Diagnosis and management of cellulitis

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e4955 (Published 7 August 2012)
Cite this as: BMJ 2012;345:e4955

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Bilateral cellulitis of the legs: does it exist?

The clinical review by Phoenix and co-authors of the diagnosis and management of cellulitis (1) was comprehensive in all respects excepting that, perhaps quite reasonably, it omitted mention of the phenomenon of ‘bilateral cellulitis’, a diagnosis of doubtful validity. It is by no means unusual to be asked to review a patient with two uncomfortable, red legs receiving intravenous antibiotic therapy following a presumed diagnosis of bilateral cellulitis. As this excellent review mentioned, cellulitis of the legs can be easily confused with florid varicose eczema and contact dermatitis, although in both instances there will usually be obvious epidermal changes that may serve to distinguish them from cellulitis.

More problematic, however, is the occurrence of lipodermatosclerosis, a sclerosing panniculitis consequent on venous insufficiency. The chronic form of this common condition presents as pigmented, indurated, bound-down skin over the gaiter regions, classically resulting in an ‘inverted champagne bottle’ shape to the leg. The acute phase of lipodermatosclerosis, however, is characterized by inflamed, painful skin over and proximal to the malleolar regions, which can readily be mistaken for cellulitis (2). These potential mimics of cellulitis of the leg are frequently, although not necessarily, bilateral, whereas cellulitis itself, usually caused by Staphylococcus aureus or Group A Streptococcus, organisms that are not known for their sense of symmetry, is invariably unilateral.

Cellulitis involving both legs synchronously probably can occur as a chance happening, but it must be almost as common as hens’ teeth, and a sound clinical diktat is that if a patient appears to have bilateral cellulitis of the legs they probably do not!

1. Phoenix G, Das S, Joshi M. Diagnosis and management of cellulitis.
BMJ 2012;345:38-42.

2. Miteva M, Romanelli P, Kirsner RS. Lipodermatosclerosis.
Dermatol Ther. 2010;23:375-88

Competing interests: None declared

Michael J. Tidman, Consultant Dermatologist

Royal Infirmary of Edinburgh, Department of Dermatology, Lauriston Building, Edinburgh, EH3 9HA,

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As a microbiologist, I would like to comment that the article did not mention orbital cellulitis. This potentially serious infection requires antibiotic cover for a mixture of possible causative organisms, including anaerobes. Also, H.influenzae Pittman type b was not included as a possible cause of periorbital cellulitis, particularly in children who have not had Hib vaccine. It will not respond to penicillin &/or flucloxacillin

Competing interests: None declared

Elizabeth H Price, retired microbiologist

Retired, Middleway, London

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I read this article with interest. I have just been dealing with a relevant case indicating difficulty in differential diagnosis. This was a 52 year old woman who had been in hospital for over a week under the care of general physicians with a diagnosis of a possible infected knee joint and prepatellar bursa and cellulitis of the lower leg. There was no fever at any time. The CRP was 145 mg/L and the WBC was 13.0 with a neutrophilia. Urate was normal at 0.09 mmol/L. Blood cultures were negative. Fluid was not withdrawn from the knee or the bursa. She had been seen by orthopaedic surgeons but not by a rheumatologist. She was treated with intravenous clindamycin with no significant effect, and after her discharge, still on oral antibiotics, I was called in to see her. The history was of a painful knee developing over a day to extreme pain with a lot of swelling, with no injury or obvious cause, followed within a day by painful swelling of the whole of the lower leg with skin erythema. On examination the knee and prepatellar bursa were swollen and painful, there was a tender popliteal cyst, and the lower leg was very swollen and erythematous.

As she told me the story I realised she was describing an acute attack of gout with a burst popliteal cyst, and I then found that her father had gout. Doppler studies after her discharge had ruled out a deep vein thrombosis. All the blood test results are compatible with acute gout, including the normal urate.

The pain and swelling of the knee rapidly resolved on treatment with diclofenac 50 mg four times daily (with a stomach protective), and the swelling and erythema of the lower leg gradually went away with the help of elevation and an elastic stocking. Strikingly, the skin over the front and sides of the knee peeled off massively during recovery, which of course is typical of gout and would not be expected after an infection.

Acute arthritis is quoted as a possible differential diagnosis in the article, and this case demonstrates that acute gout must certainly be considered.

Patient consent obtained.

Competing interests: None declared

Michael F. Grayson, Consultant rheumatologist

Private practice, Royal National Orthopaeduc Hospital, Royal National Orthopaedic Hospital, 45 Bolsover Street, London W1W 5AQ

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We thank Dr Rae, Dr Logan, Dr Martin, Dr Swann and Mr Kelley for pointing out the errors in our review, which have now been corrected.

We agree with Dr Rae that infectious disease specialists play an integral role in the management of patients with cellulitis, especially the more difficult cases. Microbiologists, and many other specialties including emergency department physicians and other healthcare professionals, such as specialist nurses, whom pay an integral part in the ambulatory management of many patients with cellulitis, should also be acknowledged. The list of specialists is endless, reflecting the ‘orphan’ nature of the condition; Kilburn et al (2003), in their recent cochrane review, mention the need for a ‘multiciplinary’ approach to treatment.[1]

It is impractical to distinguish between streptococcal and staphylococcal cellulitis, as stated by Dr Rae and Dr Logan. As mentioned in our review, Flucloxacillin (and not Amoxicillin, as incorrectly mentioned in our review) should be used to cover both or when the organism is unknown. However, when organisms are isolated, especially as the case for CA-MRSA, antibiotics may need to be tailored accordingly.

We agree with Dr Rae that in patients with a clinical suspicion of Necrotizing Fasciitis, surgical debridement should not be delayed, especially in those that are systemically unwell or haemodynamically unstable. However, a clinical diagnosis for Necrotizing Fasciitis is not always straightforward and in type B and type C infections, in which the onset is more insidious, MRI can confirm or refute diagnosis, as well as demarcating the extent of disease. [2]

As Dr Logan also mentions, investigations are often negative and identification of an organism is problematic; the review supports this statement and recommendations based on national guidelines have been mentioned.

Dr Halpern opinion that diabetes is not a risk factor is supported by higher evidence than the anecdotal and case series that support an association in our review. We have mentioned, however, that there is no evidence to suggest active management of diabetes, improves cellulitis recurrence; a more significant point in our opinion. [1] Furthermore, we did not find evidence supporting the active management of T.Pedis in reducing recurrence of cellulitis as well, including in the references stated by Dr Halpern. As mentioned, further research is required into the effect of treating predisposing factors and the impact on cellulitis, such as recurrence rates or duration of cellulitis symptoms or signs. [3]

We agree wholeheartedly with Dr Duncan regarding OPAT services; a service that has been shown by numerous studies to be both cost-effective and clinical-effective. The UK study referenced in our review acknowledges this but it also states that not all areas in the UK offer comprehensive OPAT services as of yet. We are sure this will soon change.

Dr Basak mentions the efficacy of Co-trimoxazole for CA-MRSA; Trimethoprin-Sulfamethoxazole has also been demonstrated to have good efficacy. [4] No national guidance thus far supports a single antibiotic for CA-MRSA.

We would like to point out to Dr Gada that many of the mentioned points have been addressed in the review already, which encompass both primary and secondary care. A step-by-step approach in regards to antibiotic treatment options is not currently possible on a national scale, (although we also have reccomended the use of Flucloxacillin when the organism is unknown); this may reflect the lack of strong evidence for an optimal antibiotic regime(s) [1], the multiple organisms that can cause cellulitis including new strains, and or differing local resources.

1. Kilburn S, Featherstone P, Higgins B, Brindle R, Severs M (2003) Interventions for cellulitis and erysipelas (Protocol). Cochrane Database System Rev 1: CD004299. DOI:10.1002/14651858. CD004299.

2. Carter PS, Banwell PE. Necrotising fasciitis: a new management algorithm based on clinical classification. Int Wound J 2004;1:189—198.

3. Phoenix G, Das S, Joshi M. Diagnosis and management of cellulitis. BMJ 2012;345:e4955. (7 August.)

4. Pappas G, Athanasoulia AP, Matthaiou DK, Falagas ME. Trimethoprim-sulfamethoxazole for methicillin-resistant Staphylococcus aureus: a forgotten alternative? J Chemother. 2009 Apr;21(2):115-26.

Competing interests: None declared

Gokulan K Phoenix, Core Surgical Trainee

Meera Joshi, Saroj Das

Chelsea and Westminster Hospital, 369 Fulham Road, London, SW10 9NH

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I read with interest the article written by Phoenix et al, it is a good article, but it lacks some detail.
As I work as a GP, I can write my views from Primary care side. I do feel that majority of the cases of cellulitis and skin & subcutaneous infections are managed in primary care by GPs. Only minority of patients with cellulitis are referred to secondary care for further management (either because of cases not responding to the drugs used, patients becoming septic, cellulitic patch spreading, patients request, etc). The commonest drug used in primary care for cases of cellulitis is flucloxacillin (in those who are not allergic to penicillin). It will be good to come up with list of common microbes causing cellulitis, common risk factors (modifiable and non-modifiable) and guidelines with step by step choice of antibiotics to be used. Number of cases of skin infections / cellulitis, seen in primary care should be easily calculated as almost all surgeries now are computerized. We look forward to see an article in future encompassing cases of cellulitis both covering primary and secondary care.

Competing interests: None declared

Siddappa Gada, GP

Holbrook & Shotley surgery, Ipswich

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Phoenix et al refer to the potential use of parenteral out patient antibiotic therapy (OPAT) “when available”. In fact clinical practice in the UK has progressed to the point that OPAT services are now specifically developed for this often ambulant and clinically stable patient population. Recent Department of Health guidance on antimicrobial stewardship in hospitals (“Start smart then focus”) has highlighted OPAT as one of the five antimicrobial prescribing options. [1]

Two main models of OPAT exist in the UK: as an integral part of an infection specialist led service, or as part of broader emergency department-focussed ambulatory care (also known as hospital at home). In the UK cellulitis is the most common indication for OPAT, and the majority of patients are managed without prior hospital admission. [2] For the last 12 years we have provided OPAT services to people with cellulitis referred directly from the community or emergency departments, and have treated over 1300 patients with excellent clinical outcomes. [3] In our practice, patients with cellulitis referred by a medical practitioner are assessed for suitability by a specialist nurses follow a clinical protocol and patient group direction. Specialist nurses make daily assessments for complications, progression, adverse events and suitability for IV to oral switch. [4] Using this care pathway we have shown, for uncomplicated cellulitis needing IV therapy, that nurse-led management of cellulitis via OPAT is both safe and importantly is associated with reduction in overall IV antibiotic exposure, [4] a key antimicrobial stewardship outcome. [1]

Careful patient assessment with appropriately trained staff and care pathways are essential for managing cellulitis through OPAT. This practice is supported by recently published OPAT good practice recommendations, which we commend to clinicians considering developing such a service. [2] Specifically in cellulitis, risk assessment is critical for determining OPAT suitability, and there are patient factors (e.g. diabetes) and disease factors (e.g. bursitis or MRSA infection) that may be associated with longer courses of IV therapy or poorer OPAT outcomes. [5] As well as the UK practice recommendations, US guidelines for appropriate patient selection are a useful resource for clinicians developing OPAT services. [6]

References:

1. Antimicrobial stewardship: Start smart - then focus. Department of Health, 16853, 17 Nov 2011.

2. Chapman AL, Seaton RA, Cooper MA, Hedderwick S, Goodall V, Reed C, et al. Good practice recommendations for outpatient parenteral antimicrobial therapy (OPAT) in adults in the UK: a consensus statement. J Antimicrob Chemother 2012;67(5):1053-62.

3. Barr DA, Semple L, Seaton RA. Outpatient parenteral antimicrobial therapy (OPAT) in a teaching hospital-based practice: a retrospective cohort study describing experience and evolution over 10 years. Int J Antimicrob Agents 2012;39(5):407-13.

4. Seaton RA, Bell E, Gourlay Y, Semple L. Nurse-led management of uncomplicated cellulitis in the community: evaluation of a protocol incorporating intravenous ceftriaxone. J Antimicrob Chemother 2005;55(5):764-7.

5. Seaton RA, Sharp E, Bezlyak V, Weir CJ. Factors associated with outcome and duration of therapy in outpatient parenteral antibiotic therapy (OPAT) patients with skin and soft-tissue infections. Int J Antimicrob Agents 2011;38(3):243-8.

6. Tice AD, Rehm SJ, Dalovisio JR, Bradley JS, Martinelli LP, Graham DR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004;38(12):1651-72.

Competing interests: None declared

Christopher J.A. Duncan, Specialty Registrar

Andrew Seaton

Gartnavel General Hospital, Glasgow, 1053 Great Western Road, Glasgow G12 0YN

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We welcome the review of cellulitis diagnosis and management by Phoenix et al.(1) In addition to the comments made by our infection colleagues we would like to the highlight some of the key issues faced by clinicians who manage this infection regularly and several recent changes in practice that the authors have not mentioned.
The number of hospital admissions in England in 2008/9 was 14,152,692, of which 82,113 were for cellulitis. In addition hospital visits for abscesses and cellulitis in the paper quoted increased from 17.3 to 32.5 visits per 1000 population, a ten fold difference to that quoted by Phoenix et al.(1,2)
Multiple studies have demonstrated that streptococci rather than staphylococci are the commonest cause, in contrast to the one review quoted in the paper. (3,4,5,6) The table in the review mentions some of the rarer pathogens and associated risk factors. It is important to say that even in the context of these risk factors streptococci and staphylococci are usually the major culprits. Identification of an organism is often problematic as blood cultures are often negative and skin biopsies are confounded by skin colonisation. Empiric treatment should still treat the commonest organisms.
Community-acquired (CA)-MRSA has not emerged in the UK and Europe, unlike the US, (7) as a significant pathogen and empiric treatment should remain Flucloxacillin or other similar beta-lactam antibiotics at present in these countries.
Of particular concern in the review was the management of necrotising fascitis. This is commonly caused by beta–haemolytic streptococci,usually Group A streptococci; anaerobes and Gram-negative organisms are also important, particularly if the site is below the umbilicus. Diagnosis is clinical and surgical debridement should not be delayed by imaging as the authors suggest. (8,9)
Upper limb, torso and facial cellulitis have very different aetiologies to that of the lower limb and are often more serious. The management of these varies considerably and involvement of a specialist should be sought early.
The provision of outpatient parenteral antimicrobial therapy (OPAT) for the follow-up of inpatient care has been well established.(10) However, from April 2011 provision of an ambulatory care pathway for cellulitis became one of the clinical quality indicators for all Emergency Departments in acute trusts (11).
This expects acute hospital trusts to develop and implement pathways for patients who have failed on oral antibiotics or where the infection is deemed more severe to access intravenous antibiotics and specialist input without being admitted to hospital. This is a key change in approach to managing cellulitis. In our trust the pathway has been running for 16 months. There are clear exclusion criteria relating to co-morbidity, signs of systemic sepsis, and site of cellulitis, those patients are admitted. Patients on the pathway receive one to three days of intravenous therapy with ceftriaxone and are reviewed daily by an Emergency Physician. Once stabilised the patients then complete the treatment with appropriate oral agents. The pathway was developed by the Emergency Department and Infectious Diseases teams. One hundred and thirty one patients were treated on the pathway over one year. The age range was 18-91 years. The median treatment course with once daily ceftriaxone was 2 days (range 1-6 days). Sixteen (12.1%) patients subsequently required hospital admission for a median of 3 days (range 1-7 days). Fifteen (93.4%) of these patients were admitted as they had not responded appropriately to ambulatory care pathway - with progressive infection (12), development of bursitis (2), and the development of abscess (1). Only one other patient was admitted in the subsequent 28 days with a fractured ankle.

Based on this data the introduction of a multidisciplinary pathway with access to Infectious Diseases physicians, and other experts can safely maintain many patients on an ambulatory care pathway. We estimate that we have saved the hospital more than £150,000 in in-patient bed stays based on days treated on the ambulatory care pathway.
Ambulatory care pathways, with increased input from infection doctors and other specialist services are all set to improve the experience of patients with cellulitis. It is important that clinicians are aware of all the options available for management of this challenging, common condition.

1) Phoenix G, Das S, Joshi M. Diagnosis and management of cellulitis. BMJ 2012;345:e4955.
2.) Hersh AL, Chambers HF, Mseli JH, Gonzales R. National trends in ambulatory visits and antibiotic prescribing for skin and soft tissue infections. Arch Intern Med 2008; 168:1585-91.
3.)Peralta G, Padrón E, Roiz MP, De Benito I, Garrido JC, Talledo F, Rodríguez-Lera MJ, Ansorena L, Sánchez MB.Risk factors for bacteremia in patients with limb cellulitis.Eur J Clin Microbiol Infect Dis. 2006;25(10):619.

4.)Bernard P, Bedane C, Mounier M, Denis F, Catanzano G, Bonnetblanc JM. Streptococcal cause of erysipelas and cellulitis in adults. A microbiologic study using a direct immunofluorescence technique.
Arch Dermatol. 1989;125(6):779.

5.)Semel JD, Goldin H. Association of athlete's foot with cellulitis of the lower extremities: diagnostic value of bacterial cultures of ipsilateral interdigital space samples. Clin Infect Dis. 1996;23(5):1162.

6.)Chira S, Miller LG. Staphylococcus aureus is the most common identified cause of cellulitis: A systematic review. Epidemiol Infect 2010; 138:313-7.
7.)Kock R, et al. Methicillin-resistant Staphylococcus aureus (MRSA): burden of disease and control challenges in Europe. Euro Surveill. 2010 Oct 14;15(41): 19688

8.)Brook I, Frazier EH.Clinical and microbiological features of necrotizing fasciitis.J Clin Microbiol. 1995;33(9):2382.

9.)Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, Low CO Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality.J Bone Joint Surg Am. 2003;85-A(8):1454.

10.)Barr DA, Semple L, Seaton A. Outpatient parenteral antimicrobial prescribing in a teachin hospital- based practice: A retrospective cohort study describing expererience and evolution over 10 years. Int J of Antimicrob Agents 39 (2012) 407-413
11.)http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/@dh/@en/@ps/documents/digitalasset/dh_122892.pdf

Competing interests: None declared

Sarah Logan, Infectious Disease specialist registrar

Marieke Bokhoven, Tara Sood, Susan Hopkins

Royal Free Hospital, Pond Stree. London NW3 2QG

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We read with interest the article by Pheonix et al on the diagnosis and management of cellulitis.1 As Infectious Diseases physicians, interestingly not mentioned on the list of specialists who treat cellulitis given in the article, we wish to point out some important areas where we disagree with the authors, some of which are errors.

1) Clostridium perfringens classically causes so-called “gas gangrene”, a rapidly progressive infection often associated with vascular compromise due to severe penetrating trauma or crush injuries.2 Necrotising fasciitis is often polymicrobial, with common causes including group A streptococci, Staphylococcus aureus and anaerobes. Rare causes, often in the immunocompromised, include Aeromonas hydrophilia and Vibrio vulnificus.2

2) Clinically distinguishing between streptococcal and staphylococcal cellulitis is often impossible. Recommending different treatment based on this distinction is not helpful in clinical practice. All cases of cellulitis should be treated with an antibiotic with anti-staphylococcal activity, thus amoxicillin would be inappropriate therapy. This is supported by both CREST and IDSA guidelines,2,3 in contrast to the authors’ incorrect statement that amoxicillin is recommended empirical treatment in the CREST guidance.

3) Ciprofloxacin appears to have been misspelled "ciprofloxacillin".

4) Confirmed erysipeloid (caused by Erysipelothrix rhusiopathiae) should be treated with a penicillin, such as amoxicillin, as opposed to ciprofloxacin.2

5) Cross-sectional imaging is not essential in the diagnosis of necrotising fasciitis, which is mainly clinical. Delays in obtaining imaging may lead to significant deterioration and delay in definitive surgical treatment.2,3

References
1] Phoenix G, Das S, Joshi M. Diagnosis and management of cellulitis. BMJ 2012;345:e4955.
2] Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJC, et al. Practice Guidelines for the Diagnosis and Management of Skin and Soft-Tissue Infections. Clin Infect Dis. 2005; 41:1373–406
3] DHSS Northern Ireland. CREST (Clinical Resource Efficiency Support Team) Guidelines on the Management of Cellulitis In Adults. 2005; 1–31.

Competing interests: None declared

Nikolas Rae, ST3 infectious diseases

Charis Marwick consultant infectious diseases

Ninewells Hospital, Dundee DD1 9SY

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Unfortunately there is a further microbiological error in this piece. The authors quote the CREST guidelines with regard to antibiotic treatment. The quotation is wrong as the CREST guidelines do not mention amoxicillin at all. Amoxicillin is ususally inactive against Staphyloccus aureus. The CREST guidance in fact suggests flucloxacillin - an agent with good activity against both beta-haemolytic streptococci and S. aureus, the two commonest pathogens causing cellulitis.

Competing interests: None declared

Andrew Swann, Consultant Microbiologist

University Hospitals of Leicester, Infirmary Square, Leicester, LE1 5WW

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Dear Sir/Madame,

We would like to congratulate Phoenix et al., on their paper. However with regards to the micro-organisms causing necrotising fasciitis the only causative agent mentioned is C. Perfringes. However the list of potentially causative bacteria is far greater and C. Perfringes is not the sole or even leading cause. It is therefore misleading and we would suggest that that the more common cause, synergistic infection involving streptroccus to be highlighted. Below is a more comprehensive classification of necrotising fasciitis:

Class I Polymicrobial
Class II Monomicrobial of which group A streptocci are the most common
Class III Gram Negative Bacteria including C. Perfringes
Class IV Fungal

This broad array of potentially causative micro-organisms has implications upon the choice of first line antibiotics for the clinician.

Barker FG, Leppard BJ, Seal DV Streptococcal necrotising fasciitis: comparison between histological and clinical features. J Clin Pathol 1987;40:335-341 doi:10.1136/jcp.40.3.335

Kaul R, McGeer A, Low DE, Green K, Schwartz B, Simor AE. Population-Based Surveillance for Group A Streptococcal Necrotizing Fasciitis: Clinical Features, Prognostic Indicators, and Microbiologic Analysis of Seventy-Seven Cases. American Journal of Medicine. Volume 103, Issue 1 , Pages 18-24, July 1997

Competing interests: None declared

James Kelly, Plastic Surgery

Mr Baljit Dheansa, Consultant Plastic and Burns Surgeon

Queen Victoria Hospital , Holtye Road East Grinstead, West Sussex RH19 3DZ

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