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 l Risk factors (vascular, neuropathy, diabetes itself) l Adjunctive therapy Debridement and surgery are integralDebridement and surgery are integral Wound careWound care Off-loadingOff-loading

Desirable Features of a Study §Designed to optimize enrollment: l Includes most types of diabetic foot infections (cellulitis, infected ulcer, deep tissue infection) l Allows inpatient or outpatient therapy l Allows intravenous or oral therapy l 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 l require extensive debridement or surgery, but not complete resection/amputation l be open or closed l be anywhere on foot from malleoli to toesfrom malleoli to toes dorsal or ventraldorsal or ventral l be multiple, but select one “study” lesion l have been treated with potentially effective antibiotic, but only for <72 hours

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

Exclusion Criteria (Ischemia) §Critical ischemia of affected limb, defined as: l Absence of palpable posterior tibial and dorsalis pedis pulses l Absent or abnormal Doppler waveforms + toe blood pressure < 45 mm Hg

Osteomyelitis §Occurs in > ¼ of diabetic foot infections §Can be difficult to diagnose §Can be more difficult to eradicate l requires more prolonged antibiotic therapy no good clinical data on required durationno good clinical data on required duration 4 weeks likely adequate; less if bone resected4 weeks likely adequate; less if bone resected l 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 ( )

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 l after cleansing/debriding scrape with scalpel l 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 l General wound parameters (description) l Peripheral pulses assessment l Wound measurements l Wound infection score

Probe to Bone §One study* in 76 patients: l Sensitivity 66%; Specificity 85% l + Predict. value 89%; - Predict. value 56% §Technique: 14 cm 5 F sterile metal probe l Done prior to wound debridement ( x eschar) l Use routine aseptic procedures; clinic/bedside l Holding like pencil, gently probe wound l Hard, gritty structure in wound, w/o apparent intervening soft tissue, is + test l Avoid if closed/surgically exposed wounds * Grayson et al, JAMA 1995;273:721-3 * 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 l No topical antibiotics (mupirocin, sulfa, aminoglycosides, etc.) l No topical antiseptics (H 2 O 2, iodophors, chlorhexidine, silver, etc.) §Others (non-antimicrobial) l 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 l total contact cast l special shoes/boots l 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