Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.

Abstract

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.
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.
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).
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

Page 1

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:Tocomparetheefficacyandsafetyofazithro-
mycindihydratemonotherapywiththoseofacombination
ofcefuroximeaxetilpluserythromycinasempiricaltherapy
forcommunity-acquiredpneumoniainhospitalizedpatients.
Methods:Patientswereenrolledinaprospective,random-
ized, multicenter study. The standard therapy of cefurox-
ime plus erythromycin was consistent with the American
ThoracicSociety,CanadianCommunity-AcquiredPneumo-
nia Consensus Group, and Infectious Disease Society of
Americaconsensusguidelines.Thedoseswereintravenous
azithromycin(500mgoncedaily)followedbyoralazithro-
mycin (500 mg once daily), intravenous cefuroxime (750
mgevery8hours),followedbyoralcefuroximeaxetil(500
mgtwicedaily),anderythromycin(500-1000mg)intrave-
nously or orally every 6 hours. Randomization was strati-
fiedbyseverityofillnessandage.Patientswhowereimmu-
nosuppressedorresidinginnursinghomeswereexcluded.
Results:Datafrom145patients(67receivedazithromy-
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
initialantibioticregimenforcommunity-
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
inadultswithcommunity-acquiredpneu-
moniahavebeenpublishedbytheAmeri-
can Thoracic Society, Canadian Commu-
nity-Acquired Pneumonia Consensus
Group, and the Infectious Disease Soci-
ety of America.3-5For hospitalized pa-
tients,theuseofonedrugthathasinvitro
activity against “typical” bacterial patho-
gens (Streptococcus pneumoniae and Hae-
mophilusinfluenzae)andaseconddrugthat
has in vitro activity against “atypical”
pathogens(Legionellapneumophila,Chla-
OMMUNITY-acquired
pneumonia is the most
frequent general medi-
cine discharge diagnosis
and is the sixth leading
cause of death in the United States.1,2The
mydia pneumoniae, Mycoplasma pneumo-
niae)wasrecommendedforinitialempiri-
caluse.Theseregimensincludedsecond-
orthird-generationcephalosporinsorthe
?-lactam and ?-lactamase inhibitors plus
a macrolide.
Since the publication of the 1993
AmericanThoracicSocietyguidelines,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 ?-lac-
tamwithorwithouttheadditionofamac-
rolideforpatientshospitalizedonageneral
medical ward.5Azithromycin exhibits in
vitroactivityagainstbothtypicalandatypi-
cal bacterial pathogens.6-8Furthermore,
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).
ARCH INTERN MED/VOL 160, MAY 8, 2000WWW.ARCHINTERNMED.COM
1294
©2000 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013

Page 2

plicity in administration and lower costs than those of
combination therapy. We therefore conducted a pro-
spective, randomized, multicenter study to compare
azithromycinasmonotherapyvscefuroximepluseryth-
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(10fromtheazithromycingroupand6fromthe
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-
thorizedenrollmentin1patient,improperinformedcon-
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
Patientswereeligibleforparticipationinthestudyiftheywere
adults(aged?18years)hospitalizedwithaprimarydiagno-
sis of community-acquired pneumonia. Community-
acquiredpneumoniawasdefinedas(1)anewpulmonaryin-
filtratecompatiblewithpneumoniabychestradiographand
confirmedbyaradiologist;and(2)1ormoresignsandsymp-
toms consistent with a lower respiratory tract infection, in-
cluding temperature greater than 38°C, new or increased
cough,productionofpurulentsputum,crackles,rhonchi,or
pleuriticchestpainordyspnea;or(3)anelevatedwhiteblood
cell count (?10 ? 109/L) or greater than 0.15 band forms.
Patientswereexcludedfromthestudyforthefollowing
reasons:knownhypersensitivityto?-lactamormacrolidean-
tibiotics, presence of gastrectomy or other condition affect-
ingdrugabsorption,receiptofchemotherapyorotherimmu-
nosuppressive therapy at time of pneumonia onset, known
acquiredimmunodeficiencysyndrome,severerenalimpair-
ment(creatinineclearance?0.42mL/s[?25mL/min]),neu-
tropenia(?0.5 ? 109/L),hospitalizationwithinthepreced-
ing14days,ornursinghomeresidence.Patientswhoreceived
treatmentwithanantibioticotherthanthestudydrugswithin
24hoursbeforeenrollmentwereexcluded.Thestudywasap-
provedbyeachcenter’sinstitutionalreviewboard,andwrit-
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:theVeteransAffairsHealthcareSystemsinLittleRock,
Ark, and Pittsburgh, Pa; Summa Health System, Akron,
Ohio;andSantaClaraValleyMedicalCenter,SanJose,Calif.
STUDY REGIMENS
Theexperimentalregimenwasazithromycindihydratead-
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
bycefuroximeaxetilatadosageof500mgorallytwicedaily
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-
generatedrandomnumbermethod.Patientswerefirststrati-
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.9The prognostic factors were as follows: (1) abnormal
vitalsignsasdefinedbysystolicbloodpressurelessthan90
mmHg,pulsegreaterthan120beats/min,orrespiratoryrate
greaterthan30/minand(2)ageof65yearsorgreater.Ran-
domization was then performed for patients within each of
4subgroups,eg,ageof65yearsorgreaterandabnormalvi-
talsigns.Thisminimizeddisproportionalallocationofhigh-
risk patients into one treatment regimen.
The study patients were monitored daily by the clini-
cal investigators at each participating site, and the deci-
siontoswitchtooraltherapywasmadeonthebasisofim-
provement in cough, diminution in purulent sputum
production,defervescence,andreductioninleukocytosis.
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,
includingcultureofsputumonselectivemedia,10directfluo-
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-to6-weekposttreatmentfollow-upvisits;serologicalstud-
ies for antibody against C pneumoniae and M pneumoniae at
baseline,attimeofhospitaldischarge,andagainat4-to6-week
posttreatment follow-up visits by microimmunofluores-
cenceandcomplement-fixationmethods;polymerasechain
reaction assays of oropharyngeal swab specimens for detec-
tion of L pneumophila, C pneumoniae, and M pneumoniae11;
and culture of pleural fluid or bronchoalveolar lavage when
Continued on next page
ARCH INTERN MED/VOL 160, MAY 8, 2000WWW.ARCHINTERNMED.COM
1295
©2000 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013

Page 3

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
intravenousandoraltherapy,whereaspatientsrandom-
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
comparableamongbothgroups,asexpected.Initialphysi-
calsymptoms,includingchills,cough,shortnessofbreath,
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),chronicobstructivelungdiseasein37%(25/67),coro-
naryarterydiseasein22%(15/67),type2diabetesmellitus
in18%(12/67),chronicalcoholismin16%(11/67),and
ulcerdiseasein15%(10/67).Themostcommoncomor-
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-
betesmellitusin15%(12/78),chronicalcoholismin14%
(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.Sputumsampleswereconsideredsuitableforcul-
ture if there were more than 25 polymorphonuclear leu-
kocytesandfewerthan10squamousepithelialcellsperlow-
power field on a Gram stain. The DNA banding patterns
ofHaemophilusinfluenzaewereanalyzedbymeansofpulsed-
field gel electrophoresis of SmaI digests.
Microbiologicalclassificationofpneumoniaasdefini-
tive or presumptive and identification of atypical patho-
gens were defined as follows: Definitive identification: (1)
bloodorpleuralfluidculturesyieldingapathogen;(2)iso-
lation of Legionella species from respiratory tract samples
ora4-foldriseinLegionellaantibodytiterto1:256orgreater;
(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-
sumptivediagnosisforLpneumophila,Cpneumoniae,orM
pneumoniae;(5)4-foldriseinIgGantibodytiterforCpneu-
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)
heavyormoderategrowthofapredominantbacterialpatho-
genonsputumculture;(2)lightgrowthofapathogeninwhich
thesputumGramstainshowedabacteriumcompatiblewith
the culture results; (3) in the case of multiple potential bac-
terial pathogens, if the Gram stain demonstrated the pres-
enceofmultipleorganismsconsistentwiththoseisolatedon
culture, then multiple pathogens were considered to be the
cause;(4)Lpneumophila:asingleIgMantibodytiterto1:512
or greater or positive direct fluorescent antibody stain only;
(5)Cpneumoniae:asingleIgMantibodytiterof1:32ormore
orasingleIgGantibodytiterof1:1024ormore;(6)Mpneu-
moniae: a single IgM antibody titer of 1:64 or more; and (7)
positive polymerase chain reaction assay results alone were
consideredpresumptiveevidenceofinfectionwiththeatypi-
cal pathogens.
Unknown etiology was defined as follows: (1) “nor-
mal flora” on sputum culture, (2) light growth of multiple
organismsonculture,and(3)casesnotfulfillinganyofthe
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-
tientswereassessedforsymptomsandsigns(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
of3daysoftherapywithresolutionofsymptomsandsigns
atconclusionoftherapy.Clinicalfailurewasdefinedasfail-
ure of symptoms and signs of pneumonia to resolve. Pa-
tientswereconsideredtohavenonevaluabledataforclini-
cal efficacy if (1) they received 2 days or less of antibiotic
therapy,(2)theyreceivedconcomitantantibioticsfortreat-
mentofdifferentinfections,or(3)pneumoniawasnotcon-
firmedradiographicallyafterentryintothestudy.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%confidenceintervals(CIs)fortheoverallclinicalcure
ratesandmortalityrateswerecomputedbythenormalap-
proximation to the binomial. A P value of .05 or less was
considered to be statistically significant.
ARCH INTERN MED/VOL 160, MAY 8, 2000WWW.ARCHINTERNMED.COM
1296
©2000 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013

Page 4

CAUSATIVE AGENT
The most common causative agents were S pneumoniae,
Lpneumophila,Hinfluenzae,andCpneumoniae(Table1).
The most common agents that fulfilled the criteria for
definitiveetiologywereMpneumoniae,Spneumoniae,and
L pneumophila. Mixed etiologies were seen in 24 pa-
tients.Therewere2instancesofconcurrentinfectionwith
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-
tiveetiology,including Mpneumoniae andLpneumophila
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-
philawithBranhamellacatarrhalisandHinfluenzae).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-eightpatientshadSpneumoniaepneumonia(21
presumptive,7definitive).In18patients,theisolatewas
availablefortesting,with1patienthaving2isolates.Sev-
enteenweresusceptibletoazithromycin(MIC,?2.0µg/
mL), 2 were resistant to azithromycin (MIC, ?8.0 µg/
mL),16isolatesweresusceptibletoerythromycin(MIC,
?0.25µg/mL),1wasintermediatelysusceptibletoeryth-
romycin(MIC,0.38µg/mL),and2wereresistanttoeryth-
romycin(MIC,?3.0µg/mL).Seventeenisolatesweresus-
ceptibletocefuroxime(MIC,?0.19µg/mL),and2isolates
were resistant to cefuroxime (MIC, 6.0-8.0 µg/mL). Fif-
teenisolatesweresusceptibletopenicillinG(MIC,?0.02
µg/mL), 3 were intermediately susceptible to penicillin
G(MIC,0.064-0.75µg/mL),and1wasresistanttopeni-
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,0.19µg/mL),penicillinG(MIC,
?0.12 µg/mL), and cefuroxime (MIC, ?0.19 µg/mL)
(Table2).ThreebacteremicisolatesofSpneumoniaewere
not available for in vitro susceptibility testing.
H influenzae Susceptibility
Nineteen patients had H influenzae pneumonia (18 pre-
sumptive,1definitive).In16patients,theisolatewasavail-
able for testing, with 1 patient having 3 isolates. Sixteen
weresusceptibletoazithromycin(MIC,?2.0µg/mL)and
2 were resistant (MIC, ?4.0 µg/mL). Thirteen isolates
weresusceptibletoerythromycin(MIC,?4.0µg/mL)and
5 were resistant (MIC, ?8.0 µg/mL). Seventeen isolates
were susceptible to cefuroxime (MIC, ?3.0 µg/mL) and
1wasresistant(MIC,12.0µg/mL).Twelveisolateswere
susceptible to penicillin G (MIC, ?0.75 µg/mL) and 6
were resistant to penicillin G (MIC, ?6.0 µg/mL). The
1bacteremicisolatewasuniformlysusceptibletoazithro-
mycin(MIC,0.75µg/mL),erythromycin(MIC,0.25µg/
mL), penicillin G (MIC, 0.25 µg/mL), and cefuroxime
(MIC,1.0µg/mL)(Table2).?-Lactamaseproductionwas
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
S pneumoniae†
Penicillin sensitive
(n = 14)
Penicillin resistant
(n = 4)‡
Azithromycin sensitive
(n = 16)
Azithromycin resistant
(n = 2)§
H influenzae?
Penicillin sensitive
(n = 12)
Penicillin resistant
(n = 4)¶
Azithromycin sensitive
(n = 16)
Azithromycin
Cefuroxime/
Erythromycin
CureFailureCureFailure
80 (4/5) 20 (1/5)100 (9/9) 0 (0/9)
100 (1/1) 0 (0/1)67 (2/3)33 (1/3)
80 (4/5) 20 (1/5) 91 (10/11)9 (1/11)
100 (1/1) 0 (0/1)100 (1/1) 0 (0/1)
89 (8/9) 11 (1/9)100 (3/3)0 (0/3)
50 (1/2) 50 (1/2)100 (2/2)0 (0/2)
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*
PathogenDefinitivePresumptiveTotal
Streptococcus pneumoniae
Legionella pneumophila
Haemophilus influenza a
Chlamydia pneumoniae
Mycoplasma pneumoniae
Haemophilus species
Branhamella catarrhalis
Staphylococcus aureus
Unknown
Total
7
7
1
2
21
13
18
13
1
6
28
20
19
15
13
6
12
0
0
0
6
6
6
6
. . .†
29
. . .†
84
60
173
*Includes multiple etiologies in 24 patients. Data are given as number
of diagnoses.
†Not applicable.
ARCH INTERN MED/VOL 160, MAY 8, 2000WWW.ARCHINTERNMED.COM
1297
©2000 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013

Page 5

STUDY END POINTS
The clinical cure rate was 91% (61/67) (95% CI, 82%-
97%)intheazithromycingroupand91%(71/78)(95%CI,
92%-96%)inthecefuroxime-erythromycingroup(P=.95).
For the intention-to-treat analysis of all 169 patients, the
clinical cure rates were 75% (62/83) (95% CI, 64%-84%)
fortheazithromycintreatmentgroupand83%(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.Theoverallmortalityinthe
intention-to-treatgroupwas2%(4/169);themortalitysub-
classified by treatment group (azithromycin vs cefurox-
imecombinedwitherythromycin)was4%(3/83)and1%
(1/86), respectively. The cause of death in the 3 patients
includedcerebrovascularaccident,pulmonaryembolus,and
respiratoryfailureresultingfromchronicobstructivelung
disease. Two patients did not have an etiologic diagnosis,
and1patienthadsputumcultureevidenceofpneumonia
caused by H influenzae and serological evidence of pneu-
monia caused by C pneumoniae (presumptive). The iso-
lateofHinfluenzaewasnotavailableforsusceptibilitytest-
ing.Twoofthesepatients(onewithanunknownetiology
andonewithpresumptiveevidenceofmixedinfectionwith
HinfluenzaeandCpneumoniae)receivedazithromycin,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-
remicpneumonia(definitiveetiology)causedbySpneu-
moniae treated with azithromycin (2 patients) or cefu-
roxime-erythromycin (5 patients). In 21 patients with
sputumcultureevidenceofpneumoniacausedbySpneu-
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
the4casesofLpneumophilapneumoniaclassifiedasde-
finitive etiology and 1 clinical failure of cefuroxime-
erythromycin in the case of L pneumophila classified as
definitiveetiology.In13patientswithserologicalorpoly-
merasechainreactionevidenceofpneumoniacausedby
Lpneumophila(presumptiveetiology),therewas1clini-
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)
(Table4).Intravenouscathetersitereactions(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,500to1000mgadministeredintravenouslyev-
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)
Definitive and presumptive etiologies
Streptococcus pneumoniae (n = 28)
Haemophilus influenzae (n = 19)
Branhamella catarrhalis (n = 6)
Staphylococcus aureus (n = 6)
Legionella pneumophila (n = 20)
Chlamydia pneumoniae (n = 15)
Mycoplasma pneumoniae (n = 13)
Definitive etiologies only
S pneumoniae (n = 7)
H influenzae (n = 1)
L pneumophila (n = 7)
C pneumoniae (n = 2)
M pneumoniae (n = 12)
Unknown (n = 60)
Azithromycin
Cefuroxime/Erythromycin
CureFailureCure Failure
88 (7/8)
83 (10/12)
100 (2/2)
100 (4/4)
92 (11/12)
86 (6/7)
100 (9/9)
12 (1/8)
17 (2/12)
0 (0/2)
0 (0/4)
8 (1/12)
14 (1/7)
0 (0/9)
95 (19/20)
100 (7/7)
100 (4/4)
100 (2/2)
88 (7/8)
88 (7/8)
100 (4/4)
5 (1/20)
0 (0/7)
0 (0/4)
0 (0/2)
13 (1/8)
13 (1/8)
0 (0/4)
100 (2/2)
0 (0/0)
100 (4/4)
100 (2/2)
100 (8/8)
93 (25/27)
0 (0/2)
0 (0/0)
0 (0/4)
0 (0/2)
0 (0/8)
7 (2/27)
100 (5/5)
100 (1/1)
67 (2/3)
0 (0/0)
100 (4/4)
88 (29/33)
0 (0/5)
0 (0/1)
33 (1/3)
0 (0/0)
0 (0/4)
12 (4/33)
*Data are given as percentage (number/total number). Multiple etiologies were identified in 24 patients.
ARCH INTERN MED/VOL 160, MAY 8, 2000WWW.ARCHINTERNMED.COM
1298
©2000 American Medical Association. All rights reserved.
Downloaded From: http://archinte.jamanetwork.com/ on 02/25/2013