MAJOR ARTICLE

Effects of Prior Effective Therapy on the Efficacy

of Daptomycin and Ceftriaxone for the Treatment
of Community-Acquired Pneumonia
Peter E. Pertel,1 Patricia Bernardo,1 Charles Fogarty,3 Peter Matthews,4 Rebeca Northland,5 Mark Benvenuto,1
Grace M. Thorne,1 Steven A. Luperchio,1 Robert D. Arbeit,2 and Jeff Alder1
1
Cubist Pharmaceuticals, Lexington, and 2Paratek Pharmaceuticals, Boston, Massachusetts; 3Spartanburg Medical Center, Spartanburg,
South Carolina; 4Middelburg Hospital, Middelburg, South Africa; and 5Hospital de Carabineros, Santiago, Chile

(See the editorial commentary by Powers on pages 11526)

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Objective. We sought to compare daptomycin with ceftriaxone for the treatment of patients with community-
acquired pneumonia (CAP).
Methods. Two phase-3 randomized, double-blind trials that enrolled adult patients hospitalized with CAP were
conducted. Patients received intravenous daptomycin (4 mg/kg) or ceftriaxone (2 g) once daily for 514 days.
Aztreonam could be added for patients with gram-negative infections. Clinical responses at the test-of-cure visit
among patients in the intent-to-treat and clinically evaluable populations were the primary efficacy end points.
Results. After combining data from the trials, the intent-to-treat population included 413 daptomycin-treated
patients and 421 ceftriaxone-treated patients, and the clinically evaluable population included 369 daptomycin-
treated patients and 371 ceftriaxone-treated patients. In the intent-to-treat population, the clinical cure rate among
daptomycin-treated patients with CAP was 70.9%, compared with 77.4% among ceftriaxone-treated patients (95%
confidence interval for the difference between cure rates, 12.4% to 0.6%). In the clinically evaluable population,
the clinical cure rate was lower among daptomycin-treated patients (79.4%) than among ceftriaxone-treated patients
(87.9%; 95% confidence interval for the difference between cure rates, 13.8% to 3.2%). A posthoc analysis
revealed that, among those who had received up to 24 h of prior effective therapy, cure rates were similar among
daptomycin-treated (90.7%) and ceftriaxone-treated patients (88.0%; 95% confidence interval for the difference
between cure rates, 6.1% to 11.5%).
Conclusions. Daptomycin is not effective for the treatment of CAP, including infections caused by Streptococcus
pneumoniae and Staphylococcus aureus. The observation that as little as 24 h of prior effective therapy may impact
clinical outcome suggests that trials to evaluate CAP treatment may need to exclude patients who have received
any potentially effective therapy before enrollment.

Daptomycin is rapidly bactericidal against gram-posi-
tive bacteria, including Staphylococcus aureus and Strep-
tococcus pneumoniae [1]. In rats, daptomycin concen-
trations in the lung are 20%30% of those in plasma
during the first 4 h after administration but, after 4 h,
exceed those in plasma (Cubist Pharmaceuticals, un-
Received 5 October 2007; accepted 28 November 2007; electronically published
14 March 2008.
Reprints or correspondence: Dr. Peter E. Pertel, Clinical Research, Cubist
Pharmaceuticals, 65 Hayden Ave., Lexington, Massachusetts, 02421 (peter
.pertel@cubist.com).
Clinical Infectious Diseases 2008; 46:114251
 2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4608-0003$15.00
DOI: 10.1086/533441
published data). In hamsters, daptomycin demon-
strated efficacy against S. aureus lung infections [2, 3].
Based on these data, 2 studies were conducted to com-
pare daptomycin with ceftriaxone for the treatment of
patients hospitalized with community-acquired pneu-
monia (CAP).
When the results from the first study revealed that
daptomycin did not meet predetermined criteria for
noninferiority, enrollment in the second ongoing study
was stopped. Subsequently, daptomycin was shown to
interact with pulmonary surfactant in vitro, resulting
in inhibition of antibacterial activity, and to have little
activity against S. pneumoniae in animals with bron-
cheoalveolar pneumonia [4]. This article summarizes
the results of both clinical studies.

1142 CID 2008:46 (15 April) Pertel et al.

PATIENTS AND METHODS
Study design. Study DAP-00-05 and Study DAP-CAP-00-08
were randomized, double-blind, comparative trials designed to
evaluate the safety and efficacy of daptomycin for the treatment
of patients with CAP. Both studies had similar designs, inclusion
and exclusion criteria, study populations, and assessments.
Study DAP-00-05 was conducted from October 2000 through
September 2001 in Europe, the United States, Canada, Austra-
lia, New Zealand, and South Africa. Study DAP-CAP-00-08
was conducted from July 2001 through February 2002 in South
America, Europe, Mexico, and South Africa. The studies were
conducted in accordance with the Declaration of Helsinki and
guidelines for studies involving human subjects. The protocols
were approved by the ethical review board at each site.
Patient eligibility. Patients aged 18 years who had CAP
requiring hospitalization and intravenous therapy for 5 days
were eligible. Patients were required to have a new pulmonary
infiltrate found on a chest radiograph within 48 h after en-
rollment and 2 of the following clinical characteristics: cough,
purulent sputum or change in sputum character, rales or pul-
monary consolidation, dyspnea or tachypnea, fever (oral tem-
perature, 138.0C) or hypothermia (core temperature,
!35.0C), elevated WBC count (110,000 cells/mm3) or 115%
immature neutrophils or leukopenia (WBC count, !4500 cells/
mm3), or hypoxemia (partial pressure of oxygen, !60 mm Hg,
or oxygen saturation, !90% on room air).
Patients were excluded if they had respiratory failure, severe
pneumonia (defined as a Pneumonia Severity Index of V ac-
cording to the methods of Fine et al. [5]), severe shock, possible
Legionella pneumonia, known or suspected tuberculosis, bac-
terial meningitis, nosocomial pneumonia, lung cancer or ma-
lignancy metastatic to lung, malignancy not in remission, in-
duction chemotherapy within 2 weeks before enrollment or
therapies expected to result in neutropenia (neutrophil count,
!200 cells/mm3), neutropenia, HIV infection (with a CD4+ T
cell count !200 cells/mm3) or possible Pneumocystis jiroveci
pneumonia, known bronchial obstruction or prior postobstruc-
tive pneumonia, cystic fibrosis, or a calculated creatinine clear-
ance !30 mL/min. Patients were also excluded if they were
likely to die within 48 h after receiving treatment, could not
tolerate ceftriaxone or had a b-lactam allergy, needed 3-hy-
droxy-3-methylglutaryl-coenzyme A reductase inhibitor ther-
apy, had received potentially effective antibacterial therapy for
124 h within 72 h before enrollment, had received prior dap-
tomycin therapy, or were likely to need nonprotocol systemic
antibiotics. Pregnant or nursing women were excluded.
Treatment. Patients received either intravenous daptomy-
cin (4 mg/kg) or ceftriaxone (2 g) every 24 h. Patients with
suspected or confirmed gram-negative infections may have re-
ceived aztreonam. The duration of therapy was 514 days (at
the discretion of the investigator) but could be extended.
Clinical and microbiological assessments. Clinical symp-
toms and signs were evaluated, and appropriate cultures were
performed within 24 h before starting treatment, during ther-
apy, up to 3 days after completing treatment, and 714 days
after completing treatment (i.e., the test-of-cure visit). Safety
assessments were conducted from the baseline visit to the final
visit.
Clinical cure was defined as the absence or improvement of
clinically significant symptoms and signs such that no addi-
tional therapy was required. Clinical response was defined as
clinical failure if symptoms and signs persisted or progressed,
the patient died, or the study therapy was stopped because of
an adverse event.
Sputum specimens were sent for Gram staining, with ac-
ceptable specimens determined by microscopic examination. If
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the culture yielded a gram-positive pathogen (i.e., S. pneu-
moniae or S. aureus), specimens were sent for culture during
the period of therapy until the culture result was negative.
Bronchial brushings or transtracheal aspiration were performed
if needed. Blood cultures were performed at baseline, at the
test-of-cure visit, and as needed. Gram-positive pathogens were
sent to central laboratories for confirmation and susceptibility
testing by Kirby-Bauer disk diffusion and broth microdilution
methods [68]. At the test-of-cure visit, microbiological success
was defined as eradication or presumed eradication (for pa-
tients assessed as cured if no specimens were obtained) of all
gram-positive pathogens isolated at baseline.
Statistical analysis. The enrolled population included all
patients who were randomized. The safety population included
patients who received 1 dose of study drug. The intent-to-
treat (ITT) population included patients with CAP who re-
ceived 1 dose of study drug. The modified intent-to-treat
(mITT) population included patients in the ITT population
who had S. pneumoniae or S. aureus isolated from sputum or
blood specimens at baseline. The clinically evaluable (CE) pop-
ulation included patients who received the correct study drug
for 3 days, had the required clinical assessments, and did not
receive any potentially effective therapy for 124 h (unless clas-
sified as having experienced treatment failure). The microbi-
ologically evaluable (ME) population included patients in the
CE population who had S. pneumoniae or S. aureus isolated at
baseline.
The studies were designed to show that daptomycin was
noninferior to ceftriaxone for the treatment of CAP. Primary
and secondary efficacy variables from each study and from the
pooled data were analyzed using 95% CIs for the difference in
the success rates between the daptomycin and ceftriaxone arms,
using normal approximations to the binomial distribution. The
Daptomycin for CAP CID 2008:46 (15 April) 1143
primary efficacy variables for each study were the clinical suc-
cess rates at the test-of-cure visit among the ITT and CE pop-
ulations. Noninferiority was defined as the lower limit of the
95% CI for the difference in success rates being greater than
10%. Statistical significance was defined as the 95% CI ex-
cluding zero. For additional analyses, Fishers exact test was
used to compare rates. Significance tests were 2-sided with
a p 0.05. Logistic regression analyses were used to determine
whether possible risk factors influenced success rates [9]. For
both studies, 252 clinically evaluable patients in each group
were needed to result in 80% power to detect noninferiority.
RESULTS
Patients. The numbers of the patients in each study popu-
lation, after pooling the data from both studies, are shown in
table 1. In the ITT population, 743 patients (89.0%) were
treated for 514 days; only 19 patients (2.3%) received 114
mycin and ceftriaxone groups, respectively, had a gram-positive
pathogen isolated at baseline; these patients constituted the
mITT population (table 3). Overall, S. pneumoniae was isolated
from 81.0% of patients, including 14 patients from whom S.
aureus was also isolated. Among isolates tested at the central
laboratory, 83.8% of the S. pneumoniae isolates were penicillin
susceptible, and 95.7% of the S. aureus isolates were methicillin
susceptible. All of the isolates tested were susceptible to dap-
tomycin, with MICs 0.5 mg/mL. Among S. pneumoniae iso-
lates, the MIC90 was 0.12 mg/mL (range, 0.03 to 0.5 mg/mL).
Among S. aureus isolates, the MIC90 was 0.25 mg/mL (range,
0.060.5 mg/mL). In the mITT population, 23.8% of patients
had at least 1 positive blood culture result. The pathogen most
frequently isolated from blood specimens was S. pneumoniae
(89.8% of isolates).
Outcomes. In each study and for all populations examined,
the clinical cure rates among daptomycin-treated patients were

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days of therapy. A total of 349 daptomycin-treated patients
(84.5%) and 395 ceftriaxone-treated patients (93.8%) com-
pleted therapy. The most common reasons for premature dis-
continuation of therapy were clinical failure (44 daptomycin-
treated patients and 23 ceftriaxone-treated patients) and
adverse events (15 daptomycin-treated patients and 12 ceftriax-
one-treated patients).
The demographic and clinical characteristics of the treatment
groups were similar at baseline (table 2). Concomitant az-
treonam therapy, allowed by the protocol, was administered to
96 daptomycin-treated patients (23.2%) and 66 ceftriaxone-
treated patients (15.7%; P p .007). Thirteen daptomycin-
treated patients (3.1%) and 12 ceftriaxone-treated patients
(2.9%) were excluded from the CE population, because they
received potentially effective therapy against gram-positive or-
ganisms for 124 h prior to enrollment or for 148 h during
therapy for reasons other than treatment failure.
In the ITT population, 132 and 116 patients in the dapto-
lower than the rates among ceftriaxone-treated patients. After
combining the data from the studies, cure rates were signifi-
cantly lower among daptomycin-treated patients in the ITT
and CE populations but not among those in the mITT pop-
ulation (table 4). Similar results were obtained in analyses of
all randomized and all treated patients (data not shown). The
cure rates among patients with positive blood culture results
at baseline were 66.7% (20 of 30 patients) and 75.9% (22 of
29 patients) among daptomycin-treated and ceftriaxone-treated
patients, respectively, in the mITT population (95% CI for the
difference in cure rates, 32.2% to 13.8%). In addition, there
was a positive association between increased severity of illness
(assessed by the Pneumonia Severity Index) and poor clinical
outcome among daptomycin-treated patients (data not shown).
Because most patients assessed as experiencing clinical cure
did not typically have adequate follow-up blood or sputum
cultures performed, microbiological responses were analyzed
using combined documented and presumed eradication rates.

Table 1. Pooled patient disposition.

No. (%) of patients

Daptomycin arm Ceftriaxone arm
Population Key criteria (n p 467) (n p 469)
Enrolled Randomized 467 (100) 469 (100)
Safety Received 1 dose of study drug 455 (97.4) 460 (98.1)
Intent-to-treat Received 1 dose of study drug and had CAP 413 (88.4) 421 (89.8)
Modified intent-to-treat Received 1 dose of study drug and had CAP 132 (28.3) 116 (24.7)
caused by a gram-positive organism
Clinically evaluable Received 3 days of correct study drug, had CAP, 369 (79.0) 371 (79.1)
and clinical response could be assessed
Microbiologically evaluable Received 3 days of correct study drug, had CAP 124 (26.6) 100 (21.3)
caused by a gram-positive organism, and clini-
cal response could be assessed

NOTE. CAP, community-acquired pneumonia.

1144 CID 2008:46 (15 April) Pertel et al.

 Table 2. Demographic and baseline clinical characteristics of the pooled in-
tent-to-treat population.

Treatment arm
Daptomycin Ceftriaxone
Characteristic (n p 413) (n p 421)
Sex
Male 243 (58.8) 245 (58.2)
Female 170 (41.2) 176 (41.8)
Age, mean years (range) 54.9 (1894) 55.5 (1894)
Race
White 344 (83.3) 348 (82.7)
Black 30 (7.3) 33 (7.8)
Other 39 (9.4) 40 (9.5)
Weight, mean kg (range) 71.8 (36.0141.5) 72.1 (32.0139.1)
Smoking status
Current smoker 137 (33.2) 137 (32.5)
Past smoker 104 (25.2) 110 (26.1)
Pneumonia Severity Indexa

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Low risk, class II 165 (40.0) 185 (43.9)
Low risk, class III 129 (31.2) 124 (29.4)
Moderate risk, class IV 118 (28.6) 112 (26.6)
High risk, class V 1 (0.2) 0 (0.0)
Most common prior antibacterial therapyb
Ceftriaxone 41 (9.9) 42 (10.0)
Levofloxacin 35 (8.5) 32 (7.6)
Aztreonam 26 (6.3) 21 (5.0)
Cefuroxime 18 (4.4) 23 (5.5)
Azithromycin 12 (2.9) 18 (4.3)
Cefotaxime 7 (1.7) 11 (2.6)
Clarithromycin 9 (2.2) 8 (1.9)

NOTE. Data are no. (%) of patients, unless otherwise indicated.

a
Low risk, class II, was defined by a score of !70 points; low risk, class III, was defined by
a score of 7190 points; moderate risk, class IV, was defined by a score of 91130 points; and
high risk, class V, was defined by a score of 1130 points (according to the methods of Fine et
al. [5]).
b
Patients may have received 11 prior antibacterial agent.

In the pooled ME population, the S. pneumoniae eradication
rate was significantly lower among daptomycin-treated patients
than among ceftriaxone-treated patients; the differences in S.
aureus eradication rates approached statistical significance (ta-
ble 5). Two daptomycin-treated patients assessed as experienc-
ing clinical cure had documented pathogen persistence in spu-
tum specimens; 1 had persistence of S. pneumoniae, and 1 had
persistence of S. aureus. No ceftriaxone-treated patient assessed
as experiencing cure had documented pathogen persistence.
Outcomes based on prior antimicrobial therapy. Although
few patients received potentially effective therapy for 124 h
within 72 h before enrollment (an exclusion criteria), analysis
revealed that 50% of patients had received antibacterial ther-
apy for !24 h. In a posthoc analysis to examine the effect of
this treatment on outcome, prior effective therapy was defined
as treatment with antibacterial agents with both greater potency
and longer half-lives (e.g., levofloxacin, ceftriaxone, azithro-
mycin, and clarithromycin). Patients who had not received an-
tibacterial therapy or who received therapy with only agents
with lesser potency or shorter half-lives (e.g., penicillins, tet-
racyclines, or trimethoprim-sulfamethoxazole) were classified
as having not received prior effective therapy. Among patients
in the pooled CE population who had not received prior ef-
fective therapy, the cure rate was significantly lower among
daptomycin-treated patients than among ceftriaxone-treated
patients (table 6). However, among those who had received
prior effective therapy, clinical cure rates were similar in both
treatment groups. Outcomes among patients treated with pen-
icillins (including ampicillin and amoxicillin) were similar to
the outcomes among those who received no prior antibiotic
therapy (data not shown). In Study DAP-00-05, among patients
in the ME population with S. aureus or S. pneumoniae infections
who had not received prior effective therapy, the clinical cure
rates among daptomycin-treated and ceftriaxone-treated pa-

Daptomycin for CAP CID 2008:46 (15 April) 1145

 Table 3. Baseline culture results for the pooled modified intent-to-treat population.

Treatment arm,
no. (%) of patients
Daptomycin Ceftriaxone
Variable (n p 132) (n p 116)
a
Positive culture specimen, pathogen found on culture
Respiratory 116 (87.9) 102 (87.9)
Streptococcus pneumoniae 91 83
Staphylococcus aureus 30 27
Blood 30 (22.7) 29 (25.0)
S. pneumoniae 27 26
S. aureus 3 3
b
Gram-positive pathogen isolated
S. pneumoniae
All 106 (80.3) 95 (81.9)
Penicillin susceptible 75 54
Penicillin intermediate 9 12

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Penicillin resistant 2 2
Penicillin susceptibility not determined 20 27
Ceftriaxone susceptible 102 92
Ceftriaxone intermediate 4 3
Ceftriaxone resistant 0 0
Ceftriaxone susceptibility not determined 20 27
S. aureus
All 31 (23.5) 30 (25.9)
Methicillin susceptible 23 22
Methicillin resistant 2 0
Methicillin susceptibility not determined 6 8
a
More than 1 type of positive culture specimen was possible.
b
The higher MIC value used for multiple baseline isolates. Among S. pneumoniae, the MICs for penicillin-
susceptible, intermediate, and resistant isolates were 0.06 mg/mL, 0.121.0 mg/mL, and 2.0 mg/mL, re-
spectively, and the MICs for ceftriaxone-susceptible, intermediate, and resistant isolates were 0.5 mg/mL,
1.0 mg/mL, and 2.0 mg/mL, respectively.

tients were 78.8% (63 of 80 patients) and 91.7% (55 of 60
patients), respectively (95% CI for the difference between cure
rates, 24.3% to 1.5%); among those who had received prior
effective therapy, the cure rates were 84.6% (22 of 26 patients)
and 89.7% (26 of 29 patients), respectively (95% CI for the
difference between cure rates, 22.8% to 12.7%). Multivariate
logistic regression analysis using pooled CE population data
revealed that prior effective therapy was associated with a higher
success rate only among daptomycin-treated patients (data not
shown).
Prior effective therapy also had an impact on the persistence
of S. pneumoniae in sputum specimens on or after day 2 of
study drug therapy. In Study DAP-00-05, among patients who
had not received prior effective therapy, persistence was sig-
nificantly more frequent among daptomycin-treated patients
than among ceftriaxone-treated patients (table 7). Among pa-
tients in both groups who received prior effective therapy, per-
sistence of S. pneumoniae was uncommon. Among daptomy-
cin-treated patients, rates of S. pneumoniae persistence on or
after day 2 of therapy were significantly lower (P p .011) among
those who had received prior effective therapy (4.3%) than
among those who had not received such therapy (31.9%).
Among ceftriaxone-treated patients, the persistence rate among
those who had received prior effective therapy was 0%, com-
pared with 9.4% among those who had not received such ther-
apy (P p .317).
Demographic characteristics were also examined for their
potential impact on outcome. Among daptomycin-treated pa-
tients, cure rates appeared to be higher among patients enrolled
at sites in Western Europe, North America, and South America
than among patients enrolled in Eastern Europe, Australia, New
Zealand, and South Africa, but the difference was not statis-
tically significant (P p .25 ). These findings are likely to be at-
tributable to the fact that a disproportionate number of patients
who received prior effective therapy were enrolled at sites in
North America and Western Europe (data not shown).
Safety and tolerability. Although no clinically relevant dif-
ferences in treatment-emergent adverse events were noted (ta-

1146 CID 2008:46 (15 April) Pertel et al.

 Table 4. Clinical cure rates by pooled study population.

Daptomycin arm Ceftriaxone arm

No. of patients No. of patients
cured/total no. cured/total no.
a
Population of patients Cure rate, % of patients Cure rate, % 95% CI
Intent-to-treat 293/413 70.9 326/421 77.4 12.4% to 0.6%
Modified intent-to-treat 98/132 74.2 92/116 79.3 15.6% to 5.4%
Clinically evaluable 293/369 79.4 326/371 87.9 13.8% to 3.2%
a
For the difference in cure rates.

ble 8), more ceftriaxone-treated patients developed headaches,
insomnia, dizziness, and abdominal pain, and more dapto-
mycin-treated patients developed injection site phlebitis, chest
pain, and herpes simplex virus infections. Nineteen dapto-
mycin-treated patients (4.2%) and 15 ceftriaxone-treated pa-
tients (3.3%) discontinued study drug therapy because of an
(P p .073); no death was assessed as study drug related. Causes
of death that occurred in 2 daptomycin-treated patients in-
cluded respiratory failure (n p 5), chronic obstructive airway
disease exacerbation (n p 3 ), cardiac failure (n p 3 ), and car-
diac arrest (n p 2). Among ceftriaxone-treated patients, causes
of death included pulmonary embolism (n p 3 ), septic shock

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adverse event (P p .489).
Treatment-emergent elevations in creatine phosphokinase
level (classified as adverse events) developed in 6 daptomycin-
treated patients (1.3%) and 6 ceftriaxone-treated patients
(1.3%). None of the events were assessed as serious, and none
of the patients had study drug therapy discontinued because
of the elevation. The events resolved in 5 daptomycin-treated
patients and 3 ceftriaxone-treated patients. Treatment-emergent
elevations in creatine phosphokinase level to 11000 U/L that
were not reported as adverse events developed in 4 daptomycin-
treated patients (0.9%) and 1 ceftriaxone-treated patient
(0.2%). Among daptomycin-treated patients with elevations in
creatine phosphokinase level, the level normalized in 2 patients,
improved in 1, and remained elevated in 1. This last patient
developed sepsis with renal and hepatic failure and died of
respiratory failure on day 2 of therapy. No follow-up value was
obtained for the ceftriaxone-treated patient.
Twenty-one daptomycin-treated patients (4.6%) and 12 cef-
triaxone-treated patients (2.6%) died during the studies
(n p 3), worsening pneumonia (n p 2 ), and metastases to the
brain or liver (n p 2). Including those who died, 62 dapto-
mycin-treated patients (13.6%) and 38 ceftriaxone-treated pa-
tients (8.3%) developed at least 1 serious adverse event. Most
serious events were infections (n p 33), cardiac disorders
(n p 22), or respiratory disorders (n p 18 ). Only 3 serious
events that occurred in the daptomycin-treated patients (coma,
tachyarrhythmia, and respiratory failure) and 1 that occurred
in the ceftriaxone-treated patients (neutropenia) were assessed
as possibly related to study drug.
DISCUSSION
The pooled results of these 2 trials indicate that daptomycin
was significantly less effective than ceftriaxone for the treatment
of patients hospitalized with CAP. However, 170% of dapto-
mycin-treated patients in the pooled ITT population were as-
sessed as experiencing clinical cure, and the mortality rate was
4.6%. Among daptomycin-treated patients with S. pneumoniae

Table 5. Bacteriological eradication rates by pooled study population.

Daptomycin arm Ceftriaxone arm

No. of patients No. of patients
in whom the in whom the
pathogen was pathogen was
eradicated/total Eradication eradicated/total Eradication
Population, pathogen no. of patients rate, % no. of patients rate, % 95% CIa
Modified intent-to-treat
Streptococcus pneumoniae 82/106 77.4 78/95 82.1 15.8% to 6.3%
Staphylococcus aureus 18/31 58.1 19/30 63.3 29.7% to 19.2%
Microbiologically evaluable
S. pneumoniae 82/101 81.2 78/84 92.9 21.1% to 2.3%
S. aureus 18/26 69.2 19/21 90.5 43.0% to 0.5%

NOTE. Eradication rates include eradication and presumed eradication.

a
For the difference in eradication rates.

Daptomycin for CAP CID 2008:46 (15 April) 1147

Table 6. Clinical cure rates among patients in the pooled clinically evaluable population, by prior effective antibacterial therapy.

Daptomycin arm Ceftriaxone arm

No. of No. of
cured patients/total cured patients/total
a
Prior effective therapy no. of patients Cure rate, % no. of patients Cure rate, % 95% CI
Yes 88/97 90.7 81/92 88.0 6.1% to 11.5%
No 205/272 75.4 245/279 87.8 18.8% to 6.0%
a
For the difference in cure rates.

CAP, the mortality rate was 2.8%. These results contrast with
reported mortality rates for pneumonia, which were generally
20%40% before antibiotic therapy [10] and, in 1 series, 37.7%
among adult patients hospitalized with pneumococcal pneu-
monia [11]. Although comparisons with historical data should
be interpreted with caution, the differences suggest that other
factors impacted clinical outcome.
lower among those who had received prior effective therapy
than among those who had not received prior effective therapy,
although the difference was only statistically significant among
daptomycin-treated patients. Thus, prior effective therapy may
have impacted all patients.
The duration of prior effective therapy was 1 day. Although
significantly shorter than durations generally used for the treat-

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It has been theorized that daptomycin efficacy in the lung
may be related to disease pathology [4]. Daptomycin had little
activity in a mouse model of broncheoaleveolar pneumonia but
was active in a mouse inhalation anthrax model associated with
extensive alveolar destruction and in a hamster lung infection
model in which emphysematous changes were induced prior
to lung infection [2, 4, 12]. Daptomycin was more effective
than was either vancomycin or nafcillin in a rat model of he-
matogenous S. aureus pneumonia [4]. Similarly, a posthoc anal-
ysis from 1 clinical trial revealed that daptomycin was as ef-
ficacious as vancomycin for treating septic pulmonary emboli
associated with right-sided endocarditis caused by methicillin-
resistant S. aureus, although the number of patients was small
[13].
Logistic regression analyses revealed that daptomycin-treated
patients who had received up to 24 h of effective therapy before
enrollment had higher success rates than did those who had
not received such therapy. In both treatment groups, the S.
pneumoniae persistence rates on or after day 2 of therapy were
ment of CAP requiring hospitalization, 1 day of effective ther-
apy may be sufficient for treating some cases. Several studies
have revealed that 3- or 5-day treatment courses of azithro-
mycin and 5-day courses of gemifloxacin, levofloxacin, and
telithromycin are effective for CAP [1418]. In addition, a sin-
gle high-dose formulation of azithromycin was at least as ef-
fective as a 7-day course of levofloxacin or extended-release
clarithromycin [19, 20]. It is possible that a single dose of potent
agents with relatively long half-lives could impact the clinical
outcome of CAP.
These observations may be confounded by other factors. The
antibacterial agents used prior to enrollment may have influ-
enced outcome by treating pathogens other than gram-positive
organisms, including Legionella species, other gram-negative
bacteria, Mycoplasma pneumoniae, and Chlamydophila pneu-
moniae. However, patients were screened for Legionella pneu-
monia by a urine antigen test, and the number of patients with
atypical pathogens should have been approximately equal in
both treatment groups because of the randomized study design.

Table 7. Persistence of Streptococcus pneumoniae in sputum samples on or after day 2 of treatment with the study drug, by prior
effective antibacterial therapy, Study DAP-00-05.

Daptomycin arm Ceftriaxone arm

No. of No. of
patients with patients with
persistence/total Persistence persistence/total Persistence
a
Variable no. of patients rate, % no. of patients rate, % P
Prior effective therapy: 2 days of persistence 1/23 4.3 0/24 0.0 .489
No prior therapy
2 days of persistence 22/69 31.9 5/53 9.4 .004
3 days of persistence 15/69 21.7 4/53 7.5 .043
4 days of persistence 10/69 14.5 1/53 1.9 .023

NOTE. Only patients in the microbiologically evaluable population who had an adequate number of follow-up sputum cultures performed were included.
a
Determined using Fishers exact test.

1148 CID 2008:46 (15 April) Pertel et al.

 Table 8. Adverse events that occurred in at least 2% of patients in
either treatment arm in the pooled safety population.

Treatment arm, no.

(%) of patients
Daptomycin Ceftriaxone
Adverse eventa (n p 455) (n p 460)
Headache 15 (3.3) 35 (7.6)
Nausea 19 (4.2) 27 (5.9)
Diarrhea 17 (3.7) 24 (5.2)
Constipation 15 (3.3) 15 (3.3)
Increased alanine aminotransferase level 15 (3.3) 11 (2.4)
Increased aspartate aminotransferase level 12 (2.6) 12 (2.6)
Vomiting 9 (2.0) 15 (3.3)
Insomnia 7 (1.5) 15 (3.3)
Upper abdominal pain 10 (2.2) 10 (2.2)
Lower limb edema 11 (2.4) 9 (2.0)
Injection site phlebitis 13 (2.9) 6 (1.3)
Dizziness (excluding vertigo) 5 (1.1) 10 (2.2)

Downloaded from http://cid.oxfordjournals.org/ by guest on March 17, 2016

Abdominal pain not otherwise specified 3 (0.7) 10 (2.2)
Chest pain 10 (2.2) 3 (0.7)
Herpes simplex virus infection 10 (2.2) 2 (0.4)
a
Based on preferred terms using the Medical Dictionary for Regulatory Activities,
version 3.3.

In addition, higher clinical cure rates were noted among dap-
tomycin-treated patients who had S. aureus or S. pneumoniae
infections and who had received prior effective therapy than
among those patients who had not received prior effective ther-
apy. Finally, the duration of time from pneumonia onset to the
initiation of therapy may have also impacted outcome. Data
on symptom duration before enrollment were not collected.
In conclusion, data from both studies revealed that dapto-
mycin was less efficacious than was ceftriaxone for CAP therapy.
However, for patients who received the equivalent of 1 day of
prior effective antibacterial therapy, the cure rates were similar
in both treatment groups. Because 1 day of effective therapy
may impact clinical outcome, trials designed to evaluate CAP
treatments may need to exclude patients who have received any
potentially effective therapy prior to enrollment. However, such
a study requirement may not be feasible because of the current
quality-of-care measures emphasizing early antibiotic therapy
for CAP.
PARTICIPATING INVESTIGATORS AND
INSTITUTIONS
Study DAP-00-05
Belgium. F. Jacobs (Hopital Erasme, Brussels) and L. Van-
maele (OLV Ter Linden Ziekenhuis, Knokke).
Croatia. S. Milutinovic (Sveti Duh Clinical Hospital, Za-
greb) and S. Schonwald (University Hospital of Infectious Dis-
eases, Zagreb).
Czech Republic. V. Havlik (Hospital Benesov, Benesov), L.
Kamenik (Neumocnice Milosrdynch, Praha), J. Krynska (Ba-
tova Nemocnice Zlin, Zlin), M. Kucera (Hospital Breclav, Bre-
clav), P. Prusa (Hospital Kladno, Kladno), and P. Reiterer (Mas-
aryk Hospital, Usti nad Labem).
France. J. C. Bertrand (CHU Hopital Bellevue, Saint-
Etienne), J. C. Ducreux (Hopital General de Roanne, Roanne),
E. Fournier (Polyclinique Henin-Beaumont, Henin-Beau-
mont), J.-M. Pone (Hopital dEtampes, Etampes), A.
PrudHomme (Centre Hospitalier Geneeral de Tarbes, Tarbes),
and L. Vives (Hopital Saint-Gaudens, Saint Gaudens).
Greece. G. Chrysos (District General Hospital of Piraeus,
Piraeus) and A. Gerogianni (Sotiria Hospital of Athens,
Athens).
Hungary. M. Bisits (Szent Borbala Korhaz, Tatabanya), G.
Bozoky (BKKM Onkormanyzat, Kecskemet), A. Devai (Fova-
rosi Onkormanyzat Uzsoki utcai Korhaza, Budapest), Z. Mark
(Pest Megyei, Torokbalint), G. Nagy (Szent Imre Korhaz, Bu-
dapest), S. Palinkasi (Hetenyi Geza Korhaz, Szolnok), Z. Rott
(Matrai Allami Gyogyintezet, Matrahazz), and Z. Sztancsik (Be-
kes Megyei, Gyula).
Iceland. M. Kristjansson (Landspitali University Hospital,
Reykjavick).
The Netherlands. N. Cox (Universitair Longcentrum Dek-
kerswald, Groesbeek) and A. Rudolphus (Saint Franciscusziek-
enhuis, Rotterdam).
Poland. J. Balanda (M. Koperniks Regional Hospital,
Gdansk), E. Czestochowska (Medical University of Gdansk,
Gdansk), P. Gorski (Medical University of Lodz, Lodz), W.

Daptomycin for CAP CID 2008:46 (15 April) 1149

Halota (L. Rydygiers Medical University, Bydgoszcz), J. Mal-
olepszy (Wroclaw University of Medicine, Wroclaw), W. Mly-
narczyk (K. Marcinkowski University of Medical Sciences, Poz-
nan), I. Witkiewicz (Prof. A. Sokolowskis Specialistic Hospital,
Szczecin), and K. Wrabec (Regional Specialistic Hospital,
Wroclaw).
Russia. N. G. Alieva (City Clinical Hospital No. 13, Mos-
cow), M. V. Baluda and P. G. Filippov (Moscow State Dental
University, Moscow), Y. B. Belousov (Moscow Municipal Clin-
ical Hospital No. 6, Moscow), A. G. Chuchalin (City Clinical
Hospital No. 57, Moscow), L. P. Katasonova (City Cinical Hos-
pital No. 67, Moscow), V. F. Marinin (City Clinical Hospital
No. 61, Moscow), V. G. Novozhzhenov (Municipal Clinical
Hospital No. 29, Moscow), N. P. Sanina (M.F. Vladimirsky
Clinical Institute, Moscow), A. I. Sinopalnikov (Burdenko Mil-
itary Hospital, Moscow), L. B. Sokolova (City Clinical Hospital
No. 11, Moscow), L. S. Stratchounski (Smolensk State Medical
Academy, Smolensk), S. V. Yakovlev (City Clinical Hospital No.
7, Moscow), and M. L. Zubkin (State Training Institute of
Ministry of Defense of the Russian Federation, Moscow).
Slovac Republic. O. Balint (Faculty Deder Hospital, Bra-
tislava), M. Konecny (Faculty Hospital Trnava, Trnava), B. Kral-
icek (Hospital Jihlava, Jihlava), and J. Plutinsky (Institute for
Tuberculosis and Pulmonary Diseases, Nitra-Zobor).
Spain. J. Alegre (Hospital Vall dHebron, Barcelona), E.
Calvo (H Clinico San Carlos, Madrid), J. Castillo (Hospital
Virgen del Rocio, Seville), and J. Kindelan (Hospital Reina
Sofia, Cordoba).
United States. D. Amin (Bay Area Chest Physicians, Clear-
water, FL), C. L. Anderson (Bay Pines VA Medical Center, Bay
Pines, FL), I. Baird (Remington Davis, Columbus, OH), S.
Belknap (OSF St. Francis Medical Center, Peoria, IL), M. Bernat
(Nash General Hospital, Rocky Mount, NC), M. Brown (Cres-
cent Clinical Research, Pensacola, FL), C. Carmargo (Massa-
chusetts General Hospital, Boston), P. Chang (Thomas Jefferson
University Hospital, Philadelphia, PA), K. Datz (St. Alexius
Medical Center, Bismarck, ND), T. Dickey (Baylor Medical
Center, Irving, TX), P. Dicpinigaitis (Jack D. Weiler Hospital,
Bronx, NY), R. Dotson (Mobile, AL), A. El-Solh (Erie County
Medical Center, Buffalo, NY), J. Fitz (Tacoma General Hospital,
Tacoma, WA), C. Fogarty (Spartanburg Medical Center/Mary
Black Memorial Hospital, Spartanburg, SC), J. Fraiz (St. Vin-
cents Hospitals & Health Services, Indianapolis, IN), D. R.
Graham (Springfield Clinic, Springfield, IL), C. Guerrero
(Monrovia Community Hospital, Monrovia, CA), R. R. Hanson
(Iowa Methodist Medical Center, Des Moines), M. Harrison
(Lakeland Medical Center, St. Joseph, MI), A. James (Lakeland
Medical Center, New Orleans, LA), D. L. James (Phelps County
Regional Medical Center, Rolla, MO), J. A. Kruse (Detroit Re-
ceiving Hospital, Detroit, MI), C.-F. Lee (Bellwood General
Hospital, Bellflower, CA), T. Mathias (Discovery Alliance, Hud-
1150 CID 2008:46 (15 April) Pertel et al.
son, FL), M. Natalino (Respiratory & Intensive Care Associates,
San Antonio, TX), L. Palmer (SUNY at Stony Brook, Stony-
brook, NY), A. J. Pareigis (Medical Arts Associates, Moline,
IL), J. Rehm (Mary Washington Hospital, Fredericksburg, VA),
M. Rumbak (Tampa General Hospital, Tampa, FL), D. Sorresso
(Discovery Alliance, Hudson, FL), A. B. Thompson (University
of Nebraska Medical Center, Omaha, NE), R. Tidman (Fannin
Regional Hospital, Blue Ridge, GA), J. E. Turner (Sutter Glen
Hospital-West Sacramento, El Dorado Hill, CA), and S. Yates
(Trinity Medical Center, The Colony, TX).
Canada. S. Bose (St. Pauls Hospital, Saskatoon, SK), R.
Brossoit (Theradev Clinical Research, Granby, QC), A. Dhar
(Pulmonary & Critical Care Consultants, Windsor, ON), M.
Gagnon (Centre Hospitalier de Lanaudiere, St. Charles-Bor-
romee, QC), D. Grimard (Co Ho De La Sagamie [Chicoutimi],
Chicoutimi, QC), N. Lampron (Laval Hospital, Ste. Foy, QC),
S. Landis (Hamilton Health Sciences, Hamilton, ON), and G.
Downloaded from http://cid.oxfordjournals.org/ by guest on March 17, 2016
Tellier (Zoom International, St. Jerome, QC).
Australia. M. Chapman (Royal Adelaide Hospital, Ade-
laide), P. Fogarty (Box Hill Gardens Medical Centre, Box Hill),
B. Richards (Gold Coast Hospital, Southport), W. J. McBride
(Cairns Base Hospital, Cairns), M. Phillips (Sir Charles Gaird-
ner Hospital, Perth), and D. C. Sowden (Nambour General
Hospital, Nambour).
New Zealand. K. Godfrey (Middlemore Hospital, Ota-
huhu) and D. G. Mills (Waikato Hospital, Hamilton).
South Africa. I. A. Abdulla (St. Augustines Hospital, Dur-
ban), M. J. Heystek (Mamelodi Hospital, Mamelodi), U. G.
Lalloo (King Edward Hospital, Durban), P. A. Matthews (Mid-
delburg Hospital, Middelburg), L. van Zyl (Eben Donges Hos-
pital, Worcester), J. J. Viljoen (G07 Hydromed Hospital, Bloem-
fontein), and P. Wilcox (University of Cape Town, Cape Town).
Study DAP-CAP-00-08
Argentina. C. DeSalvo (Hospital Enrique Tornu, Buenos Ai-
res), A. Dolmann (Hospital Cetrangolo, Buenos Aires), J. Gen-
tile (Hospital Santamarina, Tandil), L. Marzoratti (Sanatorio 9
de Julio, Tucuman), S. Nahabedian (Hospital Evita Lanus,
Buenos Aires), and G. Recupero (Hospital Centro Salud,
Tucuman).
Brazil. J. C. Correa (Hospital da Ordem Terceira da Pen-
itencia, Rio de Janeiro), D. Godoy (Hospital Universitario de
Caxias do Sul, Caxias), F. Lundgren (Hospital Geral Otavio de
Freitas, Recife), W. Mattos (Hospital Nossa Senhora Conceicao,
Porto Alegre), M. A. C. Moreira (Hospital das Clinicas da Univ-
ersidade, Goiania), R. Stibulov (Irmandade Santa Casa de Mis-
ericordia de Sao Paulo, Sao Paulo), and P. Z. Teixeira (Santa
Casa de POA, Porto Alegre).
Chile. M. I. Campos (Hospital Assitencia Publica, Santi-
ago), R. Northland (Hospital de Carabineros, Santiago), and
F. Saldias (Hospital Clinico PUC, Santiago).
 Peru. W. Fajardo (Hospital Dos de Mayo, Lima) and L.
Sanchez (Hospital Nacional, Lima).
Bulgaria. O. Georgiev (University Alexandrovska Hospital,
Sofia), R. Georgiev-Marinov (5th Multifunctional Hospital for
Active Treatment, Sofia), and H. Metev (Regional Dispensary
for Pulmonary Diseases, Russe).
Romania. M. Bogdan (National Institute of Pulmonary
Diseases, Bucharest) and P. J. Calistru (Spitalul de Boli Infec-
tioase, Bucharest).
Ukraine. V. Gavrysyk (Institute of Phthisiology and Pul-
monology, Kiev), V. Lisogub (City Hospital N12, Kiev), V. Mel-
nyk (Clinic of Tuberculosis and Pulmonology, Kiev), Y. Mos-
tovoy (Vinnitsa City Hospital N1, Vinnitsa), A. Svintsitskiy
(National Medical University, Kiev), V. Yefimov (City Clinical
Hospital N13, Kharkov), and N. Zamlinsky (Nikolayev City
Hospital N1, Nikolaev).
Mexico. S. H. Campos (Hospital General de Durango, Du-
rango), M. I. del Campo (Hospital General de Zona #27, Mex-
ico City), C. G. Garcia (Hospital Estatal Lic Adolfo Lopez
Mateos, Toluca), R. M. Longoria (Hospital Universitario de
Monterrey, Monterrey), S. D. Meza (Hospital Nicolas San
Juan, Toluca), J. R. J. Ocana (Hospital Regional 1 de Octu-
bre, Mexico City), and J. J. M. Reyes (Hospital Nuevo Civil
Dr. Juan I. Menchaca, Guadalajara).
South Africa. S. A. Hitchcock (Kalafong Hospital,
Atteridgeville).
Acknowledgments
Financial support. Cubist Pharmaceuticals.
Potential conflicts of interest. P.E.P., M.B., G.M.T., S.A.L., and J.A.
have been employees of Cubist Pharmaceuticals. P.B. has served as a con-
sultant for Cubist Pharmaceuticals. R.D.A. is a former employee of Cubist
Pharmaceuticals. C.F., P.M., and R.N. have received investigator grants from
Cubist Pharmaceuticals.
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