Ebook Evidence-Based dermatology (3rd edition): Part 2

(BQ) Part 2 book Evidence-Based dermatology presents the following contents: The evidence (infective skin diseases, exanthems and infestations; disorders of pigmentation; common ailments with significant cosmetic impact, other important skin disorders), the future of evidence-based dermatology.

Local treatments for cutaneous warts

Juping Chen 1 and Yan Wu 2

Cutaneous warts are extremely common, benign, and usually self-limiting.  Infection  of  epidermal  cells  with  the  human  papilloma 

virus  (HPV)  results  in  cell  proliferation  and  a  thickened,  warty 

Diagnostic testsWarts 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 medico-legal cases to investigate child abuse

All RCTs on the topical treatments for extragenital warts were iden-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 investiga-tors independently extracted data from the included studies using 

Masutaka Furue and Yuping Ran, editors

Local treatments for cutaneous warts 321

active  treatment  group  developed  cellulitis.  Minor  skin  irritation was noted occasionally in some trials

Comments

ferent 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

There is reservation about the validity of pooled data from the dif-Cryotherapy with liquid nitrogen

Efficacy

Cryotherapy versus placebo or no treatment

Two small RCTs compared cryotherapy with either placebo cream [22] or no treatment [23]. One of the two trials [22] reported a very low cure rate for cryotherapy (one of 11), while the other trial [23] showed  a  high  cure  rate  in  the  placebo  group  (eight  of  20).  The pooled data of cure rates did not demonstrate a significant differ-ence 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 [24], 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–

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 gener-ally achieved more quickly with shorter treatment intervals

Optimum number of freezes

Only  one  RCT  [32]  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)

Drawbacks

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  

custom-made  standardized  forms  and  a  third  investigator  was 

Salicylic acid or topical products

containing salicylic acid

None  of  these  three  trials  are  strong  methodologically;  thus,  the results  are  somewhat  contradictory  and  difficult  to  summarize meaningfully

Contact immunotherapy with dinitrochlorobenzene

Efficacy

Two  small  RCTs  [22,36]  of  dinitrochlorobenzene  (DNCB)  in  80 children and adults achieved a cure rate of 80% (32/40) in compari-son 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)

Drawbacks

One trial [36] 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

Comments

tion and dermatitis, which probably precludes its use outside spe-cialist centers

DNCB, a potent contact allergen, can cause significant local irrita-Photodynamic therapy

Efficacy

Photodynamic therapy versus placebo

One  trial  [37]  randomized  active  (proflavine+black  light)  and placebo (picric acid + black light) treatments for recalcitrant sym-metrical 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

ylene blue/dimethyl sulfoxide PDT with a mixture of SA and creo-sote. The cure rates were 8% and 15%, respectively

One RCT [41] including 120 adults and children compared meth-Photodynamic therapy versus cryotherapy

In one RCT [42], 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 frequency electrocautery

high-One  RCT  [43]  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 [44] 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

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 [26]. 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)  [30]. 

The  rate  of  reported  adverse  affects  was  relatively  high  with  a 

limited and contradictory. Just as the RCTs on topical SA, the het-erogeneities  of  study  designs,  methods,  and  populations  make  it 

difficult  to  draw  firm  conclusions  from  the  pooled  data.  For 

Local treatments for cutaneous warts 323

Different concentrations of bleomycin

One  RCT  [54]  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

Drawbacks

No precise data on adverse effects were provided in any of the RCTs. One  RCT  [52]  reported  “adverse  events”  in  19/62  (31%)  partici-pants, 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 [54] reported pain was seen in most participants, which was irrespective of dose. In one trial [49] of 24 participants who received bleomycin, two patients withdrew  because  of  the  pain  of  the  injections  and  pain  in  the period after the injection

Comments

comes, trial periods, units of analysis, numbers of injections, vehi-cles, and concentrations) make it impossible to organize the data from these trials

5-Fluorouracil cryotherapy versus cryotherapy+placebo

One  RCT  [56]  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  [57],  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)

Drawbacks

Only  one  trial  [57]  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 

5-Aminolevulinic acid–photodynamic therapy versus

semiconductor laser

One RCT [45] reported that ALA–PDT is superior to semiconduc-tor laser (cure rates 25/28 vs 18/28)

Methyl aminolevulinate–photodynamic therapy+chemical

keratolytic treatment versus chemical keratolytic treatment

adverse  effects  than  other  simpler  and  cheaper  local  treatments 

available.  But  for  recalcitrant  warts,  it  might  be  an  alternative 

mycin. Three trials [49–51] reported higher cure rates with bleo-mycin  than  with  placebo,  one  [52]  showed  that  placebo  was 

associated  with  higher  cure  rates  than  bleomycin,  and  one  [53] 

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 combi-nation treatments (retinoic acid cream, α-2b interferon (IFN) oint-ment,  ceramic  grinding  treatment).  The  combination  treatments were superior to single laser treatment.

CO 2 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  [83]  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

Drawbacks

Ten RCTs [60,63,65,66,69,76–80] reported the side effects caused 

pigmentation,  burning,  itching,  desquamation,  crusts,  and  scar. Most of them were mild and tolerable

by light or laser therapy, including pain, erythema, swelling, hyper-Comments

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

Efficacy

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% 

observed after 2.2 sessions in the SA+PDL group versus 3.1 ses-sions  in  the  PDL  group  (P  <  0.05).  Although  the  clearance  rate 

showed  no  difference  between  the  SA+PDL  group  and  the  PDL 

Local treatments for cutaneous warts 325

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 [133]. 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

Drawbacks

All RCTs except one trial [120] 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,  pigmenta-tion, and so on

Comments

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

est.  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

Intralesional IFN as a treatment for warts is more of historical inter-In one RCT [140] 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 com-pleted 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 com-plete 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 [141] 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 treat-ment of warts, but needs more RCTs to support

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 

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 

Tazarotene versus ftibamzone Two RCTs [109,110] (including 347 

adults  and  children  with  verruca  planar)  compared  tazarotene 

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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

typi-cally begin as small papules that enlarge to around 3–6 mm and

rarely to more than 1 cm in diameter Fully developed papules

typi-cally 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) [1]

Mollusca can be associated with a surrounding dermatitis and

occa-sionally a reactive skin eruption similar to Gianotti–Crosti

syn-drome [2]

Incidence

Infections with the molluscum contagiosum virus occur

through-out the world, but the incidence varies considerably, with higher

rates in areas with warm climates [1] 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) [4] In New Guinea, the annual

attack rate was 6% in children aged 0–9 years [6] Incidence rates

are higher in American Indians and Alaska Natives than in the

general US population [7] 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

syn-drome (AIDS): 5–18%) [8–11] A history of eczema was found in

62% of children with molluscum contagiosum in Australia [12]

Another Japanese study found that lifetime molluscum was

increased in young children with atopic eczema [13]

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 [16] Autoinoculation through scratching is also suspected, especially as lesions can develop along scratchmarks (koebnerization) [17] Outbreaks have occurred among children attending swimming pools [18,19]

PrognosisAfter 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 immuno-compromised people – for example, patients with AIDS – mollus-cum contagiosum usually does not resolve spontaneously and is often refractory to treatment [1,22]

Aims of treatmentMolluscum 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 sec-ondary 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 [1]

Relevant outcomesClinical 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 discontinu-ation 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 tions for cutaneous, nongenital infection with molluscum contagio-sum in immunocompetent patients We updated the previous

interven-Evidence-based Dermatology, Third Edition Edited by Hywel C Williams, Michael Bigby, Andrew Herxheimer, Luigi Naldi, Berthold Rzany, Robert P Dellavalle, Yuping Ran,

and Masutaka Furue.

© 2014 John Wiley & Sons, Ltd Published 2014 by John Wiley & Sons, Ltd.

Companion Website: www.evidencebasedseries.com/dermatology

RCT we have identified that provides supporting evidence for a physical destructive method in the treatment of molluscum conta-giosum [26] 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 [25], 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 [27]

Despite previous studies suggesting no benefit in treating lusca with potassium hydroxide compared with placebo [28, 29],

mol-there have been two further studies published, by Rajouria et al [30] and Uçmak et al [31], 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

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 [32]

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 treat-ment is awkward and time consuming, and causes irritation in some patients (frequency not reported) [32]

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) [33].

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 [33]

Comment

Because an efficacy greater than that of the vehicle was not strated in this study, neither salicylic acid nor phenol are recom-mended 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-to-treat analysis, the authors reported results after excluding drop-outs

demon-in a previously published abstract Salicylic acid appears to be

ben-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?

Evidence summary

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 [23] 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 [23]

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

[24], 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 [25] A study by Mutairi

et al comparing 5% imiquimod cream with cryotherapy is the only

Molluscum contagiosum 331

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 [37]

Combination of essential oil of Melaleuca alternifolia with iodine

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 [40] 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 scar-ring 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 conceal-ment 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

sali-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 [35] An RCT by Al Mutairi et al

demon-strated imiquimod 5% cream applied five times a week led to

com-plete cure at 16 weeks in 34/37 participants (22/37 at week 6),

compared with complete clearance in all 37 patients receiving

once-weekly cryotherapy after 3 weeks [26] Interestingly, a commentary

by Katz and Swetman [24] 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 [25]

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 [35] The Al Mutairi

et al study showed significantly more adverse effects with

cryo-therapy 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 [26] A pharmacokinetic study

suggested that percutaneous absorption in imiquimod was low;

however, leukopenia and neutropenia were commonly noted [36]

Comment

With a total of 23 participants included, the first study was not

sufficiently powered to show small differences [35] 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

citrio-dora) (Herbal BioScience, Oakvale, California, USA), applied once

Potassium hydroxide versus saline and tretinoin cream

Efficacy

Bazza and Ryatt reported a study where treatments were omized 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 [28] The

rand-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 [29] Pooling these data showed no significant benefit from potassium hydrox-

ide Rajouria et al compared 5% potassium hydroxide with

tretin-oin 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 [30] A

study by Uçmak et al compared treatment with potassium

hydrox-ide at concentrations of 2.5% and 5% Complete clearance was reported in 23% (3/13) and 67% (8/12) at 60 days after commenc-ing treatment with potassium hydroxide twice daily in each group respectively [31]

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% potas-sium 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

sig-nificant 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 tion in mean lesion count with both treatments, there was no sig-nificant 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 informa-tion bias, and it is unclear whether an intention-to-treat analysis

reduc-was performed Although the Uçmak et al study reduc-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

Calcarea carbonica

Efficacy

This homeopathic drug given daily for 15 days resulted in ment 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) [43]

improve-time to cure for each group respectively), though this failed to reach

statistical significance [41]

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 [41]

Comment

Based on the small number in the comparator groups and lack of

statistical difference between the groups there is insufficient

evi-dence to recommend this treatment

Benzoyl peroxide

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) [42].

Drawbacks

Side effects were limited to mild dermatitis in both treatment

groups (exact numbers not reported) [42]

Comment

Benzoyl peroxide 10% cream appears to be beneficial for

mollus-cum contagiosum However, owing to poor reporting quality and

methodological shortcomings (i.e., failure to carry out an

intention-to-treat analysis) bias cannot be ruled out [42], and better studies

are needed

Cantharidin versus placebo

Efficacy

Cantharidin is a topical vesicant that has been used to treat

mol-luscum 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

statisti-cally different [27]

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 [27]

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

Molluscum contagiosum 335

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

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

Cimetidine

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) [44].

Drawbacks

Half of the patients (19 of 38) dropped out The reasons for

with-drawal are not reported [44]

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 [26], 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

immuno-competent 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

molluscum-associated dermatitis can limit spread of lesions [2]

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,

povi-dine iopovi-dine solution with salicylic acid plaster, oral calcarea

car-bonica, and cimetidine are not recommended on the basis of the

data available Most studies have small sample sizes and may,

there-fore, 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

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.

Acknowledgments

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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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

18 Bader RE Multiple occurrence of molluscum contagiosum in the zone of a

swim-ming 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

mollus-cum 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 [23].

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

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 

without intervention. However, no research is available to substan-tiate  this  statement.  Prompt  resolution  usually  occurs  with 

ade-quate  treatment.  The  course  of  the  disease  is  usually  mild,  but 

Methods of search

lished in 2012 [8] being an extended update of earlier versions [5,7]. 

We found four systematic reviews [5–8], the Cochrane review pub-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 interven-tions 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 combina-tion 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

QuestionsWhat are the effects of treatments on the clearance of impetiginous lesions after 1 week?

Disinfecting treatments

Efficacy

Versus placebo We  found  one  small  randomized  trial  comparing hexachlorophene with placebo [9]. Scrubbing with hexachloroph-ene added no notable benefit to placebo treatment

Versus topical antibiotic treatment One multicenter RCT compared hydrogen peroxide cream with fusidic acid cream/gel [10]. There was  no  significant  difference  in  treatment  effect,  but  there  was  a tendency towards a better effect of fusidic acid cream/gel. There was 

Evidence-based Dermatology, Third Edition. Edited by Hywel C. Williams, Michael Bigby, Andrew Herxheimer, Luigi Naldi, Berthold Rzany, Robert P. Dellavalle, Yuping Ran, 

and Masutaka Furue.

© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

Companion Website: www.evidencebasedseries.com/dermatology

Versus oral antibiotics rocin  with  oral  erythromycin  were  pooled  [4,22–30],  mupirocin was  found  to  be  significantly  better  than  erythromycin  [7].  In  a small RCT, cephalexin and mupirocin were both significantly more effective than bacitracin cream [31]. A trial in patients with second-arily  infected  dermatitis  found  no  difference  between  oral cephalexin and topical retapamulin ointment [32]

When 10 RCTs that compared topical mupi-Drawbacks

ics. 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%  [16];  minor  itching/burning  occurred  in  5% versus  4%,  respectively  [18].  No  side  effects  were  reported  in Gilbert’s study [17]. Studies comparing erythromycin with mupi-rocin recorded gastrointestinal side effects in 23% versus 8% [4], none in either group [29], and an equal distribution between the two  groups  [23].  Hydrocortisone/potassium  hydroxyquinoline caused two cases (3%) of mild staining [33]. 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 [15] but only 1% in another study [20]

RCT reports usually note few, if any, side effects with local antibiot-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 charac-teristics  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

Systemic antibiotics

Efficacy

Versus placebo Only one small and inconclusive trial was found, comparing systemic antibiotics with placebo [9]

Versus topical antibiotics Discussed under topical antibiotics above

Versus each other cin,  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, 

Eleven  percent  of  the  patients  using  hydrogen  peroxide  cream 

reported  mild  side  effects  (not  specified).  No  patient  was 

Impetigo 339

  3.  McCormick A, Fleming D, Charlton J. Morbidity Statistics from General Practice:  Fourth National Study 1991–1992. 1995. London: Department of Health, Office 

  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.

12.  Gould  JC,  Smith  JH,  Moncur  H.  Mupirocin  in  general  practice:  a 

placebo-controlled  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: 

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.  ficial skin infections in general practice: a comparison of mupirocin with sodium 

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:

Implications for use of systemic antibiotics in clinical practice

There  is  good  evidence  that  local  treatment  is  equal  to  or  more 

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 

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 [11]

Methods of searchSystematic  reviews  and  randomized  clinical  trials  (RCTs)  were identified using a search strategy published elsewhere [11]. 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

QuestionsHow 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, 

Evidence-based Dermatology, Third Edition. Edited by Hywel C. Williams, Michael Bigby, Andrew Herxheimer, Luigi Naldi, Berthold Rzany, Robert P. Dellavalle, Yuping Ran, 

and Masutaka Furue.

© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

Companion Website: www.evidencebasedseries.com/dermatology

used  for  1  week  with  clotrimazole  or  miconazole  1%  used  for  4 weeks,  did  not  show  a  statistically  significant  difference  in  treat-ment  failure  (RR,  0.75;  95%  CI,  0.33–1.72).  However,  there  was considerable variation in the results of the individual trials [5].

In the study of Patel et al. [13], 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 fol-lowing 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. [10], 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 [12]

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 [5]. 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 [4]. 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 [23]

Considering the absence of more studies, it is cautious to reserve treatment with oral antifungals only for several or relapsing cases 

How do allylamine creams compare with azole

creams in curing athlete’s foot?

Athlete’s foot 343

Implications for clinical practiceAll topical antifungals (azoles, allylamines, butenafine, ciclopirox-olamine, 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

What are the most effective oral drugs in the

treatment of athlete’s foot?

What are the most effective topical drugs in the

treatment of athlete’s foot?

We applied a random-effects Bayesian mixed treatment compari-sons  (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 system-atic  review  of  the  same  databases  used  for  conventional 

meta-analysis [11]

Our  analysis  did  not  show  statistically  significant  differences 

among  all  pairwise  antifungals  assessed  (bifonazole,  butenafine, 

• 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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derivative,  used  once  daily  for  the  treatment  of  interdigital  tinea  pedis.  Int J

Dermatol 1998;37(6):450–3.

20.  Savin  R,  De  Villez  RL,  Elewski  B,  et al.  One-week  therapy  with  twice-daily 

butenafine 1% cream versus vehicle in the treatment of tinea pedis: a multicenter, 

double-blind trial. J Am Acad Dermatol 1997;36(2 Pt 1):S15–9.

21.  Syed  TA,  Hadi  SM,  Qureshi  ZA,  et al.  Butenafine  1%  versus  terbinafine  1%  in 

cream for the treatment of tinea pedis. A placebo-controlled, double-blind, com-parative study. Clin Drug Investig 2000;19(6):393–7.

CHAPTER 42

Pityriasis versicolor

Nancy Habib and Michael Bigby

Department of Dermatology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA, USA

Background

Definition

Pityriasis versicolor (also known as tinea versicolor) is an infection

of the skin caused by the lipophilic yeast genus Malassezia, which

contains at least 14 species with the modern molecular-genetically

based taxonomy; in most cases it is thought to be due to Malassezia

globosa, although other species such as Malassezia sympodialis are

likely involved in some cases [1] The disease is manifested by very

thin, scaly plaques that can be hyperpigmented, hypopigmented, or

erythematous (Figure 42.1) Lesions are generally asymptomatic,

but can be associated with pruritus The rash may be accompanied

by hyper- or hypopigmentation that often persists long after the

organism is eradicated The eruption most commonly affects the

torso, neck, ears, and the pubis, but can be widespread The face

may be affected, especially in children [2]

Incidence/prevalence

The incidence of pityriasis versicolor is not well studied As the

organism grows best in warm and wet conditions, it is more

common and more extensive in tropical climates The prevalence

was 2.1% (22/1024) among a representative sample of young Italian

sailors [3] The prevalence was 1.8% among textile workers in

Adana, Turkey, 15.5% (140/902) in a fishing village in Rio Seco,

Venezuela, 16.6% among a random sample of adults in the Central

African Republic, and 3.1% among 4267 people in Sao Paulo, Brazil

[4–7] In a total population survey in Karonga district, Malawi, 8%

(4915/61 735) were found to have extensive pityriasis versicolor and

an additional 9.9% (6085 people) had mild disease [8]

Etiology

Pityriasis versicolor is caused by the lipophilic yeast genus

Malassezia, mostly due to M globosa.

Prognosis

Untreated, the disease may lessen or remit in colder weather but

almost invariably reappears in hot weather Annual recurrences

during hot weather are common in treated and untreated patients

DiagnosisThe diagnosis can be established by KOH staining of scales obtained from affected scaly plaques On microscopy, the organism is easily recognized as spores and hyphae that resemble “spaghetti and meatballs” (Figure 42.2) Identification is enhanced by the addition

of blue–black ink and a wetting agent to the KOH preparation Under Wood’s light examination, pityriasis versicolor fluoresces a light yellow or golden color The organism can also be cultured, but the culture technique is difficult and not readily available.Aims of treatment

The aim of treatment is the eradication of the organism, which can

be verified by negative KOH preparations, and resolution of the rash The hyper- or hypopigmentation may persist after the organ-ism has been eradicated The aim of interventions for prevention is

to prevent annual recurrences during hot weather

Relevant outcomesThe primary outcomes of treatment are eradication of the organ-ism, verified by KOH preparations, and resolution of the rash The primary outcome of prevention is to stop recurrences in hot weather

Methods of search

We searched the Cochrane Library, LILACS, Medline, and Embase from inception until August 2012

QuestionsWhat are the effects of topical treatments used for the treatment of pityriasis versicolor?

Efficacy

We found one systematic review by Hu and Bigby which showed most topical treatments are effective when compared with placebo, but the data are less conclusive when comparing topical treatments with each other with different dosages and durations [9] Randomized controlled trials of topical treatments for pityriasis

Evidence-based Dermatology, Third Edition Edited by Hywel C Williams, Michael Bigby, Andrew Herxheimer, Luigi Naldi, Berthold Rzany, Robert P Dellavalle, Yuping Ran,

and Masutaka Furue.

© 2014 John Wiley & Sons, Ltd Published 2014 by John Wiley & Sons, Ltd.

Companion Website: www.evidencebasedseries.com/dermatology

treatment and higher concentrations of active agents produce greater cure rates In individual studies, the differences often do not reach statistical significance.

Although optimal regimens have not been established, the data suggest that 1–4 weeks of treatment can be recommended Ketoconazole shampoo is applied to affected areas, left on for 5–10 min and then washed off Treatment is repeated daily for 1–4 weeks The imidazole creams are applied once or twice daily for 1–4 weeks Creams are more costly than shampoos and no more effec-tive, and therefore are less cost-effective Selenium sulfide or zinc pyrithione shampoo is applied to affected areas for 5–10 min and then showered off Treatment is repeated daily for 1–4 weeks Many

of the studies lack follow-up past 1 month after completing ment, so it is difficult to assess the duration of cures

treat-Drawbacks

Topical treatments for pityriasis versicolor are generally well ated They may cause skin irritation or contact allergy Selenium sulfide is more likely to cause skin dryness and irritation than other available treatments and has a strong odor

toler-Comment

The topical treatment of pityriasis versicolor is an area in which evidence and experience coincide

Implications for clinical practice

Most topical treatments used to treat pityriasis versicolor (including imidazole antifungal creams or shampoos, zinc pyrithione shampoo, selenium sulfide shampoo, and sulfur–salicylic acid shampoo) are effective when compared with placebo with NNTs of 1–2 Data suggest that longer durations of treatment and higher concentra-tions of active agents produce greater cure rates Terbinafine is less effective than other available topical treatments Selenium sulfide is more likely to cause skin dryness and irritation than other available treatments

versicolor have increased over the past decade, but many still

involve only a small number of patients [9] Most topical treatments

used to treat pityriasis versicolor (including imidazole antifungal

creams or shampoos, zinc pyrithione shampoo, selenium sulfide

shampoo, and sulfur–salicylic acid shampoo) are effective when

compared with placebo with numbers to treat (NNTs) of 1–2

Topical terbinafine is less effective than other available topical

treat-ments The largest number of randomized studies on topical

imi-dazoles has involved ketoconazole, followed by clotrimazole and

bifonazole

Of the non-imidazole topical agents, zinc pyrithione, sulfur–

salicylic acid, and selenium sulfide have shown the greatest response

differences in comparison with placebo Some studies have assessed

the use of other non-imidazole topical agents such as lactic acid,

adapalene, 1% diclofenac gel, and Artemisia sieberi lotion [10–14]

One small study showed 10% lactic acid solution to have similar

effects as clotrimazole 1% solution at the end of 4 weeks, but at the

end of 2 weeks more patients in the lactic acid group showed

resolu-tion, with a risk difference (RD) of 56 (95% confidence interval

[CI], 33–79) and an NNT of 2 [13] Two studies compared Artemisia

sieberi lotion with clotrimazole lotion, and after 4 weeks of

treat-ment both studies showed Artemisia sieberi to have superior effects

to clotrimazole with RDs of 21 (95% CI, 3–39) and 19 (95% CI,

4–33); the NNTs were 5 and 6, respectively [10,11] In the one study

comparing 1% diclofenac gel with clotrimazole cream and placebo

cream, 1% diclofenac gel was inferior to treatment with

clotrima-zole (RD, −36; 95% CI, −58 to −14) but better than placebo (RD,

56; 95% CI, 37–75) [14] One study compared adapalene with

keto-conazole cream, and the results did not reach statistical significance

(RD, 8; 95% CI, −12 to +27) [12]

Most trials comparing different active agents or different

treat-ment regimens are underpowered to detect clinically meaningful

differences [9] However, the data suggest that longer durations of

be widespread

staining of scales obtained from affected scaly macules On microscopy, the organism is easily recognized as spores and hyphae that resemble

“spaghetti and meatballs.”

Pityriasis versicolor 347

mended for use in patients with active liver disease, elevated liver enzymes, or prior hepatotoxic reactions to other drugs (www uptodate.com)

In clinical trials with itraconazole, nausea (11%), edema (4%), hypertension (3%), headache (4%), fatigue (2–3%), malaise (1%), fever (3%), rash (9%), pruritus (3%), decreased libido (1%), hyper-triglyceridemia, hypokalemia (2%), abdominal pain (2%), anorexia (1%), vomiting (5%), diarrhea (3%), abnormal liver function tests (3%), albuminuria (1%), and dizziness (2%) were reported (www uptodate.com)

In clinical trials with fluconazole, headache (2–13%), rash (2%), nausea (4–7%), vomiting (2%), abdominal pain (2–6%), and diarrhea (2–3%) were reported Hepatitis and liver function test elevations are rare and less common than with other azoles Serious adverse reactions are rare (www.uptodate.com)

Comment

Treatment with oral azoles is an area in which evidence and ence coincide

experi-Implications for clinical practice

Extensive pityriasis versicolor can be successively and safely treated with the oral imidazole antifungals Because of their effect on the cytochrome P450 system and the associated implications on con-centrations of coadministered medications, close evaluation of a patient’s medication list is recommended Data suggest that keto-conazole 200 or 400 mg daily for 7–10 days, itraconazole 200 mg daily for 5–7 days, or fluconazole 300 mg weekly for 2–4 weeks can

be recommended

What are the effects of topical and systemic regimens used to prevent recurrences of pityriasis versicolor?

Efficacy

We found one systematic review [9] There is limited evidence from clinical trials Itraconazole 200 mg twice daily once per month for 6 months was effective in preventing recurrences compared

to placebo (response difference 32%; 95% CI, 20–43%; NNT, 4; 95% CI, 3–5) We found no randomized controlled trials using ketoconazole or fluconazole to prevent recurrences Case series suggest that ketoconazole weekly or fluconazole monthly may be effective

We found one randomized controlled clinical trial of topical regimens to prevent recurrences [17] Two different dosing sched-ules of topical bifonazole were studied Conclusions could not be drawn from this study [17]

Drawbacks

See above

Comment

Weekly or monthly doses of azole antifungals are commonly used

to prevent recurrences of pityriasis versicolor Randomized led data to support their use are scant for itraconazole and were not found for ketoconazole and fluconazole

control-Implications for clinical practice

A small randomized clinical trial suggests that itraconazole 200 mg twice daily once a month is effective in preventing recurrences Optimal regimens for ketoconazole and fluconazole have not been established Optimal regimens for topical prevention have not been established

What are the effects of systemic treatments used

for pityriasis versicolor?

Efficacy

We found one systematic review [9] Randomized controlled trials

of systemic treatments for pityriasis versicolor are generally of low

to moderate quality, usually involving small numbers of patients

and many lacking blinding or intention to treat analysis [9] Most

systemic treatments used to treat pityriasis versicolor (including

oral triazoles and imidazoles) are effective when compared with

placebo with NNTs of 1–2 The data are lacking for the efficacy of

oral terbinafine in pityriasis versicolor

Trials comparing different active agents or different treatment

regimens are underpowered to detect clinically meaningful

differ-ences [9] However, the data suggest that longer durations of

treat-ment and higher doses produce greater cure rates In individual

studies, the differences often do not reach statistical significance

Although optimal regimens have not been established, the data

suggest that ketoconazole 200 or 400 mg daily for 7–10 days,

itra-conazole 200 mg daily for 5–7 days, or fluitra-conazole 300 mg weekly

for 2–4 weeks can be recommended One study has also shown

pramiconazole 200 mg for 2–3 days to be better than placebo with

an RD of 69 (95% CI, 49–89) and an NNT of 2 [15] Response rates

tended to be dose dependent, with single-dose regimens (e.g.,

keto-conazole 400 mg or fluketo-conazole 450 mg or intraketo-conazole 400 mg)

being less effective However, the NNTs are large and the confidence

intervals wide in individual studies

Drawbacks

All of the imidazoles and triazoles inhibit the enzyme cytochrome

P450 system Therefore, these agents have many drug–drug

interac-tions Concomitant administration with other drugs which are

metabolized by the cytochrome P450 system should be monitored

closely These agents should not be administered in patients on

cisapride, astemizole, and terfenadine owing to potential rare

car-diovascular adverse events such as arrhythmias, torsade de pointes,

and death

Ketoconazole carries a Black Boxed Warning issued by the US

Food and Drug Administration (FDA) because it has been

associ-ated with hepatotoxicity, including some fatalities The frequency

is low (134 cases per 100 000 person-months (95% CI, 37–488) in

one study), but it is the highest among the oral imidazole

antifun-gals [16] Liver function tests should be checked if the duration

of treatment exceeds 1 week Ketoconazole administration is

contraindicated with use of cisapride for the reasons stated above

High doses of ketoconazole may suppress adrenocortical function

In clinical trials, nausea/vomiting (3–10%), pruritus (2%), and

abdominal pain (1%) were reported Diarrhea, dizziness, fever,

gynecomastia (androgen receptor antagonist), and headache occur

less frequently

Itraconazole, a triazole, carries a Black Boxed Warning from the

FDA for association with development of congestive heart failure

(CHF), especially in patients with a history of CHF

Coadministra-tion with cisapride, pimozide, midazolam, triazolam, simvastatin,

lovastatin, quinidine, dofetilide, and levomethadyl is

contraindi-cated due to itraconazole’s inhibition of the cytochrome P450

system Rare cases of serious cardiovascular adverse events

(includ-ing death, QT prolongation, ventricular tachycardia, and torsade de

pointes) have been observed when itraconazole is administered

with those stated agents Itraconazole has been associated with rare

cases of serious hepatotoxicity (including fatal cases and cases

within the first week of treatment) It is, therefore, not

2 Jena DK, Sengupta S, Dwari BC, et al Pityriasis versicolor in the pediatric age

group Indian J Dermatol Venereol Leprol 2005;71(4):259–61.

3 Ingordo V, Naldi L, Colecchia B, et al Prevalence of pityriasis versicolor in young

Italian sailors Br J Dermatol 2003;149(6):1270–2.

4 Sahin I, Kaya D, Parlak AH, et al Dermatophytoses in forestry workers and

farmers Mycoses 2005;48(4):260–4.

5 Acosta Quintero ME, Cazorla Perfetti DJ Clinical-epidemiological aspects of yriasis versicolor (PV) in a fishing community of the semiarid region in Falcon

pit-State, Venezuela Rev Iberoam Micol 2004;21(4):191–4 (in Spanish).

6 Belec L, Testa J, Bouree P Pityriasis versicolor in the Central African Republic: a

randomized study of 144 cases J Med Vet Mycol 1991;29(5):323–9.

7 Martins EL, Goncalves CA, Mellone FF, et al Prospective study of pityriasis

ver-sicolor incidence in a population of the city of Santo Andre (state of Sao Paulo)

Med Cutan Ibero Lat Am 1989;17(5):287–91.

8 Ponnighaus JM, Fine PE, Saul J The epidemiology of pityriasis versicolor in

Malawi, Africa Mycoses 1996;39(11–12):467–70.

9 Hu SW, Bigby M Pityriasis versicolor: a systematic review of interventions Arch

Dermatol 2010;146(10):1132–40.

10 Khosravi AR, Shokri H, Darabi MH, et al Comparative study on the effects of a new antifungal lotion (Artemisia sieberi essential oil) and a clotrimazole lotion in

the treatment of pityriasis versicolor J Mycol Med 2009;19:17–21.

11 Rad F, Aala F, Reshadmanesh N, et al Randomized comparative clinical trial of Artemisia sieberi 5% lotion and clotrimazole 1% lotion for the treatment of pityr-

iasis versicolor Indian J Dermatol 2008;53(3):115–8.

12 Shi TW, Ren XK, Yu HX, et al Roles of adapalene in the treatment of pityriasis

versicolor Dermatology 2012;224(2):184–8.

13 Sharquie KE, Noaimi AA, Oweid AM Topical 10% lactic acid solution in the treatment of pityriasis versicolor in comparison with topical 1% clotrimazole solu-

tion J Saudi Soc Dermatol Dermatol Surg 2009;13(1):35–43.

14 Sharquie KE, Al-Hamamy HM, Noaimi AA, et al Treatment of pityriasis versicolor using 1% diclofenac gel and clotrimazole cream J Saudi Soc Dermatol Dermatol

Surg 2011;15(1):19–23.

15 Faergemann J, Todd G, Pather S, et al A double-blind, randomized,

placebo-controlled, dose-finding study of oral pramiconazole in the treatment of pityriasis

versicolor J Am Acad Dermatol 2009;61(6):971–6.

16 Garcia Rodriguez LA, Duque A, Castellsague J, et al A cohort study on the risk

of acute liver injury among users of ketoconazole and other antifungal drugs Br

J Clin Pharmacol 1999;48(6):847–52.

17 Hernandez-Perez E A comparison between two different regimens of monthly

application with bifonazole spray 1% in pityriasis versicolor Int J Dermatol 1990;

29(6):438–40.

References

1 Crespo Erchiga V, Hay R Pityriasis versicolor and other malassezia skin diseases

In: Boekhout T, Gueho E, Mayser P, et al., eds Malassezia and the Skin: Science

and Clinical Practice Berlin: Springer Verlag, 2010: 175–99.

increased  in  individuals  over  the  last  80  years  [3].  In  North 

American  centers,  the  prevalence  of  onychomycosis  is  between 

approximately  6.5  and  13.8%  [4,6–8].  Onychomycosis 

predomi-nantly  affects  toenails  in  comparison  with  fingernails;  in  some 

tive family history, increasing age, male gender, trauma, immuno-suppression,  diabetes  mellitus,  poor  peripheral  circulation,  and 

smoking  [3,4,6,7,11–18].  In  addition,  for  fingernails,  persistent 

exposure to water, the use of artificial nails, and trauma induced by 

pushing back the cuticles and aggressive manicuring may also be 

predisposing factors

Prognosis

Onychomycosis  can  be  effectively  treated  with  systemic  and/or 

topical  antifungal  agents,  as  well  as  device-based  therapies. 

Traditional  systemic  agents  used  to  treat  onychomycosis  include 

Relapse  of  onychomycosis,  especially  in  the  toenails,  is  not 

uncommon,  particularly  in  predisposed  individuals.  The  reasons 

why fingernail onychomycosis responds better than toenail disease may be related to the fact that perfusion of the upper extremity is generally better than that of the lower extremity; this may result in improved drug delivery to the fingers in comparison with the toes. Also, fingernails have a faster rate of outgrowth in comparison with toenails (3 mm/month compared with 1 mm/month) [32], resulting 

in the infected fingernail growing out faster than its lower extremity counterpart

Aims of treatmentOnychomycosis may be a cosmetic problem, especially when fin-gernails are infected [33]. The treatment objectives are to reduce the  fungal  burden  within  the  nail,  ultimately  curing  the  fungal infection,  and  to  promote  healthy  regrowth  of  affected  nails.  In some instances, when onychomycosis is associated with a degree of morbidity – for example, pain, discomfort, or soft-tissue infection – timely treatment may help eliminate symptoms and prevent com-plications that could be associated with more severe consequences [34]

Relevant outcomesThe  most  commonly  reported  therapeutic  measure  of  efficacy  is mycological  cure,  which  is  defined  by  most  as  a  negative  light-microscopic  examination  and  negative  culture.  There  are  several methods by which clinical improvement has been assessed. Some studies have used the parameter of clinical success, which is defined 

as  “cleared”  or  “markedly  improved”  (90–100%  clear  nail)  [35]. Others have defined clinical success as cure or improvement suffi-cient to reduce the involved area of the target nail to less than 25% 

at  the  end  of  therapy  [36].  Another  term  that  has  been  used  is 

“clinical effectiveness,” which is taken to be mycological cure and 

at least 5 mm of new clear toenail growth [37]. Clinical cure refers 

to the post-therapy nail appearing completely cured to the naked eye. The complete cure rate is the combined result of mycological and clinical cure

These outcomes are typically reported in clinical trials in which one toenail is chosen as the target, and “cure” is based on the target toenail alone. While such standards are necessary to provide points 

of comparison for clinical efficacy, all affected nails would be cured 

if  a  regimen  was  “successful.”  There  is  a  paucity  of  clinical  data including  outcomes  for  all  affected  toenails  during  oral  therapy,  and there is evidence to suggest that not all toenails can be expected 

Evidence-based Dermatology, Third Edition. Edited by Hywel C. Williams, Michael Bigby, Andrew Herxheimer, Luigi Naldi, Berthold Rzany, Robert P. Dellavalle, Yuping Ran, 

and Masutaka Furue.

© 2014 John Wiley & Sons, Ltd. Published 2014 by John Wiley & Sons, Ltd.

Companion Website: www.evidencebasedseries.com/dermatology

in the indexed, peer-reviewed literature are far fewer. Other clinical trials have included tioconazole 28% solution, bifonazole with urea, fungoid tincture, miconazole, and tea-tree oil. The authors would like  to  bring  to  your  attention  that,  subsequent  to  the  literature search for this review, clinical trials results have been published for 

conazole  10%.  Consequently,  the  evidence  for  this  new  topical treatment is not presented

a new topical solution for the treatment of onychomycosis, efina-The use of other topical agents and cosmetic procedures such as debridement, combined with oral therapy, is not considered here, 

as most of these studies are single studies and not widely practiced 

ticularly in the more severe cases of onychomycosis, has increased, 

at this time [45–47]. However, support for adjunctive therapy, par-in an effort to improve cure rates without increasing exposure to oral  medications  [48].  Further  studies  of  such  combinations  are anticipated

We have not considered trials that used nonstandard regimens such as sequential or combination therapy (with the exception of combination of amorolfine and ciclopirox with oral therapies) and the  trials  using  ketoconazole  to  treat  onychomycosis,  given  the potential of this agent to cause hepatotoxicity and the availability 

of alternative agents

QuestionsWhat is the role of oral antifungal therapy in the management of dermatophyte onychomycosis

in adults?

Griseofulvin was the first significant oral antifungal agent available for the management of dermatomycoses. Over the years, the use of griseofulvin  in  the  treatment  of  onychomycosis  has  decreased, although it is still widely used for the treatment of tinea capitis [49]. Ketoconazole, an oral imidazole, is no longer recommended for the treatment  of  onychomycosis,  which  requires  a  long  duration  of therapy, due to the potential for hepatotoxicity [49]. The introduc-tion of the new oral antifungal agents terbinafine, itraconazole, and fluconazole has led to improved efficacy rates, decreased treatment duration, and fewer adverse events

The use of ravuconazole for the management of onychomycosis has not been considered further in this chapter, as only one pub-lished  report  of  efficacy  is  known  to  us  [27].  The  treatment  of onychomycosis with posaconazole is still under investigation [28].What are the effects of systemic treatments on fingernail and on toenail onychomycosis caused

by dermatophytes in healthy adults?

Griseofulvin

The  regimen  for  treating  onychomycosis  is  continuous  therapy using a dosage of 500 mg/day to 1 g/day, typically administered for 6–12 months in fingernail onychomycosis and for 9–18 months in toenail disease

Fingernails (quality of evidence: 2)

One  randomized  double-blind  study  compared  griseofulvin  with terbinafine  in  the  treatment  of  onychomycosis  (Table  43.1)  [50]. The methods used for generation of the randomization sequence and for the allocation concealment were not specified and a per-protocol analysis was performed with 20/92 (22%) of participants excluded

to  have  equivalent  degrees  of  clinical  cure  [38,39].  Clinicians  

should  keep  in  mind  that  the  outcomes  measured  in  clinical  

randomized  clinical  trials;  and  third,  nonrandomized  evidence. 

Evidence  was  graded  using  the  quality-of-evidence  scale  system 

Not stated

1998 Drake [60] FLUC DB, R, parallel,

multicenter, placebo controlled

1998 Drake [60] FLUC DB, R, parallel,

multicenter, placebo controlled

CC, complete cure; CR, clinical response; DB, double-blind; FLUC, fluconazole; GRIS, griseofulvin; ITRC, itraconazole continuous; ITRP, itraconazole pulse; MC, mycological cure; mo, months; R, randomized; TER, terbinafine; TERC, terbinafine continuous; TERP, terbinafine pulse; Treat., treatment; wk, weeks.

a Mycological cure defined as negative microscopy and culture, unless indicated otherwise.

b Clinical response defined as cured or markedly improved, unless indicated otherwise.

c Complete cure defined as mycological and clinical cure or markedly improved, unless indicated otherwise.

Toenails (quality of evidence: 2)

Three  systematic  reviews  were  identified.  One  systematic  review 

to-treat or per protocol) used by the included studies

of these systematic reviews specified the type of analysis (intention-Toenails: effectiveness

In the RCTs included in the first meta-analysis, 500 or 1000 mg/day 

of griseofulvin was administered for 1 year to treat onychomycosis. The pooled mycological cure rate was 60 ± 6% [51]. The dosing 

501 participants) [52], or pulsed itraconazole (search date March 2008: eight RCTs, 1181 (terbinafine and itraconazole) participants) [68].  The  meta-analysis  comparing  continuous  and  intermittent terbinafine included three open, two investigator-blinded, and four double-blinded studies (see Pulsed terbinafine, Toenails). The two RCTs included in the comparison between continuous terbinafine and  continuous  itraconazole  were  double-blind  studies,  whereas the  comparison  between  continuous  terbinafine  and  intermittent itraconazole included open and investigator-blinded studies. With the exception of one meta-analysis [67], it was not specified if the data from the studies included were from intention-to-treat or per-protocol analysis.

Toenails: effectiveness

A pooled mycological cure rate of 76 ± 3% and 77.2 ± 4.0% (SE) was obtained with terbinafine 250 mg/day for 12–16 weeks [51,53]. Studies using four different pulsed terbinafine regimens compared with a continuous dosing regimen (250 mg/day for 12–16 weeks) gave a risk ratio (RR) of 0.87 (95% confidence interval [CI], 0.80–

0.96; P = 0.003; n = 8) for per-protocol analysis of mycological cure  and  0.93  (95%  CI,  0.76–1.13;  P  =  0.44;  n  =  9)  for  per-protocol 

analysis of complete cure [67]. Similar results were obtained with intention-to-treat analyses. Thus, the chance of getting a complete cure was similar between the two types of dosing regimens, whereas the pulsed regimen had only 13% less chance than the continuous regimen  to  result  in  a  mycological  cure.  In  contrast,  continuous terbinafine (250 mg/day for 12–16 weeks) was clearly superior to pulsed itraconazole (400 mg/day for 1 week/month, 3–4 months) 

based  on  an  odds  ratio  of  2.31  (95%  CI,  1.76–3.03;  P  ≤  0.0001; 

Comments

Terbinafine is effective and safe for the treatment of onychomycosis. Terbinafine  is  an  allylamine  that  inhibits  squalene  epoxidase,  resulting in an accumulation of squalene and a deficiency of ergos-terol. The accumulation of squalene may be associated with fungi-cidal  action  [73].  There  is  a  substantial  number  of  high-quality studies that demonstrate the effectiveness of terbinafine (continu-ous) in the treatment of toenail onychomycosis, and meta-analyses showed its superiority to both continuous and pulsed itraconazole [52,68]. Moreover, a recent meta-analysis comparing the long-term recurrences of toenail onychomycosis showed that continuous ter-

regimens  used  in  the  studies  included  in  the  second  systematic 

effective  than  griseofulvin;  the  duration  of  active  therapy  is  also 

shorter  with  the  more  recently  introduced  antimycotics  [61,62]. 

The  studies  used  terbinafine  250 mg/day  for  6  weeks  [56,57],  8 

weeks  [55],  and/or  12  weeks  [5,50,56]  (Table  43.1).  Mycological 

participants; search date 1999: 19 RCTs, one open, 1393 (mycologi-cal),  and  1371  (clinical)  participants  –  presented 

sample-size-weighted  cure  rates.  One  review  did  not  specify  the  individual 

characteristics of the included studies [51]. The other study included 

15 double-blind studies and five open studies [53]. The other three 

meta-analyses included studies comparing directly continuous ter-binafine  with  pulsed  termeta-analyses included studies comparing directly continuous ter-binafine  (search  date  January  2011:  nine 

studies  (eight  RCTs,  one  retrospective  study),  1135  participants) 

[67], continuous itraconazole (search date March 2000: two RCTs, 

or  four  pulses  for  toenail  disease.  Pulse  dosing  is  the  regimen approved by the Food and Drugs Administration (FDA) regimen for infections of the fingernails when no toenail involvement has been noted [66].

Fingernails (quality of evidence: 2)

The  efficacy  of  intermittent  itraconazole  in  the  treatment  of  matophyte fingernail onychomycosis was investigated in one meta-analysis [58]. This meta-analysis (search date before 1998: 210 (two pulses) and 217 (three pulses) participants) presented sample-size-weighted cure rates without specifying the individual characteris-tics of the studies included (Table 43.1)

der-Fingernails: effectiveness

Itraconazole was given 400 mg/day for 1 week per month for 2 or 

3 months. The mycological cure rates obtained were 87 ± 8% (SE) and  97  ±  1%  and  the  clinical  response  rates  were  89  ±  6%  and 

98 ± 1%, respectively (Table 43.1)

Toenails (quality of evidence: 2)

The  efficacy  of  intermittent  itraconazole  in  the  treatment  of  matophyte toenail onychomycosis was investigated in four meta-analyses.  Two  meta-analyses  –  search  date  November  2002:  six RCTs,  318  (mycological)  and  329  (clinical)  participants)  [51]; search date before 1998: 1389 (three pulses) or 259 (four pulses) participants  [58]  –  presented  sample-size-weighted  cure  rates without  specifying  the  individual  characteristics  of  the  studies included. The third meta-analysis (search date 1999: six RCTs, five open  studies,  1486  (mycological)  or  1610  (clinical)  participants) also presented sample-size-weighted cure rates and included four double-blind studies and seven open studies [53]. The last meta-analysis  included  studies  comparing  directly  pulsed  itraconazole with continuous terbinafine (search date March 2008: eight RCTs, 

der-atic review was found for comparison between pulsed and continu-ous  itraconazole,  but  one  double-blind  placebo-controlled  RCT investigated  the  efficacy  of  the  two  dosing  regimens  for  toenail onychomycosis only [84]. Three of the 65 participants (4.6%) in the continuous  itraconazole  group  and  five  of  the  64  participants (7.8%)  in  the  pulsed  itraconazole  group  discontinued  or  were excluded from the study. The type of analysis used for the efficacy data was not explicitly stated

1181 (terbinafine and itraconazole) participants) [68]. No system-Toenails: effectiveness

In the earliest meta-analysis, similar pooled mycological cure rates were obtained for three (77 ± 5% (SE)) and four (78 ± 4%) pulses, but  not  for  clinical  response  rates  (three  pulses:  82  ±  3%;  four pulses: 92 ± 3%) [58]. A mycological cure rates of 63 ± 7%, and 70.8  ±  5.7%  (SE)  and  a  clinical  response  (cure  or  markedly improved) rates of 70 ± 11% and 73.6 ± 4.6% (SE) were obtained when pooling the results from studies using itraconazole 400 mg/day 1 week per month for 3–4 months [51,53]. As previously men-tioned  in  the  section  on  terbinafine,  intermittent  itraconazole 

Fingernails (quality of evidence: 2)

Treatment  of  dermatophyte  onychomycosis  in  fingernails  with 

Only four out of 21 participants randomized to the pulsed terbin-afine  had  both  fingernail  and  toenail  onychomycosis  and  were 

treated  with  terbinafine  500 mg/day  for  1  week  per  month  for  4 

Toenails (quality of evidence: 2)

Efficacy of continuous itraconazole for toenail onychomycosis was investigated in four meta-analyses. Two meta-analyses – search date November  2002:  seven  RCTs,  1131  participants  [51];  search  date before 1998: 20 studies (five placebo controlled, six comparative, nine open), 1741 participants [58] – presented sample-size-weighted cure rates without specifying the individual characteristics of the studies  included.  The  third  meta-analysis  (search  date  1999:  12 RCTs, 1562 participants) also calculated sample-size-weighted cure rates and included 10 double-blind studies, one open study, and one study with no specified blinding [53]. The last meta-analysis included studies comparing directly continuous itraconazole and continuous terbinafine (search date March 2000: two RCTs, 501 (itraconazole and terbinafine) participants) [52]. As previously mentioned for the intermittent itraconazole regimen, no systemic review was found for comparison between pulsed and continuous itraconazole, but one double-blind  placebo-controlled  RCT  investigated  the  efficacy  of the two dosing regimens for toenail onychomycosis only [84]

Toenails: effectiveness

In  the  earliest  meta-analysis,  a  pooled  mycological  cure  rate  of 

74  ±  3%  (SE)  was  obtained  with  200 mg/day  itraconazole  for  3 months  [58].  A  pooled  mycological  cure  rate  of  59  ±  5%  and 66.3 ± 4.2% (SE) was obtained for itraconazole 200 mg/day for 3–4 months [51,53]. Itraconazole 200 mg/day for 3 months was found 

to  be  as  effective  as  pulsed  itraconazole  (see  Pulse  itraconazole/Toenails: effectiveness), but less effective than continuous terbin-afine (see Continuous terbinafine/Toenails: effectiveness)

Drawbacks

Adverse events associated with the use of continuous itraconazole for  the  treatment  of  onychomycosis  are  not  common,  and  those experienced  are  generally  mild  to  moderate  in  severity.  Adverse events  include  gastrointestinal  disorders  (e.g.,  nausea,  abdominal pain), rashes, and central nervous system effects (e.g., headache) [58,84,87–89].  Only  a  small  proportion  of  patients  discontinue treatment with the triazole. There are drugs that are contraindicated with itraconazole (see Pulse itraconazole/Drawbacks). In addition, the triazole has several drug interactions (see Pulse itraconazole/Drawbacks). Itraconazole is contraindicated in North America in patients  with  evidence  of  ventricular  dysfunction  –  for  example, congestive heart failure or a history of heart failure. The US package insert suggests that liver function tests should be considered for all patients  receiving  continuous  therapy  [66].  Treatment  should  be stopped immediately and liver function tests should be performed whenever a patient develops signs and symptoms suggestive of liver disease [66]

Comments

Continuous itraconazole therapy is an effective and well-tolerated treatment  for  onychomycosis.  Historically,  the  treatment  of  ony-chomycosis  with  itraconazole  was  with  the  continuous  regimen; 

later, work done by de Doncker et

al. [89,90] resulted in the wide-spread  adaptation  of  pulse  therapy  for  this  indication.  The  US package insert states that when patients with toenail onychomyco-sis were treated with itraconazole continuous therapy, 21% of the overall success group had a relapse (worsening of the global score 

rate  due  to  an  adverse  event.  Itraconazole  has  the  potential  for 

numerous  drug  interactions,  and  a  thorough  review  of  current 

was found between three-pulse and four-pulse regimens of itraco-nazole  for  the  primary  efficacy  parameters  in  the  treatment  of 

toenail  onychomycosis  [90].  As  previously  mentioned,  a  recent 

meta-analysis  of  comparing  the  long-term  recurrences  of  toenail 

Fingernails (quality of evidence: no evidence found)

There was no publication on the efficacy of posaconazole therapy for fingernail onychomycosis

Toenails: (quality of evidence: 2)

One RCT compared four different regimens of posaconazole with terbinafine  (250 mg/day  for  12  weeks,  investigator  blinded)  and placebo  (double  blind)  [28].  The  participants  were  randomized according to a computer-generated randomization schedule using 

a central interactive voice response system. An intention-to-treat analysis (modified and unmodified) was used for the primary effi-cacy outcome, but the study had small sample sizes

Toenails: effectiveness

At week 48 assessment, the mycological cure rates were respectively 70% (26/37) and 79% (26/33) for 200 mg and 400 mg for 24 weeks. The corresponding complete cure rates were 54% (20/37) and 46% (15/33). These rates were obtained based on modified intention-to-treat  analysis  including  randomized  participants  who  received  

at  least  one  dose  of  posaconazole  and  with  one  postbaseline assessment

Drawbacks

Posaconazole is approved for the prophylaxis of invasive Aspergillus  and Candida infections and the treatment of oropharyngeal candi-

diasis, but not for onychomycosis [93]. The adverse events observed during  treatment  of  onychomycosis  were  mild  to  moderate  in severity.  The  most  commonly  reported  treatment-related  adverse events were diarrhea (5%), nausea (4%), dizziness (4%), and head-ache (6%). A small proportion of patients (4%) discontinue treat-ment with posaconazole because of adverse events [28]. The drugs contraindicated  with  posaconazole  are  sirolimus,  CYP3A4  sub-strates such as pimozide and quinidine, simvastatin, and ergot alka-loids [93]

Comments

The higher concentration of 400 mg did not result in higher efficacy compared  with  the  200 mg  regimen.  The  regimens  of  200  and 

400 mg  posaconazole  daily  for  24  weeks  had  similar  mycological cure  rates  and  numerically,  but  not  statistically,  higher  complete cure rates compared with the terbinafine arm included in the study (250 mg  daily  for  12  weeks;  mycological:  71%;  complete:  36%). However, when administered only for 12 weeks, 400 mg/day posa-conazole  was  clearly  inferior  to  terbinafine  for  the  same  therapy duration (mycological: 43%; complete: 20%) [28]. Thus, the dura-tion  of  the  posaconazole  therapy  must  be  much  longer  to  be  

as  effective  as  terbinafine.  This  is  consistent  with  their  in  vitro 

week  to  450 mg/week  and  the  duration  from  12  to  48  weeks.  A 

Fingernails (quality of evidence: 2)

A  systematic  review  (search  date  January  2012:  two  studies  (one 

pooled  clinical  response  (cure  or  markedly  improved)  rate  of 

66.5  ±  11.7%  (SE)  were  obtained  with  150 mg  weekly  for  3–12 

Amorolfine with griseofulvin: effectiveness

Two  months  of  daily  griseofulvin  combined  with  weekly amorolfine for 12 months resulted in similar mycological and clinical cures as 12 months of continuous griseofulvin therapy (twice  daily  for  2  months  and  once  daily  for  the  following  10 months) (Table 43.1)

twice-Amorolfine with terbinafine (quality of evidence: 2)

Three RCTs investigated the efficacy of 5% amorolfine nail lacquer combined with systemic terbinafine compared with monotherapy with  terbinafine  for  dermatophyte  onychomycosis.  Two  studies were open, included participants with toenail onychomycosis only, and  presented  results  from  intention-to-treat  analysis  [97,98], whereas the other study was also open but included both fingernail and toenail onychomycosis and presented data from per-protocol analysis  [75].  This  latter  study  included  participants  with  ony-chomycosis  caused  by  dermatophytes,  non-dermatophyte  molds, and  yeasts  and  did  not  specify  the  number  of  participants  with confirmed dermatophyte onychomycosis randomized to the three arms of the study by using a table of random numbers

Amorolfine with terbinafine: effectiveness

Complete  cure  rates  obtained  for  continuous  terbinafine  for  12 weeks combined with 15 months of weekly application of 5% amo-rolfine nail lacquer (59–72%) were superior to the complete cure rates obtained with the terbinafine monotherapy for 12 weeks (38–45%)  for  the  treatment  of  toenails  (Table  43.2)  [97,98].  Weekly amorolfine nail lacquer combined with pulse terbinafine (500 mg daily  for  1  week  per  month)  for  4  months  resulted  in  a  similar mycological cure rate (86%) to the pulse terbinafine monotherapy (89%)  for  fingernail/toenail  dermatophyte  onychomycosis  (Table 43.2) [75]

Amorolfine with itraconazole (quality of evidence: 2)

There  was  no  study  reporting  efficacy  data  for  onychomycosis caused by dermatophytes only. However, one open RCT with 75% 

of  participants  with  toenail  onychomycosis  caused  by  phytes compared continuous itraconazole therapy with and without amorolfine  nail  lacquer  [99].  Results  from  per-protocol  analysis were presented, but statistical analyses were performed and signifi-cant  for  both  per-protocol  and  intention-to-treat  analyses.  More participants  were  excluded  from  the  per-protocol  analysis  in  the itraconazole + placebo group (11/43 = 26%) than the two itraco-nazole + amorolfine arms (8/51 = 16% and 4/37 = 11%) (Table 43.2)

dermato-Amorolfine with itraconazole: effectiveness

tinuous itraconazole for 12 weeks showed a complete cure rate at week 24 of 94%, versus 69% for continuous itraconazole alone [99]

Combined use of amorolfine once weekly for 24 weeks with con-Drawbacks

The  open  design  may  produce  some  bias  in  assessment.  Blinded studies should be done to confirm the results. There was a relatively high  drop-out  rate,  with  many  patients  leaving  due  to  lack  of efficacy

Comments

pies were similar to those noted with the respective monotherapies. Combination  therapy  may  increase  efficacy,  but  further  blinded 

Follow-up  at  3  months  posttreatment  (month  9  of  the  study) 

showed  mycological  and  complete  cure  rates  of  77%  and  47%, 

respectively (Table 43.2)

Drawbacks

The  patients  should  have  no  matrix  involvement  [102].  No  

further  research  has  been  reported  on  the  use  of  amorolfine 

Once or twice weekly

weekly

GRIS: twice daily

(1) 50 (2) 48

15 mo

(44%) (2) 34/47 (72%)

(1) 6 wk (2) 12 wk

(59%) TER: daily TER: 3 mo

Not given for dermatophyte

AMOR: weekly TER: twice daily for 1 wk/mo

(1) 51 (2) 37

(84%) (2) 31/33 (94%)

ITRA: daily ITRA:

(1) 6 wk (2) 12 wk

(1) 182 (2) 188

(13%) (2) 9/156 (6%)

2005 Avner

[101] CICL + 250 mg

TER

R, comparative

(80 randomized between 2 arms)

(68%) TER: daily TER: 4 mo

(1) 21 (2) 27

(67%) (2) 19/27 (70%)

(1) 9/20 (45%) (2) 9/24 (38%)

(1) 8/20 (40%)d

(2) 8/24 (33%)d

(1) 4 wk on,

4 wk off,

4 wk on (2) 12 wk

Continued

therapy  for  63–89%  of  onychomycosis  patients  with  diabetes [106,107].

Ciclopirox 8% nail lacquer combined with oral antifungal therapy

Ciclopirox with terbinafine: (quality of evidence: 2)

Three  RCTs  comparing  monotherapy  for  terbinafine  and  bined  therapy  with  ciclopirox  nail  lacquer  for  treatment  of  der-matophyte  onychomycosis  were  identified.  Two  studies  included participants with infected fingernails and/or toenails [75,101], and one  study  included  participants  with  infected  toenails  [77].  The blinding  and  randomization  methods  were  not  specified  for  one study  [101].  One  study  was  open  and  used  a  table  of  random numbers  for  the  participants’  randomization  [75],  and  the  last study was investigator blind and used a predetermined randomiza-tion schedule [77]. Per-protocol analysis was generally used with the  exception  of  the  mycological  cure  rates  reported  in  the investigator-blinded study

com-Ciclopirox with terbinafine: effectiveness

Both continuous [77,101] and pulse [75,77] terbinafine regimens have been combined with ciclopirox nail lacquer. Combination of ciclopirox  applied  daily  for  9  months  and  terbinafine  daily  for  4 months resulted in higher mycological cure (88% vs 65%), clinical response (82% vs 59%), and complete cure (68% vs 50%) compared with  daily  terbinafine  for  4  months  (Table  43.2)  [101].  Longer therapy  with  daily  ciclopirox  daily  (48  weeks)  combined  with shorter  daily  terbinafine  therapy  (3  months)  resulted  in  higher mycological cure (70% vs 56%), but comparable clinical response (38% vs 44%) or effective cure (33% vs 35%) than 3 months of daily terbinafine only (Table 43.2) [77]. In the same study, a pulse terbin-afine regimen (daily for 4 weeks on, 4 weeks off, and 4 weeks on) combined with daily ciclopirox for 48 weeks resulted in similar cure rates to the continuous regimen (Table 43.2). A similar mycological cure rate was also observed with pulse terbinafine (500 mg daily for 

1 week per month for 4 months) with (89%) and without (89%) cicloprirox nail lacquer daily for 4 months (Table 43.2) [75]

(SE)  (Table  43.2)  [53].  A  better  complete  cure  rate  was  obtained 

with  the  new  formulation  (13%)  compared  with  the  traditional 

(from baseline)

Not given for dermatophyte

TER: twice daily for 1 wk/mo 3/2/1, 3 days/week for first month, 2 days/week for the second month, and 1 day/week for the other months; AMOR, amorolfine 5% nail lacquer; CC, complete cure; CICL, ciclopirox 8% nail lacquer; CR, clinical response; DB, double-blind; GRIS, griseofulvin, ITRA: itraconazole; MC, mycological cure; mo, months; R, randomized ;SB, single- blind;SE, standard error, TER, terbinafine; wk, weeks.

a Mycological cure defined as negative microscopy and culture, unless indicated otherwise.

b Clinical response defined as cured or markedly improved, unless indicated otherwise.

c Complete cure defined as mycological and clinical cure or markedly improvement, unless indicated otherwise.

d Effective cure defined as mycological and >90% reduction in the disease area from baseline.

Table 43.2 Continued

no treatment controlled

4 months 6 months 50%a (nails) 8%c (nails) 39%d (nails)

7 0.3 ms pulse, 2 Hz,5 mm spot size, 16 J/cm 2 , 2 tx at 6 week intervals

8 0.65 ms pulse, 2 mm spot size, 223 J/cm 2 , 2 or 3 tx at 3 week intervals

21 0.3 ms pulse, 5 Hz, 14 J/cm 2 ,

5 mm spot size, 4 tx at 1 week intervals

13 0.3 ms pulse, 5 Hz, 14 J/cm 2 ,

5 mm spot size, 1–3 treatments at 4 or 8 week intervals

CC, complete cure; CR, clinical response; MC, mycological cure; tx, treatment.

a Negative culture.

b Negative culture and periodic acid and Schiff staining.

c Markedly improved or completely cleared.

d Negative culture with at least 3 mm of clear nail growth.

e Clinical cure with mycological cure.

f Clear nail with negative microscopy.

the use of ciclopirox in combination with oral antifungals to deter-mine if combination therapy would result in higher efficacy

Comments

Most  adverse  events  possibly  related  to  study  medication  in  the 

blinded  trial  were  minimal  and  evenly  distributed  between  the 

treatment groups [77]

What are the effects of device-based therapies on

toenail onychomycosis?

Laser device systems

Laser  device  systems  use  photoselective  effects  to  kill  the  fungal 

Toenails: effectiveness

comes presented in the studies (Table 43.3). Cure rates were pre-sented as per patients or per-treated nails. The exact definition of the  mycological  cure  was  not  always  given,  but  it  was  generally defined as negative culture. A low mycological cure rate of 50–59% 

There was a lot of variability in the definition of the efficacy out-of  the  nails  was  obtained  in  the  RCT  compared  with  the  other studies, where up to 100% of the patients were cured. A rate for clinical response of 8% of the treated nails was obtained in the RCT. Complete cure rates were higher at 6-month follow-up (39–51% of the treated nails) compared with 9-month follow-up (8%)

Drawbacks

Laser device systems are new technology and the studies conducted thus  far  have  been  limited  in  terms  of  sample  size  and  method-ology.  Owing  to  the  limited  duration  of  the  follow-up  periods