Clinical Report
Clinical and microbiological features of patients admitted to the intensive care unit with nursing and healthcareassociated pneumonia
Journal of International Medical Research 2015, Vol. 43(2) 236–249 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060514551188 imr.sagepub.com
Myoung Kyu Lee, Sang-Ha Kim, Suk Joong Yong, Kye Chul Shin, Hyeon Cheol Park, Jiwon Choi, Yeun Seoung Choi, Jae Ho Seong, Ye-Ryung Jung and Won-Yeon Lee
Abstract Objective: To evaluate clinical and microbiological features in patients with nursing and healthcare-associated pneumonia (NHCAP), admitted to the intensive care unit (ICU). Methods: Demographic, clinical and microbiological data were retrospectively reviewed from patients with NHCAP admitted to a respiratory ICU. Patients were categorized into one of four NHCAP groups: (A) residence in a long-term nursing-home setting or healthcare home; (B) hospital discharge in the preceding 90 days; (C) elderly or physically disabled patients who stay at home but require healthcare; (D) continuously receiving outpatient endovascular therapy including chronic dialysis, anticancer drugs, and immunosuppressants. Pneumonia severity index (PSI), CURB-65, duration of ICU stay and 30-day mortality were evaluated. Results: Out of 428 patients reviewed (male, 67.1%; mean age, 71.2 11.9 years), 30-day mortality was 25.5%, and duration of ICU stay was 13.8 13.3 days. Mortality rate was not significantly different between the four NHCAP groups; duration of ICU stay was significantly longer in groups C and D. PSI score, serum HCO3– level, duration of ICU stay, extended spectrum b-lactamase (ESBL)-producing Klebsiella pneumoniae and multidrug resistant (MDR) Acinetobacter baumannii were significantly associated with 30-day mortality. Conclusion: ESBL-producing K. pneumoniae, MDR A. baumannii and PSI score should be considered in ICU patients with NHCAP.
Keywords Healthcare-associated, intensive care unit, multidrug resistant, mortality, pneumonia Date received: 23 March 2014; accepted: 18 August 2014 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
Corresponding author: Won-Yeon Lee, Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro Wonju, Gangwon 220-701, Republic of Korea. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed specified17, on2015 the SAGE and Open Access page Downloaded from imr.sagepub.com at LEWIS UNIV LIBRARY onasNovember (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Introduction Healthcare-associated pneumonia (HCAP) is defined as pneumonia that is present on admission, and occurs in patients who have recently been hospitalized, reside in a nursing home or have other recent healthcare exposures. In 2005, guidelines for the diagnosis and treatment of HCAP were published by the American Thoracic Society and the Infectious Disease Society of America.1 Patients with pneumonia admitted to hospital from nursing homes are considered to have nursing home-acquired pneumonia.2 The British Thoracic Society guidelines state that patients with nursing home-acquired pneumonia, which is usually categorized with HCAP, should be treated as having community-acquired pneumonia, because there is no difference in the distribution of causative pathogens between patients with nursing home-acquired pneumonia and other older adults with community-acquired pneumonia.2,3 Studies have argued that HCAP should be distinguished from community-acquired pneumonia, however, because of the higher prevalence of multidrug resistant (MDR) pathogens such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) in HCAP.4,5 Consequently, guidelines recommend empirical antibiotic therapy with activity against these pathogens.6 Despite these guidelines, there is disagreement about whether current HCAP criteria clearly identify patients at risk for MDR, and concerns that overtreatment with broad-spectrum antibiotics may produce selection pressure for MDR.7–9 Patients with HCAP have been shown to receive inappropriate initial antibiotic treatment more often than patients with community-acquired pneumonia,9,10 and inappropriate initial antibiotic treatment has been clearly associated with poor outcomes.11 In 2011, the Japan Respiratory Society guidelines documented a new pneumonia
category, known as nursing and healthcareassociated pneumonia (NHCAP), which is distinct from community-acquired pneumonia, relates to the pattern of drug-resistant pathogens and is relevant to healthcare insurance systems, including the nursingcare system.12,13 Similar healthcare/nursingcare systems exist in the Republic of Korea and many patients with NHCAP are admitted to tertiary hospitals that have an intensive care unit (ICU). Limited studies exist, however, relating to NHCAP requiring ICU admission; some studies12,13 suggest that NHCAP could be categorized into several groups according to patients’ comorbid diseases and clinical characteristics. The aim of the present study was to identify the clinical and microbiological features of patients with severe NHCAP requiring ICU treatment, and to clarify the prognostic factors for 30-day mortality. The study focused on the patients’ background, clinical characteristics, disease severity including pneumonia severity index (PSI) and CURB-65,14,15 the pathogen profile, and patient outcomes.
Patients and methods Study design and population This retrospective, observational cohort study included patients with NHCAP (aged 20 years) who were admitted to the ICU in a respiratory centre of Yonsei University Wonju Severance Christian hospital (an 850-bed tertiary hospital), Wonju, Korea between January 2008 and December 2012. Pneumonia was defined according to the criteria of the US Centers for Disease Control and Prevention. Diagnosis required two or more of the following criteria to be met: fever increase of 1 C or body temperature >38.3 C; leukocytosis (25% increase in leukocytes and 10 109/l) or leukopenia (25% decrease in leukocytes and 5 109/l); and purulent tracheal secretion (>25% neutrophils per high-power field).
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Diagnosis also required one of the following criteria to be met: new or persistent infiltration on chest radiography; some microorganisms isolated from pleural effusion and tracheal secretion; radiographic cavitation or histological evidence of pneumonia pathogens; or positive sputum culture from a quantitative bacterial bronchoalveolar lavage (BAL) culture. For the present study, the eligibility of patients with NHCAP for ICU admission was determined by the attending physicians (S.H.K., S.J.Y, K.C.S., W.Y.L.), based on PSI score and other medical conditions. Pneumonia occurring among outpatients in contact with a nursing home, healthcare system or endovascular therapy was defined as NHCAP. Patients who met the following criteria were excluded: community-acquired pneumonia; cardiac disorders including uncontrolled heart failure or acute myocardial infarction within one month of ICU admission; transfer to another hospital during the admission process; patients between 18 and 20 years old (according to the recommendation of the Institutional Review Board that required written agreement to review patients 25 in a 100 magnification microscopic field) and few squamous epithelial cells (106 CFU/ml bacteria in the sputum culture; blood culture-positive; positive urinary pneumococcal or urinary Legionella antigen-test results; positive antibody titers against M. pneumoniae and C. pneumoniae.22 Susceptibility tests focused on antibiotics frequently prescribed or recommended for the treatment of pneumonia, including antipseudomonal penicillins, carbapenems, cephalosporins, aminoglycosides and quinolones. MRSA (oxacillin minimum inhibitory concentration 4 mg/ ml), and resistant strains of P. aeruginosa, extended-spectrum b-lactamase (ESBL)producing Klebsiella pneumoniae and other Gram-negative bacilli including Acinetobacter baumannii, were designated as antibiotic-resistant organisms. Bacteria were defined as MDR if they were found
Antibiotic therapy was initiated based on the American Thoracic Society/Infectious Disease Society of America guidelines,1 but the detailed antibiotic regimen was defined by the attending physician (S.H.K. S.J.Y., K.C.S., W.Y.L.), taking into consideration patient risk factors and disease severity. Empirical antibiotic therapy was modulated according to the susceptibility test result for an identified pathogen, or the physician’s decision in response to the patient’s condition. Empirical antibiotic therapy was defined as inappropriate when the antibiotics used were not effective against the identified pathogens based on in vitro susceptibility tests.
Data collection Comorbid diseases such as chronic respiratory disease, diabetes mellitus, and cardiac, liver, renal, malignant or central nervous system diseases were reviewed according to medical records. Patients’ age, sex and laboratory data on admission to ICU (including leukocyte counts, haemoglobin, arterial blood gas analyses, serum bicarbonate ion [HCO3–], albumin, C-reactive protein [CRP], serum BUN and creatinine data) were also reviewed. Patients were classified into three groups based on PSI score: I–III (131 points),14 and were also classified into 3 groups based on CURB-65 score: 0 or 1, 2 and 3–5.15
Endpoints The primary endpoint was 30-day mortality following ICU admission. Secondary endpoints were duration of ICU stay and requirement for mechanical ventilation.
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Statistical analyses Statistical analyses were performed using SPSSÕ , version 18.0 (SPSS Inc., Chicago, IL, USA). 2-test or Fisher’s exact test were used to analyse categorical variables and Student’s t-test or Mann–Whitney U-test was used to analyse continuous variables. One-way analysis of variance was used to compare continuous variables between three or more groups. To identify independent prognostic factors for 30-day mortality among the variables that showed statistically significant associations in univariate analysis, multivariate logistic regression analysis was performed. Relative risks were expressed as odds ratio (OR) and 95% confidence interval (CI). Continuous variables are presented as mean SD and a P-value >0.05 was considered to be statistically significant.
Results Patient disposition A total of 428 patients with NHCAP were included for analyses (Figure 1), with mean age, 71.2 11.9 years and 287 (67.1%) male patients. Clinical characteristics and pneumonia severity on admission to ICU are shown (Table 1). Patients were divided into four NHCAP categories as follows: A, 120 patients (28.0%); B, 147 patients (34.3%); C, 67 patients (15.7%); and D, 94 patients (22.0%) (Table 2).
Clinical characteristics according to NHCAP category Clinical characteristics were assessed according to NHCAP category (Table 2). Patients’ age (P < 0.001) and sex (P ¼ 0.002) were significantly different between the four groups. PSI score (P < 0.001) was significantly higher, and duration of ICU stay (P ¼ 0.008) and duration of mechanical ventilation (P ¼ 0.022) were significantly longer in groups C and D compared with
groups A and B. Underlying comorbid diseases were also significantly different between the four groups. There was no statistically significant between-group difference in 30-day mortality (P ¼ 0.349; Table 2).
Comparison of clinical characteristics between survivor and nonsurvivor groups Comparison of clinical characteristics between survivor and nonsurvivor groups revealed that the mean age (70.4 12.2 versus 73.7 10.5 years, P ¼ 0.011) and PSI scores (144.1 23.3 versus 151.8 21.9, P ¼ 0.003) were significantly higher and duration of ICU stay (11.6 7.4 versus 14.5 14.8 days, P ¼ 0.008) was significantly longer in the nonsurvivor compared with the survivor group. Serum HCO3– levels on admission to ICU (23.1 6.1 versus 21.3 5.9 mEq/l, P ¼ 0.011) were significantly lower in the nonsurvivor compared with the survivor group. There were no statistically significant differences in comorbid diseases and other laboratory findings between the survivor and nonsurvivor groups (Table 3).
Microbiological distribution and antibiotic treatments in survivor and nonsurvivor groups Causative pathogens were identified in 61.8% of survivors and 67.0% of nonsurvivors (P ¼ 0.488; Table 4). MRSA was the most frequently isolated pathogen (15.4% [66/428] of patients); P. aeruginosa and S. pneumoniae were isolated in 11.9% (51/ 428) and 11.7% (50/428) of patients, respectively; polymicrobial pathogens were isolated in 3.5% (15/428) of patients. ESBLproducing K. pneumoniae (12.8% [14/109] versus 6.0% [19/319], P ¼ 0.020), MDR A. baumannii (11.9% [13/109] versus 4.1% [13/319], P ¼ 0.006) and polymicrobial pathogens (6.4% [7/109] versus 2.5%
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Figure 1. Flowchart showing identification of patients with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU). CHF, congestive heart failure; MI, myocardial infarction; MV, mechanical ventilation.
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Table 1. Demographic and clinical characteristics of patients diagnosed with nursing and healthcareassociated pneumonia (NHCAP) admitted to an intensive care unit (ICU). Characteristic
Incidence
Total patients Age, years Sex, male APACHE II score PSI score
428 71.2 11.9 287 (67.1) 23.0 5.6 146.0 23.2
PSI group Group I–III, 90 Group IV, 91–130 Group V, 131
0 (0) 114 (26.6) 314 (73.4)
CURB-65 score 0 or 1 2 3–5 Invasive MV
0 (0) 42 (9.8) 386 (90.2) 353 (82.5)
NHCAP category A B C D
120 (28.0) 147 (34.3) 67 (15.7) 94 (22.0)
Comorbid diseases Hypertension Diabetes mellitus Cardiac disease Chronic respiratory disease Cerebrovascular accident Hepatobiliary disease Chronic kidney disease Malignancy Duration of ICU stay, days Duration of MV, days 30-day mortality
224 (52.3) 109 (25.5) 142 (33.2) 122 (28.5) 139 (32.5) 79 (18.5) 45 (10.5) 91 (21.3) 13.8 13.3 10.6 11.9 109 (25.5)
Data presented as mean SD. APACHE, Acute Evaluation; CURB, blood pressure; MV, nia severity index.
n or n (%) patient incidence or physiology and Chronic Health confusion, urea, respiratory rate, mechanical ventilation; PSI, pneumo-
[8/319], P ¼ 0.029) were isolated in proportionally more patients in the nonsurvivor compared with the survivor group (Table 4).
Combination antibiotic therapy was administered to 393 (91.8%) patients, with the antipseudomonal b-lactam and fluoroquinolone combination therapy being the most commonly prescribed (144/428 [33.6%] patients; Table 5). Monotherapy was administered in 35/428 (8.2%) patients. Inappropriate antibiotic therapy was administered to proportionally more patients in the nonsurvivor than the survivor group, however the difference was not statistically significant (57.5% [42/73] versus 48.7% [96/ 197] of patients; P ¼ 0.104).
Multivariate logistic regression analysis of factors associated with 30-day mortality To identify factors associated with 30-day mortality in ICU patients with NHCAP, multivariate logistic regression analysis was performed using significant variables. Univariate analysis revealed that age, PSI score, serum HCO3 level, duration of ICU stay, and presence of ESBL-producing K. pneumoniae and MDR A. baumannii infection were statistically significant. Multivariate analysis using factors that were found to be significant by univariate analysis revealed that PSI (OR 1.015, 95% CI 1.004, 1.026; P ¼ 0.009), serum HCO3– level (OR 0.954, 95% CI 0.918, 0.993; P ¼ 0.020), duration of ICU stay (OR 0.971, 95% CI 0.950, 0.993; P ¼ 0.010), presence of ESBL-producing K. pneumoniae (OR 2.688, 95% CI 1.237, 5.840; P ¼ 0.013), MDR A. baumannii (OR 3.081, 95% CI 1.504, 6.311; P ¼ 0.002) and presence of polymicrobial pathogens (OR 4.161, 95% CI 1.414, 12.547; P ¼ 0.011) were significantly associated with 30-day mortality (Table 6).
Discussion Patients with HCAP may be at increased risk of infection with antibiotic-resistant organisms, and initial inadequate antibiotic
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Table 2. Characteristics of patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU), categorized according to NHCAP group. NHCAP group Characteristic
A n ¼ 120
B n ¼ 147
C n ¼ 67
D n ¼ 94
Statistical significance
Age, years Sex, male PSI score
69.4 14.2 89 (74.2) 145.7 24.1
69.7 11.3 91 (61.9) 137.8 18.7
81.7 5.3 35 (52.2) 154.1 21.9
68.4 8.6 72 (76.6) 153.6 24.8
P > 0.001 P ¼ 0.002 P > 0.001*
CURB-65 score 2 3–5 Invasive MV
14 (11.7) 106 (88.3) 103 (85.8)
18 (12.2) 129 (87.8) 112 (76.2)
0 (0) 67 (100) 61 (91.0)
10 (10.6) 84 (89.4) 77 (81.9)
P ¼ 0.032
Comorbid diseases Hypertension Diabetes mellitus Cerebrovascular accident Hepatobiliary disease Cardiac disease Chronic respiratory disease Chronic kidney disease Malignancy Duration of ICU stay, days Duration of MV, days 30-day mortality
68 (56.7) 41 (34.2) 102 (85.0) 10 (8.3) 25 (20.8) 15 (12.5) 6 (5.0) 12 (10.0) 13.9 12.5 10.7 11.9 32 (26.7)
76 (51.7) 26 (17.7) 0 (0) 34 (23.1) 70 (47.6) 84 (57.1) 12 (8.2) 5 (3.4) 11.1 10.1* 8.4 9.6* 30 (20.4)
29 (43.3) 12 (17.9) 7 (10.4) 24 (35.8) 28 (41.8) 11 (16.4) 7 (10.4) 10 (14.9) 15.7 11.5 12.5 10.5 19 (28.4)
51 (54.3) 30 (31.9) 12 (12.8) 11 (11.7) 19 (20.2) 12 (12.8) 20 (21.3) 64 (68.1) 16.6 18.4 12.7 15.4 28 (29.8)
NS P ¼ 0.004 P > 0.001 P > 0.001 P > 0.001 P > 0.001 P ¼ 0.001 P > 0.001 P ¼ 0.008* P ¼ 0.022* NS
P ¼ 0.039
Data presented as n (%) patient incidence or mean SD. *Groups C and D versus groups A and B. CURB, confusion, urea, respiratory rate, blood pressure; MV, mechanical ventilation; PSI, pneumonia severity index. NS, no statistically significant between-group difference (P 0.05; 2-test, Fisher’s exact test or one-way analysis of variance).
coverage may increase the mortality rate. Patients with HCAP differ from those with community-acquired pneumonia in terms of microbial aetiology, antibiotic therapy and clinical outcomes, despite similar age and sex, due to the poorer functional status.5,24,25 In the present study, PSI score, low serum HCO 3 , duration of ICU stay, ESBL-producing K. pneumonia, MDR A. baumannii and polymicorbial pathogens were significantly associated with 30-day mortality in ICU patients with NHCAP. Patients with NHCAP can be categorized into four groups.13 In the present study, each group showed different characteristics in terms of age, sex, and comorbid diseases;
groups A and B had significantly different PSI scores, duration of ICU stay, and duration of mechanical ventilation compared with groups C and D. Other studies have suggested that underlying comorbid diseases, including malignancy, may increase in-hospital mortality in patients with HCAP,24,25 however, the present investigation revealed no significant difference in 30-day mortality according to NHCAP category in ICU patients, although the comorbid diseases were found to differ between categories. The PSI score and duration of ICU stay were found to be significantly associated with 30-day mortality in the present study.
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Table 3. Clinical characteristics of patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU), categorized into survivor and nonsurvivor groups. Patient group Characteristic
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR
95% CI
Statistical significance
Age, years Sex, male PSI score CURB-65 score, 3–5
70.4 12.2 212 (66.5) 144.1 23.3 283 (88.7)
73.7 10.5 75 (68.8) 151.8 21.9 103 (94.5)
3.35 1.11 7.73 2.18
0.771, 0.698, 2.727, 0.894,
5.921 1.776 12.731 5.335
P ¼ 0.011 NS P ¼ 0.003 NS
Comorbid diseases Hypertension Diabetes mellitus Cerebrovascular accident Hepatobiliary disease Cardiac disease Chronic respiratory disease Chronic kidney disease Malignancy
171 (53.6) 81 (25.4) 100 (31.3) 61 (19.1) 110 (34.5) 91 (28.5) 24 (7.5) 62 (19.4)
53 (48.6) 28 (25.7) 39 (35.8) 18 (16.5) 32 (29.4) 31 (28.4) 9 (8.3) 29 (26.6)
0.82 1.02 1.22 0.84 0.79 1 1.11 1.5
0.530, 0.617, 0.772, 0.470, 0.492, 0.615, 0.498, 0.905,
1.266 1.672 1.928 1.490 1.267 1.612 2.459 2.496
NS NS NS NS NS NS NS NS
7.38 0.13 64.3 25.3 2.8 0.5 12.9 9.2 29.1 24.6 1.30 1.13 21.3 5.9 11.7 29.0 14.5 14.8 10.7 7.0
0 2.38 0.11 1.35 0.07 0.06 1.7 2.36 2.91 0.14
–0.027, 0.028 –3.874, 8.628 –0.009, 0.230 –0.749, 3.456 –5.306, 5.169 –0.275, 0.398 0.394, 3.015 –9.322, 4.594 0.010, 5.802 –2.102, 1.818
Laboratory findings on ICU admission pH 7.38 0.12 PaO2, mm Hg 66.7 29.7 Albumin, g/dl 2.9 0.6 CRP, mg/dl 14.2 10.9 BUN, mg/dl 29.0 23.8 Creatinine, mg/dl 1.36 1.66 HCO 23.1 6.1 3 , mEq/l PCT,a ng/ml 9.4 18.9 Duration of ICU stay, days 11.6 7.4 Duration of MV, days 10.6 13.2
NS NS NS NS NS NS P ¼ 0.011 NS P ¼ 0.008 NS
Data presented as n (%) patient incidence or mean SD. a Initial PCT results were available for 164 patients in the survivor group and 58 patients in the nonsurvivor group. BUN, blood urea nitrogen; CI, confidence interval; CRP, C-reactive protein; CURB, confusion, urea, respiratory rate, blood pressure; HCO3, serum bicarbonate ion; MV, mechanical ventilation; OR, odds ratio; PaO2, arterial oxygen pressure; PCT, procalcitonin; PSI, pneumonia severity index. NS, no statistically significant between-group difference (P 0.05; 2-test, Fisher’s exact test or Student’s t-test).
A previous report26 showed prognostic scoring, including PSI, was good for predicting mortality in nonimmunocompromised patients with HCAP. Another study27 also suggested that PSI could be applied to assess the severity of illness in the management of patients with HCAP, although the discriminatory powers of PSI for 30-day mortality were significantly lower in patients with HCAP compared with
community-acquired pneumonia. Other studies6,8,28 have proposed that advanced care, or interventions including ICU admission and invasive mechanical ventilation, may be partially responsible for increased mortality in patients with HCAP. Studies also suggest that a longer duration of ICU stay may be associated with increased chance of invasive procedure, including nasogastric tube feeding or central catheterization, which may
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Table 4. Microbiological distribution in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit, categorized into survivor and nonsurvivor groups. Patient group Microbe type
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR 95% CI
Pathogen identified Polymicrobial pathogensa
197 (61.8) 8 (2.5)
73 (67.0) 7 (6.4)
0.85 0.534, 1.356 NS 3.53 1.249, 9.997 P ¼ 0.029
9 6 14 0
1.64 0.44 1.51 0.25
Gram-positive pathogen Streptococcus pneumoniae MSSA MRSA Enterococcus species
41 (12.9) 8 (2.5) 52 (16.3) 3 (0.9)
(8.3) (5.5) (12.8) (0)
0.769, 0.150, 0.934, 0.056,
3.493 1.303 2.452 1.475
Statistical significance
NS NS NS NS
Gram-negative pathogen Pseudomonas aeruginosa; 4 (1.3)/32 (10.0) 3 (2.8)/12 (11.0) 0.8 0.418, 1.521 NS MDR, n ¼ 7; non- MDR, n ¼ 44 Klebsiella pneumonia 14 (4.4) 5 (4.6) 0.96 0.336, 2.715 NS ESBL-producing K. pneumoniae 19 (6.0) 14 (12.8) 1.56 1.047, 2.326 P ¼ 0.020 Escherichia coli Acinetobacter baumannii, MDR n ¼ 26/non-MDR n ¼ 2 Haemophilus influenza Othersb Fungi
8 (2.5) 13 (4.1)/2 (0.6) 2 (0.6) 5 (1.6) 2 (0.6)
1 (0.9) 13 (11.9)/0 (0) 0 (0) 1 (0.9) 1 (0.9)
2.78 0.343, 22.469 NS 1.74 1.230, 2.457 P ¼ 0.006 0.34 0.071, 1.421 2.22 0.543, 12.849 0.68 0.061, 7.520
NS NS NS
Data presented as n (%) patient incidence. a Polymicrobial pathogens: MRSA and ESBL-producing K. pneumoniae (n ¼ 2 in survivor, n ¼ 3 in nonsurvivor group); MRSA and K. pneumoniae (n ¼ 2 in survivor group); MRSA and A. baumannii (n ¼ 2 in survivor, n ¼ 3 in nonsurvivor group); P. aeruginosa and S. pneumoniae (n ¼ 1 in survivor group); P. aeruginosa and ESBL-producing K. pneumoniae (n ¼ 1 in nonsurvivor group); and MRSA and H. influenzae (n ¼ 1 in survivor group). b Others: Moraxella catarrhalis (n ¼ 1 in survivor, n ¼ 1 in nonsurvivor group). CI, confidence interval; ESBL, extended-spectrum b-lactamase; MDR, multidrug resistant; OR, odds ratio; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus. NS, no statistically significant between-group difference (P 0.05; 2-test and Fisher’s exact test).
cause opportunistic infections such as MRSA, Escherichia coli, P. aeruginosa, or K. pneumoniae and increased in-hospital mortality rates.4,28 A lower serum HCO 3 level is known to be associated with intracellular acidosis and tissue hypoperfusion in severely ill patients with circulatory failure, which can cause increased lactic acidosis and mortality, particularly in ICU patients.29 There is no current data, however, relating serum HCO 3 level and prognosis in patients
with NHCAP, thus further studies are required. In the present study, the most frequently identified pathogen was MRSA rather than S. pneumoniae or P. aeruginosa, however, these pathogens did not affect 30-day mortality in ICU patients with NHCAP. Several studies30,31 have suggested that MRSA does not affect pneumonia-related mortality, particularly ventilator-associated pneumonia in ICU patients. Guideline-concordant HCAP therapy in cases of S. aureus or
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Table 5. Antibiotic treatment in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit, categorized into survivor and nonsurvivor groups. Patient group Treatment Inappropriate antibiotic therapya Monotherapy Cephalosporin Antipseudomonal penicillinb Fluoroquinolone Carbapenem Combination therapy b-lactamc þ fluoroquinolone b-lactam þ macrolide b-lactam þ clindamycin b-lactam þ aminoglycoside Antipseudomonal b-lactamd þ fluoroquinolone Antipseudomonal b-lactam þ macrolide Antipseudomonal b-lactam þ clindamycin Antipseudomonal b-lactam þ aminoglycoside Antipseudomonal b-lactam þ vancomycin
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR
95% CI
96/197 (48.7)
42/73 (57.5)
0.69
0.436, 1.081
24 (7.5) 3 (0.9) 1 (0.3) 1 (0.3)
4 (3.7) 0 (0) 0 (0) 2 (1.8)
2.14 0.74 0.75 0.17
0.724, 0.703, 0.705, 0.015,
6.299 1.786 1.787 1.874
59 (18.5) 18 (5.6) 20 (6.3) 3 (0.9) 103 (32.3) 10 (3.1) 51 (16.0) 8 (2.5) 18 (5.6)
18 (16.5) 7 (6.4) 7 (6.4) 2 (1.8) 41 (37.6) 5 (4.6) 13 (11.9) 2 (1.8) 8 (7.3)
1.55 1.15 1.03 0.51 0.84 0.6 1.41 1.38 0.76
0.330, 0.466, 0.421, 0.084, 0.544, 0.198, 0.732, 0.288, 0.319,
7.302 2.827 2.497 3.081 1.299 1.843 2.697 6.582 1.789
Data presented as n (%) patient incidence. a n patients/total n patients with identified pathogens and known antibiotic sensitivity test results. b Antipseudomonal penicillin comprised piperacillin/tazobactam. c b-lactam antibiotics comprised cefotaxime, ceftriaxone and cefpiramide. d Antipseudomonal b-lactam antibiotics comprised cefoperazone/sulbactam, piperacillin/tazobactam, cefepime and carbapenem. CI, confidence interval; OR, odds ratio.
P. aeruginosa infection is also suggested to have no association with improved 30-day mortality.6 Differences in initial antibiotic treatments between survivors and nonsurvivors were analysed in the present study and therapeutic regimens (including mono- or combination therapy) did not significantly differ between the two groups. There was no statistically significant difference in administration of inappropriate antibiotic treatment between the nonsurvivor and survivor groups, suggesting that inappropriate antibiotic treatment at admission in ICU patients with NHCAP does not affect 30-day mortality rates.
Conversely, the present study showed that ESBL-producing K. pneumoniae and MDR A. baumannii were significantly associated with infections in the nonsurvivor group, and that these two pathogens were associated with 30-day mortality. A recent study32 suggested the MDR pathogens did not increase the mortality in patients with NHCAP, therefore, inappropriate overuse of broad-spectrum antibiotics should not be advised. Compared with patients with community-acquired pneumonia, however, those with HCAP were reported as frequently infected by MDR pathogens,10 and the present data also showed that 13.8% of patients with NHCAP were identified with
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Table 6. Univariate and multivariate logistic regression analyses of factors associated with 30-day mortality in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU). Statistical test Univariate
Multivariate
Variable
OR
95% CI
Statistical significance
OR
95% CI
Statistical significance
Age PSI score HCO3– at admission Duration of ICU stay ESBL-producing Klebsiella pneumoniae MDR Acinetobacter baumannii Polymicrobial pathogens
1.027 1.014 0.953 0.985 2.33
1.006, 1.005, 0.919, 0.940, 1.161,
1.048 1.024 0.989 0.995 4.578
P ¼ 0.012 P ¼ 0.003 P ¼ 0.012 P ¼ 0.008 P ¼ 0.020
1.02 1.02 0.95 0.97 2.69
0.995, 1.004, 0.918, 0.950, 1.237,
NS P ¼ 0.009 P ¼ 0.020 P ¼ 0.010 P ¼ 0.013
2.5 3.53
1.295, 4.228 1.249, 9.977
P ¼ 0.006 P ¼ 0.029
3.08 4.16
1.504, 6.311 1.414, 12.547
1.040 1.026 0.993 0.993 5.840
P ¼ 0.002 P ¼ 0.011
CI, confidence interval; ESBL, extended-spectrum b-lactamase; HCO 3 , serum bicarbonate ion; ICU, intensive care unit; MDR, multidrug resistant; OR, odds ratio; PSI, pneumonia severity index. NS, no statistically significant difference (P 0.05).
MDR pathogens. Risk factors including ICU care and poor performance score may be associated with potential MDR pathogens in patients with HCAP,33 and the present study showed that ESBL-producing K. pneumoniae and MDR A. baumannii were significantly associated with 30-day mortality. These MDR pathogens are known to be significantly associated with severity of underlying disease, duration of prior hospital admission and prior use of thirdgeneration cephalosporin.34,35 Limited antibiotic choice for treating MDR pathogens may also be associated with higher rates of in-hospital mortality, however there are few studies relating to MDR A. baumannii in patients with HCAP, even though these patients are at higher risk of potential MDR Acinetobacter species.36 The results of the present study may be limited by several factors. First, given its retrospective nature, selection bias may have influenced the significance of the present findings and the possibility of recording errors related to baseline clinical data cannot be excluded. Secondly, the present
study was performed in a single institution, thus a multicentre study is required to validate the results. Thirdly, the characteristics of the four NHCAP subcategories occasionally overlapped in some patients, therefore, a more robust classification system is required. Despite these limitations, the present study evaluated clinical features in patients with NHCAP requiring ICU treatment, categorized into four NHCAP groups, and identified prognostic factors associated with mortality. In conclusion, 30-day mortality was not significantly different between four NHCAP subcategories13 in ICU patients with NHCAP. PSI score, duration of ICU stay, serum HCO 3 level, MDR pathogens such as ESBL-producing K. pneumoniae and MDR A. baumannii or polymicorbial infection were significantly associated with 30-day mortality in ICU patients with severe NHCAP. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
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Acknowledgements The authors thank all members of the Department of Internal Medicine, Yonsei University Wonju College of Medicine, and Yonsei University Wonju Severance Christian hospital.
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10. Shindo Y, Sato S, Maruyama E, et al. Health-care-associated pneumonia among hospitalized patients in a Japanese community hospital. Chest 2009; 135: 633–640. 11. Falcone M, Venditti M, Shindo Y, et al. Healthcare-associated pneumonia: diagnostic criteria and distinction from communityacquired pneumonia. Int J Infect Dis 2011; 15: e545–e550. 12. Miyashita N, Kawai Y, Akaike H, et al. Clinical features and the role of atypical pathogens in nursing and healthcareassociated pneumonia (NHCAP): differences between a teaching university hospital and a community hospital. Intern Med 2012; 51: 585–594. 13. Kohno S, Imamura Y, Shindo Y, et al. Clinical practice guidelines for nursing- and healthcare-associated pneumonia (NHCAP) [complete translation]. Respir Investig 2013; 51: 103–126. 14. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336: 243–250. 15. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax 2003; 58: 377–382. 16. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44: S27–S72. 17. Knaus WA, Wagner DP, Draper EA, et al. The APACHE II Prognostic System: risk prediction of hospital mortality for critically ill hospitalized adults. Chest 1991; 100: 1619–1636. 18. Ishida T, Hashimoto T, Arita M, et al. Etiology of community-acquired pneumonia in hospitalized patients: a 3-year prospective study in Japan. Chest 1998; 114: 1588–1593. 19. Miyashita N, Ouchi K, Kawasaki K, et al. Comparison of serological tests for detection of immunoglobulin M antibodies to Chlamydophila pneumoniae. Respirology 2008; 13: 427–431.
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20. Ros0n B, Ferna´ndez-Sabe´ N, Carratala´ J, et al. Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia. Clin Infect Dis 2004; 38: 222–226. 21. Helbig JH, Uldum SA, Lu¨ck PC, et al. Detection of Legionella pneumophila antigen in urine samples by the BinaxNOW immunochromatographic assay and comparison with both Binax Legionella Urinary Enzyme Immunoassay (EIA) and Biotest Legionella Urin Antigen EIA. J Med Microbiol 2001; 50: 509–516. 22. Sakoda Y, Ikegame S, Ikeda-Harada C, et al. Retrospective analysis of nursing and healthcare-associated pneumonia: analysis of adverse prognostic factors and validity of the selection criteria. Respir Investig 2014; 52: 114–120. 23. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drugresistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2011; 18: 268–281. 24. Carratala´ J, Mykietiuk A, Ferna´ndez-Sabe´ N, et al. Health care-associated pneumonia requiring hospital admission: epidemiology, antibiotic therapy, and clinical outcomes. Arch Intern Med 2007; 167: 1393–1399. 25. Polverino E, Torres A, Menendez R, et al. Microbial aetiology of healthcare associated pneumonia in Spain: a prospective, multicentre, case-control study. Thorax 2013; 68: 1007–1014. 26. Carrabba M, Zarantonello M, Bonara P, et al. Severity assessment of healthcareassociated pneumonia and pneumonia in immunosuppression. Eur Respir J 2012; 40: 1201–1210. 27. Jeong BH, Koh WJ, Yoo H, et al. Performances of prognostic scoring systems in patients with healthcare-associated pneumonia. Clin Infec Dis 2013; 56: 625–632. 28. Lambert ML, Suetens C, Savey A, et al. Clinical outcomes of health-care-associated infections and antimicrobial resistance in
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Clinical and microbiological features of patients admitted to the intensive care unit with nursing and healthcareassociated pneumonia
Journal of International Medical Research 2015, Vol. 43(2) 236–249 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0300060514551188 imr.sagepub.com
Myoung Kyu Lee, Sang-Ha Kim, Suk Joong Yong, Kye Chul Shin, Hyeon Cheol Park, Jiwon Choi, Yeun Seoung Choi, Jae Ho Seong, Ye-Ryung Jung and Won-Yeon Lee
Abstract Objective: To evaluate clinical and microbiological features in patients with nursing and healthcare-associated pneumonia (NHCAP), admitted to the intensive care unit (ICU). Methods: Demographic, clinical and microbiological data were retrospectively reviewed from patients with NHCAP admitted to a respiratory ICU. Patients were categorized into one of four NHCAP groups: (A) residence in a long-term nursing-home setting or healthcare home; (B) hospital discharge in the preceding 90 days; (C) elderly or physically disabled patients who stay at home but require healthcare; (D) continuously receiving outpatient endovascular therapy including chronic dialysis, anticancer drugs, and immunosuppressants. Pneumonia severity index (PSI), CURB-65, duration of ICU stay and 30-day mortality were evaluated. Results: Out of 428 patients reviewed (male, 67.1%; mean age, 71.2 11.9 years), 30-day mortality was 25.5%, and duration of ICU stay was 13.8 13.3 days. Mortality rate was not significantly different between the four NHCAP groups; duration of ICU stay was significantly longer in groups C and D. PSI score, serum HCO3– level, duration of ICU stay, extended spectrum b-lactamase (ESBL)-producing Klebsiella pneumoniae and multidrug resistant (MDR) Acinetobacter baumannii were significantly associated with 30-day mortality. Conclusion: ESBL-producing K. pneumoniae, MDR A. baumannii and PSI score should be considered in ICU patients with NHCAP.
Keywords Healthcare-associated, intensive care unit, multidrug resistant, mortality, pneumonia Date received: 23 March 2014; accepted: 18 August 2014 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
Corresponding author: Won-Yeon Lee, Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro Wonju, Gangwon 220-701, Republic of Korea. Email: [email protected]
Creative Commons CC-BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License (http://www.creativecommons.org/licenses/by-nc/3.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed specified17, on2015 the SAGE and Open Access page Downloaded from imr.sagepub.com at LEWIS UNIV LIBRARY onasNovember (http://www.uk.sagepub.com/aboutus/openaccess.htm).
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Introduction Healthcare-associated pneumonia (HCAP) is defined as pneumonia that is present on admission, and occurs in patients who have recently been hospitalized, reside in a nursing home or have other recent healthcare exposures. In 2005, guidelines for the diagnosis and treatment of HCAP were published by the American Thoracic Society and the Infectious Disease Society of America.1 Patients with pneumonia admitted to hospital from nursing homes are considered to have nursing home-acquired pneumonia.2 The British Thoracic Society guidelines state that patients with nursing home-acquired pneumonia, which is usually categorized with HCAP, should be treated as having community-acquired pneumonia, because there is no difference in the distribution of causative pathogens between patients with nursing home-acquired pneumonia and other older adults with community-acquired pneumonia.2,3 Studies have argued that HCAP should be distinguished from community-acquired pneumonia, however, because of the higher prevalence of multidrug resistant (MDR) pathogens such as Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) in HCAP.4,5 Consequently, guidelines recommend empirical antibiotic therapy with activity against these pathogens.6 Despite these guidelines, there is disagreement about whether current HCAP criteria clearly identify patients at risk for MDR, and concerns that overtreatment with broad-spectrum antibiotics may produce selection pressure for MDR.7–9 Patients with HCAP have been shown to receive inappropriate initial antibiotic treatment more often than patients with community-acquired pneumonia,9,10 and inappropriate initial antibiotic treatment has been clearly associated with poor outcomes.11 In 2011, the Japan Respiratory Society guidelines documented a new pneumonia
category, known as nursing and healthcareassociated pneumonia (NHCAP), which is distinct from community-acquired pneumonia, relates to the pattern of drug-resistant pathogens and is relevant to healthcare insurance systems, including the nursingcare system.12,13 Similar healthcare/nursingcare systems exist in the Republic of Korea and many patients with NHCAP are admitted to tertiary hospitals that have an intensive care unit (ICU). Limited studies exist, however, relating to NHCAP requiring ICU admission; some studies12,13 suggest that NHCAP could be categorized into several groups according to patients’ comorbid diseases and clinical characteristics. The aim of the present study was to identify the clinical and microbiological features of patients with severe NHCAP requiring ICU treatment, and to clarify the prognostic factors for 30-day mortality. The study focused on the patients’ background, clinical characteristics, disease severity including pneumonia severity index (PSI) and CURB-65,14,15 the pathogen profile, and patient outcomes.
Patients and methods Study design and population This retrospective, observational cohort study included patients with NHCAP (aged 20 years) who were admitted to the ICU in a respiratory centre of Yonsei University Wonju Severance Christian hospital (an 850-bed tertiary hospital), Wonju, Korea between January 2008 and December 2012. Pneumonia was defined according to the criteria of the US Centers for Disease Control and Prevention. Diagnosis required two or more of the following criteria to be met: fever increase of 1 C or body temperature >38.3 C; leukocytosis (25% increase in leukocytes and 10 109/l) or leukopenia (25% decrease in leukocytes and 5 109/l); and purulent tracheal secretion (>25% neutrophils per high-power field).
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Diagnosis also required one of the following criteria to be met: new or persistent infiltration on chest radiography; some microorganisms isolated from pleural effusion and tracheal secretion; radiographic cavitation or histological evidence of pneumonia pathogens; or positive sputum culture from a quantitative bacterial bronchoalveolar lavage (BAL) culture. For the present study, the eligibility of patients with NHCAP for ICU admission was determined by the attending physicians (S.H.K., S.J.Y, K.C.S., W.Y.L.), based on PSI score and other medical conditions. Pneumonia occurring among outpatients in contact with a nursing home, healthcare system or endovascular therapy was defined as NHCAP. Patients who met the following criteria were excluded: community-acquired pneumonia; cardiac disorders including uncontrolled heart failure or acute myocardial infarction within one month of ICU admission; transfer to another hospital during the admission process; patients between 18 and 20 years old (according to the recommendation of the Institutional Review Board that required written agreement to review patients 25 in a 100 magnification microscopic field) and few squamous epithelial cells (106 CFU/ml bacteria in the sputum culture; blood culture-positive; positive urinary pneumococcal or urinary Legionella antigen-test results; positive antibody titers against M. pneumoniae and C. pneumoniae.22 Susceptibility tests focused on antibiotics frequently prescribed or recommended for the treatment of pneumonia, including antipseudomonal penicillins, carbapenems, cephalosporins, aminoglycosides and quinolones. MRSA (oxacillin minimum inhibitory concentration 4 mg/ ml), and resistant strains of P. aeruginosa, extended-spectrum b-lactamase (ESBL)producing Klebsiella pneumoniae and other Gram-negative bacilli including Acinetobacter baumannii, were designated as antibiotic-resistant organisms. Bacteria were defined as MDR if they were found
Antibiotic therapy was initiated based on the American Thoracic Society/Infectious Disease Society of America guidelines,1 but the detailed antibiotic regimen was defined by the attending physician (S.H.K. S.J.Y., K.C.S., W.Y.L.), taking into consideration patient risk factors and disease severity. Empirical antibiotic therapy was modulated according to the susceptibility test result for an identified pathogen, or the physician’s decision in response to the patient’s condition. Empirical antibiotic therapy was defined as inappropriate when the antibiotics used were not effective against the identified pathogens based on in vitro susceptibility tests.
Data collection Comorbid diseases such as chronic respiratory disease, diabetes mellitus, and cardiac, liver, renal, malignant or central nervous system diseases were reviewed according to medical records. Patients’ age, sex and laboratory data on admission to ICU (including leukocyte counts, haemoglobin, arterial blood gas analyses, serum bicarbonate ion [HCO3–], albumin, C-reactive protein [CRP], serum BUN and creatinine data) were also reviewed. Patients were classified into three groups based on PSI score: I–III (131 points),14 and were also classified into 3 groups based on CURB-65 score: 0 or 1, 2 and 3–5.15
Endpoints The primary endpoint was 30-day mortality following ICU admission. Secondary endpoints were duration of ICU stay and requirement for mechanical ventilation.
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Statistical analyses Statistical analyses were performed using SPSSÕ , version 18.0 (SPSS Inc., Chicago, IL, USA). 2-test or Fisher’s exact test were used to analyse categorical variables and Student’s t-test or Mann–Whitney U-test was used to analyse continuous variables. One-way analysis of variance was used to compare continuous variables between three or more groups. To identify independent prognostic factors for 30-day mortality among the variables that showed statistically significant associations in univariate analysis, multivariate logistic regression analysis was performed. Relative risks were expressed as odds ratio (OR) and 95% confidence interval (CI). Continuous variables are presented as mean SD and a P-value >0.05 was considered to be statistically significant.
Results Patient disposition A total of 428 patients with NHCAP were included for analyses (Figure 1), with mean age, 71.2 11.9 years and 287 (67.1%) male patients. Clinical characteristics and pneumonia severity on admission to ICU are shown (Table 1). Patients were divided into four NHCAP categories as follows: A, 120 patients (28.0%); B, 147 patients (34.3%); C, 67 patients (15.7%); and D, 94 patients (22.0%) (Table 2).
Clinical characteristics according to NHCAP category Clinical characteristics were assessed according to NHCAP category (Table 2). Patients’ age (P < 0.001) and sex (P ¼ 0.002) were significantly different between the four groups. PSI score (P < 0.001) was significantly higher, and duration of ICU stay (P ¼ 0.008) and duration of mechanical ventilation (P ¼ 0.022) were significantly longer in groups C and D compared with
groups A and B. Underlying comorbid diseases were also significantly different between the four groups. There was no statistically significant between-group difference in 30-day mortality (P ¼ 0.349; Table 2).
Comparison of clinical characteristics between survivor and nonsurvivor groups Comparison of clinical characteristics between survivor and nonsurvivor groups revealed that the mean age (70.4 12.2 versus 73.7 10.5 years, P ¼ 0.011) and PSI scores (144.1 23.3 versus 151.8 21.9, P ¼ 0.003) were significantly higher and duration of ICU stay (11.6 7.4 versus 14.5 14.8 days, P ¼ 0.008) was significantly longer in the nonsurvivor compared with the survivor group. Serum HCO3– levels on admission to ICU (23.1 6.1 versus 21.3 5.9 mEq/l, P ¼ 0.011) were significantly lower in the nonsurvivor compared with the survivor group. There were no statistically significant differences in comorbid diseases and other laboratory findings between the survivor and nonsurvivor groups (Table 3).
Microbiological distribution and antibiotic treatments in survivor and nonsurvivor groups Causative pathogens were identified in 61.8% of survivors and 67.0% of nonsurvivors (P ¼ 0.488; Table 4). MRSA was the most frequently isolated pathogen (15.4% [66/428] of patients); P. aeruginosa and S. pneumoniae were isolated in 11.9% (51/ 428) and 11.7% (50/428) of patients, respectively; polymicrobial pathogens were isolated in 3.5% (15/428) of patients. ESBLproducing K. pneumoniae (12.8% [14/109] versus 6.0% [19/319], P ¼ 0.020), MDR A. baumannii (11.9% [13/109] versus 4.1% [13/319], P ¼ 0.006) and polymicrobial pathogens (6.4% [7/109] versus 2.5%
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Figure 1. Flowchart showing identification of patients with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU). CHF, congestive heart failure; MI, myocardial infarction; MV, mechanical ventilation.
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Table 1. Demographic and clinical characteristics of patients diagnosed with nursing and healthcareassociated pneumonia (NHCAP) admitted to an intensive care unit (ICU). Characteristic
Incidence
Total patients Age, years Sex, male APACHE II score PSI score
428 71.2 11.9 287 (67.1) 23.0 5.6 146.0 23.2
PSI group Group I–III, 90 Group IV, 91–130 Group V, 131
0 (0) 114 (26.6) 314 (73.4)
CURB-65 score 0 or 1 2 3–5 Invasive MV
0 (0) 42 (9.8) 386 (90.2) 353 (82.5)
NHCAP category A B C D
120 (28.0) 147 (34.3) 67 (15.7) 94 (22.0)
Comorbid diseases Hypertension Diabetes mellitus Cardiac disease Chronic respiratory disease Cerebrovascular accident Hepatobiliary disease Chronic kidney disease Malignancy Duration of ICU stay, days Duration of MV, days 30-day mortality
224 (52.3) 109 (25.5) 142 (33.2) 122 (28.5) 139 (32.5) 79 (18.5) 45 (10.5) 91 (21.3) 13.8 13.3 10.6 11.9 109 (25.5)
Data presented as mean SD. APACHE, Acute Evaluation; CURB, blood pressure; MV, nia severity index.
n or n (%) patient incidence or physiology and Chronic Health confusion, urea, respiratory rate, mechanical ventilation; PSI, pneumo-
[8/319], P ¼ 0.029) were isolated in proportionally more patients in the nonsurvivor compared with the survivor group (Table 4).
Combination antibiotic therapy was administered to 393 (91.8%) patients, with the antipseudomonal b-lactam and fluoroquinolone combination therapy being the most commonly prescribed (144/428 [33.6%] patients; Table 5). Monotherapy was administered in 35/428 (8.2%) patients. Inappropriate antibiotic therapy was administered to proportionally more patients in the nonsurvivor than the survivor group, however the difference was not statistically significant (57.5% [42/73] versus 48.7% [96/ 197] of patients; P ¼ 0.104).
Multivariate logistic regression analysis of factors associated with 30-day mortality To identify factors associated with 30-day mortality in ICU patients with NHCAP, multivariate logistic regression analysis was performed using significant variables. Univariate analysis revealed that age, PSI score, serum HCO3 level, duration of ICU stay, and presence of ESBL-producing K. pneumoniae and MDR A. baumannii infection were statistically significant. Multivariate analysis using factors that were found to be significant by univariate analysis revealed that PSI (OR 1.015, 95% CI 1.004, 1.026; P ¼ 0.009), serum HCO3– level (OR 0.954, 95% CI 0.918, 0.993; P ¼ 0.020), duration of ICU stay (OR 0.971, 95% CI 0.950, 0.993; P ¼ 0.010), presence of ESBL-producing K. pneumoniae (OR 2.688, 95% CI 1.237, 5.840; P ¼ 0.013), MDR A. baumannii (OR 3.081, 95% CI 1.504, 6.311; P ¼ 0.002) and presence of polymicrobial pathogens (OR 4.161, 95% CI 1.414, 12.547; P ¼ 0.011) were significantly associated with 30-day mortality (Table 6).
Discussion Patients with HCAP may be at increased risk of infection with antibiotic-resistant organisms, and initial inadequate antibiotic
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Table 2. Characteristics of patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU), categorized according to NHCAP group. NHCAP group Characteristic
A n ¼ 120
B n ¼ 147
C n ¼ 67
D n ¼ 94
Statistical significance
Age, years Sex, male PSI score
69.4 14.2 89 (74.2) 145.7 24.1
69.7 11.3 91 (61.9) 137.8 18.7
81.7 5.3 35 (52.2) 154.1 21.9
68.4 8.6 72 (76.6) 153.6 24.8
P > 0.001 P ¼ 0.002 P > 0.001*
CURB-65 score 2 3–5 Invasive MV
14 (11.7) 106 (88.3) 103 (85.8)
18 (12.2) 129 (87.8) 112 (76.2)
0 (0) 67 (100) 61 (91.0)
10 (10.6) 84 (89.4) 77 (81.9)
P ¼ 0.032
Comorbid diseases Hypertension Diabetes mellitus Cerebrovascular accident Hepatobiliary disease Cardiac disease Chronic respiratory disease Chronic kidney disease Malignancy Duration of ICU stay, days Duration of MV, days 30-day mortality
68 (56.7) 41 (34.2) 102 (85.0) 10 (8.3) 25 (20.8) 15 (12.5) 6 (5.0) 12 (10.0) 13.9 12.5 10.7 11.9 32 (26.7)
76 (51.7) 26 (17.7) 0 (0) 34 (23.1) 70 (47.6) 84 (57.1) 12 (8.2) 5 (3.4) 11.1 10.1* 8.4 9.6* 30 (20.4)
29 (43.3) 12 (17.9) 7 (10.4) 24 (35.8) 28 (41.8) 11 (16.4) 7 (10.4) 10 (14.9) 15.7 11.5 12.5 10.5 19 (28.4)
51 (54.3) 30 (31.9) 12 (12.8) 11 (11.7) 19 (20.2) 12 (12.8) 20 (21.3) 64 (68.1) 16.6 18.4 12.7 15.4 28 (29.8)
NS P ¼ 0.004 P > 0.001 P > 0.001 P > 0.001 P > 0.001 P ¼ 0.001 P > 0.001 P ¼ 0.008* P ¼ 0.022* NS
P ¼ 0.039
Data presented as n (%) patient incidence or mean SD. *Groups C and D versus groups A and B. CURB, confusion, urea, respiratory rate, blood pressure; MV, mechanical ventilation; PSI, pneumonia severity index. NS, no statistically significant between-group difference (P 0.05; 2-test, Fisher’s exact test or one-way analysis of variance).
coverage may increase the mortality rate. Patients with HCAP differ from those with community-acquired pneumonia in terms of microbial aetiology, antibiotic therapy and clinical outcomes, despite similar age and sex, due to the poorer functional status.5,24,25 In the present study, PSI score, low serum HCO 3 , duration of ICU stay, ESBL-producing K. pneumonia, MDR A. baumannii and polymicorbial pathogens were significantly associated with 30-day mortality in ICU patients with NHCAP. Patients with NHCAP can be categorized into four groups.13 In the present study, each group showed different characteristics in terms of age, sex, and comorbid diseases;
groups A and B had significantly different PSI scores, duration of ICU stay, and duration of mechanical ventilation compared with groups C and D. Other studies have suggested that underlying comorbid diseases, including malignancy, may increase in-hospital mortality in patients with HCAP,24,25 however, the present investigation revealed no significant difference in 30-day mortality according to NHCAP category in ICU patients, although the comorbid diseases were found to differ between categories. The PSI score and duration of ICU stay were found to be significantly associated with 30-day mortality in the present study.
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Table 3. Clinical characteristics of patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU), categorized into survivor and nonsurvivor groups. Patient group Characteristic
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR
95% CI
Statistical significance
Age, years Sex, male PSI score CURB-65 score, 3–5
70.4 12.2 212 (66.5) 144.1 23.3 283 (88.7)
73.7 10.5 75 (68.8) 151.8 21.9 103 (94.5)
3.35 1.11 7.73 2.18
0.771, 0.698, 2.727, 0.894,
5.921 1.776 12.731 5.335
P ¼ 0.011 NS P ¼ 0.003 NS
Comorbid diseases Hypertension Diabetes mellitus Cerebrovascular accident Hepatobiliary disease Cardiac disease Chronic respiratory disease Chronic kidney disease Malignancy
171 (53.6) 81 (25.4) 100 (31.3) 61 (19.1) 110 (34.5) 91 (28.5) 24 (7.5) 62 (19.4)
53 (48.6) 28 (25.7) 39 (35.8) 18 (16.5) 32 (29.4) 31 (28.4) 9 (8.3) 29 (26.6)
0.82 1.02 1.22 0.84 0.79 1 1.11 1.5
0.530, 0.617, 0.772, 0.470, 0.492, 0.615, 0.498, 0.905,
1.266 1.672 1.928 1.490 1.267 1.612 2.459 2.496
NS NS NS NS NS NS NS NS
7.38 0.13 64.3 25.3 2.8 0.5 12.9 9.2 29.1 24.6 1.30 1.13 21.3 5.9 11.7 29.0 14.5 14.8 10.7 7.0
0 2.38 0.11 1.35 0.07 0.06 1.7 2.36 2.91 0.14
–0.027, 0.028 –3.874, 8.628 –0.009, 0.230 –0.749, 3.456 –5.306, 5.169 –0.275, 0.398 0.394, 3.015 –9.322, 4.594 0.010, 5.802 –2.102, 1.818
Laboratory findings on ICU admission pH 7.38 0.12 PaO2, mm Hg 66.7 29.7 Albumin, g/dl 2.9 0.6 CRP, mg/dl 14.2 10.9 BUN, mg/dl 29.0 23.8 Creatinine, mg/dl 1.36 1.66 HCO 23.1 6.1 3 , mEq/l PCT,a ng/ml 9.4 18.9 Duration of ICU stay, days 11.6 7.4 Duration of MV, days 10.6 13.2
NS NS NS NS NS NS P ¼ 0.011 NS P ¼ 0.008 NS
Data presented as n (%) patient incidence or mean SD. a Initial PCT results were available for 164 patients in the survivor group and 58 patients in the nonsurvivor group. BUN, blood urea nitrogen; CI, confidence interval; CRP, C-reactive protein; CURB, confusion, urea, respiratory rate, blood pressure; HCO3, serum bicarbonate ion; MV, mechanical ventilation; OR, odds ratio; PaO2, arterial oxygen pressure; PCT, procalcitonin; PSI, pneumonia severity index. NS, no statistically significant between-group difference (P 0.05; 2-test, Fisher’s exact test or Student’s t-test).
A previous report26 showed prognostic scoring, including PSI, was good for predicting mortality in nonimmunocompromised patients with HCAP. Another study27 also suggested that PSI could be applied to assess the severity of illness in the management of patients with HCAP, although the discriminatory powers of PSI for 30-day mortality were significantly lower in patients with HCAP compared with
community-acquired pneumonia. Other studies6,8,28 have proposed that advanced care, or interventions including ICU admission and invasive mechanical ventilation, may be partially responsible for increased mortality in patients with HCAP. Studies also suggest that a longer duration of ICU stay may be associated with increased chance of invasive procedure, including nasogastric tube feeding or central catheterization, which may
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Table 4. Microbiological distribution in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit, categorized into survivor and nonsurvivor groups. Patient group Microbe type
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR 95% CI
Pathogen identified Polymicrobial pathogensa
197 (61.8) 8 (2.5)
73 (67.0) 7 (6.4)
0.85 0.534, 1.356 NS 3.53 1.249, 9.997 P ¼ 0.029
9 6 14 0
1.64 0.44 1.51 0.25
Gram-positive pathogen Streptococcus pneumoniae MSSA MRSA Enterococcus species
41 (12.9) 8 (2.5) 52 (16.3) 3 (0.9)
(8.3) (5.5) (12.8) (0)
0.769, 0.150, 0.934, 0.056,
3.493 1.303 2.452 1.475
Statistical significance
NS NS NS NS
Gram-negative pathogen Pseudomonas aeruginosa; 4 (1.3)/32 (10.0) 3 (2.8)/12 (11.0) 0.8 0.418, 1.521 NS MDR, n ¼ 7; non- MDR, n ¼ 44 Klebsiella pneumonia 14 (4.4) 5 (4.6) 0.96 0.336, 2.715 NS ESBL-producing K. pneumoniae 19 (6.0) 14 (12.8) 1.56 1.047, 2.326 P ¼ 0.020 Escherichia coli Acinetobacter baumannii, MDR n ¼ 26/non-MDR n ¼ 2 Haemophilus influenza Othersb Fungi
8 (2.5) 13 (4.1)/2 (0.6) 2 (0.6) 5 (1.6) 2 (0.6)
1 (0.9) 13 (11.9)/0 (0) 0 (0) 1 (0.9) 1 (0.9)
2.78 0.343, 22.469 NS 1.74 1.230, 2.457 P ¼ 0.006 0.34 0.071, 1.421 2.22 0.543, 12.849 0.68 0.061, 7.520
NS NS NS
Data presented as n (%) patient incidence. a Polymicrobial pathogens: MRSA and ESBL-producing K. pneumoniae (n ¼ 2 in survivor, n ¼ 3 in nonsurvivor group); MRSA and K. pneumoniae (n ¼ 2 in survivor group); MRSA and A. baumannii (n ¼ 2 in survivor, n ¼ 3 in nonsurvivor group); P. aeruginosa and S. pneumoniae (n ¼ 1 in survivor group); P. aeruginosa and ESBL-producing K. pneumoniae (n ¼ 1 in nonsurvivor group); and MRSA and H. influenzae (n ¼ 1 in survivor group). b Others: Moraxella catarrhalis (n ¼ 1 in survivor, n ¼ 1 in nonsurvivor group). CI, confidence interval; ESBL, extended-spectrum b-lactamase; MDR, multidrug resistant; OR, odds ratio; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus. NS, no statistically significant between-group difference (P 0.05; 2-test and Fisher’s exact test).
cause opportunistic infections such as MRSA, Escherichia coli, P. aeruginosa, or K. pneumoniae and increased in-hospital mortality rates.4,28 A lower serum HCO 3 level is known to be associated with intracellular acidosis and tissue hypoperfusion in severely ill patients with circulatory failure, which can cause increased lactic acidosis and mortality, particularly in ICU patients.29 There is no current data, however, relating serum HCO 3 level and prognosis in patients
with NHCAP, thus further studies are required. In the present study, the most frequently identified pathogen was MRSA rather than S. pneumoniae or P. aeruginosa, however, these pathogens did not affect 30-day mortality in ICU patients with NHCAP. Several studies30,31 have suggested that MRSA does not affect pneumonia-related mortality, particularly ventilator-associated pneumonia in ICU patients. Guideline-concordant HCAP therapy in cases of S. aureus or
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Table 5. Antibiotic treatment in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit, categorized into survivor and nonsurvivor groups. Patient group Treatment Inappropriate antibiotic therapya Monotherapy Cephalosporin Antipseudomonal penicillinb Fluoroquinolone Carbapenem Combination therapy b-lactamc þ fluoroquinolone b-lactam þ macrolide b-lactam þ clindamycin b-lactam þ aminoglycoside Antipseudomonal b-lactamd þ fluoroquinolone Antipseudomonal b-lactam þ macrolide Antipseudomonal b-lactam þ clindamycin Antipseudomonal b-lactam þ aminoglycoside Antipseudomonal b-lactam þ vancomycin
Survivor n ¼ 319
Nonsurvivor n ¼ 109
OR
95% CI
96/197 (48.7)
42/73 (57.5)
0.69
0.436, 1.081
24 (7.5) 3 (0.9) 1 (0.3) 1 (0.3)
4 (3.7) 0 (0) 0 (0) 2 (1.8)
2.14 0.74 0.75 0.17
0.724, 0.703, 0.705, 0.015,
6.299 1.786 1.787 1.874
59 (18.5) 18 (5.6) 20 (6.3) 3 (0.9) 103 (32.3) 10 (3.1) 51 (16.0) 8 (2.5) 18 (5.6)
18 (16.5) 7 (6.4) 7 (6.4) 2 (1.8) 41 (37.6) 5 (4.6) 13 (11.9) 2 (1.8) 8 (7.3)
1.55 1.15 1.03 0.51 0.84 0.6 1.41 1.38 0.76
0.330, 0.466, 0.421, 0.084, 0.544, 0.198, 0.732, 0.288, 0.319,
7.302 2.827 2.497 3.081 1.299 1.843 2.697 6.582 1.789
Data presented as n (%) patient incidence. a n patients/total n patients with identified pathogens and known antibiotic sensitivity test results. b Antipseudomonal penicillin comprised piperacillin/tazobactam. c b-lactam antibiotics comprised cefotaxime, ceftriaxone and cefpiramide. d Antipseudomonal b-lactam antibiotics comprised cefoperazone/sulbactam, piperacillin/tazobactam, cefepime and carbapenem. CI, confidence interval; OR, odds ratio.
P. aeruginosa infection is also suggested to have no association with improved 30-day mortality.6 Differences in initial antibiotic treatments between survivors and nonsurvivors were analysed in the present study and therapeutic regimens (including mono- or combination therapy) did not significantly differ between the two groups. There was no statistically significant difference in administration of inappropriate antibiotic treatment between the nonsurvivor and survivor groups, suggesting that inappropriate antibiotic treatment at admission in ICU patients with NHCAP does not affect 30-day mortality rates.
Conversely, the present study showed that ESBL-producing K. pneumoniae and MDR A. baumannii were significantly associated with infections in the nonsurvivor group, and that these two pathogens were associated with 30-day mortality. A recent study32 suggested the MDR pathogens did not increase the mortality in patients with NHCAP, therefore, inappropriate overuse of broad-spectrum antibiotics should not be advised. Compared with patients with community-acquired pneumonia, however, those with HCAP were reported as frequently infected by MDR pathogens,10 and the present data also showed that 13.8% of patients with NHCAP were identified with
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Table 6. Univariate and multivariate logistic regression analyses of factors associated with 30-day mortality in patients diagnosed with nursing and healthcare-associated pneumonia (NHCAP) admitted to an intensive care unit (ICU). Statistical test Univariate
Multivariate
Variable
OR
95% CI
Statistical significance
OR
95% CI
Statistical significance
Age PSI score HCO3– at admission Duration of ICU stay ESBL-producing Klebsiella pneumoniae MDR Acinetobacter baumannii Polymicrobial pathogens
1.027 1.014 0.953 0.985 2.33
1.006, 1.005, 0.919, 0.940, 1.161,
1.048 1.024 0.989 0.995 4.578
P ¼ 0.012 P ¼ 0.003 P ¼ 0.012 P ¼ 0.008 P ¼ 0.020
1.02 1.02 0.95 0.97 2.69
0.995, 1.004, 0.918, 0.950, 1.237,
NS P ¼ 0.009 P ¼ 0.020 P ¼ 0.010 P ¼ 0.013
2.5 3.53
1.295, 4.228 1.249, 9.977
P ¼ 0.006 P ¼ 0.029
3.08 4.16
1.504, 6.311 1.414, 12.547
1.040 1.026 0.993 0.993 5.840
P ¼ 0.002 P ¼ 0.011
CI, confidence interval; ESBL, extended-spectrum b-lactamase; HCO 3 , serum bicarbonate ion; ICU, intensive care unit; MDR, multidrug resistant; OR, odds ratio; PSI, pneumonia severity index. NS, no statistically significant difference (P 0.05).
MDR pathogens. Risk factors including ICU care and poor performance score may be associated with potential MDR pathogens in patients with HCAP,33 and the present study showed that ESBL-producing K. pneumoniae and MDR A. baumannii were significantly associated with 30-day mortality. These MDR pathogens are known to be significantly associated with severity of underlying disease, duration of prior hospital admission and prior use of thirdgeneration cephalosporin.34,35 Limited antibiotic choice for treating MDR pathogens may also be associated with higher rates of in-hospital mortality, however there are few studies relating to MDR A. baumannii in patients with HCAP, even though these patients are at higher risk of potential MDR Acinetobacter species.36 The results of the present study may be limited by several factors. First, given its retrospective nature, selection bias may have influenced the significance of the present findings and the possibility of recording errors related to baseline clinical data cannot be excluded. Secondly, the present
study was performed in a single institution, thus a multicentre study is required to validate the results. Thirdly, the characteristics of the four NHCAP subcategories occasionally overlapped in some patients, therefore, a more robust classification system is required. Despite these limitations, the present study evaluated clinical features in patients with NHCAP requiring ICU treatment, categorized into four NHCAP groups, and identified prognostic factors associated with mortality. In conclusion, 30-day mortality was not significantly different between four NHCAP subcategories13 in ICU patients with NHCAP. PSI score, duration of ICU stay, serum HCO 3 level, MDR pathogens such as ESBL-producing K. pneumoniae and MDR A. baumannii or polymicorbial infection were significantly associated with 30-day mortality in ICU patients with severe NHCAP. Declaration of conflicting interest The authors declare that there are no conflicts of interest.
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Acknowledgements The authors thank all members of the Department of Internal Medicine, Yonsei University Wonju College of Medicine, and Yonsei University Wonju Severance Christian hospital.
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