ The study of ventilator-associated pneumonia by hvKP reported 14 isolates that showed a high prevalence of iroB, iucA, iutA, and rmpA.¹⁸ These inconsistent findings are possibly due to the small study population.

Recently, increasing antimicrobial resistance of hvKP has become a global concern as evidenced by the many new reports on the topic. Our study results showed that most usable antimicrobial drugs were more resistant in health care-associated hvKP than community origin. Cephalosporins are about 20% resistant in health care-associated hvKP. Aminoglycoside, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole also showed over 10% of resistance.

Among the 87 isolates of hvKP, 11 (12.6%) show ESBL production in China.²² That the degree of antimicrobial resistance is increasing over time has also been reported, including carbapenem-resistant hvKP.¹⁵ In a Chinese study, among the 28 isolates of carbapenem-resistant K. pneumoniae, five were identified as hypervirulent strains.²³ Another report detailed 148 meropenem-resistant K. pneumoniae strains, where 7.4% (11/148) were determined to be hypervirulent.¹⁶ In our study, all 155 isolates of hvKP showed no carbapenem resistance. ESBL production was 9.6% (15/155) lower compared with the aforementioned studies. However, divided by infection origin, health care-associated hvKP was more resistant to antibiotics. ESBL production was 20% (12/60) much higher than that by community-acquired strains.

Good susceptibility to most usable antimicrobial drugs is the well-known distinctive feature of hvKP. But, according to our study results, it is confined to community-acquired hvKP. Health care-associated hvKP showed quite different results of antimicrobial susceptibility.

There were some limitations in our study. We defined hvKP with the hypermucoviscosity by string test. But, it is unclear whether all hvKP strains are hypermucoviscous. Recently, some studies defined the hvKP with various virulence genes. Further studies are needed for the well-defined hypervirulence. There are important virulence genes associated with hvKP besides magA, rmpA, and aerobactin. Iron acquisition system is well-known in virulence genes associated with hvKP, including enterobactin (Ent), yersiniabactin (YbtS), and Kfu.

In addition, we collected hvKP only from a single center. Therefore, our study cannot represent the entire country. If we should know the alteration of hyKP over time, a nationwide study is needed.

In conclusion, a relatively large number of isolates were analyzed in our study. Thirty eight percent of hvKP originated in a health care setting. This was higher than that in previous data. Furthermore, pneumonia was the most common source of infection other than intraabdominal infection. Moreover, the well-known association with K1/K2 serotypes and rmpA gene differs in health care-associated infections. These results suggest that hvKP may have different microbiological characteristics depending on whether the infection was acquired from a health care facility or from the community at large. Higher antibiotic resistance was also more prevalent in infections originating from health care settings. Further investigation is needed for other serotypes, virulent factors, and antimicrobial resistance associated with health care-associated hvKP.

Footnotes

Acknowledgment

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2017R1C1B5077117).

Disclosure Statement

No competing financial interests exist.

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