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Cellulitis is a common problem, caused by spreading bacterial inflammation of the skin, with redness, pain, and lymphangitis. Up to 40% of affected people have systemic illness. Erysipelas is a form of cellulitis with marked superficial inflammation, typically affecting the lower limbs and the face. The most common pathogens in adults are streptococci and Staphylococcus aureus. Cellulitis and erysipelas can result in local necrosis and abscess formation. Around a quarter of affected people have more than one episode of cellulitis within 3 years.
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for cellulitis and erysipelas? What are the effects of treatments to prevent recurrence of cellulitis and erysipelas? We searched: Medline, Embase, The Cochrane Library and other important databases up to May 2007 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 14 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antibiotics, comparative effects of different antibiotic regimens, duration of antibiotics, and treatment of predisposing factors.
Cellulitis is a common problem caused by spreading bacterial inflammation of the skin, with redness, pain, and lymphangitis. Up to 40% of people have systemic illness.
Antibiotics cure 50−100% of infections, but we don't know which antibiotic regimen is most successful.
Although there is consensus that treatment of predisposing factors can prevent recurrence of cellulitis or erysipelas, we found no studies that assessed the benefits of this approach.
Cellulitis is a spreading bacterial infection of the dermis and subcutaneous tissues. It causes local signs of inflammation, such as warmth, erythema, pain, lymphangitis, and frequently systemic upset with fever and raised white blood cell count. Erysipelas is a form of cellulitis and is characterised by pronounced superficial inflammation. The term erysipelas is commonly used when the face is affected. The lower limbs are by far the most common sites affected by cellulitis and erysipelas, but any area, such as the ears, trunk, fingers, and toes, can be affected.
We found no validated recent data on the incidence of cellulitis or erysipelas worldwide. UK hospital incidence data reported 69,576 episodes of cellulitis and 516 episodes of erysipelas in 2004-2005. Cellulitis infections of the limb accounted for most of these infections (58,824 episodes).
The most common infective organisms for cellulitis and erysipelas in adults are streptococci (particularly Streptococcus pyogenes) and Staphylococcus aureus. In children, Haemophilus influenzae was a frequent cause before the introduction of the Haemophilus influenzae type B vaccination. Several risk factors for cellulitis and erysipelas have been identified in a case-control study (167 cases and 294 controls): lymphoedema (OR 71.2, 95% CI 5.6 to 908.0), leg ulcer (OR 62.5, 95% CI 7.0 to 556.0), toe web intertrigo (OR 13.9, 95% CI 7.2 to 27.0), and traumatic wounds (OR 10.7, 95% CI 4.8 to 23.8).
Cellulitis can spread through the bloodstream and lymphatic system. A retrospective case study of people admitted to hospital with cellulitis found that systemic symptoms, such as fever and raised white blood cell count, were present in up to 42% of cases at presentation. Lymphatic involvement can lead to obstruction and damage of the lymphatic system that predisposes to recurrent cellulitis. Recurrence can occur rapidly, or after months or years. One prospective cohort study found that 29% of people with erysipelas had a recurrent episode within 3 years. Local necrosis and abscess formation can also occur. It is not known whether the prognosis of erysipelas differs from cellulitis. We found no evidence about factors that predict recurrence, or a better or worse outcome. We found no good evidence on the prognosis of untreated cellulitis.
To reduce the severity and duration of infection; to relieve pain and systemic symptoms; to restore the skin to its premorbid state; to prevent recurrence; to minimise adverse effects of treatment.
Duration and severity of symptoms (pain, swelling, erythema, and fever); clinical cure (defined as the absence of pain, swelling, and erythema); recurrence; adverse effects of treatment. We found no standard scales of severity in cellulitis or erysipelas.
BMJ Clinical Evidence search and appraisal May 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2007, Embase 1980 to May 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 2. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). We also searched for retractions of studies included in this review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, at least single blinded and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).
The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.
CURE RATES Ceftriaxone compared with flucloxacillin: Intravenous ceftriaxone may be more effective at 4–30 days than intravenous flucloxacillin at increasing cure rates in people with moderate to severe cellulitis ( very low-quality evidence ). Intravenous benzylpenicillin compared with intramuscular bipenicillin (a mixture of benzylpenicillin and procaine penicillin): Intravenous benzylpenicillin may be no more effective at 10 days than intramuscular bipenicillin at increasing treatment success rates (absence of erythema, oedema, and pain) or at reducing time to recovery ( low-quality evidence ). Cefazolin plus oral probenecid compared with ceftriazone: Intravenous cefazolin plus oral probenecid is no more effective at 6–7 days than ceftriazone at increasing clinical cure rates in people with cellulitis ( moderate-quality evidence ). Penicillin compared with oral roxithromycin: Intravenous and oral penicillin is no more effective at 30 days than oral roxithromycin at increasing clinical cure rates in people with erysipelas (moderate-quality evidence). Oral azithromycin compared with oral erythromycin, or oral cloxacillin, or cefalexin: Oral azithromycin is no more effective at at 4–11 days than oral erythromycin, oral cloxacillin, or cefalexin at increasing clinical cure rates in people with cellulitis (moderate-quality evidence). Cefdinir compared with cefalexin: Cefdinir may be no more effective at 7–16 days than cefalexin at increasing clinical cure rates in people with cellulitis (low-quality evidence). Oral amoxicillin–clavulanate potassium compared with oral fleroxacin: Oral amoxicillin–clavulanate potassium may be no more effective at 3–9 days than oral fleroxacin at increasing clinical cure rates in people with cellulitis or erysipelas (low-quality evidence). Intravenous fleroxacin compared with intravenous ceftazidime: Intravenous fleroxacin may be no more effective at 21 days than intravenous ceftazidime at increasing clinical cure rates in people with cellulitis (low-quality evidence). Ampicillin/sulbactam compared with cefazolin: Intravenous ampicillin/sulbactam may be no more effective at 10 days than intravenous cefazolin at increasing clinical cure rates in people with cellulitis (low-quality evidence). SYMPTOM SEVERITY Intravenous flucloxacillin plus intravenous benzylpenicillin compared with intravenous flucloxacillin: Intravenous flucloxacillin plus intravenous benzylpenicillin may be no more effective at 5 days than intravenous flucloxacillin at reducing temperature or participant-assessed improvement in people with lower-limb cellulitis (low-quality evidence). NOTE We found no direct information about whether antibiotics are better than no active treatment.
We found no systematic review.
We found no RCTs of sufficient quality (see Methods).
We found 11 RCTs comparing different antibiotic regimens in people with various skin infections (see table 1 ). Four of the RCTs were conducted solely in people with moderate to severe cellulitis; two RCTs were conducted solely in people with erysipelas; and the other six RCTs were conducted in people with a range of skin infections and provided subgroup analysis of people with cellulitis or erysipelas. Nine of the RCTs and subgroup analyses found no significant difference between different antibiotics in clinical cure after 4–30 days. However, most of the RCTs included only small numbers of people with cellulitis or erysipelas, and were designed to test equivalence rather than detect a clinically important difference in cure rates between antibiotics. One of the RCTs conducted solely in people with cellulitis (58 people with moderate to severe cellulitis) found that intravenous ceftriaxone significantly increased clinical cure after 4–6 days compared with intravenous flucloxacillin. The results of this study should be treated with caution because only 45 people (78%) completed the study, and it would not seem that an intention to treat analysis was performed. A second RCT in people with lower-limb cellulitis, compared intravenous flucloxacillin plus intravenous benzylpenicillin versus intravenous flucloxacillin alone. It did not report on clinical cure, but found no significant difference between flucloxacillin plus benzylpenicillin and flucloxacillin alone in temperature reduction, or in participant assessed improvement. Analysis was not by intention to treat. A third RCT (112 adults hospitalised with erysipelas of the leg) found no significant difference in treatment success (defined as absence of erythema, oedema, pain, and a normal temperature) at 10 days or time to recovery between intravenous benzylpenicillin and intramuscular bipenicillin (a mixture of benzylpenicillin and procaine penicillin).
We found no systematic review.
We found no RCTs of sufficient quality (see methods).
The RCTs found no evidence of a difference in rates of adverse events with different antibiotic regimens. The RCT comparing flucloxacillin versus ceftriaxone (58 people with moderate to severe cellulitis) found no significant difference in the proportion of people experiencing adverse effects, including diarrhoea, nausea and vomiting, abdominal pain, and vaginal candidiasis (6/22 [27%] with flucloxacillin v 3/22 [14%] with ceftriaxone; RR 2.00, 95% CI 0.57 to 7.00). The RCT comparing cefazolin plus probenecid versus ceftriaxone plus placebo (134 people with moderate to severe cellulitis) found no significant difference in the proportion of people who experienced adverse effects, including nausea and vomiting, diarrhoea, headache, and dizziness (14/67 [21%] with cefazolin plus probenecid v 7/67 [10%] with ceftriaxone plus placebo; RR 2.00, 95% CI 0.86 to 4.64). The RCT comparing penicillin versus roxithromycin (69 people with erysipelas) found no significant difference in the proportion of people experiencing drug-related rashes (2/38 [5%] with penicillin v 0/31 [0%] with roxithromycin). The RCT comparing flucloxacillin plus benzylpenicillin versus flucloxacillin alone (81 people with lower-limb cellulitis) found no treatment-related adverse events. The RCTs comparing different antibiotics in a variety of skin infections gave no discrete information about adverse effects in people with cellulitis. The RCT comparing intravenous benzyl penicillin versus intramuscular bipenicillin reported that complications were more common with intravenous benzylpenicillin than with intramuscular bipenicillin (local complications including leg abscesses: 9% with intravenous benzylpenicillin v 7% with intramuscular bipenicillin; absolute numbers not reported; inflammation of veins related to route in injection: 26% with intravenous benzylpenicillin v 0% with intramuscular bipenicillin; absolute numbers not reported; P = 0.00005).
Antibiotic versus placebo or versus each other One RCT added, which found no significant difference between rates of cure or time to recovery between intravenous benzylpenicillin and intramuscular bipenicillin, but found higher rates of local complications in the intravenous benzyl penicillin group;categorisation unchanged (Unknown effectiveness).
CURE RATES Oral compared with intravenous antibiotics: Oral pencillin may have similar rates of clinical efficacy to intravenous penicillin in people with erysipelas ( very low-quality evidence ). NOTE We found no clinically important results comparing oral, intravenous, or intramuscular routes of administration of antibiotics in the treatment of people with cellulitis or erysipelas.
We found no RCTs of sufficient quality. We found one small quasi-randomised trial (73 people with erysipelas in hospital with a body temperature of more than 38.5 °C, but excluding people with clinical signs of septicaemia; alternate allocation design) comparing oral versus intravenous penicillin. It reported no difference in clinical efficacy between oral and intravenous penicillin, which was assessed by indirect measures such as temperature fall, length of hospital stay, and absence from work. It was difficult to reach a conclusion about relapse rates from the data provided.
We found no systematic reviews or RCTs.
We found no systematic reviews or RCTs.
The small quasi-randomised trial (73 people with erysipelas; see benefits above) comparing oral versus intravenous penicillin reported adverse events in 15 people taking oral penicillin (4 with rash, 7 with diarrhoea, 4 with abscess) and in 10 people taking intravenous penicillin (2 with rash, 4 with diarrhoea, 4 with cannula phlebitis).
We found no RCTs.
We found no RCTs.
No new evidence
CURE RATES 10 days' treatment compared with 5 days' treatment: Ten days of levofloxacin treatment is no more effective at increasing clinical cure rates at 14 days (without recurrence at 28 days) than 5 days of treatment with levofloxacin in people with uncomplicated cellulitis ( moderate-quality evidence ).
We found one RCT (87 people with uncomplicated cellulitis, showing improvement after 5 days of levofloxacin treatment) comparing 10 days of levofloxacin treatment versus 5 days of levofloxacin treatment plus 5 days of placebo. It found no significant difference between treatments in clinical cure rates at 14 days without recurrence at 28 days (42/43 [98%] with 10 days of levofloxacin v 43/44 [98%] with 5 days of levofloxacin; P less than 0.05). Most people took levofloxacin orally.
The RCT comparing 10 days of levofloxacin treatment versus 5 days of levofloxacin treatment plus 5 days of placebo reported no serious adverse events. However, 3/121 [3%] people enrolled into the study before randomisation stopped taking levofloxacin because of adverse effects (2/121 [2%] with gastrointestinal intolerance, 1/121 [1%] with rash; significance not reported).
No new evidence
RECURRENCE RATES Compared with no treatment: Antibiotic prophylaxis may be more effective at 15–18 months than no treatment at preventing recurrence of cellulitis or erysipelas infections ( low-quality evidence ).
We found two RCTs, which compared long-term prophylactic treatment with antibiotics versus no treatment for the prevention of recurrent cellulitis. The first RCT compared erythromycin (250 mg twice daily for 18 months) versus no treatment in people who had two or more episodes of cellulitis or erysipelas in the previous year. It found that prophylactic antibiotic treatment significantly reduced recurrence compared with no treatment at 18 months (32 people; AR: 0/16 [0%] with antibiotic v 8/16 [50%] with no treatment; P less than 0.001). The second RCT compared prophylaxis with penicillin V (1–4 g twice daily based on weight) or erythromycin if allergic (0.25–1.25 g twice daily based on weight) versus no treatment in people with recurrent erysipelas who also had major predisposing factors including venous insufficiency, lymphoedema, or both. It found fewer recurrences with prophylactic antibiotic treatment compared with no treatment after a median follow-up of 15 months, but this difference did not reach significance (40 people; AR: 2/20 [10%] with antibiotics v 8/20 [40%] with no treatment; P = 0.06). This RCT may have been underpowered to detect a clinically important difference between groups.
The first RCT found that three people (19%) taking erythromycin experienced nausea and abdominal pain, and were switched to penicillin V. The second RCT found that two people (10%) taking penicillin prophylaxis discontinued treatment because of diarrhoea or nausea.
We found limited evidence that prophylactic antibiotics may reduce future attacks of cellulitis or erysipelas in people with previous episodes. There is insufficient evidence about which people are more likely to benefit, or which antibiotics, doses, and durations of treatment are most likely to be effective.
No new evidence
We found no direct information about the effects of treating predisposing factors to prevent recurrence of cellulitis or erysipelas.
We found no systematic review or RCTs of sufficient quality about the effects of treating predisposing factors to prevent recurrence of cellulitis or erysipelas.
We found no RCTs.
Although there is a consensus that successful treatment of predisposing factors, such as lymphoedema, leg ulcers, toe web intertrigo, and traumatic wounds, reduces the risk of developing cellulitis or erysipelas (see aetiology), we found no RCTs or observational studies to support or refute this.
No new evidence