Eur J Clin Microbiol Infect Dis (2005) 24: 377383

DOI 10.1007/s10096-005-1346-2

ARTICLE

F. Gutierrez M. Masia J. C. Rodrguez C. Mirete

B. Soldan S. Padilla I. Hernandez G. Royo
A. Martin-Hidalgo

Community-acquired pneumonia of mixed etiology: prevalence,

clinical characteristics, and outcome
Published online: 2 June 2005
C Springer-Verlag 2005

Abstract Community-acquired pneumonia (CAP) of

mixed etiology has increasingly been appreciated in the
literature, but its clinical significance remains unknown.
The aim of this analysis was to describe the prevalence,
clinical characteristics, and outcome of CAP of mixed etiology. Data were obtained from a 2-year prospective study
of consecutive patients with CAP in whom an extensive
microbiological workup was performed. Predefined strict
criteria were used to establish the etiology. A total of
493 patients were included. A single pathogen was detected in 222 (45%) cases and two or more pathogens in
28 (5.7%) cases. Mixed infections were seen across all age
groups and in patients treated both in hospital and as outpatients. The most frequent combinations of pathogens were
those of a bacterium plus an atypical organism (28.6%)
and of two bacterial organisms (28.6%). Compared with patients with monomicrobial pneumonia, patients with mixed
pneumonia were more likely to have underlying conditions (64% vs. 45%, p=0.04) and dementia (25% vs. 10%,
p=0.02). The incidence of a defined series of complications
was higher in patients with mixed pneumonia (39.3% vs.
18.6%; OR=2.84; p=0.02). Community-acquired pneumonia of mixed etiology is uncommon. Patients with mixed

F. Gutierrez (
) M. Masia C. Mirete B. Soldan

S. Padilla A. Martin-Hidalgo
Unidad de Enfermedades Infecciosas, Hospital General
Universitario de Elche,
Cam de la Almazara s/n,
03203 Elche, Alicante, Spain
e-mail: gutierrez fel@gva.es
Tel.: +34-96-6679154
Fax: +34-96-6679156
J. C. Rodrguez G. Royo
Microbiology Service, Hospital General Universitario de Elche,
Cam de la Almazara s/n,
03203 Elche, Alicante, Spain
I. Hernandez
Public Health Department, University Miguel Hernandez,
Campus de San Juan,
Alicante,, Spain

pneumonia are more likely to have underlying medical

conditions, and they may have a more severe course of
disease.

Introduction
Community-acquired pneumonia (CAP) is a common acute
medical condition worldwide. It remains a major cause of
admission to hospital and mortality in developed countries
and is a large contributor to excessive healthcare resource
consumption and cost [14].
Most cases of CAP are probably caused by a single
pathogen, but dual or multiple infections have been reported increasingly in the literature [57], and there is
growing concern for the concurrent presence of a second
pathogen in a significant proportion of cases of CAP previously thought to be monomicrobial [5, 712]. The potential importance of mixed infections is highlighted by recent
retrospective studies showing that combined antimicrobial
therapy that includes a macrolide, given empirically, may
reduce mortality associated with bacteremic pneumococcal
pneumonia [1315].
The frequency of CAP of mixed etiology has varied
greatly between studies, probably depending on several
factors, including diagnostic methods and criteria used for
etiological diagnosis and the occurrence of epidemic outbreaks during some studies. Most of the studies reporting
data on the prevalence of CAP mixed infections have focused either on patients admitted to hospital or on outpatients [1622]. In addition, previous reports have provided
limited information on the characteristics of the patients,
and the clinical significance of mixed infections has not
been investigated.
The aim of the present report is to describe the prevalence, clinical characteristics, and outcome of mixed infections in a cohort of patients with a broad clinical spectrum
of CAP, including both patients admitted to hospital and
outpatients, in whom an extensive microbiological workup
was performed.

378

Patients and methods

Setting and population studied
This was a prospective observational cohort study conducted from 15 October 1999 through 14 October 2001
at the Hospital General Universitario de Elche, a 430-bed
university-affiliated teaching hospital in Spain. All adult
patients (15 years) with signs and symptoms compatible
with pneumonia over the 24-month study period were
eligible for inclusion in the study. An active surveillance
program on CAP was established, and primary care
physicians were asked to refer to the hospital all patients in
whom a diagnosis of CAP was suspected. The study was
approved by the local ethical committee. Patients were
evaluated clinically and roentgenographically, and those
with a provisional diagnosis of CAP were seen by a study
investigator to confirm the diagnosis. CAP was defined as
an acute illness associated with at least one of the following
signs or symptoms: fever, new cough with or without
sputum production, pleuritic chest pain, dyspnea, or altered
breath sound on auscultation, plus a chest radiograph
showing an opacity compatible with the presence of acute
pneumonia. Patients with a prior hospitalization within 2
weeks of a current diagnosis of pneumonia were excluded.
Demographic and clinical data were collected by a study
investigator using a written standardized questionnaire. To
calculate the severity of pneumonia at presentation, we used
the pneumonia patient outcomes research team (PORT)
severity index (PSI) [23]. A repeat chest radiograph and
blood sample were obtained between 2 and 4 weeks after
the initial diagnosis of CAP. Patients were monitored for at
least 4 weeks or until death. Mortality was defined as death
due to any cause within 30 days of diagnosis of pneumonia.
Microbiological Investigations
The following clinical specimens were obtained for laboratory workup in patients with CAP: sputum samples for
Gram stain and culture, two blood samples for culture (only
in patients with fever 38 C), urine sample for detection
of Streptococcus pneumoniae and Legionella pneumophila
urinary antigens (in all patients in whom a urine sample
could be collected at the time of assessment, including
those who had received antibiotics before the evaluation),
and serum samples for serological testing drawn during
the acute stage of illness and 24 weeks later (range, 13
34 days) in all patients, except in those who died before
the convalescent sample was due to be obtained or in those
who failed to attend the follow-up visit. When bronchoscopic samples were obtained, these were cultured as well.
Only sputum samples that met standard criteria (presence of >25 leukocytes and <10 squamous cells per
low-magnification field [10]) were evaluated. Nurses
and doctors in charge of patients were asked to collect
sputum samples prior to the start of antibiotic therapy. The
Binax immunochromatographic assays (Binax, Portland,

ME, USA) were used to detect S. pneumoniae antigen and

L. pneumophila serogroup I antigen in concentrated urine
samples collected at the time of diagnosis of CAP.
A complement fixation (CF) test was performed to detect antibodies against Mycoplasma pneumoniae, Chlamydophila spp., Coxiella burnetii, influenza viruses A
and B, parainfluenza virus, respiratory syncytial virus,
and adenovirus. An indirect immunofluorescence test was
used to detect antibodies against Legionella pneumophila
and a microimmunofluorescence test to detect antibodies
against Chlamydophila pneumoniae and Chlamydophila
psittaci.
Criteria for etiological diagnosis
The following criteria were used to classify a case of pneumonia as being of known etiology: (i) for M. pneumoniae,
C. psittaci, Coxiella burnetii, influenza viruses A and B,
parainfluenza virus, respiratory syncytial virus, and adenovirus: a fourfold or greater antibody rise; (ii) for C. pneumoniae: a fourfold rise in antibody titers to 1/128 or greater,
or the presence of immunoglobulin M (IgM) antibodies
(1/20); (iii) for L. pneumophila: isolation of the organism
from respiratory samples, detection of Legionella antigen
in urine, or fourfold or greater rise in immunofluorescence
antibody titer; (iv) for S. pneumoniae: isolation of the organism from blood or pleural fluid, detection of S. pneumoniae as the predominant organism isolated from a qualified
sputum specimen, or detection of antigen in urine; (v) for
Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, and other bacteria, including gram-negative
enterobacteria: isolation of the organism from blood or
pleural fluid, or detection of the organism as the predominant organism isolated from a qualified sputum specimen. Cases that did not fulfill the etiological diagnostic criteria described above were considered pneumonia
of unknown etiology. Cases that fulfilled the etiological diagnostic criteria described above for more than one
pathogen were considered mixed pneumonia. Because of
possible nonspecific cross-reactions, cases with a fourfold
antibody rise against more than one species of Chlamydophila were excluded from the definition of mixed
pneumonia.

Statistical analysis
Descriptive statistics were computed by standard methods.
To detect differences between specified groups, we used
the chi-square test or Fishers exact test where appropriate
for categorical variables, and the Mann-Whitney U test or
the Students t test for continuous variables. A two-tailed
p value of 0.05 was considered significant. Statistical
precision of several test indices was determined by
calculating the 95% confidence interval (CI). Statistical
analyses were performed by means of the SPSS version
11 (SPSS Software, Chicago, IL, USA).

379

Results

Identification of etiological agents

Patient characteristics

Specimens obtained included blood cultures from 302

(61.2%) patients, urine from 454 (92.1%), acute and followup sera from 401 (81.3%), sputum from 272 (55.2%), and
lower respiratory secretions obtained by a bronchoscopic
procedure from 14 (2.8%). A total of 280 microorganisms
(140 bacteria, 110 atypical pathogens, and 30 viruses) in
250 (50.7%) patients were identified.
A single pathogen was detected in 222 (45%) cases
and two or more pathogens in 28 (5.7%) cases (Table 2).
The most frequent etiological agents were S. pneumoniae
(16.8%), M. pneumoniae (7.7%), Chlamydophila spp.
(6.1%), L. pneumophila (4.3%), gram-negative bacilli,

Of 516 patients with signs and symptoms compatible with

pneumonia, 23 were subsequently found not to have CAP,
leaving 493 patients in the study cohort. The main demographic characteristics of the patients are shown in Table 1.
Three hundred sixty-one (73.2%) patients were admitted to
hospital with a mean (SD) hospital stay of 6.45 (6.46)
days. The remaining 132 (26.8%) patients were managed
as outpatients.
Of the 361 patients admitted to hospital, 24 died within
the 4-week follow-up period, with a mortality rate of 6.6%
(95%CI, 4.409.87). Five of the 132 (3.8%) ambulatory
patients eventually required admission to hospital, but all
of them had a favorable outcome. The overall mortality
rate, including both inpatients and outpatients, was 4.8%
(95%CI, 3.217.26).
Table 1 Characteristics of 493 patients with community-acquired
pneumonia
Characteristic

No. (%) of patientsa

Mean age (range)

56.6 years (1594)

Distribution of cases by age group [no. (%)]

1544 years
4564 years
6574 years
75 years
Male gender
Regular cigarette smoker
Heavy alcohol consumption
Intravenous drug user
Predisposing cause for aspirationb
Underlying disease
Chronic obstructive pulmonary disease
Diabetes mellitus
Dementia
Immunosuppresion
Neoplasia
Congestive heart failure
Chronic renal failure
Previous antibiotic therapy

161 (32.7)
109 (22.1)
87 (17.6)
136 (27.6)
308 (62.5)
111 (22.5)
63 (12.8)
3 (0.6)
60 (12.2)
227 (46)
99 (20.1)
98 (19.9)
52 (10.5)
26 (5.3)
21 (4.3)
20 (4.1)
17 (3.4)
114 (23.1%)

Distribution according to PSI score

III
III
IV
V
Admission to hospital

267 (54.2)
103 (20.9)
94 (19.1)
29 (5.9)
361 (73.2)

PSI, pneumonia PORT (patient outcome research team) severity

index
a
Except where otherwise indicated
b
Reduced level of consciousness, underlying neurological disease,
dysphagia, impaired gag reflex, severe periodontal disease

Table 2 Distribution of the causative microorganisms identified in

493 patients with community-acquired pneumonia
Microorganism

No. (%) of casesa

Monomicrobial pneumoniab
Streptococcus pneumoniae
Mycoplasma pneumoniae
Legionella pneumophila
Chlamydophilia spp.c
Influenza virus
Pseudomonas spp.
Haemophilus influenzae
Gram-negative bacilli other than
Pseudomonas spp.d
Respiratory syncytial virus
Staphylococcus aureus
Moraxella catarralis
Coxiella burnetii
Adenovirus
Varicella-zoster viruse
Mixed pneumoniaf
Unknown

222 (45.0)
83 (16.8)
38 (7.7)
21(4.3)
30 (6.1)
14 (2.8)
11 (2.2)
9 (1.8)
5 (1.0)

4 (0.8)
2 (0.4)
1 (0.2)
2 (0.4)
1 (0.2)
1 (0.2)
28 (5.7)
243 (49.3)

Specimens obtained included urine from 454 (92.1%) patients, acute

and follow-up sera from 401 (81.3%), blood cultures from 302
(61.2%), sputum from 272 (55.2%), and lower respiratory secretions
obtained by a bronchoscopic procedure from 14 (2.8%). The following tests were all performed in a core of 235 (47.7%) patients: urine
antigen detection, acute and convalescent serological assays for atypical pathogens and viruses, blood cultures, and smear/cultures from
respiratory secretions (sputum or bronchoscopic samples)
b
Fifteen of the 222 (6.8%) cases were bacteremic infectionsdue to
Streptococcus pneumoniae (12 cases) or gram-negative bacilli (3
cases)
c
Chlamydophila pneumoniae (15 cases), and Chlamydophila psittaci
(9 cases). In 6 cases there was a fourfold antibody rise against
both Chlamydophila psittaci (complement fixation test) and Chlamydophila pneumoniae (microimmunofluorescence test)
d
Klebsiella spp. (2 cases), Escherichia coli (1 case), Citrobacter spp.
(1 case), and Stenotrophomonas spp. (1 case)
e
Diagnosed on the basis of clinical history and typical cutaneous lesions consistent with chickenpox, and a fourfold antibody rise (complement fixation test)
f
Two of the 28 (7.1) cases were bacteremic infections due to Streptococcus pneumoniae (1 case) or Listeria monocytogenes (1 case)

380
Table 3 Distribution of the
causative microorganisms
identified in 28 patients with
community-acquired
pneumonia of mixed etiology

a
In one case, S. pneumoniae was
isolated from blood culture
b
Isolated from blood culture
c
Diagnosed by cutaneous
lesions consistent with
chickenpox and a fourfold rise
in antibody (complement
fixation test)

Microorganisms

No. (%) of cases

Two organisms
Streptococcus pneumoniae plus other organism
S. pneumoniae, Legionella pneumophila
S. pneumoniae, Pseudomonas spp
S. pneumoniaea , Mycoplasma pneumoniae
S. pneumoniae, influenza virus
S. pneumoniae, Coxiella burnetii
S. pneumoniae, Klebsiella spp
S. pneumoniae, Moraxella spp
S. pneumoniae, Haemophilus spp
S. pneumoniae, Staphylococcus aureus
S. pneumoniae, Enterobacter spp
Two organisms other than S. pneumoniae
Chlamydophila pneumoniae, Legionella pneumophila
Mycoplasma pneumoniae, influenza virus
Mycoplasma pneumoniae, Haemophilus influenzae
Chlamydophila psitacci, Listeria monocytogenesb
Chlamydophila pneumoniae, Coxiella burnetti
Legionella pneumophila, influenza virus
Influenza virus, respiratory syncytial virus
Influenza virus, varicella-zoster virusc
Three organisms
S. pneumoniae, Staphylococcus aureus, Mycoplasma pneumoniae
S. pneumoniae, Mycoplasma pneumoniae, influenza virus

26 (92.9)
16 (57.1)
3 (10.7)
3 (10.7)
2 (7.1)
2 (7.1)
1
1
1
1
1
1
10 (35.7)
2 (7.1)
2 (7.1)
1
1
1
1
1
1
2 (7.1)
1
1

including Pseudomonas spp. (3.2%), and influenza virus

(2.8%). In 243 (49.3%) cases, the microbial etiology
remained unknown.
Causative pathogens were identified in 11 of the 24
(45.8%) patients who died. These were S. pneumoniae
(n=6), Pseudomonas spp. (n=1), Escherichia coli (n=1),
and mixed infections (S. pneumoniae plus Pseudomonas
spp. in 2 cases, and S. pneumoniae plus Staphylococcus
aureus in 1 case).
Characteristics of mixed infections
In 28 (5.7%) cases, pneumonia was considered mixed.
There was a wide variety of combinations of pathogens
(Table 3), the most frequent being a bacterial organism
plus an atypical organism (8 cases) and a combination
of two bacterial organisms (8 cases). The most common
mixed infections were S. pneumoniae with L. pneumophila
(3 cases), and S. pneumoniae with Pseudomonas spp.
(3 cases). S. pneumoniae was involved in 18 of the 28
(64.3%) cases of mixed pneumonia. According to specified
diagnostic criteria, 17.8% of all pneumococcal infections
(18 of 101) were mixed infections; the proportion was
28.6% (8 of 28) for viruses; 22.2% (6 of 27) for Legionella,
and 15.5% (7 of 45) for M. pneumoniae.
Specimens obtained for microbiological investigations
did not differ significantly between patients with mixed infections and those with monomicrobial CAP. Urine antigen
detection, sputum cultures, acute and convalescent serological assays for atypical pathogens and viruses, and blood

cultures were performed, respectively, in 96.4%, 78.6%,

71.4%, and 67.9% of patients with mixed infections, and in
95.9%, 63.5%, 76.1%, and 66.2% of those with monomicrobial CAP. No differences were observed, either, in the
proportion of patients in whom all the above-mentioned
tests were performed (57.1% vs. 55%, p=0.84). Patients
with mixed infection did not differ significantly from patients with monomicrobial infections with respect to major clinical and epidemiological characteristics (Table 4).
However, the presence of a predefined underlying condition was more common in patients with mixed infections
(18 of 27 [64.3%] cases of mixed pneumonia vs. 100 of 221
[45.2%] cases of monomicrobial pneumonia; p=0.04). Interestingly, patients with mixed pneumonia were less likely
to have diabetes as an underlying disease (1 of 28 [3.6%]
cases of mixed pneumonia vs. 49 of 222 [22.2%] cases of
monomicrobial pneumonia; p=0.02), and they were more
likely to have dementia (7 of 28 [25%] cases of mixed
pneumonia vs. 22 of 222 [10%] cases of monomicrobial
pneumonia; p=0.02). The most frequent combination of
pathogens found in patients with dementia was that of two
bacterial organisms (4 of the 7 cases).
No significant differences were found in any of the statistical analyses of single variables of morbidity or death
between patients with mixed infections and those with monomicrobial pneumonia. Patients with mixed pneumonia
tended to have a higher PSI score, a higher frequency of
admission to hospital, a higher frequency of pleural effusion
and hypoxemia, and a higher mortality rate (Table 4). When
comparing the incidence of a defined series of complications (pleural effusion, empyema, atelectasis, mechanical

381
Table 4 Characteristics of
patients with mixed pneumonia
compared with those with
monomicrobial pneumonia

COPD, chronic obstructive

pulmonary disease; PSI,
pneumonia PORT (patient
outcome research team) severity
index
a
Data are no. of patients/no. of
patients for whom data were
available (%), unless otherwise
indicated
b
One or more of the following
conditions: diabetes, chronic
lung or heart disease, chronic
liver disease, chronic renal
insufficiency, cancer,
immunosuppression, dementia,
malnutrition

Characteristic

Mixed pneumonia
(n=28)a

Monomicrobial
pneumonia (n=222)a

p
value

Median age
Male sex
Predefined underlying conditionsb
Alcoholism or cigarette smoking
Either predefined underlying conditionsb
or alcoholism or cigarette smoking
Diabetes mellitus
Dementia
COPD
Previous antibiotic therapy
Mean PSI score
No. of patients admitted to hospital
Mean length of hospital stay SD
Pleural effusion
Empyema
Hypoxemia (PaO2 <60 mmHg)
Bacteremia
Combined therapy with a macrolide plus a
-lactam agent
Antibiotic therapy not including a macrolide
or a fluoroquinolone
Deaths
Deaths among bacteremic patients

58 years
20/28 (71.4)
18/27 (64.3)
12/28 (42.9)
23/27 (85.2)

60 years
139/222 (62.6)
100/221 (45.2)
58/221 (26.2)
134/221 (60.6)

0.5
0.4
0.04
0.076
0.01

1/28 (3.6)
7/28 (25)
8/28 (28.6)
6/28 (21.4)
70.5
23/28 (82.1)
10.216.66 days
7/28 (25)
0
12/23 (52.2)
2/19 (10.5)
11/28 (39.3)

49/221 (22.2)
22/221 (10.0)
41/221 (18.6)
47/218 (21.6)
63.0
156/221 (70.6)
9.5535 days
25/220 11.4
2/221 (0.9)
69/183 (37.7)
15/147 (10.2)
97/219 (44.3)

0.02
0.02
0.2
1.0
0.1
0.2
0.31
0.06
1.0
0.2
1.0
0.6

9/28 (32.1)

50/219 (22.8)

0.3

3/28 (10.7)
0/2

8/222 (3.6)
4/15 (26.6)

0.1
1.0

ventilation, or septic shock) as a composite variable, we

found that it was higher in patients with mixed pneumonia (11 of 28 [39.3] cases of mixed pneumonia vs. 41 of
221 [18.6] cases of monomicrobial pneumonia; OR=2.84;
95%CI 1.246.54; p=0.02).
Discussion
In this study, a low proportion of cases of CAP was considered of mixed etiology. Mixed infections were seen across
all age groups, including elderly patients, and in outpatients
as well as patients treated in hospital. Several types of organism combinations were observed, as reported by others
[19, 21, 24]. Cases of mixed pneumonia have increasingly
been reported, particularly in studies that have applied sensitive diagnostic methods to identify infection with both
bacteria and viruses [57]. The proportion of cases of dual
or multiple infection in other pneumonia studies has varied widely, from no instances found [25] to 38% [7]. The
proportion of 6% found in our study was similar to that
reported in other recent studies of CAP [19, 24].
In previous studies, mixed infections were especially
common among patients with serological evidence of
C. pneumoniae infection [20, 2628]. Marrie et al. [27]
found that a second pathogen was implicated in 11 of 18
(61%) patients with serological evidence of infection with
C. pneumoniae, and McConnell et al. [28] noted the presence of a second agent in 7 of 17 (41%) patients with
primary infection with C. pneumoniae. In a more recent
study conducted at 15 teaching centres in eight Canadian

provinces between January 1996 and October 1997, 12 of

539 (2.2%) patients had acute C. pneumoniae pneumonia,
and an additional 32 (5.9%) had possible acute infection
[29]. Interestingly, C. pneumoniae was the sole pathogen
in only 16 of 42 (38.1%) of these patients. The most common copathogens were S. pneumoniae, respiratory syncytial virus, and influenza virus type A.
The detection of mixed infections is probably very dependent on the diagnostic tests employed. Although in the
present investigation an extensive microbiological workup
was carried out, we used neither nonserological virology
tests (e.g. immunofluorescence, viral culture) nor nucleic
acid amplification techniques. Probably, the number of
mixed infections would have been higher had these methods also been employed. This may be particularly important for detecting viral pathogens and may explain the relatively low number of viral infections identified in this
study.
The significance of mixed infections remains unknown.
Whether the accompanying organism is a true pathogen, a
permissive co-factor, or just an innocent bystander is difficult to ascertain in most cases. Previous studies have shown
that viral infection may pave the way for bacterial infection [30], as occurs when influenza virus infection leads
to secondary pneumonia due to Staphylococcus aureus or
S. pneumoniae [31]. Similar mechanisms may be true for
other pairs of infecting organisms as well. The relationship between viral infections and S. pneumoniae has been
highlighted by the reduction in the incidence of pneumonia
associated with respiratory viral infections in children vaccinated with the 9-valent pneumococcal conjugate vaccine,

382

presumably by preventing superimposed bacterial coinfection [32].

The possibility that some of these mixed infections represent false-positive results of diagnostic tests cannot be
formally excluded in the absence of a satisfactory gold
standard to establish the diagnosis of infection caused by
certain pathogens, as is the case for C. pneumoniae. In
contrast to previous studies, in our cohort, C. pneumoniae
was rarely associated with a second pathogen. The diverging results may be partly related to endemic and epidemic
conditions and partly to the microbiological methods used.
To diagnose C. pneumoniae infection, we applied a strict
definition according to current recommendations [2].
The analysis of cases of mixed pneumonia identified in
our study revealed interesting information. First, S. pneumoniae was the most frequent organism involved in mixed
pneumonia, present in two-thirds of the cases. Moreover, S.
pneumoniae was associated with another etiological agent
in one of every five cases in which this pathogen was identified. The interpretation of these results should take into
account that we accepted as an etiological diagnosis the detection of the urinary antigen of S. pneumoniae. Although
this test is considered highly specific for diagnosing pneumococcal pneumonia [33], false-positive results in cases
of colonization with S. pneumoniae have been described,
especially in children [34, 35] and patients with chronic
pulmonary diseases [36]. Therefore, some of the episodes
of mixed infection involving pneumococci found in our
cohort may actually represent false-positive results of the
urinary antigen assay. The involvement of pneumococci in
mixed pneumonia, however, has been also reported in other
recent pneumonia studies [19, 21, 24]. In the CBPIS study
carried out in patients with CAP requiring hospitalization
[21], there was evidence of definite infection with two
or more organisms in 14 of 154 (9%) cases of S. pneumoniae bacteremia (atypical pathogens, 10 cases; viruses,
2 cases; other pyogenic bacteria, 2 cases) compared with
an overall proportion of 1.8% for the whole cohort. Similarly, in the study conducted by Bochud et al. [19] in
patients with CAP treated in an ambulatory setting, S.
pneumoniae was involved in two-thirds of all cases of
mixed infection. Moreover, in that study, S. pneumoniae
was found in combination with another pathogen in 10 of
the 34 (28.4%) cases of pneumococcal pneumonia (viruses,
6 cases; atypical pathogens, 4 cases), a proportion even
higher than that found in our study.
A unique aspect of the current study was the comparison between patients with mixed infections and those with
monomicrobial infections, though the reduced number of
cases of mixed pneumonia limited our ability to detect
differences. We did not find clinical or epidemiological
features that distinguish patients with mixed pneumonia
from those with monomicrobial pneumonia, and the outcomes were similar for the two groups. Patients with mixed
infections, however, were more likely to have underlying
medical conditions and dementia as an underlying disease.
Although the importance of treating multiple infecting
pathogens has not been established, a number of observational studies indicates that the use of a macrolide with a

cephalosporin, as part of an initial empirical regimen for

patients with CAP admitted to hospital, may be associated
with shorter length of hospital stay and lower mortality rate
than treatment with a cephalosporin alone [3740]. In addition, recent data suggest an advantage in using an empirical
-lactam-macrolide combination rather than a monotherapy regimen for the treatment of CAP that is subsequently
determined to be associated with pneumococcal bacteremia
[1315]. However, all of these investigations were retrospective, with design limitations and several sources of
bias [41].
In summary, according to our results, CAP of mixed etiology is uncommon, S. pneumoniae is involved in most cases
of CAP, and, in contrast to previous data, acute CAP with
C. pneumoniae is rarely associated with a co-pathogen. Although there are no clinical or radiographic features that
distinguish mixed pneumonia from monomicrobial pneumonia, patients with CAP of mixed etiology are more likely
to have underlying medical conditions.
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