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

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

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

3. 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

4. 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

5. 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

6. 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 --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

7. 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

8. Osteomyelitis • Occurs in > 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

9. 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

10. “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)

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

12. 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: forsecretions, cellulitis

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

14. 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

15. 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

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

17. 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

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

19. 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

20. 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

21. 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

22. Sample Size • Assume 80% success rate for comparator • Difference in cure rate of <10% will be considered equivalent • ?Criteria for superiority