Prevention of recurrent cellulitis

Authors: Dr. J Marie Kim (biography, no disclosures) and Dr. William Connors (biography, no disclosures)

What I did before

Background

Skin and soft tissue infections (SSTIs) are exceedingly common and account for up to 10% of all hospital admissions in Western countries [1]. Two of the most common SSTIs, “cellulitis” and “erysipelas”, refer to diffuse, superficial, spreading skin infections. They often have significant inflammation of lymphatic vessels and are by definition not associated with collection of pus [2]. In this article, they will both be referenced as “cellulitis” for simplicity [3].

Cellulitis can often recur, and studies have shown that up to 29% of admissions with cellulitis were due to repeat episodes [4]. There is a propensity for lower limb involvement, in part because aggravating factors such as edema and dermatomycosis tend to affect the legs disproportionately. Prophylactic therapies and mitigating of risk factors have been recently shown to reduce recurrence.

The focus of this article will be about prevention of recurrent, lower-extremity cellulitis (non-purulent) that is not associated with major penetrating trauma, preceding leg ulceration, or surgery.

What changed my practice

Compression Stockings

Chronic edema is a risk factor for cellulitis, and causes include venous stasis, lymphedema, and immobility, among others. It has been hypothesised that chronic edema can impair skin integrity, increasing susceptibility for bacteria to enter the skin, and altered lymphatic drainage can impair the immune response to pathogens [5]. In return, episodes of infection can cause lymphatic damage, exacerbating the cycle.

A randomised clinical trial (RCT) published in 2020 evaluated 84 patients with chronic (≥ 3 months) leg edema with history of two or more episodes of cellulitis in the same leg, comparing compression stocking therapy with controls. The trial was stopped early for efficacy, revealing a cellulitis recurrence of 15% in the compression group and 40% in the control group (HR 0.23, 95%CI 0.09-0.59 p= 0.002), suggesting a number needed to treat (NNT) of 4. A pertinent secondary outcome included hospitalisation for cellulitis favouring the compression group (RR 0.38, 95% CI 0.09-1.59) [5]. In this study, compression garments were considered therapeutic if they provided 23mmHg or more of pressure, and patients were assessed individually by lymphedema specialists.

Prophylactic Antibiotics

The most common infecting agent in lower extremity cellulitis is S. pyogenes (also known as group A Streptococcus), followed by groups C or G streptococci. Beta-hemolytic streptococci are universally sensitive to penicillin. S. pyogenes in particular does not have any reported resistance, such that previous exposure to penicillin should not give rise to concern about resistant organisms [6]. Hence, studies have looked at the role of prophylactic penicillin therapy to prevent recurrent episodes of cellulitis (‘secondary prophylaxis’).

In 2013, the PATCH-1 (Prophylactic Antibiotics for the Treatment of Cellulitis at Home) trial was published building on prior related trial results [7]. This RCT recruited 274 participants to compare the effect of twelve months of ‘low dose’ penicillin V 250mg PO BID with placebo in patients with at least two episodes of confirmed cellulitis of the leg in preceding 3 years. The primary outcome was the time to a first recurrence with participants followed for 3 years. The penicillin group had a longer time to first recurrence (626 days vs. 532 days) and fewer repeat episodes during prophylaxis phase (22% vs 37%, HR 0.55, CI 0.35-0.86 p=0.01) yielding a NNT of 5 to prevent one recurrent cellulitis episode while on prophylaxis (95%CI 4-9). However, this effect was not sustained during the post-prophylaxis period of follow-up.

The PATCH trial did not find higher incidence of adverse events including gastrointestinal symptoms in the penicillin group compared to placebo [7]. Of note, oral penicillin is associated with a small risk of C. difficile infection; recent studies including 348,000 penicillin-receiving patients found the incidence to be 0.055% [8]. This risk is considerably less than that associated with other beta-lactam antibiotics, parenteral antibiotics, or clindamycin [8, 9, 10, 11], which are usually prescribed during an acute cellulitis episode.

Notably, in British Columbia, penicillin V is available in doses of 300mg pills rather than the 250mg used in this trial. Additionally, PATCH-1 and previous trials excluded patients with preceding leg ulceration, surgery or major penetrating trauma, because these cases were more likely to be caused by staphylococci, which are typically not susceptible to penicillin.

What I do now

When assessing a patient with recurrent lower extremity cellulitis (non-purulent) I now incorporate the evolving evidence for preventative measures into a comprehensive management plan.

Lower extremity compression stockings: If chronic edema is present I advise use of compression starting 2 weeks after resolution of the acute cellulitis episode. I ask my patients to purchase compression stockings with pressure of 20-30mmHg, which are available over-the-counter at most pharmacies and cost around $30. Below-knee stockings with toe coverage are usually well-tolerated.

Compression stockings can be custom-fitted for free at select pharmacies, but prescription stockings may cost up to $180, and may not be covered under public health insurance. In individuals with severe peripheral arterial disease, compression can exacerbate risk of critical limb ischemia [12]. Hence, in those with risk factors (e.g. advanced age, smoking, diabetes), objective evaluation should be done with an Ankle-Brachial-Index [13] to inform safety of compression by referring to a local Vascular Labs Facility.

Tubular-shaped support bandages, tight socks, and elevation can also be recommended for patients who lack access or do not tolerate application. Continued use of compression stockings should be guided by persistence of edema (times of exacerbation), tolerance, and reassessed periodically. With time stockings may lose elasticity and require replacement.

Prophylactic penicillin V: For patients with at least two episodes of lower-extremity cellulitis I consider prescribing 300mg PO BID for up to 12 months. Identification of the correct target population is important, as purulence, pre-existing ulcers, preceding trauma or surgery can implicate other organisms such as S. aureus which are not typically susceptible to penicillin V. Other contraindications include allergy to penicillin. Antibiotic prophylaxis has not been shown to prevent episodes after the period of prophylaxis is over. As such, it is important that prophylactic antibiotics be considered a bridge until further measures can optimise a patient’s risk of recurrence, as outlined below.

If a patient develops a skin-and-soft-tissue infection while on this prophylaxis, the low-dose penicillin should be stopped. Penicillin resistance should not be a problem with the beta-hemolytic streptococci; the appropriate antibiotic course should be prescribed as per usual to treat the acute episode. If the patient does not need longer-term antibiotics, the penicillin prophylaxis can be resumed afterward.

Manage chronic dermatomycoses of the foot: These conditions are recognized risk factors for bacterial cellulitis of the lower extremity, as associated inflammation can provide a portal of entry for bacteria [14]. I screen my patients and treat for these conditions. Interdigital tinea pedis can commonly manifest as toe-web intertrigo, and topical terbinafine or clotrimazole 1% cream applied once daily for one week has been associated with high cure rates [15]. Onychomycosis is difficult to eradicate, and for optimal cure rates up to 70%, I recommend systemic therapy with oral terbinafine for 12 to 24 weeks [16].

Reducing exacerbating insults: Skin care, optimising contributory medical conditions, and exercise may also be helpful in reducing recurrence. Notably, regular foot inspections, especially in patients with peripheral neuropathy; achieving glycemic control in patients with diabetes, wearing properly fitting shoes, and foot hygiene to decrease auto-inoculation should be recommended to patients as relevant.

Additional Reading

1. Cellulitis: How to prevent it from returning [Internet Article]. American Academy of Dermatology. (View)
2. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clinical infectious diseases. 2014 Jul 15;59(2):e10-52. (View)

References

1. Nathwani D. The management of skin and soft tissue infections: outpatient parenteral antibiotic therapy in the United Kingdom. Chemotherapy 2001;47 Suppl 1:17-23. DOI: 10.1159/000048564. (Request with CPSBC or find via WorldCat)
2. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014 Jul 15;59(2):e10-52. DOI:10.1093/cid/ciu444. (View)
3. Dalal A, Eskin‐Schwartz M, Mimouni D, Ray S, Days W, Hodak E, Leibovici L, Paul M. Interventions for the prevention of recurrent erysipelas and cellulitis. Cochrane Database Syst Rev, 2017 Jun 20;6(6):CD009758. DOI: 10.1002/14651858.CD009758.pub2. (View)
4. Inghammar M, Rasmussen M, Linder A. Recurrent erysipelas: risk factors: risk factors and clinical presentation. BMC Infect Dis. 2014. May 18;14:270. DOI: 10.1186/1471-2334-14-270. (View)
5. Webb E, Neeman T, Bowden FJ, Gaida J, Mumford V, Bissett B. Compression therapy to prevent recurrent cellulitis of the leg. N Engl J Med. 2020 Aug 13;383(7):630-9. DOI: 10.1056/NEJMoa1917197. (Request with CPSBC or view with UBC)
6. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing. 32nd ed. CLSI supplement M100 (ISBN 978-1-68440-134-5 [Print]; ISBN 978-1-68440-135-2 [Electronic]). Clinical and Laboratory Standards Institute, Pennsylvania, USA, 2022. (View)
7. Thomas KS, Crook AM, Nunn AJ, Foster KA, Mason JM, Chalmers JR, Nasr IS, Brindle RJ, English J, Meredith SK, Reynolds NJ. Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013 May 2;368(18):1695-703. DOI: 10.1056/NEJMoa1206300. (View)
8.  Liang EH, Chen LH, Macy E. Adverse reactions associated with penicillins, carbapenems, monobactams, and clindamycin: a retrospective population-based study. The Journal of Allergy and Clinical Immunology: In Practice. 2020 Apr 1;8(4):1302-13. (View )
9. Deshpande A, Pasupuleti V, Thota P, Pant C, Rolston DD, Sferra TJ, Hernandez AV, Donskey CJ. Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. Journal of Antimicrobial Chemotherapy. 2013 Sep 1;68(9):1951-61. (View  )
10.  Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy. 2014 Apr 1;69(4):881-91. (View  )
11. Vardakas KZ, Trigkidis KK, Boukouvala E, Falagas ME. Clostridium difficile infection following systemic antibiotic administration in randomised controlled trials: a systematic review and meta-analysis. International journal of antimicrobial agents. 2016 Jul 1;48(1):1-0.  (View )
12. Stücker M, Danneil O, Dörler M, Hoffmann M, Kröger E, Reich‐Schupke S. Safety of a compression stocking for patients with chronic venous insufficiency (CVI) and peripheral artery disease (PAD). J Dtsch Dermatol Ges. 2020 Mar;18(3):207-13. DOI: 10.1111/ddg.14042 (View)
13. Kelechi TJ, Johnson JJ. Guideline for the management of wounds in patients with lower-extremity venous disease: an executive summary. J Wound Ostomy Continence Nurs. Nov-Dec 2012;39(6):598-606. DOI: 10.1097/WON.0b013e31827179e9. (View with CPSBC or UBC)
14. Roujeau JC, Sigurgeirsson B, Korting HC, Kerl H, Paul C. Chronic dermatomycoses of the foot as risk factors for acute bacterial cellulitis of the leg: a case-control study. Dermatology. 2004;209(4):301-7. DOI: 10.1159/000080853. (Request with CPSBC or view with UBC)
15. Korting HC, Tietz HJ, Bräutigam M, Mayser P, Rapatz G, Paul C. One week terbinafine 1% cream (Lamisil) once daily is effective in the treatment of interdigital tinea pedis: a vehicle controlled study. Med Mycol. 2001 Aug;39(4):335-40. DOI: 10.1080/714031040. (View)
16. Kreijkamp‐Kaspers S, Hawke K, Guo L, Kerin G, Bell‐Syer SE, Magin P, Bell‐Syer SV, van Driel ML. Oral antifungal medication for toenail onychomycosis. Cochrane Database Syst Rev. 2017 Jul 14;7(7):CD010031. DOI: 10.1002/14651858.CD010031.pub2. (View)

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