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Ertapenem versus piperacillin/tazobactam
for diabetic foot infections (SIDESTEP):
Prospective, randomised, controlled,
double-blinded, multicentre trial
Lipsky BA et al Lancet 2005;366:1695–1703.
SIDESTEP = Study of Infections in Diabetic feet comparing Efficacy,
Safety, and Tolerability of Ertapenem versus Piperacillin-tazobactam
Slide 1
Study Design

Prospective, multicenter, double-blind, randomized
10-day follow-up
assessment
DCIV
Ertapenem 1 g IV once daily
Screening
Amoxicillin/clavulanic acid
875 mg/125 mg
every 12 hours
Piperacillin-tazobactam
3.375 g IV every 6 hours
IV therapy
(minimum 5 days)
Oral therapy
(optional)
Antibiotic therapy (maximum 28 days)
DCIV=discontinuation of IV therapy; IV=intravenous
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 2
Endpoints
Primary: Compare the clinical efficacy of ertapenem
versus piperacillin-tazobactam in evaluable patients
at DCIV assessment
 Secondary: Compare ertapenem versus piperacillintazobactam at follow-up 10 days after the last dose
of antimicrobial therapy

–
Efficacy


–
Clinical response
Microbiologic response (in patients with confirmed pathogen)
Safety and tolerability profile
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 3
Primary Endpoint

Ertapenem at least as effective as piperacillin-tazobactam
in percentage of patients with favorable clinical response
(clinically evaluable patients at DCIV)
–
–
–
Favorable clinical response: cure or improvement
Expected response rate ~70% for both regimens
Noninferiority criteria


95% CI for difference in proportions (ertapenem –
piperacillin-tazobactam) contains 0
Lower limit of the CI > –15%
CI=confidence interval
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 4
Secondary Endpoint

In evaluable patients at follow-up assessment (10 days
after antibiotic therapy), ertapenem would be at least as
effective as piperacillin-tazobactam in rate of
– Favorable clinical responses
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 5
Populations for Analysis

Primary
–

Patients clinically evaluable at DCIV
Secondary
–
Patients clinically evaluable at 10-day follow-up assessment


Microbiologically evaluable, a subset of the clinically evaluable
population
Sensitivity
–
Modified intention-to-treat (MITT)

Received 1 dose of study therapy; patients with missing/
indeterminate outcomes considered treatment failures
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 6
Entry Criteria: Inclusions
Males or females ≥18 years old
 Type I or II diabetes mellitus controlled by diet
or medication
 Moderate to severe diabetic foot infection

–
–
Clinically (± microbiologically) documented
Not extending past knee
Requiring 5–28 days IV or oral antibiotic therapy
 Vancomycin acceptable in cases of proven/suspected
MRSA or Enterococcus spp

MRSA=methicillin-resistant S. aureus
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 7
Entry Criteria: Selected Exclusions
IV antibiotic not required
 Mild infections, burns, necrotizing fasciitis
 >24 hours of antibiotic therapy in prior 72 hours, unless
a clinical failure
 Osteomyelitis, unless all infected bone removed
 Requirement for revascularization

Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 8
Treatment Groups
“Moderate”
Stratum I
Grade 0B, 0D,
1B, and 1D
Randomization
Ertapenem 1 g IV once
daily + placebo at 6, 12,
18 hours
Oral amoxicillin/
clavulanic acid
875 mg/125 mg
Piperacillin-tazobactam
3.375 g IV every 6 hours
Oral amoxicillin/
clavulanic acid
875 mg/125 mg
Ertapenem 1 g IV once
daily + placebo at 6, 12,
18 hours
Oral amoxicillin/
clavulanic acid
875 mg/125 mg
586
Patients
enrolled
“Severe”
Stratum II
Grade 2B, 2D,
3B, and 3D
Randomization
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Piperacillin-tazobactam
3.375 g IV every 6 hours
Oral amoxicillin/
clavulanic acid
875 mg/125 mg
(optional)
Slide 9
Microbiologic Response Assessments
 Favorable
outcomes
–
Eradication
–
Presumed eradication
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 10
Safety Profile: Adverse Events
 Focus
on the following AEs
– Drug-related
– Serious drug-related
– Discontinuation because drug-related
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 11
Patient Enrollment and Follow-Up
Screened: 639
Randomized: 586
Treated: 574
Ertapenem (289)
Piperacillin-tazobactam (285)
Lost to follow-up: 8
Discontinued from study: 38
Lost to follow-up: 4
Discontinued from study: 54
Clinical MITT: 289
Microbiologic MITT: 244
DCIV clinical evaluation: 226
Follow-up assessment
clinical evaluation: 206
Follow-up assessment
microbiologic evaluation: 151
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Clinical MITT: 285
Microbiologic MITT: 226
DCIV clinical evaluation: 219
Follow-up assessment
clinical evaluation: 196
Follow-up assessment
microbiologic evaluation: 135
Slide 12
Baseline Patient Characteristics
Gender
Male, %
Female, %
Race, %
Black
Hispanic
White
Other
Age
Median, years (range)
Ertapenem
(n=289)
Piperacillin-tazobactam
(n=287)
61
39
68
32
9
23
67
1
9
22
68
1
59 (25–90)
57 (22–94)
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 13
Stratum and Wound Classification
at Baseline
Ertapenem
(n=289)
Piperacillin-tazobactam
(n=287)
Moderate, no. (%)
196 (68)
188 (66)
Grade 0, stage B
Grade 0, stage D
Grade 1, stage B
Grade 1, stage D
4 (1)
0
181 (63)
11 (4)
6 (2)
1 (<1)
173 (60)
8 (3)
93 (32)
99 (34)
66 (23)
4 (1)
20 (7)
3 (1)
67 (23)
5 (2)
19 (7)
8 (3)
Severe, no. (%)
Grade 2, stage B
Grade 2, stage D
Grade 3, stage B
Grade 3, stage D
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 14
Primary Endpoint Was Satisfied
Proportions of clinically evaluable patients with favorable
response at DCIV assessment
Proportion of patients (%)
100
94%
92%
80
60
40
20
0
Ertapenem
1 g once daily
(n=226)
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Piperacillin-tazobactam
3.375 g every 6 hours
(n=219)
Slide 15
Secondary Endpoint Was Satisfied
Proportions of clinically evaluable patients with favorable
response at 10-day follow-up assessment
Proportion of patients (%)
100
87%
83%
80
60
40
20
0
Ertapenem
1 g once daily
(n=206)
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Piperacillin-tazobactam
3.375 g every 6 hours
(n=196)
Slide 16
Favorable Response at Follow-Up
Proportions of patients with favorable response at 10-day
follow-up assessment (MITT analysis)
Proportion of patients (%)
100
80
71%
66%
60
40
20
0
Ertapenem
1 g once daily
(n=289)
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Piperacillin-tazobactam
3.375 g every 6 hours
(n=285)
Slide 17
Bacteriologic Response
Bacterial eradication after therapy in patients with initial positive
wound culture
Proportion of isolates (%)
100
93%
Difference: 12.5%
(95% CI: 7.2, 18.8)
81%
80
60
40
20
0
Ertapenem
1 g once daily
(n=384 isolates)
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Piperacillin-tazobactam
3.375 g every 6 hours
(n=336 isolates)
Slide 18
Favorable Clinical Response by
Baseline Pathogen*
Isolate
Ertapenem
(n=173)
Piperacillin-tazobactam
(n=151)
Difference (CI)
Aerobic gram-positive cocci
Enterococcus**
Enterococcus faecalis
Staphylococcus aureus–MS
S. aureus–MR
Streptococcus agalactiae
84.7 (149/176)
86.4 (19/22)
86.7 (13/15)
84.5 (60/71)
77.8 (14/18)
71.4 (15/21)
79.5 (132/166)
88.9 (8/9)
75.0 (12/16)
81.3 (52/64)
66.7 (10/15)
84.6 (22/26)
5.1 (–3.1, 13.6)
–2.5
11.7 (–19.2, 41.1)
3.3 (–9.9, 17.1)
11.1 (–19.8, 42.7)
–13.2 (–38.3, 10.9)
Aerobic gram-negative bacilli
Enterobacteriaceae
Pseudomonas aeruginosa
87.7 (64/73)
85.7 (36/42)
83.3 (15/18)
76.8 (43/56)
78.8 (26/33)
70.0 (7/10)
10.9 (–2.3, 25.2)
6.9 (–11.1, 25.9)
13.3 (–18.2, 48.7)
Anaerobes
Gram-positive cocci
Gram-positive bacilli
Gram-negative bacilli
Gram-negative anaerobic coccobacilli
89.2 (66/74)
88.5 (23/26)
82.5 (33/40)
84.0 (21/25)
77.4 (48/62)
70.6 (12/17)
70.0 (28/40)
68.8 (11/16)
11.8 (–0.8, 25.2)
17.9 (–6.9, 45.1)
12.5 (–7.2, 31.3)
15.3 (–10.8, 43.3)
*Species with ≥20 isolates at follow-up assessment
**No species identified
MS=methicillin susceptible; MR=methicillin resistant
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 19
Safety Profile Endpoint Satisfied
No significant differences between ertapenem and
piperacillin-tazobactam in drug-related adverse experiences
Ertapenem
(N=289)
Piperacillin-tazobactam
(N=285)
Event
n
(%)
n
(%)
Drug-related adverse events
44
15
57
20
Serious drug-related adverse
events
1
0.3
1
0.3
Discontinued due to drug-related
adverse events
3
1
6
2
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 20
SIDESTEP Conclusions

Primary endpoint confirmed: Ertapenem 1 g IV once daily
was as effective as piperacillin-tazobactam 3.375 mg IV
every 6 hours in diabetic patients with foot infections

Ertapenem as well tolerated as the comparator regimen

Clinical results and once-daily schedule of ertapenem
suggest a convenient alternative in treatment of diabetic
foot infections
Adapted from Lipsky BA et al Lancet 2005;366:1695–1703.
Slide 21
Bibliography

Please refer to notes page.
Slide 22
Ertapenem versus piperacillin/tazobactam
for diabetic foot infections (SIDESTEP):
Prospective, randomised, controlled,
double-blinded, multicentre trial
Before prescribing, please consult
the manufacturers’ prescribing information.
Merck does not recommend the use of any product
in any different manner than as described
in the prescribing information.
Copyright © 2006 Merck & Co., Inc., Whitehouse Station, NJ, USA.
All rights reserved.
1-07 IVZ 2005-W-226394-SS
Printed in USA
VISIT US ON THE WORLD WIDE WEB AT http://www.merck.com
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