SUPPLEMENT ARTICLE

Spectrum of Microbial Etiology of Community-

Acquired Pneumonia in Hospitalized Patients:
Implications for Selection of the Population
for Enrollment in Clinical Trials
Lionel A. Mandell
Clinical Infectious Diseases Editorial Advisory Board

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The title of this article implies that knowledge of the etiological pathogen may be useful in selection of patients
for clinical trials for community-acquired pneumonia (CAP). However, this remains to be seen. The clinical
course of a patient with CAP admitted to the hospital but not to the intensive care unit depends on a number
of variables, including the patient, the pathogen, and the hospital itself. The site-of-care decision can be based
on 1 of 2 prediction rules. Neither of these rules, however, correlates with the etiology of CAP, and it is not
clear whether they can be used to stratify patients according to prognostic factors. A pathogen may be found
in only approximately one-third of hospitalized patients with CAP overall. An etiological diagnosis is more
likely to be made for patients with CAP who are hospitalized in the intensive care unit (39%) than for those
hospitalized in other wards (20%). The issue of randomization to treatment regimens and possible approaches
to randomization are discussed. It seems clear, however, that randomization would have to take place im-
mediately after entry of the patient into the study. The possibility of using risks for specific pathogens or
risks for antimicrobial resistance is also addressed. However, there are no data to support the use of such
risks as prognostic factors in CAP. The best approach for noninferiority trials involving hospitalized patients
with CAP is to randomize patients who meet the inclusion criteria and to stratify them by hospital site, with
block randomization within each site. Stratification by site takes into account local epidemiology and can
balance differences in unmeasured confounders among sites.

The overall purpose of this workshop was to discuss
issues in the design and conduct of clinical trials of
antibacterial drugs for treatment of community-ac-
quired pneumonia (CAP). Because CAP is not a re-
portable disease, we do not have exact data, but it is
estimated that, every year, ∼4,000,000 people in the
United States will develop CAP. Of these, 80% receive
clinical management as outpatients, whereas 20% are
admitted to the hospital—18% receive care in a non–
Reprints or correspondence: Dr. Lionel A. Mandell, Div. of Infectious Diseases,
McMaster University/Henderson Hospital, 5th Floor, M Wing, 711 Concession St.,
Hamilton, Ontario, Canada L8V 1C3 (lmandell@mcmaster.ca).
Clinical Infectious Diseases 2008; 47:S189–92
 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4711S3-0015$15.00
DOI: 10.1086/591403
intensive care unit (ICU) hospital ward and 2% receive
treatment in the ICU. For the purposes of this article,
I focus on the 18% who are hospitalized but not in the
ICU.
The implication of the title of this article is that
knowledge of the etiological bacterium or other path-
ogen may be useful in selecting patients for clinical
trials. To select an appropriate patient population for
study, we need unambiguous inclusion and exclusion
criteria. We also must take into account the impact that
such criteria will have on our ability to recruit partic-
ipants, the effect on the overall design of the trial, and
our ability to generalize the results to the patients we
encounter in clinical practice.
Given the availability of antibacterial drugs that ap-
pear to be effective and that are generally well tolerated,

Etiologies of CAP in Hospitalized Patients • CID 2008:47 (Suppl 3) • S189

why bother to establish the microbial etiology of CAP in pa-
tients? There are, in fact, a number of reasons why it is im-
portant to know the etiological agent. Knowledge of the path-
ogen allows for specific, narrower-spectrum treatment directed
at the particular microorganism. By limiting the use of broad-
spectrum antibacterial drugs, there is less antibiotic-related se-
lection pressure and, hopefully, less development of resistance.
Through collection of information on the various etiological
pathogens responsible for CAP in a particular region and
knowledge of their susceptibility patterns, a database can be
generated that can be useful in the management of individual
cases or in the development of care pathways or of local, state,
or even national treatment guidelines. Microorganisms have
well-described patterns of infection—for example, the propen-
sity to cause meningitis, endocarditis, and so forth. Knowledge
of the etiology enhances the ability of the investigator to in-
terpret the clinical event. Last but not least, it is intellectually
satisfying to know what has caused the disease in a particular
patient.
If we look at the overall picture of an infected patient coming
into the hospital for treatment, there are 3 main variables that
might play a role in how the patient’s clinical course unfolds:
the etiological pathogen, the patient, and the hospital itself.
Although the title of this article focuses on the pathogen, it is
certainly appropriate to consider the other variables as well.
THE PATIENT
To assess a new antibacterial drug for patients ill enough to
require admission to the hospital, it is clear that participants
must be selected from among patients who are hospitalized
because they are truly ill and not because of other reasons, such
as social considerations. Patients must meet predefined criteria
that are acceptable to physicians and investigators and that have
been validated. Otherwise, it may be difficult to detect a ther-
apeutic effect in a clinical trial.
Whether to provide treatment to a patient with CAP as an
outpatient or inpatient is an extremely important decision, yet
admission rates for patients with CAP vary considerably [1, 2].
Two possible prediction rules are used to help in this selection
process. One is the pneumonia severity index, and the other
is the CURB-65 score [3, 4].
The pneumonia severity index assigns points to patients on
the basis of 20 different variables and then assigns patients to
1 of 5 risk classes on the basis of the points scored. Generally,
patients in classes I–III receive clinical management as out-
patients, whereas those in classes IV and V are admitted to the
hospital.
CURB-65 is an acronym and represents a point scale based
on confusion, urea level 17 mmol/L, respiratory rate ⭓30
breaths/min, low systolic or diastolic blood pressure, and age
⭓65 years. Patients with a score of 0 or 1 receive treatment as
S190 • CID 2008:47 (Suppl 3) • Mandell
outpatients, those with a score of 2 receive treatment in a non-
ICU hospital ward, and those with scores of ⭓3 may require
admission to the ICU.
The purpose of this article is not to discuss the merits of
these individual prediction rules. The pneumonia severity in-
dex, however, is heavily age weighted and has the potential to
underestimate serious cases, particularly among younger pa-
tients. With the CURB-65 score, it is not at all clear how any
one criterion could be selected as being more important than
another and thus used as the basis on which to stratify patients.
In considering these prediction rules, either rule could serve
as a reasonable means of selecting patients ill enough to require
inpatient management and possible enrollment in a therapeutic
trial. The prediction rules would help to exclude patients with
a low mortality risk who are generally considered to have mild-
to-moderate pneumonia. It is not clear, however, whether they
could be used to further stratify patients according to prog-
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nostic factors. There is no evidence that either of these rules
correlates with etiology.
THE PATHOGEN
A number of different pathogens may be etiological agents of
CAP. A review of 26 studies of hospitalized patients with CAP
conducted from 1994 to 2007 found that a pathogen was iden-
tified in only 3349 (33.7%) of 9933 patients [5]. Among the
patients for whom an etiological agent was found, it was a
bacterial pathogen in 2748 patients (82%) and an atypical or-
ganism in 601 patients (17.9%). The typical pathogens, in order
of decreasing frequency, were Streptococcus pneumoniae, Hae-
mophilus influenzae, and Staphylococcus aureus, and the atypical
pathogens were Mycoplasma pneumoniae, Chlamydophila pneu-
moniae, and Legionella pneumophila.
A recent study compared the clinical characteristics, etiology,
and outcomes of hospitalized patients with CAP who were
admitted to a non-ICU ward with those of patients admitted
to the ICU [6]. It was a retrospective cohort study conducted
at 2 tertiary care teaching hospitals and included a total of 730
patients: 585 in wards and 145 in the ICU. An etiological di-
agnosis was made for 177 (24%) of the 730 patients overall
but for 120 (20%) of the 585 patients in wards and 57 (39%)
of the 145 patients in the ICU. In order of decreasing frequency,
the pathogens were S. pneumoniae, S. aureus, and H. influenzae
in the wards and S. pneumoniae, S. aureus, and Pseudomonas
aeruginosa in the ICU.
For now, let us ignore the patient- and pathogen-related
variables and focus on the issue of randomization. A trial of
an antibacterial drug for treatment of CAP among hospitalized
patients likely will be a noninferiority study and will compare
patients randomly assigned to receive either the experimental
drug or a control drug. Under the assumption that patients
were screened at entry for CAP of acceptable severity, the time
of randomization becomes important. Patients could be ran-
domized either immediately after entry into the study or after
an initial course of broad-spectrum antibiotic therapy for a
defined period until a pathogen was identified.
From what we understand about the treatment of serious
pneumonia and the mechanisms of antibacterial action, the
delayed randomization method is not a true test of either the
experimental drug or the control drug. Many of the pathogens
would be killed by the initial antibiotic regimen, and there is
no washout period provided to get rid of the effects of such a
regimen. It is clear, therefore, that randomization would have
to take place immediately after entry into the study.
Unfortunately, at the time that the physician is deciding how
best to provide treatment to a seriously ill patient with CAP,
he or she usually does not know, with any degree of certainty,
what the pathogen is and certainly does not know its suscep-
tibility patterns. Therefore, using the etiological pathogen to
help select the patient population for enrollment into a clinical
trial is simply not feasible. Given this problem and the need
to begin treatment quickly, is it possible to select patients ac-
cording to risks for pathogens or risks for antimicrobial
resistance?
Risk factors for specific pathogens. Risk factors have been
defined for a number of pathogens, including both typical bac-
teria and atypical organisms. A recent review of the etiology of
CAP listed some of these factors [7]. Recognized risk factors
for S. pneumoniae, the most common of the etiological agents
of CAP, include dementia, seizure disorders, congestive heart
failure, cerebrovascular disease, chronic obstructive pulmonary
disease, HIV infection, black race, overcrowded living situation,
and smoking. Risk factors for S. aureus include advanced age,
underlying lung disease, and previous antibiotic use, whereas
the risk factors for H. influenzae are chronic obstructive pul-
monary disease treated with antibiotics or oral steroids within
the previous 3 months. For P. aeruginosa, pulmonary comor-
bidity is the major risk factor. Risks for Legionella species, the
most significant of the atypical pathogens from the perspective
of mortality, include recent repair of domestic plumbing, use
of hot tubs and whirlpool spas, renal and/or hepatic failure,
diabetes, and malignancy.
Although gram-negative bacterial pathogens, such as Enter-
obacteriaceae species and P. aeruginosa, have been recognized
as causes of CAP, their exact role and incidence has been the
subject of some debate. A study by Arancibia et al. [8] examined
consecutive patients with CAP hospitalized in a 1000-bed ter-
tiary care university teaching hospital. Gram-negative bacteria
were found in 60 (11%) of 559 patients, and a multivariate
analysis of individual risk factors for CAP due to gram-negative
bacteria found that probable aspiration, previous hospital ad-
mission, previous use of antibiotics, and pulmonary comor-
bidity were significant risk factors. The incidence of causative
Etiologies of CAP in Hospitalized Patients • CID 2008:47 (Suppl 3) • S191
gram-negative bacteria among patients with CAP increased ac-
cording to the number of risk factors present and reached 50%
in patients with at least 3 risk factors. The ORs, compared with
a baseline value, increased from 4.2 for patients with 1 risk
factor to to 39.3 for patients with 3 risk factors.
Risk factors for resistant bacteria. For the purposes of this
discussion, I focus on pneumococci and risk factors for S.
pneumoniae isolates resistant to b-lactams, macrolides, and flu-
oroquinolones. Recognized risk factors for infection caused by
b-lactam–resistant S. pneumoniae include age !2 years or 165
years, receipt of b-lactam treatment within the previous 3
months, exposure to a child who attends a day care center,
alcoholism, medical comorbidity, and immunosuppression.
A recent article examined the relative risk of infection with
macrolide- or fluoroquinolone-resistant pneumococci on the
basis of antibiotic use in the previous 3 months [9]. If no
previous antibiotic was used, the risk of infection with mac-
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rolide-resistant S. pneumoniae was !10%. If a nonmacrolide
antibiotic was used, the risk increased minimally, to ∼10%.
However, if a macrolide, particularly azithromycin, was used,
the risk increased to slightly 150% [9].
The risk of infection with fluoroquinolone-resistant pneu-
mococci was ⭐1% if there was no previous antibiotic use or
if an antibiotic other than a fluoroquinolone was used in the
previous 3 months. However, if a fluoroquinolone was used,
then the risk of infection with a fluoroquinolone-resistant
pneumococcus increased to ∼9%.
The important question now is whether there are data sug-
gesting that risks for specific pathogens or for antimicrobial
resistance can be used as prognostic factors in CAP. Unfor-
tunately, the answer is no.
Given that we are trying to select a patient population for
enrollment in a clinical trial, there are a number of questions
to be answered. What are the important prognostic indicators,
and on what basis can we stratify patients? What are the im-
portant outcome measures that will affect prognosis and
stratification?
Before we can provide answers to these questions, let us
consider certain facts. First and foremost, we do not know the
etiological pathogen or its antimicrobial susceptibility when
treatment is first started. Risk factors for pathogens and risk
factors for antimicrobial resistance often overlap, and there are
no definitive data linking risk factors for pathogens or resistance
to prognosis. Finally, it must be emphasized, once again, that
early initiation of antimicrobial therapy is important in the
management of serious CAP.
THE HOSPITAL
Ultimately, we are left with only one option—that is, to select
patients on the basis of a prediction rule (i.e., the pneumonia
severity index or CURB-65) and then to stratify patients by
hospital site, with block randomization at each site. The use
of stratification by site serves 2 important purposes. It takes
into account local epidemiology and balances differences in
unmeasured confounders among various sites. Confounders—
for example, rapidity of initiation of treatment and the use of
supportive measures, such as oxygen and fluid replacement—
may play a significant role in determining patient outcomes.
The spectrum of microbial etiology of CAP among hospitalized
patients, therefore, has no role to play in the selection of pa-
tients for enrollment in a therapeutic CAP trial. Until we have
readily available, validated, rapid diagnostic tests, it will con-
tinue not to have a role.
Acknowledgments
Supplement sponsorship. This article was published as part of a sup-
plement entitled “Workshop on Issues in the Design and Conduct of Clin-
ical Trials of Antibacterial Drugs for the Treatment of Community-Acquired
Pneumonia,” sponsored by the US Food and Drug Administration and the
Infectious Diseases Society of America.
Potential conflicts of interest. L.A.M. has received research funding
from Bayer, Chiron, Ortho-McNeil, Oscient, and Pfizer; has served as a
consultant to Bayer, Cempra, Novexel, Ortho-McNeil, Oscient, Pfizer, San-
ofi-Aventis, Targanta, and Wyeth; and has served on speakers’ bureaus for
Bayer, Ortho-McNeil, Wyeth, Oscient, Pfizer, and Sanofi-Aventis.
S192 • CID 2008:47 (Suppl 3) • Mandell
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