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