Bone Infection Unit, Nuffield Orthopaedic Cent re, Oxford FDA Anti-Infective Drugs Advisory Committee, FDA Anti-Infective Drugs Advisory Committee, October 2003 October 2003 Diabetic foot Diabetic foot infection: what infection: what remains to be remains to be discovered? discovered? Dr. Tony Berendt, BM, BCh, Dr. Tony Berendt, BM, BCh, FRCP FRCP Bone Infection Unit, Oxford Bone Infection Unit, Oxford
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
FDA Anti-Infective Drugs Advisory Committee, FDA Anti-Infective Drugs Advisory Committee, October 2003October 2003
Diabetic foot Diabetic foot infection: what infection: what remains to be remains to be discovered?discovered?Dr. Tony Berendt, BM, BCh, Dr. Tony Berendt, BM, BCh,
FRCPFRCPBone Infection Unit, OxfordBone Infection Unit, Oxford
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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 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 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 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 ulcerInternational Consensus on the Diabetic Foot, IWGDF, IDF, 1999
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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
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
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 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
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
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• 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
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 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
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
• 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
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
• 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
1Lipsky BA et al 1990 Arch Int Med 150:790-7972International Consensus on the Diabetic Foot, IWGDF, IDF, 1999
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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
Lag Log Post-exponential
Adhesin genes on
Toxin genes off
Quorum sensing
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Quorum sensing
Cyclic Cyclic octapeptoctapept
ideideagragr
Cyclic Cyclic octapeptoctapept
ideide
ToxinsToxinsRNRNA IIIA III
Cyclic Cyclic octapeptoctapept
ideide
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Pathogenesis of Staphylococcal infection
Adhesin genes off
Toxin genes on
Planktonic
Mature biofilm
Sessile
Lag Log Post-exponential
Adhesin genes on
Toxin genes off
Quorum sensing
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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
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• International Consensus on Diagnosing and
Treating the Infected Diabetic Foot (2003)• Clinical Practice Guidelines for Diabetic
Moderate >2 cm erythema, e.g onto foot from toeDeeper ulceration, more purulenceMay have involvement of bone or joint, with necrosis or gangreneMono- or polymicrobial
Severe Systemic symptomsOften have deep ulceration,gangrene, fasciitis, necrosis, extensive soft tissue or bone involvementUsually polymicrobial
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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
Bony ablation with no residual infected soft tissue
24-72 hrs
Bony ablation with residual infected soft tissue
2-4 wks
Non-ablative bony resection back to viable but potentially or definitely infected bone
4-6 wks
Retained dead bone min 3 months
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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• 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• Perfusion: Grades 1-3, in line with TASC
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Grade 1 No symptoms of signs of infection
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Grade 2 Infection involving the skin and subcutaneous tissue only, without involvement of deeper tissues or systemic signs. At least 2 of:•Local swelling or induration•Local warmth•Local tenderness or pain•Erythema 0.5-2 cm from ulcer margin•Purulent dischargeOther causes of an inflammatory response of skin should be excluded (e.g. gout, acute Charcot neuro-osteopathy, venous stasis, fracture)
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Grade 3
Erythema > 2 cm plus one of the items described above (swelling, tenderness, warmth, discharge) or
Infection involving structures deeper than skin and subcutaneous tissues such as abscess, osteomyelitis, septic arthritis, fasciitis.
No systemic inflammatory response signs as described below.
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Grade 4
Any foot infection with the following signs of a systemic inflammatory response syndrome (SIRS). This response is manifested by two or more of the following conditions: •Temperature > 38 or < 36°Celsius •Heart rate > 90 beats/min •Respiratory rate > 20 breaths/min •PaCO2 < 32 mmHg •White blood cell count > 12.000 or < 4.000/cu mm •10% immature (band) forms
Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
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• 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• Ben Lipsky, VA, Seattle• Carl Norden• Karel Bakker, Netherlands• Colleagues at Bone Infection