Editorials
Does Guideline Adherence for Empiric
Antibiotic Therapy Reduce Mortality
in Community-acquired Pneumonia?
The single most important medical advance in the treatment of
patients with community-acquired pneumonia (CAP) in the past
century was the development of effective antibiotic agents in
the 1940s, reducing mortality from 30 to 35% in the preantibiotic
era to a current average of 5% among hospitalized and ambula-
tory adults with this illness (1, 2). More recently, two antibiotic-
related processes of care for hospitalized patients with CAP,
selection of appropriate empiric antibiotic therapy and rapid
administration of such therapy, were shown to reduce short-
term mortality (35). The recognition that large variability in
clinical practices exists and that certain processes of care are
associated with improved medical outcomes has led to the devel-
opment of clinical practice guidelines for the management of
CAP endorsed by professional organizations, such as the Ameri-
can Thoracic Society and the Infectious Diseases Society of
America (6, 7).
Despite a growing evidence base, whether appropriate empir-
ical antibiotic therapy improves medical outcomes for CAP re-
mains open to debate. Although several prospective and retro-
spective cohort studies showed a positive association between
guideline adherence for initial antibiotic selection and short-
term mortality (5, 811), others did not (12, 13). A recent meta-
analysis of 24 clinical trials failed to demonstrate any survival
benefit to inpatients with CAP receiving additional antibiotic
coverage for atypical pathogens (14), a practice recommended
by specialty society guidelines and supported by empiric observa-
tional data (57). It is the authors observation that the vast
majority of clinical trials for antibiotic therapy of lower respira-
tory infections are designed to establish equivalency of newer
proprietary agents rather than establish superiority of single or
combined classes of agents. As a result, the majority of such
trials are small in size and do not contribute to the most relevant
therapeutic questions for patients with CAP, such as will anti-
biotic therapy decrease mortality or hasten time to return to
baseline level of functioning.
In this issue, Menendez and coworkers (pp. 757762) con-
ducted a prospective study of 1,228 inpatients with CAP to deter-
mine: (1) which factors were associated with better adherence to
Spanish guidelines for initial antibiotic selection, and (2) whether
guideline adherence was associated with treatment failure or mor-
tality (15). Overall guideline adherence was excellent (80%), but
with substantial variability across study sites (range, 4797%).
Factors that were independently associated with guideline adher-
ence were hospital site, specialty of the physician in charge (higher
with a pulmonary resident or attending), and a higher severity of
illness at presentation based on the Pneumonia Severity Index.
Treatment in an intensive care unit was associated with lower
guideline adherence. After adjusting for disease severity and
physician characteristics, treatment with guideline-adherent an-
tibiotics led to a lower rate of treatment failure (odds ratio [OR],
Am J Respir Crit Care Med Vol 172. pp 655659, 2005
Internet address: www.atsjournals.org
0.65; 95% confidence interval [CI], 0.50.9), and to a sizeable
reduction in 30-day mortality (OR, 0.55; 95% CI, 0.30.9).
The study by Menendez and colleagues is one of the first to
assess the factors associated with adherence to guideline recom-
mendations for empiric antibiotic therapy for CAP. Although
these authors found that severity of illness and provider specialty
were associated with higher levels of adherence, the clinical
implications of these findings are uncertain. Severity of illness
at admission is a nonmodifiable patient characteristic, and the
vast majority of patients with CAP will continue to be treated
by primary care and emergency department physicians and not
by pulmonary or infectious disease specialists. It would have
been interesting to know if there were certain provider or hospi-
tal characteristics associated with guideline adherence, particu-
larly factors representing modifiable barriers or facilitators to
appropriate prescribing practices. For example, (1 ) what was
the role of provider knowledge and attitudes toward evidence-
based guidelines for CAP? and (2 ) did the sites have pneumonia
opinion leaders, standardized order forms, or computerized re-
minders to reinforce the guideline recommendations? A recent
cluster-randomized trial demonstrated that an intensive guide-
line implementation strategy (i.e., using real-time reminders, audit
and feedback, and continuous quality improvement activities)
was most effective at improving adherence to guideline recom-
mendations for empiric antibiotic therapy (16). Clearly, more re-
search focusing on the patient, provider, and system-level barriers
and facilitators of guideline adherence is an important step to-
ward improved quality of care for CAP.
The finding of Menendez and coworkers that guideline-com-
pliant antibiotic therapy was strongly associated with improved
survival suggests that the medical field is in a position to further
reduce the mortality of CAP. However, the magnitude of the
processoutcome association observed in this study must be in-
terpreted with caution for several reasons. First, nonrandomized
study designs, in contrast to clinical trials, are subject to con-
founding by unmeasured variables. Although Menendez and
colleagues adjusted for physician characteristics (specialty and
training status) and illness severity using the Pneumonia Severity
Index, they did not adjust for other processes of care (e.g., timely
administration of antibiotics, performance of blood cultures,
treatment duration, and the treatment adherence after discharge),
local microbial resistance patterns, or hospital characteristics
(e.g., teaching status and patient volume) that may influence
short-term mortality. Second, patients who died during the first
48 hours after admission were excluded from the analyses to
avoid cases unlikely to be affected by the selection of antibiotic
therapy. This is problematic because the exclusion of patients
who may have died despite full guideline adherence may have
biased the study results in favor of guideline adherence. Third,
the reduction in mortality after guideline adherence was only
observed in the less severely ill patients admitted to medical
wards. It is difficult to understand why the beneficial effects of
guideline adherence were demonstrable in patients of lower
disease severity compared with the more severely ill patients
who were managed in an intensive care unit. Finally, although
656 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 172 2005
patients treated by the same physician and within the same
hospital tend to be treated similarly, the authors did not adjust
for clustering at the physician or site level in their analyses,
which may have decreased the 95% confidence intervals and
increased the significance level of their results.
We find the results of Menendez and coworkers encouraging
for all who believe in the meritorious effects of practice guide-
lines and their association with improved patient outcomes.
However, given the observational nature of studies that have
attempted to quantify the magnitude of this effect, we remain
skeptical that better adherence to antibiotic recommendations
reduces mortality by almost 50%. In the future, methodologically
sound clinical trials are required that clearly establish the associa-
tion between recommended antibiotic treatments and clinically
relevant medical outcomes. Such trials should establish (1 ) the
efficacy of one or more classes of antibiotic agents by testing
superiority rather than equivalency hypotheses, and (2 ) the ef-
fectiveness of the best methods to translate practice guideline
treatment recommendations into clinical practice.
Conflict of Interest Statement : D.A. does not have a financial relationship with a
commercial entity that has an interest in the subject of this manuscript. M.J.F.
received $3,500 from Aventis Pharmaceuticals in 2004 and $1,000 from Zynx
Health Inc. in 2003, 2004, and 2005 for serving on an Advisory Board. He received
$2,000 in 2002 from STA Healthcare Communications, Inc. for providing a lecture
and received royalties in the amount of $120 per year from UpToDate, Inc. for
written materials. He currently has a grant for $43,000 from Pfizer, Inc.
Drahomir Aujesky, M.D., M.Sc.
University of Lausanne
Lausanne, Switzerland
Michael J. Fine, M.D., M.Sc.
VA Pittsburgh Healthcare System
Pittsburgh, Pennsylvania
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Bigger May Be Better
Targeted 2-Agonist Therapy
2-Agonists remain the most important inhaled bronchodilators
and provide rapid symptom relief for many patients. More than
thirty years after their introduction, short-acting, inhaled, selec-
tive 2-agonists remain the mainstay bronchodilators for asthma,
chronic obstructive pulmonary disease, and airway obstruction of
all etiologies. They act principally on smooth muscle 2-adreno-
ceptors, which are widely distributed throughout the human
bronchial tree, though the highest density of 2-receptors is in
alveolar regions (1). 2-Agonists are among the most prescribed
drugs worldwide, and the metered dose (polydisperse) aerosol
inhaler remains the most popular device. Nevertheless, aspects
of their use remain controversial (2). The relationship between
adrenoceptor haplotype and acute and chronic pharmaco-
dynamic (bronchodilator) response is complex (3). The article by
Usmani and colleagues in this issue of the Journal (pp. 704712)
JT, Weber GF, Petrillo MK, Houck PM, Fine JM. Quality of care,
process, and outcomes in elderly patients with pneumonia. JAMA 1997;
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DOI: 10.1164/rccm.2506009
adds important contributions to our understanding of 2-ago-
nists and bronchodilation in asthma (4).
This novel study explores in detail the relationship between
albuterol monodisperse aerosol particle size, total and regional
lung deposition, bronchodilator response, and, to a lesser extent,
systemic effects. This is a careful, rigorous (eight randomized
plus three additional visits) study employing a well-validated
system to produce monodisperse aerosols. It adds to the available
literature in confirming the authors earlier finding (5) that uni-
form 6-m albuterol particles gave greater bronchodilation than
smaller particles (1.5 or 3 m). It has long been known that very
small (submicron) particles are mainly inhaled and re-exhaled
(6). Larger particles ( 8 m) mainly impact in more proximal
airways and deposit in the oropharynx. In asthma, 2-agonists
are logically targeted at the main smooth muscle containing