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Diabetic foot infection: what remains to be discovered?. Dr. Tony Berendt, BM, BCh, FRCP Bone Infection Unit, Oxford. FDA Anti-Infective Drugs Advisory Committee, October 2003. Take home messages. Despite considerable advances, there is much we do not know about diabetic foot infection

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slide1

Diabetic foot infection: what remains to be discovered?

Dr. Tony Berendt, BM, BCh, FRCP

Bone Infection Unit, Oxford

FDA Anti-Infective Drugs Advisory Committee, October 2003

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

take home messages
Take home messages
  • Despite considerable advances, there is much we do not know about diabetic foot infection
  • Expert consensus guidance does not fully compensate for a dearth of optimally-conducted studies, which have left many unanswered questions
  • There is an urgent need for standardised definitions of infection in the diabetic foot
    • To permit multi-centre studies
    • To permit comparison between different studies

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

overview
Overview
  • Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide4
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

epidemiology
Epidemiology
  • 250 million diabetics by 2025
  • 2-5% of diabetics develop foot ulcer annually
  • Point prevalence of ulceration estimated at 4-10%
  • 40-60% of all non-traumatic lower extremity amputations are in diabetics
  • 85% of these preceded by foot ulcer

International Consensus on the Diabetic Foot, IWGDF, IDF, 1999

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

socio economic importance
Socio-economic importance
  • Foot problems account for largest number of bed days used by diabetic persons1
  • Average length of stay if hospitalised and have foot ulcer is 30-40 days (50% longer than if no ulcer)
  • 77% of >75 yrs old undergoing amputation in USA do not return to independent living
  • Studies have shown it may be cheaper to save a limb than to amputate

1Ramsey 1999 Incidence, outcomes and cost of foot ulcers in patients with diabetes. Diabetes Care 22:382-387

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide7

Outcome

Author

Costs

Primary ulcer healing

Bouter (1998)

$10,000 (hospital)

Apelqvist (1994)

$7,000 (to healing)

Healing with amputation

Connor (1987)

$14,000 (hospital)

Bouter (1988)

$15,000 (hospital)

Bild (1989)

$8-12,000 (hospital)

Reiber (1992)

$20-25,000 (incl. rehab)

Thompson (1993)

$11,000 (hospital)

Apelqvist (1994)

$43-65,000 (to healing)

Van Houtum (1995)

$14,500 (hospital)

Long term costs (3 years)

Apelqvist (1995)

Primary healing

Healing with amputation

$16,100-26,700

$43,100-63,100

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

the importance of infection
The importance of infection
  • A major pathway to amputation1
  • A contributor to soft tissue loss
  • A reason for delayed wound healing
  • A cause of acute or chronic systemic effects (decompensated diabetes, septicaemia; malaise; cachexia)

1Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for prevention. Diabetes Care 1990;13: 516-521

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide9
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

clinical spectrum
Clinical spectrum
  • With intact soft tissue
    • Cellulitis
    • Primary musculoskeletal infection
  • Complicating ulceration
    • Paronychia
    • Infected ulcer
    • Cellulitis
    • Abscess formation
    • Chronic septic arthritis and osteomyelitis
    • Necrotising fasciitis, myositis, gangrene, septicaemia

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide11
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

definition of diabetic foot infection
Definition of Diabetic foot infection

A: Any infection (as defined by International Consensus) involving the foot (below the malleoli) in a person with diabetes

B: Any infection (as defined by International Consensus) involving the foot (below the malleoli) in a person with diabetes originating in a chronic or acute injury to the soft tissue envelope of the foot, with evidence of pre-existing neuropathy and/or ischaemia1

1Berendt and Lipsky 2003, for FDA AIDAC

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

justification
Justification
  • Neuropathy is the dominant cause of skin breaches in the feet of persons with diabetes
  • Clinical features of the majority of infections in diabetics support a “contiguous focus” model
  • The presence of ischaemia has a major bearing on the outcome of infection
  • Effective foot care services have a proven impact on amputation rates
  • No evidence that outcomes in non-neuropathic, non-ischaemic diabetic patients differ from those in non-diabetic patients

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide14
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

diagnosis
Diagnosis
  • Infection: multiplication and invasion of pathogens in host tissue, usually with an inflammatory response
  • Colonisation: non-invasion association of bacteria with a particular site
  • Contamination: abnormal presence of micro-organisms in a site (or sample)

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

diagnosing infection in a diabetic foot ulcer
Diagnosing infection in a diabetic foot ulcer
  • Clinical
    • Systemic signs of infection
    • Local signs or symptoms of infection
    • Should also suspect if gangrene, necrosis or foetid odour
  • Laboratory
    • Specificity depends upon co-morbidities
  • Imaging
    • Role in identifying collections and osteomyelitis

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

controversies over clinical diagnosis
Controversies over clinical diagnosis
  • How to diagnose infection in the context of acute Charcot neuro-osteopathy, gout, and other common comorbidities that can produce inflammation of skin?
  • Does ischaemia reduce inflammatory response enough to give false-negative signs?
  • Do clinical criteria allow us reliably to distinguish an infected from an uninfected ulcer?

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

microbiological diagnosis
Microbiological diagnosis
  • Easy to interpret
    • Culture of pus from an abscess, or positive reliable culture from a “sterile site”, e.g. muscle, tendon sheath, bone (if sampled correctly)
  • Difficult to interpret
    • Culture from an ulcer
    • Culture from necrotic tissue unless in a closed space

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

optimal sampling for diagnostic accuracy
Optimal sampling for diagnostic accuracy
  • Poor relationship between superficial and deep microbiology1
  • Debride ulcer, expose tissue at base
  • Aspirate pus if present; curette ulcer base with sterile instrument
  • Obtained deep samples though an uninfected [ideal] or debrided field wherever possible
  • Swabs, cultures of sinuses, or of exposed slough/necrosis discouraged2

1LipskyBA et al 1990Arch Int Med 150:790-797

2International Consensus on the Diabetic Foot, IWGDF, IDF, 1999

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

controversies over microbiological diagnosis
Controversies over microbiological diagnosis
  • Whether swabs from the base of a debrided ulcer are acceptable
  • Whether all microrganisms identified from reliable samples need to be treated
  • Whether quantitative microbiology can do any better than clinical judgement in diagnosing actual or incipient infection

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

pathogenesis of staphylococcal infection

Quorum sensing

Adhesin genes on

Toxin genes off

Lag

Log

Post-exponential

Pathogenesis of Staphylococcal infection

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

quorum sensing

RNA III

Toxins

Cyclic octapeptide

Cyclic octapeptide

agr

Cyclic octapeptide

Quorum sensing

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

pathogenesis of staphylococcal infection1

Quorum sensing

Adhesin genes on

Toxin genes off

Adhesin genes off

Toxin genes on

Lag

Log

Post-exponential

Sessile

Mature biofilm

Pathogenesis of Staphylococcal infection

Planktonic

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

bioburden infected and uninfected wounds
Bioburden, infected and uninfected wounds
  • Some evidence that in acute wounds or burns, there is a transition between colonisation and infection at bacterial numbers of c.105/g
  • No evidence for this in chronic wounds or diabetic foot
  • Some evidence of inter-species interference in Staphylococcal quorum sensing, which might attenuate even high pathogen loads in mixed wound flora

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide25
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

clinical guidelines
Clinical guidelines
  • International Consensus on Diagnosing and Treating the Infected Diabetic Foot (2003)
  • Clinical Practice Guidelines for Diabetic Foot Infections, IDSA (expected 2003)
  • International, multidisciplinary expert panels with clinical representation from academia and government health services
  • Consensus process
  • Unable to grade recommendations due to overall quality of studies and problems of definition

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

approach to infection
Approach to infection
  • In view of varied clinical spectrum, simple clinical classification and approach
  • Assessment of whole patient, limb, foot, ulcer
  • Assessment of severity of infection
    • Mild (superficial)
    • Moderate (limb threatening)
    • Severe (life threatening)

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

duration of antimicrobial therapy
Duration of antimicrobial therapy
  • No good data
  • Mild 1-2 weeks
  • Moderate 2 to 4 weeks, unless osteomyelitis
  • Severe: soft tissue up to 4 weeks unless osteomyelitis
  • Osteomyelitis: depends on degree of resection

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

osteomyelitis antibiotic treatment planning
Osteomyelitis: antibiotic treatment planning

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

slide31
Epidemiology and importance of infection
  • Clinical spectrum
  • Defining diabetic foot infection
  • Diagnosing diabetic foot infection
  • Where has expert opinion got to?
    • Clinical guidelines
    • Classification scheme for research purposes

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

pedis ulcer classification scheme for research purposes
PEDIS: Ulcer classification scheme for research purposes
  • Proposed by the International Consensus on the Management and Prevention of the Diabetic Foot
  • Intended to be specific rather than sensitive
  • Should allow multi-centre and comparative studies
  • Should allow categorisation of cases and description of casemix

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

pedis classification
PEDIS Classification
  • Perfusion: Grades 1-3, in line with TASC
    • Grade 1 apparently normal; Grade 2 non-critical ischaemia; Grade 3 Critical limb ischaemia
  • Extent/Size: In square centimetres.
    • Report ulcer sizes in study group in quartiles
  • Depth/Tissue loss: Grades 1-3
    • Grade 1 dermis only; Grade 2 subcutaneous tissue, muscle and tendon; Grade 3 involves bone or joint
  • Infection: Grades 1-4
  • Sensation: Grades 1 and 2
    • Grade 1 protective sensation present; Grade 2 protective sensation absent

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

what needs to be discovered
What needs to be discovered?
  • Robust definitions and classification (includes need to rationalise diagnostics)
  • Role of antimicrobials in “uninfected” ulcers and in wound healing
  • Duration of treatment for soft tissue and bone infection
  • Role of surgery in osteomyelitis
  • Cost effectiveness of limb salvage in complex ischaemia/soft tissue loss/bone infection

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

conclusions
Conclusions
  • Some progress in general understanding and in consensus on diagnosis and treatment
  • Difficulties in generating highly specific definitions and classifications; potential lack of relationship to “real world”
  • PEDIS classification may help identify casemix in studies
  • Further development of consensus definitions, e.g. of osteomyelitis, would be valuable
  • Changing practice in treatment of osteomyelitis may make inclusion in some trials more possible

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

acknowledgements
Acknowledgements
  • Ben Lipsky, VA, Seattle
  • Carl Norden
  • Karel Bakker, Netherlands
  • Colleagues at Bone Infection Unit, Oxford

Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford