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

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

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

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

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

6. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Socio-economic importance  Foot problems account for largest number of bed days used by diabetic persons 1  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 1 Ramsey 1999 Incidence, outcomes and cost of foot ulcers in patients with diabetes. Diabetes Care 22:382-387

7. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford OutcomeAuthorCosts Primary ulcer healingBouter (1998)$10,000 (hospital) Apelqvist (1994)$7,000 (to healing) Healing with amputationConnor (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

8. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford The importance of infection  A major pathway to amputation 1  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) 1 Pecoraro RE, Reiber GE, Burgess EM. Pathways to diabetic limb amputation: basis for prevention. Diabetes Care 1990;13: 516-521

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

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

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

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 ischaemia 1 1 Berendt and Lipsky 2003, for FDA AIDAC

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

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

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)

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

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?

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

19. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Optimal sampling for diagnostic accuracy Poor relationship between superficial and deep microbiology 1 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 discouraged 2 1 Lipsky BA et al 1990 Arch Int Med 150:790-797 2 International Consensus on the Diabetic Foot, IWGDF, IDF, 1999

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

21. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Pathogenesis of Staphylococcal infection LagLogPost-exponential Adhesin genes on Toxin genes off Quorum sensing

22. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Quorum sensing Cyclic octapeptide agr Toxins RNA III Cyclic octapeptide

23. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Pathogenesis of Staphylococcal infection Adhesin genes off Toxin genes on Planktonic Mature biofilm Sessile LagLogPost-exponential Adhesin genes on Toxin genes off Quorum sensing

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.10 5 /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

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

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

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)

28. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford UninfectedNo erythema, purulence Mild0.5-2 cm erythema Superficial ulceration Minimal purulence Usually monomicrobial Moderate>2 cm erythema, e.g onto foot from toe Deeper ulceration, more purulence May have involvement of bone or joint, with necrosis or gangrene Mono- or polymicrobial SevereSystemic symptoms Often have deep ulceration, gangrene, fasciitis, necrosis, extensive soft tissue or bone involvement Usually polymicrobial

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

30. 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 bonemin 3 months

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

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

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

34. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Grade 1No symptoms of signs of infection

35. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Grade 2Infection 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 discharge Other causes of an inflammatory response of skin should be excluded (e.g. gout, acute Charcot neuro- osteopathy, venous stasis, fracture)

36. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Grade 3Erythema > 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.

37. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Grade 4Any 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

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

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

40. Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford Acknowledgements Ben Lipsky, VA, Seattle Carl Norden Karel Bakker, Netherlands Colleagues at Bone Infection Unit, Oxford