# Presentation: 912513

## Presented by

- Carl Norden, M.D.
- at the
- Anti-Infective Drugs
- Advisory Committee
- meeting on October 28, 2003

## DFI Clinical Trial

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

## 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

## 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

## 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 <72 hours

## Study Exclusion Criteria

- Local (lower extremity) conditions
- Critical ischemia of affected limb*
- Expectation that entire infection will be 		resected or amputated
- > 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
- --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

## 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 < 45 mm Hg

## Osteomyelitis

- Occurs in > 1⁄4 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

## 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

- “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)

## Diagnostic Studies

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

## 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

## Wound Scoring System

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

## 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
- -------------------------------------------------------------
-     * Grayson et al, *JAMA* 1995;273:721-3

## 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

## Adjunctive Therapy

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

## 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

## Wound Dressings

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

## 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

## 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

## 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

## Sample Size

- Assume 80% success rate for comparator
- Difference in cure rate of <10% will be considered equivalent
- ?Criteria for superiority