MAJOR ARTICLE

A Study Evaluating the Efficacy, Safety,

and Tolerability of Ertapenem versus Ceftriaxone
for the Treatment of Community-Acquired
Pneumonia in Adults

Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020

Guillermo Ortiz-Ruiz,1 Jose Caballero-Lopez,2 Ian R. Friedland,3 Gail L. Woods,3 Alexandra Carides,3
and the Protocol 018 Ertapenem Community-Acquired Pneumonia Study Groupa
1
Hospital Santa Clara, Bogota, Colombia; 2Peruvian University Cayetano Heredia, Lima, Peru; and 3Merck Research Laboratories,
West Point, Pennsylvania

In a double-blind, multicenter trial, 502 patients hospitalized with community-acquired pneumonia were
randomized to receive therapy with either ertapenem or ceftriaxone (for each, 1 g given intravenously once
daily). After a minimum of 3 days, therapy could be switched to oral amoxicillin-clavulanate. The median
duration of intravenously administered therapy for the 383 clinically evaluable patients was 4 days for both
treatment groups; 345 patients (90.1%) had their treatment switched to orally administered therapy. Of the
clinically evaluable patients, 168 (92.3%) in the ertapenem group and 183 (91.0%) in the ceftriaxone group
had a favorable clinical response. Streptococcus pneumoniae was the most commonly isolated pathogen, and
high cure rates were observed both for penicillin-susceptible and -nonsusceptible infections in the ertapenem
group (28 [87.5%] of 32 patients versus 17 [100%] of 17 patients, respectively). Both treatment regimens were
generally well tolerated; the most common drug-related adverse events reported were diarrhea (2.9% versus
2.7%) and nausea (0.8% versus 2.0%) in the ertapenem and ceftriaxone groups, respectively. These results
suggest that ertapenem and ceftriaxone therapy have similar efficacy and safety in hospitalized patients with
community-acquired pneumonia.

Lower respiratory tract infections are a major cause of
morbidity and mortality worldwide. Although the ma-
jority of patients with community-acquired pneumonia
(CAP) are treated as outpatients, ∼500,000 patients
with CAP are hospitalized annually in the United States
[1]. The mean mortality rate among hospitalized pa-
tients in the United States is ∼14% [2]. Higher mortality
Received 10 September 2001; revised 5 December 2001; electronically published
18 March 2002.
Financial support: Support for the study was provided by Merck & Co., Inc.
a
Study group members are listed at the end of the text.
Reprints or correspondence: Dr. Ian R. Friedland, Merck & Co., PO Box 4, BL3-
4, West Point, PA 19486-0004 (ian_friedland@merck.com).
Clinical Infectious Diseases 2002; 34:1076–83
 2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3409-0007$03.00
rates have been reported among elderly persons and in
developing countries [3, 4].
Ertapenem is a new parenteral antimicrobial agent
with once-daily dosing that is highly active in vitro
against respiratory pathogens typically associated with
CAP, such as Streptococcus pneumoniae (including peni-
cillin-nonsusceptible isolates), Haemophilus influenzae,
and Moraxella catarrhalis. Like other b-lactams, this
structurally unique carbapenem is not active against
Mycoplasma pneumoniae or Legionella or Chlamydia
species. Its long plasma half-life (∼4 h) allows for once-
daily dosing.
The primary objective of this study was to compare
the clinical and microbiologic efficacy and the safety of
ertapenem therapy with those of ceftriaxone therapy
for the treatment of patients with CAP who require
parenteral therapy. A secondary objective was to eval-

1076 • CID 2002:34 (15 April) • Ortiz-Ruiz et al.

uate the clinical and microbiologic responses in the subgroup
of patients with pneumococcal infection, including infections
with penicillin-resistant S. pneumoniae (PRSP) strains. The reg-
imen used for comparison, 1 g of ceftriaxone given daily, is an
accepted therapy for CAP and has been shown to be safe and
effective in treating serious infections [5–7].
PATIENTS, MATERIALS, AND METHODS
Study design. A prospective, multinational, double-blind
(with sponsor blinding), randomized study was developed to
compare ertapenem with ceftriaxone therapy for patients with
CAP that required parenteral therapy. The study, which was
conducted from July 1998 through December 1999, included
62 investigator sites in North and South America, Europe, Asia,
Australia, and South Africa. Written consent was obtained from
all patients, and the institutional review board at each partic-
ipating site approved the protocol.
Patient selection. Men and women aged ⭓18 years who
had CAP diagnosed and who required parenteral antibiotic
therapy were randomized to 1 of the 2 study regimen groups
in a 1:1 ratio. The diagnosis of CAP was made on the basis of
the presence of signs and symptoms consistent with pneumonia
(fever, chills, and/or hypothermia, plus ⭓2 of the following
symptoms: cough with sputum production, rales, auscultatory
findings on pulmonary examination consistent with consoli-
dation, dyspnea, tachypnea, hypoxemia, and pleuritic chest
pain), abnormal findings on microscopic evaluation of sputum,
chest radiographic findings (new or progressive infiltrate, con-
solidation, cavitation, or pleural effusion), and other supportive
laboratory data (e.g., a peripheral WBC count of 110,000 cells/
mL or with 115% immature neutrophils, or a blood culture
positive for an organism consistent with a respiratory patho-
gen). The likelihood of enrolling patients who had atypical
pneumonia was minimized for the following reasons: (1) pa-
tients with suspected legionnaires’ disease (e.g., a urine test
positive for Legionella antigen) were excluded from the study,
and (2) patients aged !40 years had to be able to produce
purulent sputum.
Patients with any of the following conditions, treatment char-
acteristics, or laboratory findings were excluded from the study:
empyema, underlying structural lung abnormalities, lung ma-
lignancy, nosocomial pneumonia, requirement of mechanical
ventilation, active tuberculosis, any rapidly progressive or ter-
minal illness, immunocompromising disease or receipt of im-
munocompromising therapy, antibiotic treatment for ⭓24 h
during the 72 h before enrollment in the study (unless treat-
ment failure was documented), aspartate aminotransferase or
alanine aminotransferase (ALT) levels 16 times the upper limit
of normal, bilirubin or alkaline phosphatase levels 13 times the
upper limit of normal, an absolute neutrophil count of !1000
Ertapenem vs. Ceftriaxone in Pneumonia • CID 2002:34 (15 April) • 1077
neutrophils/mm3, a platelet count of !75,000 platelets/mm3,
hematocrit of !25%, or coagulation test results that were 11.5
times the upper limit of normal. Patients with laboratory values
that exceeded any of these limits were allowed to enroll in the
study, on an individual basis, if the abnormality was thought
to be the result of acute infection. Patients with elevated cre-
atinine clearance were excluded initially, but a subsequent study
amendment allowed patients with severe renal insufficiency
(creatinine clearance, !30 mL/min per 1.73 m2) to be given a
reduced dosage of ertapenem (500 mg daily).
Antimicrobial susceptibility testing was required for all base-
line pathogens isolated from sputum or blood cultures. Patients
Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020
with baseline pathogens found to be resistant to 1 or both study
drugs after they started receiving the study therapy continued
enrollment in the study at the discretion of the investigator.
At study entry, randomization was stratified, for balance, into
4 groups, on the basis of disease severity, as defined by the pneu-
monia severity index (PSI; ⭐3 or 13) and age (⭐65 or 165
years). The PSI incorporates assessment of comorbid illness,
acute physiological changes, and age; a PSI of 4 or 5 indicates
severe illness [8].
Treatment regimens. Randomization resulted in patients
having an equal chance of receiving either ertapenem (Merck
& Co.; 1 g given intravenously) or ceftriaxone (Roche Phar-
maceuticals; 1 g given intravenously) once per day for up to
14 days. Therapy that is effective against atypical respiratory
pathogens was not provided. The intravenously administered
study antibiotics were given over 30 min. Each day, patients
received 1 infusion of a study drug and 1 infusion of placebo
that matched the other study drug. To maintain blinding, a
small amount of multivitamin concentrate was added to saline
to produce placebo that matched the color of the ceftriaxone
used for infusion. The study allowed patients with documented
PRSP infection and a suboptimal clinical response to have the
dose of ertapenem or ceftriaxone increased to 2 g per day at
the discretion of the investigator. Investigators had the option
to switch the patient’s therapy to orally administered amoxi-
cillin-clavulanate (amoxicillin, 875 mg twice per day/clavulan-
ate, 125 mg twice per day, or an equivalent dosage regimen)
after ⭓3 days of receipt of parenteral therapy, provided that
the patient met protocol-specified criteria to indicate sufficient
clinical improvement. The recommended total duration of anti-
biotic therapy was 10–14 days. Receipt of therapy with other
antimicrobial agents that are potentially effective for manage-
ment of pneumonia was not permitted during treatment or in
the period before early follow-up, unless the study treatment
failed.
Microbiologic procedures. At baseline, sputum specimens
were obtained by expectoration (or by other methods of ob-
taining lower respiratory tract specimens) for Gram stain and
culture. Blood cultures were also required for all patients. All
isolated bacteria were evaluated by the investigator and judged
to be pathogenic or nonpathogenic. For all pathogens, suscep-
tibility to ertapenem, ceftriaxone, and amoxicillin-clavulanate
was evaluated at the site laboratory by use of the disk-diffusion
test, according to the guidelines of the National Committee for
Clinical Laboratory Standards [9]. For this purpose, paper disks
that contained 10 mg of ertapenem, 30 mg of ceftriaxone, or
20/10 mg of amoxicillin-clavulanate were provided to each site
by Merck Research Laboratories. In addition, 1-mg oxacillin
disks and penicillin E-test strips were provided for testing sus-
ceptibility of pneumococci to penicillin.
Efficacy assessment. Detailed clinical observations were
made at baseline and while patients were receiving intrave-
nously administered therapy. Investigators assessed the clinical
outcome when intravenously administered therapy was dis-
continued, at the early follow-up visit (7–14 days after cessation
of iv and optional oral antimicrobial therapy), and at late fol-
low-up (21–28 days after cessation of therapy). Test of cure
(TOC) was assessed at the early follow-up visit; relapse was
assessed at the late follow-up visit. For each patient, assessments
were based on signs and symptoms of pneumonia (each rated
individually), vital signs, oxygen saturation, chest radiograph
findings, and laboratory test results. The microbiologic response
for each baseline pathogen was based on culture results at the
TOC visit. If cultures were not repeated at the TOC visit, mi-
crobiologic outcomes were presumed on the basis of the clinical
response.
The evaluability of patients for the analysis of efficacy was
determined prior to unblinding study therapy and was based
on prespecified criteria. These included minimum requirements
for confirmation of the diagnosis, prior and concomitant anti-
microbial therapy within prespecified limits, treatment duration
within specified limits (5–17 days to be considered clinical cure
and 148 h to be considered clinical failure), and a follow-up
assessment done ⭓7 days after completion of all antimicrobial
therapy (including optional oral therapy).
The primary efficacy end point was the proportion of clin-
ically evaluable patients who had a favorable clinical response
assessment at TOC. In addition, a modified intent-to-treat
(MITT) analysis was done that included all patients who met
minimum requirements for diagnosis of pneumonia and who
had received ⭓1 dose of ertapenem or ceftriaxone.
Safety assessment. Safety and local tolerability were eval-
uated in all patients who received ⭓1 dose of intravenously
administered therapy. Adverse clinical and laboratory experi-
ences were evaluated during the entire antimicrobial therapy
period and for 14 days after completion of all study therapy
(intravenous and oral).
Statistical analyses. The study was designed to test for
equivalence (noninferiority) in the efficacy of ertapenem and
ceftriaxone in the clinically evaluable patients in the 2 treatment
1078 • CID 2002:34 (15 April) • Ortiz-Ruiz et al.
groups. The study was not specifically powered to demonstrate
equivalence in subgroup analyses. The sample size (150 eval-
uable patients per group) was calculated by use of Blackwelder’s
formula [10] and the following values: a, 0.025; b, 0.20; and
the expected response rate, 90%. The criteria for equivalence
were (1) that the 2-sided 95% CI for the difference in response
rates between the 2 treatment groups contained 0, and (2) the
lower limit of the 95% CI was not less than ⫺10 percentage
points. The 95% CIs were calculated by use of the normal
approximation to the binomial distribution, and the Cochran
approach [11] was used to account for stratification. A test of
treatment by stratum interaction was also performed by use of
Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020
the Breslow-Day test of homogeneity of ORs [12]. Patients with
PRSP infection were analyzed separately and were not included
in the primary evaluable patient population analyses. They were
included in the MITT analyses and in a specific analysis of
pneumococcal infection outcome.
RESULTS
Of the 502 patients enrolled in the study, 383 (76.3%) were
considered clinically evaluable; 182 were randomized to receive
ertapenem and 201 were randomized to receive ceftriaxone. A
total of 209 patients (41.6%) were microbiologically evaluable,
96 of whom were in the ertapenem group and 113 of whom
were in the ceftriaxone group. Figure 1 summarizes the number
of patients in each of the populations analyzed. The most com-
mon reasons that patients were considered clinically noneval-
uable were failure to receive sufficient study therapy or failure
to have an assessment at the TOC visit within the appropriate
time window. The most common reasons that patients were
considered microbiologically nonevaluable were that they were
not clinically evaluable or that they did not have a baseline
pathogen isolated.
Figure 1. Profile of study enrollment, summarizing the number (%) of
patients in each of the evaluated populations. MITT, modified intent-to-
treat.
 Baseline patient characteristics. The randomized and
clinically evaluable populations in the 2 treatment groups were
similar with respect to baseline characteristics (table 1). The
microbiologically evaluable population and the MITT popu-
lation were similar to the randomized population (data not
shown). In each study population, patients in both treatment
groups were comparable with respect to age, sex, race, second-
ary diagnoses, medications received, and clinical signs and
symptoms. Approximately 60% of the clinically evaluable pa-
tients were male, and a similar percentage of the evaluable
patients (men and women) were aged ⭐65 years. Almost 20%
of clinically evaluable patients were aged ⭓75 years.
group and 19 in the ceftriaxone group. S. pneumoniae ac-
counted for 24 (82.8%) of the blood isolates.
Dosage and duration of therapy. In no patient was the
dose of ertapenem adjusted for renal failure, nor was the dose
of either study drug increased to 2 g for treatment of PRSP
infection. The median duration of intravenously administered
therapy for clinically evaluable patients was 4 days (range, 2–17
days for ertapenem and 2–14 days for ceftriaxone); for total
antimicrobial therapy, the median duration was 12 days (range,
3–21 days for patients in the ertapenem group and 3–17 days
for patients in the ceftriaxone group). In clinically evaluable
patients, 165 (90.7%) in the ertapenem group and 180 (89.6%)

Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020

Baseline microbiologic findings. The 2 treatment groups
were similar with respect to the distribution and susceptibility
patterns of baseline pathogens. Of the bacteria isolated from
all patients in both treatment groups for which susceptibility
results were available, 287 (98.3%) of 292 isolates were sus-
ceptible to ertapenem and 270 (92.8%) of 291 were susceptible
to ceftriaxone. The most frequently isolated pathogen resistant
to 1 or both study drugs was methicillin-resistant Staphylococcus
aureus, which was considered resistant to ertapenem and cef-
triaxone, irrespective of reported in vitro susceptibility results.
In addition, 3 and 4 isolates of S. pneumoniae were intermediate
and resistant to ceftriaxone, respectively.
Of the clinically evaluable patients, 96 (52.7%) and 113
(56.2%) in the ertapenem and ceftriaxone groups, respectively,
had ⭓1 pathogen identified in sputum and/or blood samples.
The most commonly isolated organisms were S. pneumoniae,
H. influenzae, M. catarrhalis, and S. aureus. Twenty-nine pa-
tients (7.6%) had bacteremia at baseline: 10 in the ertapenem
in the ceftriaxone group received oral antimicrobial therapy;
overall, 334 (96.8%) received amoxicillin-clavulanate.
Efficacy results. For the TOC analysis, 92.4% (95% CI,
88.5%–96.2%) of clinically evaluable patients in the ertapenem
group and 91.3% (95% CI, 87.3%–95.3%) of those in the cef-
triaxone group were cured. The difference in response rates
between the 2 groups, adjusting (weighting) for strata, was 1.0%
(95% CI, ⫺4.9% to 7.0%), which indicated that the rates for
the 2 groups were equivalent. As shown in table 2, cure rates
in the clinically evaluable population were 190% for each stra-
tum in the ertapenem group and ranged from 86% to 91% for
those in the ceftriaxone group. Slightly lower clinical success
rates were observed in the MITT analysis (85.1% in the erta-
penem group and 85.0% in the ceftriaxone group), which re-
flects the more conservative approach in the MITT outcome
assessment, in which patients with inadequate information or
indeterminate outcomes were considered to have had treatment
failure. Also evident from table 2 are the high microbiologic

Table 1. Baseline characteristics of 502 patients with community-acquired pneumonia

enrolled in a study that compared ertapenem therapy with ceftriaxone therapy.

Randomized population, Clinically evaluable population,

treatment group treatment group
Ertapenem Ceftriaxone Ertapenem Ceftriaxone
Characteristic (n p 244) (n p 258) (np 182) (n p 201)
Male sex 142 (58.2) 145 (56.2) 107 (58.8) 115 (57.2)
Race
White 125 (51.2) 144 (55.8) 94 (51.6) 109 (54.2)
Hispanic 63 (25.8) 61 (23.6) 51 (28.0) 52 (25.9)
Black 38 (15.6) 35 (13.6) 24 (13.2) 24 (11.9)
Other ethnic group 18 (7.4) 18 (7.0) 13 (7.1) 16 (8.0)
Age, mean years  SD 55.9  20.0 57.3  19.7 56.4  19.9 56.2  19.9
Pneumonia severity index
1 46 (18.9) 42 (16.3) 27 (14.8) 34 (16.9)
2 73 (29.9) 90 (34.9) 59 (32.4) 72 (35.8)
3 63 (25.8) 52 (20.2) 51 (28.0) 38 (18.9)
4 54 (22.1) 65 (25.2) 39 (21.4) 49 (24.4)
5 7 (2.9) 9 (3.5) 5 (2.7) 8 (4.0)

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

Ertapenem vs. Ceftriaxone in Pneumonia • CID 2002:34 (15 April) • 1079

 Table 2. Outcomes of clinically evaluable, microbiologically evaluable, and modified-intent-to-
treat populations (MITT) at early follow-up (test of cure visit; 7–14 days after cessation of therapy)
in a study that compared ertapenem therapy with ceftriaxone therapy.

Ertapenem group Ceftriaxone group

Patient group, No. (%) of No. (%) of
characteristic n patients cured 95% CI n patients cured 95% CI
Clinically evaluable patients
Age, years
⭐65 110 101 (91.8) 86.7–97.0 126 115 (91.3) 86.3–96.2
165 72 67 (93.1) 87.1–99.0 75 68 (90.7) 84.0–97.3
⭓75 37 35 (94.6) 87.2–100 42 37 (88.1) 78.2–98.0
Pneumonia severity index

Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020

⭐3 138 128 (92.8) 88.4–97.1 144 134 (93.1) 88.9–97.2
13 44 40 (90.9) 82.3–99.5 57 49 (86.0) 76.9–95.1
All 182 168 (92.3) 88.4–96.2 201 183 (91.0) 87.1–95.0
Microbiologically evaluable
patientsa 96 89 (92.7) 87.5–97.9 113 107 (94.7) 90.5–98.8
b
Clinical MITT population
Age, years
⭐65 145 121 (83.4) 77.4–89.5 149 131 (87.9) 82.7–93.2
165 91 80 (87.9) 81.2–94.6 101 81 (80.2) 72.4–88.0
Pneumonia severity index
⭐3 177 153 (86.4) 81.4–91.5 178 156 (87.6) 82.8–92.5
13 59 48 (81.4) 71.3–91.4 72 56 (77.8) 68.1–87.4
All 236 201 (85.2) 80.6–89.7 250 212 (84.8) 80.3–89.3
a
Microbiologic cure rates were assessed at early follow-up and reflect eradication of all baseline pathogens.
b
Cure rates in the MITT population were assessed as described in the Patients, Materials, and Methods section.

cure rates (i.e., eradication or presumed eradication of the base-
line pathogen): 92.7% and 94.7% in the ertapenem and cef-
triaxone groups, respectively.
Table 3 compares the per-pathogen clinical response rates
between the 2 treatment groups, including patients with PRSP
infection. Four patients with pneumococcal pneumonia (1 in
the ertapenem group and 3 in the ceftriaxone group) were
infected with a penicillin-resistant isolate (MIC, ⭓2 mg/mL);
all of these patients were cured at the TOC visit.
Clinical relapse rates, assessed at the 21–28-day visit, were
low in both treatment groups: 3 (2.0%) of 148 patients in the
ertapenem group and 1 (0.6%) of 155 patients in the ceftriax-
one group had clinical relapse. No bacterial recurrences were
reported in either treatment group, and no reported persistent
pathogens acquired resistance to the study drug received.
Adverse events. Of the 502 patients randomized, 498 re-
ceived ⭓1 dose of parenteral therapy and were included in the
analysis of adverse events. During parenteral therapy, clinical
adverse events that were possibly, probably, or definitely drug
related were reported for 27 patients (11.2%) in the ertapenem
group and 43 (16.8%) in the ceftriaxone group, and drug-
related laboratory adverse events were reported in 31 patients
(13.4%) in the ertapenem group and 26 (10.7%) in the cef-
triaxone group. The most common adverse events are listed in
table 4. Of the patients with elevated liver enzyme levels, ALT
levels increased to 15 times the upper limit of normal in 4
patients (2.1%) in the ertapenem group and in 5 (2.5%) in the
ceftriaxone group. At the time of the follow-up examination,
ALT levels had returned to normal or tended to return to
baseline levels in all patients. One patient in the ertapenem
group had a seizure, which the investigator reported as probably
drug related. This seizure occurred in an 89-year-old woman
who had a generalized tonic-clonic seizure that lasted ∼1 min
on study day 10, the final scheduled day of intravenously ad-
ministered therapy. She recovered without receiving antiseizure
medication. The findings of an electroencephalograph obtained
on study day 53 were normal, and a neurologic examination
performed during follow-up revealed no sequelae. No patient
had study therapy discontinued because of a drug-related clin-
ical or laboratory adverse experience. There were no drug-
related deaths.
Local tolerability. Tolerability at the study drug intrave-
nous infusion site was assessed daily while each patient was
receiving study therapy. Of all patients who received ⭓1 dose
of study therapy, 37 (15.3%) of 242 in the ertapenem group
and 44 (17.3%) of 255 in the ceftriaxone group experienced

1080 • CID 2002:34 (15 April) • Ortiz-Ruiz et al.

Table 3. Clinical cure rates, by pathogen isolated at baseline, study on the basis of data that strongly suggested that it is as
at early follow-up (test of cure visit) in a study that compared efficacious as 2 g per day [5–7, 13–17]. In a study that directly
ertapenem therapy with ceftriaxone therapy.
compared 1 g versus 2 g of ceftriaxone given daily [6], cure
Ertapenem group Ceftriaxone group
rates in the 2 treatment arms were similar (94% in patients
a a
(n p 97) (n p 116) who received 1 g daily and 89% in those who received 2 g
Response Response daily).
Pathogen n/N b rate, % n/N b rate, % The most common pathogens isolated from respiratory spec-
Gram-positive bacteria imens and/or blood samples were S. pneumoniae, H. influenzae,
Streptococcus M. catarrhalis, and S. aureus—results similar to studies of CAP
pneumoniae published elsewhere [13, 18–20]. The rates of cure in the 2
All 44/48 91.7 56/60 93.3 treatment groups were similar for the major pathogens iden-
Penicillin-NS strainsc 11/11 100 12/13 92.3 tified. In microbiologically evaluable patients, the pathogen iso-

Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020

Staphylococcus aureus 8/8 100 4/5 80.0 lated at baseline was eradicated or presumed to have been erad-
Other 5/5 100 4/5 80.0 icated in 192% of patients in both treatment groups.
Total 57/61 93.4 64/70 91.4 S. pneumoniae accounted for 140% of the pathogens isolated
Gram-negative bacteria in this study. Among patients from whom S. pneumoniae was
Haemophilus influenzae 17/21 81.0 22/23 95.7 isolated, favorable clinical response rates were 91.7% in the
Moraxella catarrhalis 10/10 100 15/18 83.3 ertapenem group and 93.3% in the ceftriaxone group. Clinical
Other 15/16 93.7 24/25 96.0 and microbiologic response rates to ertapenem therapy were
Total 42/47 89.4 61/66 92.4 similar in patients infected with penicillin-susceptible and
NOTE. NS, nonsusceptible. -nonsusceptible S. pneumoniae isolates. This suggests that the
a
No. of evaluable patients in each treatment group. 1-g once-daily dosage of ertapenem is effective against infec-
b
No. of pathogens with favorable clinical assessments/no. of pathogens tions with S. pneumoniae that are intermediately susceptible to
with a clinical assessment.
c
Penicillin nonsusceptibility was defined as an oxacillin disk test zone size penicillin; however, the number of patients in this group was
of ⭐19 mm. relatively small. Of the 4 patients with documented PRSP in-
fection (MIC of penicillin, ⭓2.0 mg/mL), only 1 was in the
ertapenem treatment group; therefore, no meaningful conclu-
⭓1 local reaction at the infusion site. The most common symp-
sions regarding ertapenem for treatment of PRSP infection are
toms were pain, erythema, and swelling.
possible. None of the S. pneumoniae isolates in the present study
were resistant to ertapenem, which suggests that pneumococcal
DISCUSSION resistance to ertapenem is not currently a problem in the many
participating countries.
In this multicenter, double-blind study, the efficacy and safety In 1998, the Infectious Diseases Society of America (IDSA)
of ertapenem were compared with the efficacy and safety of published practice guidelines for the treatment of CAP [21],
ceftriaxone for the empiric treatment of CAP requiring par-
enteral therapy. Treatment with ertapenem (1 g once per day) Table 4. Most common drug-related clinical and laboratory ad-
was highly effective in all patient populations and was equiv- verse events reported during ertapenem and ceftriaxone therapy.
alent to therapy with ceftriaxone (1 g once per day). More than
90% of the clinically evaluable patients treated with ertapenem, No. (%) of patients,
by treatment group
including patients in high-risk groups (i.e., those aged 165 years
or with a PSI of 13), were cured. These results, however, should Adverse event Ertapenem Ceftriaxone
not be generalized to patients with excluded comorbidities, Clinical
such as lung cancer, empyema, immunocompromising disease, Diarrhea 7 (2.9) 7 (2.7)
or septic shock, because the efficacy of ertapenem for the treat- Nausea 2 (0.8) 5 (2.0)
ment of such patients was not evaluated. Also, the numbers of Headache 1 (0.4) 4 (1.6)
patients with the most severe forms of pneumonia (PSI, 13) Laboratory
were relatively small. Increased ALT level 18 (9.0) 15 (7.2)
Cure rates for both ertapenem and ceftriaxone in the present Increased AST level 15 (7.4) 13 (6.3)
study were comparable to those reported elsewhere in trials of Increased alkaline phosphatase
CAP treated with ceftriaxone, although the daily dose of cef- level 3 (1.4) 6 (2.8)

triaxone was 1 g in some studies and 2 g in others [5–7, 13–17]. Increased platelet count 4 (1.8) 3 (1.3)

The 1-g once-daily dosage of ceftriaxone was chosen in this NOTE. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Ertapenem vs. Ceftriaxone in Pneumonia • CID 2002:34 (15 April) • 1081

which were recently revised. For hospitalized patients in a gen-
eral ward, the recommended antimicrobial therapies are ce-
fotaxime plus a macrolide, ceftriaxone plus a macrolide, or a
fluoroquinolone alone [22]. However, in 1998, when the pre-
sent study was designed and initiated, coverage for these or-
ganisms was considered optional in the IDSA guidelines [21],
and therapy effective against M. pneumoniae, Chlamydia spe-
cies, or Legionella species was not used. Nevertheless, because
of the potentially serious nature of legionellosis, an attempt was
made to exclude patients with this infection by testing urine
samples for Legionella antigen. Treatment failure rates in the
present study were similar to those in studies published else-
where about CAP that included therapy with a macrolide or
quinolone [19, 23]. This suggests that, in the present study, M.
pneumoniae, Chlamydia species, and Legionella species were not
important causes of treatment failure; however, this cannot be
proved, because the frequency at which these organisms were
responsible for disease was not systematically assessed.
The safety profile and tolerability of ertapenem were similar
to those of ceftriaxone. The drug-related clinical adverse events
reported for both agents were those commonly observed in
association with cephalosporin therapy, and none of these
events resulted in discontinuation of receipt of either drug.
Only 1 serious drug-related adverse event, a seizure, occurred
among patients treated with ertapenem. This generalized sei-
zure was brief and without sequelae. The most common drug-
related laboratory adverse event was elevation of the trans-
aminase levels. The enzyme elevations were mild to moderate,
were transient, and appeared to be of little clinical importance.
In summary, in adult patients with CAP who require par-
enteral therapy, 1 g of ertapenem given intravenously once per
day for up to 14 days, with the option of switching to an orally
administered agent after clinical improvement, was highly ef-
fective both clinically and microbiologically, regardless of the
severity of the infection, and was as effective as therapy with
ceftriaxone (1 g daily), which could also be switched to oral
therapy. Ertapenem was generally well tolerated and had a safety
profile comparable to that of ceftriaxone.
STUDY GROUP MEMBERS
Investigative members of the Protocol 018 Ertapenem Com-
munity-Acquired Pneumonia Study Group are as follows:
Roger Beneitone, Springfield, MA; C. Thomas Boylen, Los
Angeles, CA; Peter Reid Bremner, Freemantle, Australia; Jose
Cipullo, Sao Jose do Rio Preto, Brazil; Luiz Carlos Correa da
Silva, Porto Alegre, Brazil; Klaus Dalhoff, Lucbeck, Germany;
Lala Dunbar, New Orleans, LA; Stephen Farkas, Akron, OH;
Scott Filler, Torrance, CA; Charles Fogarty, Spartanburg, SC;
Elliot Frank, Neptune, NJ; Ronald Geckler, Baltimore, MD;
Catherine Godfrey, Auckland, New Zealand; Fernando Gon-
1082 • CID 2002:34 (15 April) • Ortiz-Ruiz et al.
zalez-Fuenzalida, Santiago, Chile; David H. Gremillion, Raleigh,
NC; Stephen J. Hawes, Charlotte, NC; Maria Herrera, Santiago,
Chile; Gustavo Hincapie, Bogota, Colombia; Abel Jasovich,
Buenos Aires, Argentina; Howard Koffler, Sellersville, PA; James
G. Lampasso, Williamsville, NY; David Langton, Frankston,
Australia; Matthew E. Levison, Philadelphia, PA; Gustavo Lo-
pardo, Buenos Aires, Argentina; Jose Caballero Lopez, Lima,
Peru; Gifford Lorena, Savannah, GA; Wycliffe J. Many, Mont-
gomery, AL; Melanie J. Maslow, New York, NY; Maria Montes
De Oca, Caracas, Venezuela; Juan Morales-Reyes, Guadalajara,
Mexico; Roy Moser, Crestview Hills, KY; Michael Nelson,
Shawnee Mission, KS; Luis Noriega-Ricalde, Santiago, Chile;
Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020
Scott Nicholas Parkes, Launceston, Australia; Martin J. Phillips,
Nedlands, Australia; Rick Player, Birmingham, AL; Julio Ra-
mirez, Louisville, KY; Kevin D. Reed, Baton Rouge, LA; John
F. Reinhardt, Newark, DE; Guy Anthony Richards, Johannes-
burg, South Africa; Abraham R. Rubinfeld, Melbourne, Aus-
tralia; Guillermo Ortiz Ruiz, Bogota, Colombia; Silverio San-
tiago, Los Angeles, CA; Ghodrat A. Siami, Nashville, TN;
Gagrath P. Singh, Takapuna, New Zealand; Alexander Sino-
palnikov, Moscow, Russia; Harold C. Standiford, Baltimore,
MD; Keng Tan, Singapore; and Alfonzo Uribe, Lima, Peru.
References
1. Centers for Disease Control and Prevention. Introduction to table V:
premature deaths, monthly mortality and monthly physician con-
tacts—United States. MMWR Morb Mortal Wkly Rep 1997; 46:566–61.
2. Fine MJ, Smith MA, Carson CA, et al. Prognosis and outcomes of
patients with community-acquired pneumonia: a meta-analysis. JAMA
1996; 275:134–41.
3. Centers for Disease Control and Prevention. Pneumonia and influenza
death rates—United States, 1979–1994. MMWR Morb Mortal Wkly
Rep 1995; 44:535–7.
4. Riquelme R, Torres A, El-Ebiary M, et al. Community-acquired pneu-
monia in the elderly: a multivariate analysis of risk and prognostic
factors. Am J Respir Crit Care Med 1996; 154:1450–5.
5. De Palma M, Rocchi D, Canepa G, Peri A, Cantone V. Single daily
dose of cefodizime in patients with community-acquired pneumonia:
an open-label, controlled, randomized study. Clin Ther 1995; 17:
413–24.
6. Segev S, Raz R, Rubinstein E, et al. Double-blind randomized study
of 1 g versus 2 g intravenous ceftriaxone daily in the therapy of com-
munity-acquired infections. Eur J Clin Microbiol Infect Dis 1995; 14:
851–5.
7. Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime proxetil
compared with ceftriaxone in vulnerable patients with bronchopneu-
monia. J Antimicrob Chemother 1990; 26(Suppl E):71–7.
8. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-
risk patients with community acquired pneumonia. N Engl J Med
1997; 336:243–50.
9. National Committee for Clinical Laboratory Standards. Performance
standards for antimicrobial disk susceptibility tests: approved standard.
NCCLS document M2-A6. Wayne, PA: National Committee for Clin-
ical Laboratory Standards, 1997.
10. Blackwelder WC. “Proving the null hypothesis” in clinical trials. Con-
trol Clin Trials 1982; 3:345–53.
11. Cochran WG. Some methods for strengthening the common chi-square
tests. Biometrics 1954; 10:417–51.
12. Breslow NE, Day NE. The analysis of case-control studies. IARC sci-
entific publications no. 32. Lyon, France: IARC, 1980.
13. Zervos M, Nelson M. Cefepime versus ceftriaxone for empiric treat-
ment of hospitalized patients with community-acquired pneumonia.
The Cefepime Study Group. Antimicrob Agents Chemother 1998; 42:
729–33.
14. Bassetti D, Cruciani M, Solbiati F, et al. Comparative efficacy of cef-
triaxone versus ceftazidime in the treatment of nosocomial lower res-
piratory tract infections. Chemotherapy 1991; 37:371–5.
15. Mangi RJ, Peccerillo KM, Ryan J, et al. Cefoperazone versus ceftriaxone
monotherapy of nosocomial pneumonia. Diagn Microbiol Infect Dis
1992; 15:441–7.
16. Zuck P, Rio Y, Ichou F. Efficacy and tolerance of cefpodoxime proxetil
compared with ceftriaxone in vulnerable patients with bronchopneu-
monia. J Antimicrob Chemother 1990; 26(Suppl E):71–7.
17. Phillips SL, Branaman-Phillips J. The use of intramuscular cefopera-
zone versus intramuscular ceftriaxone in patients with nursing
home–acquired pneumonia. J Am Geriatr Soc 1993; 41:1071–4.
18. Fine MJ, Stone RA, Singer DE, et al. Processes and outcomes of care
Ertapenem vs. Ceftriaxone in Pneumonia • CID 2002:34 (15 April) • 1083
for patients with community-acquired pneumonia: results from the
Pneumonia Patient Outcomes Research Team (PORT) cohort study.
Arch Intern Med 1999; 159:970–80.
19. Plouffe JF, Herbert MT, File TM, et al. Ofloxacin versus standard ther-
apy in treatment of community-acquired pneumonia requiring hos-
pitalization. Antimicrob Agents Chemother 1996; 40:1175–9.
20. Leophonte P, Bertrand A, Nouvet G, et al. A comparative study of
cefipime and ceftazidime in the treatment of community-acquired
lower respiratory tract infections. J Antimicrob Chemother 1993;
32(Suppl B):165–73.
21. Bartlett JG, Breiman RF, Mandell LA, File TM Jr. Community-acquired
pneumonia in adults: guidelines for management. Infectious Diseases
Society of America. Clin Infect Dis 1998; 26:811–38.
22. Bartlett JG, Dowell SF, Mandell LA, File TM Jr, Musher DM, Fine MJ.
Practice guidelines for the management of community-acquired pneu-
Downloaded from https://academic.oup.com/cid/article/34/8/1076/283024 by guest on 29 December 2020
monia in adults. Infectious Diseases Society of America. Clin Infect
Dis 2000; 31:347–82.
23. Vergis EN, Indorf A, File TM, et al. Azithromycin vs. cefuroxime plus
erythromycin for empirical treatment of community-acquired pneu-
monia in hospitalized patients. Arch Intern Med 2000; 160:1294–300.