A total of 1,395; 2,212; and 2,760 samples were included in the community-acquired (with and without healthcare exposure), and community-acquired LRTI diagnosed 48 hours to 7 days after admission, respectively. Of the 2,212 community-acquired LRTI with recent hospital admission or residence in a LTCF, 295 were obtained from patients coming from LTCFs, while 1917 were obtained from patients with previous hospital admissions. Samples taken from female patients accounted for 1884 / 6367 (29.6%) of the entire cohort. The mean age was 60.6 ± 19.9 years (median 65, IQR = 50 - 75), and the mean CCI was 5.7 ± 4.1 (median 5, IQR = 2 – 8.5). Samples were obtained in the pediatric ward (267, 4.2%); ICU (1823, 28.6%); emergency room and internal medicine wards (3190, 50.1%); oncology and hemato-oncology wards (190, 2.5%); and surgery and orthopedics wards (897, 14.1%). Sputum samples, tracheal aspirations or broncho-alveolar lavage were used in 3912 (61.4%), 1879 (29.5%), and 576 (9%) of all specimens, respectively. These demographic data are presented in Table 1.
Table 1: Characteristics of patients with LRTI
|
Entire cohort (N=6367 samples)
|
Age (Median, IQR)
|
65 (50,75)
|
Female (N (%) )
|
1884 (30)
|
Charlson comorbidity index (Median, IQR)
|
5 (2, 8.5)
|
Place and timing of acquisition
|
|
Community with no healthcare exposure (N (%))
|
1395 (21.9)
|
Community with healthcare exposure (N (%))
|
2212 (34.7)
|
Cultures obtained 48 hours – 2 days within admission (N (%))
|
2760 (43.3)
|
Department
|
|
Pediatric (N (%))
|
267 (4.2)
|
Internal medicine (N (%))
|
3190 (50.1)
|
Surgery-orthopedic (N (%))
|
897 (14.1)
|
Hemato-oncology (N (%))
|
190 (2.5)
|
ICU (N (%))
|
1823 (28.6)
|
Source of specimen
|
|
Sputum (N (%))
|
3912 (61.4)
|
Tracheal aspiration (N (%))
|
1879 (29.5)
|
Broncho-alveolar lavage (N (%))
|
576 (9)
|
LRTI, lower respiratory tract infection
Pathogen distribution among the three study cohorts is shown in Table 2. The probability of isolating bacteria which we initially expected to be “typical” community-acquired pathogens, namely Streptococcus pneumoniae, Hemophillus influenza, Bordatella spp., Moraxella spp., was higher among patients with community-acquired LRTI and with no healthcare exposure (p<0.0001 for all comparisons). Enterobacteriacea, non-fermenting gram negative bacteria, and other gram negative bacteria, were more frequently isolated from older patients with multiple comorbidities with community-acquired LRTI with recent hospital admission or residence in a LTCF and community-acquired LRTI diagnosed 48 hours to 7 days after admission, but were by far the most common pathogens isolated in all cohorts (p<0.0001 for all comparisons ; Figures 1,2), while Staphylococcus aureus was relatively equally distributed among the three study cohorts. These observations were also true when patients were divided into age groups (12-18 years, > 18-40 years, > 40 years; Figure 1), or according to the number of comorbid conditions included in the CCI (Figure 2).
Table 2: Pathogen distribution among patients with community-acquired, healthcare-associated and hospital-acquired LRTI
LRTI diagnosed 3-7 days after admission.
Absolute number (%) (N=2,760)
|
Community-acquired LRTI with healthcare exposure
Absolute number (%)
(N=2,212)
|
Community-acquired LRTI with no healthcare exposure
Absolute number (%)
(N=1,395)
|
Bacteria
|
860 (31.2%)
|
564 (25.5%)
|
371 (26.6%)
|
Citrobacter spp., enterobacter spp, Escherichia coli, Klebsiella spp.
|
302 (10.9%)
|
280 (12.7%)
|
276 (19.8%)
|
Hemophillus spp., Bordatella spp., Moraxella spp.
|
556 (22.1%)
|
539 (24.4%)
|
210 (15.1%)
|
Pseudomonas and Burkholderia spp.
|
225 (8.2%)
|
173 (7.8%)
|
66 (4.7%)
|
Serratia, Providencia and Proteus spp.
|
407 (14.8%)
|
354 (16.0%)
|
227 (16.3%)
|
Staphylococcus aureus
|
315 (11.4%)
|
161 (7.3%)
|
69 (4.9%)
|
Stenotrophomonas and Acinetobacter spp.
|
95 (3.4%)
|
141 (6.4%)
|
176 (12.6%)
|
Streptococcus pneumoniae
|
LRTI, lower respiratory tract infection. Community-acquired LRTI consist of samples taken within 0-2 days of hospital admission. Healthcare-associated LRTI consist of samples taken within 0-2 days of hospital admission and with recent healthcare exposure. Hospital-acquired LRTI consist of samples taken within 3-7 days of hospital admission.
Overall, the number of respiratory cultures was higher among patients older than 40 years compared to other age groups. The relative proportion of samples with a growth of Streptococcus pneumoniae was significantly higher (p<0.001) among patients aged 18 to 40 years (9.8% of all samples) when compared to younger patients (7.1%), or to adults aged more than 40 years (5.9%), although the absolute number of samples positive for this bacterium was much higher among older patients. Similarly, Hemophillus influenza, Moraxella spp., and Bordatella spp., were isolated in 15.1%, 18.1% and 12.6% of samples from patients aged 12 to 18 years, > 18 to 40, and > 40 years, respectively (p<0.001 for all comparisons), but the vast majority of samples positive for these bacteria were taken from patients older than 40 years.
Pathogen distribution in samples taken from patients in the ICU is shown in Table 3. Among patients with community-acquired with or without healthcare exposure LRTI, Streptococcus pneumoniae was over-represented among patients with CA-LRTI and healthcare-associated LRTI admitted to the ICU (accounting for 20% and 10.1% among patients admitted to the ICU versus 12.6% and 6.4% among patients in these cohort, p < 0.001 for both comparisons). Other typical community pathogens (Hemophillus influenza, Moraxella spp. and Bordatella spp.), gram negative bacteria and Staphylococcus aureus were not more prevalent among patients in the ICU when compared to their relative frequency in the entire cohort.
Table 3: Frequency of typical community pathogens and Staphylococcus aureus in respiratory tract cultures from hospitalized patients
Entire cohort
N=6367
|
|
ICU
N=1823
|
|
Community acquired LRTI (no healthcare exposure)
N=1395
|
Community acquired LRTI (with healthcare exposure)
N=2212
|
LRTI diagnosed 3-7 days after admission
N=2760
|
|
Community acquired LRTI (no healthcare exposure)
N= 454
|
Community acquired LRTI (with healthcare exposure)
N=426
|
LRTI diagnosed 3-7 days after admission
N=943
|
Streptococcus pneumoniae
N (%)
|
176 (12.6)
|
141 (6.4)
|
95 (3.4)
|
Streptococcus pneumoniae
N (%)
|
91(20)
|
43 (10.1)
|
32 (3.4)
|
Hemophillus influenza, Bordatella spp., Moraxella spp.
N (%)
|
276 (19.8)
|
280 (12.7)
|
302 (10.2)
|
Hemophillus influenza, Bordatella spp., Moraxella spp.
N (%)
|
89 (19.6)
|
92 (21.6)
|
87 (9.2)
|
Staphylococcus aureus
N (%)
|
227 (16.3)
|
354 (16)
|
407 (14.8)
|
Staphylococcus aureus
N (%)
|
89 (18.9)
|
70 (16.4)
|
98 (10.4)
|
Citrobacter, Enterobacter, K. pneumoniae, E. coli
N (%)
|
371 (26.6)
|
564 (25.5)
|
860 (31.2)
|
|
Citrobacter, Enterobacter, K. pneumoniae, E. coli
N (%)
|
113 (24.9)
|
112 (26.3)
|
324 (34.3)
|
Serratia, Providencia, Proterus
N (%)
|
66 (4.7)
|
173 (7.8)
|
225 (8.2)
|
|
Serratia, Providencia, Proterus
N (%)
|
19 (4.2)
|
27 (6.3)
|
77 (8.2)
|
Pseudomonas speciese, Burkholderia
N (%)
|
210 (15.1)
|
539 (24.4)
|
556 (22.1)
|
|
Pseudomonas speciese, Burkholderia
N (%)
|
32 (7)
|
51 (12)
|
174 (18.5)
|
Stenotrophomonas, Acinetobacter
N (%)
|
69 (4.9)
|
161 (7.3)
|
315 (11.4)
|
|
Stenotrophomonas, Acinetobacter
N (%)
|
24 (5.3)
|
31 (7.3)
|
151 (16)
|
The table shows the frequency of pathogens taken from patients hospitalized in all departments and in the intensive care unit (ICU) at the time of sample acquisition.
Among the 190 patients with active malignancy, relatively more samples were obtained through the use of broncho-alveolar lavage (21% versus 9% in the entire cohort). When compared to other patients, Pseudomonas spp. (25.3%) and gram negative bacteria (30%) were slightly more commonly isolated in these immunocompromised hosts, while Streptococcus pneumoniae (4.2%) and other typical community pathogens (7.9%) were less commonly isolated.
Antibiotic susceptibilities of various bacteria are shown in Table 4. Streptococcus pneumoniae was susceptible to penicillin in only around 50% of cases, and to erythromycin in 65% of cases. Streptococcus pneumoniae bacteria were susceptible in more than 95% of cases to fluoroquinolones (both ciprofloxacin and levofloxacin) and to 3rd generation cephalosporins (ceftriaxone). Other typical community-acquired pathogens (Hemophillus influenza, Moraxella spp., and Bordatella spp.) were also nearly universally susceptible to fluoroquinolones and 3rd generation cephalosporins, but about 25% were resistant to ampicillin. Gram negative bacteria were resistant to penicillins, penicillin and β-lactamase combinations, and 2nd generation cephalosporins in more than 50% of cases. Susceptibility rates to fluoroquinolones and 3rd generation cephalosporins were around 80% and 75% respectively (Table 4).
Table 4: Antimicrobial susceptibilities of typical community pathogens and Staphylococcus aureus in LRTIs
Antibiotic
% Susceptible
|
Penicillin
% susceptible
|
Ampicillin
% susceptible
|
Amoxicillin/Clavulonic acid
% susceptible
|
Oxacillin
% susceptible
|
Cefuroxime
% susceptible
|
Ceftriaxone
% susceptible
|
Ciprofloxacin
% susceptible
|
Levofloxacin
% susceptible
|
Erythromycin
%
susceptible
|
TMP/SMZ
% susceptible
|
Clindamycin
%
susceptible
|
Linezolid
% susceptible
|
Vancomycin
%
susceptible
|
|
Hemophillus, Bordatella, Moraxella
|
Community
N= 271
|
-
|
74
|
-
|
|
98.1
|
100
|
100
|
100
|
-
|
66.7
|
-
|
-
|
-
|
Healthcare associated N=242
|
-
|
75.6
|
-
|
|
99.6
|
99.6
|
88.9
|
89.5
|
-
|
84
|
-
|
-
|
-
|
Hospital N=284
|
-
|
71.9
|
97.3
|
|
99.6
|
100
|
95.5
|
100
|
-
|
63.3
|
-
|
-
|
-
|
|
Streptococcus pneumoniae
|
Community
N=176
|
59.1
|
-
|
-
|
|
-
|
97.9
|
-
|
98.6
|
73.4
|
81.3
|
83.1
|
100
|
100
|
HCA
N=141
|
43.4
|
-
|
-
|
|
-
|
95.3
|
|
97.2
|
58.5
|
83
|
72.9
|
100
|
100
|
Hospital
N=95
|
54.5
|
-
|
-
|
|
-
|
97.2
|
-
|
100
|
62.3
|
78.9
|
-
|
100
|
100
|
|
Citrobacter, Enterobacter, E. coli, Klebsiella
|
Community
N=371
|
-
|
14.9
|
58.4
|
|
69.2
|
84.3
|
89.9
|
-
|
-
|
85
|
-
|
-
|
-
|
HCA
N=564
|
-
|
8
|
47.9
|
|
49.4
|
68.7
|
77.5
|
-
|
-
|
71.1
|
-
|
-
|
-
|
Hospital
N= 860
|
-
|
6.7
|
49.8
|
|
51.7
|
70.4
|
82.8
|
-
|
-
|
74
|
-
|
-
|
-
|
|
Staphylococcus aureus
|
Community
N=227
|
23.6
|
-
|
-
|
83.5
|
-
|
-
|
81.1
|
65.6
|
66.5
|
99.6
|
-
|
100
|
100
|
HCA
N=354
|
17.4
|
-
|
-
|
63.9
|
-
|
-
|
66.3
|
-
|
56.8
|
-
|
57.3
|
100
|
99.4
|
Hospital
N=403
|
25.9
|
-
|
-
|
66
|
-
|
-
|
69.4
|
-
|
57.6
|
98.5
|
59.1
|
100
|
99.8
|
LRTI, lower respiratory tract infection. Test susceptibility, with Ceftriaxone as a reference.
Table 5 presents the frequency of typical community pathogens, gram negative bacteria, and Staphylococcus aureus among patients who died within 14 days of obtaining the index culture. Streptococcus pneumoniae and gram negative bacteria were disproportionally represented among patients who died in the community-acquired with no healthcare exposure LRTI group. Other typical community pathogens were disproportionally represented among patients who survived in all cohorts.
Table 5: Fourteen-day mortality among patients with respiratory cultures of typical community pathogens, Staphylococcus aureus, and Gram-negative bacillii
Community acquired LRTI with no healthcare exposure
N=1395
|
|
Community acquired LRTI with healthcare exposure
N=2212
|
|
LRTI diagnosed 3-7 days after admission
N=2760
|
Bacterial species
|
Dead
(N=161)
|
Alive
(N=1234)
|
Bacterial species
|
Dead (N=342)
|
Alive (N=1870)
|
Bacterial species
|
Dead (N=551)
|
Alive (N=2209)
|
Streptococcus pneumoniae
N=181
N (%)
|
29 (18)
|
152 (12.3)
|
Streptococcus pneumoniae
N=141
N (%)
|
18 (5.3)
|
123 (6.6)
|
Streptococcus pneumoniae
N=95
N (%)
|
9 (1.6)
|
86 (3.9)
|
Hemophillus influenza, Bordatella spp., Moraxella spp.
276
N (%)
|
26 (16.1)
|
250 (20.3)
|
Hemophillus influenza, Bordatella spp., Moraxella spp.
N=280
N (%)
|
29 (8.5)
|
251 (13.4)
|
Hemophillus influenza, Bordatella spp., Moraxella spp.
N=302
N (%)
|
36 (6.5)
|
266 (12)
|
Staphylococcus aureus
N=227
N (%)
|
29 (18)
|
198 (16)
|
Staphylococcus aureus
N=354
N (%)
|
62 (18.1)
|
292 (15.6)
|
Staphylococcus aureus
N=407
N (%)
|
95 (17.2)
|
312 (14.1)
|
Citrobacter, Enterobacter, K. pneumoniae, E. coli
N=371
N (%)
|
51 (31.7)
|
320 (25.9)
|
|
Citrobacter, Enterobacter, K. pneumoniae, E. coli
N=564
N (%)
|
123 (36)
|
441 (23.6)
|
|
Citrobacter, Enterobacter, K. pneumoniae, E. coli
N=860
N (%)
|
165 (29.9)
|
695 (31.5)
|
Serratia, Providencia, Proterus
N=66
N (%)
|
8 (5)
|
58 (4.7)
|
|
Serratia, Providencia, Proterus
N=173
N (%)
|
26 (7.6)
|
147 (7.9)
|
|
Serratia, Providencia, Proterus
N=225
N (%)
|
47 (8.5)
|
178 (8.1)
|
Pseudomonas species, Burkholderia
N=210
N (%)
|
17 (10.6)
|
193 (15.6)
|
|
Pseudomonas species, Burkholderia
N=539
N (%)
|
54 (15.8)
|
485 (25.9)
|
|
Pseudomonas species, Burkholderia
N=556
N (%)
|
116 (21.1)
|
440 (19.9)
|
Stenotrophomonas, Acinetobacter
N=69
N (%)
|
6 (3.7)
|
63 (5.1)
|
|
Stenotrophomonas, Acinetobacter
N=161
N (%)
|
30 (8.8)
|
131 (7)
|
|
Stenotrophomonas, Acinetobacter
N=315
N (%)
|
83 (15.1)
|
232 (10.5)
|
Factors associated with a 14 day mortality were analyzed in the entire cohort, including gram negative bacteria and typical community pathogens (Streptococcus pneumoniae, Hemophillus influenza, Moraxella spp., and Bordatella spp.). In the multivariable analysis, factors that were associated with increased mortality in the entire cohort were: age, admission to an ICU, admission to a surgical department, community-acquired LRTI with recent hospital admission or residence in a LTCF and community-acquired LRTI diagnosed 48 hours to 7 days after admission (when compared to “pure” community acquired infections), and infections with Staphylococcus aureus, Enterobacteriaceae, or Stenotrophomonas and Acinetobacter baummannii (Tables 6a and 6b).
Table 6a: Predictors for 14-day mortality among hospitalized patients with LRTI
Predictor
|
Adjusted OR (95% CI)
|
P-value
|
Age*
|
1.026 (1.02, 1.032)
|
<0.001
|
Department
|
Internal medicine
|
1 (reference)
|
|
Pediatric
|
0.57 (0.77, 4.27)
|
0.59
|
ICU
|
3.37 (2.34, 4.85)
|
<0.001
|
Oncology-hematology
|
0.53 (0.07, 3.97)
|
0.53
|
Surgery-orthopedic
|
2.48 (1.34, 4.60)
|
0.004
|
Bacterial species
|
Streptococcus pneumonia
|
1 (reference)
|
|
Gram negative bacteria associated with community-acquired infections⁋
|
0.83 (0.57, 1.21)
|
0.34
|
Staphylococcus aureus
|
1.55 (1.10, 2.19)
|
0.01
|
Non-fermenting gram negative bacteria€
|
1.06 (0.75, 1.49)
|
0.75
|
Opportunistic bacteria common among ICU patients¥
|
1.69 (1.16, 2.45)
|
0.006
|
Enterobacteriacea
|
1.39 (1.001, 1.93)
|
0.048
|
Other gram negative bacteria£
|
1.23 (0.83, 1.82)
|
0.30
|
Timing and place of acquisition
|
Community acquired without healthcare exposure
|
1 (reference)
|
|
Community acquired with healthcare exposure
|
1.64 (1.21, 2.23)
|
0.002
|
LRTI cases diagnosed 48 hours – 7 days after admission
|
3.08 (2.28, 4.15)
|
<0.001
|
OR, odds ratio; CI, confidence interval; ICU, intensive care unit; LRTI, lower respiratory tract infection
⁋ Hemophillus influenza, Moraxella and Bordatella spp.
€ Pseudomonas and Burkholderia spp
¥ Stenotrophomonas and Acinetobacter spp
£ Serratia, Providencia, and Proteus spp
*Increase for each year
Table 6b: Predictors for 14-day mortality among patients who had respiratory cultures with typical community pathogens
Predictor
|
Adjusted OR (95% CI)
|
P-value
|
Age*
|
1.025 (0.99, 1.05)
|
0.056
|
Charlson Comorbidity Index¶
|
Charlson Comorbidity Index = 0 (reference)
|
1
|
|
Charlson Comorbidity Index 1-4
|
0.40 (0.14, 1.15)
|
0.09
|
Charlson Comorbidity Index >4
|
0.56 (0.17, 1.84)
|
0.34
|
Department
|
Internal medicine
|
1 (reference)
|
|
Children
|
0.56 (0.17, 1.84)
|
0.34
|
ICU
|
2.23 (1.44, 3.55)
|
<0.001
|
Oncology-hematology
|
1.74 (0.63, 4.78)
|
0.28
|
Surgery-orthopedic
|
1.87 (1.07, 3.26)
|
0.03
|
Timing and place of acquisition
|
Community acquired (no healthcare exposure)
|
1 (reference)
|
|
Community acquired (with healthcare exposure)
|
0.88 (0.08, 9.32)
|
0.92
|
LRTI cases diagnosed 48 hours – 3 days within admission
|
0.97 (0.20, 4.82)
|
0.97
|
OR, odds ratio; CI, confidence interval; ICU, intensive care unit;
*Increase for each year
¶ An interaction was found between the Charlson Comorbidity Index and the place of acquisition. Subgroup analysis for healthcare-associated infection is described in the text above.
In the multivariable analysis that included only typical community-acquired pathogens (Streptococcus pneumoniae, Hemophillus influenza, Moraxella spp., and Bordatella spp.), factors that were associated with an increased risk of mortality included ICU and surgical ward admission. Because of a strong interaction between the place of acquisition and the CCI, the cohort was stratified into subgroups according to the place of acquisition and the multivariable analysis for a 14-day mortality was repeated. In the subgroup of community-acquired LRTI with recent hospital admission or residence in a LTCF, a CCI between 1 and 4, as well as a CCI greater than 4 were independent predictors for a 14-day mortality (OR 12.94, 95% CI 1.65, 101.15, p=0.01; OR 14.84, 95% CI 1.70, 129.15, p=0.01, respectively). The CCI was not associated with a 14-day mortality in the other subgroups.