1. Implications for clinical trials for diabetic foot infections (DFI) Anti-Infective Drugs Advisory Committee October 28, 2003 David Ross, M.D., Ph.D. Division of Anti-Infective Drug Products Center for Drug Evaluation and Research U.S. Food and Drug Administration

2. 2 Case I CC: 74 yo male nursing home patient with a stage IV pressure ulcer. PMH:Type I diabetes, peripheral vascular disease, and chronic renal insufficiency. PEx:Afebrile. Ulcer distal to lateral left malleolus, with exposed bone; smaller ulcer on dorsum of left foot with eschar, surrounding erythema. Labs: WBC 18,700/mm 3. X-ray: no osteomyelitis Course: Piperacillin/tazobactam started; no clinical improvement. Vancomycin added for spreading cellulitis; transfer to vascular surgery service. No clinical improvement; transfer to SICU for hypoxemia. AKA under consideration.

3. 3 Public health impact In the US during calendar year 2000, there were: –1,100,000 new cases of diabetes mellitus (DM) –140,000 hospital admissions for DFI –81,000 lower extremity amputations (LEA) due to DM –>$1.1 billion in LEA-associated costs 5 year mortality after LEA is 68% National Hospital Discharge Survey; J Foot Ankle Surg 2000; 39:S1-S60.

4. 4 Published DFI randomized clinical trials TrialN Lipsky 1997108 Chantelau 199643 Grayson 199496 Lipsky 199056 Hughes 198753

5. 5 What antibiotics really work in DFI? (I) What is the clinical definition of DFI? How should true pathogens be identified in DFI? How should clinical trials handle osteomyelitis? How do we take into account adjunctive therapies and other confounders?

6. 6 What antibiotics really work in DFI? (II) What is the clinical definition of DFI? –Clinical trials ≠ clinical practice –Need high sensitivity in practice but high specificity in trials –Nonspecific definitions allow enrollment of patients without disease, obscuring differences between drugs –One possible definition: skin break + new erythema and/or swelling ± fever ± leukocytosis ± loss of glycemic control

7. 7 What antibiotics really work in DFI? (III) How should true pathogens be identified in DFI? –Accurate microbiologic dx to assess strengths and limitations of clinical efficacy data –Drugs are labeled for an infection due to specific organisms –Suggest curettage or biopsy with semi- quantitative culture

8. 8 What antibiotics really work in DFI? (IV) How should clinical trials handle osteomyelitis? –Imbalances in osteomyelitis patients across arms confounds assessments of differences in drug efficacy –Exclude osteomyelitis patients (by MRI?) if study drug is topical or has no bone penetration; roll over to separate trial if has bone penetration

9. 9 What antibiotics really work in DFI? (V) How do we take into account adjunctive therapies and other confounders? –Confounders may contribute to differences in apparent efficacy –Patient characteristics affecting outcome need to be defined –Wound classifications need to be validated for trials and don’t define infection

10. 10 “Thus it is easy to prove that the wearing of tall hats and the carrying of umbrellas en- larges the chest, prolongs life, and confers comparative immunity from disease; for the statistics shew that the classes which use these articles are bigger, healthier, and live longer than the class which never dreams of possessing such things.” George Bernard Shaw (1856-1950); preface to The Doctor’s Dilemma (1906) Confounders

11. 11 Questions 1.How does one define a “diabetic foot infection”? Please consider in your discussion the differences between cellulitis without breaks in the skin versus cases with pre-existing ulcers. 2.What distinguishes infected from non- infected ulcers? 3.What is the most accurate way to obtain microbiologic information in patients with diabetic foot infections?