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MAJOR ARTICLE
Ertapenem Once Daily Versus PiperacillinTazobactam 4 Times per Day for Treatment
of Complicated Skin and Skin-Structure
Infections in Adults: Results of a Prospective,
Randomized, Double-Blind Multicenter Study
Donald R. Graham,1 Christopher Lucasti,2 Osvaldo Malafaia,5 Ronald L. Nichols,3 Paul Holtom,4 Nora Quintero Perez,6
Andrea McAdams,7 Gail L. Woods,7 T. Paulette Ceesay,7 Richard Gesser,7 and the Ertapenem Complicated Skin
and Skin Structure Infections Study Groupa
1
Springfield Clinic, Springfield, Illinois; 2South Jersey Infectious Disease, Somers Point, New Jersey; 3Tulane University School of Medicine, New
Orleans, Louisiana; 4Los Angeles County and University of Southern California Medical Center, Los Angeles; 5Hospital Evangelico, Curitiba, Brazil;
6
Hospital Civil de Guadalajara, Mexico; and 7Merck Research Laboratories, West Point, Pennsylvania
We conducted a prospective, randomized, double-blind trial comparing ertapenem (1 g once daily) with
piperacillin-tazobactam (3.375 g every 6 h) as parenteral treatment for 540 adults with complicated skin and
skin-structure infections. The most common diagnoses were skin or soft-tissue abscesses and lower-extremity
infections associated with diabetes. The mean duration ( standard deviation) of therapy was 9.1 3.1 days
for ertapenem and 9.8 3.3 days for piperacillin-tazobactam. At the assessment of primary efficacy end point,
10–21 days after treatment, 82.4% of those who received ertapenem and 84.4% of those who received piperacillin-tazobactam were cured. The difference in response rates, adjusting for the patients’ assigned strata,
was ⫺2.0% (95% confidence interval, ⫺10.2% to 6.2%), indicating that the response rates in the 2 treatment
groups were equivalent. Cure rates for the 2 treatment groups were similar when compared by stratum,
diagnosis, and severity of infection. The frequency and severity of drug-related adverse events were similar
in the treatment groups.
Complicated skin and skin-structure infections (CSSSIs),
such as perineal cellulitis or abscesses, extensive cellulitis, posttraumatic or postsurgical skin or soft-tissue in-
Received 20 September 2001; revised 8 January 2002; electronically published
9 May 2002.
Financial support: Merck.
a
Members of the study group are listed at the end of the text.
Reprints or correspondence: Dr. Donald R. Graham, Springfield Clinic, 1025 S.
7th St., Springfield, IL 62703 ([email protected]); or Richard Gesser,
Merck & Co., Inc., 10 Sentry Pkwy., BL3-4, Blue Bell, PA 19442 (richard_gesser
@merck.com).
Clinical Infectious Diseases 2002; 34:1460–8
2002 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2002/3411-0006$03.00
1460 • CID 2002:34 (1 June) • Graham et al.
fection, and lower-extremity infections in patients with
diabetes mellitus, are deeper, more indolent, and more
severe than are routine soft-tissue infections. They are
often caused by a mixture of gram-positive and gramnegative aerobic and anaerobic bacteria, although Staphylococcus aureus and streptococci are the predominant
pathogens. In community-acquired infections, nonfermentative gram-negative bacilli, which are generally associated with nosocomial infections, are infrequently involved [1, 2].
Empiric treatment of CSSSI requires parenteral coverage of a broad spectrum of potential pathogens and
often includes an extended-spectrum cephalosporin
plus an agent active against anaerobes, such as me-
tronidazole or clindamycin, or a b-lactam/b-lactamase inhibitor combination. These regimens are effective treatment for
CSSSI, but they are complicated by the requirement for administration of multiple parenteral doses each day or administration of 11 agent. Potential limitations of such regimens
may include a greater risk for infusion-related complications,
greater difficulty arranging outpatient antibacterial therapy,
greater risk for medication errors, additional costs associated
with administering several daily infusions, and, for multipledrug regimens, a greater likelihood of drug toxicity [3–5].
Ertapenem (formerly MK-0826; Merck) is a newly approved,
once-daily parenteral b-lactam antimicrobial that can be used
as monotherapy for the treatment of various communityacquired and mixed aerobic and anaerobic infections, including
CSSSI, complicated intra-abdominal infections, communityacquired pneumonia, complicated urinary tract infections, and
acute pelvic infections. This structurally unique carbapenem is
highly active in vitro against the bacteria typically associated
with community-acquired infections, including methicillinsusceptible S. aureus (MSSA) and many streptococci, anaerobes,
and Enterobacteriaceae; it has minimal activity against enterococci and nonfermentative gram-negative bacilli, such as Pseudomonas species [6, 7]. Like other b-lactam antimicrobials, ertapenem is not effective against methicillin-resistant S. aureus
(MRSA). We undertook this study to compare the safety, tolerability, and efficacy of ertapenem with those of piperacillintazobactam for treatment of patients with CSSSI.
PATIENTS, MATERIALS, AND METHODS
Patients. Men and women ⭓18 years of age with CSSSI that
required parenteral antimicrobial therapy were eligible for the
study. Patients had to have signs and symptoms of acute infection (i.e., purulent drainage or collection or ⭓3 of the following findings: fever, WBC counts of 110,000 cells/mL [with
15% immature forms], local erythema extending 11 cm from
the wound edge, lymphangitis, or localized swelling, tenderness
or pain, fluctuance, warmth, or induration) in the absence of
chronic infection or indwelling foreign material. Surgical drainage or debridement of infected wounds or abscesses, if necessary, had to have been completed ⭐48 h after the initiation
of therapy.
Exclusion criteria for the study were as follows: pregnancy
or lactation (in women), history of serious allergy to or intolerance of any b-lactam (patients with a history of a mild
rash caused by a b-lactam could be enrolled), rapidly progressive or terminal illness, receipt of long-term immunosuppressive therapy, AIDS, infected burn wounds, necrotizing
fasciitis, osteomyelitis, septic arthritis, gangrene or need for
amputation, deep-vein thrombosis, need for concomitant systemic antimicrobials in addition to study drugs, concurrent
infection that could potentially interfere with evaluation of
the patient’s response to the study therapy, requirement for
peritoneal dialysis or hemodialysis, infection with a pathogen
known to be resistant to either of the study medications,
receipt of 124 h of systemic antimicrobial therapy known to
be effective against presumed or documented pathogens during the 72 h before study entry, and predefined abnormal
laboratory test results (i.e., hematocrit !25% or hemoglobin
!8 mg/dL; platelet count !75,000/mL, coagulation test results
11.5 times the upper limit of normal [ULN], levels of transaminases 16 times the ULN, and bilirubin or alkaline phosphatase levels 13 times the ULN). Patients previously treated
with antimicrobial therapy for 124 h could be enrolled if there
was clinical evidence of treatment failure after ⭓3 days of
therapy and if a pathogen susceptible to both study drugs was
recovered. Patients with polymicrobial infections with resistant pathogens could remain in the study at the investigator’s
discretion, if ⭓1 infecting organism was susceptible to both
study drugs.
Study design and antimicrobial therapy. The study was
a double-blind (with sponsor blinding) multicenter equivalence
trial conducted in the United States and internationally from
April 1998 through November 1999. The design of the study
followed the recommendations of the Infectious Diseases Society of America (IDSA) [8]. The institutional review board at
each participating site approved the protocol, and written consent was obtained from all patients. Patients were randomly
assigned to receive treatment for 7–14 days with either ertapenem (1 g iv once daily) or piperacillin-tazobactam (3.375 g
iv every 6 h). To ensure blinding, patients in the ertapenem
group also received subsequent placebo infusions of normal
saline every 6 h. All infusions were administered within a 30
min period. Therapy was begun in the hospital or infusion
suite; clinically stable patients, after 2 days of therapy, could
continue intravenous therapy at home or in the hospital. Follow-up oral antimicrobial therapy was not permitted.
Patients were assigned at entry to 1 of 2 strata. Stratum I
included patients with underlying decubitus ulcers, diabetes
mellitus, or other neuropathic conditions that we anticipated
could compromise the response to antibacterial therapy. Stratum II consisted of patients with all other types of CSSSI (listed
in table 1).
Microbiologic assessments. Specimens of purulent material from deep within the infection were obtained from all
patients for performance of aerobic and anaerobic culture at
baseline and, if clinically indicated, at follow-up. Blood samples
for culture were collected when clinically indicated. Wound
specimens from all international sites were shipped to the R.
M. Alden Research Laboratory, Santa Monica-University of
California at Los Angeles Medical Center (Santa Monica) for
anaerobic culture and susceptibility testing. Susceptibility to
Ertapenem vs. Pip-Taz for Skin Infections • CID 2002:34 (1 June) • 1461
Table 1. Baseline characteristics of randomized and clinically evaluable patients with complicated
skin or skin-structure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz).
Randomized patients,
by treatment group
Characteristic or diagnosis
Female sex
Ertapenem
(n p 274)
Pip-Taz
(n p 266)
Clinically evaluable patients,
by treatment group
Ertapenem
(n p 185)
Pip-Taz
(n p 174)
93 (33.9)
96 (36.1)
62 (33.5)
58 (33.3)
48.7 16.5
48.0 17.4
47.8 15.9
46.1 16.8
LE infection associated with diabetes
53 (19.3)
45 (16.9)
35 (18.9)
31 (17.8)
Othera
10 (3.7)
7 (2.7)
7 (3.8)
5 (2.9)
63 (23.0)
52 (19.5)
42 (22.7)
36 (20.7)
Cellulitis with drainage
40 (14.6)
35 (13.2)
29 (15.7)
24 (13.8)
Cutaneous abscess
26 (9.5)
35 (13.2)
20 (10.8)
24 (13.8)
Deep soft-tissue abscess
49 (17.9)
53 (19.9)
30 (16.2)
36 (20.7)
Perineal cellulitis/abscess
24 (8.8)
14 (5.3)
20 (10.8)
11 (6.3)
Age, mean years SD
Diagnosis, by stratum
Stratum I
Total
Stratum II
Posttraumatic wound
47 (17.2)
45 (16.9)
30 (16.2)
26 (14.9)
Surgical-site infection
16 (5.8)
20 (7.5)
9 (4.9)
10 (5.7)
Otherb
Total
Severe infection
NOTE.
9 (3.3)
12 (4.5)
5 (2.7)
7 (4.0)
211 (77.0)
214 (80.5)
143 (77.3)
138 (79.3)
49 (17.9)
46 (17.3)
40 (21.6)
31 (17.8)
LE, lower extremity.
a
Includes acute pressure ulcer and neuropathy with LE infection.
b
Includes complicated cellulitis with systemic signs, infected pyoderma, deep soft-tissue infection or ulcer, suppurative
hydradenitis, tenosynovitis, necrotizing soft-tissue infection, and uncomplicated skin infection (the latter 2 in the randomized
population only).
ertapenem and piperacillin-tazobactam was determined by disk
diffusion or microtiter or agar dilution in accordance with the
guidelines of the National Committee for Clinical Laboratory
Standards [9–11].
Clinical and microbiologic assessments. At baseline, the
severity of each sign and symptom was scored by the investigator. Infections were considered to be severe overall if a rating
of “severe” was assigned for all 3 wound parameters (i.e., tenderness, erythema, and swelling) and the patient had a temperature 138.4C or a WBC count of 115,000 cells/mL. Infections in bacteremic patients were considered to be severe if ⭓1
baseline wound parameter was rated “severe.” Adjuvant surgery
performed ⭐48 h after the initiation of therapy was considered
to be integral to the initial management of the infection; patients requiring nonroutine surgery thereafter were considered
to have treatment failure.
Clinical response assessments based on wound signs and
symptoms were made by the investigator on days 3–5 of study
therapy; at completion of study therapy; and at the test-of-cure
(TOC) assessment, which occurred 10–21 days after the completion of study therapy. The primary efficacy end point was
the proportion of patients with an investigator assessment of
“cure” at the TOC assessment. For this primary analysis, pa1462 • CID 2002:34 (1 June) • Graham et al.
tients had to have received ⭓48 h of therapy to be considered
to have treatment failure, and patients had to have had an
appropriately timed TOC assessment and to have received ⭓5
days of therapy to be considered to have an evaluable cure.
A microbiologic response was assessed for each pathogen
identified at baseline. For patients for whom follow-up cultures
were not performed, the microbiologic responses for baseline
pathogens were assumed on the basis of the clinical response.
The overall microbiologic response was considered to be favorable if all pathogens identified at baseline were eradicated
or presumed eradicated. Emergent pathogens were considered
to be “superinfections,” if they were first isolated during therapy, and “new infections,” if first isolated after the completion
of therapy.
Safety assessment. Patients who received ⭓1 dose of the
study drug were evaluated to determine the drug’s safety and
were monitored for adverse events daily during the period of
study therapy and for 14 days thereafter. The investigator
categorized the intensity of each clinical and laboratory adverse event (as “mild,” “moderate,” or “severe”) and the likelihood that the event had a causal relation to the study drug
(as “definitely not,” “probably not,” “possibly,” “probably,”
or “definitely”). The local tolerability of each study drug, as
indicated by reactions at the infusion site, was evaluated by
the investigator daily. At the discretion of the investigator,
these or other local reactions could also be reported as adverse
events.
Statistical analyses.
This study was designed to show
whether the response rates in the 2 treatment groups were
equivalent, in accordance with IDSA and US Food and Drug
Administration guidelines [8]. Equivalence was demonstrated
if the 95% (2-sided) confidence interval for the difference in
response rates between treatment groups (i.e., [response rate
in the ertapenem group] ⫺ [ response rate in the piperacillintazobactam group]) contained “0” and if the lower limit was
as follows: not less than ⫺10%, if the control response rate
was ⭓90%; ⫺15%, if the control response rate was !90% and
⭓80%; and ⫺20%, if the control response rate was !80% and
⭓70%.
Confidence intervals were calculated with use of the normal
approximation to the binomial distribution, accounting for
stratification by means of the Cochran approach [12, 13]. A
test of treatment by stratum interaction (the Breslow-Day test
of homogeneity of odds ratios [14]) was performed to decide
whether results could be pooled between the randomization
strata. The efficacy variables were analyzed using an evaluablepatients-only approach and a modified intent-to-treat (MITT)
approach [8]. The MITT population included all patients who
received ⭓1 dose of a study drug and who had a CSSSI. Patient
evaluability was determined under blinded conditions, before
analyses were done, on the basis of previously specified criteria.
Clinically evaluable patients were also considered to be microbiologically evaluable if a pathogen was isolated from the
wound present at baseline.
Assuming an 80% response rate in both treatment groups
and a significance level of 0.025, a sample size of 120 evaluable
patients per group was required to provide at least an 80%
probability that the lower limit of the 95% confidence interval
for the difference in the response rates between the 2 groups
would not be less than ⫺15%.
RESULTS
Patients and therapy. Five hundred forty patients were randomized to receive either ertapenem (n p 274 ) or piperacillintazobactam (n p 266). Of these, 185 in the ertapenem group
and 174 in the piperacillin-tazobactam group were clinically
evaluable. Patients were most commonly considered to be nonevaluable if their outcome assessment was either missing or did
not occur during the protocol-defined follow-up period (which
was the case for 17.2% of the patients randomized) or if they
received an inadequate or inappropriate course of study therapy
(which was the case for 15.9% of the patients randomized).
The baseline demographic characteristics and the disease
characteristics of the randomized and the clinically evaluable
populations were generally similar between the 2 treatment
groups (table 1). Baseline wound care procedures were similar
in each treatment group. In the clinically evaluable population
wound management procedures were performed before or
within 48 h of enrollment in 153 patients (82.7%) in the ertapenem group and 147 patients (84.5%) in the piperacillintazobactam group. One hundred seven patients (57.8%) in the
ertapenem group and 98 patients (56.3%) in the piperacillintazobactam group underwent incision and drainage of the
wound. Eleven patients in each group required a surgical procedure other than routine minor debridement or wound care
148 h after study therapy was begun, including lower-extremity
amputations for 6 patients in each treatment group; these patients were considered to have clinical failure.
The mean (SD) duration of study therapy in the clinically
evaluable population was 9.1 3.1 days (range, 3–16 days) for
patients in the ertapenem group and 9.8 3.3 days (range,
3–18 days) for patients in the piperacillin-tazobactam group.
The median duration of therapy was 9.0 days in both treatment
groups.
Baseline microbiologic test results. A pathogen was isolated at baseline from 155 clinically evaluable patients (83.8%)
in the ertapenem group and 151 clinically evaluable patients
(86.8%) in the piperacillin-tazobactam group. Approximately
40% of the evaluable patients in each treatment group had a
polymicrobial infection; overall, 18% were infected with ⭓1
anaerobic pathogen. The distribution of organisms was generally similar in the treatment groups. S. aureus (including 3
MRSA per group) was the most frequently isolated pathogen,
present at baseline in 37.8% and 40.8% of the clinically evaluable patients in the ertapenem and piperacillin-tazobactam
treatment groups, respectively. For 49 patients in each treatment
group, S. aureus was the only infecting pathogen; in the remainder, it was one component of a polymicrobial infection.
Most isolates tested were susceptible to both study drugs, except
enterococci (5 [31.3%] of 16 isolates susceptible to ertapenem,
and 14 [87.5%] of 16 susceptible to piperacillin-tazobactam)
and Pseudomonas aeruginosa (10 [71.4%] of 14 isolates susceptible to ertapenem, and 14 [100%] of 14 susceptible to
piperacillin-tazobactam).
Efficacy. In the clinically evaluable population, 82.4% of
patients (95% CI, 77.0%–87.8%) in the ertapenem group and
84.4% of patients (95% CI, 79.0%–89.7%) in the piperacillintazobactam group were classified as “cured” at the time of the
TOC assessment. The difference in response rates between the
groups, adjusting for assigned stratum, was ⫺2.0% (95% CI,
⫺10.2% to 6.2%), which indicated that the response rates for
the 2 groups were equivalent. In the supportive MITT analysis,
which included 527 patients (97.6% of all randomized patients),
cure rates were 69.8% for the ertapenem group and 73.5% for
Ertapenem vs. Pip-Taz for Skin Infections • CID 2002:34 (1 June) • 1463
the piperacillin-tazobactam group. Lower success rates in this
analysis reflect the more conservative approach of the MITT
assessment, in which patients with inadequate information or
indeterminate outcomes were considered to have treatment failure. The difference in rates for the MITT analysis was ⫺3.6%
(95% CI, ⫺11.6% to 4.4%), which further demonstrated that
the response rates in the 2 treatment groups were similar.
The clinical outcomes at TOC are shown in table 2 by primary diagnosis and severity of infection. Cure rates in both
treatment groups were generally similar for most diagnoses.
Among patients with cutaneous or deep abscesses, who accounted for 30.6% (110 of 359 patients) of the clinically evaluable population, cure rates were similar in the 2 groups:
90.0% (45 of 50 patients) in the ertapenem group and 95.0%
(57 of 60 patients) in the piperacillin-tazobactam group.
Among patients with severe infections, the cure rate was 80.0%
(32 of 40 patients) in the ertapenem group and 71.0% (22 of
31 patients) in the piperacillin-tazobactam group. At the end
of treatment assessment, the cure rate was 86.6% (160 of 185
patients) among patients who received ertapenem and 87.7%
(152 of 173 patients) among patients who received piperacillintazobactam. The difference, adjusted for stratum, was ⫺1.2%
(95% CI, ⫺8.6% to 6.3%), further supporting the results of
the primary efficacy analysis. For patients in stratum I, the
treatment success rate at the end of study therapy was 78.6%
(33 of 42 patients) in the ertapenem group and 77.8% (28 of
36 patients) in the piperacillin-tazobactam group; for patients
in stratum II, the rates were 88.8% (127 of 143 patients) and
90.5% (124 of 137 patients), respectively.
Bacterial eradication rates among evaluable patients at the
end of treatment and at the time of TOC, respectively, were as
follows: 83.2% (129 of 155 patients) and 82.6% (128 of 155
patients) in the ertapenem group, and 86.0% (129 of 150 patients) and 83.4% (126 of 151 patients) in the piperacillintazobactam group. Both a favorable clinical response and a
favorable microbiologic response at the time of TOC were observed in 127 (81.9%) of 155 patients in the ertapenem group
and 124 (82.1%) of 151 patients in the piperacillin-tazobactam
group. The difference, adjusting for stratum, was ⫺0.2% (95%
CI, ⫺9.3% to 9.0%), which again supported the findings of
the primary analysis. For this population, the cure rate and the
bacterial eradication rate at the time of TOC were similar for
all major pathogens (table 3).
No pathogen detected at baseline subsequently developed
resistance to either study drug, and non-baseline, emergent
pathogens were isolated infrequently. The types and frequencies
of emergent bacteria were similar in both treatment groups,
and, not surprisingly, the types of bacteria were those com-
Table 2. Proportion of clinically evaluable patients with favorable clinical (cure) response assessments
at the test of cure (TOC) visit, in a study of patients with complicated skin or skin-structure infection who
were treated with ertapenem or piperacillin-tazobactam (Pip-Taz).
Pip-Taz group
(n p 174)
Ertapenem group
(n p 185)
Proportion
of patientsa
Percentage
of patients
(95% CI)
Proportion
of patientsa
Percentage
of patients
(95% CI)
23/35
65.7 (49.8–81.7)
22/31
71.0 (54.7–87.2)
5/7
71.4b
5/5
100.0
28/42
66.7 (52.2–81.1)
27/36
75.0 (60.7–89.3)
Cellulitis with purulent drainage
27/29
93.1 (83.7–100.0)
21/24
87.5 (74.0–100.0)
Cutaneous abscess
16/20
80.0 (62.0–98.0)
23/24
95.8 (87.7–100.0)
Deep soft-tissue abscess
29/30
96.7 (90.1–100.0)
34/36
94.4 (86.9–100.0)
Perineal cellulitis/abscess
18/20
90.0 (76.5–100.0)
9/11
81.8 (57.9–100.0)
Posttraumatic wound infection
25/30
83.3 (69.8–96.9)
22/26
84.6 (70.5–98.8)
7/9
77.8b
8/10
80.0 (53.9–100.0)
2/5
b
40.0
3/7
42.9
124/143
86.7 (81.1–92.3)
120/138
87.0 (81.3–92.6)
120/145
82.8 (76.6–88.9)
125/143
87.4 (82.0–92.9)
32/40
80.0 (67.4–92.6)
22/31
71.0 (54.7–87.2)
Stratum, characteristic or diagnosis
Stratum I
LE infection associated with diabetes
Other
Total
b
Stratum II
Surgical site infection
Other
Total
b
Severity of infection
Moderate
Severe
NOTE.
a
b
LE, lower extremity.
No. of clinically evaluable patients with favorable assessment/number with assessment at the TOC visit.
Confidence intervals were calculated only for groups with ⭓10 patients.
1464 • CID 2002:34 (1 June) • Graham et al.
Table 3. Proportion of favorable clinical (cure) or microbiologic (eradication) response assessments at
the test-of-cure visit, by pathogen isolated at baseline, in a study of patients with complicated skin or skinstructure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz).
No. (%) of patients
with favorable
clinical response,
by treatment group
Isolate(s)
No. (%) of patients
with favorable
microbiologic response,
by treatment group
Ertapenem
Pip-Taz
Ertapenem
Pip-Taz
114/149 (76.5)
116/148 (78.4)
118/147 (79.6)
121/148 (81.8)
MSSA and MRSA
54/71 (76.1)
56/71 (78.9)
55/71 (77.5)
58/71 (81.7)
MSSA onlyb
54/67 (80.6)
55/68 (80.9)
54/67 (80.6)
56/68 (82.3)
4/5 (80.0)
8/11 (72.7)
4/5 (80.0)
8/11 (72.7)
Streptococcus pyogenes
13/16 (81.3)
15/16 (93.8)
14/16 (87.5)
15/16 (93.8)
Streptococcus agalactiae
7/13 (53.8)
5/10 (50.0)
7/13 (53.8)
7/10 (70.0)
Other b-hemolytic streptococci
9/9 (100)
8/11 (72.7)
9/9 (100.0)
8/11 (72.7)
18/20 (90.0)
Gram-positive aerobic cocci
Any
a
Coagulase-negative staphylococci
Other streptococci
22/23 (95.7)
18/20 (90.0)
22/23 (95.7)
Enterococci
5/10 (50.0)
6/9 (66.7)
7/10 (70.0)
7/9 (77.8)
Gram-positive aerobic bacilli
1/1 (100.0)
1/1 (100.0)
1/1 (100.0)
1/1 (100.0)
Any
55/70 (78.6)
50/66 (75.8)
58/70 (82.9)
54/66 (81.8)
Escherichia coli
16/17 (94.1)
12/15 (80.0)
17/17 (100)
12/15 (80.0)
Other Enterobacteriaceaec
26/36 (72.2)
29/35 (82.9)
27/36 (75.0)
31/36 (86.1)
Gram-negative aerobic bacilli
Pseudomonas aeruginosa
7/10 (70.0)
3/5 (60.0)
7/10 (70.0)
4/5 (80.0)
Other gram-negative aerobic bacilli
6/7 (85.7)
6/11 (54.5)
7/7 (100)
7/10 (70.0)
8/10 (80.0)
6/6 (100)
8/10 (80.0)
6/6 (100)
Any
30/35 (85.7)
24/27 (88.9)
30/35 (85.7)
25/27 (92.6)
Peptostreptococcus species
27/31 (87.1)
20/22 (90.9)
27/31 (87.1)
21/22 (95.5)
3/4 (75.0)
4/5 (80.0)
3/4 (75.0)
4/5 (80.0)
Any
47/48 (97.9)
43/50 (86.0)
48/48 (100)
44/50 (88.0)
Bacteroides fragilis group
11/11 (100)
12/13 (92.3)
11/11 (100)
12/13 (92.3)
9/9 (100)
4/5 (80.0)
9/9 (100)
4/5 (80.0)
12/12 (100)
16/17 (94.1)
12/12 (100)
17/17 (100)
15/16 (93.8)
11/15 (73.3)
16/16 (100)
11/15 (73.3)
Gram-positive anaerobic bacilli
Gram-positive anaerobic cocci
Other anaerobic gram-positive cocci
Gram-negative anaerobic bacteria
Porphyromonas species
Prevotella species
Other gram-negative anaerobic bacteriad
NOTE.
a
MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant S. aureus.
Among patients with monomicrobial infections due to MSSA and/or MRSA, cure and eradication rates, respectively, were
81.6% (40/49) and 81.6% (40/49) in the ertapenem group and 84.0% (42/50) and 86.0% (43/50) in the Pip-Taz group. Among
patients with polymicrobial infections, cure and eradication rates, respectively, were 66.7% (14/21) and 68.2% (15/22) in the
ertapenem group and 66.7% (14/21) and 71.4% (15/21) in the Pip-Taz group.
b
Among patients with monomicrobial MSSA infections, cure and eradication rates, respectively, were 83.3% (40/48) and
83.3% (40/48) in the ertapenem group and 84.0% (42/50) and 86.0% (43/50) in the Pip-Taz group. Among patients with polymicrobial infections, cure and eradication rates, respectively, were 73.7% (14/19) and 73.7% (14/19) in the ertapenem group and
72.2% (13/18) and 72.2% (13/18) in the Pip-Taz group.
c
In the ertapenem group, the following organisms were identified: Citrobacter braakii (n p 1 ), Citrobacter freundii (n p 1),
Enterobacter aerogenes (n p 3 ), Enterobacter cloacae (n p 6 ), Klebsiella oxytoca (n p 1 ), Klebsiella pneumoniae (n p 7 ), Morganella morganii (n p 3 ), Proteus vulgaris (n p 4 ), Proteus mirabilis (n p 6 ), Providencia rettgeri (n p 1 ), Serratia marcescens
(n p 2), and Serratia rubidaea (n p 1 ). In the Pip-Taz group, the following organisms were identified: Citrobacter koseri (n p 1),
C. freundii (n p 1), E. cloacae (n p 11), Enterobacter gergoviae (n p 1 ), K. pneumoniae (n p 5 ), M. morganii (n p 3 ), P. vulgaris
(n p 4), P. mirabilis (n p 8), and Providencia stuartii (n p 1).
d
In the ertapenem group, the following organisms were identified: unspecified gram-negative anaerobic rods (n p 2 ), Bacteroides capillosus (n p 2 ), Bacteroides ureolyticus (n p 3 ), Bilophila wadsworthia (n p 1 ), Dialister pneumonosintes (n p 1),
unspecified Fusobacterium species (n p 1 ), Fusobacterium gonidiaformans (n p 3 ), Fusobacterium naviforme (n p 1 ), and Fusobacterium necrophorum (n p 2 ). In the Pip-Taz group, the following organisms were identifed: unspecified gram-negative
anaerobic rods (n p 2), B. ureolyticus (n p 1 ), B. wadsworthia (n p 3 ), D. pneumonosintes (n p 4 ), unspecified Fusobacterium
species (n p 1), Fusobacterium necrophorum (n p 1), Fusobacterium nucleatum (n p 1), and Veillonella species (n p 2).
monly associated with skin infections or acquired in the hospital setting.
Safety profile. Two hundred seventy-one patients in the
ertapenem group and 258 patients in the piperacillin-tazobactam group were included in the safety analyses. Drug-related
clinical adverse events were reported during therapy for 67
patients (24.7%) in the ertapenem group and 60 patients
(23.3%) in the piperacillin-tazobactam group; investigators reported that laboratory adverse events occurred in 36 patients
(14.2%) in the ertapenem group and 36 patients (14.6%) in
the piperacillin-tazobactam group. The most common drugrelated adverse events are listed in table 4. There were no seizures reported in patients while they were receiving study therapy. Therapy was discontinued due to a drug-related adverse
clinical event for 3 patients in the ertapenem group and 6 in
the piperacillin-tazobactam group. Two patients receiving piperacillin-tazobactam and 0 patients in the ertapenem group
stopped therapy due to a drug-related adverse laboratory event.
One patient in the piperacillin-tazobactam group died during
study therapy, and 1 patient in each group had an adverse event
during study therapy that resulted in death after therapy was
completed. No deaths were attributed to use of a study drug.
Local tolerability. A local reaction of moderate to severe
intensity was recorded for 19 (7.0%) of 270 patients in the
ertapenem group and 23 (8.9%) of 258 patients in the piperacillin-tazobactam group. The most common symptoms were
pain and erythema. Study therapy was discontinued due to an
infused vein complication for 1 patient in the piperacillintazobactam group and for 0 patients in the ertapenem group.
DISCUSSION
In this study of CSSSIs, the cure rates among patients who
received ertapenem and among patients who received piperacillin-tazobactam were equivalent overall (82.4% vs. 84.4%)
and similar to or somewhat higher than those reported in
other, similarly designed clinical trials [15–19]. As shown by
others, cure rates for foot infections associated with diabetes,
which are often complicated by compromised vascularity,
were lower for both treatment groups in this study. Clinical
response rates for diabetes-associated lower-extremity infections in this study were ∼78% in both treatment groups at
the completion of study therapy and decreased slightly to
65.7% (ertapenem group) and 71.0% (piperacillin-tazobactam group), at the TOC assessment (10–21 days after the end
of treatment). This finding reflected the need for subsequent
surgical intervention for patients with complicating underlying conditions, such as vascular insufficiency.
The organisms identified in this study and the response
rates associated with each pathogen are also similar to those
seen in other studies [15, 17], with one exception. In our
1466 • CID 2002:34 (1 June) • Graham et al.
Table 4. Most common drug-related clinical and laboratory adverse events reported among patients with complicated skin or
skin-structure infection who were treated with ertapenem or piperacillin-tazobactam (Pip-Taz).
No. (%) of patients,
by treatment group
Adverse effect
Ertapenem
Pip-Taz
Clinical
Local infusion-related reactions
a
17 (6.3)
14 (5.4)
Diarrhea
15 (5.5)
23 (8.9)
Nausea
10 (3.7)
7 (2.7)
5 (1.8)
3 (1.2)
Increased ALT levelc
9 (4.3)
8 (3.7)
d
b
Rash
Laboratory value
Increased AST level
12 (5.1)
10 (4.2)
Increased alkaline phosphatase
2 (0.8)
5 (2.1)
Increased platelet count
8 (3.2)
4 (1.7)
NOTE.
ALT, alanine transaminase; AST, aspartate transaminase.
a
The most common local reactions were pain (ertapenem group, 4.0% of
patients; Pip-Taz group, 3.9%), phlebitis (ertapenem group, 3.0%; Pip-Taz
group, 2.7%), and erythema (ertapenem group, 3.0%; Pip-Taz group, 1.6%).
b
Two patients with diarrhea in each treatment group had pseudomembranous colitis.
c
Values were 58–134 U/L for the ertapenem group and 40–271 U/L for the
Pip-Taz group. For patients with data from follow-up, ALT level elevations were
transient, and later values were within normal limits.
d
Values were 54–228 U/L for the ertapenem group and 40–131 U/L for the
Pip-Taz group. For patients with data from follow-up, AST level elevations were
transient, and later values were within normal limits, except for 1 patient in
the Pip-Taz group, whose AST level increased to 3.3 times the upper limit of
normal.
study, anaerobes were recovered from 17%–20% of clinically
evaluable patients; in studies that have focused primarily on
the microbiology of skin and soft-tissue infections, 33%–52%
of specimens have yielded anaerobes [1, 2]. One possible reason for this difference is that, in our study, specimens from
sites in various nations were mailed to a reference laboratory
in California for culture, and fastidious anaerobes may not
have survived. Additionally, anaerobic culture and identification methods used at the local laboratories likely varied
from site to site.
As is the case for most studies of skin infections, S. aureus
was the pathogen most commonly isolated in this study. As
anticipated, because both study drugs lacked activity against
MRSA in vitro, cure rates for all patients infected with S.
aureus (both MSSA and MRSA) were lower (ertapenem
group, 76.1%; piperacillin-tazobactam group, 78.9%) than for
patients infected with MSSA only (80.6% and 80.9%, respectively). To more accurately assess the efficacy of study
drugs against MSSA in patients with complicated infections,
cure rates were determined separately for monomicrobial and
polymicrobial infections. Not surprisingly, treatment success
rates were higher for patients with monomicrobial MSSA infections (ertapenem group, 83.3%; piperacillin-tazobactam
group, 84.0%) than for patients infected with MSSA as part
of a polymicrobial infection (73.7% and 72.2%, respectively).
Bacterial eradication rates for all S. aureus (i.e., MSSA and
MRSA) infections in this study (table 3) were similar to rates
reported elsewhere (60% to ∼85%) [15–18].
Ertapenem has excellent in vitro activity against MSSA and
many streptococci, gram-negative enteric bacilli, and anaerobes, all of which are frequently involved in communityacquired and mixed infections of the skin and soft tissues. In
contrast to imipenem and meropenem, which are often used
to treat nosocomial infections, ertapenem has minimal in vitro activity against P. aeruginosa and Acinetobacter species.
Although none of these carbapenems is considered to be firstline therapy against enterococci, imipenem has the most activity against them and ertapenem, the least. For empiric treatment of community-acquired infections of the skin and skin
structures, however, therapy directed specifically against these
organisms generally is not required. P. aeruginosa and enterococci are identified in ∼2%–8% of such infections [2], and,
because most infections are polymicrobial, the pathogenicity
of these organisms is uncertain.
In this study, we recovered 19 enterococcal isolates (3.1%
of the total isolates) and 15 P. aeruginosa isolates (2.5% of
the total), and most were components of a polymicrobial
infection. This low rate of isolation of these bacteria is consistent with rates reported by other investigators. Clinical and
microbiologic success rates for patients infected with each of
these organisms were generally similar in both treatment
groups (table 3), regardless of the susceptibility of these bacteria. However, the small numbers preclude our drawing
meaningful conclusions about the role of P. aeruginosa or
enterococci as pathogens or the efficacy of ertapenem or piperacillin-tazobactam for treatment of infections with these
organisms.
The most common drug-related adverse events for both
drugs were infused-vein complications, diarrhea, nausea, and
mild to moderate transient elevations of liver transaminase
levels. Serious adverse events were equally uncommon in both
treatment groups. Although patients in both groups received
4 daily infusions of study agents and, therefore, theoretically
were at equal risk for infusion-related complications, 3 infusions in the ertapenem group were placebo. In practice,
patients treated with ertapenem would receive a single daily
infusion and thus would be expected to have fewer venous
complications.
In summary, in this study, ertapenem at a dosage of 1 g once
daily was as effective as piperacillin-tazobactam at a dosage of
3.375 g 4 times daily for the treatment of CSSSIs. Ertapenem
was generally well tolerated, and its safety and tolerability profile
was similar to that of piperacillin-tazobactam.
MEMBERS OF THE COMPLICATED SKIN AND
SKIN STRUCTURE INFECTIONS STUDY GROUP
J. Eric Bauwens (Phoenix, AZ), Francie Ekengren (Wichita, KS),
Robert Eng (East Orange, NJ), Robert Brooks Gainer II, (Morgantown, WV), Claudia Garreaud (Santiago, Chile), Ronald
Geckler (Baltimore, MD), Michael Gelfand (Memphis, TN),
John Gezon (Salt Lake City, UT), Donald R. Graham (Springfield, IL), Charles Hanna (Spartanburg, FL), Abel Jasovich
(Buenos Aires, Argentina), Stanley Klein (Torrance, CA), Terrance Kurtz, (Des Moines, IA), Juan Lema (Lima, Peru), David
Livingston (Newark, NJ), Gustavo Lopardo (Buenos Aires, Argentina), Christopher Lucasti (Somers Point, NJ), Ana Lucia
(Sao Paulo, Brazil), Jon T. Mader (Galveston, TX), Osvaldo
Malafaia (Curitiba Brazil), Eugene Mangiante (Memphis, TN),
Hector Marcano (Caracas, Venezuela), Barry Miskin (Palm
Beach, FL), Ronald Nahass (Somerville, NJ), Ronald L. Nichols
(New Orleans, LA), Pablo Okhuysen (Houston, TX), Lawrence
Parish (Philadelphia, PA), Michael Patzakis (Los Angeles, CA),
Nora Quintero Perez (Guadalajara, Mexico), John Poole (Guatemala City, Guatemala), Russell Postier (Oklahoma City, OH),
Jeffrey Salomone (Atlanta, GA), Robert Schwartz (Fort Myers,
FL), Harold Standiford (Baltimore, MD), James Tan (Akron,
OH), Alan Tice (Tacoma, WA), Samuel Eric Wilson (Orange,
CA), and Dietmar Wittmann (Milwaukee, WI).
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