Ebook Evidence-Based dermatology (3rd edition): Part 2
S E C T I O N 3
Infective skin diseases, exanthems, and infestations
Masutaka Furue and Yuping Ran, editors
Local treatments for cutaneous warts Juping Chen1 and Yan Wu2 1
Department of Dermatology, Second Clinical Medical College of Yangzhou University, Yangzhou, China Department of Dermatology, No.1 Hospital of China Medical University, Shenyang, China
Background Definition Cutaneous warts are extremely common, benign, and usually selflimiting. Infection of epidermal cells with the human papilloma virus (HPV) results in cell proliferation and a thickened, warty
papule on the skin. The most common sites involved are hands and feet, though any area of skin can also be infected. Genital warts are also common and frequently sexually transmitted, but are not discussed in this chapter. Prevalence There are few reliable, population-based data on the prevalence of cutaneous warts. The prevalence rate varies according to different ages, populations, and periods of time, and it is the highest in children and young adults. Two large population-based studies revealed prevalence rates of 0.84% and 12.9% [1,2]. Studies in school populations showed rates of 12% in 4–6-year-olds and 24% in 16–18-yearolds [3,4]. Etiology and risk factors Warts are caused by HPV, of which there are over 70 different types. Lesions are most common at sites of trauma, and probably result from inoculation of virus into minimally damaged areas of epithelium. Plantar warts are often acquired from common bare-foot areas; severe hand warts showed an occupational risk in butchers and meat handlers [5,6]. Prognosis Non-genital warts in immunocompetent people are harmless and usually resolve spontaneously as a result of natural immunity within months or years. The rate of resolution is highly variable and probably depends on a number of factors, including host immunity, age, HPV type, and site of infection. One frequently cited study of an institutionalized population showed that two-thirds of warts resolved within a 2-year period . Evaluation of clearance rates in
control groups in randomized controlled trials (RCTs) may also give some indication of natural clearance tendency, although a nonspecific benefit of vehicle bases may make interpretation difficult. Twenty-three RCTs discussed in this chapter showed an average cure rate of 18% (range 0–73%) with placebo preparations after an average period of 10 weeks (range 4–24 weeks). Diagnostic tests Warts are frequently diagnosed clinically. Microscopic examination obtained surgically can confirm the diagnosis if there is doubt. HPV typing is used in research laboratories and occasionally in medicolegal cases to investigate child abuse. Aims of treatment To clear warts completely and permanently. Relevant outcomes • Cure rate (total clearance rate); • recurrence; • adverse reactions, such as pain and blistering. Methods of search
Data sources and search strategy
All RCTs on the topical treatments for extragenital warts were identified, without limitation of language or publication status. The Medline, Embase, Cochrane Library, the Meta Register of Controlled Trials, CBM, and CNKI were searched. Reference lists of prior reviews, systematic reviews, and trials were also checked. The most recent searches were completed in June 2012.
Study selection and data extraction
Two investigators independently screened studies for inclusion, retrieved potentially relevant studies, and determined eligible studies. Disagreements were resolved by consensus. Two investigators independently extracted data from the included studies using
custom-made standardized forms and a third investigator was assigned with the checking process.
active treatment group developed cellulitis. Minor skin irritation was noted occasionally in some trials.
The criteria recommended by the Cochrane Collaboration Handbook were used to assess the methodological quality of included trials. It mainly focused on description of randomization (sequence generation progress), allocation concealment, blinding, addressing of incomplete outcome data, reporting of selective outcome, and other potential threats to validity . The judgment for each entry was based on the answer of a question, with “yes” indicating “low risk of bias,” “no” indicating “high risk of bias,” and “unclear” indicating “either lack of information or uncertainty over the potential for bias” . Disagreements were resolved by group consensus.
The primary outcome is the cure rate (total clearance rate). The secondary outcome is adverse reactions.
All statistical analyses were performed using the duplicate data entry facility of Revman 5.0.25 (evidence-based medicine software) by two investigators . In addition to 95% confidence intervals (CIs), relative risks (RRs) and mean differences (MDs) were respectively used for dichotomous and continuous outcomes. The χ2 (chisquare test) statistic was calculated to determine the proportion of between-study variation due to heterogeneity. The value ranged from 0 to 100%, and high values indicated strong heterogeneity. If heterogeneity was low (P > 0.1, χ2 < 50%), a fixed-effect model was used, otherwise a random-effect model was used. Intention to treat (ITT) was done for efficacy evaluation, and per-protocol (PP) analysis was done for adverse reaction evaluation.
Results Salicylic acid or topical products containing salicylic acid
Salicylic acid versus placebo Five RCTs [10–14] compared salicylic acid (SA) with placebo. SA preparations gave a higher cure rate of 73% versus that of 48% with placebo. The RR was 1.60, 95% CI was 1.16–2.23, number needed to treat (NNT) was 4 (95% CI, 3–7). Salicylic acid versus cryotherapy Three RCTs [15–17] compared SA with cryotherapy. The cure rates were respectively 60% and 70% in the two groups, and no significant difference was seen between the two treatments (RR, 0.85; 95% CI, 0.59–1.21).
There is reservation about the validity of pooled data from the different RCTs, because of the generally low quality of trials and the heterogeneity of their design and methodology. For instance, the RCTs included used different topical SA products, or some RCTs included patients with refractory warts whereas others excluded them. Despite this, we consider that there is good evidence for a modest benefit of SA in treating non-genital warts. Cryotherapy with liquid nitrogen
Cryotherapy versus placebo or no treatment Two small RCTs compared cryotherapy with either placebo cream  or no treatment . One of the two trials  reported a very low cure rate for cryotherapy (one of 11), while the other trial  showed a high cure rate in the placebo group (eight of 20). The pooled data of cure rates did not demonstrate a significant difference between the cryotherapy group and control group: 35% versus 34% (RR, 0.88; 95% CI, 0.26–2.95). Cryotherapy versus salicylic acid Three RCTs [15–17] compared SA with cryotherapy. The results have already been mentioned in the section entitled “Salicylic acid versus cryotherapy.” Cryotherapy versus bleomycin Two RCTs compared cryotherapy with intralesional bleomycin [24,25]. Because of heterogeneity of methodology and design, the two trials are described separately. One trial , which used 1 mg/ mL bleomycin, obtained cure rates of 76.5% in the cryotherapy group and 94.9% in the bleomycin group (RR, 0.18; 95% CI, 0.03– 0.90, P = 0.04). Another RCT , using 0.5 mg/mL bleomycin, had a cure rate of 68.2% in the cryotherapy group and 100% in the bleomycin group (RR, 1.27 (1 < RR < 1.6); P < 0.05). Length of freeze Four RCTs [26–29] compared aggressive and gentle cryotherapy in 592 adults and children. However, the definitions of “aggressive” and “gentle” used differed, and some studies included refractory warts whereas others did not. Overall, cure rates were 52% with aggressive cryotherapy and 31% with gentle cryotherapy (RR, 1.90; 95% CI, 1.15–3.15; NNT, 5; 95% CI, 3–7). Interval between freezes Three RCTs [15,30,31] showed no significant difference in cure rates among 2-week, 3-week, and 4-week intervals. Cure was generally achieved more quickly with shorter treatment intervals.
Other comparisons Seven RCTs [15,18–21] compared different products containing SA or compared SA with other topical treatments, such as glutaraldehyde and dithranol. The heterogeneous trials showed no convincing advantage of any particular delivery system for SA.
Optimum number of freezes Only one RCT  examined this question in 115 adults and children who did not cure 3 months after 3-weekly cryotherapy and showed no benefit of prolonging cryotherapy for a further 3 months. The cure rates were 43% and 38% in the treated and untreated groups, respectively (no data available for calculating the odds ratio).
Generally, topical SA was reported to have no significant harmful effects. In one RCT that compared a mixture of monochloroacetic acid and 60% SA with placebo , one of the 29 patients in the
Only two RCTs included precise data on adverse events. Pain or blistering was reported by 64 of 100 participants (64%) treated with an “aggressive” (10 s) regimen, in comparison with 44 of 100
322 The evidence
participants (44%) treated with a “gentle” (brief freeze) regimen (RR, 1.45; 95% CI, 1.12–2.31). Five participants withdrew from the aggressive-regimen group and one from the gentle-regimen group because of pain and blistering . Pain or blistering was reported in 29%, 7%, and 0% of those treated at 1-week, 2-week, and 3-week intervals, respectively (no data available for the odds ratio) . The rate of reported adverse affects was relatively high with a shorter interval, but this is likely to be a reporting artifact, as these participants were seen sooner after each treatment.
The evidence from the available RCTs of cryotherapy for warts is limited and contradictory. Just as the RCTs on topical SA, the heterogeneities of study designs, methods, and populations make it difficult to draw firm conclusions from the pooled data. For instance, some trials included all types of warts on the hands and feet in all age groups, whereas others were more selective and simply focused on hand warts, or excluded certain groups such as those with mosaic plantar warts or refractory warts. Of particular note is the likelihood that the “populations” in these studies may have very different characteristics at different periods of time. For example, studies conducted in the 1970s in the UK would have included a higher proportion of participants with incident warts, which have a greater chance of cure or spontaneous resolution. In the 1980s and 1990s, more people with warts were treated in primary care. Thus, clinics would have had a more selected population with a higher proportion of refractory warts and correspondingly lower cure rates. Occlusive treatment with duct tape
Duct tape versus placebo Two published trials did this comparison and did not show good cure rates with duct tape [33,34]. The trial by De Haen et al.  included 103 primary-school children who were randomly assigned to continuous duct tape and a no occlusive corn pad once a week. After 6 weeks, recurrence occurred in eight of 51 (16%) versus three of 52 (6%) of the trial warts. Curiously, other untreated warts resolved in 21% and 27% of the children, respectively. Wenner et al.  conducted a trial comparing occlusive duct tape (obscured by a sticky-backed fabric called moleskin) with the moleskin alone in 90 adult patients (the trial population had an unusually high age of 54 years). After 8 weeks, relapse occurred in eight of 39 (21%) versus nine of 41 (22%), respectively. Among the cured patients, six of eight (75%) and three of 10 (30%), respectively, had relapsed again after 6 months. Duct tape versus cryotherapy One trial compared occlusive treatment with duct tape and cryotherapy in 61 children and young adults . The duct tape was applied for 6.5 days every 7 days, cryotherapy was given for 10 s every 2–3 weeks up to a maximum of six times. The cure rates were 22 of 30 (71%) and 15 of 31 (46%), respectively (RR, 1.52; 95% CI, 0.99–2.31). There were limitations to the trial: the number of patients was relatively small, 10 s of cryotherapy was inadequate, an unspecified number of outcome assessments were carried out over the phone, and it was not entirely clear how long after the treatment period was done.
Duct tape is simple, safe, and cheap. No significant adverse events were mentioned in any of these trials.
None of these three trials are strong methodologically; thus, the results are somewhat contradictory and difficult to summarize meaningfully. Contact immunotherapy with dinitrochlorobenzene
Two small RCTs [22,36] of dinitrochlorobenzene (DNCB) in 80 children and adults achieved a cure rate of 80% (32/40) in comparison with 38% (15/40) in the placebo/no treatment groups (RR, 2.12; 95% CI, 1.38–3.26; NNT, 2; 95% CI, 2–4).
One trial  commented that six of 20 participants treated with 2% DNCB were sensitized only after the second application. All of them subsequently experienced significant local irritation, with blistering, when they were treated with 1% DNCB. None withdrew from the study.
DNCB, a potent contact allergen, can cause significant local irritation and dermatitis, which probably precludes its use outside specialist centers. Photodynamic therapy
Photodynamic therapy versus placebo One trial  randomized active (proflavine+black light) and placebo (picric acid + black light) treatments for recalcitrant symmetrical verrucae vulgaris, on the left and right sides of the body. The result showed no significant difference. Three trials [38–40] compared 5-aminolevulinic acid (ALA)–photodynamic therapy (PDT) with placebo–PDT, and all patients locally used keratolytic. Meta-analysis showed no significant difference (RR, 1.53; 95% CI, 0.86–2.73). Photodynamic therapy versus salicylic acid One RCT  including 120 adults and children compared methylene blue/dimethyl sulfoxide PDT with a mixture of SA and creosote. The cure rates were 8% and 15%, respectively. Photodynamic therapy versus cryotherapy In one RCT , four different types of light source for PDT were compared with cryotherapy. Topical SA was used for all patients. More warts were completely healed after white light–PDT than after red/blue light–PDT and cryotherapy. 5-Aminolevulinic acid–photodynamic therapy versus highfrequency electrocautery One RCT  including 60 patients with plantar warts did this comparison. The cure rates of ALA treatment group were 37.5% (12 of 32 patients) and 17.86% (five of 28 warts), which were higher than those of the high-frequency electrocautery treatment group. 5-Aminolevulinic acid–photodynamic therapy+salicylic acid versus microwave therapy One trial  including 126 plantar warts patients showed the cure rates were similar between two groups, while the recurrence rate was lower in the ALA treatment group than that in the microwave treatment group.
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5-Aminolevulinic acid–photodynamic therapy versus semiconductor laser One RCT  reported that ALA–PDT is superior to semiconductor laser (cure rates 25/28 vs 18/28).
Different concentrations of bleomycin One RCT  in 26 adults, comparing 0.25, 0.5, and 1.0 IU/mL bleomycin, showed cure rates of 73%, 88%, and 90% of warts, respectively; the differences were not statistically significant.
Methyl aminolevulinate–photodynamic therapy+chemical keratolytic treatment versus chemical keratolytic treatment One trial  evaluated methyl aminolevulinate (MAL)–PDT with or without chemical keratolytic treatment for hand warts in a population of renal transplant patients. The number of vanished warts showed no significant difference between two treatments.
5-Aminolevulinic acid–photodynamic therapy+CO2 laser versus CO2 laser In one trial , a total of 70 patients with plantar warts were randomly divided into two groups. The cure rates were 48.6% (17 of 35 patients) and 20% (seven of 35 warts) in ALA–PDT+CO2 laser treatment group, higher than those of CO2 laser treatment group.
One RCT  focused on the pain induced by PDT of warts, by filling in questionnaires about pain immediately and 24 h after each treatment. Forty-five patients were enrolled in a randomized, placebo-controlled trial with six consecutive ALA– and placebo– PDT treatments for recalcitrant foot and hand warts. Severe or unbearable pain was reported from a median of 17% (6–31%) of the ALA-treated warts and from a median of 2% (0–15%) from the placebo-treated warts immediately after the treatments. With increasing treatments, no significant change in pain intensity was observed, no significant relation was found between the pain intensity and the relative change in wart area. The pain was primarily characterized as burning and shooting. The pain lasted about 30 h (range: 1–96 h). Nine RCTs [38–40,42–47] reported the side effects during or after the PDT treatment. Pain, burning, itching, local anesthesia, swelling, and erythema were common; most were mild/moderate and acceptable. No treatments were suspended because of pain.
The fact that most trials used different protocols of PDT (different photosensitizer, different light sources, different treatment intervals, and so on) makes it difficult to draw a definite conclusion. So far, PDT appears to offer no particular advantages in cure rates or adverse effects than other simpler and cheaper local treatments available. But for recalcitrant warts, it might be an alternative approach, which should be proved by further research. Intralesional bleomycin
Bleomycin versus placebo Conflicting results were reported in five RCTs of intralesional bleomycin. Three trials [49–51] reported higher cure rates with bleomycin than with placebo, one  showed that placebo was associated with higher cure rates than bleomycin, and one  showed no significant differences between bleomycin and placebo. The pooled results showed that bleomycin was more effective than placebo in the treatment of cutaneous warts (RR, 3.84; 95% CI, 2.19–6.71). Bleomycin versus cryotherapy Two RCTs [24,25] compared liquid-nitrogen cryotherapy with intralesional bleomycin. The results were shown in the section “Cryotherapy with liquid nitrogen.”
No precise data on adverse effects were provided in any of the RCTs. One RCT  reported “adverse events” in 19/62 (31%) participants, but the nature of the adverse events and the proportions in the active treatment and placebo groups were not specified. Three of the trials [49,50,54] reported that most participants experienced pain. In two trials [50,51], local anesthetic was used routinely before the injection of bleomycin. One trial  reported pain was seen in most participants, which was irrespective of dose. In one trial  of 24 participants who received bleomycin, two patients withdrew because of the pain of the injections and pain in the period after the injection.
Again, methodological and statistical heterogeneity (different outcomes, trial periods, units of analysis, numbers of injections, vehicles, and concentrations) make it impossible to organize the data from these trials. 5-Fluorouracil
5-Fluorouracil versus placebo One RCT  compared 5-fluorouracil with placebo. Altogether, 60 patients (including 40 children) were randomized to be treated with topical 5-fluorouracil for 4 weeks and placebo. During the procedure, 31 patients were lost to the active treatment and the cure rate was 60%, versus three lost to the placebo treatment and the cure rate was 17%. There were statistically significant difference between the two treatments (RR, 7.44; 95% CI, 2.86–19.35). 5-Fluorouracil cryotherapy versus cryotherapy+placebo One RCT  compared cryotherapy combination with 5- fluorouracil and cryotherapy combination with placebo; the cure rates were 58.57% and 65.29% respectively. There was no significant difference (RR, 0.55; 95% CI, 0.22–1.40). 5-Fluorouracil+duct tap versus duct tape One RCT , including 40 patients, treated with 5-fluorouracil combined with duct tape and duct tape alone for 12 weeks. The cure rates were 95% (19/20) and 10% (2/20) respectively (RR, 9.50; 95% CI, 2.54–35.51).
Only one trial  mentioned topical 5-fluorouracil side effects. Eleven cases of fingertip or periungual warts had nail separation after topical 5-fluorouracil treatment; the rate was 22.9% out of 48 cases in total. However, the nature and proportion of the side effects of the treatment were not elaborated.
Methodological and statistical heterogeneity (different outcomes, trial periods, units of analysis, vehicles, and concentrations) make it impossible to organize the data from these trials. Localized heat therapy
Localized heat therapy versus placebo Two RCTs [58,59] compared localized heat therapy with placebo; because of heterogeneity in methodology and design, the two trials
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are described separately. One trial  including 13 patients (29 warts) used local hyperthermia at 50 °C lasting 30 min. The cure rates were 86% (25/29) in the treatment group and 41% (7/17) in the control group, the difference was statistically significant (RR, 8.93; 95% CI, 2.14–37.34). Another RCT  used local hyperthermia at 44° lasting 30 min once a day for three consecutive days. Two weeks later, patients received similar treatments for two consecutive days. Patients in the control group received a red spot on the targeted lesion without experiencing a heating sensation. Three months later, the cure rates were 53.57% (15/28) and 11.54% (3/26), respectively. The difference was statistically significant (RR, 8.85; 95% CI, 2.15–36.37).
One trial  showed that 80% of patients (12/15) in the treatment group who had initial complaints of load-bearing pain reported a decreased sensation of pain, one experienced an increased sensation of pain, and two remained stable. In the control group, 14.3% of patients (2/14) reported a decreased sensation of pain, five experienced an increased sensation of pain, and three remained stable. There was a significant difference between the two groups (RR, 24; 95% CI, 3.38–170.38).
Methodological and statistical heterogeneity (different outcomes, trial periods, units of analysis, vehicles, and concentrations) make it impossible to organize the data from these trials. Light and laser treatment
Intense pulsed light In one trial , 79 patients with recalcitrant hand and foot warts were included and randomized into treatments with either paring of warts followed by intense pulsed light (IPL) or paring of warts alone. No significant difference in cure rate was found between the two intervention groups, but the pain intensity after paring plus IPL was significantly higher than that after paring alone. Pulsed dye laser One trial  compared the efficacy and safety of pulsed dye laser (PDL) (595 nm PDL + cooling pulses) with a placebo (cooling pulses alone) in the treatment of patients presenting palmoplantar warts. For both groups, hyperkeratosis was removed manually with a scalpel before each session. The results showed that 64% (48/75) of warts in the laser group resolved completely compared with 13% (4/30) in the placebo group (P < 0.001). Three trials [62–65] (including adults and children) compared PDL therapy with cryotherapy and no superior efficacy was found (RR, 1.02; 95% CI, 0.85–1.21). One controlled study  included 66 lesions from 19 patients. PDL was applied to 33 lesions following 30% SA application twice a day for 5 days; the remaining 33 lesions underwent PDL therapy alone. PDL was administered in both groups at 4-week intervals varying from one to five sessions. Complete clearance was observed after 2.2 sessions in the SA+PDL group versus 3.1 sessions in the PDL group (P < 0.05). Although the clearance rate showed no difference between the SA+PDL group and the PDL group after all the sessions, adding SA to PDL decreased the number of sessions to an extent. Q-switched laser Two trials [67,68] (including 212 adults and children with verruca planar) compared Q-switched laser therapy with cryotherapy. All
patients took transfer factor capsules; 92 patients were injected with immnunoenhancement for 3 weeks. Q-switched laser therapy obtained higher cure rates (RR, 1.26; 95% CI, 1.12–1.43). The other two trials [69,70] compared Q-switched laser therapy with combination treatments (retinoic acid cream, α-2b interferon (IFN) ointment, ceramic grinding treatment). The combination treatments were superior to single laser treatment. CO2 laser Three trials [71–73] (including 453 adults) compared CO2 laser therapy with cryotherapy. A significant difference was found between the two treatments (RR, 1.36; 95 % CI, 1.01–1.83). Two trials [74,75] (including 575 adults) compared CO2 laser therapy with microwaves therapy. CO2 laser therapy did not give higher cure rates (RR, 1.05; 95% CI, 0.78–1.41). Another nine trials [64,72,76–82] compared topical treatments (α-2b IFN ointment, semiconductor laser, different types of CO2 laser, retinoin acid drugs, etc.) combined with or without CO2 laser therapy. The results showed that combination treatments were superior to single laser treatment. Holmium laser One trial  including 120 children and adult patients with plantar warts compared holmium laser with cryotherapy. The cure rate was 97.5% (78/80) versus 55% (22/40). A significant difference was found between the two treatments, but high risk of bias was found in this trial.
Ten RCTs [60,63,65,66,69,76–80] reported the side effects caused by light or laser therapy, including pain, erythema, swelling, hyperpigmentation, burning, itching, desquamation, crusts, and scar. Most of them were mild and tolerable.
PDL appears to be an effective treatment in non-genital cutaneous warts, but the efficacy seems to be no superior to that of traditional treatments (cryotherapy). Other laser treatments (Q-switched laser, CO2 laser, etc.) seem to be more effective than cryotherapy, but more placebo-controlled trials should be undertaken to prove the results. The combination treatment could be considered in clinical practice. Imiquimod
Imiquimod versus retinoic acid drugs Four RCTs [84–87] (including 308 adults and children) did this comparison. Topical 5% imiquimod cream did not give higher cure rates (RR, 1.26; 95% CI, 0.98–1.63). Imiquimod+retinoic acid drugs versus retinoic acid drugs Three trials [84,88,89] (including 216 adults and children) did this comparison. The cure rate was 42.99% versus 24.04%. A significant difference was found between the two treatments (RR, 1.80; 95% CI, 1.20–2.70). Imiquimod+retinoic acid drugs versus imiquimod Three trials [84,90,91] (including 229 adults and children) did this comparison. The cure rate was 52.63% versus 22.61%. A significant difference was found between the two treatments (RR, 2.33; 95% CI, 1.59–3.42).
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Other comparisons Nine trials [92–100] compared topical treatments (α-2b IFN ointment, traditional Chinese medicine, cryotherapy, microwave, hot water immersion, etc.) with or without imiquimod cream. The limited evidence showed the combination treatments were superior to single treatment.
or topical treatments in 16 trials [91,97,111–124], seven trials [84,89,90,125–128], five trials [120,129–132], and one trial . The limited evidence showed that the combination treatments were superior to the single treatment. However, all the trials had a high risk of bias, so the results were less worthy of belief.
All RCTs except one trial  reported the side effects caused by retinoic acid drugs. The most common drawbacks were erythema, itching, and desquamation. Most patients could get better after treatment cessation, using vitamin E ointment, reducing treatment frequency, or even keeping on treatment. Other side effects were burning, swelling, photosensitive, tight skin, tingling, pigmentation, and so on.
Sixteen RCTs reported the side effects caused by imiquimod cream, including erythema, burning, tingle, swelling, erosion, itching, edema, desquamation, and pigmentation. No systemic side effects were reported.
No evidence showed good efficacy of 5% imiquimod cream on non-genital cutaneous warts. Although the pooled data showed combined treatment with retinoic acid drugs to be effective in verruca planar, the results should be verified by high-quality RCTs. Retinoic acid drugs
Retinoic acid Retinoic acid versus α-2b interferon Two RCTs [101,102] (including 218 adults and children) compared retinoic acid ointment with α-2b IFN ointment. Topical retinoic acid ointment did not give higher cure rates (RR, 0.87; 95% CI, 0.59–1.31). Retinoic acid+α-2b interferon versus retinoic acid Three RCTs [101–103] (including 324 adults and children) did this comparison. A significant difference was found between the two treatments (RR, 1.99; 95% CI, 1.53–2.57). Retinoic acid+α-2b interferon versus α-2b interferon Four RCTs [101,102,104,105] compared retinoic acid cream combined with α-2b IFN ointment in 350 adults and children. The pooled data showed a significant difference between the two treatments (RR, 1.84; 95 % CI, 1.45–2.32). Tazarotene Tazarotene+α-2b interferon versus tazarotene Two RCTs [106,107] did this comparison in 68 patients with verruca planar and 104 patients with plantar warts. The combination treatment group had a higher cure rate than the tazarotene ointment only group (RR, 2.79; 95% CI, 1.62–4.81). Tazarotene+α-2b interferon versus α-2b interferon In one RCT , 98 adults and children with verruca planar were randomized into two groups (topical tazarotene cream combined with α-2b IFN ointment group and topical α-2b IFN ointment alone group). After 4 weeks, the cure rates were 48.08% (25/52) versus 23.91% (11/46). The former had greater efficacy than the latter on treatment of verruca planar. Tazarotene versus ftibamzone Two RCTs [109,110] (including 347 adults and children with verruca planar) compared tazarotene cream with ftibamzone ointment. The pooled data did not demonstrate a significant difference in cure rates (RR, 1.15; 95% CI, 0.80–1.63). Other comparisons Retinoic acid ointment, tazarotene cream, adapalene gel, and isotretinoin gel were respectively compared with different products
It was hard to draw a definite conclusion on the efficacy of retinoic acid drugs because high-quality placebo-controlled trials were absent. Although the pooled data showed that retinoic acid drugs combined with α-2b IFN treatment were effective in verruca planar, the generally low quality of trials means there are reservations. Furthermore, clinical heterogeneity made it impossible to organize the data from most trials. So there was no compelling evidence to give retinoic acid drugs to non-genital cutaneous warts patients. Other local treatments for warts Intralesional IFN as a treatment for warts is more of historical interest. Six trials [134–139], most dating from the 1970s and 1980s, were found using this treatment; evidence provided by all the trials was severely limited by heterogeneity of the methodology and design, and overall did not suggest any striking efficacy. In one RCT  of intralesional antigen therapy, a form of local immunotherapy was designed to elicit an immune reaction in warts, and patients were injected with Candida, mumps, or Trichophyton antigens. Unfortunately, the design of the trial was made more complex by the addition of intralesional IFN, resulting in four treatment arms (antigen with or without IFN and placebo with or without IFN) rather than two, which would have given much clearer data. Up to five injections were given at 3-weekly intervals into the largest wart in each patient. Blinding involved only the patients and not the investigators, introducing a source of potentially significant bias. The main outcome reported was a reduction of more than 75% in the wart surface area at the end of treatment – an outcome of no relevance to patients (who naturally want their warts cleared). No long-term follow-up appears to have been carried out. A total of 201 patients with refractory warts completed the trial; 57 of 95 patients (60%) injected with antigen with or without additional IFN experienced the resolution of at least one wart, in comparison with 25 of 106 patients (24%) injected with saline or IFN alone. The number of patients who experienced complete clearance of all warts is a little difficult to ascertain from the paper, but it appears to have been 21 of 95 (22%) in the treatment groups and 11 of 106 (10%) in the “placebo” groups. For a fairly painful and expensive treatment, this does not appear to offer any striking advantages. One RCT  compared 20% zinc oxide and 15% SA complex, involving 44 patients who were randomized to the two treatments twice a day for 3 months. The results showed that the cure rates of zinc oxide and SA complex group were respectively 50% and 42%, and there was no statistically difference between the two treatments (RR, 1.44; 95% CI, 0.44–4.76). Topical zinc oxide is a possible treatment of warts, but needs more RCTs to support.
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One RCT  compared topical α-lactalbumin-oleic acid with placebo. The trial employed an unusual hybrid molecule (consisting of a combination of α-lactalbumin from human breast milk and oleic acid), which was said to be lethal to a wide range of transformed cells but harmless to normal ones. The trial was properly randomized and double blinded, and the analysis focused on the main outcome of a more than 75% reduction in wart volume, rather than the more relevant complete clearance of warts. Unfortunately, the trial defaulted to an open-label design after 3 months, making the long-term follow-up data unconvincing. Although 100% of patients in the treatment group were reported to have experienced a reduction in wart volume of more than 75%, only 21% of the lesions in the treatment group resolved completely. Nine of 20 patients (45%) with active treatment experienced the resolution of at least one wart, in comparison with three of 20 (15%) in the placebo group (RR, 3.0; 95% CI, 0.95–9.48). Given the size of the trial, and consequently the wide CIs, the results were unconvincing. One RCT  compared smoke from leaves of Populus euphratica Olivier and conventional cryotherapy, once a week, for 10 times. After 22 weeks, the cure rates were 68% (16/24) and 46% (13/28) respectively (RR, 2.31; 95% CI, 0.75–17.13). No RCTs were identified that studied the efficacy of the following treatments: surgical excision, curettage and cautery, formaldehyde, podophyllin, and podophyllotoxin.
Key points • Topical preparations containing SA are generally effective and safe for treating warts. • The available, rather limited, evidence shows that no significant difference was seen between cryotherapy and topical treatments containing SA. • Contact immunotherapy with DNCB appears to be a promising treatment, but is probably best reserved for highly refractory warts. • PDT and PDL therapy do not appear to have any particular advantage in terms of higher cure rates or fewer adverse effects than the other simpler and cheaper local treatments available. • There is no compelling evidence for the efficacy of intralesional bleomycin.
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Molluscum contagiosum Minh L. Lam Dermatology Department, Queen’s Medical Centre, Nottingham, UK
Background Definition Molluscum contagiosum is a benign infection of the skin and mucous membranes caused by the molluscum contagiosum pox virus. Most people with mollusca have multiple lesions, which typically begin as small papules that enlarge to around 3–6 mm and rarely to more than 1 cm in diameter. Fully developed papules typically have a central umbilication or depression that contains a white, waxy, curd-like core. Most lesions resolve without scarring, but they may cause discomfort and/or itching (Figure 39.1) . Mollusca can be associated with a surrounding dermatitis and occasionally a reactive skin eruption similar to Gianotti–Crosti syndrome . Incidence Infections with the molluscum contagiosum virus occur throughout the world, but the incidence varies considerably, with higher rates in areas with warm climates . Children are most often affected [3–5]. In a British study, the incidence was 243 per 100 000 person-years (py) in males and 231 per 100 000 py in females. Ninety percent of cases were reported in children aged 0–14 years (incidence 1265 per 100 000 py) . In New Guinea, the annual attack rate was 6% in children aged 0–9 years . Incidence rates are higher in American Indians and Alaska Natives than in the general US population . Patients with weakened immune system are particularly prone to molluscum infection and have increased difficulty in clearing lesions (point prevalence in patients with human immunodeficiency virus/acquired immune deficiency syndrome (AIDS): 5–18%) [8–11]. A history of eczema was found in 62% of children with molluscum contagiosum in Australia . Another Japanese study found that lifetime molluscum was increased in young children with atopic eczema . Etiology Molluscum contagiosum, also known as Molluscipoxvirus, is a member of the pox virus (Poxviridae) family [14,15]. Transmission of molluscum occurs during contact with infected lesions, contami-
nated fomites, or sexual contact . Autoinoculation through scratching is also suspected, especially as lesions can develop along scratchmarks (koebnerization) . Outbreaks have occurred among children attending swimming pools [18,19]. Prognosis After a variable incubation period (2–6 months), the lesions usually persist for several months and resolve as a result of an inflammatory response which may develop spontaneously, following trauma (e.g., scratching) or secondary bacterial infection [1,20,21]. In immunocompromised people – for example, patients with AIDS – molluscum contagiosum usually does not resolve spontaneously and is often refractory to treatment [1,22]. Aims of treatment Molluscum contagiosum is self-limiting in immunocompetent individuals. Many parents of children with molluscum may seek treatment because of concerns about the appearance of the lesions, lesions becoming sore due to friction from clothing and in skin folds, persistence of lesions, spread of lesions, concern about secondary infection, or because of other people’s comments. The aims of treatment are to shorten the duration of the condition, to resolve discomfort (e.g., itching), to limit spread, and to prevent secondary bacterial infection . Relevant outcomes Clinical cure of all infected lesions is the clinically most relevant outcome. Treatment success is defined as the proportion of patients completely cleared of all molluscum contagiosum lesions. Treatment success should ideally be assessed 4–8 weeks after the discontinuation of treatment because of the tendency of molluscum to heal spontaneously in healthy children. Secondary outcomes include the time to clearance of all lesions and the cosmetic result. Methods of search We included randomized controlled trials (RCTs) of all interventions for cutaneous, nongenital infection with molluscum contagiosum in immunocompetent patients. We updated the previous
RCT we have identified that provides supporting evidence for a physical destructive method in the treatment of molluscum contagiosum . The clearance rate of 100% (37 out of 37 subjects) was the highest out of all studies, though clearly tolerability and scarring are major drawbacks. This study also found a 92% (34/37) clearance rate with imiquimod after 16 weeks, in contrast to the previously discussed Papadopoulos studies , which found clearance rates of 24% (112/470 – pooled data) after 18 weeks. Cantharidin, a blister beetle extract, has been widely used to treat viral warts as well as molluscum contagiosum. However, the only RCT we found for the treatment of mollusca suggests that there was no significant improvement compared with placebo, though it was a small study that may have been underpowered . Despite previous studies suggesting no benefit in treating mollusca with potassium hydroxide compared with placebo [28, 29], there have been two further studies published, by Rajouria et al.  and Uçmak et al. , showing a greater reduction in mean lesion count and improved complete clearance with potassium hydroxide. However, in both studies, patient numbers were small and no control groups were present.
Sodium nitrite Figure 39.1 Molluscum contagiosum.
edition’s chapter by searching the Cochrane Controlled Trials Register (May 2013), the Cochrane Library for systematic reviews (May 2013), and Medline (June 2006–May 30, 2013).
Question In immunocompetent patients with cutaneous, nongenital molluscum contagiosum, what is the efficacy (defined as the proportion of patients completely cleared of all lesions at 4–8 weeks after discontinuation of treatment) of physical destructive methods, topical and systemic treatments, or waiting for spontaneous resolution?
A Cochrane review on the interventions for cutaneous molluscum contagiosum was published in 2006 and subsequently updated to include studies published up to June 2009 . Only 11 studies, with a total number of 495 participants, could be analysed. Study limitations included no blinding (four studies), high drop-out rates (three studies), and no intention-to-treat analysis, and the small study sizes meant inadequate power to detect possible important differences. The overall conclusion from the authors was that no single intervention has been shown to be convincingly effective in the treatment of molluscum contagiosum . We identified another seven relevant studies, including two of the largest RCTs ever conducted in the intervention of molluscum contagiosum. These two studies, identified by Katz and Swetman , suggest that imiquimod 5% is no more effective than placebo in achieving clearance of mollusca, yet these studies have never been published in a peer-reviewed journal . A study by Mutairi et al. comparing 5% imiquimod cream with cryotherapy is the only
Efficacy After 3 months of treatment with sodium nitrite 5%–salicylic acid 5% cream with occlusion on each lesion overnight, 75% of patients (12/16) completely cleared, in comparison with 25% of children (4/16) treated with salicylic acid 5% cream . Drawbacks Brown staining of the skin was recorded in six patients out of 16 with active treatment, but in none in the control group. The treatment is awkward and time consuming, and causes irritation in some patients (frequency not reported) . Comment Because of potential staining, sodium nitrite is not recommended for facial molluscum contagiosum. It appears to be beneficial for lesions on the trunk, although larger trials are needed to confirm the results.
Salicylic acid, phenol
Efficacy Salicylic acid 12%, lactic acid 4% gel (Salatac) applied once to twice weekly, and 10% phenol in a 70% alcohol solution applied once daily had similar clearance rates to those of the vehicle (Salatac 57% (21/37) versus phenol 42% (17/41) versus placebo 44% (16/36); completely cleared, P = 0.38) . Drawbacks Significantly more patients discontinued treatment due to stinging in the salicylic acid group in comparison with phenol and vehicle. No serious adverse events occurred . Comment Because an efficacy greater than that of the vehicle was not demonstrated in this study, neither salicylic acid nor phenol are recommended. The sample size of the study was quite small, and important treatment differences might have been missed. In contrast to the full-text paper, in which the results were based on an intention-totreat analysis, the authors reported results after excluding drop-outs in a previously published abstract. Salicylic acid appears to be ben-
Molluscum contagiosum 331
eficial in the per-protocol analysis, highlighting the potential of misleading inferences due to inappropriate statistical methods [33,34].
Imiquimod versus vehicle and cryotherapy
Efficacy Theos et al. found imiquimod 5% cream applied three times a week for 12 weeks was not superior to the vehicle in inducing complete clearance (imiquimod 33.3% completely cleared (4/12) versus vehicle 9.1% (1/12); P = 0.32); partial responses (defined as at least a 30% reduction in the lesion count) were more frequent in patients treated with imiquimod . An RCT by Al Mutairi et al. demonstrated imiquimod 5% cream applied five times a week led to complete cure at 16 weeks in 34/37 participants (22/37 at week 6), compared with complete clearance in all 37 patients receiving onceweekly cryotherapy after 3 weeks . Interestingly, a commentary by Katz and Swetman  in 2013 on the deficiencies of US law in failing to mandate that important negative studies are published in full in peer-reviewed journals highlighted two unpublished RCTs (by Papadopoulos in 2006) conducted in comparing imiquimod 5% used three times weekly for up to 16 weeks against placebo . Both studies found no statistical difference in complete clearance rates of those treated with imiquimod, 52/217 and 60/253 (both 24%) compared with placebo, 60/253 and 35/216 (24% and 16%). Drawbacks Tolerability did not differ significantly between imiquimod and the vehicle in the study by Theos et al. with local skin reactions and pruritus commonly reported in both groups . The Al Mutairi et al. study showed significantly more adverse effects with cryotherapy compared with imiquimod, including blistering (9/37), pigmentary changes (15/37), and scarring (8/37). Together with the treatment-associated pain of cryotherapy, this represents a major drawback of the use of this modality in young children. Pain during application (27/37) and erythema (28/37) were also common side effects reported with imiquimod . A pharmacokinetic study suggested that percutaneous absorption in imiquimod was low; however, leukopenia and neutropenia were commonly noted . Comment With a total of 23 participants included, the first study was not sufficiently powered to show small differences . The Al Mutairi et al. study reported high clearance at 16 weeks, for both imiquimod and cryotherapy, but given the self-limiting nature of molluscum, the lack of a placebo arm in this trial was a significant flaw, as was the lack of description of method of randomization and subsequent allocation concealment and blinding. The unpublished trials cited by Katz and Swetman highlight the problem of publication bias against studies with negative results. The original manufacturer of imiquimod and clinicians involved in their pivotal studies chose not to publish the results of these studies in a journal, yet they are available on the US Foods and Drugs Administration (FDA) website. As a result, these key studies have not been picked up and included in dermatology textbooks, reference guides, and even the Cochrane review on the interventions for cutaneous molluscum contagiosum.
Australian lemon myrtle (Backhousia citriodora)
Efficacy The essential oil of the Australian lemon myrtle (Backhousia citriodora) (Herbal BioScience, Oakvale, California, USA), applied once
daily for 21 days, induced partial remission (defined as at least a 90% reduction in the lesion count) in 56% (9/16) of patients, in comparison with 0% (0/15) treated with the vehicle. Complete response rates are not reported . Drawbacks None. The treatment was well tolerated in the study . Comment Australian lemon myrtle appears to beneficial against molluscum contagiosum. However, complete response rates are not reported, and complete clearance is probably of most relevance for the patient . Further evidence has suggested cytotoxic effects associated with the use of this oil [38,39], which has led the research group (Centre for Biomedical Research Inc.) to evaluate another formulation of lemon myrtle to improve safety and efficacy .
Combination of essential oil of Melaleuca alternifolia with iodine
Efficacy The same company that evaluated Backhousia citriodora went on to test another essential plant oil obtained from Melaleuca alternifolia, more widely known as tea tree oil. They compared melaleuca oil against melaleuca plus iodine versus iodine alone in a three-armed RCT of 53 children and found that 16 out of 19 children (84%) had a greater than 90% reduction of lesions in the combination group, compared with one out of 16 (6%) and three out of 18 (17%) for the iodine and melaleuca-only groups (P < 0.01) by the end of day 30 using an intention-to-treat analysis . Complete response rates are not reported. Drawbacks Adverse effects were limited to application site redness that did not result in any children withdrawing from the study. Long-term scarring after resolution of the lesions was not assessed. Comment This study suggests that a specially formulated combination of tea tree oil and iodine is more effective than either product used alone, although the absence of a vehicle-only group is a limitation given the tendency of molluscum to resolve spontaneously. The internal validity of this company-sponsored trial is questionable given that the method of randomization and subsequent allocation concealment is not described, and although parents and the evaluating physicians were reported to have been blinded to the treatment allocation, it is unclear whether assessment was truly blinded given that iodine stains the skin. Plant extracts could have a beneficial effect in inducing local clearance of mollusca, and an independent trial of tea tree oil plus iodine versus a vehicle of similar colour and smell with blinded assessment of complete clinical response might be worthwhile.
Povidone iodine solution combined with salicylic acid plaster
Efficacy Ohkuma found that 10% povidone iodine solution and 50% salicylic acid plaster was effective in curing 20/20 participants (100%) compared with 3/5 who received povidine iodine alone (60%) and 7/10 who received salicylic acid plaster alone (70%). Thus, the combination treatment cured more participants than either component alone (and more rapidly – 26 days, 86 days, and 47 days were mean
332 The evidence
time to cure for each group respectively), though this failed to reach statistical significance . Drawbacks All participants developed local redness within 3–7 days of starting treatment. The duration of redness was variable, and the more marked the inflammation the earlier the cure was . Comment Based on the small number in the comparator groups and lack of statistical difference between the groups there is insufficient evidence to recommend this treatment.
Efficacy In total, 73% (11/15) of patients treated with benzoyl peroxide 10% cream twice daily for a total of 4 weeks had complete remission of all lesions at week 6, in comparison with 33% (5/15) of patients treated with tretinoin 0.05% cream (relative risk [RR], 2.20; 95% confidence interval [CI], 1.01–4.79; P = 0.05) . Drawbacks Side effects were limited to mild dermatitis in both treatment groups (exact numbers not reported) . Comment Benzoyl peroxide 10% cream appears to be beneficial for molluscum contagiosum. However, owing to poor reporting quality and methodological shortcomings (i.e., failure to carry out an intentionto-treat analysis) bias cannot be ruled out , and better studies are needed.
Cantharidin versus placebo
Efficacy Cantharidin is a topical vesicant that has been used to treat molluscum for several decades. It is an extraction from blister beetles, Cantharis vesicatoria, and when applied to the skin it produces a small intraepidermal blister that usually heals without scarring. In this randomized double-blind study, 15% (2/13) of those who received cantharidin and 6% (1/16) of those who received vehicle achieved complete clearance after 8 weeks, which was not statistically different . Drawbacks Although the placebo vehicle had an identical texture and smell to the active drug, there were significant differences in reported adverse effects in that blistering was reported in 12/13 of those who received cantharidin, but in only 8/16 receiving placebo. The active group also experienced more pigmentary changes (6/13 vs 0/16). Three patients in the cantharidin group were excluded because they were later found not to meet the inclusion criteria . Comment Despite anecdotal evidence supporting the use of cantharidin, this study is the first prospective, placebo-controlled, randomized trial evaluating the safety and efficacy of cantharidin for molluscum contagiosum. Although the performance of cantharidin was similar to that of placebo in this study, it was probably too small to be conclusive.
Potassium hydroxide versus saline and tretinoin cream
Efficacy Bazza and Ryatt reported a study where treatments were randomized to the right or left side of the body. Application of 5% potassium hydroxide was compared with 0.9% saline. In both groups, 85% (17/20) of patients were cured at 12 weeks . The same comparison was made by Short et al., where treatment with 10% potassium hydroxide was successful after 3 months in 70% (7/10) compared with 20% (2/10) in the saline group . Pooling these data showed no significant benefit from potassium hydroxide. Rajouria et al. compared 5% potassium hydroxide with tretinoin 0.05% cream in a nonrandomized controlled study, with 25 patients allocated to each treatment, and found at 4 weeks a mean reduction in lesion count from 9.48 (±3.00 standard deviation [SD]) to 1.67 (±0.58 SD) and from 8.35 (±2.82 SD) to 2.00 (±1.00 SD) for potassium hydroxide and tretinoin respectively . A study by Uçmak et al. compared treatment with potassium hydroxide at concentrations of 2.5% and 5%. Complete clearance was reported in 23% (3/13) and 67% (8/12) at 60 days after commencing treatment with potassium hydroxide twice daily in each group respectively . Drawbacks Four patients (two in each group) dropped out of the Rajouria et al. study due to noncompliance, and a table of side effects for the remainder of the participants showed erythema (14/23), edema (5/23), and burning (4/23) reported in those treated with 5% potassium hydroxide, though erosions (6/23) and ulceration (1/23) were also reported. Side effects from potassium hydroxide were common in the study by Uçmak et al., with at least one side effect reported in 86.4% and 91.7% of those treated with 2.5% and 5% potassium hydroxide respectively. The exact number and nature of side effects were not reported. Tretinoin 0.05% cream appeared to produce milder adverse effects. Comment The studies by Bazza and Ryatt and by Short et al. showed no significant benefit of potassium hydroxide in clearing molluscum. The Rajouria et al. study focused on a reduction in lesion count rather than clearance at 4 weeks. Although there was a significant reduction in mean lesion count with both treatments, there was no significant difference between the treatments and no placebo arm to assess the mean reduction in those without any treatment. Therefore, the study suggests potassium hydroxide (and tretinoin cream) improve the resolution of mollusca, but how much better than spontaneous resolution is unclear. This study was also nonblinded and nonrandomized, which is at high risk of selection and information bias, and it is unclear whether an intention-to-treat analysis was performed. Although the Uçmak et al. study was reported as randomized, allocation concealment was unclear. Despite efforts to blind study participants, it is unclear whether assessors had been blinded, and in fact the same observer was used for all follow-up visits, risking significant information bias. This study would also have benefitted from a control arm.
Efficacy This homeopathic drug given daily for 15 days resulted in improvement in 93% (13/14) participants in the treatment arm and 17% (1/6) in the placebo arm of the trial (RR, 5.57; 95% CI, 0.93–33.54; not statistically significant) .
Melaleuca alternifolia alone Iodine alone
Salicylic acid 12%, lactic acid 4% gel (Salatac)
Imiquimod 5% cream
Essential oil of Australian lemon myrtle
Benzoyl peroxide 10% cream
Cimetidine 35 mg/ kg/day
Melaleuca alternifolia + iodine
5% imiquimod cream
10% povidone iodine solution and 50% salicylic acid plaster
(a) 10% phenol in 70% alcohol, (b) 70% alcohol (placebo)
Salicylic acid 5% cream alone
Sodium nitrite 5%– salicylic acid 5% cream
Ormerod (1999) 
First author, ref.
Children (2–9 years)
Children (2–8 years)
Children (6.3 ± 5.1 years)
Children (1–16 years)
Children (not reported)
Children (4.6 ± 3.1 years)
Children (4.7 ± 1.9 years)
Children (1–15 years)
Children (median age 6 years)
Sample size (n)
Table 39.1 Summary of RCTs identified on molluscum contagiosum in otherwise healthy individuals.
Duration of active treatment
Complete clearance Time to cure
Complete clearance rate after 16 weeks
Proportion of patients with reduction of lesions >90%
Complete clearance rate after 4 months
Complete clearance rate at week 6
Proportion of patients with reduction of lesions >90%
Complete clearance rate at week 12
Complete clearance rate after 6 months
Complete clearance rate after 3 months
10% povidone iodine solution and 50% salicylic acid plaster 20/20 completely cleared at 26 days vs 10% povidone iodine solution alone 3/5 at 68 days vs salicylic acid plaster alone 7/10 at 47 days (P > 0.05)
Study quality: Randomizationa Blindingb Statistical analysisc
Molluscum contagiosum 333
Imiquimod cream 5%
5% potassium hydroxide
10% potassium hydroxide
5% potassium hydroxide
5% potassium hydroxide
Coloe Dosal (2012) 
Papadopoulos (2006) 
Bazza (2007) 
Short (2006) 
Rajouria (2011) 
Uçmak (2013) 
Manchanda (1997) 
2.5% potassium hydroxide
0.05% tretinoin cream
0.9% normal saline
Children and adults (0–30 years)
Children (15 months–18 years)
Children (6 months–14 years)
Children (2–12 years)
Children (2–12 years)
Children (2–12 years)
Children (5–10 years)
Sample size (n)
Nonrandomized controlled trial
Duration of active treatment
RCT, randomized controlled trial. a Adequate, if clear description of method of randomization and concealment of allocation of randomization given. b Adequate, if assessors and participants were completely blinded to the study interventions. c Adequate, if an intention-to-treat analysis was carried out; that is, all patients originally randomized were included in the final main analysis.
Study quality: Randomizationa Blindingb Statistical analysisc
334 The evidence
Molluscum contagiosum 335
Drawbacks The study duration, time to resolution, dosing regimen, and adverse events were not reported and the study was not analyzed by an intention-to-treat principle. The number of dropouts (20/104 for the whole trial, including other skin conditions) is unclear for the molluscum participants. Comment For the above reasons, calcarea carbonica is not recommended as a treatment for molluscum.
Efficacy Oral cimetidine 35 mg/kg per day for 3 months added no notable benefit compared with placebo treatment: cimetidine 50% (4/8) versus placebo 46% (5/11), completely cleared after 4 months (P > 0.05) . Drawbacks Half of the patients (19 of 38) dropped out. The reasons for withdrawal are not reported . Comment Cimetidine is not recommended in the treatment of molluscum contagiosum.
Destructive methods such as cryotherapy, electrodessication, physical squeezing
Apart from the Al Mutairi et al. study of the trial that compared imiquimod with cryotherapy , we were not able to identify any trials demonstrating the efficacy of these commonly used physical destructive treatments against each other or against no treatment. Although this study demonstrated high cure rates within a short period (37/37 completely cleared at 3 weeks), like most destructive methods this benefit must be balanced against tolerability in young children and adverse effects such as scarring.
Implications for clinical practice
Molluscum contagiosum is a self-limiting disease in the immunocompetent host. Treatment is not necessary in most cases, since natural resolution occurs. Topical treatments that do not leave scars and are not associated with severe adverse events may be tried in order to limit the spread, shorten the course of the disease, for cosmetic reasons, and/or to suppress accompanying symptoms. The decision to treat must take in to account these issues as well as patient factors, such as a child’s age, history of atopy, secondary infection, and so on. It is unclear whether treatment of molluscumassociated dermatitis can limit spread of lesions . Treatment options for mollusca that can be recommended on the basis of the existing scant evidence are 5% sodium nitrite with 5% salicylic acid cream for nonfacial lesions and cryotherapy. Salicylic acid preparations, phenol, cantharidin, imiquimod 5% cream, povidine iodine solution with salicylic acid plaster, oral calcarea carbonica, and cimetidine are not recommended on the basis of the data available. Most studies have small sample sizes and may, therefore, be underpowered to detect differences in clinical outcomes. A summary of trials for the treatment of molluscum contagiosum is presented in Table 39.1. The evidence base for treatment and prevention of spread of mollusca is very poor considering it is such a common condition.
Future studies need to be much larger, randomized, include blinded assessment of responses, and should be prospectively registered and fully reported. The unit of analysis should be number of people and not numbers of lesions, and placebo or no treatment arms should be included. The importance of publishing studies with negative results should also be emphasized in order to avoid persistent use of treatments that have been proven not to work any better than placebo.
Key points • Molluscum contagiosum in otherwise healthy people is self-limiting. • Treatment is not necessary in most people. • Many popular treatments, including physical destruction, have not been evaluated properly with well-designed, prospective, double-blinded randomized control trials. • Topical sodium nitrite, cryotherapy, and possibly benzoyl peroxide preparations appear to shorten the duration of the disease. • Current evidence suggests that salicylic acid preparations, phenol, cantharidin, imiquimod, and oral cimetidine are no more effective than placebo.
I would like to thank Jochen Schmitt and Thomas L. Diepgen, the authors of this chapter in the second edition, for their contribution.
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336 The evidence
17. Stulberg DL, Hutchinson AG. Molluscum contagiosum and warts. Am Fam Physician 2003;67:1233–40. 18. Bader RE. Multiple occurrence of molluscum contagiosum in the zone of a swimming pool. Attempt at an epidemiological analysis. Arch Hyg Bakteriol 1967;151: 388–402 (in German). 19. Niizeki K, Kano O, Kondo Y. An epidemic study of molluscum contagiosum. Relationship to swimming. Dermatologica 1984;169:197–8. 20. Waugh MA. Molluscum contagiosum. Dermatol Clin 1998;16:839–41, xv. 21. Hawley TG. The natural history of molluscum contagiosum in Fijian children. J Hyg (Lond) 1970;68:631–2. 22. Schwartz JJ, Myskowski PL. Molluscum contagiosum in patients with human immunodeficiency virus infection. A review of twenty-seven patients. J Am Acad Dermatol 1992;27:583–8. 23. Van der Wouden JC, van der Sande R, van Suijlekom-Smit LWA, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev 2009;(4): CD004767. 24. Katz KA, Swetman GL. Imiquimod, molluscum, and the need for a better “Best Pharmaceuticals for Children” Act. Pediatrics 2013;132:1–3. 25. Papadopoulos EJ. Clinical Executive Summary [Imiquimod]. 2006. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/ DevelopmentResources/UCM162961.pdf (accessed December 6, 2012). 26. Al Mutairi N, Al Doukhi A, Al Farag S, et al. Comparative study on the efficacy, safety, and acceptability of imiquimod 5% cream versus cryotherapy for molluscum contagiosum in children. Pediatr Dermatol 2010;27:388–94. 27. Coloe Dosal J, Stewart PW, Lin JA, et al. Cantharidin for the treatment of molluscum contagiosum: a prospective, double-blinded, placebo-controlled trial. Pediatr Dermatol 2014; in press. doi: 10.1111/j.1525-1470.2012.01810.x [Epub ahead of print]. 28. Bazza MA, Ryatt KS. Sterile normal 0.9% saline as a effective 5% potassium hydroxide in treatment of molluscum contagiosum, and safer. 2007. Unpublished trial, cited in . 29. Short KA, Fuller LC, Higgins EM. Double-blind, randomized, placebo-controlled trial of the use of topical 10% potassium hydroxide solution in the treatment of molluscum contagiosum. Pediatr Dermatol 2006;23:279–81. 30. Rajouria EA, Amatya A, Karn D. Comparative study of 5 % potassium hydroxide solution versus 0.05% tretinoin cream for molluscum contagiosum in children. Kathmandu Univ Med J 2011;36(4):291–4. 31. Uçmak D, Akkurt MZ, Kacar SD, et al. Comparative study of 5% and 2.5% potassium hydroxide solution for molluscum contagiosum in children. Cutan
Ocul Toxicol 2013;in press. doi: 10.3109/15569527.2013.796479 [Epub ahead of print]. 32. Ormerod AD, White MI, Shah SA, et al. Molluscum contagiosum effectively treated with a topical acidified nitrite, nitric oxide liberating cream. Br J Dermatol 1999;141:1051–3. 33. Leslie KS, Dootson G, Sterling JC. Topical salicylic acid gel as a treatment for molluscum contagiosum in children. J Dermatolog Treat 2005;16:336–40. 34. Leslie KS, Dootson G, Sterling JC. Does treatment of molluscum contagiosum affect clearance? [Abstract PA-3, 84th BAD Annual Meeting 6–9 July 2004, Belfast, UK.] Br J Dermatol 2004;151:67. 35. Theos AU, Cummins R, Silverberg NB, et al. Effectiveness of imiquimod cream 5% for treating childhood molluscum contagiosum in a double-blind, randomized pilot trial. Cutis 2004;74:134–2. 36. Myhre PE, Levy ML, Eichenfield LF, et al. Pharmacokinetics and safety ofimiquimod 5% cream in the treatment of molluscum contagiosum in children. Pediatr Dermatol 2008;25(1):88–95. 37. Burke BE, Baillie JE, Olson RD. Essential oil of Australian lemon myrtle (Backhousia citriodora) in the treatment of molluscum contagiosum in children. Biomed Pharmacother 2004;58:245–7. 38. Hayes AJ, Markovic B. Toxicity of Australian essential oil Backhousia citriodora (lemon myrtle). Part 1. Antimicrobial activity and in vitro cytotoxicity. Food Chem Toxicol 2002;40(4):535–43. 39. Hayes AJ, Markovic B. Toxicity of Australian essential oil Backhousia citriodora (lemon myrtle). Part 2. Absorption and histopathology following application to human skin. Food Chem Toxicol 2003;41(10):1409–16. 40. Markum E, Baillie J. Combination of essential oil of Melaleuca alternifolia and iodine in the treatment of molluscum contagiosum in children. J Drugs Dermatol 2012;11(3):349–54. 41. Ohkuma M. Molluscum contagiosum treated with iodine solution and salicylic acid plaster. Int J Dermatol 1990;29(6):443–5. 42. Saryazdi S. The comparative efficacy of benzoyl peroxide 10% cream and tretinoin 0.05% cream in the treatment of molluscum contagiosum. [Abstract, 10th World Congress on Pediatric Dermatology.] Pediatr Dermatol 2004;21:399. 43. Manchanda RK, Mehan N, Nahl R, et al. Double blind placebo controlled clinical trials of homeopathic medicines in warts and molluscum contagiosum. CCRH Q Bull 1997;19:25–9. 44. Antony F, Cliff S, Ahmad A, et al. Double-blind placebo-controlled study of oral cimetidine treatment for molluscum contagiosum. Br J Dermatol 2001; 145:126.
Impetigo Sander Koning1, Renske van der Sande1, Lisette W.A. van Suijlekom-Smit2, and Johannes C. van der Wouden3 1
Department of General Practice, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands Department of Paediatrics, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands 3 Department of General Practice, VU University Medical Center, Amsterdam, Netherlands 2
Background Definition Impetigo (Figure 40.1) is a contagious superficial skin infection, characterized by superficial erosions covered with honey-colored crusts, most often on the face. A distinction is made between bullous and nonbullous impetigo. Impetigo may be primary or secondary to other skin diseases, such as atopic eczema. Incidence Impetigo is most frequent in children; the incidence rates peak at 1–8 years of age. Population-based incidence rates are unknown. Impetigo is common in general practice, with incidence rates of around 20 episodes per 1000 children per year seen by general practitioners in the UK and the Netherlands [1–3]. Etiology In moderate climates, the primary pathogen in nonbullous impetigo is Staphylococcus aureus. However, in warm and humid climates, Streptococcus pyogenes or a combination of S. pyogenes and S. aureus are often isolated. The relative frequency of S. aureus infections has also changed with time. It was predominant in the 1940s and 1950s, and then group-A streptococci became more prevalent. In the last decade of the 20th century, S. aureus has been reported to have become more common again . Bullous impetigo is a staphylococcal disease. Prognosis Impetigo is believed to be self-limiting, taking several weeks to cure without intervention. However, no research is available to substantiate this statement. Prompt resolution usually occurs with adequate treatment. The course of the disease is usually mild, but sometimes general symptoms such as fever and lymphadenopathy occur. Streptococcal impetigo can be complicated by nephritis. Aims of treatment Impetigo is treated to accelerate cure and to prevent spreading of the infection.
Relevant outcomes Clinical cure (clearance of crusts, blisters, and redness) is the most relevant outcome. Criteria such as relief of pain, itching, and soreness, and bacteriological cure can be considered as secondary outcomes. Methods of search We found four systematic reviews [5–8], the Cochrane review published in 2012  being an extended update of earlier versions [5,7]. As the Cochrane review, with 68 included randomized controlled trials (RCTs), is the most recent and most comprehensive one, it has provided the basis for discussing treatments in this chapter. The Cochrane review included randomized trials of all interventions for impetigo by using the following search terms in Medline: impetigo (Medical Subject Headings, MeSH) or (MeSH) or impetigo (in title or abstract) or pyoderma (in title or abstract), in combination with the standard search strategy for identifying randomized trials. For this Cochrane review update, the literature was searched up to July 2010. Owing to space limitations, we only report here on nonbullous impetigo, and on the most relevant comparisons and outcomes.
Questions What are the effects of treatments on the clearance of impetiginous lesions after 1 week?
Efficacy Versus placebo We found one small randomized trial comparing hexachlorophene with placebo . Scrubbing with hexachlorophene added no notable benefit to placebo treatment. Versus topical antibiotic treatment One multicenter RCT compared hydrogen peroxide cream with fusidic acid cream/gel . There was no significant difference in treatment effect, but there was a tendency towards a better effect of fusidic acid cream/gel. There was
All other studies comparing topical antibiotics were small and each studied a unique comparison of two antibiotics. Versus oral antibiotics When 10 RCTs that compared topical mupirocin with oral erythromycin were pooled [4,22–30], mupirocin was found to be significantly better than erythromycin . In a small RCT, cephalexin and mupirocin were both significantly more effective than bacitracin cream . A trial in patients with secondarily infected dermatitis found no difference between oral cephalexin and topical retapamulin ointment .
Figure 40.1 A child with impetigo (reproduced with permission of A.P.
no significant difference between hexachlorophene and bacitracin ointment in a small and older study . Versus oral antibiotic treatment There was no significant difference between hexachlorophene scrubbing and oral treatment with penicillin . Drawbacks Eleven percent of the patients using hydrogen peroxide cream reported mild side effects (not specified). No patient was withdrawn from the study because of side effects . No adverse effects of scrubbing with hexachlorophene were recorded . Comment Disinfectants, such as povidone iodine and chlorhexidine advised in some guidelines, have not been compared with a placebo. Hydrogen peroxide cream showed good treatment results in a relatively large trial. However, the procedure for blinding in this trial was considered inappropriate. Implications for topical disinfectants in clinical practice There is no good evidence for the value of disinfecting measures in the treatment of impetigo.
Efficacy Versus placebo Six studies compared a topical antibiotic with placebo treatment. Mupirocin has been studied in three placebo-controlled trials, all of which found a better effect with mupirocin [11–13]. One other RCT showed that fusidic acid was much more effective than placebo (55% of patients cured vs 13%) . A result of similar magnitude was found for retapamulin versus placebo (86% vs 52%) . Versus each other Several topical antibiotics have been compared directly. Mupirocin and fusidic acid were compared in four studies [16–19], none of which showed a significant difference in treatment effect. In a large study (>500 patients), the difference between retapamulin and fusidic acid was not statistically significant . An old study found better results for gentamycin than for neomycin .
Drawbacks RCT reports usually note few, if any, side effects with local antibiotics. The two studies comparing mupirocin with placebo reported none [11,12]. In studies comparing mupirocin with fusidic acid, the greasy nature of mupirocin was reported as a side effect in 7% of patients versus 1% ; minor itching/burning occurred in 5% versus 4%, respectively . No side effects were reported in Gilbert’s study . Studies comparing erythromycin with mupirocin recorded gastrointestinal side effects in 23% versus 8% , none in either group , and an equal distribution between the two groups . Hydrocortisone/potassium hydroxyquinoline caused two cases (3%) of mild staining . In general, resistance rates against topical antibiotics such as fusidic acid and mupirocin will rise when the antibiotic is used excessively. Retapamulin caused itching in 7% of cases in one study  but only 1% in another study . Comments Most studies date back 20 years or more. Many RCTs deal with a range of (skin) infections, including impetigo. Only trials that reported separate results for the group of impetigo patients were included here. The follow-up periods and definitions of “cure” and “improvement” differ and are often not clear, making comparison difficult. There is a lack of placebo-controlled studies. Implications for topical antibiotics in clinical practice Although they are traditionally considered less effective than oral therapy, there is good evidence that local treatments are equal to or more effective than oral treatment. In general, oral antibiotics have more side effects, especially gastrointestinal side effects. Fusidic acid, mupirocin, and retapamulin are equally effective. Resistance patterns have changed since then. Contemporary and local characteristics and resistance patterns of the causative bacteria should always be taken into account when choosing treatment. When a large area is affected, or when the patient has general symptoms such as fever, oral therapy seems more appropriate. However, this assumption has never been tested properly.
Efficacy Versus placebo Only one small and inconclusive trial was found, comparing systemic antibiotics with placebo . Versus topical antibiotics Discussed under topical antibiotics above. Versus each other Two RCTs compared penicillin and erythromycin, both finding erythromycin to be more effective [34,35]. Cloxacillin was significantly superior to penicillin in two studies [36,37]. All other comparisons were each made in only one study,
and none of these showed a relevant difference between treatments. Drawbacks The incidences of side effects were: • azithromycin – 17%, mainly mild gastrointestinal ; • cephalexin – 11%, mainly mild gastrointestinal , 11% mainly diarrhea , no adverse effects in one study ; • cefdinir – 16%, mainly diarrhea ; • erythromycin – up to 17% gastrointestinal side effects, mainly diarrhea . Comments Many RCTs have been carried out on a range of “soft-tissue” infections, with a subset of impetigo patients. Only trials reporting separate results for the group of impetigo patients were considered in this chapter, although it should be pointed out that most trials in patients with “soft-tissue” infections did not provide results for impetigo separately. There is a lack of placebo-controlled studies. Resistance rates of the bacteria were determined in some studies, and differed from study to study. The follow-up periods differ widely between the studies, making comparison difficult. Implications for use of systemic antibiotics in clinical practice There is good evidence that local treatment is equal to or more effective than oral treatment. Macrolide antibiotics provide better treatment results than penicillin. In general, oral antibiotics have more side effects than topical treatments, especially gastrointestinal side effects. Most studies date back 20 years or more, and resistance patterns have changed since then. Contemporary local characteristics and the resistance patterns of the causative bacteria should always be taken into account when choosing treatment. When a large area is affected, or when the patient has general symptoms such as fever, oral therapy seems preferable. As mentioned above, this assumption has never been tested properly. Key points • The natural history of impetigo is not known. • Few placebo-controlled studies have been done. • Many different antibiotic treatments have been studied against each other, often in small studies showing no significant differences. • There is no evidence supporting the value of disinfecting treatments. • Topical antibiotics such as mupirocin and fusidic acid are equal to or more effective than oral antibiotics such as erythromycin and have fewer side effects. • Macrolide and cephalosporin antibiotics are more effective than penicillins that are not resistant to beta-lactamase. • For extensive infections accompanied by general symptoms such as fever, oral antibiotics may be preferable. • Resistance patterns in causative bacteria change over time, and this should be taken into account when choosing a therapy for impetigo.
1. Koning S, Mohammedamin RSA, van der Wouden JC, et al. Impetigo: incidence and treatment in Dutch general practice in 1987 and 2001; results from two national surveys. Br J Dermatol 2006;154:239–43. 2. Van der Ven-Daane I, Bruijnzeels MA, van der Wouden JC, et al. Occurrence and treatment of impetigo vulgaris in children. Huisarts Wet 1993;36:291–3.
3. McCormick A, Fleming D, Charlton J. Morbidity Statistics from General Practice: Fourth National Study 1991–1992. 1995. London: Department of Health, Office of Population Censuses and Royal College of General Practitioners. 4. Dagan R, Bar-David Y. Double-blind study comparing erythromycin and mupirocin for treatment of impetigo in children: implications of a high prevalence of erythromycin-resistant Staphylococcus aureus strains. Antimicrob Agents Chemother 1992;36:287–90. 5. Van Amstel L, Koning S, van Suijlekom-Smit LWA, et al. The treatment of impetigo contagiosa, a systematic review. Huisarts Wet 2000;43:247–52. 6. George A, Rubin G. A systematic review and meta-analysis of treatments of impetigo. Br J Gen Pract 2003;53:480–7. 7. Koning S, Verhagen AP, van Suijlekom-Smit LW, et al. Interventions for impetigo. Cochrane Database Syst Rev 2004;(2):CD003261. 8. Koning S, van der Sande R, Verhagen AP, et al. Interventions for impetigo. Cochrane Database Syst Rev 2012;(1):CD003261. 9. Ruby RJ, Nelson JD. The influence of hexachlorophene scrubs on the response to placebo or penicillin therapy in impetigo. Pediatrics 1973;52:854–9. 10. Christensen OB, Anehus S. Hydrogen peroxide cream: an alternative to topical antibiotics in the treatment of impetigo contagiosa. Acta Derm Venereol 1994;74: 460–2. 11. Eells LD, Mertz PM, Piovanetti Y, et al. Topical antibiotic treatment of impetigo with mupirocin. Arch Dermatol 1986;122:1273–6. 12. Gould JC, Smith JH, Moncur H. Mupirocin in general practice: a placebocontrolled trial. In: Wilkinson DS, Price JD, eds. Mupirocin: A Novel Topical Antibiotic. International Congress and Symposium Series, No. 80. London: Royal Society of Medicine, 1984:85–93. 13. Rojas R, Eells LD, Eaglstein W, et al. The efficacy of Bactroban ointment and its vehicle in the treatment of impetigo: a doubleblind comparative study. In: Dobson RL, Leyden JJ, Nobel WC, eds. Bactroban (Mupirocin): Proceedings of an International Symposium, Nassau, Bahama Islands, 21–22 May 1984. Amsterdam: Excerpta Medica, 1985: 96–102. 14. Koning S, van Suijlekom-Smit LWA, Nouwen JL, et al. Fusidic acid cream in the treatment of impetigo in general practice: double blind randomised placebo controlled trial. BMJ 2002;324:203–6. 15. Koning S, van der Wouden JC, Chosidow O, et al. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial. Br J Dermatol 2008;158:1077–82. 16. Morley PAR, Munot LD. A comparison of sodium fusidate ointment and mupirocin ointment in superficial skin sepsis. Curr Med Res Opin 1988;11: 142–8. 17. Gilbert M. Topical 2% mupirocin versus 2% fusidic acid ointment in the treatment of primary and secondary skin infections. J Am Acad Dermatol 1989;20:1083–7. 18. White DG, Collins PO, Rowsell RB. Topical antibiotics in the treatment of superficial skin infections in general practice: a comparison of mupirocin with sodium fusidate. J Infect 1989;18:221–9. 19. Sutton JB. Efficacy and acceptability of fusidic acid cream and mupirocin ointment in facial impetigo. Curr Ther Res 1992;51:673–8. 20. Oranje AP, Chosidow O, Sacchidanand S, et al. Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observerblinded, noninferiority study. Dermatology 2007;215:331–40. 21. Farah FS, Kurban AK, Malak JA, et al. The treatment of pyoderma with gentamicin. Br J Dermatol 1967;79:85–8. 22. Barton LL, Friedman AD, Sharkey AM, et al. Impetigo contagiosa III. Comparative efficacy of oral erythromycin and topical mupirocin. Pediatr Dermatol 1989;6: 134–8. 23. Britton JW, Fajardo JE, Krafte-Jacobs B. Comparison of mupirocin and erythromycin in the treatment of impetigo. J Pediatr 1990;117:827–9. 24. Dux PH, Fields L, Pollock D. 2% topical mupirocin versus systemic erythromycin and cloxacillin in primary and secondary skin infections. Curr Ther Res 1986;40: 933–40. 25. Esterly NB, Markowitz M. The treatment of pyoderma in children. JAMA 1970; 212:667–70. 26. Goldfarb J, Crenshaw D, O’Horo J, et al. Randomized clinical trial of topical mupirocin versus oral erythromycin for impetigo. Antimicrob Agents Chemother 1988;32:1780–3. 27. Gratton D. Topical mupirocin versus oral erythromycin in the treatment of primary and secondary skin infections. Int J Dermatol 1987;26:472–3. 28. McLinn S. Topical mupirocin vs. systemic erythromycin treatment for pyoderma. Pediatr Infect Dis J 1988;7:785–90. 29. Mertz PM, Marshall DA, Eaglstein WH, et al. Topical mupirocin treatment of impetigo is equal to oral erythromycin therapy. Arch Dermatol 1989;125: 1069–73. 30. Rice TD, Duggan AK, DeAngelis C. Cost-effectiveness of erythromycin versus mupirocin for the treatment of impetigo in children. Pediatrics 1992;89:210–4.
340 The evidence
31. Bass JW, Chan DS, Creamer KM, et al. Comparison of oral cephalexin, topical mupirocin, and topical bacitracin for treatment of impetigo. Pediatr Infect Dis J 1997;16:708–9. 32. Parish LC, Jorizzo JL, Breton JJ, et al. Topical retapamulin ointment (1% wt/wt) twice daily for 5 days versus oral cephalexin twice daily for 10 days in the treatment of secondarily infected dermatitis; results of a randomized controlled trial. J Am Acad Dermatol 2006;55:1003–13. 33. Jaffe GV, Grimshaw JJ. A clinical trial of hydrocortisone/potassium hydroxyquinoline sulphate (Quinocort) in the treatment of infected eczema and impetigo in general practice. Pharmatherapeutica 1986;4:628–36. 34. Demidovich CW, Wittler RR, Ruff ME, et al. Impetigo: current etiology and comparison of penicillin, erythromycin, and cephalexin therapies. Am J Dis Child 1990; 144:1313–5. 35. Barton LL, Friedman AD. Impetigo: a reassessment of etiology and therapy. Pediatr Dermatol 1987;4:185–8.
36. Gonzalez A, Schachner LA, Cleary T, et al. Pyoderma in childhood. Adv Dermatol 1989;4:127–41. 37. Pruksachatkunakorn C, Vaniyapongs T, Pruksakorn S. Impetigo: an assessment of etiology and appropriate therapy in infants and children. J Med Assoc Thai 1993; 76:222–9. 38. Kiani R. Double-blind, double-dummy comparison of azithromycin and cephalexin in the treatment of skin and skin structure infections. Eur J Clin Microbiol Infect Dis 1991;10:880–4. 39. Tack KJ, Keyserling CH, McCarty J, et al. Study of use of cefdinir versus cephalexin for treatment of skin infections in pediatric patients. Antimicrob Agents Chemother 1997;41:739–42. 40. Faye O, Hay RJ, Diawara I, et al. Oral amoxicillin vs. oral erythromycin in the treatment of pyoderma in Bamako, Mali: an open randomized trial. Int J Dermatol 2007;46(Suppl 2):19–22.
Athlete’s foot Inajara Rotta1, Michel F. Otuki1, and Cassyano J. Correr2 1
Pharmaceutical Sciences Postgraduate Program, Federal University of Paraná, Curitiba, Paraná, Brazil Pharmacy Department, Federal University of Parana, Ponta Grossa, Paraná, Brasil
Background Definition Athlete’s foot, or tinea pedis, is commonly caused by dermatophyte invasion of the skin of the feet. It is clinically presented as interdigital, moccasin, or vesicobullous forms, with interdigital being the most common. Moccasin infection affects soles, heels, and sides of the feet, characterized by dry and hyperkeratotic skin. With less frequency, vesicobullous is the most severe form of athlete’s foot. It appears as an acute and intense inflammation with vesicles, pustules, and bubbles, usually on the soles of feet [1–3] (Figure 41.1). Incidence/prevalence It has been estimated that 15% of the general population have athlete’s foot. It is thought to occur when individuals regularly use communal changing rooms and swimming pools. There are studies indicating higher prevalence in male and elderly people [4,5]. Etiology Athlete’s foot is usually caused by Trichophyton rubrum, Trichophyton mentagrophytes var. interdigitale, and Epidermophyton floccosum. Individuals with athlete’s foot may be susceptible to secondary bacterial infection with, for instance, group A streptococcus . Diagnostic tests Diagnosis of dermatophytosis is based on clinical and laboratory data. Clinical diagnostic procedure must include physical exam of the lesions and epidemiological history survey, whereas mycological tests consist of microorganisms visualization in microscopy and culture growth [2,7,8]. Aims of treatment The management of dermatophytosis consists of topical formulations, oral therapy, or a combination of them. An oral drug is needed when the affected area is wide, the patient is immunocompromised, or the disease is chronic or recurrent with failure on topical treatment [2,9]. The aim of treatment is to decrease signs and symptoms, such as redness, itching, and flaking, and also to eradicate the infection,
being that the course of treatment is partially determined by the severity level . Topical antifungals are available as over-the-counter drugs in most countries and are divided into two main classes: azoles, in which the mechanism of action is fungistatic, and alylamines, acting as fungicides. Other “non-azoles” and “non-allylamines,” such as tolnaftate and undecenoic acid, are also commercialized over the counter and, commonly, cost less than the others [2,10]. Relevant outcomes The efficacy outcomes evaluated were mycological cure at the end of treatment (MCET) and sustained cure (SC), defined as cure obtained up to 7 days after therapy conclusion and cure maintained for at least 14 days following the end of treatment, respectively. Efficacy of treatment was evaluated by meta-analysis, and the mycological cure was the main outcome considered, evidenced by microscopic negative or absence of growth of dermatophytes in culture . Methods of search Systematic reviews and randomized clinical trials (RCTs) were identified using a search strategy published elsewhere . This was updated to June 2012 using the same strategy. We included studies that compared the use of antifungals among themselves or with placebo in the treatment of any clinical form of athlete’s foot. Only studies that had patients diagnosed mycologically with the disease were included.
Questions How effective are allylamine creams in the treatment of athlete’s foot? Two meta-analysis published comparing allylamines (terbinafine and naftifine 1%) with placebo, used for 1–4 weeks, show that the two antifungals are similarly effective and better than placebo [5,10]. In a third meta-analysis were identified 12 RCTs (n = 1418) comparing naftifine 1% and terbinafine 1% or 3% with placebo,
used for 1 day (single-dose) to 28 days. For both efficacy outcomes, allylamines were better than placebo. In terms of MCET, metaanalysis of data from nine RCTs estimated the pooled odds ratio (OR) as 5.87 (95% confidence interval [CI], 2.46–14.01) and number needed to treat (NNT) of 3. For SC outcome, combined data from 11 studies, with follow-up period lasting from 2 to 12 weeks after the cessation of treatment, resulted in an OR of 14.22 (95% CI, 9.49–21.32) and NNT of 2 . How effective are azole creams in the treatment of athlete’s foot? Two systematic reviews were found comparing the azoles clotrimazole 1%, tioconazole 1%, bifonazole 1%, econazole 1%, and miconazole 2% with placebo, used for 4–6 weeks. The antifungals were similarly effective and better than placebo [5,10]. Another systematic review (n = 1223) compared econazole 1%, miconazole 2%, oxiconazole 1%, sertaconazole 2%, and clotrimazole 1% with placebo, used for 28–42 days . For MCET, the data interpolation from seven RCTs resulted in an OR of 5.54 (95% CI, 3.01–10.19) and NNT of 3. For SC outcome, pooled data of four trials with follow-up period lasted from 2 to 4 weeks after the cessation of treatment shows an OR of 6.64 (95% CI, 4.65–9.48) and NNT of 2 . How do allylamine creams compare with azole creams in curing athlete’s foot? A meta-analysis of nine RCTs (n = 1003) indicate better mycological cure rate with allylamines cream (terbinafine and naftifine 1%) in comparison with azoles cream (clotrimazole 1–2% and bifonazole 1%), used for 4–6 weeks. The relative reduction in treatment failure was 37%, favoring allylamines (relative risk [RR], 0.63; 95% CI, 0.42–0.94) . Considering different treatment regimens, data collected at 6 weeks from five trials (n = 962), which compared terbinafine 1%
used for 1 week with clotrimazole or miconazole 1% used for 4 weeks, did not show a statistically significant difference in treatment failure (RR, 0.75; 95% CI, 0.33–1.72). However, there was considerable variation in the results of the individual trials . In the study of Patel et al. , terbinafine was more effective than clotrimazole after 1 week of therapy (RR, 1.51; 95% CI, 1.16– 1.98), but there were no differences between the classes in the following weeks. We performed a meta-analysis of two studies (n = 955) [14,15], which compared terbinafine 1% cream twice daily for 1 week and clotrimazole 1% cream twice daily for 4 weeks. Terbinafine was better than clotrimazole for the MCET outcome (OR, 0.28; 95% CI, 0.09–0.85), without differences for the SC outcome, 6 weeks after the end of the treatment (OR, 0.40; 95% CI, 0.07–2.38). A result favoring the use of allylamines (RR, 0.88; 95% CI, 0.78–0.99) was also obtained by Hart et al. , although some language bias was detected. In another systematic review, eight trials (n = 1300) comparing oxiconazole 1%, clotrimazole 1%, miconazole 2%, or bifonazole 1% with naftifine and terbinafine, both 1%, were pooled. The OR of 0.55 obtained for MCET was statistically favorable to allylamines (95% CI, 0.33–0.92) with an NNT of 41. The results of nine RCTs (n = 1523) were interpolated for the SC outcome, giving an OR of 0.39 (95% CI, 0.22–0.67) and NNT of 13, in favor of the allylamines . How effectively do creams that can be bought in the supermarket cure athlete’s foot? Meta-analysis data indicates that tolnaftate (RR, 1.56; 95% CI, 1.05–2.31) and undecenoic acid (RR, 2.83; 95% CI, 1.91–4.19) are more effective than placebo . We performed a meta-analysis of RCTs comparing ciclopiroxolamine (0.77% and 1%) used for 4 weeks with placebo (three trials, n = 654) [16–18]. The ORs obtained were statistically favorable to the antifungal: 6.67 (95% CI, 3.47–12.80) for MCET and 8.98 (95% CI, 2.27–35.53) for the SC outcome. Other studies have similar results [5,10]. Finally, we performed a meta-analysis of four trials (n = 711) [19–22] comparing butenafine 1% cream with placebo, used for 1–4 weeks. A result favoring the use of butenafine was obtained for MCET (OR, 7.25; 95% CI, 2.25–23.38) and SC (OR, 12.33; 95% CI, 6.16–24.71) outcomes. Are oral drugs more effective than topical formulations in the treatment of athlete’s foot? The major advantage of oral drugs is a decrease on the duration of the treatment, which can improve a patient’s compliance . On the other hand, its cost is higher than the treatments based on topical agents, including the costs with medical care. One RCT (n = 137) compared the efficacy of interdigital tinea pedis treatment with oral (terbinafine 250 mg once daily for 1 week) and topical antifungal (clotrimazole 1% cream twice daily for 4 weeks). At week 4, the mycological cure rates were similar for the two drugs (72% for allylamine and 71% for clotrimazole). Although at week 1 the patients treated with terbinafine showed more rapid clinical improvement, higher levels of relapse were observed between weeks 4 and 12 after treatment with this drug (17% vs 5%). Both treatments were well tolerated, with incidence of adverse events equal between the groups . Considering the absence of more studies, it is cautious to reserve treatment with oral antifungals only for several or relapsing cases of athlete’s foot, when there is no topical treatment response .
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What are the most effective oral drugs in the treatment of athlete’s foot? The efficacy of oral drugs is not influenced by the type of tinea pedis . A meta-analysis of 12 RCTs (n = 700) showed no significant differences between terbinafine (250 mg/day for 2 weeks) and itraconazole (100 mg/day for 4 weeks); between fluconazole 50 mg and either itraconazole 100 mg or ketoconazole 200 mg, used for 6 weeks; or between griseofulvin 1000 mg and ketoconazole 200 mg, used for 4 weeks . For the same treatment length (2 weeks), terbinafine 250 mg was more effective than itraconazole 100 mg. Moreover, terbinafine 250 mg cures 52% more patients than griseofulvin 500 mg, when used once daily for 4–6 weeks . Adverse effects were reported for all drugs, with gastrointestinal effects, such as diarrhea and nausea, being the most commonly reported. There were no long-duration or harming adverse events . The oral therapy with terbinafine, itraconazole, and fluconazole was associated with low incidence of adverse events in an immunocompetent population . What are the most effective topical drugs in the treatment of athlete’s foot? We applied a random-effects Bayesian mixed treatment comparisons (MTC) model to combine placebo-controlled and direct topical antifungals comparison trials. Our analysis included 41 clinical trials published until June 2012 retrieved through a systematic review of the same databases used for conventional metaanalysis . Our analysis did not show statistically significant differences among all pairwise antifungals assessed (bifonazole, butenafine, clotrimazole, ciclopiroxolaminae, econazole, flutrimazole, ketoconazole, miconazole, naftifine, oxiconazole, sertaconazole, and terbinafine) for the MCET outcome. For the SC outcome, the ORs for butenafine, naftifine, and terbinafine were statistically superior to oxiconazole: 5.10 (95% CI, 1.16– 22.47), 4.61 (95% CI, 1.23–17.33), and 6.05 (95% CI, 1.74–21.05), respectively. Terbinafine also showed better response when compared with clotrimazole (OR, 2.88; 95% CI, 1.27–6.53). Terbinafine, butenafine, and naftifine, which occupied the first three places in the ranking, might be the best strategies for cure maintenance. Drawbacks Our analysis of published clinical trials has showed no differences in safety in all direct comparisons made between antifungals and placebo and among antifungal class. Few serious adverse events were reported, and the most common adverse events reported were burning, stinging, and itching, all confined to the site of application [11,12]. All oral antifungals were associated with the occurrence of adverse events. The lowest prevalence of events wase obtained with fluconazole (11%) and the highest with terbinafine (18%) . Comments There is consistent evidence regarding the superiority of antifungals in comparison with placebo. For athlete’s foot, allylamines are better than azoles in providing and maintaining mycological cure. Oral antifungals are not more effective than topical ones in the management of athlete’s foot. Additionally, higher rates of infection relapse, adverse events, and costs of the treatment were observed in patients treated with oral agents .
Implications for clinical practice All topical antifungals (azoles, allylamines, butenafine, ciclopiroxolamine, tolnaftate, and undecenoic acid) can be recommended to the treatment of athlete’s foot. Allylamines are superior to azoles in obtaining and maintaining cure, with the advantage of requiring a shorter period of time that can be associated with greater rates of compliance. Nevertheless, owing to their higher cost compared with other antifungals, an individual analysis for each patient must be done. Oral therapy must be considered only for severe infections or in relapses cases.
Key points • All topical antifungals are better than placebo in the treatment of athlete’s foot. • Direct comparisons of allylamines versus azoles used in the treatment of athlete’s foot show allylamines to be generally more efficacious than azoles. • MTC results do not show statistical differences among the antifungals considering the MCET outcome. Terbinafine, butenafine, and naftifine might be the best strategies for cure maintenance. • There is evidence to suggest that oral drugs are no more effective than creams in producing a cure for athlete’s foot and still produce more adverse events. • No differences were found in safety in all direct comparisons established between antifungals and placebo and between antifungals with each other.
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