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Slide 1 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford FDA Anti-Infective Drugs Advisory Committee, October 2003 Diabetic foot infection: what remains to be discovered? Dr. Tony Berendt, BM, BCh, FRCP Bone Infection Unit, Oxford
Slide 2 - 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
Slide 3 - 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
Slide 4 - 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
Slide 5 - 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 ulcer International Consensus on the Diabetic Foot, IWGDF, IDF, 1999
Slide 6 - 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
Slide 7 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 8 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford 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
Slide 9 - 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
Slide 10 - 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
Slide 11 - 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
Slide 12 - 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
Slide 13 - 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
Slide 14 - 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
Slide 15 - 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)
Slide 16 - 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
Slide 17 - 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?
Slide 18 - 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
Slide 19 - 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 150:790-797 2International Consensus on the Diabetic Foot, IWGDF, IDF, 1999
Slide 20 - 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
Slide 21 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Pathogenesis of Staphylococcal infection
Slide 22 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Quorum sensing
Slide 23 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Pathogenesis of Staphylococcal infection Planktonic
Slide 24 - 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
Slide 25 - 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
Slide 26 - 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 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
Slide 27 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford 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)
Slide 28 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 29 - 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
Slide 30 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Osteomyelitis: antibiotic treatment planning
Slide 31 - 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
Slide 32 - 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
Slide 33 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford 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
Slide 34 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 35 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 36 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 37 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford
Slide 38 - 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
Slide 39 - 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
Slide 40 - Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Acknowledgements Ben Lipsky, VA, Seattle Carl Norden Karel Bakker, Netherlands Colleagues at Bone Infection Unit, Oxford