# Presentation: 093652

## Diabetic foot infection: what remains to be discovered?

**Diabetic foot infection: what remains to be discovered?**

**Dr. Tony Berendt, BM, BCh, FRCP**
**Bone 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

**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 ulcer**

- International 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 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**

- 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

## Slide 7

- 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)**

- 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

**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

**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 ischaemia****1**

- 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

**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 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**

- 1Lipsky BA et al 1990 Arch 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

**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

- Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

## Quorum sensing

- Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

## Pathogenesis of Staphylococcal infection

**Planktonic**

- 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**

- 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

**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 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

**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

| Uninfected | No erythema, purulence |
| --- | --- |
| Mild | 0.5-2 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 |
| Severe | Systemic symptoms
Often have deep ulceration,
gangrene, fasciitis, necrosis, extensive soft tissue or bone involvement
Usually 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

**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

**P****erfusion: Grades 1-3, in line with TASC**
**Grade 1 apparently normal; Grade 2 non-critical ischaemia; Grade 3 Critical limb ischaemia**
**E****xtent/Size: In square centimetres.  **
**Report ulcer sizes in study group in quartiles**
**D****epth/Tissue loss: Grades 1-3**
**Grade 1 dermis only; Grade 2 subcutaneous tissue, muscle and tendon; Grade 3 involves bone or joint**
**I****nfection: Grades 1-4**
**S****ensation: Grades 1 and 2**
**Grade 1 protective sensation present; Grade 2 protective sensation absent**

- Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

## Slide 34

| Grade 1 | No symptoms of signs of infection |
| --- | --- |

- Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford

## Slide 35

| 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 discharge
Other 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

## Slide 36

| 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

## Slide 37

| 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 Unit, Oxford**

- Bone Infection Unit, Nuffield Orthopaedic Centre, Oxford