What I did before
Skin and soft tissue infections (SSTIs) are exceedingly common and account for up to 10% of all hospital admissions in Western countries . 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 . In this article, they will both be referenced as “cellulitis” for simplicity .
Cellulitis can often recur, and studies have shown that up to 29% of admissions with cellulitis were due to repeat episodes . 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
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 . 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) . In this study, compression garments were considered therapeutic if they provided 23mmHg or more of pressure, and patients were assessed individually by lymphedema specialists.
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 . 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 . 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 . 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% . 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 . Hence, in those with risk factors (e.g. advanced age, smoking, diabetes), objective evaluation should be done with an Ankle-Brachial-Index  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 . 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 . 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 .
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.
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