Azithromycin vs Cefuroxime Plus Erythromycin for Empirical Treatment of Community-Acquired Pneumonia in Hospitalized Patients: A Prospective, Randomized, Multicenter Trial

University of Louisville, Louisville, Kentucky, United States
Archives of Internal Medicine (Impact Factor: 17.33). 05/2000; 160(9):1294-300. DOI: 10.1001/archinte.160.9.1294
Source: PubMed
ABSTRACT
Objective
To compare the efficacy and safety of azithromycin dihydrate monotherapy with those of a combination of cefuroxime axetil plus erythromycin as empirical therapy for community-acquired pneumonia in hospitalized patients.
Methods
Patients were enrolled in a prospective, randomized, multicenter study. The standard therapy of cefuroxime plus erythromycin was consistent with the American Thoracic Society, Canadian Community-Acquired Pneumonia Consensus Group, and Infectious Disease Society of America consensus guidelines. The doses were intravenous azithromycin (500 mg once daily) followed by oral azithromycin (500 mg once daily), intravenous cefuroxime (750 mg every 8 hours), followed by oral cefuroxime axetil (500 mg twice daily), and erythromycin (500-1000 mg) intravenously or orally every 6 hours. Randomization was stratified by severity of illness and age. Patients who were immunosuppressed or residing in nursing homes were excluded.
Results
Data from 145 patients (67 received azithromycin and 78 received cefuroxime plus erythromycin) were evaluable. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% (28/145) and 13% (19/145), respectively. The atypical pathogens accounted for 33% (48/145) of the etiologic diagnoses; Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae were identified in 14% (20/145), 10% (15/145), and 9% (13/145), respectively. Clinical cure was achieved in 91% (61/67) of the patients in the azithromycin group and 91% (71/78) in the cefuroxime plus erythromycin group. Adverse events (intravenous catheter site reactions, gastrointestinal tract disturbances) were significantly more common in patients who received cefuroxime plus erythromycin (49% [30/78]) than in patients who received azithromycin (12% [8/67]) (P<.001).
Conclusions
Treatment with azithromycin was as effective as cefuroxime plus erythromycin in the empirical management of community-acquired pneumonia in immunocompetent patients who were hospitalized. Azithromycin was well tolerated.

Full-text

Available from: Emanuel N Vergis
Azithromycin vs Cefuroxime Plus Erythromycin
for Empirical Treatment of Community-Acquired
Pneumonia in Hospitalized Patients
A Prospective, Randomized, Multicenter Trial
Emanuel N. Vergis, MD; Amy Indorf, MD; Thomas M. File, Jr, MD; James Phillips, MD; Joseph Bates, MD;
James Tan, MD; George A. Sarosi, MD; J. Thomas Grayston, MD; James Summersgill, MD; Victor L. Yu, MD
Objective: To compare the efficacy and safety of azithro-
mycin dihydrate monotherapy with thoseof a combination
of cefuroxime axetil plus erythromycin as empirical therapy
for community-acquired pneumonia in hospitalized patients.
Methods: Patients were enrolled in a prospective, random-
ized, multicenter study. The standard therapy of cefurox-
ime plus erythromycin was consistent with the American
Thoracic Society, Canadian Community-Acquired Pneumo-
nia Consensus Group, and Infectious Disease Society of
America consensus guidelines. The doses were intravenous
azithromycin (500 mg once daily) followed by oral azithro-
mycin (500 mg once daily), intravenous cefuroxime (750
mg every 8 hours), followed by oral cefuroxime axetil (500
mg twice daily), and erythromycin (500-1000 mg) intrave-
nously or orally every 6 hours. Randomization was strati-
fied by severity of illness and age. Patients who were immu-
nosuppressed or residing in nursing homes were excluded.
Results: Data from 145 patients (67 received azithromy-
cin and 78 received cefuroxime plus erythromycin)
were evaluable. Streptococcus pneumoniae and Haemophi-
lus influenzae were isolated in 19% (28/145) and 13%
(19/145), respectively. The atypical pathogens
accounted for 33% (48/145) of the etiologic diagnoses;
Legionella pneumophila, Chlamydia pneumoniae, and
Mycoplasma pneumoniae were identified in 14% (20/
145), 10% (15/145), and 9% (13/145), respectively.
Clinical cure was achieved in 91% (61/67) of the
patients in the azithromycin group and 91% (71/78) in
the cefuroxime plus erythromycin group. Adverse
events (intravenous catheter site reactions, gastrointesti-
nal tract disturbances) were significantly more common
in patients who received cefuroxime plus erythromycin
(49% [30/78]) than in patients who received azithromy-
cin (12% [8/67]) (P,.001).
Conclusions: Treatment with azithromycin was as ef-
fective as cefuroxime plus erythromycin in the empiri-
cal management of community-acquired pneumonia in
immunocompetent patients who were hospitalized.
Azithromycin was well tolerated.
Arch Intern Med. 2000;160:1294-1300
C
OMMUNITY-acquired
pneumonia is the most
frequent general medi-
cine discharge diagnosis
and is the sixth leading
cause of death in the United States.
1,2
The
initial antibiotic regimen for community-
acquired pneumonia is generally empiri-
cal, since precise knowledge of the caus-
ative agent is not known at the time of
admission. Guidelines for initial therapy
in adults with community-acquired pneu-
monia have been published by the Ameri-
can Thoracic Society, Canadian Commu-
nity-Acquired Pneumonia Consensus
Group, and the Infectious Disease Soci-
ety of America.
3-5
For hospitalized pa-
tients, the use of one drug that has in vitro
activity against “typical” bacterial patho-
gens (Streptococcus pneumoniae and Hae-
mophilus influenzae) and a second drug that
has in vitro activity against “atypical”
pathogens (Legionella pneumophila, Chla-
mydia pneumoniae, Mycoplasma pneumo-
niae) was recommended for initial empiri-
cal use. These regimens included second-
or third-generation cephalosporins or the
b-lactam and b-lactamase inhibitors plus
a macrolide.
Since the publication of the 1993
American Thoracic Society guidelines, the
parenteral form of the new macrolide
azithromycin has become available for
commercial use. The Infectious Disease
Society of America guidelines recom-
mended empirical therapy with a b-lac-
tam with or without the addition of a mac-
rolide for patients hospitalized on a general
medical ward.
5
Azithromycin exhibits in
vitro activity against both typical and atypi-
cal bacterial pathogens.
6-8
Furthermore,
azithromycin has improved pharmacoki-
netics and excellent lung tissue penetra-
tion, allowing for once-daily administra-
tion and a shorter course of therapy.
Monotherapy has the advantages of sim-
ORIGINAL INVESTIGATION
From the Infectious Disease
Sections, Veterans Affairs
Medical Center and University
of Pittsburgh, Pittsburgh, Pa
(Drs Vergis and Yu), and
Summa Health System, Akron,
and Northeastern Ohio
Universities College of Medicine,
Rootstown, Ohio (Drs Indorf,
File, and Tan); Medical Service,
John L. McClellan Memorial
Veterans Affairs Medical Center,
Little Rock, Ark (Drs Phillips
and Bates); Medical Service,
Veterans Affairs Medical Center,
San Jose, and Stanford
University Medical School,
Stanford, Calif (Dr Sarosi);
School of Public Health and
Community Medicine, University
of Washington, Seattle
(Dr Grayston); and Infectious
Disease Laboratory, University
of Louisville School of Medicine,
Louisville, Ky (Dr Summersgill).
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plicity in administration and lower costs than those of
combination therapy. We therefore conducted a pro-
spective, randomized, multicenter study to compare
azithromycin as monotherapy vs cefuroxime plus eryth-
romycin for the treatment of hospitalized patients with
community-acquired pneumonia. The latter combina-
tion is a commonly prescribed regimen consistent with
American Thoracic Society, Canadian Community-
Acquired Pneumonia Consensus Group, and Infectious
Disease Society of America guidelines.
3-5
RESULTS
One hundred sixty-nine patients were enrolled. Sixteen
patients (10 from the azithromycin group and 6 from the
cefuroxime-erythromycin group) were excluded be-
cause (1) the diagnosis of pneumonia was not con-
firmed, including questionable evidence of pulmonary
infiltrate on chest radiograph in 5 patients, pulmonary
edema in 3 patients, and acute pericarditis in 1 patient,
and (2) protocol violations occurred, including unau-
thorized enrollment in 1 patient, improper informed con-
sent or withdrawal of consent in 3 patients, concurrent
antibiotic treatment at enrollment in 2 patients, and er-
roneous administration of both study regimens in 1 pa-
tient. An additional 8 patients (6 from the azithromycin
group and 2 from the cefuroxime-erythromycin group)
were excluded on the basis of clinical nonevaluability;
specifically, 7 patients received 48 hours or less of study
drug and 1 patient had infective endocarditis.
PATIENTS AND METHODS
STUDY POPULATION
Patients were eligible for participation in the study if they were
adults (aged $18 years) hospitalized with a primary diagno-
sis of community-acquired pneumonia. Community-
acquired pneumonia was defined as (1) a new pulmonary in-
filtrate compatible with pneumonia by chest radiograph and
confirmed by a radiologist; and (2) 1 or more signs and symp-
toms consistent with a lower respiratory tract infection, in-
cluding temperature greater than 38°C, new or increased
cough, production of purulent sputum, crackles, rhonchi, or
pleuritic chest pain or dyspnea; or (3) an elevated white blood
cell count (.10 3 10
9
/L) or greater than 0.15 band forms.
Patients were excluded from the study for the following
reasons: known hypersensitivity to b-lactam or macrolide an-
tibiotics, presence of gastrectomy or other condition affect-
ing drug absorption, receipt of chemotherapy or other immu-
nosuppressive therapy at time of pneumonia onset, known
acquired immunodeficiency syndrome, severe renal impair-
ment (creatinine clearance ,0.42 mL/s[,25mL/min]), neu-
tropenia (,0.5 3 10
9
/L), hospitalization within the preced-
ing 14 days, or nursing home residence. Patients who received
treatment with an antibiotic other than the study drugs within
24 hours before enrollment were excluded. The study was ap-
proved by each center’s institutional review board, and writ-
ten informed consent was obtained from all patients.
STUDY DESIGN
This prospective randomized, comparative, multicenter
study was conducted from 1994 to 1996 at 4 medical cen-
ters: the Veterans Affairs Healthcare Systems in Little Rock,
Ark, and Pittsburgh, Pa; Summa Health System, Akron,
Ohio; and Santa Clara Valley Medical Center, San Jose, Calif.
STUDY REGIMENS
The experimental regimen was azithromycin dihydrate ad-
ministered intravenously as a 1-hour infusion at a dosage
of 500 mg once daily for 2 to 5 days, followed by 500 mg
orally to complete a total of 7 to 10 days of therapy. The
control regimen was cefuroxime combined with erythro-
mycin. Cefuroxime was administered intravenously at a
dosage of 750 mg every 8 hours for 2 to 7 days, followed
by cefuroxime axetil at a dosage of 500 mg orally twice daily
to complete a total of 7 to 10 days of therapy. In addition,
erythromycin lactobionate or erythromycin base at a dos-
age of 500 to 1000 mg was given intravenously or orally
every 6 hours and continued for up to 21 days. This study
was nonblinded because of differences in drug dosing fre-
quency between azithromycin and cefuroxime combined
with erythromycin.
Patients were allocated to the regimens by computer-
generated random number method. Patients were first strati-
fied by severity of illness as defined by vital signs at onset
and age; these factors have been reported to be prognostic
of outcome in patients with community-acquired pneumo-
nia.
9
The prognostic factors were as follows: (1) abnormal
vital signs as defined by systolic blood pressure less than 90
mm Hg, pulse greater than 120 beats/min, or respiratory rate
greater than 30/min and (2) age of 65 years or greater. Ran-
domization was then performed for patients within each of
4 subgroups, eg, age of 65 years or greater and abnormal vi-
tal signs. This minimized disproportional allocation of high-
risk patients into one treatment regimen.
The study patients were monitored daily by the clini-
cal investigators at each participating site, and the deci-
sion to switch to oral therapy was made on the basis of im-
provement in cough, diminution in purulent sputum
production, defervescence, and reduction in leukocytosis.
MICROBIOLOGICAL INVESTIGATIONS
The following were routinely ordered for each study pa-
tient: a sputum specimen for culture and Gram stain; 2 sets
of blood cultures; specialized testing for Legionella species,
including culture of sputum on selective media,
10
direct fluo-
rescent antibody stains (monoclonal and polyclonal), uri-
nary antigen, serological studies (IgG and IgM) for L pneu-
mophila serogroups 1 through 6 and Legionella micdadei at
baseline (acute), at time of hospital discharge, and again at
4- to 6-week posttreatment follow-up visits; serological stud-
ies for antibody against C pneumoniae and M pneumoniae at
baseline, at time of hospital discharge, and again at 4- to 6-week
posttreatment follow-up visits by microimmunofluores-
cence and complement-fixation methods; polymerase chain
reaction assays of oropharyngeal swab specimens for detec-
tion of L pneumophila, C pneumoniae, and M pneumoniae
11
;
and culture of pleural fluid or bronchoalveolar lavage when
Continued on next page
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One hundred forty-five patients were assessed for
clinical response. Sixty-seven patients were assigned to
receive azithromycin and 78 patients were assigned to
receive cefuroxime-erythromycin. Patients randomized
to receive azithromycin received an average of 8 days of
intravenous and oral therapy, whereas patients random-
ized to receive cefuroxime plus erythromycin received
an average of 10 days of intravenous and oral therapy.
Thirteen patients (5 from the azithromycin group and 8
from the cefuroxime-erythromycin group) were admit-
ted to the intensive care unit during the course of the
study. Stratification variables of age and vital signs were
comparable among both groups, as expected. Initial physi-
cal symptoms, including chills, cough, shortness of breath,
and pleuritic chest pain, were comparable among both
groups (data not shown). The most common comorbid
illnesses and risk factors among patients in the azithro-
mycin group included cigarette smoking in 51% (34/
67), chronic obstructive lung disease in 37% (25/67), coro-
nary artery disease in 22% (15/67), type 2 diabetes mellitus
in 18% (12/67), chronic alcoholism in 16% (11/67), and
ulcer disease in 15% (10/67). The most common comor-
bid illnesses and risk factors in the cefuroxime-
erythromycin group included cigarette smoking in 56%
(44/78), chronic obstructive lung disease in 35% (27/
78), coronary artery disease in 36% (28/78), type 2 dia-
betes mellitus in 15% (12/78), chronic alcoholism in 14%
(11/78), and ulcer disease in 17% (13/78). The alloca-
tion of comorbid illnesses and risk factors was similar
for each treatment arm.
available. Sputum samples were considered suitable for cul-
ture if there were more than 25 polymorphonuclear leu-
kocytes and fewer than 10 squamous epithelial cells per low-
power field on a Gram stain. The DNA banding patterns
of Haemophilus influenzae were analyzed by means of pulsed-
field gel electrophoresis of SmaI digests.
Microbiological classification of pneumonia as defini-
tive or presumptive and identification of atypical patho-
gens were defined as follows: Definitive identification: (1)
blood or pleural fluid cultures yielding a pathogen; (2) iso-
lation of Legionella species from respiratory tract samples
or a 4-fold rise in Legionella antibody titer to 1:256 or greater;
(3) positive urinary antigen for L pneumophila serogroup
1; (4) positive polymerase chain reaction result with an-
other positive test result fulfilling the criteria for a pre-
sumptive diagnosis for L pneumophila, C pneumoniae,orM
pneumoniae; (5) 4-fold rise in IgG antibody titer for C pneu-
moniae to 1:32 or greater; or (6) 4-fold rise in IgG anti-
body titer for M pneumoniae to 1:32 or greater.
Presumptive identification was defined as follows: (1)
heavy or moderate growth of a predominant bacterial patho-
gen on sputum culture; (2) light growth of a pathogen in which
the sputum Gram stain showed a bacterium compatible with
the culture results; (3) in the case of multiple potential bac-
terial pathogens, if the Gram stain demonstrated the pres-
ence of multiple organisms consistent with those isolated on
culture, then multiple pathogens were considered to be the
cause; (4) L pneumophila: a single IgM antibody titer to 1:512
or greater or positive direct fluorescent antibody stain only;
(5) C pneumoniae: a single IgM antibody titer of 1:32 or more
or a single IgG antibody titer of 1:1024 or more; (6) M pneu-
moniae: a single IgM antibody titer of 1:64 or more; and (7)
positive polymerase chain reaction assay results alone were
considered presumptive evidence of infection with the atypi-
cal pathogens.
Unknown etiology was defined as follows: (1) “nor-
mal flora” on sputum culture, (2) light growth of multiple
organisms on culture, and (3) cases not fulfilling any of the
above conditions.
It should be noted that we applied stricter serological
criteria for the establishment of an etiologic diagnosis of an
atypical pathogen than were used in previous studies.
12,13
IN VITRO SUSCEPTIBILITY TESTING
Susceptibility testing was performed using agar-based
quantitative minimum inhibitory concentration (MIC)
determinations (E-test; AB BIODISK, Piscataway, NJ) for S
pneumoniae and broth microdilution (Clinical Microbiol-
ogy Institute, Tualain, Ore) for H influenzae. Susceptibility
to azithromycin was defined according to the 1997
National Committee for Clinical Laboratory Standards
(NCCLS) as an MIC of 2 µg/mL or less for S pneumoniae
and 4 µg/mL or less for H influenzae. Susceptibility to cefu-
roxime was defined according to the 1998 NCCLS as an
MIC of 0.5 µg/mL or less for S pneumoniae and 4 µg/mL or
less for H influenzae. Susceptibility to penicillin G was
defined according to the 1997 NCCLS as an MIC of 0.06
µg/mL or less for S pneumoniae and 0.75 µg/mL or less for
H influenzae.
END POINT ASSESSMENTS
Clinical response was the primary efficacy end point. Pa-
tients were assessed for symptoms and signs (cough, dysp-
nea, crackles, rhonchi, pleuritic chest pain) of infection at
baseline, day 3, and every 5 to 7 days during therapy, and
within 10 to 14 days and 4 to 6 weeks after treatment.
Clinical cure was defined as the receipt of a minimum
of 3 days of therapy with resolution of symptoms and signs
at conclusion of therapy. Clinical failure was defined as fail-
ure of symptoms and signs of pneumonia to resolve. Pa-
tients were considered to have nonevaluable data for clini-
cal efficacy if (1) they received 2 days or less of antibiotic
therapy, (2) they received concomitant antibiotics for treat-
ment of different infections, or (3) pneumonia was not con-
firmed radiographically after entry into the study. Second-
ary end points included adverse events and in-hospital
mortality.
STATISTICAL ANALYSIS
A sample size estimate of 140 was chosen to detect a dif-
ference in clinical response rates between azithromycin
and cefuroxime plus erythromycin of 14% with a power
of 80%. The calculations assumed an 85% cure rate in the
cefuroxime therapy group and 2-sided significance level
of 5%.
Clinical cure rates were compared between treat-
ment groups by the 2-sided Fisher exact test. Two-sided
95% confidence intervals (CIs) for the overall clinical cure
rates and mortality rates were computed by the normal ap-
proximation to the binomial. A P value of .05 or less was
considered to be statistically significant.
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CAUSATIVE AGENT
The most common causative agents were S pneumoniae,
L pneumophila, H influenzae, and C pneumoniae (
Table 1).
The most common agents that fulfilled the criteria for
definitive etiology were M pneumoniae, S pneumoniae, and
L pneumophila. Mixed etiologies were seen in 24 pa-
tients. There were 2 instances of concurrent infection with
2 definitive etiologies (S pneumoniae and M pneumoniae;
S pneumoniae and C pneumoniae); 5 instances of concur-
rent infection with a definitive etiology and a presump-
tive etiology, including M pneumoniae and L pneumophila
in 2 cases and M pneumoniae and Haemophilus species in
3 cases; and 3 instances of concurrent infection with 1
definitive etiology and 2 presumptive etiologies (M pneu-
moniae with C pneumoniae and L pneumophila; L pneumo-
phila with S pneumoniae and H influenzae; and L pneumo-
phila with Branhamella catarrhalis and H influenzae). The
remaining 14 multiple infections consisted of presump-
tive etiologies. No pathogens were identified in 41% of
patients (60/145).
SUSCEPTIBILITY TESTING
Nineteen isolates of S pneumoniae (5 from bloodstream
in 4 patients and 14 from sputum culture in 14 pa-
tients) and 18 isolates of H influenzae (1 from blood-
stream in 1 patient and 17 from sputum culture in 15
patients) were available for in vitro susceptibility test-
ing (
Table 2).
S pneumoniae Susceptibility
Twenty-eight patients had S pneumoniae pneumonia (21
presumptive, 7 definitive). In 18 patients, the isolate was
available for testing, with 1 patient having 2 isolates. Sev-
enteen were susceptible to azithromycin (MIC, #2.0 µg/
mL), 2 were resistant to azithromycin (MIC, $8.0 µg/
mL), 16 isolates were susceptible to erythromycin (MIC,
#0.25 µg/mL), 1 was intermediately susceptible to eryth-
romycin (MIC, 0.38 µg/mL), and 2 were resistant to eryth-
romycin (MIC, $3.0 µg/mL). Seventeen isolates were sus-
ceptible to cefuroxime (MIC, #0.19 µg/mL), and 2 isolates
were resistant to cefuroxime (MIC, 6.0-8.0 µg/mL). Fif-
teen isolates were susceptible to penicillin G (MIC, #0.02
µg/mL), 3 were intermediately susceptible to penicillin
G (MIC, 0.064-0.75 µg/mL), and 1 was resistant to peni-
cillin (MIC, 2.0 µg/mL). The 4 bacteremic isolates of S
pneumoniae that were available for testing were uni-
formly susceptible to azithromycin (MIC, #1.5 µg/
mL), erythromycin (MIC, 0.19 µg/mL), penicillin G (MIC,
#0.12 µg/mL), and cefuroxime (MIC, #0.19 µg/mL)
(Table 2). Three bacteremic isolates of S pneumoniae were
not available for in vitro susceptibility testing.
H influenzae Susceptibility
Nineteen patients had H influenzae pneumonia (18 pre-
sumptive, 1 definitive). In 16 patients, the isolate was avail-
able for testing, with 1 patient having 3 isolates. Sixteen
were susceptible to azithromycin (MIC, #2.0 µg/mL) and
2 were resistant (MIC, $4.0 µg/mL). Thirteen isolates
were susceptible to erythromycin (MIC, #4.0 µg/mL) and
5 were resistant (MIC, $8.0 µg/mL). Seventeen isolates
were susceptible to cefuroxime (MIC, #3.0 µg/mL) and
1 was resistant (MIC, 12.0 µg/mL). Twelve isolates were
susceptible to penicillin G (MIC, #0.75 µg/mL) and 6
were resistant to penicillin G (MIC, $6.0 µg/mL). The
1 bacteremic isolate was uniformly susceptible to azithro-
mycin (MIC, 0.75 µg/mL), erythromycin (MIC, 0.25 µg/
mL), penicillin G (MIC, 0.25 µg/mL), and cefuroxime
(MIC, 1.0 µg/mL) (Table 2). b-Lactamase production was
documented in 5 isolates of H influenzae.
Table 2. Clinical Efficacy for Isolates
of
Streptococcus pneumoniae
and
Haemophilus influenzae
Subclassified by In Vitro Susceptibility*
Pathogen
Azithromycin
Cefuroxime/
Erythromycin
Cure Failure Cure Failure
S pneumoniae
Penicillin sensitive
(n = 14)
80 (4/5) 20 (1/5) 100 (9/9) 0 (0/9)
Penicillin resistant
(n = 4)‡
100 (1/1) 0 (0/1) 67 (2/3) 33 (1/3)
Azithromycin sensitive
(n = 16)
80 (4/5) 20 (1/5) 91 (10/11) 9 (1/11)
Azithromycin resistant
(n = 2)§
100 (1/1) 0 (0/1) 100 (1/1) 0 (0/1)
H influenzae
\
Penicillin sensitive
(n = 12)
89 (8/9) 11 (1/9) 100 (3/3) 0 (0/3)
Penicillin resistant
(n = 4)¶
50 (1/2) 50 (1/2) 100 (2/2) 0 (0/2)
Azithromycin sensitive
(n = 16)
82 (9/11) 18 (2/11) 100 (5/5) 0 (0/5)
*
Data are given as percentage (number/total number).
Isolates from 18 of 28 patients were available for in vitro testing.
Fourteen isolates were susceptible to both azithromycin and penicillin,
2 isolates were resistant to both azithromycin and penicillin, and 2 isolates
were susceptible to azithromycin but resistant to penicillin.
Minimum inhibitory concentration range, 0.064 to 2 µg/mL.
§
Minimum inhibitory concentration range, 8 to greater than 256 µg/mL.
\
Isolates from 16 of 19 patients were available for in vitro testing. Twelve
isolates were susceptible to both azithromycin and penicillin, and 4 isolates
were susceptible to azithromycin but resistant to penicillin.
Minimum inhibitory concentration range, 6 to greater than 32 µg/mL.
Table 1. Etiologic Diagnoses in 145 Patients
With Community-Acquired Pneumonia*
Pathogen Definitive Presumptive Total
Streptococcus pneumoniae
72128
Legionella pneumophila
71320
Haemophilus influenza a
11819
Chlamydia pneumoniae
21315
Mycoplasma pneumoniae
12 1 13
Haemophilus
species 0 6 6
Branhamella catarrhalis
066
Staphylococcus aureus
066
Unknown . . .† . . .† 60
Total 29 84 173
*
Includes multiple etiologies in 24 patients. Data are given as number
of diagnoses.
Not applicable.
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STUDY END POINTS
The clinical cure rate was 91% (61/67) (95% CI, 82%-
97%) in the azithromycin group and 91% (71/78) (95% CI,
92%-96%) in the cefuroxime-erythromycin group (P = .95).
For the intention-to-treat analysis of all 169 patients, the
clinical cure rates were 75% (62/83) (95% CI, 64%-84%)
for the azithromycin treatment group and 83% (71/86) (95%
CI, 73%-90%) for the cefuroxime-erythromycin treat-
ment group (P = .26). The overall mortality rate was 2%
(3/145); the mortality subclassified by treatment group
(azithromycin vs cefuroxime combined with erythromy-
cin) was 3% (2/67) (95% CI, 0.4%-10%) and 1% (1/78)
(95% CI, 0%-7%), respectively. The overall mortality in the
intention-to-treat group was 2% (4/169); the mortality sub-
classified by treatment group (azithromycin vs cefurox-
ime combined with erythromycin) was 4% (3/83) and 1%
(1/86), respectively. The cause of death in the 3 patients
included cerebrovascular accident, pulmonary embolus, and
respiratory failure resulting from chronic obstructive lung
disease. Two patients did not have an etiologic diagnosis,
and 1 patient had sputum culture evidence of pneumonia
caused by H influenzae and serological evidence of pneu-
monia caused by C pneumoniae (presumptive). The iso-
late of H influenzae was not available for susceptibility test-
ing. Two of these patients (one with an unknown etiology
and one with presumptive evidence of mixed infection with
H influenzae and C pneumoniae) received azithromycin, and
the remaining patient (unknown etiology) received cefu-
roxime plus erythromycin.
CLINICAL RESPONSE BY SPECIFIC PATHOGENS
Clinical cure and failure rates by subclassified pathogen
for both antibiotic regimens are presented in
Table 3.
There were no clinical failures among cases with bacte-
remic pneumonia (definitive etiology) caused by S pneu-
moniae treated with azithromycin (2 patients) or cefu-
roxime-erythromycin (5 patients). In 21 patients with
sputum culture evidence of pneumonia caused by S pneu-
moniae (presumptive etiology), there was 1 clinical fail-
ure for both azithromycin and cefuroxime-erythromy-
cin. The 1 case of bacteremic pneumonia (definitive
etiology) from H influenzae was cured with cefuroxime-
erythromycin. In 18 patients with sputum culture evi-
dence (presumptive etiology) of pneumonia from H in-
fluenzae, there were 2 clinical failures of azithromycin.
There were no clinical failures of azithromycin among
the 4 cases of L pneumophila pneumonia classified as de-
finitive etiology and 1 clinical failure of cefuroxime-
erythromycin in the case of L pneumophila classified as
definitive etiology. In 13 patients with serological or poly-
merase chain reaction evidence of pneumonia caused by
L pneumophila (presumptive etiology), there was 1 clini-
cal failure of azithromycin.
ADVERSE EVENTS
Overall, there were 46 treatment-related adverse events
(8 among patients treated with azithromycin and 38
among patients treated with cefuroxime-erythromycin)
(
Table 4). Intravenous catheter site reactions (pain, swell-
ing, and redness) and gastrointestinal tract distur-
bances (nausea, vomiting, abdominal pain, and diar-
rhea) were more commonly seen with cefuroxime-
erythromycin than with azithromycin (P,.001).
DRUG COSTS
The antibiotic acquisition costs for azithromycin, cefu-
roxime, and erythromycin were obtained from each of
the 4 participating sites. The average drug cost per day
of hospitalization for 500 mg of azithromycin adminis-
tered intravenously once daily was $15.84 (range,
$13.50-$18.49). The average drug cost per day for 750
mg of cefuroxime administered intravenously every 8
hours was $10.45 (range, $8.10-$15.39), and for eryth-
romycin, 500 to 1000 mg administered intravenously ev-
ery 6 hours was $17.02 (range, $0.52-$29.12). The av-
erage drug cost per day after switchover to oral drug for
Table 3. Clinical Response Rate in 145 Hospitalized Patients*
Pathogen (N = 173)
Azithromycin
Cefuroxime/Erythromycin
Cure Failure Cure Failure
Definitive and presumptive etiologies
Streptococcus pneumoniae
(n = 28) 88 (7/8) 12 (1/8) 95 (19/20) 5 (1/20)
Haemophilus influenzae
(n = 19) 83 (10/12) 17 (2/12) 100 (7/7) 0 (0/7)
Branhamella catarrhalis
(n = 6) 100 (2/2) 0 (0/2) 100 (4/4) 0 (0/4)
Staphylococcus aureus
(n = 6) 100 (4/4) 0 (0/4) 100 (2/2) 0 (0/2)
Legionella pneumophila
(n = 20) 92 (11/12) 8 (1/12) 88 (7/8) 13 (1/8)
Chlamydia pneumoniae
(n = 15) 86 (6/7) 14 (1/7) 88 (7/8) 13 (1/8)
Mycoplasma pneumoniae
(n = 13) 100 (9/9) 0 (0/9) 100 (4/4) 0 (0/4)
Definitive etiologies only
S pneumoniae
(n = 7) 100 (2/2) 0 (0/2) 100 (5/5) 0 (0/5)
H influenzae
(n = 1) 0 (0/0) 0 (0/0) 100 (1/1) 0 (0/1)
L pneumophila
(n = 7) 100 (4/4) 0 (0/4) 67 (2/3) 33 (1/3)
C pneumoniae
(n = 2) 100 (2/2) 0 (0/2) 0 (0/0) 0 (0/0)
M pneumoniae
(n = 12) 100 (8/8) 0 (0/8) 100 (4/4) 0 (0/4)
Unknown (n = 60) 93 (25/27) 7 (2/27) 88 (29/33) 12 (4/33)
*
Data are given as percentage (number/total number). Multiple etiologies were identified in 24 patients.
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500 mg of azithromycin once daily was $8.69 (range,
$7.26-$10.22). The average drug cost per day for 500 mg
of cefuroxime axetil twice daily was $8.10 (range,
$6.10-$10.38), and for erythromycin, 500 to 1000 mg
taken every 6 hours was $0.48 (range, $0.32-$0.88). Costs
related to preparation and administration and adverse
events were not calculated, such that the pharmacoeco-
nomic superiority of monotherapy with azithromycin was
underestimated when compared with standard combi-
nation therapy given 3 to 4 times daily.
COMMENT
Antibiotic studies in community-acquired pneumonia
have been difficult to evaluate for a number of reasons:
(1) inclusion of patients with chronic bronchitis, (2) com-
parison with an antibiotic that is not an acceptable stan-
dard for community-acquired pneumonia, (3) dispro-
portionate inclusion of sicker patients to one arm of the
study more than another, and (4) failure to classify mi-
crobial etiologies as definitive or presumptive.
14
Our study incorporated a number of features de-
signed to overcome these weaknesses: (1) explicit clini-
cal and radiographic definitions for pneumonia were given
to ensure that patients with exacerbations of chronic bron-
chitis were excluded; (2) randomization was stratified by
age and severity of illness to minimize disproportionate
allocation of patients with poor prognostic factors; (3)
the study drug was compared with a standard antibiotic
regimen consistent with the American Thoracic Soci-
ety,
3
Canadian Community-Acquired Pneumonia Con-
sensus Group,
4
and Infectious Disease Society of America
5
guidelines; (4) etiologic diagnoses were classified as ei-
ther presumptive or definitive; and (5) extensive diag-
nostic modalities for the “atypical” pathogens were ap-
plied. The end points in our study were (1) clinical cure
as defined by the resolution of initial symptoms and signs
by 3 days after the initiation of antibiotic therapy and (2)
mortality.
Azithromycin treatment resulted in a 91% (61/67)
clinical cure, which was identical to the 91% (71/78) clini-
cal cure obtained with cefuroxime-erythromycin. The
mortality rate subclassified by treatment with azithro-
mycin vs cefuroxime-erythromycin was only 3% (2/67)
and 1.3% (1/78), respectively, despite the fact that 9%
of the patients were admitted to the intensive care unit.
None of the deaths were attributed to antibiotic failure.
The rank order of etiologic diagnoses was compa-
rable with that in many previous studies,
12,15-21
with S
pneumoniae being the most common etiologic agent, fol-
lowed by either H influenzae or L pneumophila. This study
also confirmed the rarity of aerobic gram-negative bacilli
or Pseudomonas aeruginosa as etiologic agents in immuno-
competent patients with community-acquired pneumo-
nia. Although gram-negative bacilli were isolated from spu-
tum culture in 5 patients, Gram stain confirmation was
lacking, and these were not considered pathogenic. Two
of these 5 patients were randomized to the azithromycin
group, and all experienced clinical cure, providing circum-
stantial evidence that these gram-negative bacilli were colo-
nizing rather than pathogenic microorganisms. It should
be noted that, despite the uncertainty of precisely delin-
eating a cause with current laboratory methods, both regi-
mens were effective therapy for virtually all patients.
The serum concentrations of azithromycin are rela-
tively low compared with those of b-lactam agents, such
that concern has been raised about its efficacy for pneu-
mococcal bacteremia. In our study, clinical cures were docu-
mented in the 2 patients with bacteremic pneumonia caused
by S pneumoniae treated with azithromycin. Similar clini-
cal cure rates were found for both regimens in our 28 pa-
tients with pneumonia caused by S pneumoniae. The effi-
cacy of azithromycin for patients with pneumococcal
bacteremia has been confirmed in other studies.
22-24
The S
pneumoniae sputum isolates from 2 patients in whom treat-
ment with azithromycin or cefuroxime-erythromycin failed
were both susceptible to azithromycin (MIC range, 1.5-
2.0 µg/mL) and to cefuroxime (MIC range, 0.047-0.19 µg/
mL), respectively (Table 2). The sputum isolate obtained
from the patient in whom cefuroxime-erythromycin treat-
ment failed was intermediately susceptible to both eryth-
romycin (MIC, 0.38 µg/mL) and penicillin G (MIC, 0.064
µg/mL). Azithromycin resistance in vitro has been re-
ported to be as high as 71% in penicillin-resistant pneu-
mococci.
25-27
It should be noted that azithromycin concen-
trations and half-life in alveolar macrophages, lung tissue,
and respiratory secretions are high compared with those
of other antimicrobial agents,
28-30
so correlation between
in vitro azithromycin resistance of pneumococci and sub-
sequent outcome is important. In one study of patients who
received erythromycin for pneumococcal pneumonia, the
presence of erythromycin resistance in vitro did not cor-
relate with subsequent outcome.
31
In our study, despite in
vitro resistance to azithromycin (MIC, 8.0 µg/mL) in S pneu-
moniae isolated from sputum, this patient was cured with
azithromycin (Table 2).
A clinical failure rate of 17% (2/12) was observed with
azithromycin in patients with pneumonia caused by H in-
fluenzae. The sputum isolates from these 2 patients were
susceptible in vitro to azithromycin (MIC, 2.0 µg/mL). An
increase in resistance to both azithromycin (MIC range, 8.0-
16.0 µg/mL) and erythromycin (MIC, $16 µg/mL) was ob-
served in 3 distinct sputum isolates of H influenzae from
the same patient obtained during azithromycin therapy. In
2 comparative studies of community-acquired pneumo-
nia, the bacteriological efficacy of azithromycin for pa-
Table 4. Incidence of Adverse Events by Antibiotic Regimen*
Adverse Event Azithromycin
Cefuroxime/
Erythromycin
P
All adverse events 12 (8/67) 49 (38/78) ,.001
Intravenous catheter site reaction† 6 (4/67) 36 (28/78) ,.001
Gastrointestinal tract‡ 1 (1/67) 23 (18/78) .002
Abnormal liver injury markers§ 7 (5/67) 3 (2/78) NS\
Ototoxic effects 0 (6/7) 1 (1/78) NS
*
Except for
P
, data are given as percentage (number/total number). Includes
multiple adverse events in 14 patients.
Includes pain, swelling, and redness.
Includes nausea, vomiting, abdominal pain, and diarrhea.
§
Includes elevated levels of alanine aminotransferase,
aspartate aminotransferase,
g
-glutamyltransferase, alkaline phosphatase,
and lactate dehydrogenase.
\
NS indicates not significant (
P.
.02).
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tients infected with H influenzae ranged from 94% (15/
16)
22
to 100% (30/30)
24
; interestingly, the comparative
regimens used had lower success rates (73% [8/11] and 85%
[29/34], respectively) than azithromycin, but the differ-
ences were not statistically significant. Oral azithromycin
(95%) was significantly superior to cefaclor (61%) for H
influenzae in a blinded study of 272 patients with acute lower
respiratory tract infection.
32
Clinical failures of azithromycin and cefuroxime-
erythromycin were seen in 8% (1/12) and 13% (1/8), re-
spectively, of patients with pneumonia caused by L pneu-
mophila. Similarly, clinical failures of azithromycin and
cefuroxime-erythromycin were seen in 14% (1/7) and 13%
(1/8), respectively, among patients with pneumonia
caused by C pneumoniae. There were no clinical failures
of either regimen in patients with pneumonia caused by
M pneumoniae.
Azithromycin was well tolerated. The incidence of
drug-related intravenous site reactions and gastrointes-
tinal intolerance was significantly less than with the ce-
furoxime-erythromycin regimen (P,.001) (Table 4).
We conclude that, for the initial, empirical treatment
of patients hospitalized for community-acquired pneumo-
nia, azithromycin as monotherapy was comparable with
cefuroxime-erythromycin with respect to clinical cure.
Azithromycin was significantly better tolerated than cefu-
roxime-erythromycin, with fewer adverse events. Finally,
azithromycin was less expensive than the combination of
cefuroxime plus erythromycin. The once-daily dose of
azithromycin may also result in better patient acceptance
and in compliance with the oral form once the switch is
made from intravenous therapy. (Appendices containing
information about the clinical failures with S pneumoniae
and H influenzae and information on aerobic gram-
negative bacilli are available on request.)
Accepted for publication October 14, 1999.
This study was supported in part by an educational
grant from Pfizer Laboratories, Inc, New York, NY.
Presented in part at the 35th Infectious Disease Soci-
ety of America Conference, San Francisco, Calif, Septem-
ber 15, 1997.
Reprints: Victor L. Yu, MD, Infectious Disease Sec-
tion (111E-U), Veterans Affairs Medical Center, Univer-
sity Drive C, Pittsburgh, PA 15240 (e-mail: vly+@pitt.edu).
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  • Source
    • "Two to fifteen percent of all hospitalizations for community-acquired pneumonias in Europe and North America are caused by Legionella and recent studies suggest that rates of legionellosis may be increasing [2]. The optimal antibiotic treatment of legionellosis has never been investigated in a randomized clinical trial, but most clinicians use either macrolides or fluoroquinolones [3,4] alone or combined with rifampicin [5]. "
    [Show abstract] [Hide abstract] ABSTRACT: Legionella is a common cause of bacterial pneumonia. Community-acquired [CAL] and hospital-acquired legionellosis [HAL] may have different presentations and outcome. We aimed to compare clinical characteristics and examine predictors of mortality for CAL and HAL. We identified hospitalized cases of legionellosis in 4 Danish counties from January 1995 to December 2005 using the Danish national surveillance system and databases at departments of clinical microbiology. Clinical and laboratory data were retrieved from medical records; vital status was obtained from the Danish Civil Registration System. We calculated 30- and 90-day case fatality rates and identified independent predictors of mortality using logistic regression analyses. We included 272 cases of CAL and 60 cases of HAL. Signs and symptoms of HAL were less pronounced than for CAL and time from in-hospital symptoms to legionellosis diagnosis was shorter for CAL than for HAL (5.5 days vs. 12 days p < 0.001). Thirty-day case fatality was 12.9% for CAL and 33.3% for HAL; similarly 90-day case fatalities in the two groups were 15.8% and 55.0%, respectively. In a logistic regression analysis (excluding symptoms and laboratory tests) age >65 years (OR = 2.6, 95% CI: 1.1-5.9) and Charlson comorbidty index > or =2 (OR = 2.7, 95% CI: 1.1-6.5) were associated with an increased risk of death in CAL. We identified no statistically significant predictors of 30-day mortality in HAL. Signs and symptoms were less pronounced in HAL compared to CAL. Conversely, 30-day case fatality was almost 3 times higher. Clinical awareness is important for the timely diagnosis and treatment especially of HAL. There is a need for further studies of prognostic factors in order to improve the therapeutic approach to legionellosis and potentially reduce mortality.
    Full-text · Article · May 2010 · BMC Infectious Diseases
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    • "La durée optimale du traitement antibiotique en cas de pneumonies communautaires sévères ayant nécessité l'hospitalisation en réanimation n'est pas connue. Les seuls travaux publiés qui ont essayé de répondre à cette question ont en fait porté sur des pneumonies peu sévères et en règle générale ont comparé deux molécules différentes, par exemple un macrolide de longue durée d'action ou une fluoroquinolone et une bêtalactamine1234. Il est cependant intéressant de noter que les recommandations récentes , qu'il s'agisse de celles faites par l'ATS (American Thoracic Society) ou par la Société européenne de pneumologie proposent de raccourcir la durée de traitement à sept à dix jours [5, 6] . "
    [Show abstract] [Hide abstract] ABSTRACT: A high number of controlled studies have shown that early and adequate antimicrobial treatment significantly improves the prognosis of severe infections in critically ill patients. In contrast, few well-designed trials have evaluated the optimal duration of antibiotic therapy. Consequently, current recommendations regarding this question are based primarily on clinical experience and expert opinions. In most cases, the number of organisms is significantly reduced within 24 hours provided that: antibiotics are appropriate, the patient is immunocompetent, the source of infection is controlled and there is no foreign material. In the majority of patients, a long duration (>8 days) is not justified and may contribute to increase the selection pressure for resistance. A recent prospective, randomised trial has shown that 8 days of adequate antibiotic therapy is an adequate duration for ventilator-associated pneumonia. Future trials will probably compare predefined different duration or discontinuation policies based on clinical response and evolution of biological markers.
    Preview · Article · Jun 2006 · Réanimation
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