Dalal Adam, Eskin-Schwartz Marina, Mimouni Daniel, Ray Sujoy, Days Walford, Hodak Emmilia, Leibovici Leonard, Paul Mical
Department of Dermatology, Beilinson Hospital, Rabin Medical Center, 39 Jabotinski Street, Petah Tikva, Israel, 49100.
Cochrane Database Syst Rev. 2017 Jun 20;6(6):CD009758. doi: 10.1002/14651858.CD009758.pub2.
Erysipelas and cellulitis (hereafter referred to as 'cellulitis') are common bacterial skin infections usually affecting the lower extremities. Despite their burden of morbidity, the evidence for different prevention strategies is unclear.
To assess the beneficial and adverse effects of antibiotic prophylaxis or other prophylactic interventions for the prevention of recurrent episodes of cellulitis in adults aged over 16.
We searched the following databases up to June 2016: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registry databases, and checked reference lists of included studies and reviews for further references to relevant randomised controlled trials (RCTs). We searched two sets of dermatology conference proceedings, and BIOSIS Previews.
Randomised controlled trials evaluating any therapy for the prevention of recurrent cellulitis.
Two authors independently carried out study selection, data extraction, assessment of risks of bias, and analyses. Our primary prespecified outcome was recurrence of cellulitis when on treatment and after treatment. Our secondary outcomes included incidence rate, time to next episode, hospitalisation, quality of life, development of resistance to antibiotics, adverse reactions and mortality.
We included six trials, with a total of 573 evaluable participants, who were aged on average between 50 and 70. There were few previous episodes of cellulitis in those recruited to the trials, ranging between one and four episodes per study.Five of the six included trials assessed prevention with antibiotics in participants with cellulitis of the legs, and one assessed selenium in participants with cellulitis of the arms. Among the studies assessing antibiotics, one study evaluated oral erythromycin (n = 32) and four studies assessed penicillin (n = 481). Treatment duration varied from six to 18 months, and two studies continued to follow up participants after discontinuation of prophylaxis, with a follow-up period of up to one and a half to two years. Four studies were single-centre, and two were multicentre; they were conducted in five countries: the UK, Sweden, Tunisia, Israel, and Austria.Based on five trials, antibiotic prophylaxis (at the end of the treatment phase ('on prophylaxis')) decreased the risk of cellulitis recurrence by 69%, compared to no treatment or placebo (risk ratio (RR) 0.31, 95% confidence interval (CI) 0.13 to 0.72; n = 513; P = 0.007), number needed to treat for an additional beneficial outcome (NNTB) six, (95% CI 5 to 15), and we rated the certainty of evidence for this outcome as moderate.Under prophylactic treatment and compared to no treatment or placebo, antibiotic prophylaxis reduced the incidence rate of cellulitis by 56% (RR 0.44, 95% CI 0.22 to 0.89; four studies; n = 473; P value = 0.02; moderate-certainty evidence) and significantly decreased the rate until the next episode of cellulitis (hazard ratio (HR) 0.51, 95% CI 0.34 to 0.78; three studies; n = 437; P = 0.002; moderate-certainty evidence).The protective effects of antibiotic did not last after prophylaxis had been stopped ('post-prophylaxis') for risk of cellulitis recurrence (RR 0.88, 95% CI 0.59 to 1.31; two studies; n = 287; P = 0.52), incidence rate of cellulitis (RR 0.94, 95% CI 0.65 to 1.36; two studies; n = 287; P = 0.74), and rate until next episode of cellulitis (HR 0.78, 95% CI 0.39 to 1.56; two studies; n = 287). Evidence was of low certainty.Effects are relevant mainly for people after at least two episodes of leg cellulitis occurring within a period up to three years.We found no significant differences in adverse effects or hospitalisation between antibiotic and no treatment or placebo; for adverse effects: RR 0.87, 95% CI 0.58 to 1.30; four studies; n = 469; P = 0.48; for hospitalisation: RR 0.77, 95% CI 0.37 to 1.57; three studies; n = 429; P = 0.47, with certainty of evidence rated low for these outcomes. The existing data did not allow us to fully explore its impact on length of hospital stay.The common adverse reactions were gastrointestinal symptoms, mainly nausea and diarrhoea; rash (severe cutaneous adverse reactions were not reported); and thrush. Three studies reported adverse effects that led to discontinuation of the assigned therapy. In one study (erythromycin), three participants reported abdominal pain and nausea, so their treatment was changed to penicillin. In another study, two participants treated with penicillin withdrew from treatment due to diarrhoea or nausea. In one study, around 10% of participants stopped treatment due to pain at the injection site (the active treatment group was given intramuscular injections of benzathine penicillin).None of the included studies assessed the development of antimicrobial resistance or quality-of-life measures.With regard to the risks of bias, two included studies were at low risk of bias and we judged three others as being at high risk of bias, mainly due to lack of blinding.
AUTHORS' CONCLUSIONS: In terms of recurrence, incidence, and time to next episode, antibiotic is probably an effective preventive treatment for recurrent cellulitis of the lower limbs in those under prophylactic treatment, compared with placebo or no treatment (moderate-certainty evidence). However, these preventive effects of antibiotics appear to diminish after they are discontinued (low-certainty evidence). Treatment with antibiotic does not trigger any serious adverse events, and those associated are minor, such as nausea and rash (low-certainty evidence). The evidence is limited to people with at least two past episodes of leg cellulitis within a time frame of up to three years, and none of the studies investigated other common interventions such as lymphoedema reduction methods or proper skin care. Larger, high-quality studies are warranted, including long-term follow-up and other prophylactic measures.
丹毒和蜂窝织炎（以下简称“蜂窝织炎”）是常见的细菌性皮肤感染，通常累及下肢。尽管它们具有发病负担，但不同预防策略的证据尚不清楚。
评估抗生素预防或其他预防性干预措施对预防16岁以上成年人蜂窝织炎复发的有益和不良影响。
截至2016年6月，我们检索了以下数据库：Cochrane皮肤小组专业注册库、Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、Embase和LILACS。我们还检索了五个试验注册数据库，并检查了纳入研究和综述的参考文献列表，以获取更多相关随机对照试验（RCT）的参考文献。我们检索了两组皮肤病学会议论文集以及BIOSIS Previews。
评估任何预防复发性蜂窝织炎治疗方法的随机对照试验。
两位作者独立进行研究选择、数据提取、偏倚风险评估和分析。我们预先设定的主要结局是治疗期间及治疗后蜂窝织炎的复发情况。次要结局包括发病率、至下一次发作的时间、住院情况、生活质量、抗生素耐药性的产生、不良反应和死亡率。
我们纳入了六项试验，共有573名可评估参与者，平均年龄在50至70岁之间。纳入试验的参与者之前很少有蜂窝织炎发作，每项研究中发作次数在1至4次之间。六项纳入试验中有五项评估了腿部蜂窝织炎参与者使用抗生素的预防效果，一项评估了手臂蜂窝织炎参与者使用硒的预防效果。在评估抗生素的研究中，一项研究评估了口服红霉素（n = 32），四项研究评估了青霉素（n = 481）。治疗持续时间从6个月到18个月不等，两项研究在预防措施停止后继续对参与者进行随访，随访期长达一年半到两年。四项研究为单中心研究，两项为多中心研究；这些研究在五个国家进行：英国、瑞典、突尼斯、以色列和奥地利。基于五项试验结果，与未治疗或安慰剂相比，抗生素预防（在治疗阶段结束时“进行预防”）可使蜂窝织炎复发风险降低69%（风险比（RR）0.31，95%置信区间（CI）0.13至0.72；n = 513；P = 0.007），为获得额外有益结局所需治疗人数（NNTB）为6（95% CI 5至15），我们将该结局的证据确定性评为中等。在预防性治疗下，与未治疗或安慰剂相比，抗生素预防使蜂窝织炎发病率降低56%（RR 0.44，95% CI 0.22至0.89；四项研究；n = 473；P值 = 0.02；中等确定性证据），并显著降低至下一次蜂窝织炎发作的发生率（风险比（HR）0.51，95% CI 0.34至0.78；三项研究；n = 437；P = 0.002；中等确定性证据）。抗生素预防措施停止后（“预防后”），其对蜂窝织炎复发风险（RR 0.88，95% CI 0.59至1.31；两项研究；n = 2,87；P = 0.52）、蜂窝织炎发病率（RR 0.94，95% CI 0.65至1.36；两项研究；n = 287；P = 0.74）以及至下一次蜂窝织炎发作发生率（HR 0.78，95% CI 0.39至1.56；两项研究；n = 287）的保护作用消失。证据确定性较低。这些效果主要与在长达三年的时间内至少发生过两次腿部蜂窝织炎的人群相关。我们发现抗生素组与未治疗或安慰剂组在不良反应或住院情况方面无显著差异；不良反应方面：RR 0.87，95% CI 0.58至1.30；四项研究；n = 469；P = 0.48；住院情况方面：RR 0.77，95% CI 0.37至1.57；三项研究；n = 429；P = 0.47，这些结局的证据确定性评为低。现有数据无法让我们充分探究其对住院时间的影响。常见的不良反应为胃肠道症状，主要是恶心和腹泻；皮疹（未报告严重皮肤不良反应）；以及鹅口疮。三项研究报告了导致停止分配治疗的不良反应。在一项研究（红霉素）中，三名参与者报告腹痛和恶心，因此他们的治疗改为青霉素。在另一项研究中，两名接受青霉素治疗的参与者因腹泻或恶心退出治疗。在一项研究中，约10%的参与者因注射部位疼痛而停止治疗（活性治疗组给予苄星青霉素肌肉注射）。纳入的研究均未评估抗菌药物耐药性的产生或生活质量指标。关于偏倚风险，两项纳入研究偏倚风险较低，我们判断另外三项研究偏倚风险较高，主要原因是缺乏盲法。
就复发、发病率和至下一次发作的时间而言，与安慰剂或未治疗相比，抗生素可能是预防性治疗下肢复发性蜂窝织炎的有效方法（中等确定性证据）。然而，抗生素停用后这些预防效果似乎会减弱（低确定性证据）。抗生素治疗不会引发任何严重不良事件，相关不良事件轻微，如恶心和皮疹（低确定性证据）。证据仅限于在长达三年的时间内至少有过两次腿部蜂窝织炎发作的人群，且没有研究调查其他常见干预措施，如减轻淋巴水肿的方法或适当的皮肤护理。有必要开展更大规模、高质量的研究，包括长期随访和其他预防措施。
