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Nankervis H, Thomas KS, Delamere FM, et al. Scoping systematic review of treatments for eczema. Southampton (UK): NIHR Journals Library; 2016 May. (Programme Grants for Applied Research, No. 4.7.)

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Scoping systematic review of treatments for eczema.

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Chapter 6Antimicrobials including antibiotics, antiseptics and antifungal agents

Background

Antimicrobials refer to a group of agents that share the common aim of reducing the possibility of infection and sepsis. Antibiotics are often derived from moulds or are made synthetically and are absorbed into the body with the aim of killing bacteria (bactericidal) or preventing their multiplication (bacteriostatic). Antibiotics can be given parenterally (intramuscularly, intravenously), orally, or applied topically to the skin in the form of a cream or ointment. Antiseptics on the other hand are substances that are applied to the skin but not absorbed significantly and which are able to reduce the possibility of infection. Disinfectants can destroy micro-organisms including bacteria on non-living objects such as toilets. Antifungal agents are drugs that share the common property of killing or inhibiting the growth of fungi, including yeasts. Antifungals can be given intravenously, orally or topically.

Rationale

The relationship between secondary infection or skin colonisation with the bacterium S. aureus and atopic eczema disease activity has been debated for many years. People with atopic eczema carry S. aureus in about 90% of clinically involved areas and about 75% of clinically uninvolved areas. S. aureus represents about 90% of the total aerobic bacterial flora of such individuals compared with 30% in normal skin. The density of S. aureus tends to increase with the clinical severity of the atopic eczema lesions. It has been suggested that the dry skin of atopic eczema is deficient in certain inhibitory fatty acids, which may encourage growth of the organism. S. aureus may also show enhanced adherence properties to skin cells, which has been shown when comparing atopic eczema sufferers with normal control subjects.240,241 Other studies reviewed elsewhere242,243 have suggested that the balance of pathogenic and synbiotic bacterial species on the skin is altered in atopic eczema, resulting in an agitated skin microbiome.

Few clinicians would dispute that grossly infected atopic eczema with oozing and sore pus spots requires treatment with some form of antibiotic or antiseptic, and that the bacteria are contributing at least in part to that particular flare-up. However, the role of S. aureus in non-clinically infected atopic eczema skin or for borderline infection (e.g. with just redness and oozing) is far from clear and the definition of what constitutes ‘clinically infected atopic eczema’ among physicians is also not clear. Skin swabs taken for bacteriological culture are of little use because of the almost universal colonisation of atopic eczema skin with S. aureus, although such swabs may reveal additional bacteria such as streptococci species.

If S. aureus does play a pathogenic role in atopic eczema, then this could be mediated in a number of ways including direct chemical irritation, a non-specific reaction of the protein A component of the bacterium to immune cells and by the production of specific exotoxins called superantigens. Superantigens are capable of activating large populations of T lymphocytes distant from the site of colonisation, giving rise to widespread eczematous inflammation.

Although in many cases of non-clinically infected atopic eczema, the presence of S. aureus could be considered as an ‘innocent bystander’, which has simply colonised a dry and broken skin surface, there is at least some rationale for considering the role of S. aureus in more acute forms of atopic eczema. This has led to the use of many antimicrobial compounds, such as oral antibiotics that are active against S. aureus given in short or prolonged courses, topically applied antibiotics and antiseptic agents applied directly or by mixing with emollients applied directly to the skin or within bath additives.

Existing systematic reviews

The efficacy of antimicrobials and antiseptics for eczema has been reviewed in a Cochrane review that was published in 2008 by Birnie and colleagues.244 This has since been updated in 2010, although not as a Cochrane review, with a new search ending in March 2009.245 A systematic review in 2007, with a search end date in September 2005, assessed the safety of topical therapies for atopic dermatitis and this included topical antibiotics and antiseptic treatments.80 All three of the current eczema guidelines from the AAD,94 SIGN42 and NICE41 cover antimicrobials and antiseptics.

Scope of this chapter

This chapter is divided into different sections describing the antibiotic, antiseptic and antifungal treatments for which RCTs have been published:

  • antibacterials:
    • topical: fusidic acid, mupirocin, tetracycline
    • oral: clarithromycin, tetracycline
  • antiseptics: triclosan, bleach
  • antifungals:
    • oral: itraconazole, ketoconazole
    • topical: ciclopirox olamine, ketoconazole shampoo, miconazole.

Antibacterials (topical)

Fusidic acid

Fusidic acid (Fucidin®; Leo Laboratories Ltd) is a bacteriostatic agent that inhibits bacterial protein synthesis. Its biological action is attributed to its effect on Gram-positive bacteria such as staphylococcus and streptococcus species.

Studies

There were no studies looking at fusidic acid for eczema before the year 2000.

Three new studies have emerged since 2000.102,150,246 One of the trials, by Ravenscroft and colleagues,246 is discussed in more detail later in this chapter (see Mupirocin).

A four-arm, open-label, parallel-group trial conducted in a single centre in Taiwan by Hung and colleagues150 compared four treatments or treatment combinations: 0.05% fluticasone propionate with 2% fusidic acid cream; 0.05% fluticasone propionate; 0.03% tacrolimus ointment with 2% fusidic acid; and 0.03% tacrolimus ointment. All 60 participants had eczema diagnosed according to the Hanifin and Rajka8 criteria, without overt infection.

Larsen and colleagues102 conducted a European parallel-group multicentre trial consisting of three arms. The trial had industry sponsorship. The three arms consisted of Fucicort® Lipid cream (20 mg/g fusidic acid plus 1 mg/g betamethasone 17-valerate) (LEO Pharma), Fucicort® in a new lipid cream formulation and the lipid cream vehicle alone. The constituents of the new lipid cream were not reported. The 629 participants with a clinical diagnosis of infected eczema aged ≥ 6 years applied the treatments to all areas of eczema apart from the face, twice a day for 2 weeks. If required, participants could use hydrocortisone in a lipocream (Mildison®; Yamanouchi Pharmaceutical Co.) for facial lesions. The participants were also allowed to use an emollient cream (Locobase®; Yamanouchi Pharmaceutical Co.) on the areas not being treated with the trial medication.

Assessment of risk of bias

Table 45 provides the risk-of-bias assessment for the new studies.

TABLE 45

TABLE 45

Fusidic acid: risk of bias of the included studies

Benefits

As reported later in the section on mupirocin, the trial by Ravenscroft and colleagues246 showed a difference in reduction in eczema severity as assessed by the participant-assessed global severity score between those treated with mupirocin and betamethasone and those treated with fusidic acid and betamethasone.

The trial by Hung and colleagues150 found no statistically significant differences in severity (p = 0.81) after 2 weeks of treatment between the group using tacrolimus only and the group using tacrolimus and fusidic acid. There was also no statistically significant difference in severity after 2 weeks between the group treated with fluticasone propionate only and the group using fluticasone propionate and fusidic acid (p = 0.82). There was also no significant difference between these groups after 8 weeks.

The non-inferiority trial by Larsen and colleagues102 reported that the lipid formation of Fucicort was not inferior to the Fucicort cream after 2 weeks of treatment. The difference in the total severity score between the treatments was 0.23% (95% CI –3.83% to 4.30%). However, the Fucicort lipid preparation was superior to the vehicle preparation alone, with an estimated treatment difference for the total severity score of 48.3% (95% CI 41.0% to 55.7%; p < 0.001).

Harms

The only adverse events reported in the trial by Ravenscroft and colleagues246 were minor skin irritation in two participants treated with mupirocin and one participant treated with fusidic acid.

In the trial by Hung and colleagues150 information about adverse events was not reported. Two participants who used a treatment with fusidic acid added were found to have fusidic acid-resistant strains of S. aureus on their skin at the end of the study period.

In the trial by Larsen and colleagues102 the proportion of adverse events in each group was similar; however, only the nature and distribution of the adverse events relating to the skin reactions were reported.

Overall implications for research and practice

The largest trial on fusidic acid serves only to deliver a different vehicle preparation of a topical corticosteroid and fusidic acid preparation to market and is not clinically relevant as there is no comparison with another active treatment.102 The two remaining trials,150,246 which compare different active treatment regimens, were not designed with a primary research question to investigate the effect of fusidic acid on the severity of eczema and so may not be appropriately powered to answer this question. These trials also have a high risk of bias because of inadequate blinding. For clinically infected eczema there is currently no evidence of additional benefit from adding fusidic acid to other topical treatments over adding mupirocin.246 For non-infected eczema, there is no evidence of benefit from adding fusidic acid to short-term topical corticosteroid treatment. Trials that seek to pragmatically answer the question, ‘Which is the most effective treatment regimen for reducing severity and clearing infection in infected eczema?’, are needed to give clinicians the most relevant information for clinical practice. The ChildRen with Eczema, Antibiotic Management (CREAM) trial (HTA 09/118/03) is currently addressing this question [see www.nets.nihr.ac.uk/projects/hta/0911803 (accessed 14 January 2016)].

Mupirocin

Mupirocin (Bactroban®; GlaxoSmithKline) is an antibiotic that is bacteriostatic at low concentrations and bactericidal at high concentrations. It is effective against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA).

Studies

One trial was reported before 200055 (see Appendix 3).

Four new studies have emerged since the 2000 HTA report.55 One of the trials, by Huang and colleagues,205 which used topical mupirocin applied to nasal carriage sites as part of an anti-infective intervention that included bleach baths, is discussed in more detail in the antiseptics section of this chapter.

A trial by Gong and colleagues247 conducted in China compared a dual treatment regimen of the topical corticosteroid hydrocortisone butyrate (Pandel®; Tianjing Yaoye Ji-tuan Co., Ltd) followed by topical mupirocin 1–2 hours later against the dual treatment regimen of the topical corticosteroid hydrocortisone butyrate and the base ointment only 1–2 hours later. The treatments were applied every morning for 28 days. The 119 participants were aged between 2 and 65 years and had eczema as defined by the Hanifin and Rajka8 criteria.

A UK trial by Ravenscroft and colleagues246 compared 2% fusidic acid plus 0.1% betamethasone cream with mupirocin ointment plus 0.1% betamethasone cream. The treatments were applied to all affected areas twice daily for 2 weeks. The trial included 46 participants from the community who had eczema that warranted the use of potent topical corticosteroids for 2 weeks according to an assessing clinician.

A three-arm trial by Canpolat and colleagues248 compared hydrocortisone used concurrently with mupirocin or hydrocortisone with emollient only as a control. All treatments were applied twice daily to affected areas for up to 7 days. The potency of the hydrocortisone and the mupirocin ointment were not reported. Eighty-three infants aged from 6 months to 2 years with mild to moderate eczema based on the Hanifin and Rajka8 criteria and with 2–30% body surface area involvement were randomised.

Assessment of risk of bias

Table 46 provides the risk-of-bias assessment for the new studies.

TABLE 46

TABLE 46

Mupirocin: risk of bias of the included studies

Benefits

The trial by Gong and colleagues247 did not find any difference in eczema severity, measured using the EASI scoring system, between treatment with mupirocin plus hydrocortisone butyrate and treatment with hydrocortisone butyrate alone in the whole trial population. The mupirocin group decreased from a score of 13.9 (SD 8.4) to 1.4 (SD 2.3) and the control group decreased from 13.6 (SD 8.5) to 2.5 (SD 5.2). In what appears to be a post hoc subgroup analysis, a significant beneficial effect was reported from the addition of mupirocin when the EASI severity score was ≥ 7 on the seventh day of treatment; however, this effect was not apparent during the rest of the treatment period. The rates of colonisation by S. aureus showed no significant difference and were reported as matching the improvements in eczema severity.

In the trial by Ravenscroft and colleagues246 the primary objective was not to investigate clinical improvements in eczema; however, the severity of eczema was assessed using both objective and subjective outcomes. A modification of Costa and colleagues’ simple scoring system,249 with a maximum score of 98, showed no significant difference in the change in severity between the two combinations of treatment after 2 weeks. Participant-assessed global severity also showed no significant difference in the change in severity after 2 weeks. Both treatments showed clinically relevant reductions in severity, from 23 to 6 for the fusidic acid group and from 28.5 to 8 for the mupirocin group for the objective severity measure. There was a strong correlation between improvement in eczema severity and reduction in carriage of S. aureus (p = 0.866) analysed over three time points for the entire trial population, but this was not significant when assessed for each individual participant.

The trial by Canpolat and colleagues248 did not include any patient-reported outcomes. There was a significant difference in eczema severity, measured by the EASI scoring system, for the mupirocin and hydrocortisone group compared with the hydrocortisone-only group at the end of treatment (day 8) [4.2 (range 2–6) vs. 5.1 (range 2–7)]. The emollient-only group had an EASI score of 5.5 (range 2–8) at the end of treatment. For eczema measured by the SCORAD system, at day 8 the difference between the emollient-only group [30 (range 23–34)] and the hydrocortisone-only group [27 (range 20–33); p = 0.014] and between the hydrocortisone-only group [range 27 (20–33)] and the hydrocortisone and mupirocin group [26 (range 21–32); p = 0.006], was significant. There was a significant difference in treatment success, defined as a ≥ 50% reduction in lesion severity scores (measured using EASI/SCORAD), between the emollient-only group (36%) and the hydrocortisone-only group (65%) and the hydrocortisone and mupirocin group (74%) (p = 0.014 and p = 0.006, respectively) after 60 days.

Harms

No information about adverse events was reported for the trial by Gong and colleagues.247 In the trial by Ravenscroft and colleagues246 minor skin irritation was reported for 1 out of 28 participants treated with fusidic acid and 2 out of 18 participants treated with mupirocin. No participants stopped study treatment early. The trial by Canpolat and colleagues248 did not report any information about adverse events, despite stating that they would record these in the trial.

Overall implications for research and practice

In the trial by Gong and colleagues247 many methodological aspects are unclear, such as prespecified outcomes and the amount of study treatments and co-treatments applied. The trial does show a beneficial effect from adding mupirocin, but this must be treated with caution as so little methodological information is reported. The trial by Ravenscroft and colleagues246 provided no evidence of benefit for the addition of antibiotics to steroid treatment for non-infected eczema over a 2-week period. It is important to remember that this trial was powered to answer the question, ‘Does treatment with a topical corticosteroid/fusidic acid combination lead to an increased rate of carriage of fusidic acid-resistant S. aureus’, and may not be as appropriate for assessing any potential clinical benefit. The trial by Canpolat and colleagues248 also provides some evidence of benefit by statistical comparison, but the magnitude of effect appears quite small for the treatment period and it is possible that some participants may have been added to the control group because of their preference for not using pharmacological treatment. The long-term follow-up results seem to provide more clinically relevant reductions for steroid or combined treatment than for emollient, but the hydrocortisone-only and hydrocortisone and mupirocin groups are not compared and participants could use other eczema treatments, the levels of use of which are not reported.

The current trials do not provide any convincing evidence of benefit for the addition of mupirocin to topical corticosteroid treatment compared with topical corticosteroid treatment only for non-infected eczema. Indeed, one trial highlights that it is important to carefully consider the use of antimicrobial treatment as it carries risks associated with antimicrobial resistance. Researching antimicrobials for clinically non-infected eczema is unlikely to be taken forward given the lack of beneficial signals to date and concerns about promoting antimicrobial resistance, and research on antimicrobial therapy should concentrate on clinically overt, secondarily infected eczema.

Tetracycline

Tetracycline is a broad-spectrum antibiotic produced by Streptomyces species of Actinobacteria.

Studies

No trials investigating tetracycline for eczema were found before 2000.

One new trial has been reported since 2000.250 This trial, conducted in the Netherlands by Schuttelaar and Coenraads,250 compared a combination of the moderate-potency topical corticosteroid triamcinolone acetonide (0.1%) plus topical tetracycline (3%) against triamcinolone acetonide alone. The 44 participants with moderate to severe clinically non-infected eczema (SCORAD score of ≥ 25) diagnosed according to the Hanifin and Rajka8 criteria applied the treatment twice daily all over the body for 2 weeks. After the 2 weeks of randomised treatment, all participants were then treated with 0.1% triamcinolone acetonide for a further 6 weeks and followed up to assess maintenance treatment.

Assessment of risk of bias

Table 47 provides the risk-of-bias assessment for the new study.

TABLE 47

TABLE 47

Tetracycline: risk of bias of the included study

Benefits

The trial reported that there were no significant differences in the severity of eczema measured by both objective SCORAD and SASSAD scores after 2 weeks, although the differences in the scores were not reported. No significant differences in severity between the two treatment groups were found in the 6-week maintenance period. No participant-assessed outcomes were recorded for this trial. The tetracycline and triamcinolone acetonide combination was reported as having a significantly better rate of antibacterial efficacy, with 14 out of 22 participants having their colonisation with S. aureus eradicated, compared with 5 out of 22 participants in the placebo group.

Harms

The authors reported a low to moderate level of folliculitis in both groups but there is no information whether this occurred in the RCT phase, the maintenance phase of therapy or the maintenance open-label period.

Overall implications for research and practice

This fairly well-reported trial did not find any benefit of adding tetracycline to topical corticosteroid treatment in people with eczema without overt signs of clinical infection. Although bacterial counts were reduced in the intervention group, these were not matched by clinical benefit, raising doubts about whether the bacteria (S. aureus) are playing a pathogenic role. Additional research evidence on combining tetracycline with topical corticosteroids in uninfected eczema is probably not needed.

Antibacterial (oral)

Clarithromycin

One trial by Capella and colleagues251 compared oral montelukast against a ‘standard’ treatment combination of clarithromycin, cetirizine and mometasone furoate. No data were presented for clarithromycin treatment alone and so it is impossible to draw any conclusions about the use of clarithromycin for eczema on its own from this one trial.

Antiseptics

Triclosan

This antiseptic and disinfectant is widely used in everyday items such as toothpaste, chopping boards and rubbish bags.

Studies

Two trials were reported that tested triclosan before 200055 (see Appendix 3).

Two new trials have been reported since 2000. A small manufacturer-sponsored trial by Tan and colleagues252 of a 1% triclosan-containing emollient compared with vehicle emollient was conducted in 60 participants aged between 12 and 40 years. All participants were required to use 0.025% betamethasone valerate cream once a day for 27 days as well as the study treatment; after this, participants could choose to discontinue betamethasone valerate use. It was reported that most participants did use the topical corticosteroid during the trial period.

A small manufacturer-sponsored trial by Breneman and colleagues253 compared a soap bar containing triclosan (1.5%) against a ‘placebo’ soap bar that did not contain any antibacterials. Fifty participants (age not reported) with moderate eczema defined using the Hanifin and Rajka8 criteria were randomised to wash their whole body at least once a day for 63 days using the treatment. The participants had their other eczema treatments standardised so that all participants used a non-medicated cleansing bar, non-medicated moisturising cream and only 0.025% triamcinolone acetonide as the topical corticosteroid treatment. For the last 21 days of treatment, no topical corticosteroid was allowed.

Assessment of risk of bias

Table 48 provides the risk-of-bias assessment for the new studies.

TABLE 48

TABLE 48

Triclosan: risk of bias of the included studies

Benefits

The trial by Tan and colleagues252 measured the use of topical corticosteroids and noted that the triclosan group used significantly less than the vehicle group. However, no data were reported to support this statement. The primary outcome, which was the number of participants achieving a ≥ 20-point improvement on the SCORAD index from baseline, was statistically significantly different between the groups (triclosan group, n = 9; vehicle group, n = 4; p < 0.05). The secondary outcome, change in eczema severity from baseline using the SCORAD score, was significantly different only at day 14 (triclosan group –8.86, vehicle group –4.75, 95% CI –8.58 to 0.32; p > 0.05).

The trial report by Breneman and colleagues253 contained mostly summary results with no additional data, including no baseline data. The trial report states that, for itching, the participants using the soap bar containing triclosan experienced less itching than those using the placebo soap bar and that this effect was carried through the final 21 days of treatment without use of topical corticosteroids. For the dermatologist global assessment, no baseline scores are provided on the graph and the scores do not appear to differ between the groups, but no statistical analysis between groups is provided. The report states that there was a significant difference in favour of the triclosan-containing soap bar for disease extent and severity components of SASSAD but the total SASSAD scores are not reported.

Harms

A quarter of the study population in the trial by Tan and colleagues252 reported adverse events, but only four adverse events were considered to be related to treatment. Three participants in the triclosan group experienced application site stinging and one participant in the vehicle group experienced application site pruritus.

In the trial by Breneman and colleagues253 it was reported that there was only one study-related event. One participant withdrew because of worsening of eczema but it was not stated which treatment group they were in. No other information about adverse events was reported.

Overall implications for research and practice

Although the sample size in the trial by Tan and colleagues252 was powered as per an appropriate calculation, it is not clear what previous work the assumption of a SCORAD response rate of 90% for the triclosan group and 50% for the vehicle group was based on and this perhaps seems overly optimistic. Also, the amount of the study emollient used in each group, an essential factor in assessing the comparative effectiveness of these two active treatments, was not recorded. The trial report by Breneman and colleagues253 provides so few data that it is impossible to interpret the slight beneficial effect reported for the triclosan soap bar. The two pre-2000 previous trials added triclosan and benzalkonium chloride together, making it impossible to assess the impact of triclosan alone, and these trials were also difficult to interpret. Until trials that assess triclosan with clear, appropriate methodology are published it is impossible to assess the potential benefits and harms of this antimicrobial agent.

Bleach baths

Common household bleach should not be applied to the skin as it can cause burns on contact and is toxic if ingested. However, research has investigated the use of extremely small amounts of a certain form of bleach. The amount of bleach added to the bath makes the concentration very dilute.

Studies

There were no studies looking at bleach baths for eczema before 2000.

One new trial was reported after 2000.205 This trial, by Huang and colleagues,205 compared a regimen of half a cup of bleach in a bath (0.005%) twice weekly for 5–10 minutes and topical mupirocin applied to the nares of the nose for 5 consecutive days per month with a regimen of half a cup of water in the bath twice weekly for 5–10 minutes and petroleum ointment applied to the nares of the nose for 5 consecutive days per month. The treatment regimen was followed for 3 months and 31 children aged from 6 months to 17 years with moderate to severe infected eczema were randomised. Children who were currently or recurrently using topical antimicrobials were excluded from the trial. In addition to the participants, all other members in each participant’s household had to apply mupirocin (treatment arm) or petroleum (placebo arm) intranasally twice a day for 5 consecutive days of the month.

The participants could bathe without the treatment as often as they wished. All of the participants had to use a stable treatment regimen of emollients and topical corticosteroids throughout the trial. Additionally, patients received Cefalexin (Keflex®; Flynn Pharma) at 50 mg/kg per day (maximum daily dose 2 g) divided into three daily doses for 2 weeks.

Assessment of risk of bias

Table 49 provides the risk-of-bias assessment for the new study.

TABLE 49

TABLE 49

Bleach bath: risk of bias of the included study

Benefits

This trial by Huang and colleagues205 reported a statistically significant difference in the change in severity compared with baseline between the treatments, as assessed using the EASI score, favouring the bleach bath and mupirocin for the area of the body in contact with the bath water. This was based on a post hoc subgroup analysis at 1 month and 3 months [bleach bath and mupirocin group (mean ± standard error) –15.3 ± 3.8, placebo group (mean ± standard error) –3.2 ± 1.6; p = 0.004]. The baseline EASI scores were quite different between the groups [bleach bath and mupirocin group (mean ± SD) 22.1 ± 13.3, placebo group (mean ± SD) 16.6 ± 9.8] as was the body surface area affected [bleach bath and mupirocin group (mean ± SD) 37.8 ± 21.6, placebo group (mean ± SD) 28.1 ± 18.2] and it was unclear if these baseline imbalances were adjusted for in the final analyses. For the IGA, the treatment groups were significantly different at month 1 (p = 0.024) but not at month 3. There was a decrease of 67% in eczema severity score measured using the IGA in the bleach bath and mupirocin group and a 15% decrease in the placebo group at month 3.

Harms

One participant in the treatment group developed irritation and itching; he then failed to comply with the treatment regimen and subsequently developed a community-acquired MRSA infection, was hospitalised and received intravenous antibiotics; he resumed the study once he had recovered.

Overall implications for research and practice

The use of dilute bleach baths and 5 out of 28 days of intranasal mupirocin application (by participants and members of their household) resulted in a significant improvement in eczema severity over 3 months. Because of this, the low cost of treatment and ease of administration this intervention shows promise. The evidence from this trial should be treated with caution, however, as baseline severity and body surface area were very different at baseline, being higher in the treatment group. The analysis of the area of the body submerged in the bath against the head and neck was a post hoc analysis and was unlikely to have been powered correctly. It is interesting that the IGA does not show the same significant difference between groups. As the mupirocin and bleach baths were trialled only as a combined treatment, it is impossible to know how effective each treatment would be on its own. It is disappointing that no participant-assessed outcomes were reported. Only one adverse event was reported; a patient who failed to follow the treatment regime after developing skin irritation and pruritus subsequently developed an MRSA infection for which hospitalisation and intravenous antibiotics were needed. Although this could easily be just ‘bad luck’, the potential side effects of this intervention need greater scrutiny. Although there is not enough strong evidence from one trial, this intervention is worth pursuing in larger, long-term treatment trials.

Antifungal agents

Rationale for antifungal agents

The role of fungi and yeasts in eczema is not clear. Although fungal infections such as athlete’s foot (tinea pedis) can result in secondary eczematisation, secondary fungal infection co-existing or superimposed on atopic eczema lesions is apparently uncommon. However, it has been suggested that allergic sensitisation to Malassezia yeast species, which is common on the scalp and head, may contribute to some patterns of atopic eczema affecting the head and neck in adults. Although the role of fungi and yeasts in atopic eczema is tenuous, some have used antifungal agents combined with topical corticosteroids and some have used antifungals in shampoo or tablet form in an attempt to improve atopic eczema, and these will be discussed at the end of this chapter.

Ketoconazole (oral and topical)

Ketoconazole is an antifungal agent available in oral and topical forms. The topical form (Nizoral® shampoo; Janssen-Cilag) is used in shampoos for dandruff and scalp psoriasis but is not currently licensed for the treatment of eczema.

In July 2013, the European Medicines Agency’s Committee for Medicinal Products for Human Use issued a statement that oral medicines containing ketoconazole should no longer be used for the treatment of fungal infections because of safety concerns regarding the risk of developing hepatotoxicity and adrenal insufficiency, and the potential for fatal drug interactions.254 As such, the use of ketoconazole in developed countries has been largely superseded by newer azoles, such as itraconazole (Sporanox®; Janssen-Cilag), because of a lower risk of liver toxicity and drug interactions.

Studies

One trial involving ketoconazole shampoo was reported before 200055 (see Appendix 3).

Two trials of oral ketoconazole were reported after 2000. A trial in Finland by Lintu and colleagues255 compared 200 mg of oral ketoconazole per day with placebo in 80 adults with eczema who were also shown to be sensitive to the fungi Pityrosporum orbiculare, Candida albicans or Saccharomyces cerevisiae. The treatment was given for 30 days and the participants were followed up 3 months after treatment. Topical treatment with 1% hydrocortisone was allowed during the trial as long as the same brand was used throughout.

A trial in Sweden by Back and Bartosik256 compared 200 mg of oral ketoconazole per day against placebo for 3 months in 32 adults with eczema and specific serum antibodies to Malassezia furfur or P. orbiculare above 3.5 kU/l and an elevated serum IgE level (> 400 kU/l).

Assessment of risk of bias

Table 50 provides the risk-of-bias assessment for the new studies.

TABLE 50

TABLE 50

Ketoconazole: risk of bias of the included studies

Benefits

The trial by Lintu and colleagues255 looked at the severity of eczema using the SCORAD index, total serum IgE level, sensitivity and allergy, and presence of P. orbiculare, C. albicans or S. cerevisiae. This trial gave results of the improvement within each treatment group after the treatment period but did not compare the two treatment groups against each other. The mean SCORAD score in the ketoconazole group reduced by 7.9 (SD 13.1) points, whereas that in the placebo group reduced by 2.9 (15.3) points. The trial report states that the data for the follow-up period, when study treatment had stopped, were not reliable for therapeutic effect because of the use of extra topical treatment. No participant-assessed outcomes were reported for this trial.

The trial by Back and Bartosik256 did not find any significant difference in the severity of eczema measured using the SCORAD index after 3 months of treatment (p = 0.533), but the actual SCORAD values were regrettably not reported. The report states that the use of betamethasone was correlated with the improvement in the placebo group in the second and third months (r = 0.66, p = 0.013) but not in the ketoconazole group (r = 0.15, p = 0.61), but no values were reported. The participants’ evaluation of eczema improvement was reported as not significantly different between the groups, but no data were reported.

Harms

The trial by Lintu and colleagues255 did not report any information about adverse events. The trial by Back and Bartosik256 reported that there were only rare adverse events in the ketoconazole group, with two participants complaining of intense dreams, nausea and abdominal pain.

Overall implications for research and practice

The evidence for or against oral ketoconazole is difficult to interpret as neither trial reported the appropriate data for evaluating whether one treatment arm was better than the other. Both trials also allowed all participants to use topical corticosteroids as required and have not provided enough data on the levels used to be certain whether any beneficial or harmful effects seen are likely to be from use of ketoconazole or use of rescue treatment with topical corticosteroids. Difficulties with recruitment to these trials were mentioned because of pre-treatment ‘washout’ of topical ketoconazole being required. Potential participants were satisfied with their current treatment of topical ketoconazole, especially ketoconazole shampoo, and topical corticosteroids as required and so were not motivated to join the trial. This would indicate little need to pursue treatment alternatives such as oral ketoconazole. There is no good evidence of benefit for oral ketoconazole from these trials and it is probably not an area where further trials are needed.

Miconazole (topical)

Miconazole is an imidazole agent that is used topically to treat fungal infections. When taken orally it has also been shown to be effective against some forms of leishmaniasis and it also has some antibacterial properties.

Studies

One trial involving miconazole was reported before 200055 (see Appendix 3).

One trial has been reported since 2000. A within-person trial by Wong and colleagues115 in Hong Kong compared a combined treatment regimen of miconazole and 1% hydrocortisone against 1% hydrocortisone only, applied twice daily for 2 weeks. The trial included 30 children aged between 5 and 14 years with eczema, defined according to the UK Working Party’s criteria,9 symmetrically distributed (at knees or elbows), of whom 80% were classified as severe using the Nottingham Eczema Severity Score.257

Assessment of risk of bias

Table 51 provides the risk-of-bias assessment for the new study.

TABLE 51

TABLE 51

Miconazole: risk of bias of the included study

Benefits

The trial mainly relied on participants reporting which treatment gave better relief of eczema symptoms after 2 weeks of treatment and after another 6 weeks with no treatment. Two independent dermatologists also assessed outcomes using photographs. The two dermatologists gave vastly different interpretations of the eczema photographs, with one recording nearly all as ‘no difference’ and the other being equally split between ‘better with miconazole’, ‘better with hydrocortisone only’ and ‘no difference’, so this method proved to be unreliable and therefore difficult to interpret. The participants also reported no differences between the treatments using the same scoring system. There was also no difference in topical corticosteroid-free days between the two treatment groups in the follow-up period.

Harms

The trial report stated that there were no reported side effects.

Overall implications for research and practice

This small and poorly reported trial did not show any evidence of a beneficial effect of a topical combination of hydrocortisone and miconazole over hydrocortisone alone. The trial did not use any reliable objective or subjective measures of eczema severity.

Itraconazole (oral)

Itraconazole belongs to the triazole group of antifungal medications. It has a broad spectrum of action against fungi including yeasts and dermatophytes. It is similar to fluconazole but also treats Aspergillus infections.

Studies

There were no trials before 2000 looking at the use of itraconazole for eczema.

One new, small, three-arm trial258 concentrating on the head and neck area compared 200 mg or 400 mg of itraconazole against placebo in adults whose head and neck eczema was more severe than the eczema elsewhere on their body. The treatment was given for only 7 days but the follow-up period lasted for 105 days. The results reported do not include the follow-up at 105 days and concentrate on day 7 and day 14 measurements, thus giving only a short-term picture of any treatment effect. If a participant required adjuvant treatment during the trial then the trial protocol was violated and the participant was withdrawn.

Assessment of risk of bias

Table 52 provides the risk-of-bias assessment for the new study.

TABLE 52

TABLE 52

Itraconazole: risk of bias of the included study

Benefits

The severity of eczema in the head and neck region was significantly reduced compared with baseline for both 200 mg and 400 mg of itraconazole. Comparison of improvement between all three groups showed a statistically significant difference only for 200 mg of itraconazole (mean difference of 4.5, extrapolated from a graph) compared with placebo (mean difference of 16, extrapolated from a graph) at day 14 (p = 0.0318). For the primary success criterion, measured using the SCORAD index, 8 out of 35 participants using itraconazole reported a reduction in severity of > 50% compared with baseline compared with 2 out of 18 participants using placebo. Both the participant and investigator global assessment were reported as showing no significant differences in overall improvement in eczema severity, but the complete data for these outcomes were not reported.

Harms

This trial reported no adverse events in the itraconazole groups and there were no withdrawals because of adverse events. Over half of each treatment group withdrew, mainly because of exacerbations of eczema requiring additional treatment. Most of the withdrawals occurred after study treatment had stopped.

Overall implications for research and practice

Giving itraconazole as the first-line treatment without the use of adjuvant treatments resulted in over half of the trial population withdrawing from the study, mostly between days 14 and 56 because of the need for additional treatments. A post hoc decision to report the results for day 14 and draw conclusions about this 7-day treatment course accordingly diverts attention away from the potential unsuitability of a 7-day course of itraconazole as a long-term treatment for eczema. The number of participants was small and no formal power calculation was reported. Although there is some evidence of a beneficial effect of 200 mg of itraconazole after 14 days, the 400-mg dose appears to be no more effective than placebo, a result that is counterintuitive and raises the suspicion that the positive finding at 14 days for the lower-dose group was just a chance finding. Given that another similar oral antifungal, ketoconazole, has failed to provide any clear benefit for people with mainly head and neck eczema, further trials of oral antifungals are probably not a priority.

Ciclopirox olamine (topical)

Ciclopirox olamine is a hydroxypyridine antifungal agent. It has been shown to be highly effective against Malassezia species, which have been implicated in difficult-to-treat atopic eczema in the head and neck area.

Studies

There were no studies on ciclopirox olamine for eczema before the year 2000.

One study was reported after 2000. This trial, by Mayser and colleagues,259 compared 1% topical ciclopirox olamine against the base cream, which was applied twice daily to the head and neck region for 28 days. The 50 randomised participants had had moderate to severe eczema for at least 6 months. The eczema was defined according to the Hanifin and Rajka8 criteria and an IGA of score of ≥ 3, and all presented with ≥ 10% coverage in the head and neck region. All of the participants had to have at least a class I reaction for specific IgE to M. sympodialis and M. furfur and enterotoxin A and B. The trial followed the participants until 2 weeks after treatment had stopped.

Assessment of risk of bias

Table 53 provides the risk-of-bias assessment for the new study.

TABLE 53

TABLE 53

Ciclopirox olamine: risk of bias of the included study

Benefits

Only 29 out of the 50 participants who completed the study were included in the analysis. The assessments of eczema severity on the head and neck using the IGA tool and EASI showed significant between group differences at 28 days compared with baseline.

Harms

The trial report did not provide any information about adverse events or other potential harms.

Overall implications for research and practice

The results of this trial should be treated with caution because of the high dropout rate and failure to perform an intention-to-treat analysis. In a group with moderate to severe eczema, failure to permit rescue therapy was perhaps unethical given the lack of a priori evidence of benefit of ciclopirox olamine; instead, the use of rescue therapy could have been recorded as a study outcome. The results of this one small, short-term trial in those with moderate to severe eczema on the head and neck and sensitive to M. sympodialis, M. furfur and enterotoxin A and B do not provide any clear evidence of benefit from ciclopirox olamine, but do provide some weak evidence of a worsening in severity when the treatment is stopped. Given the lack of a beneficial signal in this study, further research with ciclopirox olamine is probably not a priority.

Summary of antimicrobials including antiseptics and antifungals

Antibiotics

Topical fusidic acid

  • There were no trials on fusidic acid reported before 2000.
  • For non-infected eczema, one trial reported in 2003, with a mostly high risk of bias, did not provide any evidence of benefit for a combination of fusidic acid (2%) and topical corticosteroid compared with a combination of mupirocin and topical corticosteroid.
  • For non-infected eczema, one four-arm trial reported in 2007, with a mostly unclear risk of bias and a high risk of blinding bias, did not provide any evidence of benefit for a combination of fusidic acid (2%) and topical corticosteroid treatment compared with topical corticosteroid alone or for a combination of fusidic acid (2%) and topical tacrolimus compared with topical tacrolimus alone.
  • The largest trial, reported in 2007, with a mixed risk of bias, provided evidence of benefit for a combination of fusidic acid and betamethasone 17-valerate in a lipid base compared with the lipid base alone for people with infected eczema. This trial also compared a combination of fusidic acid and betamethasone 17-valerate in a cream base against the same treatments in the lipid base and provided evidence of non-inferiority.

Topical mupirocin

  • One small pre 2000 trial, with a mostly unclear risk of bias, provided evidence of a large beneficial effect for mupirocin ointment compared with placebo in people whose eczema was not overtly infected. The participants could use emollients and topical corticosteroids.
  • Three trials, two small and one moderately sized, reported in 2003, 2012 and 2006, respectively, and with a mixed risk of bias, did not provide any evidence of benefit from using mupirocin in combination with topical corticosteroids compared with topical corticosteroids alone in people with non-infected eczema. One of these trials primarily evaluated the carriage of fusidic acid-resistant S. aureus.
  • A fourth small trial, reported in 2009, with a mostly unclear risk of bias, provided evidence for combined mupirocin treatment of the nostrils and bleach baths against compared with placebo for children with infected eczema.

Topical tetracycline

  • There were no trials using tetracycline for eczema reported before 2000.
  • One small trial reported in 2008, with an overall low risk of bias, did not provide any evidence of benefit for a combination of tetracycline and topical corticosteroid compared with topical corticosteroid alone in people with clinically non-infected eczema.

Clarithromycin

  • One trial compared oral montelukast against a ‘standard’ treatment combination of clarithromycin, cetirizine and mometasone furoate. No data were presented for clarithromycin treatment alone and so it is impossible to draw any conclusions about the use of clarithromycin for eczema on its own from this one trial.

Antiseptics

Triclosan

  • Two very small trials reported pre 2000 provided evidence of benefit for a bath additive containing 2% triclosan and benzalkonium chloride (6% w/w) compared with the same bath additive without antiseptics.
  • Two small trials funded by the manufacturer reported in 2000 and 2010, with a mostly unclear risk of bias, provided evidence of benefit for a triclosan 1.5%- or 1.0%-containing soap bar or emollient, respectively, compared with vehicle in people with eczema that was not infected. One of the trials provided hardly any data in the trial report.
  • The four trials using triclosan for eczema have been designed and reported in a way that makes it difficult to interpret the results and therefore there is no clear evidence on the benefits or harms of triclosan for eczema.

Bleach baths

  • There were no trials of bleach baths reported before 2000.
  • One small trial reported in 2009, with a mostly unclear risk of bias, provided evidence of a benefit at 1 month in a post hoc subgroup analysis, but not at 3 months, for bleach baths once a week and a 5-day treatment of mupirocin to the nostrils once a month compared with placebo.

Antifungals

Oral ketoconazole

  • There were no trials of oral ketoconazole for eczema reported before 2000.
  • Two small trials reported in 2001, with an overall unclear risk of bias, did not provide any evidence of benefit for oral ketoconazole (200 mg) compared with placebo in people with eczema who were sensitive to fungi.

Topical miconazole

  • One small trial reported pre 2000, with a mostly unclear risk of bias, did not provide any evidence of benefit for a combination of miconazole, topical corticosteroid and ketoconazole shampoo compared with topical corticosteroid and shampoo.
  • One very small trial reported in 2008, with an overall unclear risk of bias, did not provide any evidence of benefit for a combination of miconazole and topical hydrocortisone compared with hydrocortisone alone.

Oral itraconazole

  • One small trial reported in 2004, with an unclear risk of bias, did not find any evidence of benefit for itraconazole compared with placebo.

Topical ciclopirox olamine

  • One trial reported in 2006, with a mostly unclear risk of bias, did not find any evidence of benefit for topical ciclopirox olamine compared with the base cream.
Copyright © Queen’s Printer and Controller of HMSO 2016. This work was produced by Nankervis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.

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Bookshelf ID: NBK363143

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