Diagnostic Microbiology and Infectious Disease 82 (2015) 87–91
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Comparison of the clinical characteristics and outcomes of Klebsiella pneumoniae and Streptococcus pneumoniae meningitis Jiwon Jung a, Ki-Ho Park b, Seong Yeon Park c, Eun Hee Song d, Eun Jung Lee e, Seong-Ho Choi f, Eun Ju Choo g, Yee Gyung Kwak h, Heungsup Sung i, Sung-Han Kim a, Sang-Oh Lee a, Mi-Na Kim i, Yang Soo Kim a, Jun Hee Woo a, Sang-Ho Choi a,⁎ a
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, University of Ulsan, Seoul, Republic of Korea Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Republic of Korea c Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea d Department of Infectious Diseases, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea e Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea f Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea g Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea h Division of Infectious Diseases, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea i Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 22 August 2014 Received in revised form 11 February 2015 Accepted 14 February 2015 Available online 20 February 2015 Keywords: Klebsiella pneumoniae Streptococcus pneumoniae Meningitis
a b s t r a c t This multicenter, retrospective cohort study compared the clinical characteristics and outcomes of communityacquired Klebsiella pneumoniae meningitis (CA-KPM) with those of community-acquired Streptococcus pneumoniae meningitis (CA-SPM). Eighty-three adult patients, 27 with CA-KPM and 56 with CA-SPM, were included. Diabetes mellitus (48.1% versus 21.4%; P = 0.01) and liver cirrhosis (22.2% versus 5.4%; P = 0.05) were more commonly associated with CA-KPM. Comatose mental status (40.7% versus 12.5%; P = 0.01), septic shock (44.4% versus 8.9%; P b 0.001), and concomitant extrameningeal infections (40.7% versus 7.1%; P = 0.001) were also more common in the CA-KPM group. The 28-day mortality (44.4% versus 10.7%; P b 0.001) and inhospital mortality (51.9% versus 14.3%; P b 0.001) were higher in the CA-KPM group. In conclusion, diabetes mellitus and liver cirrhosis are more common in the CA-KPM patients who were also more likely to present with severe manifestations and poor outcomes. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Community-acquired bacterial meningitis still remains one of the most feared infectious diseases, as it is often associated with substantial mortality and long-term neurologic complications. In adult patients, the most common pathogens for meningitis are Streptococcus pneumoniae and Neisseria meningitidis (Durand et al., 1993; Hussein and Shafran, 2000; Okike et al., 2014; Thigpen et al., 2011). The aerobic gramnegative bacilli are known as the significant pathogen to cause community-acquired meningitis in immunocompromised patients or in individuals older than 50 years (van de Beek et al., 2012). Epidemiologic trends between western and eastern countries appear to differ in the percentage contributions of gram-negative bacilli and the major species inducing meningitis. In surveys from western countries, aerobic gram-negative bacilli account for 4.3–12.3% of the pathogens causing bacterial meningitis (Cabellos et al., 2009; Durand et al., 1993; Hussein and Shafran, 2000; Okike et al., 2014; Thornorethardottir et al., 2014), with Escherichia coli as the leading pathogen among them. In Asia, the ⁎ Corresponding author. Tel.: +82-2-3010-3304; fax: +82-2-3010-6970. E-mail address: [email protected] (S.-H. Choi). http://dx.doi.org/10.1016/j.diagmicrobio.2015.02.006 0732-8893/© 2015 Elsevier Inc. All rights reserved.
overall incidence of meningitis caused by gram-negative bacilli is 7.6–28.8% (Chan et al., 2002; Chang et al., 2008; Hui et al., 2005; Lu et al., 2000; Moon et al., 2010; Tang et al., 1999), which is about twice the incidence in the western countries, and among the implicated gram-negative pathogens, Klebsiella pneumoniae is the most common. Several studies by Taiwanese researchers have reported that K. pneumoniae meningitis (KPM) is often associated with male gender, diabetes mellitus, alcoholism, and liver cirrhosis (Lee et al., 2003; Lu et al., 2002; Tang et al., 1997). KPM-associated mortality in these reports has a wide range (33–93%) (Fang et al., 2000; Jang et al., 1993; Lee et al., 2004; Lu et al., 2002; Tang et al., 1997). However, these earlier studies have several limitations. First, they do not distinguish between acquisition sites; community-acquired and hospital-acquired cases, including postneurosurgical meningitis, are often grouped together (Lu et al., 2002; Tang et al., 1997). Second, one of these studies didn't distinguish between meningitis in adults and children (Tang et al., 1997). Finally, most previous studies fail to include adequate controls. In a recent Korean multicenter analysis, K. pneumoniae ranked third as the cause of all community-acquired bacterial meningitis, followed by S. pneumoniae and Staphylococcus aureus (Moon et al., 2010). This observation suggests that K. pneumoniae is also a significant cause of meningitis in South
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Korea. Since S. pneumoniae meningitis (SPM) is the best known type of bacterial meningitis, we speculated that important characteristics of KPM may emerge through a comparison with SPM. Therefore, using patients with community-acquired SPM (CA-SPM) as controls, we characterized the clinical and laboratory features of community-acquired KPM (CA-KPM) in adult patients in our current study. 2. Materials and methods 2.1. Patients This multicenter retrospective cohort study involved patients from 8 general hospitals within the Republic of Korea. Using our institutional clinical microbiology computerized databases, all patients whose cerebrospinal fluid (CSF) culture yielded K. pneumoniae or S. pneumoniae between January 1997 and March 2013 were identified. Among these cases, adult patients (≥16 years old) with clinical meningitis acquired from the community were included in the analysis. 2.2. Data collection Clinical information including patient demographics, underlying disease and medical conditions, clinical manifestations, initial laboratory results including CSF profiles, results of an antimicrobial susceptibility test, and the prescribed antimicrobial therapy was obtained from the patients' medical records. The outcomes assessed included the length of intensive care unit (ICU) stay, the length of hospital stay, mortality, and the presence of neurologic sequelae at discharge. Microbiologic identification and antimicrobial susceptibility tests were performed using various automated systems in each hospital. The study was approved by each respective hospital institutional review board, and the requirement for informed consent was waived due to the retrospective nature of the analysis. 2.3. Definitions Bacterial meningitis was diagnosed if all of the following criteria applied: i) isolation of K. pneumoniae or S. pneumoniae in 1 or more CSF cultures; ii) typical CSF findings including pleocytosis, decreased glucose level, and increased protein concentration; and iii) clinical manifestations including fever, change in mental status, and meningismus (Lu et al., 2002). Community-acquired meningitis was defined as meningitis that occurred within 48 hours of admission without a prior history of hospital admission or neurosurgical treatment within the previous year (Moon et al., 2010). Patients with risk factors for healthcareassociated infection and those with indwelling foreign devices, such as ventriculoperitoneal shunts, or those meeting the criteria for a nosocomial infection according to the CDC criteria were excluded (Garner et al., 1988). Focal neurologic signs included dilated nonreactive pupils, abnormalities of ocular motility, abnormal visual fields, gaze palsy, and arm or leg drift (Tunkel et al., 2004). Appropriate antimicrobial therapy was defined as the administration of 1 or more antimicrobial agents shown to be effective against bacterial pathogens in susceptibility tests and capable of passing through the blood–brain barrier at appreciable levels (Lu et al., 2002). 2.4. Statistical analysis Data were analyzed using IBM SPSS for Windows (version 20.0; SPSS, Chicago, IL, USA). Results were expressed as the median (interquartile range [IQR]). Either the chi-square test or Fisher's exact test was used to compare categorical variables, and the Student's t test or the Mann–Whitney U test was used to compare continuous variables, as appropriate. A P value of less than 0.05 was considered statistically significant. Survival curves for patients with CA-KPM and
Table 1 Demographic features and predisposing conditions of the 83 study patients with CA-KPM or CA-SPM.
Sex, male, n (%) Age, median years (range) Underlying diseases, n (%) Diabetes mellitus Alcoholism Solid tumor Liver cirrhosis Sinusitis Chronic otitis media Chronic obstructive pulmonary disease Congestive heart failure Hematologic malignancy
CA-KPM
CA-SPM
n = 27
n = 56
P value
All
15 (55.6) 59 (22–84)
31 (55.4) 59 (16–98)
0.99 0.23
46 (55.4) 59 (16–98)
13 (48.1) 6 (22.2) 4 (14.8) 6 (22.2) 0 (0.0) 1 (3.7) 0 (0.0)
12 (21.4) 5 (8.9) 6 (10.7) 3 (5.4) 4 (7.1) 3 (5.4) 3 (5.4)
0.01 0.10 0.72 0.05 0.30 1.00 0.55
25 (30.1) 11 (13.3) 10 (12.0) 9 (10.8) 4 (4.8) 4 (4.8) 3 (3.6)
0 (0.0) 0 (0.0)
2 (3.6) 1 (1.8)
1.00 1.00
2 (2.4) 1 (1.2)
n = 83
CA-SPM were prepared according to the Kaplan–Meier method. The log-rank test was used to determine significance between the 2 survival curves. 3. Results 3.1. Patient characteristics A total of 83 adult patients were identified with community-acquired meningitis confirmed by a positive CSF culture for K. pneumoniae or S. pneumoniae. Twenty-seven (32.5%) patients had CA-KPM, and 56 (67.5%) patients had CA-SPM. During the study period, 3873 patients had community-acquired K. pneumoniae bacteremia, 716 patients had community-acquired S. pneumoniae bacteremia, and 1013 patients had community-acquired K. pneumoniae liver abscess. The demographic characteristics and underlying conditions of these patients are summarized in Table 1. Men accounted for 55.4% of all patients, and the median age of both groups was 59 years (range, 16–98 years). All patients were Korean, except for 1 Japanese man. When compared to the CA-SPM group, diabetes mellitus (CA-KPM, 48.1% versus CA-SPM, 21.4%, P = 0.01) and liver cirrhosis (CA-KPM, 22.2% versus CA-SPM, 5.4%, P = 0.05) were more common in the CA-KPM group. Chronic alcoholism tended to be more common in patients with CA-KPM (22.2% versus 8.9%, P = 0.10). 3.2. Clinical manifestations, initial laboratory findings, and CSF profiles The clinical manifestations and laboratory data for the study patients are summarized in Table 2. Fever (CA-KPM, 85.2% versus CA-SPM, 75.0%, P = 0.29) and headache (CA-KPM, 59.3% versus CA-SPM, 75.5%, P = 0.14) were common symptoms in both groups. When compared to the CA-SPM group, concomitant extrameningeal infection was more common in the CA-KPM group (40.7% versus 7.1%, P = 0.001). Of 11 CA-SPM patients who had an extrameningeal infection, 9 had concomitant pneumonia, 4 had a liver abscess, 2 had endophthalmitis, and 1 had a brain abscess. Three patients had 2 concomitant extrameningeal infections, and 1 patient had 3 concomitant extrameningeal infections. More patients initially presented with septic shock (44.4% versus 8.9%, P b 0.001) and comatose mental status (40.7% versus 12.5%, P = 0.01) in the CA-KPM group. Similarly, the initial median Glasgow Coma Scale score was significantly lower in the CA-KPM group (7 [IQR, 3–15] versus 9 [IQR, 3–15]; P = 0.01). Concomitant bacteremia was present in 65.4% of the CA-KPM group versus 43.6% of the CA-SPM group, respectively (P = 0.07). Concomitant bacteriuria was also significantly more common in the CA-KPM group than the CA-SPM group (50% versus 8.1%, P b 0.001). Neither the median value of total CSF white blood cell (WBC) counts and polymorphonuclear cell counts, nor CSF protein and glucose level
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Table 2 Initial clinical and laboratory characteristics of patients with CA-KPM and CA-SPM.
Clinical manifestation Duration of symptoms before CSF tapping, median days (IQR) Fever, n (%) Neck stiffness, n (%) Headache, n (%) Nausea/vomiting, n (%) Seizure, n (%) Focal neurologic deficit, n (%) Extrameningeal infection, n (%)a Pneumonia Liver abscess Endophthalmitis Brain abscess Septic shock Concomitant bacteremia, n (%) Concomitant bacteriuria, n (%) Initial consciousness level, n (%) Alert Drowsy or stupor Comatose Initial GCS score, median value (range) CSF finding WBC(/μL), median value (IQR) Polymorphonucelar cell count (%), median value (IQR) Protein (mg/dL), median value (IQR) Glucose (mg/dL), median value (IQR) CSF/serum glucose ratio, median value (IQR) Gram stain positivity, n (%) Peripheral blood, complete blood cell count, and chemical test, median value (IQR) White blood cell (/μL) Platelet (/μL) C-reactive protein concentration (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Bilirubin total (mg/dL)
CA-KPM
CA-SPM
n = 27
n = 56
2 (1–5) 23 (85.2) 16/23 (69.6) 16 (59.3) 12 (44.4) 6 (22.2) 5 (18.5) 11 (40.7) 9 (33.3) 4 (14.8) 2 (7.4) 1 (3.7) 12 (44.4) 17/26 (65.4) 11/22 (50.0) 3 (11.1) 8 (48.1) 10 (40.7) 7 (3–15) 7680 (930–25,600) 92 (84–96) 550.0 (286.0–1037.0) 8 (2–47) 0.03 (0.01–0.24) 18 (66.7) 10,110 (5,400–14,100) 54,000 (24,000–158,000) 20.6 (5.9–28.8) 22 (11–38) 1.2 (0.8–1.7) 1.7 (1.3–4.8)
2 (1–5) 42 (75.0) 39/51 (76.5) 40/53 (75.5) 33 (58.9) 10/54 (18.5) 9 (16.1) 4 (7.1) 2 (3.6) 0 (0.0) 0 (0.0) 2 (3.6) 5 (8.9) 24/55 (43.6) 3/37 (8.1) 11 (19.6) 38 (67.9) 7 (12.5) 9 (3–15) 3245 (903–8448) 93 (84–97) 572.8 (270.0–732.0) 4 (1–17) 0.02 (0.01–0.07) 41/55 (74.5) 16,600 (11,863–21,740) 208,000 (151,250–246,500) 22.4 (11.0–27.0) 17 (12–21) 0.9 (0.7–1.1) 0.9 (0.6–1.4)
P value
All n = 83
0.92 0.29 0.53 0.14 0.22 0.69 0.76 0.001 b0.001 0.007 0.083 1.000 b0.001 0.07 b0.001 Ref 0.03 0.01 0.01 0.15 0.41 0.91 0.10 0.13 0.50 b0.001 b0.001 0.66 0.06 0.04 b0.001
2 (1–5) 65 (78.3) 55/74 (74.3) 56/80 (70.0) 45 (54.2) 16/81 (19.8) 14 (16.9) 15 (18.1) 11 (13.3) 4 (4.8) 2 (2.4) 3 (3.6) 17 (20.5) 41/81 (50.6) 14/59 (23.7) 14 (16.9) 51 (61.4) 18 (21.7) 9 (3–15) 3250 (910–10,630) 93 (84–96) 561.7 (276.0–753.8) 6 (10–29) 0.02 (0.01–0.10) 59/82 (72.0) 14,200 (9,840–20,040) 176,000 (69,000–237,000) 22.2 (9.7–27.6) 17 (12–23) 0.9 (0.7–1.3) 1.1 (0.7–2.0)
GCS = Glasgow Coma Scale. a Two patients had pneumonia and liver abscess; 1 patient had liver abscess and endophthalmitis; and 1 patient had pneumonia, liver abscess, and endophthalmitis, concomitantly.
differed significantly between the groups, whereas median WBC counts in peripheral blood (CA-KPM, 10,110/μL versus CA-SPM, 16,600/μL, P b 0.001) and platelet counts (CA-KPM, 54,000/μL versus CA-SPM, 208,000/μL, P b 0.001) were significantly lower in the CA-KPM group.
3.3. Course of illness, treatment, and outcomes The clinical course and outcomes of the study patients are provided in Table 3. ICU admission was required frequently in both groups (CA-
Table 3 Treatments and outcomes in study patients with CA-KPM and CA-SPM.
Course of illness ICU admission, n (%) Mechanical ventilation, n (%) Length of the hospital stay in surviving patients, median days (IQR) Length of the ICU stay in surviving patients, median days (IQR) Treatment, n (%) Initial empirical therapy Vancomycin plus ceftriaxone or cefotaxime Appropriate antimicrobial therapy within 24 hours Definitive therapya Third-generation cephalosporin Fluoroquinolone Penicillin G Carbapenem Other antibiotics Outcome, n (%) In hospital mortality 1-day mortality 2-day mortality 3-day mortality 7-day mortality 28-day mortality Neurologic sequelae at discharge a b
CA-KPM
CA-SPM
n = 27
n = 56
P value
All n = 83
21 (77.8) 19 (70.4) 31 (12–44) 18 (7–32)
46 (82.1) 13 (23.2) 26 (16–41) 8 (5–15)
0.64 b0.001 0.91 0.18
20 (74.1) 23 (85.2)
48 (85.7) 54 (96.4)
0.23 0.08
68 (81.9) 77 (92.8)
14/19 (73.7) 0 (0) 0 (0) 2/19 (10.5) 3/19 (15.8)b
49/54 (90.7) 2/54 (3.7) 3/54 (5.6) 0 (0) 0 (0)
0.11
63/73 (86.3) 2/73 (2.7) 3/73 (4.1) 2/73 (2.7) 3/73 (4.1)
14 (51.9) 5 (18.5) 8 (29.6) 8 (29.6) 8 (29.6) 12 (44.4) 7/13 (53.8)
8 (14.3) 0 (0) 2 (3.6) 2 (3.6) 5 (8.9) 6 (10.7) 13/48 (27.1)
b0.001 0.003 0.002 0.002 0.02 b0.001 0.10
22 (26.5) 5 (6.0) 10 (12.0) 10 (12.0) 13 (15.7) 18 (21.7) 20/61 (32.8)
Patients who died before their CSF culture were available excluded from the analysis. One patient received cefepime and vancomycin, another patient received both ceftriaxone and moxifloxacin, and the remaining patient received vancomycin.
67 (80.7) 32 (38.6) 26 (16–41) 9 (5–19)
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Fig. 1. Kaplan–Meier survival estimates of overall survival after diagnosis of meningitis in patients with CA-KPM compared to cases of CA-SPM.
KPM, 77.8% versus CA-SPM, 82.1%, P = 0.64), while assisted mechanical ventilation was needed more frequently in the CA-KPM group (70.4% versus 23.2%, P b 0.001). Among the surviving patients, median length of hospital stay (CA-KPM, 31 days [IQR, 12–44] versus CA-SPM, 26 days [IQR, 16–41]; P = 0.91) and median ICU stay (CA-KPM, 18 days [IQR, 7–32] versus CA-SPM, 8 days [IQR, 5–15]; P = 0.18) were not significantly different. Vancomycin plus third-generation cephalosporin (cefotaxime or ceftriaxone) was the most frequently used initial empirical therapy (CA-KPM, 74.1% versus CA-SPM, 85.7%, P = 0.23) in both groups. Appropriateness of initial empirical therapy tended to be lower in the CA-KPM group (85.2% versus 96.4%, P = 0.08). Inhospital mortality (51.9% versus 14.3%, P b 0.001), 1-day mortality (18.5% versus 0%, P = 0.003), 3-day mortality (29.6% versus 3.6%, P = 0.002), 7-day mortality (29.6% versus 8.9%, P = 0.02), and 28-day mortality (44.4% versus 10.7%, P b 0.001) were all significantly higher in the CA-KPM group. Kaplan–Meier survival analysis also showed that patients with CA-KPM had significantly poorer survival than patients with CA-SPM (log-rank P b 0.001; Fig. 1). Neurologic sequelae at discharge tended to be more common in the CA-KPM group than in the CA-SPM group (53.8% [7/13] versus 27.1% [13/48]; P = 0.10). 4. Discussion In our current multicenter study, we investigated the differences in the predisposing factors, clinical manifestations, CSF findings, and clinical outcomes between patients affected by CA-KPM versus CA-SPM. Diabetes mellitus and liver cirrhosis were more frequently comorbid in patients predisposed to infection by CA-KPM. Although CSF findings were indistinguishable between these 2 groups, patients with CA-KPM presented with more severe initial manifestations and more commonly had concomitant extrameningeal foci of infection. Clinical outcomes were also significantly poorer in patients with CA-KPM. To our knowledge, this is the first study to directly compare the clinical features and outcomes of meningitis caused by S. pneumoniae versus K. pneumoniae. The strength of our study design is that all of our patients were “definitive” meningitis cases whose CSF yielded culturable K. pneumoniae or S. pneumoniae. Also, using strict selection criteria for community-acquired infection, we excluded healthcare-associated and hospital-acquired cases including postneurosurgical meningitis. Since the 1980s, invasive liver abscess syndrome has been emerging in the Asian Pacific Rim including Taiwan (Chang and Chou, 1995; Cheng et al., 1991; Liu et al., 1986; Wang et al., 1998), Hong Kong (Lok et al., 2008), Singapore (Yeh et al., 2007), and Republic of Korea (Chung et al., 2007; Chung et al., 2008). This syndrome is characterized by a K. pneumoniae liver abscess with metastatic spread to distant sites (such as the eyes, central nervous system, lungs, prostate, and soft tissues) resulting from bacteremia (Siu et al., 2012). The infection essentially originates from the community, and affected patients are mostly immunocompetent without hepatobiliary disease. An Asian ethnicity,
diabetes mellitus, the presence of rmpA or magA genes, and K1 or K2 capsular serotype have all been reported as strong risk factors for invasive liver abscess syndrome (Fang et al., 2007; Kawai, 2006; Kim et al., 2009; Sheu et al., 2011; Yoon et al., 2014). In our current results, KPM displayed a more significant association with diabetes mellitus, alcoholism, and liver cirrhosis than SPM. Those findings are in accord with the previous results of Taiwanese descriptive studies (Lu et al., 2002; Tang et al., 1997). Neither liver cirrhosis nor alcoholism has been previously reported as a risk factor for invasive liver abscess syndrome by K. pneumoniae. Meningitis appears more frequently in complicated community-dwelling immunocompromised hosts, such as patients with cirrhosis or alcoholism. Our present findings suggest that when a patient with diabetes mellitus or liver cirrhosis exhibits an altered mental status with severe sepsis, clinicians should initially consider the possibility of KPM, which could mimic hepatic encephalopathy. We found in our current investigation that two thirds of our patients with CA-KPM (65.4%) had concurrent bacteremia and more than onethird of these cases (40.7%) had an extrameningeal focus. Since roughly half of our CA-KPM patients (48% [13/27]) did not undergo abdominal computed tomography (CT) for the evaluation of a suspected intraabdominal focus, the actual rate of concomitant extrameningeal infection might be higher than that indicated by our results. Notably, among 8 of our study patients who died within 48 hours of a lumbar puncture, 5 of these cases did not undergo an abdominal CT scan, mainly due to a refractory shock that prevented moving out of the ICU. If CA-KPM is suspected, prompt evaluation for an extrameningeal focus is important because drainage is often necessary for effective treatment of a liver or brain abscess. Delayed treatment of endophthalmitis can also lead to permanent loss of vision. Our current CSF findings were indistinguishable between our 2 study groups. Previous Taiwanese studies have reported that the median values for WBC, protein, and lactate levels in the CSF were significantly higher in KPM patients compared to non-Klebsiella meningitis cases (Tang et al., 1997). However, since there were considerable data overlaps between these 2 groups, those differences were not sufficiently convincing to guide the development of a reliable differential diagnosis in clinical practice. In our current patient subjects, the median values of WBC and platelet counts in peripheral blood were significantly lower in the KPM group. The higher proportion of cirrhotic patients and more frequent incidence of septic shock in the KPM group may be responsible for these findings. These factors also appear to be associated with the higher mortality in the CA-KPM group. Overall inhospital mortality rate of the KPM group in our study (51.9%) is within the range shown in the prior Taiwanese and Singaporean reports (33.3–93.0%) (Fang et al., 2000; Jang et al., 1993; Lee et al., 2004; Lu et al., 2002; Tang et al., 1997). Notably, of 14 deceased patients in our CA-KPM group, 8 patients (57.1%) died within 2 days of the diagnosis of bacterial meningitis. This suggests that a high degree of suspicion by the attending physician is crucial for the early diagnosis and optimal management of CA-KPM.
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Our present study has several limitations to note. First, the retrospective nature of this investigation limited our ability to collect a detailed medical history of our patients. Certain underlying diseases such as liver cirrhosis or alcoholism may have been underestimated, especially in the cases who first visited our hospitals. Second, the number of patients we analyzed was relatively small. It may have affected the statistical significance of the results. For example, although the proportion of our study patients with neurologic sequelae at discharge was almost twice as high in the CA-KPM group as in the CA-SPM group, this was not statistically significant. Finally, since bacterial isolates were not available, we could not assess the hypermucoviscous phenotype, K antigen serotype, or the presence of magA and rmpA, which are pathogenic factors known to be prevalent in invasive K. pneumoniae syndrome. In conclusion, compared to CA-SPM, CA-KPM is more commonly associated with diabetes mellitus and liver cirrhosis, a higher incidence of concomitant extrameningeal infections, and generally poorer outcomes. Conflict of interest The authors have no potential conflicts of interest to report. Acknowledgment The study was supported by a grant from the Asan Institute of Life Sciences (grant 2014-389). References Cabellos C, Verdaguer R, Olmo M, Fernandez-Sabe N, Cisnal M, Ariza J, et al. Communityacquired bacterial meningitis in elderly patients: experience over 30 years. Medicine (Baltimore) 2009;88:115–9. Chan YC, Wilder-Smith A, Ong BK, Kumarasinghe G, Wilder-Smith E. Adult community acquired bacterial meningitis in a Singaporean teaching hospital. A seven-year overview (1993–2000). Singapore Med J 2002;43:632–6. Chang FY, Chou MY. Comparison of pyogenic liver abscesses caused by Klebsiella pneumoniae and non-K. pneumoniae pathogens. J Formos Med Assoc 1995;94: 232–7. Chang WN, Lu CH, Huang CR, Tsai NW, Chuang YC, Chang CC, et al. Changing epidemiology of adult bacterial meningitis in southern Taiwan: a hospital-based study. Infection 2008;36:15–22. Cheng DL, Liu YC, Yen MY, Liu CY, Wang RS. Septic metastatic lesions of pyogenic liver abscess. Their association with Klebsiella pneumoniae bacteremia in diabetic patients. Arch Intern Med 1991;151:1557–9. Chung DR, Lee SS, Lee HR, Kim HB, Choi HJ, Eom JS, et al. Emerging invasive liver abscess caused by K1 serotype Klebsiella pneumoniae in Korea. J Infect 2007; 54:578–83. Chung DR, Lee HR, Lee SS, Kim SW, Chang HH, Jung SI, et al. Evidence for clonal dissemination of the serotype K1 Klebsiella pneumoniae strain causing invasive liver abscesses in Korea. J Clin Microbiol 2008;46:4061–3. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness Jr VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328:21–8. Fang CT, Chen YC, Chang SC, Sau WY, Luh KT. Klebsiella pneumoniae meningitis: timing of antimicrobial therapy and prognosis. QJM 2000;93:45–53.
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Fang CT, Lai SY, Yi WC, Hsueh PR, Liu KL, Chang SC. Klebsiella pneumoniae genotype K1: an emerging pathogen that causes septic ocular or central nervous system complications from pyogenic liver abscess. Clin Infect Dis 2007;45:284–93. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128–40. Hui AC, Ng KC, Tong PY, Mok V, Chow KM, Wu A, et al. Bacterial meningitis in Hong Kong: 10-years' experience. Clin Neurol Neurosurg 2005;107:366–70. Hussein AS, Shafran SD. Acute bacterial meningitis in adults. A 12-year review. Medicine (Baltimore) 2000;79:360–8. Jang TN, Wang FD, Wang LS, Yu KW, Liu CY. Gram-negative bacillary meningitis in adults: a recent six-year experience. J Formos Med Assoc 1993;92:540–6. Kawai T. Hypermucoviscosity: an extremely sticky phenotype of Klebsiella pneumoniae associated with emerging destructive tissue abscess syndrome. Clin Infect Dis 2006; 42:1359–61. Kim JK, Chung DR, Wie SH, Yoo JH, Park SW. Risk factor analysis of invasive liver abscess caused by the K1 serotype Klebsiella pneumoniae. Eur J Clin Microbiol Infect Dis 2009;28:109–11. Lee PY, Chang WN, Lu CH, Lin MW, Cheng BC, Chien CC, et al. Clinical features and in vitro antimicrobial susceptibilities of community-acquired Klebsiella pneumoniae meningitis in Taiwan. J Antimicrob Chemother 2003;51:957–62. Lee HL, Lee HC, Guo HR, Ko WC, Chen KW. Clinical significance and mechanism of gas formation of pyogenic liver abscess due to Klebsiella pneumoniae. J Clin Microbiol 2004; 42:2783–5. Liu YC, Cheng DL, Lin CL. Klebsiella pneumoniae liver abscess associated with septic endophthalmitis. Arch Intern Med 1986;146:1913–6. Lok KH, Li KF, Li KK, Szeto ML. Pyogenic liver abscess: clinical profile, microbiological characteristics, and management in a Hong Kong hospital. J Microbiol Immunol Infect 2008;41:483–90. Lu CH, Chang WN, Chang HW. Adult bacterial meningitis in Southern Taiwan: epidemiologic trend and prognostic factors. J Neurol Sci 2000;182:36–44. Lu CH, Chang WN, Chang HW. Klebsiella meningitis in adults: clinical features, prognostic factors and therapeutic outcomes. J Neurol Sci 2002;9:533–8. Moon SY, Chung DR, Kim SW, Chang HH, Lee H, Jung DS, et al. Changing etiology of community-acquired bacterial meningitis in adults: a nationwide multicenter study in Korea. Eur J Clin Microbiol Infect Dis 2010;29:793–800. Okike IO, Ribeiro S, Ramsay ME, Heath PT, Sharland M, Ladhani SN. Trends in bacterial, mycobacterial, and fungal meningitis in England and Wales 2004-11: an observational study. Lancet Infect Dis 2014;14:301–7. Sheu SJ, Kung YH, Wu TT, Chang FP, Horng YH. Risk factors for endogenous endophthalmitis secondary to klebsiella pneumoniae liver abscess: 20-year experience in Southern Taiwan. Retina 2011;31:2026–31. Siu LK, Yeh KM, Lin JC, Fung CP, Chang FY. Klebsiella pneumoniae liver abscess: a new invasive syndrome. Lancet Infect Dis 2012;12:881–7. Tang LM, Chen ST, Hsu WC, Chen CM. Klebsiella meningitis in Taiwan: an overview. Epidemiol Infect 1997;119:135–42. Tang LM, Chen ST, Hsu WC, Lyu RK. Acute bacterial meningitis in adults: a hospital-based epidemiological study. QJM 1999;92:719–25. Thigpen MC, Whitney CG, Messonnier NE, Zell ER, Lynfield R, Hadler JL, et al. Bacterial meningitis in the United States, 1998–2007. N Engl J Med 2011;364:2016–25. Thornorethardottir A, Erlendsdottir H, Sigurethardottir B, Harethardottir H, Reynisson IK, Gottfreethsson M, et al. Bacterial meningitis in adults in Iceland, 1995–2010. Scand J Infect Dis 2014;46:354–60. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267–84. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012;380:1693–702. Wang JH, Liu YC, Lee SS, Yen MY, Chen YS, Wang JH, et al. Primary liver abscess due to Klebsiella pneumoniae in Taiwan. Clin Infect Dis 1998;26:1434–8. Yeh KM, Kurup A, Siu LK, Koh YL, Fung CP, Lin JC, et al. Capsular serotype K1 or K2, rather than magA and rmpA, is a major virulence determinant for Klebsiella pneumoniae liver abscess in Singapore and Taiwan. J Clin Microbiol 2007;45:466–71. Yoon JH, Kim YJ, Jun YH, Kim SI, Kang JY, Suk KT, et al. Liver abscess due to Klebsiella pneumoniae: risk factors for metastatic infection. Scand J Infect Dis 2014;46:21–6.
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Comparison of the clinical characteristics and outcomes of Klebsiella pneumoniae and Streptococcus pneumoniae meningitis Jiwon Jung a, Ki-Ho Park b, Seong Yeon Park c, Eun Hee Song d, Eun Jung Lee e, Seong-Ho Choi f, Eun Ju Choo g, Yee Gyung Kwak h, Heungsup Sung i, Sung-Han Kim a, Sang-Oh Lee a, Mi-Na Kim i, Yang Soo Kim a, Jun Hee Woo a, Sang-Ho Choi a,⁎ a
Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, University of Ulsan, Seoul, Republic of Korea Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, Kyung Hee University School of Medicine, Seoul, Republic of Korea c Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Republic of Korea d Department of Infectious Diseases, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Republic of Korea e Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Republic of Korea f Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea g Division of Infectious Diseases, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea h Division of Infectious Diseases, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Goyang, Republic of Korea i Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 22 August 2014 Received in revised form 11 February 2015 Accepted 14 February 2015 Available online 20 February 2015 Keywords: Klebsiella pneumoniae Streptococcus pneumoniae Meningitis
a b s t r a c t This multicenter, retrospective cohort study compared the clinical characteristics and outcomes of communityacquired Klebsiella pneumoniae meningitis (CA-KPM) with those of community-acquired Streptococcus pneumoniae meningitis (CA-SPM). Eighty-three adult patients, 27 with CA-KPM and 56 with CA-SPM, were included. Diabetes mellitus (48.1% versus 21.4%; P = 0.01) and liver cirrhosis (22.2% versus 5.4%; P = 0.05) were more commonly associated with CA-KPM. Comatose mental status (40.7% versus 12.5%; P = 0.01), septic shock (44.4% versus 8.9%; P b 0.001), and concomitant extrameningeal infections (40.7% versus 7.1%; P = 0.001) were also more common in the CA-KPM group. The 28-day mortality (44.4% versus 10.7%; P b 0.001) and inhospital mortality (51.9% versus 14.3%; P b 0.001) were higher in the CA-KPM group. In conclusion, diabetes mellitus and liver cirrhosis are more common in the CA-KPM patients who were also more likely to present with severe manifestations and poor outcomes. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Community-acquired bacterial meningitis still remains one of the most feared infectious diseases, as it is often associated with substantial mortality and long-term neurologic complications. In adult patients, the most common pathogens for meningitis are Streptococcus pneumoniae and Neisseria meningitidis (Durand et al., 1993; Hussein and Shafran, 2000; Okike et al., 2014; Thigpen et al., 2011). The aerobic gramnegative bacilli are known as the significant pathogen to cause community-acquired meningitis in immunocompromised patients or in individuals older than 50 years (van de Beek et al., 2012). Epidemiologic trends between western and eastern countries appear to differ in the percentage contributions of gram-negative bacilli and the major species inducing meningitis. In surveys from western countries, aerobic gram-negative bacilli account for 4.3–12.3% of the pathogens causing bacterial meningitis (Cabellos et al., 2009; Durand et al., 1993; Hussein and Shafran, 2000; Okike et al., 2014; Thornorethardottir et al., 2014), with Escherichia coli as the leading pathogen among them. In Asia, the ⁎ Corresponding author. Tel.: +82-2-3010-3304; fax: +82-2-3010-6970. E-mail address: [email protected] (S.-H. Choi). http://dx.doi.org/10.1016/j.diagmicrobio.2015.02.006 0732-8893/© 2015 Elsevier Inc. All rights reserved.
overall incidence of meningitis caused by gram-negative bacilli is 7.6–28.8% (Chan et al., 2002; Chang et al., 2008; Hui et al., 2005; Lu et al., 2000; Moon et al., 2010; Tang et al., 1999), which is about twice the incidence in the western countries, and among the implicated gram-negative pathogens, Klebsiella pneumoniae is the most common. Several studies by Taiwanese researchers have reported that K. pneumoniae meningitis (KPM) is often associated with male gender, diabetes mellitus, alcoholism, and liver cirrhosis (Lee et al., 2003; Lu et al., 2002; Tang et al., 1997). KPM-associated mortality in these reports has a wide range (33–93%) (Fang et al., 2000; Jang et al., 1993; Lee et al., 2004; Lu et al., 2002; Tang et al., 1997). However, these earlier studies have several limitations. First, they do not distinguish between acquisition sites; community-acquired and hospital-acquired cases, including postneurosurgical meningitis, are often grouped together (Lu et al., 2002; Tang et al., 1997). Second, one of these studies didn't distinguish between meningitis in adults and children (Tang et al., 1997). Finally, most previous studies fail to include adequate controls. In a recent Korean multicenter analysis, K. pneumoniae ranked third as the cause of all community-acquired bacterial meningitis, followed by S. pneumoniae and Staphylococcus aureus (Moon et al., 2010). This observation suggests that K. pneumoniae is also a significant cause of meningitis in South
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Korea. Since S. pneumoniae meningitis (SPM) is the best known type of bacterial meningitis, we speculated that important characteristics of KPM may emerge through a comparison with SPM. Therefore, using patients with community-acquired SPM (CA-SPM) as controls, we characterized the clinical and laboratory features of community-acquired KPM (CA-KPM) in adult patients in our current study. 2. Materials and methods 2.1. Patients This multicenter retrospective cohort study involved patients from 8 general hospitals within the Republic of Korea. Using our institutional clinical microbiology computerized databases, all patients whose cerebrospinal fluid (CSF) culture yielded K. pneumoniae or S. pneumoniae between January 1997 and March 2013 were identified. Among these cases, adult patients (≥16 years old) with clinical meningitis acquired from the community were included in the analysis. 2.2. Data collection Clinical information including patient demographics, underlying disease and medical conditions, clinical manifestations, initial laboratory results including CSF profiles, results of an antimicrobial susceptibility test, and the prescribed antimicrobial therapy was obtained from the patients' medical records. The outcomes assessed included the length of intensive care unit (ICU) stay, the length of hospital stay, mortality, and the presence of neurologic sequelae at discharge. Microbiologic identification and antimicrobial susceptibility tests were performed using various automated systems in each hospital. The study was approved by each respective hospital institutional review board, and the requirement for informed consent was waived due to the retrospective nature of the analysis. 2.3. Definitions Bacterial meningitis was diagnosed if all of the following criteria applied: i) isolation of K. pneumoniae or S. pneumoniae in 1 or more CSF cultures; ii) typical CSF findings including pleocytosis, decreased glucose level, and increased protein concentration; and iii) clinical manifestations including fever, change in mental status, and meningismus (Lu et al., 2002). Community-acquired meningitis was defined as meningitis that occurred within 48 hours of admission without a prior history of hospital admission or neurosurgical treatment within the previous year (Moon et al., 2010). Patients with risk factors for healthcareassociated infection and those with indwelling foreign devices, such as ventriculoperitoneal shunts, or those meeting the criteria for a nosocomial infection according to the CDC criteria were excluded (Garner et al., 1988). Focal neurologic signs included dilated nonreactive pupils, abnormalities of ocular motility, abnormal visual fields, gaze palsy, and arm or leg drift (Tunkel et al., 2004). Appropriate antimicrobial therapy was defined as the administration of 1 or more antimicrobial agents shown to be effective against bacterial pathogens in susceptibility tests and capable of passing through the blood–brain barrier at appreciable levels (Lu et al., 2002). 2.4. Statistical analysis Data were analyzed using IBM SPSS for Windows (version 20.0; SPSS, Chicago, IL, USA). Results were expressed as the median (interquartile range [IQR]). Either the chi-square test or Fisher's exact test was used to compare categorical variables, and the Student's t test or the Mann–Whitney U test was used to compare continuous variables, as appropriate. A P value of less than 0.05 was considered statistically significant. Survival curves for patients with CA-KPM and
Table 1 Demographic features and predisposing conditions of the 83 study patients with CA-KPM or CA-SPM.
Sex, male, n (%) Age, median years (range) Underlying diseases, n (%) Diabetes mellitus Alcoholism Solid tumor Liver cirrhosis Sinusitis Chronic otitis media Chronic obstructive pulmonary disease Congestive heart failure Hematologic malignancy
CA-KPM
CA-SPM
n = 27
n = 56
P value
All
15 (55.6) 59 (22–84)
31 (55.4) 59 (16–98)
0.99 0.23
46 (55.4) 59 (16–98)
13 (48.1) 6 (22.2) 4 (14.8) 6 (22.2) 0 (0.0) 1 (3.7) 0 (0.0)
12 (21.4) 5 (8.9) 6 (10.7) 3 (5.4) 4 (7.1) 3 (5.4) 3 (5.4)
0.01 0.10 0.72 0.05 0.30 1.00 0.55
25 (30.1) 11 (13.3) 10 (12.0) 9 (10.8) 4 (4.8) 4 (4.8) 3 (3.6)
0 (0.0) 0 (0.0)
2 (3.6) 1 (1.8)
1.00 1.00
2 (2.4) 1 (1.2)
n = 83
CA-SPM were prepared according to the Kaplan–Meier method. The log-rank test was used to determine significance between the 2 survival curves. 3. Results 3.1. Patient characteristics A total of 83 adult patients were identified with community-acquired meningitis confirmed by a positive CSF culture for K. pneumoniae or S. pneumoniae. Twenty-seven (32.5%) patients had CA-KPM, and 56 (67.5%) patients had CA-SPM. During the study period, 3873 patients had community-acquired K. pneumoniae bacteremia, 716 patients had community-acquired S. pneumoniae bacteremia, and 1013 patients had community-acquired K. pneumoniae liver abscess. The demographic characteristics and underlying conditions of these patients are summarized in Table 1. Men accounted for 55.4% of all patients, and the median age of both groups was 59 years (range, 16–98 years). All patients were Korean, except for 1 Japanese man. When compared to the CA-SPM group, diabetes mellitus (CA-KPM, 48.1% versus CA-SPM, 21.4%, P = 0.01) and liver cirrhosis (CA-KPM, 22.2% versus CA-SPM, 5.4%, P = 0.05) were more common in the CA-KPM group. Chronic alcoholism tended to be more common in patients with CA-KPM (22.2% versus 8.9%, P = 0.10). 3.2. Clinical manifestations, initial laboratory findings, and CSF profiles The clinical manifestations and laboratory data for the study patients are summarized in Table 2. Fever (CA-KPM, 85.2% versus CA-SPM, 75.0%, P = 0.29) and headache (CA-KPM, 59.3% versus CA-SPM, 75.5%, P = 0.14) were common symptoms in both groups. When compared to the CA-SPM group, concomitant extrameningeal infection was more common in the CA-KPM group (40.7% versus 7.1%, P = 0.001). Of 11 CA-SPM patients who had an extrameningeal infection, 9 had concomitant pneumonia, 4 had a liver abscess, 2 had endophthalmitis, and 1 had a brain abscess. Three patients had 2 concomitant extrameningeal infections, and 1 patient had 3 concomitant extrameningeal infections. More patients initially presented with septic shock (44.4% versus 8.9%, P b 0.001) and comatose mental status (40.7% versus 12.5%, P = 0.01) in the CA-KPM group. Similarly, the initial median Glasgow Coma Scale score was significantly lower in the CA-KPM group (7 [IQR, 3–15] versus 9 [IQR, 3–15]; P = 0.01). Concomitant bacteremia was present in 65.4% of the CA-KPM group versus 43.6% of the CA-SPM group, respectively (P = 0.07). Concomitant bacteriuria was also significantly more common in the CA-KPM group than the CA-SPM group (50% versus 8.1%, P b 0.001). Neither the median value of total CSF white blood cell (WBC) counts and polymorphonuclear cell counts, nor CSF protein and glucose level
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Table 2 Initial clinical and laboratory characteristics of patients with CA-KPM and CA-SPM.
Clinical manifestation Duration of symptoms before CSF tapping, median days (IQR) Fever, n (%) Neck stiffness, n (%) Headache, n (%) Nausea/vomiting, n (%) Seizure, n (%) Focal neurologic deficit, n (%) Extrameningeal infection, n (%)a Pneumonia Liver abscess Endophthalmitis Brain abscess Septic shock Concomitant bacteremia, n (%) Concomitant bacteriuria, n (%) Initial consciousness level, n (%) Alert Drowsy or stupor Comatose Initial GCS score, median value (range) CSF finding WBC(/μL), median value (IQR) Polymorphonucelar cell count (%), median value (IQR) Protein (mg/dL), median value (IQR) Glucose (mg/dL), median value (IQR) CSF/serum glucose ratio, median value (IQR) Gram stain positivity, n (%) Peripheral blood, complete blood cell count, and chemical test, median value (IQR) White blood cell (/μL) Platelet (/μL) C-reactive protein concentration (mg/dL) Blood urea nitrogen (mg/dL) Creatinine (mg/dL) Bilirubin total (mg/dL)
CA-KPM
CA-SPM
n = 27
n = 56
2 (1–5) 23 (85.2) 16/23 (69.6) 16 (59.3) 12 (44.4) 6 (22.2) 5 (18.5) 11 (40.7) 9 (33.3) 4 (14.8) 2 (7.4) 1 (3.7) 12 (44.4) 17/26 (65.4) 11/22 (50.0) 3 (11.1) 8 (48.1) 10 (40.7) 7 (3–15) 7680 (930–25,600) 92 (84–96) 550.0 (286.0–1037.0) 8 (2–47) 0.03 (0.01–0.24) 18 (66.7) 10,110 (5,400–14,100) 54,000 (24,000–158,000) 20.6 (5.9–28.8) 22 (11–38) 1.2 (0.8–1.7) 1.7 (1.3–4.8)
2 (1–5) 42 (75.0) 39/51 (76.5) 40/53 (75.5) 33 (58.9) 10/54 (18.5) 9 (16.1) 4 (7.1) 2 (3.6) 0 (0.0) 0 (0.0) 2 (3.6) 5 (8.9) 24/55 (43.6) 3/37 (8.1) 11 (19.6) 38 (67.9) 7 (12.5) 9 (3–15) 3245 (903–8448) 93 (84–97) 572.8 (270.0–732.0) 4 (1–17) 0.02 (0.01–0.07) 41/55 (74.5) 16,600 (11,863–21,740) 208,000 (151,250–246,500) 22.4 (11.0–27.0) 17 (12–21) 0.9 (0.7–1.1) 0.9 (0.6–1.4)
P value
All n = 83
0.92 0.29 0.53 0.14 0.22 0.69 0.76 0.001 b0.001 0.007 0.083 1.000 b0.001 0.07 b0.001 Ref 0.03 0.01 0.01 0.15 0.41 0.91 0.10 0.13 0.50 b0.001 b0.001 0.66 0.06 0.04 b0.001
2 (1–5) 65 (78.3) 55/74 (74.3) 56/80 (70.0) 45 (54.2) 16/81 (19.8) 14 (16.9) 15 (18.1) 11 (13.3) 4 (4.8) 2 (2.4) 3 (3.6) 17 (20.5) 41/81 (50.6) 14/59 (23.7) 14 (16.9) 51 (61.4) 18 (21.7) 9 (3–15) 3250 (910–10,630) 93 (84–96) 561.7 (276.0–753.8) 6 (10–29) 0.02 (0.01–0.10) 59/82 (72.0) 14,200 (9,840–20,040) 176,000 (69,000–237,000) 22.2 (9.7–27.6) 17 (12–23) 0.9 (0.7–1.3) 1.1 (0.7–2.0)
GCS = Glasgow Coma Scale. a Two patients had pneumonia and liver abscess; 1 patient had liver abscess and endophthalmitis; and 1 patient had pneumonia, liver abscess, and endophthalmitis, concomitantly.
differed significantly between the groups, whereas median WBC counts in peripheral blood (CA-KPM, 10,110/μL versus CA-SPM, 16,600/μL, P b 0.001) and platelet counts (CA-KPM, 54,000/μL versus CA-SPM, 208,000/μL, P b 0.001) were significantly lower in the CA-KPM group.
3.3. Course of illness, treatment, and outcomes The clinical course and outcomes of the study patients are provided in Table 3. ICU admission was required frequently in both groups (CA-
Table 3 Treatments and outcomes in study patients with CA-KPM and CA-SPM.
Course of illness ICU admission, n (%) Mechanical ventilation, n (%) Length of the hospital stay in surviving patients, median days (IQR) Length of the ICU stay in surviving patients, median days (IQR) Treatment, n (%) Initial empirical therapy Vancomycin plus ceftriaxone or cefotaxime Appropriate antimicrobial therapy within 24 hours Definitive therapya Third-generation cephalosporin Fluoroquinolone Penicillin G Carbapenem Other antibiotics Outcome, n (%) In hospital mortality 1-day mortality 2-day mortality 3-day mortality 7-day mortality 28-day mortality Neurologic sequelae at discharge a b
CA-KPM
CA-SPM
n = 27
n = 56
P value
All n = 83
21 (77.8) 19 (70.4) 31 (12–44) 18 (7–32)
46 (82.1) 13 (23.2) 26 (16–41) 8 (5–15)
0.64 b0.001 0.91 0.18
20 (74.1) 23 (85.2)
48 (85.7) 54 (96.4)
0.23 0.08
68 (81.9) 77 (92.8)
14/19 (73.7) 0 (0) 0 (0) 2/19 (10.5) 3/19 (15.8)b
49/54 (90.7) 2/54 (3.7) 3/54 (5.6) 0 (0) 0 (0)
0.11
63/73 (86.3) 2/73 (2.7) 3/73 (4.1) 2/73 (2.7) 3/73 (4.1)
14 (51.9) 5 (18.5) 8 (29.6) 8 (29.6) 8 (29.6) 12 (44.4) 7/13 (53.8)
8 (14.3) 0 (0) 2 (3.6) 2 (3.6) 5 (8.9) 6 (10.7) 13/48 (27.1)
b0.001 0.003 0.002 0.002 0.02 b0.001 0.10
22 (26.5) 5 (6.0) 10 (12.0) 10 (12.0) 13 (15.7) 18 (21.7) 20/61 (32.8)
Patients who died before their CSF culture were available excluded from the analysis. One patient received cefepime and vancomycin, another patient received both ceftriaxone and moxifloxacin, and the remaining patient received vancomycin.
67 (80.7) 32 (38.6) 26 (16–41) 9 (5–19)
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Fig. 1. Kaplan–Meier survival estimates of overall survival after diagnosis of meningitis in patients with CA-KPM compared to cases of CA-SPM.
KPM, 77.8% versus CA-SPM, 82.1%, P = 0.64), while assisted mechanical ventilation was needed more frequently in the CA-KPM group (70.4% versus 23.2%, P b 0.001). Among the surviving patients, median length of hospital stay (CA-KPM, 31 days [IQR, 12–44] versus CA-SPM, 26 days [IQR, 16–41]; P = 0.91) and median ICU stay (CA-KPM, 18 days [IQR, 7–32] versus CA-SPM, 8 days [IQR, 5–15]; P = 0.18) were not significantly different. Vancomycin plus third-generation cephalosporin (cefotaxime or ceftriaxone) was the most frequently used initial empirical therapy (CA-KPM, 74.1% versus CA-SPM, 85.7%, P = 0.23) in both groups. Appropriateness of initial empirical therapy tended to be lower in the CA-KPM group (85.2% versus 96.4%, P = 0.08). Inhospital mortality (51.9% versus 14.3%, P b 0.001), 1-day mortality (18.5% versus 0%, P = 0.003), 3-day mortality (29.6% versus 3.6%, P = 0.002), 7-day mortality (29.6% versus 8.9%, P = 0.02), and 28-day mortality (44.4% versus 10.7%, P b 0.001) were all significantly higher in the CA-KPM group. Kaplan–Meier survival analysis also showed that patients with CA-KPM had significantly poorer survival than patients with CA-SPM (log-rank P b 0.001; Fig. 1). Neurologic sequelae at discharge tended to be more common in the CA-KPM group than in the CA-SPM group (53.8% [7/13] versus 27.1% [13/48]; P = 0.10). 4. Discussion In our current multicenter study, we investigated the differences in the predisposing factors, clinical manifestations, CSF findings, and clinical outcomes between patients affected by CA-KPM versus CA-SPM. Diabetes mellitus and liver cirrhosis were more frequently comorbid in patients predisposed to infection by CA-KPM. Although CSF findings were indistinguishable between these 2 groups, patients with CA-KPM presented with more severe initial manifestations and more commonly had concomitant extrameningeal foci of infection. Clinical outcomes were also significantly poorer in patients with CA-KPM. To our knowledge, this is the first study to directly compare the clinical features and outcomes of meningitis caused by S. pneumoniae versus K. pneumoniae. The strength of our study design is that all of our patients were “definitive” meningitis cases whose CSF yielded culturable K. pneumoniae or S. pneumoniae. Also, using strict selection criteria for community-acquired infection, we excluded healthcare-associated and hospital-acquired cases including postneurosurgical meningitis. Since the 1980s, invasive liver abscess syndrome has been emerging in the Asian Pacific Rim including Taiwan (Chang and Chou, 1995; Cheng et al., 1991; Liu et al., 1986; Wang et al., 1998), Hong Kong (Lok et al., 2008), Singapore (Yeh et al., 2007), and Republic of Korea (Chung et al., 2007; Chung et al., 2008). This syndrome is characterized by a K. pneumoniae liver abscess with metastatic spread to distant sites (such as the eyes, central nervous system, lungs, prostate, and soft tissues) resulting from bacteremia (Siu et al., 2012). The infection essentially originates from the community, and affected patients are mostly immunocompetent without hepatobiliary disease. An Asian ethnicity,
diabetes mellitus, the presence of rmpA or magA genes, and K1 or K2 capsular serotype have all been reported as strong risk factors for invasive liver abscess syndrome (Fang et al., 2007; Kawai, 2006; Kim et al., 2009; Sheu et al., 2011; Yoon et al., 2014). In our current results, KPM displayed a more significant association with diabetes mellitus, alcoholism, and liver cirrhosis than SPM. Those findings are in accord with the previous results of Taiwanese descriptive studies (Lu et al., 2002; Tang et al., 1997). Neither liver cirrhosis nor alcoholism has been previously reported as a risk factor for invasive liver abscess syndrome by K. pneumoniae. Meningitis appears more frequently in complicated community-dwelling immunocompromised hosts, such as patients with cirrhosis or alcoholism. Our present findings suggest that when a patient with diabetes mellitus or liver cirrhosis exhibits an altered mental status with severe sepsis, clinicians should initially consider the possibility of KPM, which could mimic hepatic encephalopathy. We found in our current investigation that two thirds of our patients with CA-KPM (65.4%) had concurrent bacteremia and more than onethird of these cases (40.7%) had an extrameningeal focus. Since roughly half of our CA-KPM patients (48% [13/27]) did not undergo abdominal computed tomography (CT) for the evaluation of a suspected intraabdominal focus, the actual rate of concomitant extrameningeal infection might be higher than that indicated by our results. Notably, among 8 of our study patients who died within 48 hours of a lumbar puncture, 5 of these cases did not undergo an abdominal CT scan, mainly due to a refractory shock that prevented moving out of the ICU. If CA-KPM is suspected, prompt evaluation for an extrameningeal focus is important because drainage is often necessary for effective treatment of a liver or brain abscess. Delayed treatment of endophthalmitis can also lead to permanent loss of vision. Our current CSF findings were indistinguishable between our 2 study groups. Previous Taiwanese studies have reported that the median values for WBC, protein, and lactate levels in the CSF were significantly higher in KPM patients compared to non-Klebsiella meningitis cases (Tang et al., 1997). However, since there were considerable data overlaps between these 2 groups, those differences were not sufficiently convincing to guide the development of a reliable differential diagnosis in clinical practice. In our current patient subjects, the median values of WBC and platelet counts in peripheral blood were significantly lower in the KPM group. The higher proportion of cirrhotic patients and more frequent incidence of septic shock in the KPM group may be responsible for these findings. These factors also appear to be associated with the higher mortality in the CA-KPM group. Overall inhospital mortality rate of the KPM group in our study (51.9%) is within the range shown in the prior Taiwanese and Singaporean reports (33.3–93.0%) (Fang et al., 2000; Jang et al., 1993; Lee et al., 2004; Lu et al., 2002; Tang et al., 1997). Notably, of 14 deceased patients in our CA-KPM group, 8 patients (57.1%) died within 2 days of the diagnosis of bacterial meningitis. This suggests that a high degree of suspicion by the attending physician is crucial for the early diagnosis and optimal management of CA-KPM.
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Our present study has several limitations to note. First, the retrospective nature of this investigation limited our ability to collect a detailed medical history of our patients. Certain underlying diseases such as liver cirrhosis or alcoholism may have been underestimated, especially in the cases who first visited our hospitals. Second, the number of patients we analyzed was relatively small. It may have affected the statistical significance of the results. For example, although the proportion of our study patients with neurologic sequelae at discharge was almost twice as high in the CA-KPM group as in the CA-SPM group, this was not statistically significant. Finally, since bacterial isolates were not available, we could not assess the hypermucoviscous phenotype, K antigen serotype, or the presence of magA and rmpA, which are pathogenic factors known to be prevalent in invasive K. pneumoniae syndrome. In conclusion, compared to CA-SPM, CA-KPM is more commonly associated with diabetes mellitus and liver cirrhosis, a higher incidence of concomitant extrameningeal infections, and generally poorer outcomes. Conflict of interest The authors have no potential conflicts of interest to report. Acknowledgment The study was supported by a grant from the Asan Institute of Life Sciences (grant 2014-389). References Cabellos C, Verdaguer R, Olmo M, Fernandez-Sabe N, Cisnal M, Ariza J, et al. Communityacquired bacterial meningitis in elderly patients: experience over 30 years. Medicine (Baltimore) 2009;88:115–9. Chan YC, Wilder-Smith A, Ong BK, Kumarasinghe G, Wilder-Smith E. Adult community acquired bacterial meningitis in a Singaporean teaching hospital. A seven-year overview (1993–2000). Singapore Med J 2002;43:632–6. Chang FY, Chou MY. Comparison of pyogenic liver abscesses caused by Klebsiella pneumoniae and non-K. pneumoniae pathogens. J Formos Med Assoc 1995;94: 232–7. Chang WN, Lu CH, Huang CR, Tsai NW, Chuang YC, Chang CC, et al. Changing epidemiology of adult bacterial meningitis in southern Taiwan: a hospital-based study. Infection 2008;36:15–22. Cheng DL, Liu YC, Yen MY, Liu CY, Wang RS. Septic metastatic lesions of pyogenic liver abscess. Their association with Klebsiella pneumoniae bacteremia in diabetic patients. Arch Intern Med 1991;151:1557–9. Chung DR, Lee SS, Lee HR, Kim HB, Choi HJ, Eom JS, et al. Emerging invasive liver abscess caused by K1 serotype Klebsiella pneumoniae in Korea. J Infect 2007; 54:578–83. Chung DR, Lee HR, Lee SS, Kim SW, Chang HH, Jung SI, et al. Evidence for clonal dissemination of the serotype K1 Klebsiella pneumoniae strain causing invasive liver abscesses in Korea. J Clin Microbiol 2008;46:4061–3. Durand ML, Calderwood SB, Weber DJ, Miller SI, Southwick FS, Caviness Jr VS, et al. Acute bacterial meningitis in adults. A review of 493 episodes. N Engl J Med 1993;328:21–8. Fang CT, Chen YC, Chang SC, Sau WY, Luh KT. Klebsiella pneumoniae meningitis: timing of antimicrobial therapy and prognosis. QJM 2000;93:45–53.
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