Presented byCarl Norden, M.D.

at the Anti-Infective Drugs Advisory Committee

meeting on October 28, 2003

DFI Clinical TrialDFI Clinical Trial

Differs from cSSSI trialDiffers from cSSSI trial Risk factors (vascular, neuropathy, Risk factors (vascular, neuropathy,

diabetes itself)diabetes itself) Adjunctive therapyAdjunctive therapy

• Debridement and surgery are integralDebridement and surgery are integral• Wound careWound care• Off-loadingOff-loading

Desirable Features of a StudyDesirable Features of a Study

Designed to optimize enrollment:Designed to optimize enrollment: Includes mostIncludes most types types of diabetic foot of diabetic foot

infections (cellulitis, infected infections (cellulitis, infected ulcer, ulcer, deep tissue infection)deep tissue infection)

Allows Allows inpatientinpatient or or outpatientoutpatient therapytherapy

Allows Allows intravenousintravenous or or oraloral therapy therapy Allows Allows additional antibioticadditional antibiotic agents agents

for for resistant organismsresistant organisms

Study Inclusion Criteria - 1Study Inclusion Criteria - 1Male or female over age 18Male or female over age 18Be able & willing to give informed consent Be able & willing to give informed consent

and complete all study activitiesand complete all study activitiesDiabetes mellitus (by ADA criteria); Diabetes mellitus (by ADA criteria);

either type, any treatment acceptableeither type, any treatment acceptableInfected lesion of lower extremity: Infected lesion of lower extremity:

cellulitis, deep soft tissue infection, cellulitis, deep soft tissue infection, infected ulcer, septic arthritis, infected ulcer, septic arthritis,

paronychia, paronychia, abscessabscess

Study Inclusion Criteria - 2Study Inclusion Criteria - 2

Infected lesion canInfected lesion can require extensive debridement or require extensive debridement or

surgery, surgery, but but notnot complete complete resection/amputationresection/amputation

be open or closedbe open or closed be anywhere on footbe anywhere on foot

• from malleoli to toesfrom malleoli to toes• dorsal or ventraldorsal or ventral

be multiple, but select one “study” lesionbe multiple, but select one “study” lesion have been treated with potentially have been treated with potentially

effective effective antibiotic, but only for <72 antibiotic, but only for <72 hourshours

Study Exclusion CriteriaStudy Exclusion CriteriaLocal (lower extremity) conditionsLocal (lower extremity) conditions

Critical ischemia of affected limb*Critical ischemia of affected limb* Expectation that entire infection will be Expectation that entire infection will be

resected or amputatedresected or amputated > 72 h of agent active against all pathogens> 72 h of agent active against all pathogens Infected device that can/will not be removedInfected device that can/will not be removed Require additional antibiotic for any reasonRequire additional antibiotic for any reason Presence of extensive dry/wet gangrenePresence of extensive dry/wet gangrene----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Exclusion Criteria (Ischemia)Exclusion Criteria (Ischemia)

Critical ischemia of affected limb, Critical ischemia of affected limb, defined as:defined as: Absence of palpable posterior tibial Absence of palpable posterior tibial

and dorsalis pedis pulsesand dorsalis pedis pulses Absent or abnormal Doppler Absent or abnormal Doppler

waveformswaveforms+ toe blood pressure < 45 mm Hg+ toe blood pressure < 45 mm Hg

OsteomyelitisOsteomyelitisOccurs in > ¼ of diabetic foot Occurs in > ¼ of diabetic foot

infectionsinfectionsCan be difficult to diagnoseCan be difficult to diagnoseCan be more difficult to eradicate Can be more difficult to eradicate

requires more prolonged antibiotic requires more prolonged antibiotic therapytherapy• 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

may require surgical may require surgical debridement/resectiondebridement/resection

Exclusion Criteria Exclusion Criteria (Osteomyelitis)(Osteomyelitis)

Open wound, bone visibleOpen wound, bone visibleOpen wound, probe to bone Open wound, probe to bone

positivepositiveBaseline X-ray or MRI read as Baseline X-ray or MRI read as

active osteomyelitis (criteria for active osteomyelitis (criteria for osteomyelitis to be established in osteomyelitis to be established in protocol)protocol)

Nuclear scan alone is not Nuclear scan alone is not sufficient to exclude osteomyelitissufficient to exclude osteomyelitis

““I shall not today attempt to define I shall not today attempt to define the kinds of material the kinds of material (pornography) - but I know it (pornography) - but I know it when I see it.”when I see it.”

Justice Potter Stewart (1915-Justice Potter Stewart (1915-1985)1985)

Diagnostic StudiesDiagnostic Studies

Plain X-rayPlain X-rayProbe to bone for open lesionsProbe to bone for open lesionsCulture/sensitivity testingCulture/sensitivity testingWound description (photography)/ Wound description (photography)/

wound scorewound scoreVascular evaluationVascular evaluation

Wound CulturesWound Cultures Obtain from all enrolled patients- no more Obtain from all enrolled patients- no more

than 24 hours prior to enrollmentthan 24 hours prior to enrollment Set-up for aerobes & anaerobes at local labSet-up for aerobes & anaerobes at local lab SwabSwab specimens are specimens are notnot acceptable acceptable CurretageCurretage of wound base of wound base

after cleansing/debriding scrape with scalpelafter cleansing/debriding scrape with scalpel send tissue on blade in sterile containersend tissue on blade in sterile container

TissueTissue specimens: obtain at bedside/OR specimens: obtain at bedside/OR Aspiration: Aspiration: forfor secretions, cellulitissecretions, cellulitis

Wound Scoring SystemWound Scoring System

Designed to give objective wound Designed to give objective wound scorescore

Includes quantifiedIncludes quantified General wound parameters General wound parameters

(description)(description) Peripheral pulses assessmentPeripheral pulses assessment Wound measurementsWound measurements Wound infection scoreWound infection score

Probe to BoneProbe to Bone One study* in 76 patients:One study* in 76 patients:

Sensitivity 66%; Specificity 85%Sensitivity 66%; Specificity 85% + Predict. value 89%; - Predict. value 56%+ Predict. value 89%; - Predict. value 56%

Technique: 14 cm 5 F sterile metal probeTechnique: 14 cm 5 F sterile metal probe Done prior to wound debridement (Done prior to wound debridement (xx eschar) eschar) Use routine aseptic procedures; clinic/bedsideUse routine aseptic procedures; clinic/bedside Holding like pencil, gently probe woundHolding like pencil, gently probe wound Hard, gritty structure in wound, w/o Hard, gritty structure in wound, w/o

apparent intervening soft tissue, is + testapparent intervening soft tissue, is + test Avoid if closed/surgically exposed woundsAvoid if closed/surgically exposed wounds--------------------------------------------------------------------------------------------------------------------------

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

TreatmentTreatment

Drug vs. comparator (gold Drug vs. comparator (gold standard) – IV or POstandard) – IV or PO

Can add other agents for activity Can add other agents for activity against organisms not covered by against organisms not covered by the study drugthe study drug

7 – 21 days of antibiotics; 14 days 7 – 21 days of antibiotics; 14 days is usual durationis usual duration

Adjunctive TherapyAdjunctive Therapy

Debridement/surgeryDebridement/surgeryDressing changesDressing changesOff-loadingOff-loadingNot allowed: topical antibiotic, Not allowed: topical antibiotic,

anti-septic, or other antimicrobial anti-septic, or other antimicrobial agents (i.e., Betadine)agents (i.e., Betadine)

Topical TherapyTopical Therapy

AntimicrobialsAntimicrobials No topical antibiotics (mupirocin, No topical antibiotics (mupirocin,

sulfa, aminoglycosides, etc.)sulfa, aminoglycosides, etc.) No topical antiseptics (HNo topical antiseptics (H22OO22, iodophors, , iodophors,

chlorhexidine, silver, etc.)chlorhexidine, silver, etc.)Others (non-antimicrobial)Others (non-antimicrobial)

Agents such as becaplermin, collagen, Agents such as becaplermin, collagen, etc. etc. are allowed, but not encouraged are allowed, but not encouraged

Wound DressingsWound Dressings

Many available types- none proven Many available types- none proven bestbest

Moist environment preferredMoist environment preferredNo antimicrobial products allowedNo antimicrobial products allowedMoist-to-damp saline dressing Moist-to-damp saline dressing

adequateadequateOther types permissibleOther types permissible

Wound Off-LoadingWound Off-Loading

Helpful to curing infection and Helpful to curing infection and crucial crucial healing woundhealing wound

Many devices used- none proven Many devices used- none proven bestbest total contact casttotal contact cast special shoes/bootsspecial shoes/boots crutches, wheelchair, etccrutches, wheelchair, etc

Efficacy Evaluations (1)Efficacy Evaluations (1)

Follow-up for test-of-cure at 14 – Follow-up for test-of-cure at 14 – 21 days after end of therapy21 days after end of therapy

Clinical response to therapy – Clinical response to therapy – defined as resolution of pre-defined as resolution of pre-therapy clinical signs and therapy clinical signs and symptoms of infectionsymptoms of infection

Final categories: cured, failed, Final categories: cured, failed, indeterminateindeterminate

Efficacy Evaluations (2)Efficacy Evaluations (2)

Surgical debridement is allowed Surgical debridement is allowed during the trial and is considered during the trial and is considered part of standard carepart of standard care

Complete resection of the infected Complete resection of the infected area will remove patient from the area will remove patient from the trialtrial

Sample SizeSample Size

Assume 80% success rate for Assume 80% success rate for comparatorcomparator

Difference in cure rate of <10% will Difference in cure rate of <10% will be considered equivalentbe considered equivalent

?Criteria for superiority?Criteria for superiority