Title: Antibiotic Therapy for Diabetic Foot Infections: Comparison of Two Parenteral-to-Oral Regimens.

Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6489 Total no. of patients: Inclusion: Ofloxacin— Aminopenicillin Third to
Baseline = 108 Patients who had diabetes 400 mg of — 1-2 g of seventh Therapy resulted in a cure or in improved
Level of Ofloxacin regimen-55 mellitus and a foot infection ofloxacin ampiciIIin/0.5-1 day or until conditions for 85% of the evaluable ofloxacin
evidence: 8 excluded that required antibiotic intravenously g of sulbactam therapy recipients and for 83% of the evaluable
() Final number-47 therapy, as evidenced by that was intravenously was aminopenicillin recipients.
Aminopenicillin regimen-53 purulent drainage, erythema, changed when every 6 hours completed
Study 12 excluded and swelling, and who were appropriate to that was Cured or Failed To
type: Final number- 41 18 years of age or older. 400 mg of changed when improved tal
RCT ofloxacin orally appropriate to condition
Any patient for whom culture of Exclusion: every 12 500 mg of Ofloxacin 40 7 47
Authors: the admission specimen was hours. amoxicillin/125 Aminope 34 7 41
Lipsky et sterile or yielded pathogens that Patients who had evidence mg of clavulanic nicillin
al. (1997) were resistant to the study of osteomyelitis, usually Metronidazole acid orally every Total 74 14 88
drugs or who developed suspected because of was added if 8 hours. Cured- disappearance of all signs and
osteomyelitis (as diagnosed by clinical, laboratory, and plain patient not symptoms associated with active infection
the investigator) during radiograph findings, or who improving(for Gentamicin, Improved- incomplete abatement of the signs or
treatment with the study drugs had an infection known to be improved trimethoprimsulf symptoms
was withdrawn from the study. caused by a microorganism coverage of amethoxazole, Failed- no improvement during therapy
resistant to any of the study anaerobic or another agent
The total duration of therapy drugs, were allergic to any of bacteria) to the (for broader Relative Risk- 40/47 ÷ 34/41 = 1.02
was to be 14 to 28 days, as the study drugs or related ofloxacin regi- coverage of
clinically indicated. compounds, were grossly men. gram-negative The mean number of pathogens isolated from
underweight, had a seizure bacilli) to the cultures of wound specimens taken at the time
Baseline characteristics: or major psychiatric disorder, aminopenicillin of enrolment of the evaluable patients was 1.6
were pregnant or nursing, regimen. (range, 0-7).
There were no statistically were undergoing renal
significant differences in the dialysis, or were likely to die Cultures of specimens obtained while the
demographic characteristics of during the study. Patients patients were receiving therapy yielded an
the patients randomized to who had received potentially average of 0.2 isolate.
receive the two therapeutic effective antimicrobial
arms. therapy within 48 hours While those of specimens taken after completion
before presentation. Those of therapy yielded a mean of 0.1 isolate.
The severity of infections was, patients who required a
on average, nearly identical in second systemic Microbiological outcomes:
the two treatment groups. antimicrobial for any reason
 other than as defined below
Setting: or who were receiving a Cured or Failed To
12 centres across United States topical antimicrobial at .the partially tal
site of infection cured
Ofloxacin 39 8 47
Aminope 36 5 41
nicillin
Total 75 13 88
Cured- eradication of the original pathogen(s)
Partially cured- eradication of some but not all
of the original pathogens
Failed- persistence of the original pathogen(s).

Relative Risk- 39/47 ÷ 36/41 = 0.94

Eradication of Gram Positive)67%) and

Negative (27%) organisms

Ofloxacin Aminpenicillin
33/47 38/43 Positive
18/19 15/18 Negative

Adverse events

Potential side effects were experienced by 36%

of the ofloxacin recipients and 22% of the
aminopenicillin recipients (not a statistically
significant difference).

Adverse No Tota
event adverse l
event
Ofloxacin 17 30 47
Aminope 9 32 41
nicillin
Total 26 62 88

Relative Risk- 17/47 ÷ 9/41 = 1.65

Additional comments:
Randomisation was performed. Blinding performed. Allocation concealment not mentioned. All parameters were not analysed as intention to treat. Confounding not mentioned.
Power calculation not mentioned. Patients lost to follow up and excluded after randomisation was justified.
 Reference: Lipsky, BA, Baker, PD, Landon, GC, Fernau, R Antibiotic therapy for diabetic foot infections: comparison of two parenteral-to-oral regimens. Clinical Infectious
Diseases 1997; 24: 643-48.

Title: Use of Ampicillin/Sulbactam Versus Imipencm/Cilastatin in the Treatment of Limb-Threatening Foot Infections in Diabetic Patient.
Level of Patient Population/ Selection/Inclusion criteria Interventio Comparison Follow-up Outcome and Results
Evidence Characteristics n
ID: 4151 Total no. of patients: Inclusion: Imipenem/ Ampicillin/sulbac Daily for Table 1: Clinical and microbiological outcomes of
Baseline = 92 cilastatin tam (A/S; 3 g-IV first 6 days antibiotic therapy, as assessed on day 5 of
Level of No. of events-97 Requirement for (I/C; 500 every 6 hours) and then empirical therapy and at the conclusion of
evidence: 1 excluded (exacerbation of hospitalization, age of ≥18 mg-IV regularly parenteral therapy.
() gout) years, and presence of every 6 Doses were until
Final no. of events: 96 diabetes mellitus and limb- hours) adjusted in therapy No. of episodes per group in which
Study I/C- 48 infections in 46 patients threatening infection involving patients with was indicated outcome was noted
type: A/S- 48 infections in 47 the lower extremity (limb- Doses impaired renal completed. I/C (48 episodes) A/S (48 episodes)
RCT patients. threatening infection was were function. Assess Day 5 End of Day 5 End of
defined by at least the adjusted in ment therapy therapy
Authors: Patients' therapy was routine presence of cellulitis, with or patients 45 infections Clinical
Grayson and consisted of bed rest, without ulceration or purulent with completed 20- Cure 28 39 29 41
et al. surgical drainage and discharge). impaired dose regimen Improvem 17 0 18 0
(1994) debridement of infected ulcers Also included were patients renal 2 infections- ent
and necrotic tissue, vigorous who had recently received function. added another Failure 3 8 1 6
control of diabetes mellitus, and antibiotic therapy but had antibiotic Indetermi 0 1 0 1
use of sterile wound dressings failed to demonstrate clinical 45 1 infection- nate
(gauze soaked with normal improvement and whose infections discharged after Microbiological
saline or one-quarter-strength cultures revealed one or more completed 4 days of Eradicatio 17 32 20 36
povidone-iodine). When pathogens were eligible 20-dose therapy n
appropriate, arterial circulation regimen Partial 18 8 15 5
of the lower limb was evaluated Exclusion: 2 eradicat
by non-invasive and infections- ion
arteriographic techniques. Known hypersensitivity to β- inadvertent Persisten 7 2 6 3
Surgery to improve the arterial lactam antibiotics; requirement ly received ce
circulation or amputation of for other concomitant antibiotic only 19 Superinfe 0 2 0 3
unsalvageable tissues was treatment; serum creatinine doses of ction
performed at the discretion of level of ≥3.5 mg/dL; preg- study drug- Indetermi 6 4 7 1
the attending surgeon. nancy; illness so severe that both were nate
the patient was likely to die clinically
Baseline characteristics: within 48 hours; severe cured
underlying disease that might 1 infection-
I/C interfere with evaluation of the marked Upon completion of definitive parenteral therapy, cure
Mean age: 61 years therapeutic response; immune nausea was achieved in 81% of episodes treated with A/S and
Duration of diabetes: 19 years depression by virtue of and given
 underlying disease, prior organ 13 doses 85% of those treated with 1/C (difference in cure rates,
A/S transplantation, or only. 4%; 95% confidence interval, -11 % to 19%).
Mean Age: 59 years immunosuppressive drug
Duration of diabetes: 20 years therapy; and current Cure No cure Total
involvement in a clinical study I/C 41 7 48
The vast majority of patients of an investigational drug. A/S 39 9 48
had relatively acute infection or Total 80 16 96
exacerbated chronic infection
with prominent local signs of Relative Risk- 41/47 ÷ 39/41 = 1.07
aggressive infection. Patients in
the treatment groups were Microbiological outcomes:
similar in regard to severity of
diabetes and presence of Eradication No Total
peripheral vascular disease, eradication
sensory neuropathy, and renal I/C 36 12 48
impairment. The sites and A/S 32 16 48
severity of infection, including Total 68 28 96
the frequency of osteomyelitis,
were similar for both treatment
groups.
Relative Risk- 36/47 ÷ 32/41 = 0.98

Eradication of Gram Positive and Negative

Setting:
organisms
Not mentioned
Imipenem/cilast Ampicillin/sulba
atin ctam
14/47 21/45 Gram positive
alone
0/47 0/45 Gram negative
alone

Osteomyelitis:

Underlying osteomyelitis was associated with 11 of the

14 failures (six infections treated with A/S and five with
I/C).

However, among all patients, osteomyelitis was not

associated with failure to eliminate soft-tissue infection;
at the end of therapy, treatment failure was noted in 11
(19%) of the 59 infections in patients with osteomyelitis
and three (8%) of the 37 infections in patients without
 osteomyelitis (p= 0.26).

Recurrence of infection after average 1 year follow

up:

Recurrence of infection at the original site was noted in

9 of 39 assessable patients treated with A/S and 8 of 41
assessable patients who received I/C.

Adverse events:

No. (%) of patients with adverse

reactions
Adverse I/C (48 A/S (48
reactions episodes) episodes)
Significant 7 (15) 9 (19)
Moderate/possi 8 (17) 6 (13)
ble
Mild/unlikely 1 (2) 2 (4)
Total 16 16
Significant- a severe reaction necessitating withdrawal
of the study agent or specific treatment
Moderate- a reaction that did not necessitate
withdrawal of the study agent or specific treatment
Mild- an event uncertainly associated with the study
drug
The total incidence of adverse reactions was similar in
both treatment groups
Additional comments:
Because pathogen identification and antimicrobial susceptibility testing is frequently not complete for 5 days in cases of polymicrobial infection, the initial 5 days or 120 hours of study
therapy were considered to be the period of empirical therapy. A clinical and microbiological assessment was made at the end of empirical therapy. A final assessment of treatment
outcome was made at the end of iv antimicrobial therapy.
Randomisation was performed. Blinding performed. Allocation concealment not mentioned. All parameters were not analysed as intention to treat. Confounding not mentioned. Power
calculation not mentioned. Patients lost to follow up and excluded after randomisation was justified.
Reference: Grayson, ML, Gibbons, GW, Habershaw, GM, Freeman, DV, Pomposelli, FB, Rosenblum, BI, Levin, E, Karchmer, AW Use of
ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients.[Erratum appears in Clin Infect Dis 1994
Oct;19(4):820]. Clinical Infectious Diseases 1994; 18: 683-93.
Title: Prospective, Randomized Comparison of Ampicillin/Sulbactam and Cefoxitin for Diabetic Foot Infections.
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 3174 Total no. of patients: Inclusion: Cefoxitin-2 g Ampicillin/sulbac Daily until
Baseline = 36 At least Grade 1 foot infection every six tam — 3 g every therapy Table: Clinical outcomes
Level of Cefoxitin- 18 and had not received hours six hours was
evidence: Ampicillin/sulbactam- 18 successful antimicrobial stopped Cefoxitin Ampicillin/sulba
() therapy within the previous Therapy was Therapy was ctam
No other antimicrobials were four-day period, as noted by given for at given for at least Cured 7 1
Study administered during clinical improvement. least 5 days 5 days but Improvement 9 14
type: hospitalization, unless a patient but maximum maximum Treatment 2 3
RCT failed to respond to the study Exclusion: duration was duration was left failures
antimicrobial therapy within left to to discretion of Total 18 18
Authors: forty-eight hours, in which case Known hypersensitivity to discretion of attending Cured- complete alleviation of signs and
Erstad et the patient was withdrawn from penicillins or cephalosporins, a attending surgeon. symptoms of infection
al. (1997) the investigation. calculated creatinine clearance surgeon. Improvement- partial alleviation of signs and
less than 15 mL/minute, a symptoms of infection
Baseline characteristics: recent history of drug or Failure- no improvement
alcohol abuse, or a concomi-
There were no significant tant infection at a site other Relative Risk- 7/18 ÷ 1/18 = 7.05
differences in the baseline than the foot that required
characteristics of the patients in additional antimicrobials. There was a significant difference (P-0.03)
the two groups on study entry Patients were also excluded if between treatment groups with more patients in
they were terminally ill, neu- the cefoxitin group classified as cured.
Setting: tropenic (neutrophil count
3
University medical centre- <1500/m ), pregnant, or However, there was no significant difference in
Southern Arizona breastfeeding. treatment outcome between the
ampicillin/sulbactam (15/17) and cefoxitin (16/17)
groups when both cure and improvement were
considered.

Relative Risk- 15/18 ÷ 16/18 = 0.94

Similarly, there was no significant difference

between groups in the proportion of patients who
had changes in clinical signs and symptoms from
baseline (just prior to study medication
administration) to the end of therapy.

Duration of Hospitalisation
 The mean (range) duration of hospitalization was
21.1 (6.0-58.0) days in the ampicillin/sulbactam
group and 12.1 (4.0-39.0) days in the cefoxitin
group.

Bacteriologic evaluation:

6 patients in the ampicillin/sulbactam group and

11 patients in the cefoxitin group were evaluable
for bacteriologic outcome (ie, these patients had
culturable material from the infected site prior to
initiating the study antimicrobial).

Eradication of the causative organisms occurred in

all patients in the ampicillin/sulbactam group 6/6
(100%) compared with 8/11 (73%) patients in the
cefoxitin group.

Adverse events:

Most adverse events were of minor clinical

importance, gastrointestinal disturbances being
particularly common in both the ampicillin/sul-
bactam and the cefoxitin groups (39% and 33% of
patients, respectively).

Relative Risk- 6/18 ÷ 7/18 = 0.86

Additional comments:
Randomisation was performed. Blinding performed. Allocation concealment not mentioned. Confounding not mentioned. Power calculation not mentioned. Patients lost to follow up and
excluded after randomisation was not mentioned. All parameters were analysed as intention to treat.
Ten patients in the ampicillin/sulbactam group and 7 patients in the cefoxitin group had failed outpatient antimicrobial therapy prior to hospital admission. Most of the patients in the
former group had received ciprofloxacin (at least 6 patients), and patients in the latter group had received a variety of antimicrobial agents. Three patients did not complete the five-day
course of antimicrobial therapy, although all were included in the intention-to-treat analysis.
Reference: Erstad, BL, McIntyre, J Prospective, randomized comparison of ampicillin/sulbactam and cefoxitin for diabetic foot infections. Vascular Surgery
1997; 31: 419-26.
Title: An Open-Label, Randomized Study Comparing Efficacy and Safety of Intravenous Piperacillin/Tazobactam and Ampicillin/Sulbactam for Infected Diabetic Foot
Ulcers.
Level of Patient Population/ Selection/Inclusion Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics criteria
ID: 4446 Total no. of patients: Inclusion: I.V. piperacillin I.V. ampicillin/ Day 4, day
Baseline = 314 Adult patients with /tazobactam sulbactam (A/S- 7, at the The rates of clinical success(defined as cure or
Level of P/T- 155 diabetes mellitus and (P/T) (4 g/0.5 2 g/1 g q6h). end of improvement for the patient-level clinical response) in
evidence: Modified all-treated (MAT)- 139 open infected foot g q8h). treatment the MAT population between treatment groups were:
() A/S- 159 ulcers that met the visit, and at 71.2% of the patients in the piperacillin/tazobactam
Modified all-treated - 150 University of Texas Doses Patients with the test-of- group and 66.7% of the patients in the ampicillin/sul-
Study Grade IB, ID, IIB, or IID adjusted in MRSA or cure visit bactam group.
type: MAT-population comprised of classification of foot patients with methicillin-resis- (occurred
RCT all patients who received at ulcers , have at least renal function tant within 14- Clinical No clinical Total
least one dose of study drug one full- or partial-thick- in both groups. Staphylococcus 21 days of success success
Authors: and did not have any ness infected ulcer at epidermidis completion P/T 99 40 139
Harkless osteomyelitis. or below the ankle. Pa- (MRSE) present of therapy) A/S 100 50 150
et al. tients were also as part of a Total 199 90 289
(2005) Standard wound care, including required to have polymicrobial
off-loading, sharp debridement purulent drainage or infection were Relative Risk- 99/139 ÷ 100/150 = 1.07
of devitalized tissue, and moist two of the following: also given
dressings, were followed during Erythema, local edema, vancomycin at 1 There were no substantial differences in clinical
the study, and the one-time use fluctuance, induration, g ql2h success rates when results were compared by age,
of a topical antiseptic was increased local warmth, gender, race, or smoking status.
allowed after a surgical or fever.
procedure or debridement. Eradication of Gram Positive and Negative
Exclusion: organisms
Baseline characteristics:
Pregnancy or lactation; P/T Ampicillin/sulba
Overall, patients' demographic anticipated amputation ctam
characteristics, baseline of the infected area 51/65 46/64 Gram positive
diagnoses, wound classes and within two months; 6/7 0/0 Gram negative
ulcer locations, and conditions requiring
concomitant diseases were concurrent topical
similarly distributed in the two antibiotics to the ulcer Adverse events:
treatment groups. site or any other
systemic antibacterials
Adverse event P/T A/S
Setting: during the study period;
(n=155) (n=159)
Regional areas in United States creatinine clearance With at least 1 117 105
less than 40 mL/min;
adverse event
conditions requiring
immunosuppressive With at least 1 29 21
drug treatments; treatment related
gangrene or severely adverse event
 impaired arterial supply With at least 1 42 46
to any portion of the serious adverse
affected foot; event
hypersensitivity to Relative Risk- 29/155 ÷ 21/159 = 1.41
penicillins, /S-
lactamase inhibitors, or The majority of adverse events were mild-to-moderate
vancomycin; presence in severity, and the incidence and severity of all
of organisms known or adverse events and treatment-related adverse events
suspected to be were comparable between the two groups.
resistant to either study
drug; renal insufficiency
requiring renal
replacement therapy;
osteomyelitis; or
thrombocytopenia.

A patient could be
withdrawn from the
study for noncompli-
ance, adverse events,
investigator belief that
withdrawal was in the
best interest of the
patient, patient choice,
lack of efficacy, patient
loss to follow-up, or
death. Additionally,
patients who had
infections caused by
organisms resistant to
randomized treatment
were withdrawn from
the study.
Additional comments:
Randomisation was performed. Open-labelled. Power calculation used. Allocation concealment not mentioned. Confounding mentioned. Patients lost to follow up and excluded after
randomisation was mentioned. All parameters were not analysed as intention to treat.
Reference: Harkless, L, Boghossian, J, Pollak, R, Caputo, W, Dana, A, Gray, S, Wu, D An open-label, randomized study comparing efficacy and safety of
intravenous piperacillin/tazobactam and ampicillin/sulbactam for infected diabetic foot ulcers. Surgical Infections 2005; 6: 27-40.
Title: Treatment of hospitalised patients with complicated skin and structure infections: double-blind, randomised, multicentre study of piperacillin-tazobactam versus
ticarcillin-clavulanate
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 10637 Total no. of patients: Inclusion: Dosed every 6 Dosed every 6 h Patients were
Patients 16 years of age and h with with ticarcillin- evaluated for Table: Clinical responses at endpoint for
Level of A patient was considered older with complicated skin or pipcracillin- clavuianatc their clinical evaluable patients.
evidence: evaluable if each of the skin structure infections like tazobactam (T/C), 3 g and responses to
() following criteria was met: a ischemic or diabetic foot infec- (P/T), 3 g and 100 mg, therapy daily for Outcome P/T T/C p value
pretherapy pathogen tions, present with purulent 375 mg, respectively for the duration of Cured/im 12 7 0.90
Study susceptible to either study drug drainage or collection and at respectively 5 days and at treatment in the proved
type: was present, susceptibility data least three of the following: for 5 days and least 48h after hospital, at 24 to
for at least one pathogen were Unfavour 6 10
RCT temperature greater than at least 48h resolution of 72 h after the able
available, no other antibacterial
agents were administered 38°C, peripheral leukocyte after resolution signs and completion of total 18 17
Authors: concomitantly during the study, count greater than of signs and symptoms. therapy (early
3
Tan et al. there were at least 5 days of 10,000/mm with greater than symptoms. follow-up), and Relative Risk- 12/18 ÷ 7/17 = 1.62
(1993) treatment with the study 5% immature neutrophils, local at 10 to 14 days
medication (to qualify for a erythema, local swelling, after the Adverse Events:
favourable outcome), and the tenderness, pain, or completion of
patient underwent at least one fluctuance. therapy (late Data not extractable for patients with
post-therapy follow-up (to follow-up). diabetic foot infection.
qualify for a favourable Exclusion:
outcome). For an unfavourable
outcome, at least 3 days of Known or suspected
.
therapy were required hypersensitivity to beta-lactam
antibiotics or {3-lactamasc
inhibitors; moderate to severe
Surgical debridement or renal dysfunction; evidence of
drainage was allowed and was active liver disease; peripheral
accepted as an integral part of granulocyte counts of
patient management. 3
<l,000/mm or platelet counts
3
of <50,000/mm ; receipt of
Baseline characteristics: more than two doses of
another antibacterial agent
The distribution of patients by within 72 h prior to enrolment;
race and sex was comparable receipt of another investiga-
between the two treatment tional drug within 1 month prior
arms and the mean ages to enrolment; active or treated
among all treated patients were leukaemia; AIDS; the need for
similar. Differences in the haemodialysis, peritoneal
distributions of clinical dialysis, plasmapheresis, or
diagnoses were not significant haemoperfusion; osteomyelitis
between the two treatment contiguous with a skin or skin
 arms. structure infection; potential
requirement for amputation of
Setting: the infected area; pressure
20 centers ulcer infections of greater than
2 weeks' duration {because of
the. known difficulty in
eradicating organisms from
chronic decubitus ulcers); and
a concomitant infection other
than the skin and skin
structure infection.
Additional comments:
Randomisation was performed. Blinding performed. Power calculation used. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to follow up and
excluded after randomisation was mentioned. All parameters were analysed as intention to treat.
Reference: Tan, JS, Wishnow, RM, Talan, DA, Duncanson, FP, Norden, CW Treatment of hospitalized patients with complicated skin and skin structure
infections: double-blind, randomized, multicenter study of piperacillin-tazobactam versus ticarcillin-clavulanate. The Piperacillin/Tazobactam Skin and Skin
Structure Study Group. Antimicrobial Agents & Chemotherapy 1993; 37: 1580-1586.

Title: Treatment of diabetic foot infection: an open randomised comparison of imipenem/cilastatin and piperacillin/clindamycin combination therapy.
Level of Patient Population/ Selection/Inclusion Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics criteria
ID: 1702 Total no. of patients: Inclusion: Piperacillin Imipenem/cilast Every 3 days Efficacy:
Baseline = 46 3000 mg QID atin (I/C)- 500 and after
Level of I/C- 22 (1 excluded due to Diabetic foot lesions, in combination mg QID completion of Table: Assessment of clinical response to
evidence: being included twice) Wagner Stages II, III or with antibiotic treatment with imipcncm/cilastalin or the
() I/C-21 IV, and have an clindamycin Dosages therapy. combination of piperacillin with clindamycin
P/LC- 24 ankle/brachial index 600 mg reduced in
Study (AB1) of at least 0.45. (P/CL)- TID patients with Clinical Imipenem/ Piperacillin/
type: The minimum length of renal or liver outcome cilastatin clindamycin
RCT treatment required for Exclusion: Dosages function (n-21) (n-24)
evaluability was at least 10 reduced in impairment. Cured 4 6
Authors: days. Antibiotic therapy was Patients known to be patients with Improved 16 12
Bouter et discontinued if the patient's hypersensitive to any of renal or liver Failed 0 2
al. (1996) clinical condition worsened
after 72 h and questions
were raised about the
appropriateness of therapy.
In case of chronic
osteomyelitis, antibiotic
therapy was continued with
oral quinolone (ciprofloxacin
500 mg BID or ofloxacin 400
mg BID) and/or clindamycin
600 mg TID depending on
culture results.
Baseline characteristics:
The two study populations
were similar with regard to
age, sex, type of diabetes
mellitus and associated
conditions.
The two study groups were
comparable in terms of
baseline severity.
Setting:
Bosch McdiCentre, Den
Bosch and the Eemland
Hospital, Amersfoort, The
Netherlands.
the study drugs or who
had received
antimicrobial therapy
known or presumed
effective against the
infecting pathogens
within 48 h preceding
initiation of treatment
were excluded from the
study. Patients with a
high probability of death
within 48 h were also
excluded from the study
as were patients known
to be infected with Xa n -
thomonas
m a l t o p h i l i a other
microorganisms known or
presumed resistant to the
study drugs.
function Died 1 4
impairment.
In the IC study population, four (19.0%) patients
were considered to be clinically cured, 16 (76.2%)
improved. No patients were classified as a clinical
failure.
In the PCL study population, six (25.0%) patients
were considered to be clinically cured, 12 (50.0%)
improved. Two patients (8.3%) were classified as
a clinical failure due to persistence or aggravation
of clinical signs of infection
Relative Riskcured- 6/24 ÷ 4/21 = 1.31
Relative Riskcured and improved -18/24 ÷ 20/21 = 0.79
Bacteriological response:
Table 2: Assessment of bacteriological response
to treatment with imipenem/ cilastatin or the
combination of piperacillin with clindamycin
Bacteriologic Imipenem/ Piperacillin/
al outcome cilastatin clindamycin
(n = 20) ( n = 23)
Eradication 9 16
Partial 3 1
eradication
Failure 1 3
Superinfection 4 3
Relapse 3 0
In the IC treatment group eradication of baseline
pathogens was in 9 and partial eradication in 3
patients. 1patient was considered to be a
bacteriological failure.
In the PCL patient group antibiotic treatment
resulted in eradication of baseline pathogens in 16
patients. 3 patients were classified as a
 bacteriological failure.

Relative Risk- 16/24 ÷ 9/21 = 1.56

Adverse Events:

Table: Adverse events reported during treatment

with miipcnem/cilastatin or the combination of
piperacillin with clindamycin

Adverse Imipenem/ Piperacillin/

event cilastatin clindamycin
(n-21) (n-24)
Yes 3 12
No 18 12

Significantly more patients treated with PCL than

patients treated with IC experienced side effects
that were probably related to the study drugs ( P <
0.05).
Relative Risk- 12/24 ÷ 3/21 = 3.50

Additional comments:
Randomisation was performed. Blinding performed. Power calculation not mentioned. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to follow up
and excluded after randomisation was mentioned. All parameters were not analysed as intention to treat.
Reference: Bouter, KP, Visseren, FLJ, Van Loenhout, RMM, Bartelink, AKM, Erkelens, DW, Diepersloot, RJA Treatment of diabetic foot infection: An open randomised
comparison of imipenem/cilastatin and piperacillin/clindamycin combination therapy. International Journal of Antimicrobial Agents 1996; 7: 143-47.
Title: Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-tazobactam/amoxicillin-Clavulanate.
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6518 Total no. of patients: Inclusion: IV therapy piperacillin- Patients were Efficacy
Baseline = 607 for at least 3 tazobactam evaluated
Level of 306 randomised to moxifloxacin At least 18 years of age, with a days with (P/T) (3.0 regularly until Table 1: Clinical cure rates at the TOC (test-of
evidence: 311 to P/T-A/C cSSSI (complicated skin and moxifioxacin g/0.375 g every 10-42 after cure) visit (10-42 days post-therapy) in the
() ITT (intention-to treat)-127 skin structure infections). Each (400 6 h) for at least completing the efficacy-valid population
63 to moxifloxacin enrolled patient had to have al mg/day). 3 days. study therapy. DFI Moxifloxacin P/T- p-
least three of the following
Study 64 to P/T-A/C Then Then switched definition A/C value
signs or symptoms of wound
type: Efficacy valid population(EVP)- switched to to amoxicillin- Per 25/37 25/4 0.54
infection: drainage or
RCT 78 oral therapy clavulanate investigator 1
discharge, erythema,
37- moxifloxacin with (A/C)suspension (efficacy
fluctuance, localized heat or
Authors: 41- P/T-A/C warmth, pain or tenderness, moxifloxacin 800 mg every 12 valid
Lipsky et swelling or induration, fever, 400 mg/day h population)
al. (2007) ITT- and safety populations Ieucocyiosis or >15% ITT 28/63 25/6 0.54
were defined as all randomized immature neutrophils on 4
patients who received at least peripheral blood smear. The
one dose of study medication investigators only enrolled Relative Risk (EVP)- 25/37 ÷ 25/41 = 1.10
patients with an infection of
The efficacy-valid population sufficient severity to require Relative Risk (ITT)- 28/63 ÷ 25/64 = 1.14
consisted of patients who met hospitalization and iv
the entry criteria, had an antimicrobial therapy. Bacteriologic response
investigator-defined
DFI, received study medication Exclusion: Bacteriologic eradication rates for the
for the minimum duration (2 microbiologically-valid population at TOC for
days if a clinical failure and >5 Excluded patients who had patients in the moxifloxacin(n-29) and
days if a clinical cure), received received antibiotic therapy for comparator (n-32)treatment arms were not
no non-study systemic or >24h within 3 days prior to statistically significantly different overall (69%
topical antibiotic agent for >72h study enrolment or those who versus 66%, P = 1.00).
prior to enrolment and had no needed concomitant systemic Relative Risk (EVP)- 20/29 ÷ 21/32 = 1.05
protocol violations that would antibiotic therapy for treatment
have influenced treatment of other infections. We also Eradication of Gram positive and Negative
efficacy. excluded patients with a DFI organisms
who had suspected or Moxifioxacin P/T
Patients in the documented osteomyelitis, Gram positive 24/27 27/42
microbiologically-valid unless the infected bone was aerobes
population consisted of those in fully or partially resected and Gram positive 0/1 ¾
the efficacy-valid population any residual soft tissue anerobes
with one or more causative infection could be adequately Gram 2/7 8/12
organism(s) identified at treated with study drug for < negative
enrolment. 14 days. aerobes
 Baseline characteristics: Gram 1/3 3/6
negative
There were no statistically anerobes
significant differences between
patients in the two treatment Adverse events:
groups in their demographic or
clinical characteristics at Table 2: Adverse events by treatment group
baseline for all variables Moxifloxacin P/T-A/C
N= 63 N= 64
Setting: Any adverse 52 42
68 centres in 6 countries. event
Drug-related 20 8
adverse
event
Serious 15 15
adverse
effect
Study drug 8 7
discontinued
due
to adverse
event

Almost a quarter of patients experienced a

serious adverse event, and in ~11% this led to
their study drug being discontinued
prematurely.

More patients in the moxifioxacingroup than in

the comparator group experienced a drug-
related adverse event (28 versus 8).

No severe drug-related adverse events

occurred in any patient in the moxifioxacin
group, compared with two that occurred in
patients in the comparator group.

Relative Risk (ITT)- 52/63 ÷ 42/64 = 1.26

Additional comments:
Randomisation was performed. Blinding performed. Power calculation not used. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to follow up and
excluded after randomisation was mentioned. All parameters were analysed as intention to treat.
 Reference: Lipsky, BA, Giordano, P, Choudhri, S, Song, J Treating diabetic foot infections with sequential intravenous to oral moxifloxacin compared with piperacillin-
tazobactam/amoxicillin-clavulanate. Journal of Antimicrobial Chemotherapy 2007; 60: 370-376.

Title: Topical versus Systemic Antimicrobial Therapy for Treating Mildly Infected Diabetic Foot Ulcers: A Randomized, Controlled, Double-Blinded, Multicenter Trial of Pexiganan Cream.

Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6523 Total no. of patients: Inclusion: Pexiganan Ofloxacin Patients were Clinical Outcome
Men or women aged ≥18 cream-twice tablets-200mg- evaluated at 3,
Level of Study 303 years who had diabetes daily orally-twice daily 10, 14, and 21 Table 1: Clinical outcomes (cured or improvement)
evidence: mellitus (according to Or Or days after at end of treatment (EOT) and follow-up visits for
() Baseline = 493 American Diabetes Placebo Placebo tablets- enrollment; at patients who received either pexiganan or
Association definitions), cream-twice 200mg-orally- end of treatment ofloxacin in the intention-to-treat populations.
Study ITT (intention-to treat)- had an infected wound daily twice daily (EOT); and at
type: Pexiganan= 247 below the malleoli that follow-up (2 Visit and Pexiganan Ofloxacin
RCT ITTM(intention-to treat exceeded 0.5 cm2 in area weeks after study treatment treatment
microbiological)= 189 after appropriate EOT).
Authors: debridement, wounds had group group
Lipsky et ITT-Ofloxacin= 246 to be full thickness, the DFI EOT
al. (2008) ITTM= 198 had to be severe enough to 303 210/247 224/246
require antibiotic therapy, 304 153/171 153/171
Study 304 but it had to be amenable
to outpatient treatment. Follow-up
Baseline = 342 303 186/243 201/240
Exclusion: 304 134/163 137/163
ITT -Pexiganan= 171
ITTM= 138 If they had an abscess, The difference in the rates of clinical cure or
extensive gangrene, an improvement in study 304 was within the 95% CIs
ITT-Ofloxacin= 171 imminently limb- for equivalence at both EOT (89% for both the
ITTM= 140 threatening infection, ofloxacin group and the pexiganan group) and
evidence of systemic infec- follow-up (84% for the ofloxacin group and 82%
tion (e.g., fever, chills, or for the pexiganan group).
hypotension), plain
This study involved 2 radiograph findings Relative Risk (304-EOT)- 153/171 ÷ 153/171 = 1
groups: study 303 and suggestive of
304. osteomyelitis, no palpable Relative Risk (304-Follow up)- 134/163 ÷ 137/163
dorsalis pedis or posterior = 0.98
Investigators performed tibial pulse or a pedal
appropriate local wound systolic pressure (by In study 303, however, pexiganan did not
care, including any Doppler) of ≤40 mm Hg on demonstrate equivalence to ofloxacin either at
necessary debridement the affected limb, EOT (rates of clinical cure or improvement were
and pressure off-loading
of the infected she, and
they obtained wound
tissue specimens for
aerobic and anaerobic
culture al enrolment.
Nonstudy systemic or
topical anti-infective
agents were not allowed
after enrolment.
requirement for renal
dialysis, need for
immunosuppressive
medication, or hyper-
sensitivity to either study
medication.
85% and 91%, respectively) or follow-up (77% and
84%, respectively).
Relative Risk (303-EOT))- 210/247 ÷ 224/246 =
0.93
Relative Risk (303-Follow up)- 186/243 ÷ 201/240
= 0.91
Microbiological Outcome:

Baseline characteristics: Table 2: Microbiological outcomes* at end of

treatment (EOT) and follow-up visits for patients
Baseline characteristics of who received either pexiganan or ofloxacin in the
patients randomized to the intention-to-treat populations.
2 treatment groups in
each of the 2 studies were *- in whom some or all of the initially isolated
not statistically different. pathogens were eradicated, in whom there were
no new pathogens isolated, and who experienced
Setting: clinical cure or improvement.
Various centres in United
States.
Visit and Pexiganan Ofloxacin
study treatment treatment
group group
EOT
303 91/189 94/198
304 63/138 66/140
Follow-up
303 78/185 90/194
304 55/130 62/134

The percentages of patients who were

microbiological responders in both trials were not
significantly different between the ofloxacin and
pexiganan arms at both the EOT (~47% for each)
and follow-up (46% and 42%, respectively) time
points.

Rates of microbiological failure at follow-up were

low, and similar rates were noted for the
pexiganan and ofloxacin groups in studies 303
(8% and 6%, respectively) and 304 (10% and 8%,
respectively).

Relative Risk (303-EOT))- 91/189 ÷ 94/198 = 1.01

Relative Risk (303-Follow up)- 78/185 ÷ 90/194 =

0.91

Relative Risk (304-EOT)- 63/138 ÷ 66/140 = 0.97

Relative Risk (304-Follow up)- 55/130 ÷ 62/134 =

0.91

Eradication of Gram positive and Negative

organisms

Pexiganan Ofloxacin
Gram positive 209/383 243/396
Gram 82/119 77/110
negative

Wound Assessments:

There were no statistically significant differences

between the ofloxacin- and pexiganan-treated
patients al baseline in the mean total wound score
or wound infection score or in median wound area
or depth. The wound assessment scores
decreased at the EOT visit for all measurements
in both studies for both treatment arms, and they
decreased further for each measurement at the
follow-up visit. The magnitude of the decrease in
score was similar for the 2 treatment groups.

Adverse events:

The overall incidence and types of systemic and

cutaneous adverse events were comparable in the
2 treatment arms of both studies.

In study 303, adverse events were experienced

 by 98 (39.8%) of the pexiganan-treated patients
and by 109 (44.3%) of the ofioxacin-lrealed
patients.

Relative Risk (303)- 98/247 ÷ 109/246 = 0.9

In study 304, they occurred in 76 (44.4%) of the

pexiganan-treated patients and 84 (49.1%) of the
ofloxacin-treated patients.

Relative Risk (304)- 76/171 ÷ 84/171 = 0.9

Additional comments:
Randomisation was performed. Blinding performed (not sue). Power calculation used. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to follow up
and excluded after randomisation was mentioned. All parameters were analysed as intention to treat.
Reference: Lipsky, BA, Holroyd, KJ, Zasloff, M Topical versus systemic antimicrobial therapy for treating mildly infected diabetic foot ulcers: a randomized,
controlled, double-blinded, multicenter trial of pexiganan cream. Clinical Infectious Diseases 2008; 47: 1537-45.

Title: Treating Foot Infections in Diabetic Patients: A Randomized, Multicenter, Open-Label Trial of Linezolid versus Ampidllm-Sulbactam/ Amoxicillin-
Clavulanate.
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6504 Total no. of patients: Inclusion: Linezolid (600 ampicillin- The test-of-cure Efficacy
Baseline = 371 Men and women (age, ≥18 mg ql2 h either sulbaclam (A/S, evaluation was
Level of Linezolid- 241 years) with diabetes iv or per oral) 1.5-3 g q6h iv}, conducted 15-21 Table 1: Clinical cure rates for the intent-to-treat
evidence: After exclusion mellitus, a foot infection or amoxicillin- days after population, by selected parameters.
() Linezolid- 203 (cellulitis, paronychia, clavulanate treatment was
A/S and A/C- 120 infected ulcer, deep soft- (A/C, 500-875 completed No. of patients cured/ No. of
Study After exclusion tissue infection, septic mg every 8-12 h patients assessed(%)*
type: A/S and A/C- 108 arthritis, abscess, or per oral). Linezolid Aminopenicill
RCT osteomyelitis) were (n- 241) in / β
Patients with presumed potentially eligible. lactamase
Authors: osteomyelitis were allowed inhibitor
Lipsky et to be enrolled if the in- Exclusion: (n-=120)
al. (2004) vestigator believed 4 weeks Overall 165/203 77/108 (71)
of antibiotic therapy was If they had critical (81)
sufficient for treatment. ischemia of the affected Type of
limb, if they had a wound **
infection
Patients received twice-daily with prosthetic materials Infected 131/161 57/84 (68)
dressing changes (which or devices; if they had an ulcer (81)
consisted of any sterile infection requiring >28 Cellulitis 68/86 (79) 40/54 (74)
nonadherent type selected days of antibiotic
by the investigator) and pe- treatment; or if they had a Deep soft- 20/32 (63) 8/14 (57)
riodic debridement, as wound with extensive tissue
needed throughout the gangrene. Patients were infection
study. also excluded if they had Paronychia 11/12 (92) 9/11 (82)
received potentially Abscess 5/5 (100) 1/1 (100)
Baseline characteristics: effective antibiotic therapy Osteomyeliti 27/44 (61) 11/16(69)
for >72 h in the week s
There were no significant before enrollment, if they Route of
differences between the 2 needed additional initial
treatment groups at baseline treatment with antibiotics treatment
with respect to demographic not tested in our study, if Intravenous 41/53 (77) 15/22 (68)
characteristics, medical they had an absolute Oral 124/150 62/86 (72)
histories, findings of neutrophil count of <500 (83)
3
physical examination, and cells/mm , if they were
results of laboratory tests. pregnant or lactating, or if *- Excludes patients with indeterminate and
they had a history of missing outcomes
Setting: hypersensitivity to **- Patients could have had >1 baseline diagnosis.
45 sites in 8 countries. linezolid, penicillin, or
vancomycin. There was no statistically significant difference
between the treatment groups in the overall
clinical cure rate.

When analyzed by primary diagnosis, however,

statistically significantly more patients with an
infected ulcer in the linezolid arm were clinically
cured than in the aminopenicillin//3-lactamase
inhibitor arm (81% vs. 68%, respectively; 95% CI,
1.9-25.2; P = .018).

Clinical outcomes were similar between treatment

groups among patients with cellulitis, deep soft-
tissue infection, paronychia, abscess, and
osteomyelitis.

Relative Risk (overall)- 165/203 ÷ 77/108 = 1.14

Relative Risk (infected ulcer)- 131/161 ÷ 57/84 =

1.20

Relative Risk (Osteomyelitis)- 27/44 ÷ 11/16 =

0.89

Adverse events:
 Linezolid group

No. of patients- 64
Patients who discontinued therapy- 18

Aminopenicillin / β lactamase inhibitor

No. of patients- 12
Patients who discontinued therapy- 4

Overall, significantly fewer patients experienced a

drug-related adverse event in the
aminopenicillin/β-laclamase inhibitor groups than
in the linezolid group (12 [10%] of 120 patients vs.
64 [27%] of 241 patients, respectively; P = .001),
but the frequencies of drug-related events leading
to drug discontinuation were comparable (4 [3%]
of 120 patients vs. 18 [8%] of 241 patients,
respectively; P - 0.16)

Treatment-related adverse events occurred in

55% and 53% of patients in the linezolid and
aminopenkillin/ /J-lactamase inhibitor groups,
respectively ( P = .82) Events were generally mild
to moderate in intensity and of limited duration.

Relative Risk- 64/241 ÷ 12/120 = 2.65

Additional comments:
Randomisation (ratio 2:1) was performed. Open-labelled. Power calculation not used. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to follow up
and excluded after randomisation was mentioned. All parameters were analysed as intention to treat.
Reference: Lipsky, BA, Itani, K, Norden, C, Linezolid Diabetic Foot Infections Study Group Treating foot infections in diabetic patients: a randomized,
multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clinical Infectious Diseases 2004; 38: 17-24.
Title: Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing daptomycin with vancomycin or semi-synthetic
penicillins for complicated skin and skin-structure infections.
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6512 Total no. of patients: Inclusion: Daptomycin Vancomycin 1 g Patients were
Baseline = 133 Eligible patients were those [4mg/kg every every 12h iv assessed at Table 1: Clinical success rates for patients
Level of 103-clinically evaluable with diabetes between the 24h over 60min or a 'end-of- with infected diabetic ulcers by antibiotic
evidence: 47-Daptomycin ages of 18 and 85 years who intravenously semi-synthetic therapy' (i.e. treatment group (clinically evaluable
() 56-comparator required hospitalization for an (iv) over penicillin within 3 days population).
infected ulcer that was known 30min] (nafcillin. of the last
Study For suspected or proven or suspected (based on a oxacillin, dose of study Comparator Daplomycin* Comparator
type: polymicrobial infection, the Gram-stained smear) to be cloxacillin or drug); 'test-of-
group (n=47) (n= 56)
RCT investigator was allowed caused by a Gram-positive llucloxa-cillin, cure' (i.e.
Pooled 66.0 (31/47) 70.0 (39/56)
to add aztreonam to cover organism. per the within 6-20
Semi- 64.0 (16/25) 70.4 (19/27)
Authors: gram-negative bacteria or Exclusion: investigator's days after
synthetic
Lipsky et metronidazole lo cover choice) given in completing the
penicillin
al. (2005) obligate anaerobic Patients with minor or equally divided study drug);
superficial skin infections, doses totalling and 'post- Vancomycin 71.4 (10/14) 69.0 (20/29)
bacteria, at his or her
discretion. uncomplicated cellulitis, 4-12g/day iv]. study' (i.e. *- Pre-randomization assignment unavailable
myositis, multiple infected within 20-28 in 8 subjects
Baseline characteristics: ulcers at distant sites, infected days after
third-degree burn wounds, completing the The overall clinical success rate was 66% for
Patients in the daptomycin osteomyelitis, known study drug). patients treated with daptomycin and 70% for
and comparator groups bacleraemic shock, patients treated with a comparator agent (95% CI,
were statistically equiv- hypotension, or any disorder -14.4-21.8).
alent with respect to all that could interfere with the
noted baseline variables, treatment evaluation were Relative Risk(? Methodology)- 31/47 ÷ 39/56 =
including mean age (60 excluded. Other exclusions 0.95
and 63 years), sex (54% were pregnancy, infection due
and 54% male) and race to an organism known to be Looking at individual comparators, the clinical
(80% and 78% white), resistant lo any study drug success rates for patients randomized to
respectively. before study entry, body daptomycin versus a semi-synthetic penicillin were
weight less than 40kg, history 64.0% and 70.4%, respectively.
Setting: of hypersensitivity reaction lo
134 sites in the United any study drug, need for Relative Risk- 16/25 ÷ 19/27 = 0.91
States, Europe. South haemodialysis or peritoneal
Africa, Australia, and dialysis, impaired renal Whereas for those randomized to daptomycin
Israel function (creatinine clearance versus vancomycin rates were 71.4% and 69.0%,
less than 30ml7min). respectively. None of these differences was
immunosuppression, serum statistically significant.
creatine phosphoki-nase Relative Risk- 10/14 ÷ 20/29 = 1.03
(CPK) more than 50% above
the upper limit of normal, or Adverse events:
 the use of any 3-hydroxy-3-
metlwlghitaryl coenzyme The most common events in both groups were
reductase inhibitor (statin) gastrointestinal; most adverse events were
drugs. Patients were also deemed unrelated to the study medications, were
excluded if they had received of mild to moderate intensity, and rarely required
more than 24h of systemic
that the drug be discontinued.
antibiotic therapy for the
infected ulcer within the
previous 48 h. Of the 56 adverse events that were possibly or
probably related to treatment, 37 (66%) occurred
in the 72 patients in the comparator group, and 19
(34%) occurred in the 61 patients in the dapto-
mycin group.

Relative Risk(? Methodology)- 19/61 ÷ 37/72 =

0.60

Additional comments:
Randomisation was performed but partially.. Blinding performed. Power calculation not used. Allocation concealment not mentioned. Confounding not mentioned. Patients lost to
follow up and excluded after randomisation was mentioned. All parameters were not analysed as intention to treat.
Reference: Lipsky, BA, Stoutenburgh, U Daptomycin for treating infected diabetic foot ulcers: evidence from a randomized, controlled trial comparing
daptomycin with vancomycin or semi-synthetic penicillins for complicated skin and skin-structure infections. Journal of Antimicrobial Chemotherapy 2005; 55:
240-245.

Title: Ertapenem Versus Piperacillin/Tazobactam for Diabetic Foot Infections (SIDESTEP): Prospective/Randomized, Controlled, Double-Blinded, Multicentre Trial
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 6511 Total no. of patients: Inclusion: Intravenous Intravenous Day 5 of The proportion of patients with a favourable clinical
Baseline = 586 Presented with diabetes ertapenem (1 g piperacillin/tazobac intravenous response at the DCIV timepoint, adjusted for baseline
Level of mellitus (type 1 or type 2, controlled bolus, followed tam (P/T-3-375 g therapy, at the time severity, was 94% (213 of 226) for the ertapenem group
evidence: 295- ertapenem by diet or medications) and a foot by a saline every 6 h). of discontinuation and 92% (202 of 219) for the piperaciliin/lazobaclam
() 289- clinical MITT (modified- infection that did not extend placebo every 6 of intravenous group.
intention-to-treat) above the knee and required h for three therapy (DCIV), at
Study 244- microbiological MITT intravenous antibiotics. All additional the time of Relative Risk- 213/226 ÷ 202/219 = 1.02
type: 226 DCIV clinically evaluable patients had purulent drainage doses). discontinuation of
RCT 206-FUA clinically evaluable or at least three other any subsequent At the 10-day FUA timepoint, the clinical response rate,
151-microbiologically evaluable indicators of infection. oral antibiotic adjusted for baseline severity, was 87% (180 of 206) in
Authors: therapy, and at the the ertapenem group and 83% (162 of 196) in the
Lipsky et 291-P/T Exclusion: follow-up piperacillin/tazobactam group.
al. (2005) 285-clinical MITT assessment (FUA)
226-mocrobiological MITT Patients who had infections that 10 days after the Relative Risk- 180/206 ÷ 162/196 = 1.06
219-DCIV clinically evaluable
196-FUA clinically evaluable
135-microbiologically evaluable
Investigators sharply debrided any
wounds that had callus or
devitalized tissue at baseline, and
whenever necessary during the
study.
To ensure adequate antibiotic
coverage for potentially antibiotic
resistant Enlerococcus spp and
meticillin-resistant S aureus
(MRSA), investigators could
administer vancomycin to patients in
either treatment group if these
organisms were known or
suspected pathogens.
After 5 days of intravenous therapy,
the investigator could elect to switch
patients in either group to oral
antibiotic therapy with amoxicillin/
clavulanic acid (875/125 mg every
12 h).
Baseline characteristics:
The baseline characteristics—
including details of peripheral neuro-
pathy, palpable pedal pulses, and
wound severity—of those
randomized, which were similar
between groups.
At baseline, we stratified patients
with the University of Texas
Diabetic Wound Classification.
Stratum I patients had a
relatively superficial wound with
were: mild and did not require last dose of study
parenteral antibiotic therapy; antibiotic therapy Among the 574 patients in the more conservative MITT
known at entry to be caused by (intravenous or analysis (those who received at least one dose of study
pathogens resistant to either study oral). drug, with patients with missing or indeterminate
drug; predominantly caused by outcomes considered treatment failures), the proportion
thermal bums; categorised as with a favourable clinical response at the 10-day FUA
necrotising fasciitis; known or was 71% (206 of 289) and 66% {188 of 285), respectively
suspected to be associated with (treatment difference 5%, 95% CI —2-6 to 12-5).
underlying osteomyelitis,
complicated by indwelling foreign Relative Risk- 206/289 ÷ 188/285 = 1.08
or prosthetic material; or
associated with gangrenous tissue None of these differences between treatment groups is
that could not be adequately significant.
removed by surgical debridement.
We also excluded women who Table1: Rate of favourable clinical response at 10-
were pregnant, nursing, or fertile day FUA, by baseline stratum and wound
and not using contraception, as classification
well as patients with: a history of a
serious reaction to any β lactam Ertapenem P/T (n=196)
antibiotic; a need for any additional (n=206)
concomitant systemic antibacterial Moderate 127/142 129/135
agent other than the study drug(s) Severe 53/64 43/61
or vancomycin; diabetes or Grade 0 2/2 5/5(
impaired glucose tolerance that Grade 1 125/140 114/130
was secondary; arterial perfusion Grade 2 43/51 33/48
insufficiency of the affected limb,
Grade 3 10/13 10/l3
requiring a revascularisation
procedure; any rapidly progressive Stage B 172/195 156/187
or terminal illness; a requirement Stage D 8/11 6/9
for dialysis; immunosuppression of
any cause; or receiving Clinical cure rates were generally similar between
corticosteroid therapy {2=40 mg treatment groups for patients with either moderate or
prednisone daily or its equivalent). severe infections, and for every stage and grade. There
Laboratory variables for which was a trend towards lower success rates with deeper
patients were excluded were: wounds (moving from grade 0 to grade 3}, and patients
markedly abnormal liver function with an ischemic limb (stage D) generally had lower
tests; haemalocril of less than 25%, clinical success rates than patients with adequate
haemoglobin of less than 8 g/L, perfusion (stage B).
platelet count of less than 75
1
OOO/mm ; or coagulation test Microbiological outcome:
results more than 1.5 times the
upper limit of normal (unless on Among individuals with a positive wound culture, 358 of
anticoagulant therapy). Finally, we 384 (93%) isolates were known or presumed to be
 or without ischemia (grade 0 or
1, stages B or D), and
Stratum II patients had a
deeper wound (grades 2 or 3,
stages B or D).
Setting:
USA
excluded patients who had been eradicated in those in the ertapenem group compared
treated for more than 24 h with with 271 of 336 (81%) in the piperacillin/tazobactam
systemic antibiotic therapy likely to group (difference 12-5%, 95% CI 7-2-18-8).
be effective for their infection within
the 72 h before study screening, Relative Risk- 358/384 ÷ 271/336 = 1.16
unless there was clinical evidence
of treatment failure with an Adverse Events:
associated deep-tissue culture that
yielded pathogen(s). Most adverse events were unrelated to the study drugs.
137 (47%) patients on ertapenem and 136 (47%) on
piperacillin/tazobactam had at least one adverse event
during parenteral therapy.

There were no significant differences between treatment

groups in drug-related adverse events (n=44 [15%] for
ertapenem; n=57 [20%] for piperacillin/tazobactam)

Relative Risk- 44/295 ÷ 57/291 = 0.76

Additional comments:
Randomisation was performed. Open-labelled. Power calculation used. Allocation concealment mentioned. Confounding mentioned. Patients lost to follow up and excluded after
randomisation was mentioned. All parameters were analysed as intention to treat.
Reference: Lipsky, BA, Armstrong, DG, Citron, DM, Tice, AD, Morgenstern, DE, Abramson, MA Ertapenem versus piperacillin/tazobactam for diabetic foot
infections (SIDESTEP): prospective, randomised, controlled, double-blinded, multicentre trial. Lancet 2005; 366: 1695-703

Title: Treatment and Long-Term Follow-Up of Foot Infections in Patients with Diabetes or Ischemia: A Randomized, Prospective, Double-Blind Comparison of Cefoxitin
and Ceftizoxime
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: 4914 Total no. of patients: Inclusion: Ceftizoxime, Cefoxitin, up to2 Every 3 days. Table 1: Clinical responses
Baseline = 63 (1) a history or clinical evi- up to 4 gm IV gm IV every four Subsequent
Level of Ceftizoxime – 33 dence of peripheral arterial every eight hours. follow-up evalu- Number with Satisfactory
evidence: (5 unevaluable) insufficiency or diabetes hours. ations were Clinical Response/ Total
() mellitus; (2) isolation of Dosages of made after 3, 6, Number Treated
Cefoxitin- 30 bacterial organisms from Dosages of study 9, and 12 Ceftizoxime Cefoxitin
Study (5-unevaluable) wound, soft tissue, or study medication were months. All evaluable 23/28 17/25
type: bone; (3) two or more signs medication reduced for patients
RCT Some patients, after of infection, including local were reduced patients with Osteomyelitis 10/14 8/12
completing the study, heat, drainage, erythema, for patients renal Soft tissue 13/14 9/13
Authors: received oral antibiotics for or temperature greater with renal dysfunction. infections
Hughes variable lengths of time at than 38 °C. dysfunction. Infections 0/1 1/4
et al. the discretion of their associated
(1987) physician.
Baseline characteristics:
Evaluable patients were
similar with regard to age,
sex, duration of therapy, and
associated conditions.
Setting:
2 Veterans Administration
medical centers (VAMC)
Exclusion:
Excluded for previous
penicillin or cephalosporin
allergy, rapidly progressive
underlying disease,
concomitant infection, or
antibiotic therapy effective
against the bacterial
isolates within three days
preceding initiation of-the
study.
Placebo with
infusions were bacteremia
given at
appropriate Satisfactory clinical responses were observed in
intervals to 82% of patients treated with ceftizoxime and 68%
patients in the of patients treated with cefoxitin.
ceftizoxime
group to Relative Risk- 23/28 ÷ 17/25 = 1.20
maintain
double-blind Treatment of osteomyelitis with either agent was
conditions. particularly encouraging, being only slightly less
successful than treatment of soft tissue infections.
Infections associated with bacteremia frequently
were clinically unsatisfactory.
There was no significant difference between
responses of patients with peripheral vascular
disease alone and responses of diabetics with or
without apparent peripheral vascular disease.
The in vitro susceptibilities of selected bacterial
isolates are 161 of 185 (87%) isolates tested were
susceptible to ceftizoxime and 148 of 183 (81%)
were susceptible to cefoxitin.
Long term Follow up
3 months
After three months of follow-up, six patients in
each group had relapses of infection at the same
site, which required parenteral antibiotics.
12 months
After 12 months, of 23 patients who initially had
satisfactory clinical responses to ceftizoxime, eight
were free of infection (at the same site), nine had
relapsed, two had died of unknown causes, and
four had failed to return for follow-up.
Seventeen patients had initially satisfactory clinical
responses to cefoxitin. After 12 months, seven
remained free of infection, eight had relapsed, and
 two had not returned for follow-up.

Five of 12 patients with soft tissue infections and

two of 11 with osteomyelitis were known to have
satisfactory long-term outcomes.

Adverse events

Adverse effects were observed in 16/33 (48%)

patients receiving ceftizoxime and in 19/30 (63%)
patients receiving cefoxitin. These consisted
mostly of minor laboratory abnormalities, which
resolved with discontinuation of therapy.

Relative Risk- 16/33 ÷ 19/30 = 0.76

Additional comments:
Randomisation (Computer-generated Code) was performed. Blinding performed. Power calculation not used. Allocation concealment not mentioned. Confounding not mentioned.
Patients lost to follow up and excluded after randomisation was mentioned. All parameters were not analysed as intention to treat.
Reference: Hughes, CE, Johnson, CC, Bamberger, DM, Reinhardt, JF, Peterson, LR, Mulligan, ME, Gerding, DN, George, WL, Finegold, SM Treatment and
long-term follow-up of foot infections in patients with diabetes or ischemia: a randomized, prospective, double-blind comparison of cefoxitin and ceftizoxime.
Clinical Therapeutics 1987; 10: Suppl-49.
Title: Outpatient management of uncomplicated lower-extremity infections in diabetic patients.
Level of Patient Population/ Selection/Inclusion criteria Intervention Comparison Follow-up Outcome and Results
Evidence Characteristics
ID: HTA Total no. of patients: Inclusion: I (n = 27 C (n = 29 Not mentioned. Results at 2 weeks
paper Baseline = 56 non-limbthreatening patients): patients):
I= 27 lower extremity infections. Clindamycin Cephalexin 500 Complete healing:
Level of C= 29 Clinically infected lesions were 300 mg orally, mg orally, four
evidence: defined as the recent four times times daily for 2 I: 10/25 (40%)
() At the initial evaluation, lesions development of purulence or daily for 2 weeks C: 9/27 (33%)
were cleaned with half-strength at least two of the following: weeks.
Study hydrogen peroxide, debrided erythema, warmth, Relative Risk- 10/25 ÷ 9/27 = 1.21
type: mechanically and covered with tenderness, induration,
RCT a gauze dressing. fluctuance, drainage Improved lesions:

Authors: Baseline characteristics: Exclusion: I: 14/25 (56%)

Lipsky et C: 18/27 (67%)
al. (1990) Mean ± SEM age: Systemic or topical
I: 59.4 ± 2.3 years antimicrobial therapy within the Relative Risk- 14/25 ÷ 18/27 = 0.83
C: 62.7 ± 2.4 years preceding 2 weeks, presence
of systemic toxicity, an Lesions not improved:
Patients with an ulcerated infection that was immediately
lesion: threatening to life or limb, I: 1/25 (4%)
I: 24/27 (89%) patient unable to perform daily C: 0/27 (0%)
C: 27/29 (93%) wound care, history of
nonadherence with outpatient Adverse effects:
Setting: treatment, unwilling to return
Washington State Veterans for outpatient visits, allergy to I: 1 patient had mild Diarrhoea
Affairs Medical Centre study drugs.
C: 2 patients had mild nausea and
diarrhoea

No tests of statistical significance

reported

Additional comments:

Randomisation was performed (method not stated). Blinding performed. Power calculation not used. Patients lost to follow up and excluded after randomisation was mentioned. All
parameters were not analysed as intention to treat.
Reference: Lipsky BA, Pecoraro RE, Larson SA et al. (1990) Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Archives of
Internal Medicine 150: 790-7.