Carl Norden, M.D.

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Presented by Carl Norden, M.D. at the
Anti-Infective Drugs Advisory Committee meeting
on October 28, 2003
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DFI Clinical Trial

• Differs from cSSSI trial
• Risk factors (vascular, neuropathy, diabetes
  itself)
• Adjunctive therapy
• Debridement and surgery are integral
• Wound care
• Off-loading

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Desirable Features of a Study

• Designed to optimize enrollment
• Includes most types of diabetic foot infections
  (cellulitis, infected ulcer, deep tissue
  infection)
• Allows inpatient or outpatient therapy
• Allows intravenous or oral therapy
• Allows additional antibiotic agents for
  resistant organisms

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Study Inclusion Criteria - 1

• Male or female over age 18
• Be able willing to give informed consent and
  complete all study activities
• Diabetes mellitus (by ADA criteria) either
  type, any treatment acceptable
• Infected lesion of lower extremity
• cellulitis, deep soft tissue infection,
  infected ulcer, septic arthritis, paronychia,
  abscess

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Study Inclusion Criteria - 2

• Infected lesion can
• require extensive debridement or surgery, but
  not complete resection/amputation
• be open or closed
• be anywhere on foot
• from malleoli to toes
• dorsal or ventral
• be multiple, but select one study lesion
• have been treated with potentially effective
  antibiotic, but only for lt72 hours

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Study Exclusion Criteria

• Local (lower extremity) conditions
• Critical ischemia of affected limb
• Expectation that entire infection will be
  resected or amputated
• gt 72 h of agent active against all pathogens
• Infected device that can/will not be removed
• Require additional antibiotic for any reason
• Presence of extensive dry/wet gangrene
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Exclusion Criteria (Ischemia)

• Critical ischemia of affected limb, defined as
• Absence of palpable posterior tibial and dorsalis
  pedis pulses
• Absent or abnormal Doppler waveforms
• toe blood pressure lt 45 mm Hg

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Osteomyelitis

• Occurs in gt ¼ of diabetic foot infections
• Can be difficult to diagnose
• Can be more difficult to eradicate
• requires more prolonged antibiotic therapy
• no good clinical data on required duration
• 4 weeks likely adequate less if bone resected
• may require surgical debridement/resection

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Exclusion Criteria (Osteomyelitis)

• Open wound, bone visible
• Open wound, probe to bone positive
• Baseline X-ray or MRI read as active
  osteomyelitis (criteria for osteomyelitis to be
  established in protocol)
• Nuclear scan alone is not sufficient to exclude
  osteomyelitis

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• I shall not today attempt to define the kinds of
  material (pornography) - but I know it when I
  see it.
• Justice Potter Stewart (1915-1985)

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Diagnostic Studies

• Plain X-ray
• Probe to bone for open lesions
• Culture/sensitivity testing
• Wound description (photography)/ wound score
• Vascular evaluation

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Wound Cultures

• Obtain from all enrolled patients- no more than
  24 hours prior to enrollment
• Set-up for aerobes anaerobes at local lab
• Swab specimens are not acceptable
• Curretage of wound base
• after cleansing/debriding scrape with scalpel
• send tissue on blade in sterile container
• Tissue specimens obtain at bedside/OR
• Aspiration for secretions, cellulitis

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Wound Scoring System

• Designed to give objective wound score
• Includes quantified
• General wound parameters (description)
• Peripheral pulses assessment
• Wound measurements
• Wound infection score

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Probe to Bone

• One study in 76 patients
• Sensitivity 66 Specificity 85
• Predict. value 89 - Predict. value 56
• Technique 14 cm 5 F sterile metal probe
• Done prior to wound debridement (x eschar)
• Use routine aseptic procedures clinic/bedside
• Holding like pencil, gently probe wound
• Hard, gritty structure in wound, w/o apparent
  intervening soft tissue, is test
• Avoid if closed/surgically exposed wounds
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• Grayson et al, JAMA 1995273721-3

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Treatment

• Drug vs. comparator (gold standard) IV or PO
• Can add other agents for activity against
  organisms not covered by the study drug
• 7 21 days of antibiotics 14 days is usual
  duration

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Adjunctive Therapy

• Debridement/surgery
• Dressing changes
• Off-loading
• Not allowed topical antibiotic, anti-septic, or
  other antimicrobial agents (i.e., Betadine)

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Topical Therapy

• Antimicrobials
• No topical antibiotics (mupirocin, sulfa,
  aminoglycosides, etc.)
• No topical antiseptics (H2O2, iodophors,
  chlorhexidine, silver, etc.)
• Others (non-antimicrobial)
• Agents such as becaplermin, collagen, etc. are
  allowed, but not encouraged

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Wound Dressings

• Many available types- none proven best
• Moist environment preferred
• No antimicrobial products allowed
• Moist-to-damp saline dressing adequate
• Other types permissible

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Wound Off-Loading

• Helpful to curing infection and crucial healing
  wound
• Many devices used- none proven best
• total contact cast
• special shoes/boots
• crutches, wheelchair, etc

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Efficacy Evaluations (1)

• Follow-up for test-of-cure at 14 21 days after
  end of therapy
• Clinical response to therapy defined as
  resolution of pre-therapy clinical signs and
  symptoms of infection
• Final categories cured, failed, indeterminate

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Efficacy Evaluations (2)

• Surgical debridement is allowed during the trial
  and is considered part of standard care
• Complete resection of the infected area will
  remove patient from the trial

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Sample Size

• Assume 80 success rate for comparator
• Difference in cure rate of lt10 will be
  considered equivalent
• ?Criteria for superiority