Scandinavian Journal of Infectious Diseases, 2014; 46: 21–26
ORIGINAL ARTICLE
Liver abscess due to Klebsiella pneumoniae: Risk factors for metastatic infection
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JAI HOON YOON1, YOUN JEONG KIM2, YOON HEE JUN2, SANG IL KIM2, JI YOUNG KANG2, KI TAE SUK1 & DONG JOON KIM1 From the 1Department of Internal Medicine, The Hallym University College of Medicine, Chuncheon, and 2Departments of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, South Korea
Abstract Introduction: Klebsiella pneumoniae-associated liver abscess (KPLA) is often accompanied by extrahepatic complications. We investigated the clinical features and outcomes of patients with and without metastatic infections and compared the 2 groups. Methods: We retrospectively reviewed the medical records of 161 patients with KPLA who were admitted to 2 tertiary referral hospitals in Korea. Results: In total, 9.9% had a metastatic infection. The most commonly involved distant sites were the eyes (n ⫽ 7) and the lungs (n ⫽ 6). In multivariate analysis, diabetes mellitus as an underlying disease (odds ratio (OR) 2.30, 95% confidence interval (CI) 1.05–9.51; p ⫽ 0.03) and a platelet count ⬍ 80,000/mm3 (OR 11.60, 95% CI 2.53–53.26; p ⫽ 0.002) were associated with metastatic infection. Extended-spectrum beta-lactamase (ESBL) production was not observed in K. pneumoniae from patients with metastatic infection, whereas 3.4% of the bacteria in patients without metastatic infection had ESBL production. However, this difference was not statistically significant (p ⫽ 0.45). The in-hospital mortality rate was not significantly different (0% vs. 2.8%; p ⫽ 0.52). By multivariate analysis, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was independently associated with mortality among patients with KPLA (OR 1.5, 95% CI 1.12–2.00; p ⫽ 0.006). Conclusions: Clinicians must be aware of potential metastatic infections in patients with KPLA, especially if they have diabetes mellitus and thrombocytopenia. The APACHE II score was predictive of mortality in patients with KPLA.
Keywords: Liver abscess, invasive syndrome, Klebsiella pneumoniae, pyogenic liver abscess, prognosis
Introduction The epidemiological profile of pyogenic liver abscesses differs between countries. Liver abscesses are mostly caused by polymicrobial infections, and Escherichia coli was the most common pathogen causing liver abscesses worldwide until the 1980s [1,2]. Liver abscesses caused by Klebsiella pneumoniae have recently become widely prevalent. This is already known for the Asian countries; however the prevalence of K. pneumoniae-associated liver abscesses (KPLA) is gradually increasing in Western countries as well, indicating a shift in the cause from E. coli to K. pneumoniae [3–6]. Since 1986, a distinct syndrome of community-acquired pyogenic
liver abscess due to K. pneumoniae in which metastatic infectious complications can develop, such as endophthalmitis or central nervous system (CNS) infections, has been reported in several countries, with the first report from Taiwan [7,8]. The reported mortality rate in patients with liver abscesses ranges from 6% to 12% [9,10]. The metastatic complications in patients with KPLA are usually severe and are associated with a poor outcome and a high mortality rate. However, some studies have demonstrated that the severity of the disease and the presence of other underlying diseases are associated with the prognosis of patients with liver abscesses [5,9].
Correspondence: Y. J. Kim, Division of Infectious Disease, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 505 Banpodong, Seochogu 137-701, South Korea. Tel: ⫹ 82 2258 6073. Fax: ⫹ 82 2 2258 1254. E-mail: [email protected] (Received 30 June 2013 ; accepted 26 September 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.851414
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J. H. Yoon et al.
In this study, we analyzed the clinical features, laboratory findings, antimicrobial susceptibility, and clinical outcomes in patients with KPLA and compared these variables in patients with and without a metastatic infection.
the laboratory. Phenotypic confirmation for ESBL detection was performed using the double-disk diffusion method in our clinical microbiology laboratories, as recommended by the CLSI. Statistics
Patients and methods
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Study design We performed a retrospective study at 2 university hospitals in Korea from 2004 to 2011. All patients aged ⬎ 18 y who were discharged from the hospitals with a diagnosis of liver abscess made on the basis of computed tomography, ultrasonography, or magnetic resonance imaging, and who had definite signs of infection, were identified. Patients with K. pneumoniae isolated from an abscess or blood were included in this study. Data collection The demographic characteristics of the patients, including associated medical information, clinical and laboratory parameters, microbiology results, and outcomes, were reviewed. We included 379 patients with liver abscesses in the initial screening. A metastatic infection was defined as an extrahepatic complication such as endophthalmitis, CNS infections, lung abscesses, and skin and soft tissue infections in patients with a liver abscess from which K. pneumoniae was isolated. Sepsis-induced hypotension was defined as a systolic blood pressure ⬍ 90 mmHg in the absence of other causes of hypotension [11]. Invasive procedures to treat abscesses included aspiration, percutaneous drainage, and surgical interventions. Overall in-hospital mortality was defined as death during the same hospital stay. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital and Hallym University.
Antimicrobial susceptibility of bacterial isolates and extended-spectrum beta-lactamase (ESBL) detection Abscess or blood specimens were cultured for bacteria using a VITEK GNI automated system (bioMérieux, USA). The antimicrobial susceptibility was tested by VITEK GNI automated system, and results interpreted in accordance with the guidelines established by the Clinical and Laboratory Standards Institute (CLSI) [12]. Both aerobic and anaerobic cultures were performed for abscess and blood samples. An aseptic technique was used in the aspiration of abscesses to obtain samples for anaerobic culture. Specimens were transported rapidly in the syringe to
The Student’s t-test was used for the analysis of continuous variables and the Chi-square test or Fisher’s exact test for categorical variables. Univariate and multivariate logistic regression analyses were used to analyze the risk factors associated with mortality. The statistical analysis was performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA); a p-value of ⬍ 0.05 was considered statistically significant.
Results In total, 298 organisms were identified in the 259 patients who had abscess or blood specimens. Four patients with a liver abscess due to a polymicrobial infection were excluded, and finally a total of 161 patients with a liver abscess caused by monomicrobial K. pneumoniae were included. Of the 298 organisms identified, K. pneumoniae was the predominant pathogen, accounting for 55.4% of all infections (165/298) (Table I). The average age of the 161 patients included was 61.2 ⫾ 13.7 y, and 60.9% were men. Hypertension was the most common underlying disease (n ⫽ 48, 29.8%), followed by diabetes mellitus (n ⫽ 44, 27.3%). Cholelithiasis was observed in 14 patients (8.7%), and 15 patients (9.3%) had a malignancy (8 had hepatocellular carcinoma, 2 pancreatic cancer, 1 biliary cancer, and 4 non-gastrointestinal cancers). Sixteen patients had a metastatic infection (9.9%) and 7 patients (43.7%) Table I. Etiology of liver abscess. Total Gram-negative species Klebsiella pneumoniae Escherichia coli Enterobacter species Pseudomonas species Citrobacter species Others Gram-positive species Staphylococcus aureus Enterococcus species Streptococcus species Streptococcus epidermidis Anaerobes Bacteroides Others Mycobacterium tuberculosis Ameba
231 165 39 9 7 4 7 35 5 21 8 1 11 4 7 5 16
(77.5%) (55.4%) (13.1%) (3.0%) (2.3%) (1.3%) (2.3%) (11.7%) (1.7%) (7.0%) (2.7%) (0.3%) (3.7%) (1.3%) (2.3%) (1.7%) (5.4%)
Klebsiella pneumoniae liver abscess
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Table II. Comparison of the demographic characteristics of patients with liver abscess due to Klebsiella pneumoniae between those with and those without a metastatic infection.
Age, y, mean ⫾ SD Sex, male, n (%) Underlying disease, n (%) Diabetes mellitus Hypertension Liver disease Hepatitis B Hepatitis C Others Cholelithiasis Malignancy Hepatocellular carcinoma Biliary cancer Pancreas cancer Others Previous hepatobiliary procedure, n (%) Dialysis, n (%) Sepsis induced hypotension, n (%) APACHE II score, mean ⫾ SD Invasive procedure, n (%) Mortality, n (%) Length of hospital stay, days, mean ⫾ SD Length of hospital stay before diagnosis, days, mean ⫾ SD Inappropriate empirical antimicrobial therapy, n (%)
Metastatic infection (n ⫽ 16)
No metastatic infection (n ⫽ 145)
p-Value
58.0 ⫾ 15.2 12 (75.0%)
61.5 ⫾ 13.6 88 (59.3%)
0.32 0.22
10 (62.5%) 4 (25.0%)
34 (23.4%) 44 (30.3%)
0.001 0.65 0.25
2 0 0 2
(12.5%) (0%) (0%) (12.5%)
4 2 1 12
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (6.3%) 3 (18.8%) 5.1 ⫾ 3.3 14 (87.5%) 0 (0%) 29.0 ⫾ 14.7 1.9 ⫾ 2.4 0 (0%)
(3.0%)a (1.5%)a (0.7%) (8.3%)
0.57 0.77
8 (5.5%) 1 (0.7%) 2 (1.4%) 4 (2.8%) 9 (6.2%) 4 (2.8%) 13 (9.0%) 6.0 ⫾ 3.8 124 (85.5%) 4 (2.8%) 22.4 ⫾ 14.7 1.5 ⫾ 1.8 6 (4.1%)
0.31 0.45 0.21 0.33 0.83 0.52 0.04 0.34 0.41
SD, standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation. total of 133 patients performed serology test such as hepatitis B and hepatitis C.
aA
had infection foci at more than 2 distant sites: 7 endophthalmitis, 6 septic emboli in the lung, 5 skin and soft tissue infection, 2 CNS infection, 1 psoas muscle abscess, and 1 spleen abscess. A comparison of the demographic characteristics between patients with and without KPLA metastatic infection is presented in Table II. Patients with a metastatic infection were slightly younger than patients without a metastatic infection, but this difference was not statistically significant (58.0 ⫾ 15.2 y vs. 61.5 ⫾ 13.6 y; p ⫽ 0.32). With regard to underlying diseases, a higher proportion of patients with a metastatic infection had diabetes mellitus compared to those without a metastatic infection (62.5% (10/16) vs. 23.3% (34/145); p ⫽ 0.001). Patients with a metastatic infection did not have any malignancies and had not undergone a previous hepatobiliary procedure. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was not significantly different between the 2 groups (5.1 ⫾ 3.3 vs. 6.0 ⫾ 3.8; p ⫽ 0.33). Patients with a metastatic infection had a longer hospital stay than those without (29.0 ⫾ 14.7 days vs. 22.4 ⫾ 14.7 days; p ⫽ 0.04). Inappropriate antimicrobial therapy was not associated with metastatic infection (0% vs. 4.1% (6/145); p ⫽ 0.41).
The antimicrobial resistance of the isolated K. pneumoniae is shown in Table III. In metastatic infections, 6.3% were resistant to cefazolin, whereas in non-metastatic infections, this proportion was 5.5% (p ⫽ 0.90). Resistance to ceftazidime was not observed in metastatic infections, although in nonmetastatic infections, 4.1% were resistant to ceftazidime Table III. Antimicrobial resistance and ESBL production of isolated Klebsiella pneumoniae.
Antimicrobial Amikacin Ciprofloxacin Cefazolin Cefoxitin Ceftazidime Cefepime Piperacillin Piperacillin/tazobactam Meropenem Imipenem Amoxicillin/clavulanic acid ESBL production
Metastatic infection (n ⫽ 16) 0 0 1 0 0 0 5 0 0 0 0
(0%) (0%) (6.3%) (0%) (0%) (0%) (31.2%) (0%) (0%) (0%) (0%)
No metastatic infection (n ⫽ 145) 2 4 8 9 6 5 58 4 0 0 10
0 (0%)
ESBL, extended spectrum beta-lactamase.
(1.4%) (2.7%) (5.5%) (6.2%) (4.1%) (3.4%) (40.0%) (2.8%) (0%) (0%) (6.9%)
5 (3.4%)
p-Value 0.64 0.56 0.90 0.31 0.40 0.45 0.49 0.50 – – 0.28 0.45
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J. H. Yoon et al. Table IV. Comparison of laboratory findings in patients with Klebsiella pneumoniae liver abscess between those with and those without metastatic infection.
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White blood cells, per mm3 Platelets, per mm3 Creatinine, mg/dl Albumin, g/dl AST, IU/l ALT, IU/l Alkaline phosphatase, IU/l r-GTP, IU/l Total bilirubin, mg/dl C-reactive protein, mg/dl
Metastatic infection (n ⫽ 16)
No metastatic infection (n ⫽ 145)
p-Value
17,251 ⫾ 12,365 136,562 ⫾ 100,925 1.5 ⫾ 1.7 2.8 ⫾ 0.6 90.8 ⫾ 105.1 96.1 ⫾ 107.9 240.3 ⫾ 200.6 214.6 ⫾ 258.9 1.7 ⫾ 1.3 18.7 ⫾ 9.0
13,302 ⫾ 9284 222,179 ⫾ 118,849 1.1 ⫾ 0.9 3.2 ⫾ 0.5 105.6 ⫾ 140.8 105.7 ⫾ 134.8 244.1 ⫾ 200.1 157.7 ⫾ 154.6 1.5 ⫾ 1.8 13.8 ⫾ 9.2
0.12 0.006 0.34 0.01 0.68 0.78 0.66 0.45 0.77 0.05
AST, aspartate aminotransferase; ALT, alanine aminotransferase; r-GTP, r-glutamyl transpeptidase.
(p ⫽ 0.40). ESBL production was not observed in metastatic infections, while 3.4% of patients without a metastatic infection had ESBL-producing bacteria, but the difference was not statistically significant (p ⫽ 0.45). Patients with a metastatic infection more often had sepsis-induced hypotension as an initial manifestation than those without; however this difference was not statistically significant (18.8% vs. 9.0%; p ⫽ 0.21) (Table II). The length of hospital stay before diagnosis of liver abscess was not different between the 2 groups (p ⫽ 0.34) (Table II). Patients with a metastatic infection had a lower platelet count (136,562 ⫾ 100,925/mm3 vs. 222,179 ⫾ 118,849/mm3; p ⫽ 0.006), lower albumin level (2.8 ⫾ 0.65 g/dl vs. 3.2 ⫾ 0.5 g/dl; p ⫽ 0.01), and higher C-reactive protein level (18.7 ⫾ 9.0 mg/dl vs. 13.8 ⫾ 9.2 mg/dl; p ⫽ 0.05) than those without (Table IV). By univariate analysis, the risk factors for a metastatic infection among patients with KPLA were diabetes mellitus as an underlying disease (OR 5.44, 95% CI 1.83–16.06; p ⫽ 0.002), platelet count ⬍ 80,000/mm3 (OR 14.93, 95% CI 3.8–58.6; p ⫽ 0.0001), and a low albumin level (OR 0.33, 95% CI 0.13–0.835; p ⫽ 0.002) (Table V). Multivariate
analysis showed diabetes mellitus as an underlying disease (OR 2.30, 95% CI 1.05–9.51; p ⫽ 0.03) and a platelet count ⬍ 80,000/mm3 (OR 11.60, 95% CI 2.53–53.26; p ⫽ 0.002) to be independently associated with metastatic infection among patients with KPLA. Four patients died during their hospital stay and all belonged to the group without a metastatic infection. The in-hospital mortality rate was not significantly different between the 2 groups (0% vs. 2.8%; p ⫽ 0.52). However, the hospital stay was longer in patients with a metastatic infection than in those without. The patients who died were older than those who survived (77.0 ⫾ 11.6 vs. 60.0 ⫾ 13.5 y; p ⫽ 0.02) and had a higher APACHE II score (14.3 ⫾ 5.9 vs. 5.7 ⫾ 3.5; p ⫽ 0.001). ESBL production (3.2% vs. 0%; p ⫽ 0.72), the presence of a metastatic infection (0% vs. 9.0%; p ⫽ 0.53), and invasive procedures (100% vs. 85.8%, p ⫽ 0.42) were not different in the patients who died and those who survived (data not shown). The univariate analysis showed age (OR 1.13, 95% CI 1.02–1.26, p ⫽ 0.02) and APACHE II score (OR 1.49, 95% CI 1.16–1.92, p ⫽ 0.002) to be associated with mortality among patients with KPLA.
Table V. Risk factors for metastatic infection among patients with liver abscess due to Klebsiella pneumoniae. Univariate analysis OR Age Diabetes mellitus Sepsis induced hypotension APACHE II score Platelets ⬍ 800,000/mm3 Albumin C-reactive protein Bacteremia
0.98 5.44 2.34 0.92 14.93 0.33 1.06 1.99
95% CI
p-Value
0.94–1.02 1.83–16.06 0.59–9.30 0.78–1.08 3.8–58.6 0.13–0.83 0.99–1.12 0.68–5.78
0.32 0.002 0.22 0.33 0.0001 0.02 0.06 0.20
Multivariate analysis OR
95% CI
p-Value
2.30
1.05–9.51
0.03
11.60 0.41 1.03
2.53–53.26 0.12–1.39 0.96–1.11
0.002 0.15 0.35
OR, odds ratio; CI, confidence interval; APACHE, Acute Physiology and Chronic Health Evaluation.
Klebsiella pneumoniae liver abscess By multivariate analysis, the APACHE II score was found to be independently associated with mortality (OR 1.5, 95% CI 1.12–2.00, p ⫽ 0.006).
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Discussion KPLA with extrahepatic complications, especially endophthalmitis, skin and soft tissue infections, septic emboli in the lungs, and CNS infections, is referred to as a new invasive liver abscess syndrome [13]. The prevalence rate of invasive liver abscess syndrome has increased in Asia, where Taiwan has the highest prevalence, followed by South Korea. This syndrome has recently emerged as a globally prevalent disease. Our study demonstrated that in South Korea, 9.9% of the patients with KPLA had extrahepatic complications; this rate is similar to that reported in Taiwan [14]. Our study also showed that thrombocytopenia and diabetes mellitus were independently associated with metastatic infection in patients with KPLA. Diabetes mellitus is a wellknown concomitant disease in patients with KPLA, and the prevalence differs between countries (⬎ 60% in Taiwan and 33% in the USA) [6,14,15]. Patients with diabetes mellitus have decreased cell-mediated and humoral responses to infection; however it is unclear what mechanism is responsible for the high susceptibility to the development of KPLA in patients with diabetes mellitus. Yu et al. reported that patients with diabetes mellitus had a higher percentage of liver abscess due to non-K1/K2 serotypes, which are considered to be less virulent than the K1/K2 serotypes [16]. K. pneumoniae serotypes were not determined in the present study. Further studies examining the role of diabetes mellitus and virulence factors in invasive liver abscess syndrome are warranted. However our study indicates that clinicians should consider a potential metastatic infection if a patient with KPLA is admitted to the hospital with severe conditions such as thrombocytopenia, and if the patient has diabetes mellitus. In our study, only 3.4% of patients with a liver abscess had ESBL-producing K. pneumoniae, and none of the patients with metastatic infection had ESBLproducing K. pneumoniae isolates. In addition, most of the isolated strains were susceptible to antimicrobial agents excluding piperacillin. Although a high prevalence of ESBL-producing K. pneumoniae has been observed in China, Thailand, and India, the rates of ESBL-producing K. pneumoniae were extremely low in patients with liver abscesses in Korea [17,18]. Clinicians tend to choose newer, broader spectrum antibiotics, expecting these agents to be more efficacious in the treatment of infectious diseases. Our results provide evidence for the use of standard antibiotic choices for
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K. pneumoniae, rather than carbapenems. However, as drug resistance may develop over time, continued surveillance is necessary to evaluate future trends. Several studies have reported old age, metastatic infection, severity of disease, and septic shock to be predictors of mortality in patients with KPLA [14,19]. However, a study from Taiwan demonstrated that the 2-y mortality of patients with septic ocular or CNS involvement was similar to that for patients without complications [20]. Our study also showed older age and a higher APACHE II score in the patients who died. The presence of a metastatic infection was not associated with mortality in our study, probably because only a small number of patients were included and ⬎ 85% of the patients had undergone an invasive procedure. This result suggests that the disease severity at the time of admission and the source control of KPLA could have influenced their outcomes. Six (86%) of the patients with endophthalmitis lost their vision; this value is similar to that reported for the prognosis in patients with endophthalmitis caused by K. pneumoniae, showing that the prognosis is very poor [21,22]. The overall in-hospital mortality rate in our study was 2.5%, similar to the rate in another study from Korea [4]. This mortality rate is relatively low compared with those reported from previous studies in other countries [9,23,24]. Early diagnosis through imaging and rapid interventions may have been associated with a favorable outcome; in this study 93.5% (130/139) of patients were subjected to an intervention within 72 h after admission. However further nationwide multicenter studies on the risk factors for mortality are needed. Our study has some limitations. This was a retrospective study including only 2 hospitals. We could not determine the virulence factors, including serotypes of K. pneumoniae. Recently, capsular type K1 or K2 antigen and the presence of rmpA have been described as virulence factors in K. pneumoniae, and these factors contribute to the development of the invasive syndrome. Further investigation of the virulence factors associated with metastatic infections in KPLA patients are needed. In summary, 9.9% of patients with a liver abscess caused by K. pneumoniae had an extrahepatic metastatic infection. Patients with a metastatic infection did not have a higher mortality rate than those without, and disease severity was associated with outcomes. Catastrophic disabilities such as loss of vision were the main problem faced by these patients. Declaration of interest: Each of the authors declares that he has no conflict of interest associated with this manuscript.
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ORIGINAL ARTICLE
Liver abscess due to Klebsiella pneumoniae: Risk factors for metastatic infection
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JAI HOON YOON1, YOUN JEONG KIM2, YOON HEE JUN2, SANG IL KIM2, JI YOUNG KANG2, KI TAE SUK1 & DONG JOON KIM1 From the 1Department of Internal Medicine, The Hallym University College of Medicine, Chuncheon, and 2Departments of Internal Medicine, The Catholic University of Korea College of Medicine, Seoul, South Korea
Abstract Introduction: Klebsiella pneumoniae-associated liver abscess (KPLA) is often accompanied by extrahepatic complications. We investigated the clinical features and outcomes of patients with and without metastatic infections and compared the 2 groups. Methods: We retrospectively reviewed the medical records of 161 patients with KPLA who were admitted to 2 tertiary referral hospitals in Korea. Results: In total, 9.9% had a metastatic infection. The most commonly involved distant sites were the eyes (n ⫽ 7) and the lungs (n ⫽ 6). In multivariate analysis, diabetes mellitus as an underlying disease (odds ratio (OR) 2.30, 95% confidence interval (CI) 1.05–9.51; p ⫽ 0.03) and a platelet count ⬍ 80,000/mm3 (OR 11.60, 95% CI 2.53–53.26; p ⫽ 0.002) were associated with metastatic infection. Extended-spectrum beta-lactamase (ESBL) production was not observed in K. pneumoniae from patients with metastatic infection, whereas 3.4% of the bacteria in patients without metastatic infection had ESBL production. However, this difference was not statistically significant (p ⫽ 0.45). The in-hospital mortality rate was not significantly different (0% vs. 2.8%; p ⫽ 0.52). By multivariate analysis, the Acute Physiology and Chronic Health Evaluation II (APACHE II) score was independently associated with mortality among patients with KPLA (OR 1.5, 95% CI 1.12–2.00; p ⫽ 0.006). Conclusions: Clinicians must be aware of potential metastatic infections in patients with KPLA, especially if they have diabetes mellitus and thrombocytopenia. The APACHE II score was predictive of mortality in patients with KPLA.
Keywords: Liver abscess, invasive syndrome, Klebsiella pneumoniae, pyogenic liver abscess, prognosis
Introduction The epidemiological profile of pyogenic liver abscesses differs between countries. Liver abscesses are mostly caused by polymicrobial infections, and Escherichia coli was the most common pathogen causing liver abscesses worldwide until the 1980s [1,2]. Liver abscesses caused by Klebsiella pneumoniae have recently become widely prevalent. This is already known for the Asian countries; however the prevalence of K. pneumoniae-associated liver abscesses (KPLA) is gradually increasing in Western countries as well, indicating a shift in the cause from E. coli to K. pneumoniae [3–6]. Since 1986, a distinct syndrome of community-acquired pyogenic
liver abscess due to K. pneumoniae in which metastatic infectious complications can develop, such as endophthalmitis or central nervous system (CNS) infections, has been reported in several countries, with the first report from Taiwan [7,8]. The reported mortality rate in patients with liver abscesses ranges from 6% to 12% [9,10]. The metastatic complications in patients with KPLA are usually severe and are associated with a poor outcome and a high mortality rate. However, some studies have demonstrated that the severity of the disease and the presence of other underlying diseases are associated with the prognosis of patients with liver abscesses [5,9].
Correspondence: Y. J. Kim, Division of Infectious Disease, Department of Internal Medicine, Seoul St. Mary’s Hospital, The Catholic University of Korea, 505 Banpodong, Seochogu 137-701, South Korea. Tel: ⫹ 82 2258 6073. Fax: ⫹ 82 2 2258 1254. E-mail: [email protected] (Received 30 June 2013 ; accepted 26 September 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.851414
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J. H. Yoon et al.
In this study, we analyzed the clinical features, laboratory findings, antimicrobial susceptibility, and clinical outcomes in patients with KPLA and compared these variables in patients with and without a metastatic infection.
the laboratory. Phenotypic confirmation for ESBL detection was performed using the double-disk diffusion method in our clinical microbiology laboratories, as recommended by the CLSI. Statistics
Patients and methods
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Study design We performed a retrospective study at 2 university hospitals in Korea from 2004 to 2011. All patients aged ⬎ 18 y who were discharged from the hospitals with a diagnosis of liver abscess made on the basis of computed tomography, ultrasonography, or magnetic resonance imaging, and who had definite signs of infection, were identified. Patients with K. pneumoniae isolated from an abscess or blood were included in this study. Data collection The demographic characteristics of the patients, including associated medical information, clinical and laboratory parameters, microbiology results, and outcomes, were reviewed. We included 379 patients with liver abscesses in the initial screening. A metastatic infection was defined as an extrahepatic complication such as endophthalmitis, CNS infections, lung abscesses, and skin and soft tissue infections in patients with a liver abscess from which K. pneumoniae was isolated. Sepsis-induced hypotension was defined as a systolic blood pressure ⬍ 90 mmHg in the absence of other causes of hypotension [11]. Invasive procedures to treat abscesses included aspiration, percutaneous drainage, and surgical interventions. Overall in-hospital mortality was defined as death during the same hospital stay. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital and Hallym University.
Antimicrobial susceptibility of bacterial isolates and extended-spectrum beta-lactamase (ESBL) detection Abscess or blood specimens were cultured for bacteria using a VITEK GNI automated system (bioMérieux, USA). The antimicrobial susceptibility was tested by VITEK GNI automated system, and results interpreted in accordance with the guidelines established by the Clinical and Laboratory Standards Institute (CLSI) [12]. Both aerobic and anaerobic cultures were performed for abscess and blood samples. An aseptic technique was used in the aspiration of abscesses to obtain samples for anaerobic culture. Specimens were transported rapidly in the syringe to
The Student’s t-test was used for the analysis of continuous variables and the Chi-square test or Fisher’s exact test for categorical variables. Univariate and multivariate logistic regression analyses were used to analyze the risk factors associated with mortality. The statistical analysis was performed using SPSS 13.0 (SPSS Inc., Chicago, IL, USA); a p-value of ⬍ 0.05 was considered statistically significant.
Results In total, 298 organisms were identified in the 259 patients who had abscess or blood specimens. Four patients with a liver abscess due to a polymicrobial infection were excluded, and finally a total of 161 patients with a liver abscess caused by monomicrobial K. pneumoniae were included. Of the 298 organisms identified, K. pneumoniae was the predominant pathogen, accounting for 55.4% of all infections (165/298) (Table I). The average age of the 161 patients included was 61.2 ⫾ 13.7 y, and 60.9% were men. Hypertension was the most common underlying disease (n ⫽ 48, 29.8%), followed by diabetes mellitus (n ⫽ 44, 27.3%). Cholelithiasis was observed in 14 patients (8.7%), and 15 patients (9.3%) had a malignancy (8 had hepatocellular carcinoma, 2 pancreatic cancer, 1 biliary cancer, and 4 non-gastrointestinal cancers). Sixteen patients had a metastatic infection (9.9%) and 7 patients (43.7%) Table I. Etiology of liver abscess. Total Gram-negative species Klebsiella pneumoniae Escherichia coli Enterobacter species Pseudomonas species Citrobacter species Others Gram-positive species Staphylococcus aureus Enterococcus species Streptococcus species Streptococcus epidermidis Anaerobes Bacteroides Others Mycobacterium tuberculosis Ameba
231 165 39 9 7 4 7 35 5 21 8 1 11 4 7 5 16
(77.5%) (55.4%) (13.1%) (3.0%) (2.3%) (1.3%) (2.3%) (11.7%) (1.7%) (7.0%) (2.7%) (0.3%) (3.7%) (1.3%) (2.3%) (1.7%) (5.4%)
Klebsiella pneumoniae liver abscess
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Table II. Comparison of the demographic characteristics of patients with liver abscess due to Klebsiella pneumoniae between those with and those without a metastatic infection.
Age, y, mean ⫾ SD Sex, male, n (%) Underlying disease, n (%) Diabetes mellitus Hypertension Liver disease Hepatitis B Hepatitis C Others Cholelithiasis Malignancy Hepatocellular carcinoma Biliary cancer Pancreas cancer Others Previous hepatobiliary procedure, n (%) Dialysis, n (%) Sepsis induced hypotension, n (%) APACHE II score, mean ⫾ SD Invasive procedure, n (%) Mortality, n (%) Length of hospital stay, days, mean ⫾ SD Length of hospital stay before diagnosis, days, mean ⫾ SD Inappropriate empirical antimicrobial therapy, n (%)
Metastatic infection (n ⫽ 16)
No metastatic infection (n ⫽ 145)
p-Value
58.0 ⫾ 15.2 12 (75.0%)
61.5 ⫾ 13.6 88 (59.3%)
0.32 0.22
10 (62.5%) 4 (25.0%)
34 (23.4%) 44 (30.3%)
0.001 0.65 0.25
2 0 0 2
(12.5%) (0%) (0%) (12.5%)
4 2 1 12
0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 1 (6.3%) 3 (18.8%) 5.1 ⫾ 3.3 14 (87.5%) 0 (0%) 29.0 ⫾ 14.7 1.9 ⫾ 2.4 0 (0%)
(3.0%)a (1.5%)a (0.7%) (8.3%)
0.57 0.77
8 (5.5%) 1 (0.7%) 2 (1.4%) 4 (2.8%) 9 (6.2%) 4 (2.8%) 13 (9.0%) 6.0 ⫾ 3.8 124 (85.5%) 4 (2.8%) 22.4 ⫾ 14.7 1.5 ⫾ 1.8 6 (4.1%)
0.31 0.45 0.21 0.33 0.83 0.52 0.04 0.34 0.41
SD, standard deviation; APACHE, Acute Physiology and Chronic Health Evaluation. total of 133 patients performed serology test such as hepatitis B and hepatitis C.
aA
had infection foci at more than 2 distant sites: 7 endophthalmitis, 6 septic emboli in the lung, 5 skin and soft tissue infection, 2 CNS infection, 1 psoas muscle abscess, and 1 spleen abscess. A comparison of the demographic characteristics between patients with and without KPLA metastatic infection is presented in Table II. Patients with a metastatic infection were slightly younger than patients without a metastatic infection, but this difference was not statistically significant (58.0 ⫾ 15.2 y vs. 61.5 ⫾ 13.6 y; p ⫽ 0.32). With regard to underlying diseases, a higher proportion of patients with a metastatic infection had diabetes mellitus compared to those without a metastatic infection (62.5% (10/16) vs. 23.3% (34/145); p ⫽ 0.001). Patients with a metastatic infection did not have any malignancies and had not undergone a previous hepatobiliary procedure. The Acute Physiology and Chronic Health Evaluation II (APACHE II) score was not significantly different between the 2 groups (5.1 ⫾ 3.3 vs. 6.0 ⫾ 3.8; p ⫽ 0.33). Patients with a metastatic infection had a longer hospital stay than those without (29.0 ⫾ 14.7 days vs. 22.4 ⫾ 14.7 days; p ⫽ 0.04). Inappropriate antimicrobial therapy was not associated with metastatic infection (0% vs. 4.1% (6/145); p ⫽ 0.41).
The antimicrobial resistance of the isolated K. pneumoniae is shown in Table III. In metastatic infections, 6.3% were resistant to cefazolin, whereas in non-metastatic infections, this proportion was 5.5% (p ⫽ 0.90). Resistance to ceftazidime was not observed in metastatic infections, although in nonmetastatic infections, 4.1% were resistant to ceftazidime Table III. Antimicrobial resistance and ESBL production of isolated Klebsiella pneumoniae.
Antimicrobial Amikacin Ciprofloxacin Cefazolin Cefoxitin Ceftazidime Cefepime Piperacillin Piperacillin/tazobactam Meropenem Imipenem Amoxicillin/clavulanic acid ESBL production
Metastatic infection (n ⫽ 16) 0 0 1 0 0 0 5 0 0 0 0
(0%) (0%) (6.3%) (0%) (0%) (0%) (31.2%) (0%) (0%) (0%) (0%)
No metastatic infection (n ⫽ 145) 2 4 8 9 6 5 58 4 0 0 10
0 (0%)
ESBL, extended spectrum beta-lactamase.
(1.4%) (2.7%) (5.5%) (6.2%) (4.1%) (3.4%) (40.0%) (2.8%) (0%) (0%) (6.9%)
5 (3.4%)
p-Value 0.64 0.56 0.90 0.31 0.40 0.45 0.49 0.50 – – 0.28 0.45
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J. H. Yoon et al. Table IV. Comparison of laboratory findings in patients with Klebsiella pneumoniae liver abscess between those with and those without metastatic infection.
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White blood cells, per mm3 Platelets, per mm3 Creatinine, mg/dl Albumin, g/dl AST, IU/l ALT, IU/l Alkaline phosphatase, IU/l r-GTP, IU/l Total bilirubin, mg/dl C-reactive protein, mg/dl
Metastatic infection (n ⫽ 16)
No metastatic infection (n ⫽ 145)
p-Value
17,251 ⫾ 12,365 136,562 ⫾ 100,925 1.5 ⫾ 1.7 2.8 ⫾ 0.6 90.8 ⫾ 105.1 96.1 ⫾ 107.9 240.3 ⫾ 200.6 214.6 ⫾ 258.9 1.7 ⫾ 1.3 18.7 ⫾ 9.0
13,302 ⫾ 9284 222,179 ⫾ 118,849 1.1 ⫾ 0.9 3.2 ⫾ 0.5 105.6 ⫾ 140.8 105.7 ⫾ 134.8 244.1 ⫾ 200.1 157.7 ⫾ 154.6 1.5 ⫾ 1.8 13.8 ⫾ 9.2
0.12 0.006 0.34 0.01 0.68 0.78 0.66 0.45 0.77 0.05
AST, aspartate aminotransferase; ALT, alanine aminotransferase; r-GTP, r-glutamyl transpeptidase.
(p ⫽ 0.40). ESBL production was not observed in metastatic infections, while 3.4% of patients without a metastatic infection had ESBL-producing bacteria, but the difference was not statistically significant (p ⫽ 0.45). Patients with a metastatic infection more often had sepsis-induced hypotension as an initial manifestation than those without; however this difference was not statistically significant (18.8% vs. 9.0%; p ⫽ 0.21) (Table II). The length of hospital stay before diagnosis of liver abscess was not different between the 2 groups (p ⫽ 0.34) (Table II). Patients with a metastatic infection had a lower platelet count (136,562 ⫾ 100,925/mm3 vs. 222,179 ⫾ 118,849/mm3; p ⫽ 0.006), lower albumin level (2.8 ⫾ 0.65 g/dl vs. 3.2 ⫾ 0.5 g/dl; p ⫽ 0.01), and higher C-reactive protein level (18.7 ⫾ 9.0 mg/dl vs. 13.8 ⫾ 9.2 mg/dl; p ⫽ 0.05) than those without (Table IV). By univariate analysis, the risk factors for a metastatic infection among patients with KPLA were diabetes mellitus as an underlying disease (OR 5.44, 95% CI 1.83–16.06; p ⫽ 0.002), platelet count ⬍ 80,000/mm3 (OR 14.93, 95% CI 3.8–58.6; p ⫽ 0.0001), and a low albumin level (OR 0.33, 95% CI 0.13–0.835; p ⫽ 0.002) (Table V). Multivariate
analysis showed diabetes mellitus as an underlying disease (OR 2.30, 95% CI 1.05–9.51; p ⫽ 0.03) and a platelet count ⬍ 80,000/mm3 (OR 11.60, 95% CI 2.53–53.26; p ⫽ 0.002) to be independently associated with metastatic infection among patients with KPLA. Four patients died during their hospital stay and all belonged to the group without a metastatic infection. The in-hospital mortality rate was not significantly different between the 2 groups (0% vs. 2.8%; p ⫽ 0.52). However, the hospital stay was longer in patients with a metastatic infection than in those without. The patients who died were older than those who survived (77.0 ⫾ 11.6 vs. 60.0 ⫾ 13.5 y; p ⫽ 0.02) and had a higher APACHE II score (14.3 ⫾ 5.9 vs. 5.7 ⫾ 3.5; p ⫽ 0.001). ESBL production (3.2% vs. 0%; p ⫽ 0.72), the presence of a metastatic infection (0% vs. 9.0%; p ⫽ 0.53), and invasive procedures (100% vs. 85.8%, p ⫽ 0.42) were not different in the patients who died and those who survived (data not shown). The univariate analysis showed age (OR 1.13, 95% CI 1.02–1.26, p ⫽ 0.02) and APACHE II score (OR 1.49, 95% CI 1.16–1.92, p ⫽ 0.002) to be associated with mortality among patients with KPLA.
Table V. Risk factors for metastatic infection among patients with liver abscess due to Klebsiella pneumoniae. Univariate analysis OR Age Diabetes mellitus Sepsis induced hypotension APACHE II score Platelets ⬍ 800,000/mm3 Albumin C-reactive protein Bacteremia
0.98 5.44 2.34 0.92 14.93 0.33 1.06 1.99
95% CI
p-Value
0.94–1.02 1.83–16.06 0.59–9.30 0.78–1.08 3.8–58.6 0.13–0.83 0.99–1.12 0.68–5.78
0.32 0.002 0.22 0.33 0.0001 0.02 0.06 0.20
Multivariate analysis OR
95% CI
p-Value
2.30
1.05–9.51
0.03
11.60 0.41 1.03
2.53–53.26 0.12–1.39 0.96–1.11
0.002 0.15 0.35
OR, odds ratio; CI, confidence interval; APACHE, Acute Physiology and Chronic Health Evaluation.
Klebsiella pneumoniae liver abscess By multivariate analysis, the APACHE II score was found to be independently associated with mortality (OR 1.5, 95% CI 1.12–2.00, p ⫽ 0.006).
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Discussion KPLA with extrahepatic complications, especially endophthalmitis, skin and soft tissue infections, septic emboli in the lungs, and CNS infections, is referred to as a new invasive liver abscess syndrome [13]. The prevalence rate of invasive liver abscess syndrome has increased in Asia, where Taiwan has the highest prevalence, followed by South Korea. This syndrome has recently emerged as a globally prevalent disease. Our study demonstrated that in South Korea, 9.9% of the patients with KPLA had extrahepatic complications; this rate is similar to that reported in Taiwan [14]. Our study also showed that thrombocytopenia and diabetes mellitus were independently associated with metastatic infection in patients with KPLA. Diabetes mellitus is a wellknown concomitant disease in patients with KPLA, and the prevalence differs between countries (⬎ 60% in Taiwan and 33% in the USA) [6,14,15]. Patients with diabetes mellitus have decreased cell-mediated and humoral responses to infection; however it is unclear what mechanism is responsible for the high susceptibility to the development of KPLA in patients with diabetes mellitus. Yu et al. reported that patients with diabetes mellitus had a higher percentage of liver abscess due to non-K1/K2 serotypes, which are considered to be less virulent than the K1/K2 serotypes [16]. K. pneumoniae serotypes were not determined in the present study. Further studies examining the role of diabetes mellitus and virulence factors in invasive liver abscess syndrome are warranted. However our study indicates that clinicians should consider a potential metastatic infection if a patient with KPLA is admitted to the hospital with severe conditions such as thrombocytopenia, and if the patient has diabetes mellitus. In our study, only 3.4% of patients with a liver abscess had ESBL-producing K. pneumoniae, and none of the patients with metastatic infection had ESBLproducing K. pneumoniae isolates. In addition, most of the isolated strains were susceptible to antimicrobial agents excluding piperacillin. Although a high prevalence of ESBL-producing K. pneumoniae has been observed in China, Thailand, and India, the rates of ESBL-producing K. pneumoniae were extremely low in patients with liver abscesses in Korea [17,18]. Clinicians tend to choose newer, broader spectrum antibiotics, expecting these agents to be more efficacious in the treatment of infectious diseases. Our results provide evidence for the use of standard antibiotic choices for
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K. pneumoniae, rather than carbapenems. However, as drug resistance may develop over time, continued surveillance is necessary to evaluate future trends. Several studies have reported old age, metastatic infection, severity of disease, and septic shock to be predictors of mortality in patients with KPLA [14,19]. However, a study from Taiwan demonstrated that the 2-y mortality of patients with septic ocular or CNS involvement was similar to that for patients without complications [20]. Our study also showed older age and a higher APACHE II score in the patients who died. The presence of a metastatic infection was not associated with mortality in our study, probably because only a small number of patients were included and ⬎ 85% of the patients had undergone an invasive procedure. This result suggests that the disease severity at the time of admission and the source control of KPLA could have influenced their outcomes. Six (86%) of the patients with endophthalmitis lost their vision; this value is similar to that reported for the prognosis in patients with endophthalmitis caused by K. pneumoniae, showing that the prognosis is very poor [21,22]. The overall in-hospital mortality rate in our study was 2.5%, similar to the rate in another study from Korea [4]. This mortality rate is relatively low compared with those reported from previous studies in other countries [9,23,24]. Early diagnosis through imaging and rapid interventions may have been associated with a favorable outcome; in this study 93.5% (130/139) of patients were subjected to an intervention within 72 h after admission. However further nationwide multicenter studies on the risk factors for mortality are needed. Our study has some limitations. This was a retrospective study including only 2 hospitals. We could not determine the virulence factors, including serotypes of K. pneumoniae. Recently, capsular type K1 or K2 antigen and the presence of rmpA have been described as virulence factors in K. pneumoniae, and these factors contribute to the development of the invasive syndrome. Further investigation of the virulence factors associated with metastatic infections in KPLA patients are needed. In summary, 9.9% of patients with a liver abscess caused by K. pneumoniae had an extrahepatic metastatic infection. Patients with a metastatic infection did not have a higher mortality rate than those without, and disease severity was associated with outcomes. Catastrophic disabilities such as loss of vision were the main problem faced by these patients. Declaration of interest: Each of the authors declares that he has no conflict of interest associated with this manuscript.
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