2 CPD credits: Clinical Review: Cellulitis

2 CPD CREDITS Complete the full activity at mimslearning.co.uk/dermatology

SECTION 1: EPIDEMIOLOGY AND AETIOLOGY

Cellulitis is an inflammatory condition of the deep dermis and subcutaneous tissue caused by infection. If the infection is confined to the superficial dermis and subcutis, the disease is called erysipelas. The entities can overlap, so management is similar for both conditions.¹ In 2013-2014, there were 104,598 recorded cases of cellulitis treated in secondary care in the UK, of which 69,229 hospital admissions involved a mean and median bed stay of 6.2 and three days, respectively.²
The actual incidence is much higher because many cases are treated in primary care. The mean age of patients was 63 years and 36.5% were aged 75 years or older.²
Based on an estimated 2008 figure of £225 for a bed stay, the cost of treating inpatient cellulitis has been estimated at £96.6m.³ Most cases of cellulitis (86%) affected the limbs, excluding fingers and toes.²
Streptococcus pyogenes (particularly group A) and Staphylococcus aureus are the common organisms involved.¹ However, others include Haemophilus influenzae, Strep pneumoniae, Gram-negative bacilli and anaerobes such as Aeromonas hydrophila and Pseudomonas aeruginosa.^4,5 Atypical organisms are more likely to be found in children, older people and immunocompromised individuals.¹
The site of entry for infection may be obvious, such as trauma or minor injury to the skin, leg ulceration, tinea infection or existing skin conditions such as eczema. Other risk factors for cellulitis include chronic venous insufficiency, lymphoedema, peripheral vascular disease and immunosuppression, including diabetes and alcoholism.⁶
Chronic compromise to the lymphatic system, often as a result of previous episodes of cellulitis, can increase patients’ susceptibility to recurrence of the disease.¹

SECTION 2: MAKING THE DIAGNOSIS

Cellulitis can occur anywhere in the body, but is more likely to affect the lower limbs.⁵ In this case, differential diagnoses (see box 1) include DVT, stasis eczema, superficial thrombophlebitis, panniculitis and lipodermatosclerosis.¹

Cellulitis of the head and neck tends to occur more commonly in children, in which case, sinus X-rays may be justified to establish any presence of concurrent sinus infection.⁴ If there is periorbital involvement, consider referral to an ophthalmology specialist for further review.⁷
Other differentials that can occur anywhere in the body include necrotising fasciitis, gangrene, acute gout, adverse drug reaction (such as aspirin or penicillin) and, rarely, metastatic cancer in the form of carcinoma erysipeloides.^1,7
The common initial presentation is an area of localised inflammation with erythema, swelling, pain and warmth. The erythema may be well defined and can be marked with a pen to assess its resolution.⁷
There may or may not be a systemic response present, which includes fever and raised infection markers, including a high WCC and CRP.¹
If the presentation is severe, blisters, pustules, bruising, petechiae or necrotic tissue may be found, as well as localised lymphadenopathy and lymphangitis.^1,7
Grading systems for cellulitis include the Eron^5,6,8 and the Dundee classifications.^6,9 In practice, these systems are not often cited, but similar principles of clinical judgment are applied when determining the severity of cellulitis and deciding on the best approach to management.⁵

Examination and investigations

A full clinical examination of the affected skin should be carried out, with particular vigilance for potential entry points for infection and systemic involvement.^4,7 Consider the possibility of deeper involvement, such as is the case with necrotising fasciitis and myositis.¹
If the lower limbs are affected, carefully inspect the feet, including toenails and between the toes, for possible fungal infection. In this situation, mycology nail clippings and skin scrapings should be taken. If there are signs of serious systemic effects, blood tests should include FBC, renal function tests, LFT and CRP. Blood cultures and swab samples should be obtained from areas of broken skin. Punch skin biopsies and aspirates for culture may be considered if the diagnosis is doubtful.^4,5

Tinea infection in the right big toenail (Photograph: Dept Medical Illustration, Norfolk & Norwich University Hospital)

SECTION 3: MANAGING THE CONDITION

The ideal antibiotic treatment for cellulitis is unclear, as demonstrated by a Cochrane review in 2010 on interventions for cellulitis and erysipelas.¹⁰ For obvious reasons, no trials existed to compare antibiotic therapy with placebo.⁵
The choice of antibiotic is influenced by which organism is likely to be the target, clinical experience and recommendations of local hospital guidelines.^5,6,10 Antibiotics that have been prescribed include the penicillin-based antibiotics, macrolides, streptogramins, cephalosporins, carbapenems, linezolid, vancomycin and quinolones (see box 2).¹⁰

Initiating antibiotic treatment is usually empirical⁵ and can take place as either an outpatient or an inpatient, depending on the severity of the cellulitis.^5-7,11 In an outpatient setting, oral antibiotics can be initiated in uncomplicated cellulitis in an immunocompetent adult. Common combinations usually consist of phenoxymethylpenicillin and flucloxacillin to cover both group A streptococci and staphylococci.¹ For those who are allergic to penicillin, a macrolide such as erythromycin or clarithromycin would be a suitable alternative.⁴
Patients who do not respond to oral antibiotics, who are systemically unwell or who are immunosuppressed may require parenteral antibiotic therapy, sometimes in hospital.^5,7,8
Given the increasing recognition of community-acquired MRSA (particularly in the US),¹² an initial screen for this should be carried out and antibiotics for MRSA cover may be recommended.^1,6,12 If there is head and neck involvement, co-amoxiclav has been recommended to ensure H influenzae cover⁴ and most Gram-negative and anaerobe organisms.^4,5 If mycology results are positive, treat for tinea infection. Box 3 outlines the recommended antibiotic treatment for cellulitis in specific situations, such as contamination with a dog bite.

Hospital-acquired cellulitis will require treatment according to local resistance patterns seen in the common organisms and the site involved. In this case, discussion with medical microbiologists is recommended.
During antibiotic treatment, elevation of the affected limb while immobile is encouraged. If blistering or exudate are present, wet dressings, such as saline soaks, should be applied.¹ Analgesia (paracetamol or NSAIDs) may be useful, but be wary of the possibility of masking signs of deeper infection.¹
Signs of response to treatment include settling systemic symptoms, a reduction in fever, regressing erythema on the skin and decreasing inflammatory markers.⁵ Skin discoloration may persist long after the resolution of infection.
IV antibiotics, if given, can be switched to an oral preparation by this stage and the total course duration is typically seven to 14 days, although this can be prolonged on a case-by-case basis.^5,10 Consider readjusting the antibiotic prescription after discussion with the medical microbiologist, if there are positive cultures.^4,5 Clinical judgment should be exercised because empirical treatment of cellulitis rarely requires changing as a result of a positive blood culture, even in complex cellulitis.¹³
These are reasonable first-line approaches, but the best intervention for cellulitis is still uncertain.¹⁰ Among three trials included in the Cochrane review, macrolide and streptogramin were slightly more effective than penicillin in resolving the symptoms of cellulitis.¹⁰ With another two trials reviewed, oral antibiotics appeared more effective than IV therapy, but sample sizes were small, suggesting that further investigations are needed.¹⁰
Consultation with the medical microbiology service and adherence to local guidelines will ensure that the most appropriate antibiotic is delivered,⁵ to reduce resistance.
Outpatient parenteral antibiotic therapy services have been shown to reduce hospital admission,^5,6,14 and to be more convenient for the patient and more cost-effective, using a once-daily preparation, such as ceftriaxone.^5,6,10,14
In the UK, patients with cellulitis can be managed in an outpatient setting through shared primary and secondary care.
In one study, referrals of suspected cellulitis from primary care and other hospital specialties were reviewed in a dermatology department for diagnosis. The patients were then treated with daily IV ceftriaxone, either by attending hospital daily or by receiving treatment from community nurses. Of the 67% confirmed cases of lower limb cellulitis, 407 out of 425 patients did not require hospital admission for management.¹⁴

Complications
Acute complications include necrotising fasciitis, myositis, acute glomerulonephritis, lymphadenitis and septicaemia, including subacute bacterial endocarditis.^1,7 Necrotising fasciitis requires urgent surgical assessment and treatment.
Clindamycin is a suitable antibiotic to use with surgery, but monitoring for the consequential risk of clindamycin-induced Clostridium difficile is essential.⁵
With regard to long-term complications, there may be persistent leg ulceration and lymphoedema owing to long-term damage to the lymphatic system as a result of the inflammation from infection.^7,11 Assessment for long-term compression bandaging or hosiery would then be reasonable, particularly if it would help to reduce the risk of recurrent cellulitis.⁵

Prevention
Risk factors that predispose to cellulitis, such as tinea infection, should be assessed and treated. In a large double-blind placebo-controlled study, prophylactic phenoxymethylpenicillin 250mg twice daily for 12 months was shown to reduce recurrent lower limb cellulitis.¹⁵ The same treatment probably also helped to reduce recurrent lower limb cellulitis after a first infection.¹⁶
The PATCH I and II studies have demonstrated a reduction in the number of recurrences by 29% during their trial period, which included a one- to two-year follow-up, with no significant increase in costs.¹⁷
Other prophylactic antibiotics include erythromycin 250mg twice daily and IM penicillin depot injections administered intermittently over one to two years.⁵
A systematic review and meta-analysis supported antibiotic prophylaxis in preventing cases of recurrent cellulitis.¹⁸

SECTION 4: PROGNOSIS

A 12-month prophylactic course of phenoxymethylpenicillin can reduce recurrence of lower limb cellulitis by 45%, but this effect is limited to the period of prophylaxis.^15,17
A single episode of cellulitis increases the risk of recurrence and each episode leads to further lymphatic damage. The lymphatic damage increases susceptibility to future infection, so early prevention is important in the prevention of chronic lymphoedema and recurrent infections.^11,15 Further research is needed to identify the best strategies to achieve this.

• Dr Ava Lee is clinical fellow and Dr Nick Levell is clinical director for dermatology, at Norfolk and Norwich University Hospital

Competing interests: None declared

References
1. Bologna JL, Jorizzo JL, Schaffer JV. Dermatology (third edition). Philadelphia, Elsevier Saunders, 2012.
2. Health & Social Care Information Centre. Hospital Episode Statistics. 
3. NHS Institute for Innovation and Improvement. Quality and service improvement tools. Length of stay – reducing length of stay.
4. Lebwohl MG, Heymann WR, Berth-Jones J et al. Treatment of skin disease: comprehensive therapeutic strategies (third edition). Philadelphia, Saunders Elsevier, 2010.
5. Guidelines and Audit Implementation Network. CREST guidelines on the management of cellulitis in adults. Belfast, GAIN, June 2005.
6. Phoenix G, Das S, Joshi M. Diagnosis and management of cellulitis. BMJ 2012; 345: e4955.
7. NICE. Clinical Knowledge Summaries. Cellulitis – acute. London, NICE, June 2015. 
8. Eron J. Infections of skin and soft tissue: outcomes of a classification scheme. Clin Infect Dis 2000; 31: 287(A432).
9. Marwick C, Broomhall J, McCowan C et al. Severity assessment of skin and soft tissue infections: cohort study of management and outcomes for hospitalized patients. J Antimicrob Chemother 2011; 66: 387-97.
10. Kilburn SA, Featherstone P, Higgins B et al. Interventions for cellulitis and erysipelas. Cochrane Database Syst Rev 2010, Issue 6. Art No: CD004299. DOI: 10.1002/14651858.CD004299.pub2
11. British Lymphology Society. Consensus document on the management of cellulitis in lymphoedema. London, BLS, April 2015. 
12. Horseman M, Bowman JD. Is community-acquired methicillin-resistant Staphylococcus aureus coverage needed for cellulitis? Infect Dis Ther 2013; 2: 175-85.
13. Paolo WF, Poreda AR, Grant W et al. Blood culture results do not affect ?treatment in complicated cellulitis. J Emerg Med 2013; 45(2): 163-7.
14. Levell NJ, Wingfield CG, Garioch JJ. Severe lower limb cellulitis is best diagnosed by dermatologists and managed with shared care between primary and secondary care. Br J Dermatol 2011; 164: 1326-8.
15. Thomas KS, Crook AM, Nunn AJ et al. Penicillin to prevent recurrent leg cellulitis. N Engl J Med 2013; 368(18): 1695-703.
16. UK Dermatology Clinical Trials Network’s PATCH Trial Team, Thomas K, Crook A et al. Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg: results of the UK Dermatology Clinical Trials Network’s PATCH II trial. Br J Dermatol 2012; 166: 169-78.
17. Mason JM, Thomas KS, Crook AM et al. Prophylactic antibiotics to prevent cellulitis of the leg: economic analysis of the PATCH I & II trials. PLoS One 2014; 9(2): e82694.
18. Oh CC, Ko HC, Lee HY et al. Antibiotic prophylaxis for preventing recurrent cellulitis: a systematic review and meta-analysis. J Infect 2014; 69(1): 26-34.