Background
Description of the condition
Biology and symptoms
Impetigo or impetigo contagiosa is a contagious superficial bacterial skin infection most frequently encountered in children. It is typically classified as either primary (e.g. direct bacterial invasion of previously normal skin), secondary, or common impetigo (where the infection is secondary to some other underlying skin disease that disrupts the skin barrier, such as scabies or eczema). Impetigo is also classified as bullous or non-bullous impetigo. Bullous impetigo simply means that the skin eruption is characterised by bullae (blisters). The term 'impetigo contagiosa' is sometimes used to mean non-bullous impetigo, and at other times it is used as a synonym for all impetigo.
Non-bullous impetigo is the most common form of impetigo. The initial lesion is a thin-walled vesicle on previously normal skin that rapidly ruptures. It then leaves superficial erosion covered with yellowish-brown or honey-coloured crusts. The crusts eventually dry, separate, and disappear, leaving a red mark that heals without scarring. The most frequently affected areas are the face and limbs. The lesions are sometimes painful. Usually, there are no systemic symptoms such as fever, malaise, or anorexia. Swelling of the lymph nodes draining the infected area of skin is common. It is believed that, in most cases, spontaneous resolution may be expected within two to three weeks without treatment but more prompt resolution occurs with adequate treatment. Diagnostic confusion can occur with a variety of skin disorders including shingles, cold sores, cutaneous fungal infections, and eczema (Hay 1998; Resnick 2000). Pyoderma is sometimes used as a synonym for impetigo in tropical countries. This is usually to denote streptococcal, as opposed to staphylococcal, impetigo.
Bullous impetigo is characterised by larger bullae or blisters that rupture less readily and can persist for several days. Usually there are fewer lesions and the trunk is affected more frequently than in non-bullous impetigo. Diagnostic confusion can occur with thermal burns, blistering disorders (e.g. bullous pemphigoid), and Stevens Johnson syndrome.
Causes
Staphylococcus aureus (S. aureus) is considered to be the main bacterium that causes non-bullous impetigo. However, Streptococcus pyogenes (S. pyogenes), or both S. pyogenes and S. aureus, are sometimes isolated from the skin. In moderate climates, staphylococcal impetigo is more common, whereas in warmer and more humid climates, the streptococcal form predominates. In moderate climates, the relative frequency of S. aureus infections has also changed with time (Dagan 1993). It was predominant in the 1940s and 1950s, after which Group A streptococci became more prevalent. In the past two decades, S. aureus has become more common again. Bullous impetigo is always caused by S. aureus.
Secondary impetigo may occur as a complication of many dermatological conditions (notably eczema). The eruption appears clinically similar to non-bullous impetigo. Usually S. aureus is involved. The underlying skin disease may improve with successful treatment of the impetigo, and the converse may also be true.
Complications of non-bullous impetigo are rare, but local and systemic spread of infection can occur that may result in cellulitis, lymphangitis, or septicaemia. Non-infectious complications of S. pyogenes infection include guttate psoriasis, scarlet fever, and glomerulonephritis (an inflammation of the kidney that can lead to kidney failure). It is thought that most cases of glomerulonephritis result from streptococcal impetigo rather than streptococcal throat infection, and this has always been an important rationale for antibiotic treatment. The incidence of acute glomerulonephritis has declined rapidly over the last few decades. Baltimore 1985 stated that the risk of developing glomerulonephritis is not altered by treatment of impetigo; however, certain subtypes of Group A streptococci are associated with a much greater risk (Dillon 1979b).
Epidemiology
In the Netherlands, most people with impetigo consult their general practitioner and only approximately 1% of the cases are referred to a dermatologist (Bruijnzeels 1993). Although the incidence of impetigo in general practice has been declining, recent data show an increase in consultations for impetigo (Koning 2006; Van den Bosch 2007). Impetigo is still a common disease particularly in young children. It is the third most common skin disorder in children after dermatitis/eczema and viral warts (Bruijnzeels 1993; Dagan 1993; Mohammedamin 2006). Impetigo is the most common skin infection that is presented in general practice by children aged one to four years of age (Mohammedamin 2006). In British general practice, 2.8% of children aged 0 to 4 and 1.6% aged 5 to 15 consult their GP about impetigo each year (McCormick 1995). In the Netherlands in the late 1980s, the consultation rate was 1.7% of all children under 18 years of age; this increased to 2.1% in 2001 (Koning 2006). Peak incidence occurs between the ages of one and eight years (Koning 2006). In some tropical or developing countries the incidence of impetigo seems to be higher than elsewhere (Canizares 1993; Kristensen 1991).
Description of the intervention
Management options for impetigo include the following:
- no pharmacological treatment, waiting for natural resolution, hygiene measures;
- topical disinfectants (such as saline, hexachlorophene, povidone iodine, and chlorhexidine);
- topical antibiotics (such as neomycin, bacitracin, polymyxin B, gentamycin, fusidic acid, mupirocin, retapamulin, or topical steroid/antibiotic combination); and
- systemic antibiotics (such as penicillin, (flu)cloxacillin, amoxicillin/clavulanic acid, erythromycin, and cephalexin).
The aim of treatment includes resolving the soreness caused by lesions and the disease's unsightly appearance (especially on the face), as well as preventing recurrence and spread to other people. An ideal treatment should be effective, cheap, easy to use, and accepted by people. It should be free from side-effects, and it should not contribute to bacterial resistance. For this reason, antibiotics should not have an unnecessarily broad spectrum (Espersen 1998; Smeenk 1999), and if a topical antibiotic is used, it should, preferably, not be one which may be needed for systemic use (Carruthers 1988; Smeenk 1999).
Waiting for natural resolution could be acceptable if the natural history were known and benign. Impetigo is considered to be self-limiting by many authors (Hay 1998; Resnick 2000). However, there are no robust data on the natural history of impetigo. Reported cure rates of placebo creams vary from 8% to 42% at 7 to 10 days (Eells 1986; Ruby 1973). Topical cleansing used to be advised in the 1970s as an alternative for antibiotic treatment, but this was later said to be no more effective than placebo (Dagan 1992). Guidelines and treatment advice often do not mention topical cleansing as a treatment because the main concern is preventing the spread of the infection to other children.
A choice has to be made between topical and systemic antibiotic treatment, although in some situations clinicians prescribe both topical and systemic antibiotics. An advantage of the use of topical antibiotics is that the drug can be applied where it is needed, avoiding systemic side-effects such as gastrointestinal upset. Also, compliance may be better (Britton 1990).
The disadvantages of using topical antibiotics include the risks of developing bacterial resistance and sensitisation, e.g. developing an allergic contact dermatitis to one of the constituents of the topical preparation (Carruthers 1988; Smeenk 1999). This is especially common with the older antibiotics, such as gentamycin, bacitracin, and neomycin (Smeenk 1999). Some preparations (e.g. tetracycline) can cause staining of the skin and clothes.
Staphylococcal resistance against penicillin and erythromycin is common (Dagan 1992). Bacterial resistance against the newer topical antibiotics, such as mupirocin ointment and fusidic acid ointment, is increasing (Alsterholm 2010; de Neeling 1998). Another advantage of the newer topical antibiotics is that mupirocin is never, and fusidic acid not often, used systemically.
How the intervention might work
All treatment options listed above aim to either eradicate or prevent growth of the bacteria.
Why it is important to do this review
Guidelines concerning treatment vary widely - some recommend oral antibiotic treatment, others local antibiotic treatment or even just disinfection in mild cases (Hay 1998; Resnick 2000) - so clinicians have many treatment options. The evidence on what works best is not clear. There is potential conflict between what is in the best interest of the individual and what would best benefit the community in terms of cost and the increase in antibiotic resistance.
Objectives
To assess the effects of treatments for impetigo, including waiting for natural resolution.
Methods
Criteria for considering studies for this review
Types of studies
We included randomised controlled trials.
Types of participants
We included people who have impetigo or impetigo contagiosa diagnosed by a medically trained person (and preferably confirmed by bacterial culture). We recorded whether or not bacterial culture was performed. The diagnosis could be either non-bullous or bullous impetigo. Studies using a broader diagnostic category such as 'bacterial skin infections' or 'pyoderma' were eligible if a specific subgroup with impetigo could be identified, for which the results were separately described. Studies on secondary impetigo or impetiginised dermatoses were included.
Types of interventions
We included any program of topical or systemic (oral, intramuscular, or intravenous) treatment, including antibiotics, disinfectants, or any other intervention for impetigo, such as 'awaiting natural response'. We excluded studies that only compared different dosages of the same drug.
Types of outcome measures
Primary outcomes
1) Cure as defined by clearance of crusts, blisters, and redness as assessed by the investigator.
2) Relief of symptoms such as pain, itching, and soreness as assessed by participants.
Secondary outcomes
1) Recurrence rate.
2) Adverse effects such as pain, allergic sensitisation, and complications.
3) Development of bacterial resistance.
Search methods for identification of studies
We aimed to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
We updated our searches of the following databases on 27 July 2010:
- the Cochrane Skin Group Specialised Register using the following search terms: (impetig* or pyoderma or ((staphylococc* or streptococc*) and skin and infection*)) and (therap* or treatment* or intervention*);
- the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library using the search strategy in Appendix 1;
- MEDLINE (from 2005 to the present) using the search strategy in Appendix 2;
- EMBASE (from 2007 to the present) using the search strategy in Appendix 3; and
- LILACS (Latin American and Caribbean Health Science Information database, from 1982 to the present) using the search strategy in Appendix 4.
Please note: The UK and US Cochrane Centres have an ongoing project to systematically search MEDLINE and EMBASE for reports of trials which are then included in the CENTRAL database. Searching has currently been completed in MEDLINE, from inception to 2004 and in EMBASE, from inception to 2006. Further searches of these two databases to cover the years not searched by the UK and US Cochrane Centres for CENTRAL were undertaken for this review as described above.
A final prepublication search for this review was undertaken on 16 August 2011. Although it has not been possible to incorporate RCTs identified through this search within this review, relevant references are listed under Studies awaiting classification. They will be incorporated into the next update of the review.
Ongoing Trials
We updated our searches of the following ongoing trials databases on 3 August 2010, using the terms 'impetigo' and 'pyoderma':
- The metaRegister of Controlled Trials (www.controlled-trials.com).
- The US National Institutes of Health Ongoing TrialsRegister (www.clinicaltrials.gov).
- The Australian New Zealand Clinical Trials Registry (www.anzctr.org.au).
- The World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch).
- The Ongoing Skin Trials Register (www.nottingham.ac.uk/ongoingskintrials).
Searching other resources
Handsearching
We handsearched the Yearbook of Dermatology (1938 to 1966) and the Yearbook of Drug Therapy (1949 to 1966) for the pre-PubMed era.
References from published studies
We checked references from published studies, including secondary review articles, for further studies.
Unpublished literature
We corresponded with authors and pharmaceutical companies to search for unpublished studies and grey literature.
Language
We did not apply any language restrictions.
Data collection and analysis
Selection of studies
Two authors (JCvdW and SK or RvdS) independently read all abstracts or citations of trials. If one of the authors thought the article might be relevant, a full copy of the article was acquired for further data collection. The reasons for exclusion were recorded for every excluded abstract or citation. Only full reports were included. Two authors independently screened all full-copy articles (LvSS, SK, RvdS, JCvdW). The articles were selected according to the inclusion criteria. Reasons for exclusion were recorded on a specially-designed registration form (see the 'Characteristics of excluded studies' table). In the case of doubt, the opinion of a third author was obtained. Many trials studied a range of (skin) infections including impetigo. Frequently, the results of the subgroup of impetigo participants were not reported separately. In these studies, provided they were published in the last 10 years, we contacted trial authors and asked them to provide the results of the subgroup of impetigo participants. We obtained data in this way in only two instances (Blaszcyk 1998; Claudy 2001).
Data extraction and management
Two authors (ADM and CCB), using a pre-piloted data abstraction form, carried out the full data extraction. The form contained key elements such as time and setting of the study, participant characteristics, bacterial characteristics, type of interventions, outcomes, and side-effects. We resolved disagreements with the help of a third author (SK).
For this update, RvdS and JCvdW carried out data extraction from newly included papers. When studies assessed outcome measures more than once, we included the assessment that was nearest to one week after the start of therapy. When studies had more than two arms and two of these arms were different dosages of the same drug, we combined these arms.
Assessment of risk of bias in included studies
Assessment of methodological quality
Two independent authors (JCvdW, RvdS and/or AV) assessed the methodological quality of all trials according to the updated guidelines (Higgins 2008). Because we could not read the Japanese study by Ishii 1977, this 'Risk of bias' table was completed by Tetsuri Matsumura. The two studies on which authors of this review were co-authors (Koning 2003; Koning 2008) were assessed by other authors. The items that were addressed are shown in the 'Risk of bias' table. For feasibility reasons, the methodological quality assessment was not performed under masked conditions. There is no consensus over whether assessment should be done blinded for authors, institutions, journal, or publication year (Jadad 1998).
Unit of analysis issues
In the case of studies with more than two treatment arms, we deemed that pooling these studies under separate comparisons, without adjustment, would result in unit-of-analysis errors (overcounting). Should this have occurred, the problem was to be solved by dividing the group size by the number of comparisons.
Assessment of heterogeneity
We used the I² statistic to assess statistical heterogeneity, with I² statistic > 50% regarded as substantial heterogeneity.
Data synthesis
Where there was no statistical evidence of heterogeneity we used the fixed-effect model to estimate effects. Otherwise, we used the random-effects model. For dichotomous outcomes we reported risk ratios with 95% confidence intervals.
Sensitivity analysis
We prespecified the following factors for sensitivity analyses:
- the quality of the studies;
- whether there was observer blinding;
- whether there was just a clinical diagnosis or bacterial swab confirmation;
- primary versus secondary impetigo;
- bullous versus non-bullous; and
- staphylococcal or streptococcal predominance.
During the update, we decided that an overall quality score per study was not useful. Furthermore, most trials were observer-blind, took bacterial swabs, studied primary impetigo, and had staphylococcal predominance. Sensitivity analyses for these items were, therefore, not possible.
When we analysed the data we decided to consider the results for bullous and non-bullous impetigo separately.
Results
Description of studies
See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies.
Results of the search
Our initial search identified approximately 700 papers, 221 of which were selected for full copy reading. For this update, we identified more than 1000 additional papers. Two reviewers screened titles and abstracts, after which, approximately, 60 papers were studied in full copy.
Included studies
For the first version of the review we included 56 papers describing 57 trials. This update identified 12 additional studies, of which 2 were published before 2000 (Farah 1967; Ishii 1977). One study, which was previously included, was excluded because it turned out not to be a randomised trial (Park 1993), bringing the total number of included studies to 68. The lists of ongoing studies (Ongoing studies) and studies awaiting assessment (Studies awaiting classification) show studies that might be eligible for a future update of this review. Regarding the excluded studies, we only report on the most relevant ones (Excluded studies; Characteristics of excluded studies).
Most trials were reported in the English language. Four included studies were reported in Japanese, and one paper each was reported in Thai, Portuguese, Spanish, French, and Danish (some of these had abstracts and tables in English). Trials in Russian, Chinese, German, and French were among those that were excluded (not for language reasons). In instances where none of the authors were competent in the language of the paper, translators provided assistance.
We found an appreciable number of studies from the early 1940s (e.g. MacKenna 1945). These studies were often carried out in military populations, in which impetigo was a frequent disease at the time. These study reports did not meet the inclusion criteria of our review because of inadequate randomisation. The distribution of the included studies by decade is as follows: 1960s - 1 study, 1970s - 5 studies (7%), 1980s - 31 studies (46%), 1990s - 20 studies (29%), and 2000 to 2008 - 11 studies (16%). Five included studies evaluating mupirocin were presented at an international symposium in 1984; we found no publication other than the conference proceedings for three of these (Kennedy 1985; Rojas 1985; Wainscott 1985). Two were published elsewhere as well (Eells 1986; Gould 1984).
Design
All studies were parallel group trials, but there were important design differences between the studies. As mentioned before, many trials included participants with infections other than impetigo, while some trials studied only impetigo. Ages of included participants differed widely, as some studies were carried out exclusively in either adults or children. The average age of study participants in trials that studied a range of skin infections was usually higher than in studies focusing on impetigo alone. With the exception of four studies (Faye 2007; Ishii 1977; Rice 1992; Vainer 1986), all studies performed bacteriological investigations. Although a number of studies explicitly stated that participants with a negative culture were excluded, other studies may also have excluded culture negative participants without reporting those exclusions. No study reported a predominantly streptococcal impetigo. The only studies not to report a preponderance of staphylococcal impetigo were Mertz 1989 and Ruby 1973 (carried out in Puerto Rico and Texas respectively).
Sample sizes
The 68 studies had a total of 5578 evaluable participants; this is an average of 82 participants and a median of 60.5 participants per study (see the 'Characteristics of included studies' tables). In 23 studies the number of participants with impetigo was less than 50; in 10 studies it was less than 20.
Setting
Twenty-nine of the studies were carried out in North America (in 13 Canadian/Northern states, in 8 Southern states, in 8 multicentres), 15 in Europe, 9 in Central/South America, 10 in Asia, 1 in Africa, and 4 were worldwide multicentre trials. Most studies were carried out in hospital out-patient clinics (paediatrics or dermatology, 60 studies), but some were carried out in general practice.
Participants
Only three studies exclusively addressed participants with bullous impetigo (Dillon 1983; Ishii 1977; Moraes Barbosa 1986). Seven trials included both bullous and non-bullous impetigo participants (Barton 1989; Ciftci 2002; Dagan 1992; Koning 2008; Kuniyuki 2005; Oranje 2007; Pruksachat 1993). Three studies on secondary impetigo were included (Fujita 1984; Rist 2002; Wachs 1992). Three other trials included both primary and secondary impetigo participants (Faye 2007; Gonzalez 1989; Tamayo 1991). Thirty-nine trials studied impetigo alone whereas 29 trials studied participants with a range of (usually skin) infections, impetigo being 1 of them. This was the typical study design when a new antibiotic was studied. This type of study design imposed problems in retrieving outcome data as the outcomes were often presented for all the participants together. We included these studies only if the main outcome measure was presented separately for the subgroup of impetigo participants.
Interventions
The 68 trials evaluated 50 different treatments (26 oral treatments and 24 topical treatments - both including placebo). The systemic treatments that were studied were all administered orally (tablets). A total of 74 different comparisons were made. Some comparisons were made in several studies; some studies made more than one comparison. Sixty-eight comparisons were made only once. Six different comparisons were made in more than 1 trial, especially when topical mupirocin was studied (topical mupirocin versus oral erythromycin was considered in 10 studies, mupirocin versus fusidic acid was considered in 4 studies, mupirocin versus placebo was considered in 3 studies). For each of these comparisons we pooled the outcomes of the different studies (see Data and analyses).
The most common type of comparison was between 2 different oral antibiotic treatments (29 studies including duplicates). Cephalosporins (15 studies) and macrolide antibiotics, especially erythromycin and azithromycin (9 studies), were most often involved. A topical antibiotic treatment was compared with an oral antibiotic treatment in 22 studies. Nineteen of these comparisons contained erythromycin, mupirocin, or both.
Only two trials studied antiseptic or disinfecting treatments (Christensen 1994; Ruby 1973).
Only seven placebo controlled trials were found (Eells 1986; Gould 1984; Ishii 1977; Koning 2003; Koning 2008; Rojas 1985; Ruby 1973). The latter is the only trial that compared an oral treatment with placebo.
Three studies had three arms but the treatment in two of these were different dosages of the same drug (Blaszcyk 1998; Bucko 2002a; Bucko 2002b). We combined these arms. Nine other studies had more than two arms but with different treatments: three arms (Bass 1997; Demidovich 1990; Dux 1986; Rodriguez-Solares 1993; Vainer 1986; Wachs 1976), four arms (Kuniyuki 2005; Moraes Barbosa 1986), and five arms (Ruby 1973). Only two of the comparisons in these multiple-arm studies could be pooled with other studies: erythromycin versus penicillin V from Demidovich 1990, and mupirocin versus erythromycin from Dux 1986. For this reason we refrained from adjusting for multiple treatment comparisons.
Outcomes
Cure as assessed by investigator was our main outcome measure. This was often not defined. Researchers sometimes combined the categories 'cured' and 'improved' and presented those participants as one group. The length of follow-up varied widely, and it was sometimes not even specified; however, we tried to retrieve the data for follow up as close as possible to seven days after the start of treatment. The development of bacterial resistance to the study drug was reported in only 10 studies.
Excluded studies
One hundred and sixty-five of the studies did not meet the inclusion criteria for the first version of the review, and 33 more were excluded when updating the review (see the 'Characteristics of excluded studies' tables). The most common reasons included the following: the study was not about impetigo, the outcomes of impetigo participants were not reported separately, or studies were not randomised.
Studies awaiting classification
In the previous version of this review, four studies were awaiting classification. For this update two of these studies were included (Ciftci 2002; Claudy 2001) and two were excluded (Liu 1986; Parish 2000).
Ten studies that were found during the update process are listed in the 'Characteristics of studies awaiting classification' tables, as are a further 6 studies that were identified at the prepublication search. We are currently unable to include or exclude these due to insufficient information about them. We hope to fully incorporate them into future updates of this review.
Ongoing studies
Seven studies that were found during the update process are listed in the 'Characteristics of ongoing studies' tables. These will be fully incorporated into future updates of this review when they are completed.
Risk of bias in included studies
For many of the items that were assessed, the studies did not provide enough information (Figure 1; Figure 2).
 | Figure 1. Methodological quality summary: review authors' judgements about each methodological quality item for each included study. |
 | Figure 2. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies. |
Sequence generation
Fourteen of the studies reported an adequate generation of the randomisation scheme. All other papers did not report on this item.
Allocation
All but two of the included studies were described as randomised as this was a selection criterion. For two papers in Japanese, this was unclear, and these papers were given the benefit of the doubt (see Figure 1). Most papers did not describe the method of randomisation in detail, so the method could not be judged as appropriate. Only 19 of the 68 studies provided information on allocation concealment. In most cases (18 of 19), treatment allocation was considered to be concealed.
Blinding
In many cases it was not clear whether the participant, the caregiver, or the outcome assessor were blinded. A total of 15 studies were considered to be adequately blinded (see Figure 1). In 24 studies, at least 1 party was considered not to be blinded. In 29 papers, the information was insufficient to judge blinding.
Inclusion and exclusion criteria of the trials
In 10 of our included studies, the inclusion and exclusion criteria of the trial were not specified in more detail than saying 'patients with impetigo' (see Figure 1).
Incomplete outcome data
In some studies, high numbers lost to follow up were recorded. Thirty-four studies either included an intention-to-treat analysis or had fewer than 10% dropouts balanced between groups. For some other studies, an intention-to-treat analysis could be calculated from the data presented in the study.
Effects of interventions
Primary outcomes: 1) clinical cure
The first primary outcome was clinical cure (or improvement) as assessed by the investigator. When this was assessed more than once, we only included the assessment that was nearest one week from commencement of treatment.
Under the following two main headings ('non-bullous impetigo' and 'bullous impetigo') we have grouped all studies that either included only primary impetigo, combined primary and secondary impetigo, or did not specify whether participants had primary or secondary impetigo. The third heading 'secondary impetigo' addresses all studies that focused exclusively on secondary impetigo (see Background for an explanation).
(a) Non-bullous impetigo
(i) Topical antibiotics
Topical antibiotics versus placebo (six studies, four comparisons)
Overall topical antibiotics showed better cure rates or more improvement than placebo (pooled risk ratio (RR) 2.24, 95% CI 1.16 to 3.13 using a random-effects model, I² = 53%) (see Analysis 1.1). This result was consistent for mupirocin (RR 2.21, 95% CI 1.59 to 3.05; 3 studies - Eells 1986; Gould 1984; Rojas 1985) (see Analysis 1.1), fusidic acid (RR 4.42, 95% CI 2.39 to 8.17; 1 study - Koning 2003) (see Analysis 1.1), and retapamulin (RR 1.64, 95% CI 1.30 to 2.07; 1 study - Koning 2008) (see Analysis 1.1). In one small study (Ruby 1973), bacitracin did not show a significant difference in cure rate compared with placebo (RR 3.71, 95% CI 0.16 to 85.29) (see Analysis 1.1).
Topical antibiotic versus another topical antibiotic (14 studies, 15 comparisons)
Only one topical antibiotic showed superiority over another topical antibiotic - in a single study: gentamycin over neomycin (RR 1.43, 95% CI 1.03 to 1.98; Farah 1967) (see Analysis 2.1). Also from a single study, the difference between retapamulin over fusidic acid was not statistically significant (RR 1.05, 95% CI 1.00 to 1.11; Oranje 2007) (see Analysis 2.1). There were 12 different comparisons: 4 studies (Gilbert 1989; Morley 1988; Sutton 1992; White 1989) compared mupirocin with fusidic acid (RR 1.03, 95% CI 0.95 to 1.11) (see Analysis 2.1), and the remaining 11 were all only represented by a single study.
Topical antibiotics versus oral (systemic) antibiotics (16 studies, 17 comparisons)
Pooling 10 studies which compared mupirocin with oral erythromycin showed significantly better cure rates, or more improvement, with mupirocin (RR 1.07, 95% CI 1.01 to 1.13) (see Analysis 3.1). However, no significant differences were seen between mupirocin and dicloxacillin (Arredondo 1987), cephalexin (Bass 1997), or ampicillin (Welsh 1987). Bacitracin was significantly worse than oral cephalexin in one small study (Bass 1997), but no difference was seen between bacitracin and erythromycin (Koranyi 1976), or penicillin (Ruby 1973).
A sensitivity analysis on the influence of blinding the outcome assessor on the comparison of mupirocin versus erythromycin (10 studies) revealed that there was no clear relationship between blinding of the outcome assessor and the outcome.
Pooling the 2 studies with observer blinding (Britton 1990; Dagan 1992) showed high heterogeneity (I² statistic = 79%) and resulted in a non-significant difference between the 2 drugs (random-effects model, RR 1.12, 95% CI 0.86 to 1.46) (see Analysis 3.2).
Topical antibiotics versus disinfecting treatment (two studies)
In one study (Ruby 1973), no statistically significant difference in cure/improvement was seen when bacitracin was compared to hexachlorophene (RR 3.71, 95% CI 0.16 to 85.29) (see Analysis 4.1). In another study (Christensen 1994), there was a tendency for fusidic acid cream to be more effective than hydrogen peroxide, but this just failed to reach statistical significance (RR 1.14, 95% CI 1.00 to 1.31) (see Analysis 4.1). When the 2 studies were pooled, topical antibiotics were significantly better than disinfecting treatments (fixed-effect model, RR 1.15, 95% 1.01 to 1.32, I² statistic 0%) (see Analysis 4.1).
Topical antibiotic versus antifungal (one study)
Only one study compared a topical antibiotic to an antifungal, comparing topical mupirocin to topical terbinafine (Ciftci 2002). No statistical difference was seen (RR 1.39, 95% CI 0.98 to 1.96) (see Analysis 5.1).
Topical antibiotic + oral antibiotic vs topical antibiotic + oral antibiotic (one study, three comparisons)
In a four-armed study, three arms addressed the following combinations of a topical antibiotic and an oral antibiotic: topical tetracycline combined with oral cefdinir compared to topical tetracycline combined with oral minomycin, topical tetracycline combined with oral cefdinir compared to topical tetracycline combined with oral fosfomycin, and topical tetracycline combined with oral minomycin compared to topical tetracycline combined with oral fosfomycin (Kuniyuki 2005). None of the three comparisons showed a statistically significant difference (see Analysis 6.1).
Topical antibiotic versus topical antibiotic + oral antibiotic (one study, three comparisons)
The fourth arm of the study described under the previous heading (Kuniyuki 2005) was tetracycline. None of the comparisons with the other three treatments (see above) showed a statistically significant difference (see Analysis 7.1).
(ii) Oral antibiotics
Oral antibiotics versus placebo (one study)
A single study (Ruby 1973) found no significant difference between oral penicillin and placebo (RR 7.74, 95% CI 0.43 to 140.26) (see Analysis 8.1).
Oral antibiotic versus another oral antibiotic: cephalosporin versus another antibiotic (six studies)
All comparisons consisted of single studies (or arms of a single study); only one comparison - cephalexin versus penicillin - showed a significant difference (Demidovich 1990) (see Analysis 9.1).
Oral antibiotic versus another oral antibiotic: one cephalosporin versus another cephalosporin (seven studies)
No significant differences were seen between cephalexin and cefadroxil (Hains 1989), cefdinir (Giordano 2006; Tack 1997; Tack 1998); cefaclor and cefdinir (Arata 1989a), or cefditoren and cefadroxil (Bucko 2002b). Cefditoren turned out to be less effective than cefuroxime (Bucko 2002a) (see Analysis 10.1).
Oral antibiotic versus another oral antibiotic: macrolides (erythromycin, azithromycin, clindamycin) versus penicillins (penicillin V, dicloxacillin, amoxacillin, cloxacillin, flucloxacillin) (seven studies)
In two studies (Barton 1987; Demidovich 1990), erythromycin showed a better cure rate or more improvement than penicillin (pooled fixed-effect model, RR 1.29, 95% CI 1.07 to 1.56, I² statistic 0%) (see Analysis 11.1). The other five comparisons consisted of single studies, and they did not show significant differences between macrolides and penicillins.
Oral antibiotic versus another oral antibiotic: macrolide versus another macrolide (one study)
In a single study (Daniel 1991a), no difference in cure rate or improvement was seen between azithromycin and erythromycin (RR 1.18, 95% CI 0.88 to 1.58) (see Analysis 12.1).
Oral antibiotic versus another oral antibiotic: penicillin versus other oral antibiotics (including other penicillins) (four studies)
In 1 study (Dagan 1989), amoxicillin plus clavulanic acid showed a better cure rate than amoxicillin alone (RR 1.40, 95% CI 1.04 to 1.89) (see Analysis 13.1), but when amoxicillin plus clavulanic acid was compared with fleroxacin in another study (Tassler 1993), no significant difference was seen (RR 1.14, 95% CI 0.80 to 1.62) (see Analysis 13.1). Cloxacillin was significantly superior to penicillin in 2 studies (Gonzalez 1989; Pruksachat 1993) although these studies were statistically heterogeneous (I² statistic 57%) (pooled RR 1.59, 95% CI 1.21 to 2.08) (see Analysis 13.1).
Other comparisons of oral antibiotics (two studies)
In two studies (Arata 1989b; Claudy 2001), no difference in cure rates/improvement could be detected between lomefloxacin and norfloxacin nor between (oral) fusidic acid and pristinamycin (see Analysis 14.1).
Oral antibiotics versus disinfecting treatments (one study)
In a single small study (Ruby 1973), no difference in cure rates/improvement could be detected between penicillin and hexachlorophene (RR 7.74, 95% CI 0.43 to 140.26) (see Analysis 15.1).
(iii) Disinfecting treatments
Disinfecting treatments versus placebo (one study)
In a single small study (Ruby 1973), no participants in either the hexachlorophene (n = 11) or placebo group (n = 13) showed cure or improvement. Comparisons of disinfecting treatments with antibiotics are given above.
(b) Bullous impetigo
(i) Topical antibiotics
Topical antimicrobial versus placebo (one study)
In one study (Ishii 1977), topical Eksalbe simplex (a drug containing killed Eschelichia, Staphylococcus, Streptococcus, and Pseudomonas) was compared to placebo. The active drug turned out to be superior (cure/improvement RR 2.30, 95% CI 1.10 to 4.79) (see Analysis 16.1).
Topical antibiotics versus other topical antibiotics (one study, three comparisons)
In a small study (Moraes Barbosa 1986), fusidic acid was significantly more effective than both neomycin/bacitracin (RR 10.00, 95% CI 1.51 to 66.43) (see Analysis 17.1) and chloramphenicol (RR 5.00, 95% CI 1.38 to 18.17) (see Analysis 17.1). In the same study, no difference was detected between chloramphenicol and neomycin/bacitracin (RR 2.00, 95% CI 0.21 to 19.23) (see Analysis 17.1).
Topical antibiotics versus oral antibiotics (one study, three comparisons)
The same study (Moraes Barbosa 1986) showed that neomycin/bacitracin was significantly less effective than oral erythromycin (RR 0.14 95% CI 0.02 to 0.99) (see Analysis 18.1). There was no significant difference between either erythromycin and fusidic acid (RR 1.43, 95% CI 0.83 to 2.45) (see Analysis 18.1) or chloramphenicol (RR 0.29, 95% CI 0.07 to 1.10) (see Analysis 18.1).
(ii) Oral antibiotics
Oral antibiotic versus another oral antibiotic (one study)
No significant difference was seen between cephalexin and dicloxacillin (Dillon 1983; RR 1.17, 95% CI 0.95 to 1.45) (see Analysis 19.1).
(c) Secondary impetigo
(i) Topical antibiotics
Topical antibiotic versus oral antibiotic (one study)
No significant difference was seen between mupirocin and cephalexin (Rist 2002) (see Analysis 20.1).
Antibiotic versus steroid versus antibiotic plus steroid (one study)
In a three-armed study (Wachs 1976), the comparisons of betamethasone with gentamycin alone or with betamethasone plus gentamycin did not show significant differences (see Analysis 21.1 and Analysis 22.1). The combination of betamethasone and gentamycin cream was significantly more effective than gentamycin alone (RR 2.43, 95% CI 1.29 to 4.57) (see Analysis 23.1).
(ii) Oral antibiotics
In a very small study, no significant difference was detected between cephalexin and enoxacin (Fujita 1984) (see Analysis 24.1).
Primary outcomes: 2) relief of symptoms
The second primary outcome was relief of symptoms, such as pain, itching, and soreness, as assessed by study participants. Although some studies asked about overall satisfaction, acceptability, or treatment preference (McLinn 1988; Rice 1992; Rist 2002; Sutton 1992; White 1989), only one study asked participants to rate their symptoms at follow-up (Giordano 2006). However, this was a study addressing not only impetigo but other skin infections as well, and results for this outcome were not reported for impetigo separately.
Secondary outcomes: 1) recurrence rate
No relevant data were provided by any study for this outcome.
Secondary outcomes: 2) adverse effects
(i) Topical antibiotics
The trials included in this review usually reported few, if any, side-effects from topical antibiotics (see Table 1). The studies comparing mupirocin, bacitracin, and placebo reported none (Eells 1986; Ruby 1973). The study that compared fusidic acid to placebo recorded more side-effects in the placebo group (Koning 2003). Three of 4 studies comparing mupirocin with fusidic acid recorded side-effects: minor skin side-effects were reported for mupirocin by 10 out of 368 participants (3%) and for fusidic acid by 4 out of 242 participants (2%). The study that compared retapamulin to placebo found more itching in the group treated with retapamulin (7% vs 1%; P = 0.17) (Koning 2008). In the other study of retapamulin, this side-effect was reported in less than 1% of cases (Oranje 2007). Most other trials comparing topical antibiotics reported no side-effects or reported minor skin side-effects in low numbers (less than 5% of participants).
Topical versus oral treatments
Of the 10 trials comparing erythromycin with mupirocin, 9 reported side-effects. All trials recorded more side-effects from erythromycin, with the exception of two trials (Britton 1990 - equally divided minor gastrointestinal side-effects - and Rice 1992 - nil reported). Gastrointestinal side-effects (nausea, stomach ache, vomiting, diarrhoea) were recorded in 80 out of 297 participants (27%) in the erythromycin groups, versus 17 out of 323 participants (5%) in the mupirocin groups. Skin side-effects (itching, burning) were recorded in 5 out of 297 participants (2%) in the erythromycin groups versus 23 out of 323 participants (7%) in the mupirocin groups. Most other trials comparing topical and oral antibiotics did not record data on side-effects (see Table 1).
(ii) Oral antibiotics
Eleven of the 31 trials comparing oral antibiotics did not report on side-effects (see Table 1). Three of the 6 trials that studied erythromycin recorded side-effects; the highest frequency was reported by Faye 2007: 11/65 participants reported gastrointestinal side-effects (mainly diarrhoea). The other trials, usually making unique comparisons, mainly reported gastrointestinal side-effects in small percentages. In five trials, a considerable difference in side-effects was reported. Gastrointestinal complaints were recorded in 1 out of 113 participants (10%) in the enoxacin group compared to 4 out of 110 participants (4%) in the cefalexin group (Fujita 1984). Fourteen out of 327 (4%) of the cefadroxil-treated participants versus 2 out of 234 (1%) flucloxacillin-treated participants had 'severe' side-effects, such as stomach ache, rash, fever, and vomiting (Beitner 1996). Cefaclor caused more diarrhoea than amoxicillin plus clavulanic acid (5 out of 16 participants (31%) vs 2 out of 18 participants (11%)) (Jaffe 1985). Pristinamycin caused more upper and lower gastrointestinal side-effects than oral fusidic acid (12% vs 7% and 17% vs 2%, respectively) (Claudy 2001). Finally, the clindamycin group of participants reported more side-effects (any side-effect) than the dicloxacillin-treated group (Blaszcyk 1998).
(¡¡¡) Disinfecting treatments
Eleven per cent of the participants using hydrogen peroxide cream reported mild side-effects (not specified) versus seven per cent in the fusidic acid group (Christensen 1994). No participant was withdrawn from the study because of side-effects. No adverse effects of scrubbing with hexachlorophene were recorded (Ruby 1973) (see Table 1).
Secondary outcomes: 3) Development of bacterial resistance
Most studies either did not report on susceptibility of isolated pathogens to the study drugs or presented only baseline data. Ten studies provided information on the development of resistance to the study drug during the study period (Barton 1988; Bucko 2002a; Bucko 2002b; Dagan 1992; Giordano 2006; Goldfarb 1988; Gould 1984; Tack 1998; Tassler 1993; White 1989). In most of these studies, none or only a few of the participants' pathogens had developed resistance. The only exception was Dagan 1992, where 14/18 (78%) of positive cultures after 3 days of follow-up showed resistance to erythromycin, compared to 27/91 (28%) at baseline. The other study that included erythromycin (Goldfarb 1988) showed only 3% (1/32) resistance at follow-up.
Discussion
Summary of main results
Overall, topical antibiotics showed better cure rates than topical placebo. No differences were found between the two most studied topical antibiotics: mupirocin and fusidic acid. Topical mupirocin was superior to oral erythromycin. In most other comparisons, topical and oral antibiotics did not show significantly different cure rates, nor did most trials comparing oral antibiotics. Penicillin V was inferior to erythromycin and cloxacillin, and there is a lack of evidence to suggest that using disinfectant solutions improves impetigo.
The reported number of side-effects was low. Oral antibiotic treatment caused more side-effects, especially gastrointestinal ones, than topical treatment. A striking finding is that the trials comparing erythromycin with mupirocin recorded more (gastrointestinal) side-effects in the erythromycin group than the trials that compared erythromycin with other oral antibiotics.
Overall completeness and applicability of evidence
The large number of treatments evaluated (50) supports the view that there is no widely accepted standard therapy for impetigo. Most studies did not contribute clear answers about the vast choice of treatment options. Many of the studies were underpowered; this is partly due to the fact that many trials included several skin infections, impetigo being only one of them (these studies are directed at the drug rather than at the disease). In many cases, significant differences became insignificant when impetigo participants were considered after excluding participants with other sorts of infection. Another drawback of this type of study is that the age of participants is much higher than the typical age at which people contract impetigo (e.g. Blaszcyk 1998; Bucko 2002a; Bucko 2002b; Kiani 1991). The dosage of studied antibiotics may differ between studies, complicating the comparability of studies; however, the same doses were usually used (e.g. erythromycin 40 mg/kg/day). Cure rates of specific treatments can be different between studies, e.g. of fusidic acid and mupirocin (Sutton 1992; White 1989). This may be explained by the fact that investigations were done in different regions and times, and inclusion criteria differed.
Little is known about the 'natural history' of impetigo. Therefore, the paucity of placebo-controlled trials is striking, given that impetigo can be considered a minor disease. Only seven placebo-controlled studies have been conducted (Eells 1986; Gould 1984; Ishii 1977; Koning 2003; Koning 2008; Rojas 1985; Ruby 1973). The 7-day cure rates of placebo groups in these studies varied but can be considerable (0% to 42%).
The disinfectant agents, such as povidone iodine and chlorhexidine, recommended in some guidelines (Hay 1998; Resnick 2000), usually as supplementary treatment, have been inadequately studied and not compared to placebo treatment. Hydrogen peroxide cream was not significantly less effective than fusidic acid (cure rate 72% versus 82%) in a relatively large trial (Christensen 1994). We judged that blinding in this trial was inadequate.
There is a commonly accepted idea that more serious forms of impetigo (e.g. participants with extensive lesions, general illness, fever) need oral rather than topical antibiotic treatment. This principle cannot be evaluated using the data included in our review as trials that study local treatments usually exclude participants with more serious forms of impetigo.
One of our primary outcomes was relief of symptoms, such as pain, itching, and soreness, as assessed by participants (or parents). Surprisingly, only one of the studies addressed this outcome (Giordano 2006).
Resistance patterns of staphylococci - which causes impetigo - change over time. Outcomes of studies dating back more than 10 years, which form the majority of trials in this review, may not be applicable to the current prevalence of infecting agents. Also, resistance between regions and countries may vary considerably. Thus, up-to-date, local characteristics and resistance patterns of the causative bacteria should always be taken into account when choosing antibiotic treatment. In addition, health authorities and other relevant bodies may advise against prescribing certain antibiotics for impetigo, in order to restrict the development of bacterial resistance and reserve these drugs for more serious infections.
Quality of the evidence
Although the total number of randomised trials we identified was considerable, the average number of participants per study was small. In this update, the newly added studies made this average increase from 62 to 84 per study. This was partly due to studies that assessed a range of infections and randomised a large number of participants, but in which those with impetigo were only a minority. Through the years, we found an increase in the quality of the studies; the average number of items scored positively increased from less than three in the 1970s to almost five for studies published in the new millennium. This is a problem shared with many other reviews. Details of the design of the studies were often lacking in the published reports, leading to a lot of question marks in the 'Risk of bias' tables.
Potential biases in the review process
Several studies included participants with impetigo next to participants with other conditions, but they did not report results of those with impetigo separately. However, as the number of participants with impetigo was often small in these studies, we do not expect that our conclusions would be different.
Three authors on this review are authors of one included trial (Sander Koning, Lisette WA van Suijlekom-Smit, Johannes C van der Wouden; Koning 2003), Sander Koning and Johannes C van der Wouden were also involved in a second trial (Koning 2008) which was initiated by the manufacturer of the drug. These authors were not involved in the assessment of the risk of bias for both studies.
Agreements and disagreements with other studies or reviews
Topical mupirocin and fusidic acid can be considered as effective as, or more effective than, oral antibiotics, and these topical agents have fewer side-effects. This finding is in sharp contrast to the previously held view that oral treatment is superior to topical treatment (Baltimore 1985; Tack 1998). Other topical antibiotics, excluding retapamulin, were generally inferior to mupirocin, fusidic acid, and oral antibiotics. The study by Vainer is an exception: no difference was seen between tetracycline/bacitracin cream, neomycin/bacitracin cream, and fusidic acid (Vainer 1986). Fusidic acid, mupirocin, and retapamulin are the only topical antibiotics that have been compared to placebo (and shown to be more effective).
For the results of the study comparing topical fusidic acid to retapamulin (Oranje 2007), the P value computed by Review Manager (RevMan) differs from the study report (0.07 in RevMan vs 0.062 in the study report) due to different methods (94.8% vs 90.1% cure, favouring retapamulin).
None of the studies reported cases of acute (post-streptococcal) glomerulonephritis. This complication has always been an important rationale for oral antibiotic treatment. This reported absence of glomerulonephritis may reflect the reduced importance of streptococci in impetigo. It should be noted that study sizes are small and glomerulonephritis is rare.
Several of the interventions used for impetigo have also been applied in other situations where Staphylococcus aureus, the main bacterium causing impetigo, plays a role. Here we review some of these, as reported in recently published Cochrane reviews. The effect of mupirocin ointment for preventing S. aureus infections in nasal carriers was superior to that of placebo or no treatment (van Rijen 2008). Birnie 2008 assessed interventions to reduce S. aureus in the management of atopic eczema, but the review did not find clear evidence of benefit for any of these. A review of the treatment of bacteraemia due to S. aureus is under way (Cheng 2009), as is a review of antibiotics for S. aureus pneumonia in adults (Shankar 2007). Mastitis in breastfeeding women is also caused by S. aureus. A recent Cochrane review found insufficient evidence to confirm or refute the effectiveness of antibiotic therapy (Jahanfar 2009).
Authors' conclusions
Implications for practice Implications for topical disinfectants in clinical practice There is a lack of evidence from RCTs for the value of disinfecting measures in the treatment of impetigo, as a sole or supplementary treatment. Implications for topical antibiotics in clinical practice There is good evidence that the topical antibiotics mupirocin and fusidic acid are equal to, or possibly more effective than, oral treatment for people with limited disease. Fusidic acid, mupirocin, and retapamulin are probably equally effective; other topical antibiotics seem less effective. In general, oral antibiotics have more side-effects than topical antibiotics, especially gastrointestinal side-effects. Implications for use of systemic antibiotics in clinical practice What is stated in the previous paragraph regarding the comparison with topical antibiotics is equally relevant here. The only oral antibiotic that has been compared to placebo is penicillin, and this was in an old study (Ruby 1973): no difference was found, and the confidence interval was large. Based on the available evidence on efficacy, no clear preference can be given for B-lactamase resistant narrow-spectrum penicillins such as cloxacillin, dicloxacillin and flucloxacillin, or for broad spectrum penicillins such as ampicillin, amoxicillin with clavulanic acid, cephalosporins or macrolides. General considerations regarding the choice of antibiotics Other criteria, such as price, (unnecessary) broadness of spectrum, and wish to reserve a particular antibiotic for specific conditions, can be decisive. Resistance rates against erythromycin seem to be rising. In general, oral antibiotics have more side-effects, especially gastrointestinal ones. There is insufficient evidence to say whether oral antibiotics are better than topicals for more serious and extensive forms of impetigo. From a practical standpoint, oral antibiotics might be an easier option for people with very extensive impetigo. |
Implications for research Trials should be powered to compare treatments for a specific disease entity, rather than the effectiveness of a specific antibiotic on a variety of (skin) infections, as treatment may impact differently on separate subtypes of skin and soft tissue infections. As seen in this review, trials that study one treatment for several diseases often show inconclusive results for specific diagnoses. Future research on impetigo should make a careful power calculation as most included studies included too few participants with impetigo to meaningfully assess differences in treatment effect. Establishing the natural course of impetigo without any form of antibiotic treatment would be useful. However, although impetigo can be considered a minor ailment, studies with a non-intervention arm seem ethically impracticable. Comparator treatments may include the best identified options for non-antibiotic management. The relative absence of data on the efficacy of topical disinfectants is a research gap that needs to be filled. These agents may not contribute to antibiotic resistance, and they are cheap. This research may be of particular importance for developing countries. Preferably, a trial on impetigo should:
As part of the issue of antibiotic resistance, impetigo studies that establish the contribution of the studied treatment to the development of bacterial resistance are desirable. |
Acknowledgements
The authors would like to thank the following people from the editorial base for their substantial contribution to this review: Finola Delamere, Philippa Middleton, and Tina Leonard. They would also like to thank Seungsoo Sheen for his help in assessing a Korean paper, Mingming Zhang for assessing two Chinese papers, Alain Claudy for providing the outcomes for the participants with impetigo in his study, and Tetsuri Matsumura for assessing the risk of bias and extracting data from Ishii 1977.
The Cochrane Skin Group editorial base would like to thank the following people who commented on this update: our Key Editor Sue Jessop, our Statistical Editor Jo Leonardi-Bee, our Methodological Editor Philippa Middleton, Inge Axelson who was the clinical referee, and Philip Pocklington who was the consumer referee.
Data and analyses
- Top of page
- Background
- Objectives
- Methods
- Results
- Discussion
- Authors' conclusions
- Acknowledgements
- Data and analyses
- Appendices
- What's new
- History
- Contributions of authors
- Declarations of interest
- Sources of support
- Differences between protocol and review
- Notes
- Index terms
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Appendices
Appendix 1. CENTRAL search strategy
#1(impetig* or pyoderma ):ti
#2MeSH descriptor Impetigo explode all trees in MeSH products
#3(#1 OR #2)
#4SR-SKIN in All Fields in all products
#5(#3 AND NOT #4)
Appendix 2. MEDLINE (OVID) search strategy
1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. clinical trials as topic.sh.
6. randomly.ab.
7. trial.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. (animals not (human and animals)).sh.
10. 8 not 9
11. exp Staphylococcal Infections/ or stapylococcal skin infections.mp.
12. impetigo.mp. or exp Impetigo/
13. exp Pyoderma/ or pyoderma.mp.
14. 11 or 13 or 12
15. 10 and 14
Appendix 3. EMBASE (OVID) search strategy
1. random$.mp.
2. factorial$.mp.
3. (crossover$ or cross-over$).mp.
4. placebo$.mp. or PLACEBO/
5. (doubl$ adj blind$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
6. (singl$ adj blind$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
7. (assign$ or allocat$).mp.
8. volunteer$.mp. or VOLUNTEER/
9. Crossover Procedure/
10. Double Blind Procedure/
11. Randomized Controlled Trial/
12. Single Blind Procedure/
13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
14. impetigo.mp. or exp IMPETIGO/
15. exp PYODERMA/ or pyoderma.mp.
16. exp Staphylococcus Aureus/ or stapylococcus aureus.mp.
17. 16 or 15 or 14
18. 13 and 17
Appendix 4. LILACS search strategy
((Pt RANDOMIZED CONTROLLED TRIAL OR Pt CONTROLLED CLINICAL TRIAL OR Mh RANDOMIZED CONTROLLED TRIALS OR Mh RANDOM ALLOCATION OR Mh DOUBLE-BLIND METHOD OR Mh SINGLE-BLIND METHOD OR Pt MULTICENTER STUDY) OR ((tw ensaio or tw ensayo or tw trial) and (tw azar or tw acaso or tw placebo or tw control$ or tw aleat$ or tw random$ or (tw duplo and tw cego) or (tw doble and tw ciego) or (tw double and tw blind)) and tw clinic$)) AND NOT ((CT ANIMALS OR MH ANIMALS OR CT RABBITS OR CT MICE OR MH RATS OR MH PRIMATES OR MH DOGS OR MH RABBITS OR MH SWINE) AND NOT (CT HUMAN AND CT ANIMALS)) [Palavras] and (impetigo or pyoderma or piodermia or piodermitis or (staphyloccus aureus) or estafilococo) [Palavras]
What's new
Last assessed as up-to-date: 27 July 2010.
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History
Protocol first published: Issue 4, 2001
Review first published: Issue 2, 2004
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Contributions of authors
Conceiving the review - SK, JCvdW, and LvSS
Designing the review - SK, JCvdW, LvSS, CCB, and AM
Co-ordinating the review - SK and JCvdW
Data collection for the review - SK, JCvdW, and RvdS
Developing the search strategy - JCvdW
Undertaking searches - JCvdW, SK, and RvdS
Screening search results - JCvdW, SK, and RvdS
Organising retrieval of papers - JCvdW, SK, and RvdS
Screening retrieved papers against inclusion criteria - LvSS, SK, and RvdS
Appraising quality of papers - JCvdW, AV, and RvdS
Abstracting data from papers - CCB, AM, RvdS, and JCvdW
Writing to trial authors of papers for additional information - SK, RvdS, and JCvdW
Obtaining and screening data on unpublished studies - JCvdW, SK, and RvdS
Data management for the review - SK, RvdS, and JCvdW
Entering data into RevMan - SK, JCvdW, and RvdS
Analysis of data - SK, RvdS, and JCvdW
Interpretation of data - all authors
Providing a methodological perspective - JCvdW
Providing a clinical perspective - SK and CCB
Providing a policy perspective - SK and CCB
Writing the review - SK, RvdS, and JCvdW
Providing general advice on the review - all authors
Securing funding for the review - JCvdW
Performing previous work that was the foundation of current study - LvSS, JCvdW, and SK
Declarations of interest
Three authors of this review are authors of one included trial (Sander Koning, Lisette WA van Suijlekom-Smit, Johannes C van der Wouden; Koning 2003).
Sander Koning and Johannes C van der Wouden were also involved in a second trial (Koning 2008), which was initiated by the manufacturer of the drug. As employees of Erasmus MC, Rotterdam, Johannes C van der Wouden and Sander Koning received research funding from GlaxoSmithKline for participating in a study comparing retapamulin to placebo in participants with impetigo. The funding was used to pay staff involved in field work. They were also involved in publishing the results. The study was included in the update of this review.
Sources of support
Internal sources
- Department of General Practice, Erasmus MC - University Medical Center Rotterdam, Netherlands.
External sources
- No sources of support supplied
Differences between protocol and review
In case of studies assessing cure at more than one point in time, the protocol did not specify what time point to select for data extraction. From the start of the review, we chose the assessment that was closest to one week from the start of treatment.
For this update, the scoring of methodological quality was changed into the newly recommended 'Risk of bias' table (Higgins 2008).We also used risk ratio as recommended by the Cochrane Skin Group.
Notes
Sponsored research
Industry sponsorship or organisation of the trial was declared to be present in 20 trials (29%): 5 mupirocin studies (Goldfarb 1988; Mertz 1989; Rist 2002; Wainscott 1985; White 1989), 2 with cefdinir (Tack 1997; Tack 1998), 2 with cefadroxil (Beitner 1996; Hains 1989), 2 with azithromycin (Daniel 1991a; Daniel 1991b), 2 with cefditoren (Bucko 2002a; Bucko 2002b); 2 with retapamulin (Koning 2008; Oranje 2007); 1 of amoxicillin plus clavulanic acid (Jaffe 1985), cefalexin (Dillon 1983; Giordano 2006), clindamycin (Blaszcyk 1998), and fusidic acid (Sutton 1992). Five trials (9%) were supported by other organisations. In the remaining 48 (67%) trials, no statement of sponsorship or funding was made (see Table 2 'Declared sponsorship or funding').
Index terms
Medical Subject Headings (MeSH)
Administration, Oral; Administration, Topical; Anti-Bacterial Agents [*therapeutic use]; Impetigo [*drug therapy]; Randomized Controlled Trials as Topic
MeSH check words
Humans
* Indicates the major publication for the study