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What’s New in the New Diabetic Foot Infection Guidelines?

Benjamin A. Lipsky, MD, FACP, FIDSA, FRCP Professor of Medicine, University of Washington

Director, Primary Care Clinic & Antibiotic Research

VA Puget Sound Health Care System, Seattle, Washington, USA

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Web of Science: “Diabetic Foot Infections”

Citations & Publications in Past Decade

ISI Web of Science March 2012

Published Items/year Citations/year

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Diabetic LE Complications USA 1988-2009: Rate/1000 diabetic population

CDC, 2012: http://www.cdc.gov/diabetes/statistics

Number of hospital d/c for diabetic patients with peripheral arterial disease

(PAD), ulcer/Inflammation/Infection, or neuropathy as 1st listed diagnosis

Amputations Hospitalizations

Ulcer, Infection

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There is No Shortage of Diabetic Foot Guidelines! Partial Listing of PubMed Search for 2000-2010

Apelqvist J et al. Practical guidelines on the management...[PMID: 11637896]

Hinchliffe RJ et al. Specific guidelines on wound care ...[PMID: 18442188]

Bus SA et al. Specific guidelines on footwear for diabetic...[MID: 18442186]

Apelqvist J et al. The development of global consensus...[PMID: 18442162]

Steed DL et al. Guidelines for the prevention and treatment...[PMID: 18318802]

Orsted HL et al. Best practice recommendations for manage...[PMID: 18091117]

Société de… Infectieuse de Langue Française. [Management of diabetic foot..

Ollenschläger G et al. [The German Program for Diseases...[PMID: 17345021]

Frykberg RG et al. Diabetic foot disorders. A clinical...[PMID: 17280936]

Steed DL et al. Guidelines for the treatment of diabetic ...[PMID: 17199833]

Frykberg RG. A summary of guidelines for managing...[PMID: 15920373]

Pinzur MS et al. Guidelines for diabetic foot disorders...[PMID: 15680122]

Wraight PR et al. Creation of a multidisciplinary diabetic ...[PMID: 15660728]

Fabregas B. [Care of the diabetic foot. A multidisciplin...[PMID: 15551638]

Matwa P et al. Experiences and guidelines for diabetic...[PMID: 14509114]

Schaper NC et al. The international consensus a...[PMID: 14611743]

Association of Physicians of India.. Indian diabetes guidelines...[PMID: 12038678]

Inlow S et al. Best practices for the prevention of...[PMID: 11889737]

Rollins G. Guidelines on diabetic foot diseases...[PMID: 11902248]

Frykberg RG et al. Diabetic foot disorders: a cinicall...[PMID: 11280471]

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Diabetic Foot Infections: Management Guidelines

Infection Consensus

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DFI Guidelines: What a Year!

• NICE: Diabetic Foot Inpatient Management of People with

Diabetic Foot Ulcers and Infection. Clinical Guidelines

119, March 2011; http://publications.nice.org.uk/

diabetic-foot-problems-cg119

• International Working Group on the Diabetic Foot:

Expert opinion on the management of infections in the

diabetic foot (revised). Lipsky et al, Diab Met Res Rev

2012; Feb;28 Suppl 1:163-78; www.idf.org

• Infectious Diseases Society of America: Clinical

Practice Guidelines for the Diagnosis & Treatment of

Diabetic Foot Infections (revised). Lipsky et al, Clin Infect

Dis 2012;54[June 15]:e132-73;

www.idsociety.org

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Is the IDSA DFI Severity Classification Valid?

Lavery, et al, Clin Infect Dis, 2007;44:562

00%

25%

50%

75%

100%

No Infection Mild Moderate Severe

Hospitalization AmputationProspective study:1666 patients with DFU

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0

10

20

30

40

50

60

70

80

Mild Moderate Severe

Failure

Amputation

Osteo devel

Req Surgery

Noel, Lipsky, et al; Ceftobiprole vs Vanco+Ceftazadime for DFI (n=257)

0

10

20

30

40

50

60

70

80

Mild Severe

CRP/2

WBC

PMN>75%

SIRS%

Deep Inf

Relationship of IDSA Severity to Clinical Severity & Outcomes

p<.004 p<.001

Mild Moderate Severe Mild Moderate Severe

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IWGDF Classification Predicts LE Amputation

Factor significantly associated with amputation

5.45

12.61

3.5 3.7

1.53

2.56

1.32 1.552.43

4.395.08

2.16 2.43.45

5.88

10.07

1.08

2.02

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Neuropathy ESRD Ischemia Neuropathy Grade of

infection

Depth of

wound

Major amputations Toe amputation

OR

, 95%

CI

Widatalla et al. Int J Diabetes Dev Countries 2009;29:1

Prospective study Sudan 2003-5; 2321 DFU patients

28.5% underwent LE amputation; 65% were toes

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Have DFI Guidelines Been Found to be Useful? Outcome of Implementing DFI Guidelines in France

• 2003 audit of microbiological assessment of DFI – Many clinically uninfected wounds cultured

– Most cultures collected by suboptimal techniques

– Frequently isolated MDROs (especially MRSA)

– Isolated many low-virulence (likely colonizing) species

• Developed & implemented IDSA-based guidelines

emphasizing appropriate wound culture methods

• Re-audited clinical & micro data on 405 pts 2003-8 – Micro lab workload; inappropriate antibiotics

– Cost saving from both of > € 231,000

Sotto et al, Diabetologia 2010 ;53:2249

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UK NICE Guidelines

http://publications.nice.org.uk/diabetic-foot-problems-cg119

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NICE: Inpatient Management Diabetic Foot

Problems– Initial Evaluation & Assessment (CG 119)

• Examine for evidence of systemic or local (foot)

infection, as well as other foot complications

• Refer patient to multidisciplinary team w/n 24 hours

• Obtain plain X-rays (R/O osteo, Charcot, foreign body)

• Obtain urgent advice from appropriate specialist if

– Signs of systemic sepsis

– Evidence of deep-seated infection

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NICE: Inpatient Management Diabetic Foot

Problems– Antibiotics for Diabetic Foot Infection

• Antibiotic treatment is crucial to treat diabetic foot

infections but evidence inconclusive & of low quality,

precluding recommendations on individual agents

• Each hospital should have antibiotic guidelines for

Rx DFI; MRSA Rx based on local/national guidance

• Don’t delay antibiotic Rx for suspected osteomyelitis

pending MRI results

• Start empirical antibiotic Rx based on severity; definitive

regimen should be informed by microbiology results

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NICE: Inpatient Management Diabetic Foot

Problems– Antibiotics for Diabetic Foot Infection

• Select antibiotics with lowest acquisition cost

appropriate for the clinical situation & severity

• Use antibiotics with activity against:

– Gram + organisms for mild infections

– Both Gram + & Gram - (± anaerobic bacteria) for

moderate /severe infections

• Route of administration should be:

– oral for mild infections

– oral or IV (based on clinical situation) for moderate

– IV initially for severe infections then reassess

• Don’t give prolonged Rx for mild soft tissue infections

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IWGDF Revised Guideline on DFI

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IWGDF DFI Guidelines: Table of Contents • Introduction • Pathophysiology • Classification • Diagnosis

– Soft tissue infection – Osteomyelitis – Clinical evaluation – Probe-to-bone test – Blood tests – Imaging studies

• Plain radiography • Magnetic resonance • Nuclear medicine • Other imaging studies

– Bone biopsy • Assessing severity

Microbiological considerations − When to send specimen − How to obtain specimen − Interpreting culture result

Bone infection Treatment Antimicrobial therapy

− Indications for therapy − Route of therapy − Choice of antibiotics − Duration of therapy

Wound care Treating osteomyelitis Adjunctive therapies Outcome of treatment Developing country issues

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Common Imaging Features of DF Osteomyelitis

Table 2

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Clinical Characteristics Suggesting a More

Serious Diabetic Foot Infection (Table 3A)

Wound specific

-Wound: Penetrates into subcutaneous tissues, e.g.

fascia, tendon, muscle, joint, bone

-Cellulitis: Extensive (>2 cm), distant from ulceration, or

rapidly progressive

-Local signs: Severe inflammation, crepitus, bullae,

marked induration, discoloration, necrosis/

gangrene, ecchymoses, or petechiae

General

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Clinical Characteristics Suggesting a More

Serious Diabetic Foot Infection (Table 3A)

General -Presentation: Acute or rapidly progressive -Systemic signs: Fever, chills, hypotension,

confusion, volume depletion, -Laboratory tests: Leukocytosis, severe or worsening

hyperglycemia, acidosis, azotemia, electrolyte abnormalities

-Complicating Presence of a foreign body features (accidental or surgically implanted),

puncture wound, abscess, arterial or venous insufficiency, lymphedema

-Current treatment: Progression while on presumably appropriate antibiotic therapy

Wound Specific

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Factors Suggesting Hospitalization May be

Necessary (Table 3B)

• Severe infection (see Table 3A)

• Metabolic instability

• IV Rx needed (& not available/appropriate as

outpt)

• Diagnostic tests needed not available as outpatient

• Critical foot ischemia present

• Surgical procedures (more than minor) required

• Failure of outpatient management

• Patient unable/unwilling to comply with outpt Rx

• Need for complex dressing changes

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Factors that may Influence Choices of Antibiotic Therapy for Diabetic Foot Infections (Table 4)

⧫ Infection related - Clinical severity of the infection - H/O antibiotic therapy w/n 3 mos - Bone infection (presumed/ proven) ⧫ Pathogen related - Likelihood of non-GPC pathogen(s) - H/O MDROs colonization/ infection - Local rates of antibiotic resistance ⧫ Patient related - Allergies to antibiotics - Impaired immunological status - Patient treatment preferences - Renal or hepatic insufficiency - Impaired gastrointestinal absorption - Arterial insufficiency in affected limb - risk MDROs, unusual pathogens

Drug related - Safety profile (frequency & severity of AEs) - Drug interaction potential - Frequency of dosing - Formulary availability/ restrictions - Cost considerations (acquisition & administrn) - Approval for indication - Likelihood of inducing C. difficile disease or antibiotic resistance - Published efficacy data

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Selecting Empiric Antibiotics for DFI (Table 5)

Lipsky et al, Diab Met Res Rev 2012;28 Suppl 1:234

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Figure 1. Approach to the

infected diabetic foot

pathogen

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Issues of Importance in Developing Countries

• Causes of infections: often related to poorly

protective or absent footwear

• Delay in seeking healthcare: related to lack of

finances and/or education

• Use of home remedies of ? value/harm

• Non-prescription antibiotics: over-the-counter

(pharmacist), borrowed, expired, short-course

• Difficulty adhering to prescribed regimen

• Difficulty in following up with healthcare workers

• Limited diagnostic and therapeutic modalites

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Outcome of Treatment

• Mild infections: Usually resolve with appropriate Rx

• Moderate/Severe infections: – Many require surgical debridement (soft tissue ±

bone) or LE amputation (usually partial/minor)

– With extensive infection LEA rates up to 50-60%

(most foot-sparing), but cure in ~80%

• Recurrence of foot infection in 20-30% ( w/ osteo)

• Evidence of cure of infection – Resolution of signs/symptoms of infection

– Normalization of inflammatory markers

– Signs of bone healing on x-ray

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IDSA DFI Guidelines: Revised

Clinical Infectious Diseases 2012;54(12):132–173

Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2012.

DOI: 10.1093/cid/cis346

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What’s New in the New IDSA Guidelines?

• New format: 10 questions selected, each with

“recommendations” and “evidence summary”

• GRADE system to rank evidence: – Strength of recommendation: Strong or Weak – Quality of evidence: High, Moderate, Low, Very Low

• Systematic review of the literature (& limitations)

• Updated references (345)

• Recommendations for future work – Implementation – Regulatory changes – Research questions

• Potential performance measures: outcomes,

process

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Revised IDSA Guideline: The 10 Questions

1. In which diabetic patients with a foot wound should I suspect infection & how should I classify foot wounds?

2. How should I assess a diabetic patient presenting with a foot infection?

3. When should I request a consultation for a patient with a DFI, & from whom?

4. Which patients with a DFI should I hospitalize, & what criteria should they meet before discharge?

5. When and how should I send specimen(s) for culture from a patient with a diabetic foot wound?

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Diabetic Foot Infection: Revised IDSA Guideline

6. How should I initially select, and when should I

modify, an antibiotic regimen for a DFI?

7. When should I consider imaging studies to

evaluate a DFI, and which should I select?

8. How should I diagnose and treat osteomyelitis of

the foot in a patient with diabetes?

9. In which patients with a DFI should I consider surgical intervention & what procedures may be appropriate?

10. What type of wound care techniques and dressings should I use for a patient with a diabetic foot wound?

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IDSA/IWGDF Classifications DFI

Erythema >0.5 cm to ≤2 cm around ulcer

Table 2

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DFI Wound Score

Lipsky et al Wound Repair

Regen 2009;17:671

Table 3

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Interpretation of Results of Ankle Brachial Index

Table 4

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Collecting Specimens for Culture From Wounds

Table 5

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Antibiotic Selection Overview: Consideratons

-positive

Table 6

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Consider Empirical Anti-MRSA Rx if

• History of MRSA infection/colonization in past year

• Local % S. aureus clinical isolates that are

methicillin-resistant) is high (~50% for mild, 30%

for moderate soft tissue infection

• Infection is sufficiently severe that failing to

empirically cover MRSA while awaiting definitive

cultures would pose unacceptable risk of failure

• For suspected osteomyelitis, obtain specimen of bone for

culture for most cases in which MRSA posible

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Antibiotics for DFI: Revised IDSA Guidelines Route & Agent Mild Moderate/Severe Comments Table 8

Dicloxacillin (po) ✔ [* = ≥1 DFI trial] Requires QID dosing, inexpensive

Cephalexin (po)* ✔ [Ital=FDA aprvd] Requires QID dosing, inexpensive

Clindamycin (po,IV)*t ✔ [t=covers MRSA] GP aer/ana-robes; ±MRSA; D-test

Trimeth/Sulfa (po,IV)t ✔ [Bold=common] GPC (± streps), GNR, C-A MRSA

Amoxicillin/clav(po)* ✔ Relatively broad-spectrum

Levofloxacin (po,IV)* ✔ ✔ QD dosing; suboptimal S. aureus

Moxifloxacin (po,IV)* ✔ QD dosing; better for anaerobes

Cefoxitin (IV)* ✔ 2nd gen cephalosporin- for anaerobes

Ceftriaxone (IV,IM) ✔ 3rd gen cephalosporin; QD dosing

Ampicillin/sulb (IV)* ✔ Rel. broad-spectrum, not Ps aerug.

Linezolid (po,IV)*t ✔ GPs & MRSA; $$; toxicity >2 weeks

Daptomycin (IV)*t ✔ GPs & MRSA; $$; QD; monitor CK

Vancomycin (IV)*t ✔ Cheap; MIC creep; monitor for creat

Ertapenem (IV)* ✔ QD; rel. broad-spect, not Ps aerug.

Tigecycline (IV)*t ✔ Broad-spect. & MRSA;N/V; efficacy

Piperacillin/tazo(IV)* ✔ TID/QID; broad-spect. & Ps aerug.

Imipenem-cilast (IV)* ✔ Broad-spect. & ESBLs; not MRSA

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Suggested Route, Setting, & Duration of Antibiotic Therapy, by Syndrome (Soft Tissue)

Table

11

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Courtesy: E. Senneville, MD

Bone Biopsy for Diabetic Foot Osteomyelitis

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In Which Situations Is Diagnostic Bone Biopsy

Most Recommended?

• Uncertainty regarding the diagnosis of osteomyelitis

despite clinical and imaging evaluations;

• Absence (or confusing mix) of culture data from soft

tissue specimens;

• Failure to respond to empiric antibiotic\therapy; or,

• Desire to use antibiotic agents that may be especially

effective for osteomyelitis but have a high potential

for selecting resistant bacteria (eg, rifampin, FQs)

Table 9

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Management Suspected DFO

• If X-ray changes suggestive of osteomyelitis

– Treat for presumptive osteomyelitis, preferably

– After obtaining appropriate specimens for culture

(consider obtaining bone biopsy, if available)

• If the radiographs show no evidence of osteomyelitis,

– Rx antibiotics ≤2 weeks if soft tissue infection, and

– Optimal wound care and off-loading

– Repeat plain x-rays; if negative

• If wound improving, PTB-, osteomyelitis unlikely

• If wound not improving or PTB+, further dx studies

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Approach to Treating Diabetic Foot Osteomyelitis

Table 10

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Approach to Treating DF Osteomyelitis (contin)

Table 10 (continued)

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Suggested Route, Setting, & Duration of Antibiotic Therapy, by Syndrome (DFO)

Table 11 (contin.)

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Surgical Intervention in Diabetic Foot Infections

• Seek surgical consultation for infection with gas in deeper tissues, abscess, substantial nonviable tissue, necrotizing fasciitis, extensive bone or joint involvement, bullae, neurologic loss, new anesthesia

• The surgeon should have knowledge of foot anatomy & experience in dealing DFIs

• Evaluate limb’s arterial supply; consider revascularization

4 central spaces

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Questions to Ask When Dealing With DFI

Nonresponse or Recurrence

Table 13

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Questions to Ask When Dealing With DFI

Nonresponse or Recurrence

Table 13 (contin)

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Potential Performance Measures for Managing Diabetic Foot Infection

Table 14

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Potential Performance Measures for Managing Diabetic Foot Infection

Table 14 (contin.)

situations

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Diabetic Foot Infections: Summary

• Common, complex and costly problem

• Classification: based on severity (± ischemia)

• Culture tissue (rather than swab) specimens

• Causative organisms: GPC >> GNR > Anaerobes

• Antibiotic therapy: choosing empiric, definitive

• Often need debridement, I&D; ± revascularization

• Osteomyelitis: difficult to diagnosis & to treat

• Adjunctive measures occasionally helpful

• Multidisciplinary teams lead to improved outcomes

• How do we improve– implement, audit, study

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The Role of Guidelines

“Guidelines are

like a map

K. Bakker, MD

Chair, International

Working Group on

the Diabetic Foot

Implementation

is the journey”

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Teşekkür ederim!

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Signs of a Possibly Imminently Limb Threatening Infection

Table 12

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When Rx of DFO Fails, Consider

• Was the original diagnosis correct?

• Is there residual necrotic/infected bone or

surgical hardware that should be

resected/removed?

• Was selected antibiotic regimen likely to cover

causative organism(s), achieve adequate

bone levels, given for a sufficient duration?

• Is a noninfectious complication (eg, inadequate

offloading, blood supply), not failure to

eradicate bone infection, the problem?

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NICE: Inpatient Management Diabetic Foot

Problems– Investigating Possible DFI (CG 119)

• If moderate-severe soft tissue wound infection suspected

– Send tissue sample from base of debrided wound for

microbiological examination

– If not possible, a superficial swab may provide useful

information on the choice of antibiotic therapy

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NICE: Inpatient Management Diabetic Foot

Problems– Investigation Possible DFI (CG 119)

• If moderate-severe soft tissue wound infection suspected

– Send tissue sample from base of debrided wound for

microbiological examination

– If not possible, a superficial swab may provide useful

information on the choice of antibiotic therapy

• If osteomyelitis suspected but not confirmed by X-ray

– Order a MRI study

– If unavailable/contraindicated consider WBC scan

• For suspected osteomyelitis, do not

– Exclude by negative X-rays or probe-to-bone alone

– Diagnose by nuclear medicine bone scans

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Studies of Antibiotic Rx for DFI Since 2004

Table 7

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Clinical Classification Diabetic Foot Infection

No purulence or inflammation (erythema, pain, warmth tenderness, or induration)

Infected but any erythema ≤2 cm around ulcer & infection limited to skin & superficial subcutaneous tissues

1 of following: cellulitis >2 cm; lymphangitis; subQ spread; deep abscess; gangrene; muscle, tendon, joint or bone involved

Systemic toxicity or metabolic instability

IDSA IWGDF Clinical Manifestations* Severity PEDIS

Uninfected 1

Mild 2

Moderate 3

Severe 4

*Severity worsened by ischemia

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Diabetic Foot Infection Guidelines Panels

IDSA: Benjamin A. Lipsky (Chair)

• Anthony R. Berendt †^ • Adolph W. Karchmer

• David G. Armstrong *P • Eric Senneville *†^

• Paul B. Cornia *G • Edgar J. Peters *†^

• H. Gunner Deery • James C. Pile *H

• John M. Embil †^ • Michael Pinzur *O

• Warren S. Joseph P

IWGDF panel: Benjamin A. Lipsky (Chair)

• William Jeffcoate D • Larry Lavery P� • Karel Bakker D • Vilma Rovan-UrbancicD

*New; †Non-US; PPodiatrist; OOrthopedist; GGeneralist; HHospitalist; D Diabetol. ^ Also a member of the IWGDF

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Situations in Which to Consider Non-Surgical

Management of Diabetic Foot Osteomyelitis

• No acceptable surgical target (ie, radical cure of

infection would unacceptable functional

loss)

• Patient has limb ischemia caused by

unreconstructable vascular disease but

wishes to avoid amputation

• Infection confined to the forefoot, & there is

minimal soft tissue loss

• Patient & healthcare professionals agree that

surgical management carries excessive risk or

is otherwise not appropriate or desirable

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Potential Suggested Performance Measures

• Composition & meeting frequency of DF Teams

• % patients with DFI see by a multidisciplinary team

• Waiting times for initial evaluation & referral to the

specialist foot care team

• Time intervals between key management milestones

– clinical assessment to appropriate imaging, to

– initiation of treatment, or completion surgery

• Average and median length of hospital stay for a DFI

• Frequency of providing appropriate foot care services

on discharge from the hospital

• Existence and use of locally agreed protocols, and

evidence of audit of compliance

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Systematic Review of Effectiveness of

Interventions for Managing DFIs: IWGDF

• 7517 papers; 33 met criteria; 29 RCTs; 4 cohort studies

• Comparisons antibiotic regimens for skin/soft-tissue ±

bone infection: none showed significant difference

• 2 health economic analyses; 1 w/ small saving for 1 arm

• No data supported superiority of a particular route of

delivery or optimal duration of antibiotic therapy

• Possible benefit (weak studies): bone culture-guided

antibiotics; early surgical intervention; superoxidized

water; G-CSF

• No infection benefit shown for systemic HBO

Peters et al, Diabetes Metab Res Rev 2012 Feb;28 Suppl 1:142

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Characteristics Suggesting a More Serious DFI

Wound specific

Wound Penetrates into subcutaneous tissues

Cellulitis Extensive (>2 cm) or rapidly progressive

Local signs Crepitus, bullae, discoloration, necrosis, gangrene, ecchymoses or petechiae

General

Presentation Acute onset or rapidly progressive

Systemic signs Fever, chills, hypotension, confusion, volume

Laboratory tests Leukocytosis, severe hyperglycemia, acidosis, azotemia, electrolyte abnormalities

Complicating features

Foreign body, puncture wound, abscess, arterial or venous insufficiency, lymphedema

Current treatment Progression while on apparently appropriate antibiotic therapy

Lipsky et al, IWGDF. Diabetes Metab Res Rev 2012;28 Suppl 1:234

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Management Suspected DFO: continued

• Repeat X-rays 2–4 weeks after initial radiographs

– If remain normal but osteomyelitis still possible:

• Where wound depth is decreasing & PTB

negative, osteomyelitis unlikely

• Where wound not improving or PTB +,

consider

–Additional imaging studies, preferably MRI

–Bone biopsy for culture and histology

–Empiric treatment: (based on available

cultures) X 2–4 weeks then repeat X-rays

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Conclusions: Effects of DFI Guidelines

Better recognition of clinically infected ulcers

Better techniques for obtaining specimens for culture

# of cultured wounds

in number of bacteria/specimen

prevalence colonizers (23% →6%)

laboratory workload broad-spectrum antibiotic prescriptions

COST-SAVINGS 20,555 € 210,585 €

Decreased prevalence of MDRO (35%→16%)

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Systematic Review of Effectiveness of

Interventions for Managing DFIs: IWGDF

• 7517 papers; 33 met criteria; 29 RCTs; 4 cohort studies

• Comparisons antibiotic regimens: 12 for skin/soft-tissue,

7 for SSTI + bone infection: none showed difference

• 2 health economic analyses; 1 w/ small saving for 1 arm

• No data supported superiority of a particular route of

delivery or optimal duration of antibiotic therapy

• Possible benefit (weak studies): bone culture-guided

antibiotics; early surgical intervention; superoxidized

water; G-CSF

• No infection benefit shown for systemic HBO

Peters et al, Diabetes Metab Res Rev 2012 Feb;28 Suppl 1:142

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Systematic Reviews of Antibiotic Therapy RCTs of Treatment Diabetic Foot Inections

• 18 published RCTs comparing antibiotics

• Overall observed treatment failure rate: 23%

• Rates for direct comparison various agents similar

• Combining patients, failures with carbapenems

• Failure rates for MRSA (alone or mixed): 35%

• Rates similar +/- osteomyelitis: 26%

• Variations in study design, inclusion criteria,

definitions of clinical & microbiological endpoints

• Cannot determine most appropriate regimen

Vardakas et al, Diabetes Res Clin Pract 2008;80:344

Crouzet et al Int J Inf Dis 2011;15(9):e601-10

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Critical Review of Randomized Clinical Trials

of Antibiotic Therapy of DFI (1999-2009)

• From 123 papers found,14 were RCTs – 6 double-blind: 2 single-blind; 6 open-label

– 15 supported by pharmaceutical companies

– 12 excluded cases with osteomyelitis

• Duration follow-up: 1 wk to 2 months

• Discrepancies in study design, inclusion criteria,

statistical methodology, & varying definitions

of clinical & microbiological endpoints make

comparisons difficult

• Cannot determine most appropriate regimen

Crouzet et al Int J Inf Dis 2011;15(9):e601-10

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IDSA DFI Guidelines: Revised 2012

1. In which diabetic patients with a foot wound should I

suspect infection and how should I classify it?

2. How should I assess a diabetic patient presenting

with a foot infection?

3. When should I request a consultation for a patient

with a diabetic foot infection, and from whom?

4. Which patients with a diabetic foot infection should I

hospitalize, and what criteria should they meet

before I discharge them?

5. When and how should I obtain specimen(s) for

culture from a patient with a diabetic foot wound?

Lipsky et al, Clin Infect Dis (in press)

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IDSA DFI Guidelines: Revised 2012

6. How should I initially select, and when should I modify,

an antibiotic regimen for a diabetic foot infection?

7. When should I consider imaging studies to evaluate a

diabetic foot infection, and which should I select?

8. How should I diagnose and treat osteomyelitis of the

foot in a patient with diabetes?

9. In which patients with a diabetic foot infection should I

consider surgical intervention and what type of

procedure may be appropriate?

10. What types of wound care techniques and dressings

are appropriate for diabetic foot wounds?

Lipsky et al, Clin Infect Dis (in press)

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Randomized Antibiotic Trials for DFI Past 5 yrs • Linezolid (vs aminopenicillin/β-lactamase inhibitor)1

• Daptomycin (vs vancomycin or nafcillin) 2

• Moxifloxacin (vs pip/tazo or amoxicillin/clavulanate)3,3a,4a

• Ertapenem (vs piperacillin/tazobactam)4

• Piperacillin/tazobactam (vs ampicillin/sulbactam)5

• Pexiganan cream (vs oral ofloxacin)6

• Tigecycline (vs ertapenem)7

• Ceftobiprole (vs ceftazidime + vancomycin)8,8a

1Lipsky et al, Clin Inf Dis 2004;38:17;4Lipsky et al. Lancet 2005; 366:1695 2Lipsky et al, J Antimicrob Chemother 2005;55:240; 8aNoel et al (in prep) 3Lipsky et al, J Antimicrob Chemother 2007; 60:370 3aVick-Fragosos et al, Infection 2009 (epub Sept); 4aShaper, ECCMID ’10 5Harkless et al, Surg Infect (Larchmt) 2005;6:27;8Noel et al CID 2009;46 6Lipsky et al, Clin Inf Dis 2008;47:1537; 7Sabol et al, IDSA abst 2009

Clinical cure rates ~70-85% in all; no differences between agents

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OPIDA: Outcome of Hospitalized DFI Patients

• Prospective study 291 pts at 38 French hospitals • Most wounds on toes/forefoot; mostly “moderate”; 50%

osteomyelitis; ~60% PAD; mostly GPC (esp. S. aureus)

• Antibiotics IV in 49%; changed in 56% (mismatch)

• Outcomes – In hospital LEA in 35%; 52% good outcome

– 1 year after d/c for 150 non-amputated patients:

19% had amputation, 79% had healed wounds

• Independent risks amputation: toes; severity; osteo

• PAD: associated w/ poor prognosis; often neglected

• Overall 48% had LEA (despite specialized DFUs)

Richard et al, Diabetes Metab 2011;37:208

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Treating DFI: Approach Based on Infection Severity

Infection Hospitalization Initial Surgery Antibiotic Life/Limb Severity Required Antibiotic Consult Spectrum Threatening

Mild No Topical/Oral Rarely Narrow No

Moderate Occasionally Oral / IV Often, Broader Occasionally

elective (limb)

Severe Yes IV Usually, Very Yes

& urgent broad (limb & life)

Lipsky et al, IDSA revised guidelines, in preparation 2010

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General Approach to Antibiotic Therapy for

Diabetic Foot Infections

• Initial therapy: often empirical – best guess

- Can be narrow-spectrum if mild; broad if severe

- Alter based on clinical response & culture results

- Often do not need to treat all isolates

• Definitive therapy: to completion of course; based on

- Culture & sensitivity results, and

- Clinical response to empiric therapy

• Duration of therapy - 1-2 weeks for mild/moderate

- Longer only if slow to respond or bone infection

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Independent Risk Factors for Adverse Outcomes

in Diabetic Foot Infections

Outcome Associated Factor P value OR 95% CI

Resistant bacteria Prev amputation 0.018 7.2 1.4–34.0

Antibiotic w/n 30 d 0.032 3.8 1.1–12.8

Osteomyelitis Wound >4.5 cm2 0.041 2.8 1.0–7.5

Amputation Prev foot infection 0.005 7.0 1.8–26.7

Osteomyelitis 0.015 6.2 1.4–26.7

Failure of Treatment Resistant bacteria 0.016 5.3 1.4–20.7

Prospective study 96 hospitalized patients in Turkey

Ertugrul et al, Eur J Clin Microbiol Infect Dis 2012, e-pub Feb 22

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Expert Panel on Diabetic Foot Infections

Benjamin A. Lipsky, Chair

Anthony R. Berendt, Vice-Chair

Paul B. Cornia, James C. Pile, Edgar J.G. Peters,

David G. Armstrong, H. Gunner Deery, John

M. Embil, Warren S. Joseph, Adolf W.

Karchmer, Michael S. Pinzur, Eric Senneville

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Change in Format

• All new IDSA Guidelines must have standardized format (www.idsociety.org)

– Question

– Recommendations

– Evidence Summary

• Evidence is now summarized using the BMJ “GRADE” system

– Strength of recommendation (High, moderate, weak)

– Level of Evidence

– i.e. “Strong, Low”

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Grading of Recommendations Assessment,

Development and Evaluation (GRADE)

• Working Group began in 2000 as informal

collaboration to address shortcomings of

available grading systems in health care

• Developed a common, sensible & transparent

approach to grading

– Quality of evidence (high, moderate, low,

very low)

– Strength of recommendations (strong, weak)

• Many international organizations provided

input into the development & are using it

http://www.gradeworkinggroup.org

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Diabetic Foot Infection: Advice, circa 1980s

• Most diabetic foot ulcers are infected

• Hospitalize most patients with an infected ulcer

• Infections are almost always polymicrobial

• Initial antibiotic therapy should be parenteral

• Select a broad-spectrum antibiotic regimen

• Treat for weeks, until the wound heals

• Resect/amputate all infected bone

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Diabetic Foot Infections: 2010

• Only half of diabetic foot ulcers are clinically infected

• Only clinically infected ulcers need antibiotic therapy

• Properly obtained cultures are strongly recommended

• Likely more organisms that previously thought

• Narrow-spectrum (for GPCs) agents usually adequate

• Oral antibiotic therapy generally adequate

• Relatively short courses of therapy usually sufficient

• Surgical resection not needed for all osteomyelitis

• Antibiotics are necessary, but not sufficient

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Antimicrobial Therapy of DFI by Clinical Situation

Type Infection

Soft tissue

Route Location Duration

- Mild Oral Outpatient all 1-2 weeks

- Moderate/

- Severe

Oral (± init.

IV)

IV, switch po

Outpatient most

Inpatient all

2-3 weeks

Lipsky et al, IDSA Guidelines, Clin Inf Dis 2004;39:885

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Antimicrobial Therapy of DFI by Clinical Situation

Type Infection

Soft tissue

Route Location Duration

- Mild Oral Outpatient all 1-2 weeks

- Moderate/

- Severe

Oral (± init.

IV)

IV, switch po

Outpatient most

Inpatient all

2-3 weeks

Bone

- Resected IV or oral Inpatient→ outpt < 1 week

- Debrided IV or oral Inpatient→ outpt 4-6 weeks

- No surgery IV, then oral Outpatient ≥ 3 months

Lipsky et al, IDSA Guidelines, Clin Inf Dis 2004;39:885

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Special Concerns in Developing Countries

• Delayed treatment related to lack of money/access

• Limited availability of clinical microbiology testing

• Cost of antibiotics, surgery, adjunctive therapy

• Over-the-counter (non-prescribed) antibiotic therapy

– Need to educate patients, family

– ? Need to educate pharmacists

• Limited specialists (eg, podiatry, vascular surgery)

• Lack of availability or adherence to wound care

– Off-loading

– Dressings

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Overview: The New Guidelines on

Diabetic Foot Infections 2011 • IDSA Expert Panel Guidelines:

– 1st revision (since 2004) – New format: questions & evidence – GRADE system: quality & strength recommendations – Performance measures

• IWGDF Expert Opinion: – 1st revision (since 2004) – Incorporating IWGDF osteomyelitis review (2008) – Informed by systematic review of treatment (2011) – Specific guidelines: 2 page consensus document

• NICE (UK) Inpatient Diabetic Foot Management – Newly issued guidelines – Will highlight infection section

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Evaluating a Diabetic Patient with a Foot Wound

Check for sensation (monofilament)

Check arterial circulation (pulses, Dopplers)

Cleanse and debride ulcer (preferably surgically)

Evaluate for infection (pus, inflammation); if present obtain appropriate cultures + select antibiotic regimen

Probe wound (foreign bodies, bone?)

Consider need for: hospitalization; surgery

Adequately offload pressure; apply proper dressing

Set up appropriate follow-up

Educate patient/family about 2º prevention

Lipsky et al, IDSA DFI Guidelines, Clin Inf Dis 2004; 39:885

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Summary of General Approach to Antibiotic

Therapy for Diabetic Foot Infections • Initial therapy: usually empirical (best guess)

-Narrow spectrum for mild, no previous treatment

-Broad for severe, previously treated

• Definitive therapy: evidence based

- Based on clinical response & culture results

- Often do not need to treat all isolates

• Duration of therapy

- 1-2 weeks for most mild/moderate infections

- Longer only if slow to respond or bone infection

Adjunctive Tx: Antibiotics necessary but insufficient

- Wound care: debridement, off-loading, dressings

- HBO, G-CSF, negative-pressure, maggots