Guidance
Rationales
The recommendations in this guideline are for adults and are based on the evidence identified and the experience of the committee. No evidence was found for children with leg ulcers and recommendations were made for adults only.
Treatment
Why the committee made the recommendations
Recommendations 1.1.1 to 1.1.5
The committee agreed that health professionals should be aware that there are many causes of leg ulcers and that, although most leg ulcers are colonised by bacteria, few are infected. They discussed that it is important to ensure that underlying conditions, such as venous insufficiency and oedema, are managed appropriately.
The committee discussed that antibiotics should only be offered for adults with a leg ulcer when there are symptoms or signs of infection. They agreed that there was no difference in outcomes between treatment with antibiotics and standard care in people with uninfected leg ulcers (although this was from a small, very low-quality study with no details reported on dosage or route of administration).
Evidence showed no difference in complete healing of the leg ulcer with antibiotics compared with standard care or placebo. However, in all but 1 study, the ulcer was either uninfected or the infection status was unclear. No study stated that children and young people (under 18 years) were included. The committee agreed that this age group are very unlikely to develop a leg ulcer and if they do the cause is likely to be from a condition that needs specialist management. Therefore, it was not appropriate to extrapolate evidence for adults to children and young people and so the committee made recommendations for adults only.
The committee agreed that antibiotics should be offered to all adults with a leg ulcer if there are symptoms or signs of an infection, because untreated infection causes delays in ulcer healing, affecting quality of life and sometimes resulting in hospital admission. The committee discussed that studies did not use consistent criteria for identifying infection in ulcers, and some signs of infection (such as localised redness, discharge and unpleasant smell) could be present in all leg ulcers, regardless of infection status, especially once compression is removed. Therefore, they agreed that the symptoms or signs to use to determine if the ulcer is infected may include redness or swelling spreading beyond the ulcer, localised warmth, increased pain or fever. The committee noted that healthcare professionals should be aware that redness, 1 of the signs of infection, may be less visible on darker skin tones.
Based on experience, the committee agreed that antibiotic choice will depend on the severity of symptoms or signs of infection (for example, how rapidly the infection is progressing or expanding), the person's risk of complications (possibly because of comorbidities, such as diabetes or immunosuppression) and any previous antibiotic use (which may have led to antimicrobial resistance).
In line with the NICE guideline on antimicrobial stewardship: systems and processes for effective antimicrobial medicine use and Public Health England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first if the person can take them, and if the severity of their infection does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.
The committee discussed and agreed that samples for microbiological testing should not routinely be taken from a leg ulcer at initial presentation, whether it is thought to be infected or not. Most leg ulcers are colonised by bacteria, and bacterial growth from a sample is likely regardless of infection status. Universal sampling could lead to inappropriate antibiotic prescribing. If the leg ulcer is clinically infected, the most likely causative organism is Staphylococcus aureus, which would be covered by empirical treatment with flucloxacillin.
Topical antiseptics
Evidence comparing antibiotics with povidone-iodine (an antiseptic) for leg ulcer infection was limited by small sample size. Most of the evidence was in adults with unclear infection status or uninfected leg ulcer.
There was some evidence of effect for cadexomer‑iodine and silver dressings in people with infected leg ulcer (compared with standard care and non-adherent foam dressing respectively). But there were severe limitations, including an unclear definition of 'infection' (1 being reliant on laboratory growth and the other stating that inflammation was the only symptom required). For the comparison of silver dressings and foam dressings, the only sign of infection required was inflammation, there were very wide confidence intervals, and both study arms had the option to use antibiotics (and the number of people taking systemic antibiotics was not reported). Silver dressings can be expensive and could have considerable resource impact. Therefore, because of the inadequate definition of infection, the confounding issue of antibiotic use, the uncertainty of the effect estimate and the potential cost, the committee agreed not to recommend silver dressings.
The committee were also concerned about the adverse effects with cadexomer‑iodine. These were mainly local skin irritation, rash and pain, all of which can make leg ulcers worse. No adverse effects were reported for silver dressings, but this may have been because of the small sample size. The committee were also aware of issues with the availability of iodine-based preparations, particularly in community settings.
In clinical practice, topical antiseptics are used for leg ulcers, often to manage minor, localised infections. However, the committee agreed that they could not make any recommendations on the use topical antiseptics for treating infected leg ulcers because of the limitations of the evidence and the unclear benefit. The inability to differentiate between a more localised or widespread infection both in the evidence and in clinical practice makes it difficult to define any place in therapy for topical antiseptics. The committee decided that it was appropriate to make a recommendation for research on the effectiveness of topical treatments (antiseptics and antibiotics) compared with oral antibiotics.
Reassessment
Why the committee made the recommendations
Recommendations 1.1.7 to 1.1.11
Based on experience, the committee agreed when adults with an infected leg ulcer should be reassessed. If symptoms of the infection worsen rapidly or significantly at any time, or do not start to improve within 2 to 3 days, this may indicate that the person has a more serious illness requiring referral, or a resistant infection (possibly because of previous antibiotic use). People with leg ulcers have routine reviews, often by nurses. However, this review and any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve even after a course of effective antibiotics.
The committee agreed that adults should be reassessed if they have severe pain out of proportion to the infection because this can be a symptom of necrotising fasciitis, which is a rare but serious bacterial infection.
Although microbiological sampling is not required at initial presentation, the committee agreed that it is appropriate to consider this if symptoms or signs of the infection are worsening or have not improved as expected. This will guide future antibiotic choice if the person has a resistant infection. The committee agreed that before microbiological sampling the wound should be cleaned to remove surface contaminants, slough or necrotic tissue, in line with Public Health England's guidance on venous leg ulcers: infection diagnosis and microbiological investigation guide for primary care.
When microbiological results are available, the choice of antibiotic should be reviewed and changed according to results if symptoms or signs of the infection are not improving, using a narrow-spectrum antibiotic if appropriate to minimise the risk of antimicrobial resistance.
Referral or seeking specialist advice
Why the committee made the recommendations
Recommendations 1.1.12 and 1.1.13
Based on experience, the committee agreed that adults with symptoms or signs suggesting a more serious illness or condition should be referred to hospital. Some people may have an infected leg ulcer that is more difficult to treat, for example, because they have a higher risk of complications or other underlying conditions, or they have a resistant infection. In these cases, referral or specialist advice should be considered (which may include giving intravenous antibiotics or adopting other non-antimicrobial management strategies).
Choice of antibiotic
Why the committee made the recommendations
There was very limited evidence on the choice of antibiotics in adults with an infected leg ulcer. Only 1 study compared antibiotics with standard care, and this was limited by the criteria for diagnosing infection. It was unclear whether wounds had symptoms and signs of clinical infection at baseline or whether they were just colonised with bacteria.
Based on experience, current practice and resistance data, the committee agreed that the first-choice oral antibiotic in adults with an infected leg ulcer is flucloxacillin (a penicillin). This is a relatively narrow-spectrum penicillin, which has good penetration for skin and soft tissue infections and is effective against gram‑positive organisms, including the most common causative organism Staphylococcus aureus.
The alternative first-choice antibiotics in adults with penicillin allergy or in whom flucloxacillin is unsuitable are doxycycline (a tetracycline), or clarithromycin or erythromycin (in pregnancy), which are macrolides. These all have a similar spectrum of activity to flucloxacillin. The committee agreed that the doses provided in the prescribing table were suitable for people with poor vascular flow.
The committee discussed the MHRA Public Assessment Report on the safety of macrolide antibiotics in pregnancy. This found that the available evidence is insufficient to confirm with certainty whether there is a small increased risk of birth defects or miscarriage when macrolides are taken in early pregnancy. They agreed with the UK Teratology Information Service monograph on the use of macrolides in pregnancy. They decided that there should be an informed discussion of the potential benefits and harms of treatment. Then, after such a discussion, macrolides can be used if there is a compelling clinical need and there are no suitable alternatives with adequate pregnancy safety data. Erythromycin is the preferred choice if a macrolide is needed during pregnancy, for example, if there is true penicillin allergy and the benefits of antibiotic treatment outweigh the harms. This is because there is more documented experience of its use than for other macrolides.
The committee agreed that the second-choice oral antibiotics if the first-choice oral antibiotics are not effective (guided by microbiological results when available) are the broader-spectrum antibiotics co-amoxiclav (a penicillin with a beta-lactamase inhibitor) or co‑trimoxazole (in penicillin allergy). These are more active against gram-negative organisms. The presence of gram‑negative organisms may be a reason why an infected leg ulcer is not healing; these antibiotics are therefore appropriate second-choice antibiotics. However, the committee noted that it is important to only use broad-spectrum antibiotics if first-choice antibiotics are not effective. Broad-spectrum antibiotics can create a selective advantage for bacteria resistant to these agents, allowing such strains to proliferate and spread. By disrupting normal flora, broad-spectrum antibiotics can also leave people susceptible to harmful bacteria such as Clostridium difficile in community settings. The committee discussed that cephalosporins are not an appropriate option as a second-choice oral antibiotic because they do not provide adequate cover for anaerobes.
Oral antibiotics should be given first line if possible. But based on experience and resistance data, the committee agreed that several intravenous antibiotics (or combinations of antibiotics) can be used for adults who are severely unwell or unable to take oral antibiotics. This enables antibiotics to be selected based on individual patient factors, likely pathogens, and antibiotic susceptibilities from microbiological results (if known).
In people who are severely unwell, broader antimicrobial cover is needed because both anaerobes and gram-negative bacteria may be present. However, in line with the principles of antimicrobial stewardship, narrower-spectrum antibiotics should be used where possible.
For adults with an infected leg ulcer who require intravenous antibiotics, the committee agreed that flucloxacillin was the most appropriate first choice, with or without the addition of gentamicin (a broad-spectrum aminoglycoside) and/or metronidazole.
The committee agreed that additional choices would be:
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co-amoxiclav with or without gentamicin
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co-trimoxazole with or without gentamicin and/or metronidazole (if penicillin allergy).
The committee discussed that metronidazole (which is used for anaerobic bacteria) may be useful for people with leg ulcers related to arterial disease or diabetes. These people may have a reduced blood supply that can encourage anaerobic bacterial growth. Because metronidazole has good oral bioavailability, this could be given orally instead of intravenously if people were able to take oral antibiotics.
Second choice intravenous antibiotics (guided by microbiological results when available or following specialist advice) are:
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piperacillin with tazobactam (a penicillin with a beta-lactamase inhibitor) or
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ceftriaxone (a third-generation cephalosporin) with metronidazole.
The committee discussed that intravenous ceftriaxone may be given as an outpatient without the need for hospital admission.
Meticillin‑resistant Staphylococcus aureus (MRSA) may be found on swabbing, but the current likelihood of MRSA infection is very low. The committee agreed that if MRSA infection is suspected or confirmed, 1 of the following intravenous antibiotics with activity against MRSA should be added to the treatment regimen:
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vancomycin (a glycopeptide) or
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teicoplanin or
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linezolid (an oxazolidinone; if vancomycin or teicoplanin cannot be used, following specialist advice only).
Course length and dosage and route of administration
There was very little evidence on antibiotic dosage, course length and route of administration. Therefore, recommendations were based on the committee's experience of current practice. Flucloxacillin has poor oral bioavailability and in people with an infected leg ulcer who could have impaired circulation, a higher (off‑label dose) of up to 1 g, 4 times a day orally, may be needed to adequately treat the infection.
The committee agreed that the shortest course that is likely to be effective should be prescribed to minimise adverse effects and reduce the risk of antimicrobial resistance, but that this should be balanced against the need for a course length that provides effective treatment.
In the absence of evidence for optimum course length, the committee agreed, based on experience and extrapolation of evidence from people with cellulitis and diabetic foot infection, that a course of 7 days is appropriate for most people with an infected leg ulcer. They discussed that a decision for a longer course of antibiotics may be made on review if the infection is not improving, particularly for people with poor healing and a higher risk of complications because of comorbidities. However, 7 days should be adequate for most people if their wound and any underlying condition is being managed appropriately. Any decision on the need for further antibiotics should take into account the fact that a leg ulcer infection will take some time to resolve, even after a course of effective antibiotics.
The committee also discussed safety concerns around longer courses of flucloxacillin or co-amoxiclav, particularly in older people, because of the risk of cholestatic jaundice or hepatitis.
In line with the NICE guideline on antimicrobial stewardship and Public Heath England's antimicrobial stewardship: start smart – then focus toolkit, oral antibiotics should be given first line if the person can take them, and the severity of their condition does not require intravenous antibiotics. The use of intravenous antibiotics should be reviewed by 48 hours (taking into account the person's response to treatment and any microbiological results) and switched to oral treatment where possible.