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Potential conflicts of interest. All authors: no

Mario Bonadio,1 Elisabetta Boldrini,2
Stefano Mori,1 Elena Matteucci,2
and Ottavio Giampietro2
Infectious Diseases Section and 2Metabolic Unit,
Department of Internal Medicine,
University Hospital, Pisa, Italy

1. Ribera Montes C, Pascual Perez R, Perez Barba
C, Orozco Beltran D, Pedrera Carbonell V. Risk
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2. Bonadio M, Boldrini E, Forotti G, et al. Asymptomatic bacteriuria in women with diabetes:
influence of metabolic control. Clin Infect Dis
2004; 38:e415.
3. Geerlings SE, Stolk RP, Camps MJ, et al.
Asymptomatic bacteriuria may be considered a
complication in women with diabetes. Diabetes





Mellitus Women Asymptomatic Bacteriuria

Utrecht Study Group. Diabetes Care 2000; 23:
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P, Miccoli R, Navalesi R. Urinary tract infection
in women with controlled diabetes. In: Losse
H, Asscher AW, Lison AE, Andriole VT, eds.
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Mogensen CE. How to protect the kidney in
diabetic patients: with special reference to
IDDM. Diabetes 1997; 46 (Suppl 2):S10411.
Matteucci E, Cinapri V, Rossi L, Lucchetti A,
Giampietro O. Glycated hemoglobin measurement: intermethod comparison. Diabetes Nutr
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medical care. Diabetes Care 2004; 27:S1535.

Reprints or correspondence: Dr. Mario Bonadio, Infectious

Diseases Section, Dept. of Internal Medicine, Ospedale S.
Chiara, 56100 Pisa, Italy (
Clinical Infectious Diseases 2004; 39:17334
 2004 by the Infectious Diseases Society of America. All
rights reserved. 1058-4838/2004/3911-0035$15.00

Legionnaires Disease and

the Updated IDSA Guidelines
for Community-Acquired
SirHaving read the updated Infectious
Diseases Society of America (IDSA) practice guidelines for the management of
community-acquired pneumonia (CAP)
in immunocompetent adults by Mandell
et al. [1], we agree that an update is appropriate, given the voluminous information that has accumulated during the
past 3 years. The key point that the
NCCLS cutoff points for resistance to penicillin and third-generation cephalosporins were not accurate in predicting outcome was appropriately emphasized [2, 3].
Unfortunately, the update on legionnaires
disease is not of the same rigor and quality
as other updates. In fact, the recommendations are not evidence-based, and data
to support opposing conclusions are
In recommendation 2, the IDSA guidelines recommend testing for Legionella
species only for patients with enigmatic
pneumonia, patients in the presence of an
epidemic, or patients who do not respond

1734 CID 2004:39 (1 December) CORRESPONDENCE

to b-lactam therapy. This recommendation is inconsistent with numerous studies

documenting that underdiagnosis of legionnaires disease is common and that the
incidence of Legionella pneumonia increases in direct relationship to the intensity of application of Legionella testing [4
9]. Moreover, in many observational
studies, Legionella is the third or fourth
most common cause of CAP in immunocompetent hosts [10]. The large-scale
pneumonia study conducted in Ohio by
the Centers for Disease Control and Prevention (CDC) [5] suggested that, in the
United States, only 3% of sporadic cases
of community-acquired legionnaires disease are diagnosed. Thus, we recommend
testing for Legionella species for all patients
admitted to the hospital with CAP. Our
recommendation is consistent with the basic infectious diseases principle of emphasizing laboratory diagnosis to allow targeted antibiotic therapy [11].
The IDSA guidelines recognize that a
delay in therapy is associated with an increased mortality rate [1, p. 1419]. However, illogically, they do not endorse testing
for all patients admitted to the hospital
with CAP, but instead endorse testing for
Legionella species if the patient does not
respond to therapy with a b-lactam; obviously, this will lead to a significantly
higher mortality, as has been documented
in a number of studies [12, 13].
Surprisingly, the IDSA guidelines suggest that some clinical features are suggestive of legionnaires disease. It has been
well established that the clinical syndrome
of Legionella pneumonia is nonspecific
and that accurate diagnosis requires laboratory testing that is specific for Legionella species. From 1982 through 2003, numerous studies demonstrating the lack of
any pathogonomic symptoms or signs
were published [1420].
The IDSA guidelines cite an unpublished CDC abstract in which a multivariate model was used to identify parameters
suggestive of legionnaires disease [21]. Although such an approach is interesting, it

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the HbA1c assay using immunological and

HPLC methods [7].
In addition, we note that recently, according to the American Diabetic Association [8], a preprandial plasma glucose
level of 90130 mg/dL has been recommended. These values are slightly lower
than those found in our diabetic women.
Furthermore, in our study [2], microalbuminuria and an increased plasma fibrinogen level (a well-known marker of
inflammation) were not demonstrated as
risk factors for ASB. Pyuria did occur at
a similar rate in bacteriuric women with
and without diabetes.
We confirm that, in our cohort of 176
women with type 2 diabetes, there was a
significant association between an increase
in the HbA1c level and the risk of developing ASB. We agree with Ribera Montes
et al. [1] that it is difficult to compare the
results of different reported studies, because patients included in the studies may
be very heterogeneous. For this reason,
studies are in progress in our laboratory
to identify further risk factors for ASB, in
addition to the role played by the degree
of metabolic control of diabetes.

for their recommendations as A IIIgood

evidence based on consensuswhen, in
actuality, the evidence supporting our recommendation of performing Legionella
diagnostic testing for all patients hospitalized with CAP is A IIgood evidence
with numerous supportive studies.
In recommendation 3, the IDSA guidelines indicate that treatment is appropriate
when there is epidemiological evidence of
disease despite negative test results. This
is a safe recommendation, and we do not
disagree with it. However, we point out
that it is now recognized that epidemic
is often not an appropriate term for legionnaires disease, because it connotes a
cluster of infections from a single-point
source over a short time period. Some
cooling towerassociated outbreaks of
large magnitude occur over a longer period of time (e.g., months) [28] and might
be more accurately described as areas of
endemicity in which a cluster of infections
is fortuitously discovered. In these instances, attention should be focused on
increasing the implementation of tests
specific for Legionella species, especially
urinary antigen tests, rather than on administering indiscriminate empiric antibiotic therapy to all individuals with CAP
in a large geographic area. Because some
of these cases may be caused by species of
Legionella other than Legionella pneumonphila serogroup 1 [29], culture of respiratory tract specimens on Legionella speciesselective media may be useful both in
identifying the pathogen and in allowing
identification of the source by molecular
subtyping of Legionella isolated from the
patient and the putative source.
Recommendation 4, the 21-day recommendation for the duration of antibiotic therapy, is obsolete. Cure rates of
90%100% have been reported for patients receiving antibiotics for 714 days,
including those receiving azithromycin [4,
30], clarithromycin [31], dirithromycin
[32], roxithromyicn [33], levofloxacin [26,
34], ofloxacin [35, 36] , sparfloxacin [37],
and grepafloacin [38]. A 35 day course

of therapy with oral azithromycin resulted

in a 100% cure rate in 2 studies [39, 40],
although we do not favor such a short
duration of antibiotic therapy. We recommend prolonged therapy only if the
patient has not responded (as defined by
objective signs, such as defervescence)
within 5 days after initiation of therapy.
It is important to keep in mind that the
original experience that suggested that a
longer duration of therapy was necessary
involved hospitalized patients and occurred without the knowledge that Legionella species could be in the water supply [41]. We suspect that many of these
patients, rather than experiencing relapses,
were merely reinfected with contaminated
water after treatment.
Although the IDSA recommendations
for a preferred treatment include erythromycin, most authorities agree that this
antimicrobial agent is no longer indicated.
Clinical experience with erythromycin
therapy was sufficiently poor that we recommended the addition of rifampin to
regimens that include erythromycin.
Given the advent of new macrolides, use
of erythromycin (and routine use of rifampin) is now obsolete for treatment of
Legionella pneumonia [42, 43].
The newer macrolides have morepotent intracellular activity and superior
penetration into lung tissue, alveolar macrophages, and WBCs. Moreover, they have
pharmacoeconomic advantages over earlier drugs, including once- or twice-daily
dosing. In comparative trials, azithromycin therapy was associated with a significantly lower incidence of adverse effects
and was cheaper than erythromycin therapy [4, 44].
In summary, the updated IDSA guidelines are generally appropriate, with the
exception of their comments on legionnaires disease. This portion of the guidelines is not only inaccurate, but could lead
to unwarranted morbidity and mortality
if clinicians heed these nonevidencebased recommendations.

CORRESPONDENCE CID 2004:39 (1 December) 1735

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is accepted that a validation study must

be done before such recommendations
can be taken seriously. The validation
study by Fernandez-Sabe et al. [22], however, showed that the criteria used in the
CDC abstract failed to differentiate legionnaires disease from pneumococcal
pneumonia. Unlike the CDC study, the
Winthrop University Hospital point-scale
formulated by Cunha [23] has been published. Moreover, it has been validated by
an independent investigator [24]. However, this study [23] was not cited in the
IDSA guidelines. The fatal flaw of those
studies that use various scoring systems to
assess etiologies of CAP is that the gold
standard, positive results of laboratory
tests for Legionella species, was often
skewed toward patients who had symptoms that were considered to be classic for
legionnaires diseasean overwhelming
bias, involving circular reasoning, that
would confound the study results.
We point out that the Winthrop University Hospital point scale (and other
scores) might be used to screen patients
for application of testing for Legionella
species, but with an emphasis diametrically opposite to that of the IDSA guidelines [25]. If the criteria are fulfilled, then
the patient should immediately receive antibiotics active against Legionella species as
empiric therapy without undergoing laboratory testing for Legionella species. But
if the criteria were not fulfilled, testing for
Legionella species could be performed for
those patients who may have legionnaires
disease without the classic syndrome. This
would minimize the chance of overlooking a treatable pneumonia with a high
Two recent studies [26, 27] show that
more than one-quarter of patients do not
have the classic risk factors of cigarette
smoking or chronic obstructive pulmonary disease, thus underscoring the fact
that using a syndromic approach will overlook patients who already have a high established mortality. The IDSA guidelines
incorrectly rated the supportive evidence

Potential conflicts of interest. V.L.Y. has received research funding from Abbott, Pfizer, and
Ortho-McNeil. All other authors: no conflicts.
Victor L. Yu,1 Julio Ramirez,2 Jorge Roig,3
and Miguel Sabria4



Veterans Affairs Medical Center, University of

Pittsburgh, Pennsylvania, and 2Division of Infectious
Disease, University of Louisville School of
Medicine, Kentucky; and 3Hospital Nostra Senyora
de Meritxell, Pulmonary Division, Andorra, and
Hospital Universitario i German Trias I Pujol,
Autonomous University of Barcelona, Spain











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Reprints or correspondence: Dr. Victor L. Yu, VA Medical

Center, Infectious Disease Section, University Dr. D, Pittsburgh, PA 15240 (
Clinical Infectious Diseases 2004; 39:17347
 2004 by the Infectious Diseases Society of America. All
rights reserved. 1058-4838/2004/3911-0036$15.00

Reply to Yu et al.
SirWe appreciate the opportunity to respond to the letter of Yu et al. [1], but we
were disappointed by its inflammatory
tone and by the fact that many of their
concerns resulted from incorrect interpretation or selective referencing of the Infectious Diseases Society of America
(IDSA) guidelines on management of
community-acquired pneumonia (CAP)
[2]. Their criticism of our recommendations for Legionella testing suggests that
Legionella species are the third or fourth
most common cause of CAP in immunocompetent hosts. This is clearly incorrect; their own article [3] deals with cases
of severe CAP, not all CAP cases.
They refer to the principle of emphasizing laboratory diagnosis to allow targeted antibiotic therapy. We in fact do exactly this. Recognizing the morbidity and
mortality associated with CAP among
hospitalized patients, we stressed initial
empiric therapy aimed at the pneumococcus and Legionella species, which are
the pathogens associated with the highest

mortality in the subset of patients with

severe CAP.
The reason for the specific wording that
we chose is that the guidelines must be
practical, and we must recognize that the
guidelines become medical legal documents. The reality of clinical practice is
that the majority of patients with CAP undergo no diagnostic studies for an etiological agent, other than blood cultures.
The Medicare audit of 18,000 patients
with CAP indicated that only 5% of those
admitted to intensive care units had undergone testing for Legionella species (Peter Houck, personal communication).
Our guidelines [2] attempted to reflect
some of the realities of clinical practice and
the need to establish good practice standards by stating that it is appropriate to
test for Legionella species in any patient
hospitalized with CAP, particularly if that
patient is seriously ill. Perhaps even more
importantly, we recommend rapid treatment with antibiotics that are always active
against Legionella species.
Yu et al. [1] state that, although we acknowledge that a delay in therapy is associated with an increased mortality rate,
we are illogical in not recommending that
all patients hospitalized with CAP receive
testing for Legionella species. They seem
to be confusing diagnostic tests with treatment and have missed the point entirely.
As stressed in the IDSA guidelines [2],
rapid treatment aimed at the likeliest pathogen, including Legionella species, is entirely in keeping with our concern for the
patient and our desire to minimize morbidity and mortality. The statement that
this will lead to a significantly higher
mortality [1] is a nonsequitur and is incorrect. The statement that tests for Legionella species should be used more
frequently, rather than administering indiscriminate empiric antibiotic therapy to
all individuals with CAP, [1] exemplifies
the letters misinterpretation coupled with
a propensity for inflammatory and misleading comments.
The IDSA guidelines, in agreement with
the American Thoracic Society guidelines

and the Canadian CAP guidelines, have

stressed the rationale behind both initial
empiric therapy and the specific regimens
recommended. The guidelines have been
repeatedly validated, and their use results
in a statistically significant decrease in the
cost, length of stay, and mortality associated with CAP.
Regarding duration of treatment, Yu et
al. [1] reject our recommendation of 21
days of therapy as obsolete, but they refuse to accept the findings of 2 studies
involving a short-course regimen of azithromycin [4, 5]. Actually, our exact recommendation was 1021 days, but it
should be less for azithromycin [2, p.
1419]. Accuracy and attention to detail
would strengthen their case considerably.
Although 21 days was the outside limit of
our recommendation, it was taken from
an article by Dr. Yu: A 21 day course has
been recommended for immunosuppressed patients or those with extensive disease
on chest radiographs [6, p. 685]. We are
not convinced that the differences here are
particularly profound.
The communication by Yu et al. [1] is
particularly disconcerting because it closes
with an unproven claim that appears to
prey on the fears of physicians. We recommend treating ambulatory and hospitalized patients with CAP with drugs that
are effective against legionnaires disease.
We fail to see how our recommendations
could possibly be construed as leading to
unwarranted morbidity and mortality. In
fact, these guidelines should substantially
improve outcomes for patients with legionnaires disease.

Potential conflicts of interest. L.A.M. has received research funding from Bayer, Bristol-Myers
Squibb, and Pharmacia; is a consultant for Bayer,
Pfizer, Aventis, and Ortho-McNeil; and is a member of the speakers bureau for Pfizer, Aventis, Wyeth, Ortho-McNeil, and Bayer. J.G.B. is on the HIV
Advisory Board of Bristol-Myers Squibb. T.M.F.
has received research funding from Abbott,
AstraZeneca, Bayer, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, and Wyeth; is a consultant for
Aventis, Bayer, GlaxoSmithKline, Ortho-McNeil,
Pfizer, and Wyeth; and is a member of the speak-

CORRESPONDENCE CID 2004:39 (1 December) 1737

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