Download PDF - Skin Therapy Letter

Volume 17 • Number 7 • July-August 2012
Indexed by the US National Library of Medicine and PubMed
Biofilms in Dermatology
Aron G. Nusbaum, BS1; Robert S. Kirsner, MD, PhD1,2; Carlos A. Charles, MD3
Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
2
University of Miami Hospital, Miami, FL, USA
3
Department of Dermatology, Weill Cornell Medical College, New York, NY, USA
1
ABSTRACT
Biofilms are diverse communities of microorganisms embedded within a self-produced matrix of extracellular polymeric substance
which are firmly attached to biotic or abiotic surfaces. Approximately 80% of all human infections are associated with biofilms
and evidence for their role in an ever-growing number of cutaneous disorders is constantly unfolding. Biofilms present a difficult
challenge to clinicians due to their persistent nature, inability to be cultured with standard techniques, and resistance to conventional
antimicrobial therapy. Although limited treatment options are presently available, better understanding of the molecular biology of
biofilms and their pathogenicity will likely lead to the development of novel anti-biofilm agents for clinical use.
Key words: bacterial colonization, biofilms, skin infection, wounds
Introduction
While bacteria have classically been viewed from the perspective
of planktonic, free floating pathogens proliferating and exerting
their virulence as individual organisms, it is now recognized
that microbes also can exist as multicellular consortiums known
as biofilms.1,2 (Figure 1) Several advantages exist for bacteria
that live in a biofilm phenotype including structural stability,
firm adherence to biotic or abiotic surfaces, increased virulence,
and resistance to both antimicrobial therapy and the host
immune response. Organisms within biofilms are embedded in
a glycocalyx, a self-produced matrix of extracellular polymeric
substance (EPS) composed of polysaccharides, proteins, lipids,
and extracellular DNA (eDNA). The EPS is considered to be the
hallmark of biofilm formation and in addition to facilitating
attachment, it also serves a protective function by preventing
neutrophilic penetration, 2 masking phagocytic detection
of opsonins, 3 and sequestering host antibodies, as well as
complement factors.4 The formation and behavior of the entire
biofilm community is directed by signaling molecules that are
produced when microorganisms reach a critical number. This
phenomenon is termed quorum sensing (QS) and has also been
shown to regulate the expression of virulence factors as well as
modulate host immunity.5
Biofilms have been associated with approximately 80% of all
human infections, yet their detection is extremely difficult
with the use of routine culture techniques.6 New methods to
detect biofilm-associated organisms are under development.
For example, denaturating gradient gel electrophoresis and
Figure 1. Scanning electron micrograph demonstrating the
presence of mixed species biofilm in a chronic wound. Both
cocci and bacilli are seen embedded in an amorphous matrix
characteristic of biofilm formation.
Figure from James GA, Swogger E, Wolcott R, et al. Biofilms in chronic
wounds. Wound Repair Regen. 2008 Jan-Feb;16(1):page 42, Figure 1D.
Reprinted with permission from John Wiley and Sons.
16S rRNA sequencing are currently being used successfully in
the research setting and may someday be available for use in
clinical practice.7,8 Currently, biofilms cannot be visualized in skin
biopsies submitted for routine light microscopy due to collapse of
the glycocalyx during the dehydration process9 and require special
techniques for visualization of the intact biofilm structure such as
electron, epifluorescence, or confocal laser scanning microscopy
ALSO IN THIS ISSUE: A Look at Epidermal Barrier Function in Atopic Dermatitis:
Physiologic Lipid Replacement and the Role of Ceramides (page 6) & Update on Drugs (page 10)
(CLSM). Conventional therapy is characteristically ineffective
against biofilms, as the minimum inhibitory concentration (MIC)
of antimicrobial agents has been shown to be 10 to 1000 fold
greater than for planktonic organisms.10 Antimicrobial resistance
can be attributed to the EPS serving as a physical barrier to
antibiotic penetration, plasmid exchange facilitated by close
proximity between organisms, and the low metabolic activity and
growth rate observed within biofilms.4,6,11 In addition, decreased
susceptibility to antimicrobial agents may also be related to an
increased frequency of mutations, which result in upregulation
of efflux pumps and antibiotic degrading enzymes such as betalactamase.12
Biofilms present a unique challenge to today’s clinician and
evidence for their involvement throughout dermatology is
constantly unfolding. Herein, we will present current knowledge
regarding the role of biofilms in cutaneous disease along with
potential therapeutic strategies for the management of biofilmassociated infections.
Wounds
In the United States, approximately 6.5 million patients are
affected by chronic wounds13 and their treatment significantly
impacts the health care system with an estimated $25 billion spent
annually.14,15 Chronic wounds present an optimal environment
for microbial proliferation and while the association between
infection and delayed wound closure has long been established,
little is known regarding the mechanisms by which bacteria
inhibit healing. In a clinical study of 66 wounds of various
etiologies, 60% of chronic wounds were shown to contain biofilms
as compared to 6% of acute wounds, indicating the possible role
of biofilms in wound chronicity.16 This study also demonstrated
the presence of multiple species within the chronic wound
environment existing in the form of highly organized biofilms.
Traditional cultures identified Staphylococcus, Pseudomonas, and
Enterococcus as the predominant organisms, while molecular
analysis additionally revealed the presence of strictly anaerobic
species.16 In fact, a recent profiling study utilizing 16S RNA
sequencing in 15 chronic wounds demonstrated an average
of 17 genera in each wound, with the majority being anaerobic
bacteria.17 These polymicrobial communities have long been
underappreciated due to the shortcomings of standard culture
techniques, yet they have important clinical implications as
interspecies interactions are likely operative in promoting biofilm
pathogenicity.17 Biofilms have a negative effect on wound healing
as evidenced by their ability to induce keratinocyte apoptosis
in vitro18 and inhibit re-epithelialization in an in vivo animal
wound model.19 In addition, biofilms may also augment the
inflammatory response characteristic of chronic wounds, thus
promoting tissue damage and further contributing to the nonhealing phenotype.20
It has been suggested that a biofilm-based wound care regimen
would incorporate a multifaceted approach with debridement
as its most essential component.6 In addition to removing
devitalized tissue that serves as a fertile environment for
bacteria, debridement physically disrupts the biofilm structure,
resulting in a period of reassembly during which organisms are
increasingly susceptible to antimicrobial therapies.21 Novel antibiofilm agents that have been proposed for use in chronic wounds
2
include lactoferrin, which inhibits bacterial adhesion and has
been shown to decrease biofilm mass,4 as well as xylitol, which
disrupts glycocalyx formation. 7 When used in combination,
these agents exhibit a synergistic effect and, in vitro, have been
shown to decrease the viability of a dual species Staphylococcus
aureus (S. aureus) and Pseudomonas aeruginosa biofilm when
added to a silver dressing.22 Future anti-biofilm therapies may
also target quorum sensing, as promising results were shown in a
murine wound model, where RNAIII inhibiting peptide, a specific
staphylococcal quorum sensing inhibitor, resulted in deficient
biofilm formation and improved the rate of healing.19
Atopic Dermatitis
Atopic dermatitis (AD) affects 10-20% of children with 60% of
cases occurring within a child’s first year and 85% before the age
of 5.23 Although spontaneous resolution is seen in a majority of
patients by 18 years of age, many cases persist into adulthood
as evidenced by the 1-3% prevalence of AD among the adult
population.24 It is well known that AD patients are colonized with
S. aureus and this organism has been shown to exist in both dry
skin as well as areas of severe dermatitis.25 Disease severity has
been directly correlated to the degree of S. aureus colonization
and therapy generally fails to improve symptoms in the presence
of high S. aureus counts.26 CLSM has demonstrated the presence
of biofilms on mouse skin inoculated with AD S. aureus isolates,27
as well as in skin stripping and biopsy specimens from 11 AD
patients.9
The difficulty in eradicating S. aureus colonization with
conventional antibiotic therapy may be due to the presence of
biofilms. It is hypothesized that normal skin microflora, such as
Staphylococcus epidermidis (S. epidermidis), has an important role
in suppressing the growth of S. aureus by metabolizing sebum
and, thus, creating a low pH environment that is inhibitory to
pathogenic organisms.28 Since S. aureus and S. epidermidis exhibit
similar antibiotic susceptibility, a logical rationale for therapy
may be to specifically target S. aureus biofilm. A recent in vitro
study29 examined the effects of farnesol and xylitol on S. aureus
biofilms and showed that each agent alone inhibited a different
stage of biofilm formation and, when used concomitantly, they
inhibited biofilm formation and also disrupted mature biofilm.
The MIC of farnesol was lower for S. aureus than S. epidermidis,
indicating the potential of this agent to selectively target the
pathogenic organism. In a clinical study of 17 patients with AD,28
a 0.02% farnesol and 5% xylitol (FX) combination emollient
cream significantly decreased the number of S. aureus organisms,
as well as the ratio of S. aureus to total aerobic skin microflora
with an observed increase in coagulase-negative staphylococci.
S. aureus biofilm, demonstrated in the intercellular spaces of the
stratum corneum prior to therapy, was completely absent after
7 days of FX topical application. No adverse effects of FX were
noted after 4 weeks of therapy. Ideal topical agents for the
treatment of AD should selectively reduce pathogenic biofilm and
restore the balance of skin microflora without the irritant effects
typically seen with current topical germicides.29
Acne
Acne affects approximately 45 million individuals in the United
States with most patients aged 12-24 years old, where the
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
prevalence has been shown to be as high a s 85%.30 Evidence for
the presence of biofilms in acne is predominantly derived from
the ability of Propionibacterium acnes (P. acnes) to form biofilms
both in vitro and on implanted medical devices. In addition,
sequencing of the P. acnes genome reveals the presence of genes
involved in the production of EPS and QS molecules.31 P. acnes
strains isolated from acne patients form biofilms in vitro that
are characterized by increased lipase activity as compared to
planktonic organisms.32 This may explain a pathogenic role
for P. acnes biofilms in acne, as lipase is not only a well known
virulence factor, but it also produces irritant fatty acids that
promote inflammation33 and enhance P. acnes adhesion to the
sebaceous follicle.34 Keratin plugging has long been considered a
key component of acne pathogenesis, and the adhesive properties
of the EPS produced by P. acnes biofilms in sebum may be
responsible for the tenacious binding of keratinocytes to the
infundibular epithelium.35
The observed clinical trend towards decreased efficacy of topical
antibiotics may be explained by their usage over time or by the
presence of biofilms, as biofilm-associated P. acnes exhibits
increased resistance to commonly used anti-acne agents.36 In
addition, the extended length of treatment necessary for acne to
respond to oral antibiotics further suggests that biofilms are a key
pathogenic factor in this condition.37 An in vitro study32 evaluating
multiple anti-acne agents alone or in combination found that only
0.1% triclosan, 5% benzoyl peroxide + 0.5% erythromycin, and
5% benzoyl peroxide + 1% clindamycin were effective in both
reducing biofilm mass and killing >99% of biofilm-associated
P. acnes. Interestingly, 5% benzoyl peroxide alone was ineffective
unless combined with erythromycin or clindamycin, possibly as
a result of antibiotics inhibiting protein synthesis and, therefore,
making P. acnes cells vulnerable to benzoyl peroxide generated
radicals. It should be noted that although 30mM azelaic acid was
bactericidal, it did not reduce biofilm mass. Minocycline was the
only agent in its class that removed biofilm and displayed the
greatest bactericidal effect of all the tetracyclines tested.
It has been postulated that the success of isotretinoin therapy may
be related to reduction of sebaceous gland size with a subsequent
decrease in sebum production, thus depleting the nutrient source
for P. acnes biofilm.35 The effectiveness of photodynamic therapy
may also be due to an indirect effect on biofilms mediated by
decreased sebaceous gland activity.38 Future acne therapies may
incorporate specific biofilm production antagonists or agents that
alter the physical and biochemical properties of the pilosebaceous
unit in order to create an unfavorable environment for P. acnes
biofilm.39
Candidiasis
Candida albicans (C. albicans) is a dimorphic yeast that typically
exists in a commensal state on mucocutaneous surfaces.40 In
the setting of predisposing factors such as immunosuppression,
systemic antibiotic therapy, endocrinopathies, excessive moisture,
or ill-fitting dentures, this organism becomes an opportunistic
pathogen causing local infections of the skin, nails, and mucous
membranes, and in some cases disseminated systemic disease.41
Recent in vivo animal models demonstrate the ability of C. albicans
to form biofilms on mucosal surfaces suggesting that biofilm
formation and its characteristic tissue adherence play a key role
in promoting Candida infections in these sites.42 Although it has
been suggested that C. albicans forms mucosal biofilms when
there are changes in host immunity or alterations in the mucosal
ecology or integrity, it is unknown if this organism always exists
as a biofilm, even in its commensal state.43 Cutaneous Candida
infections such as intertrigo and onychomycosis may also involve
biofilm-associated organisms, although this has not been studied.
Oropharyngeal candidiasis (OPC) is seen in 5% of newborns,
10% of the elderly, and is the most common opportunistic
infection in AIDS, affecting 90% of these patients. 42 Acute
pseudomembranous candidiasis, or thrush, is a common clinical
presentation with its characteristic white plaques presumably
due to biofilm formation.44 In a murine OPC model, BCR1, the
master transcription factor for Candida biofilms, was shown
to be involved in attachment to host cells, promoting epithelial
invasion, and protecting C. albicans from neutrophilic attack.45
C. albicans biofilms have also been shown to overexpress the
cell wall polysaccharide, β-glucan, which may be involved in
regulating the host immune response and promoting antifungal
resistance.44 Chronic atrophic candidiasis, also known as denture
stomatitis, is seen in up to 70% of denture wearers and is caused
by ill-fitting dentures compromising what is normally an effective
mucosal barrier.46 Denture stomatitis can be directly linked to
biofilm formation as dentures are abiotic surfaces that have been
demonstrated to harbor C. albicans biofilms.47 Angular cheilitis
is commonly seen in patients with denture stomatitis, suggesting
that biofilms may also play a role in this type of infection.
While routine and uncomplicated candidiasis typically responds
to treatment with traditional antifungals such as the azoles,
the ineffectiveness of these agents in recurrent and persistent
Candida infections is thought to result from the presence of
biofilms. Most of the information regarding Candida biofilm drug
resistance stems from in vitro studies, yet these findings are likely
applicable to the clinical setting, as in vitro and in vivo C. albicans
biofilms have similar architectural structure, growth kinetics,
and genetic determinants.42 Candida biofilms exhibit a 30 to
2000 fold increase in resistance to amphotericin B, fluconazole,
itraconazole, and ketoconazole as compared to planktonic
organisms.48 Subpopulations of cells that exhibit extremely high
levels of antifungal resistance49 as well as the drug penetration
barrier function of the EPS 50 have been demonstrated in
C. albicans biofilms.
Recently developed antifungal agents such as the echinocandins
and liposomal formulations of amphotericin B have been shown
to be effective against C. albicans biofilms,51 but are currently
available only for intravenous administration. Gentian violet has
shown efficacy on in vitro isolates from OPC lesions and may act
by inhibiting germination and forming radicals, which enhance
penetration through the biofilm matrix.52 Additional therapeutic
strategies that may hold promise for the treatment of Candida
biofilm infections include quorum sensing inhibitors, vaccines,
anti-candidal antibodies, cytokine therapy, and specific inhibitors
of BCR1 and its target genes.53
Fillers
Adverse reactions to fillers were previously thought to be due
to allergic or foreign body reactions, yet it is now recognized
that painful inflammatory nodules in this setting should be
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
3
considered to be infectious in etiology and immediately treated
with antibiotic therapy.54 Biofilms are possibly the causative factor
as evidenced by the persistent nature of filler reactions, difficulty
in culturing organisms with routine measures, and the reported
high incidence of biofilm-infected medical implants. This has
been corroborated by visualization of bacterial aggregates with
surrounding eDNA within the filler gel and intervening dermis
in biopsies of 8 patients with reactions to polyacrylamide gel.55
Seven of these patients had been treated with intralesional or
systemic steroids, suggesting that reactions to polyacrylamide
fillers be treated with antibiotics and that steroids should be
avoided. The choice of antibiotic agents as well as the length and
mode of administration should be selected based on the filler
type and the onset, severity, and duration of infection. Incision
and drainage for fluctuant lesions is recommended. Additionally,
performing biopsy and cultures is essential for late onset reactions
or when particulate fillers are used, keeping in mind that routine
cultures are often negative in the case of biofilms.54 Finally, the
performance of filler injections with aseptic precautions is crucial
and antibiotic prophylaxis should be considered when injecting
into highly colonized areas or acne affected skin.
Other Dermatologic Diseases
S. aureus biofilms have been demonstrated in specimens of
bullous impetigo and pemphigus foliaceus 9 while biofilms
containing both S. aureus and Streptococcus pyogenes have been
identified in non-bullous impetigo.56 The effects of acetic acid
(AA) and hydrochloric acid on S. aureus biofilm formation were
evaluated in bullous impetigo and pemphigus foliaceus isolates
and were both shown to decrease glycocalyx production. 9 AA
had a superior effect in reducing biofilm-associated S. aureus
counts, indicating a specific effect of AA unrelated to low pH. In
the clinical setting, AA 2.5% ointment was reported to reduce
S. aureus counts in pemphigus foliaceus lesions, although no
supporting data was presented.9
Biofilm formation has also been demonstrated in a murine model
inoculated with S. aureus isolated from a furuncle.57 Treatment
with a combination of imipenem and roxithromycin showed
significantly reduced S. aureus counts in lesional skin, while
treatment with either agent alone showed no effect.
Biofilms have been implicated in miliaria by a clinical study in
which only EPS producing S. epidermidis was capable of inducing
lesions after inoculation and occlusion.58 Biopsy specimens
revealed sweat glands blocked with EPS material, further
supporting a pathogenic role for biofilms in this condition.
Evidence is lacking to support the presence of biofilms in
onychomycosis. Nevertheless, several factors including firm
adherence of dermatophytes to the nail plate, presence of dormant
fungal elements, ability of yeast to form biofilms, and difficulty
of eradication all suggest that biofilms may be operative in this
condition.59
Conclusion
Biofilms are known to be ubiquitous in nature and modern
medical technology continues to unveil their role in an evergrowing number of disease processes. In the field of dermatology,
biofilms appear to be taking center stage, and their presence
likely explains the chronic nature of many cutaneous disorders.
4
It is expected that further knowledge regarding the molecular
mechanisms that govern biofilm formation, their virulence,
and drug resistance will vastly improve the limited therapeutic
options currently available to today’s clinician.
References
1. Charles CA, Ricotti CA, Davis SC, et al. Use of tissue-engineered skin to study
in vitro biofilm development. Dermatol Surg. 2009 Sep;35(9):1334-41.
2. Davis SC, Ricotti C, Cazzaniga A, et al. Microscopic and physiologic evidence
for biofilm-associated wound colonization in vivo. Wound Repair Regen. 2008
Jan-Feb;16(1):23-9.
3. Thomson CH. Biofilms: do they affect wound healing? Int Wound J. 2011
Feb;8(1):63-7.
4. Davis SC, Martinez L, Kirsner R. The diabetic foot: the importance of biofilms
and wound bed preparation. Curr Diab Rep. 2006 Dec;6(6):439-45.
5. Nakagami G, Morohoshi T, Ikeda T, et al. Contribution of quorum sensing to
the virulence of Pseudomonas aeruginosa in pressure ulcer infection in rats.
Wound Repair Regen. 2011 Mar-Apr;19(2):214-22.
6. Wolcott R, Dowd S. The role of biofilms: are we hitting the right target? Plast
Reconstr Surg. 2011 Jan;127(Suppl 1):28S-35S.
7. Black CE, Costerton JW. Current concepts regarding the effect of wound
microbial ecology and biofilms on wound healing. Surg Clin North Am. 2010
Dec;90(6):1147-60.
8. Martin JM, Zenilman JM, Lazarus GS. Molecular microbiology: new
dimensions for cutaneous biology and wound healing. J Invest Dermatol. 2010
Jan;130(1):38-48.
9. Akiyama H, Hamada T, Huh WK, et al. Confocal laser scanning microscopic
observation of glycocalyx production by Staphylococcus aureus in skin lesions
of bullous impetigo, atopic dermatitis and pemphigus foliaceus. Br J Dermatol.
2003 Mar;148(3):526-32.
10. Donlan RM, Costerton JW. Biofilms: survival mechanisms of clinically relevant
microorganisms. Clin Microbiol Rev. 2002 Apr;15(2):167-93.
11. Percival SL, Hill KE, Malic S, et al. Antimicrobial tolerance and the significance
of persister cells in recalcitrant chronic wound biofilms. Wound Repair Regen.
2011 Jan-Feb;19(1):1-9.
12. Hoiby N, Bjarnsholt T, Givskov M, et al. Antibiotic resistance of bacterial
biofilms. Int J Antimicrob Agents. 2010 Apr;35(4):322-32.
13. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and
snowballing threat to public health and the economy. Wound Repair Regen.
2009 Nov-Dec;17(6):763-71.
14. Brem H, Stojadinovic O, Diegelmann RF, et al. Molecular markers in
patients with chronic wounds to guide surgical debridement. Mol Med. 2007
Jan-Feb;13(1-2):30-9.
15. Tomic-Canic M, Ayello EA, Stojadinovic O, et al. Using gene transcription
patterns (bar coding scans) to guide wound debridement and healing. Adv
Skin Wound Care. 2008 Oct;21(10):487-92.
16. James GA, Swogger E, Wolcott R, et al. Biofilms in chronic wounds. Wound
Repair Regen. 2008 Jan-Feb;16(1):37-44.
17. Han A, Zenilman JM, Melendez JH, et al. The importance of a multifaceted
approach to characterizing the microbial flora of chronic wounds. Wound
Repair Regen. 2011 Sep-Oct;19(5):532-41.
18. Kirker KR, Secor PR, James GA, et al. Loss of viability and induction of
apoptosis in human keratinocytes exposed to Staphylococcus aureus biofilms
in vitro. Wound Repair Regen. 2009 Sep-Oct;17(5):690-9.
19. Schierle CF, De la Garza M, Mustoe TA, et al. Staphylococcal biofilms impair
wound healing by delaying reepithelialization in a murine cutaneous wound
model. Wound Repair Regen. 2009 May-Jun;17(3):354-9.
20. Fazli M, Bjarnsholt T, Kirketerp-Moller K, et al. Quantitative analysis of the
cellular inflammatory response against biofilm bacteria in chronic wounds.
Wound Repair Regen. 2011 May-Jun;19(3):387-91.
21. Wolcott RD, Rumbaugh KP, James G, et al. Biofilm maturity studies indicate
sharp debridement opens a time- dependent therapeutic window. J Wound
Care. 2010 Aug;19(8):320-8.
22. Ammons MC, Ward LS, James GA. Anti-biofilm efficacy of a lactoferrin/xylitol
wound hydrogel used in combination with silver wound dressings. Int Wound J.
2011 Jun;8(3):268-73.
23. Krakowski AC, Eichenfield LF, Dohil MA. Management of atopic dermatitis in
the pediatric population. Pediatrics. 2008 Oct;122(4):812-24.
24. Leung DY, Bieber T. Atopic dermatitis. Lancet. 2003 Jan 11;361(9352):151-60.
25. Ikezawa Z, Komori J, Ikezawa Y, et al. A role of Staphylococcus aureus,
interleukin-18, nerve growth factor and semaphorin 3A, an axon guidance
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
molecule, in pathogenesis and treatment of atopic dermatitis. Allergy Asthma
Immunol Res. 2010 Oct;2(4):235-46.
Akiyama H, Yamasaki O, Tada J, et al. Adherence characteristics and
susceptibility to antimicrobial agents of Staphylococcus aureus strains
isolated from skin infections and atopic dermatitis. J Dermatol Sci. 2000
Aug;23(3):155-60.
Akiyama H, Huh WK, Yamasaki O, et al. Confocal laser scanning microscopic
observation of glycocalyx production by Staphylococcus aureus in mouse
skin: does S. aureus generally produce a biofilm on damaged skin? Br J
Dermatol. 2002 Nov;147(5):879-85.
Katsuyama M, Kobayashi Y, Ichikawa H, et al. A novel method to control the
balance of skin microflora Part 2. A study to assess the effect of a cream
containing farnesol and xylitol on atopic dry skin. J Dermatol Sci. 2005 Jun;
38(3):207-13.
Katsuyama M, Ichikawa H, Ogawa S, et al. A novel method to control the
balance of skin microflora. Part 1. Attack on biofilm of Staphylococcus aureus
without antibiotics. J Dermatol Sci. 2005 Jun;38(3):197-205.
White GM. Recent findings in the epidemiologic evidence, classification, and
subtypes of acne vulgaris. J Am Acad Dermatol. 1998 Aug;39(2 Pt 3):S34-7.
Coenye T, Honraet K, Rossel B, et al. Biofilms in skin infections:
Propionibacterium acnes and acne vulgaris. Infect Disord Drug Targets. 2008
Sep;8(3):156-9.
Coenye T, Peeters E, Nelis HJ. Biofilm formation by Propionibacterium acnes
is associated with increased resistance to antimicrobial agents and increased
production of putative virulence factors. Res Microbiol. 2007 May;158(4):
386-92.
Jappe U. Pathological mechanisms of acne with special emphasis on
Propionibacterium acnes and related therapy. Acta Derm Venereol. 2003;
83(4):241-8.
Gribbon EM, Cunliffe WJ, Holland KT. Interaction of Propionibacterium acnes
with skin lipids in vitro. J Gen Microbiol. 1993 Aug;139(8):1745-51.
Burkhart CG, Burkhart CN. Expanding the microcomedone theory and acne
therapeutics: Propionibacterium acnes biofilm produces biological glue
that holds corneocytes together to form plug. J Am Acad Dermatol. 2007
Oct;57(4):722-4.
Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons
from clinical studies. Br J Dermatol. 2005 Aug;153(2):395-403.
James KA, Burkhart CN, Morrell DS. Emerging drugs for acne. Expert Opin
Emerg Drugs. 2009 Dec;14(4):649-59.
Hongcharu W, Taylor CR, Chang Y, et al. Topical ALA-photodynamic therapy
for the treatment of acne vulgaris. J Invest Dermatol. 2000 Aug;115(2):183-92.
Burkhart CN, Burkhart CG. Microbiology’s principle of biofilms as a
major factor in the pathogenesis of acne vulgaris. Int J Dermatol. 2003
Dec;42(12):925-7.
Seneviratne CJ, Jin L, Samaranayake LP. Biofilm lifestyle of Candida: a mini
review. Oral Dis. 2008 Oct;14(7):582-90.
Wolff K, Goldsmith LA, Katz SI, et al. (eds). Fitzpatrick’s dermatology in general
medicine. 7th ed. New York: McGraw Hill; 2008.
42. Ganguly S, Mitchell AP. Mucosal biofilms of Candida albicans. Curr Opin
Microbiol. 2011 Aug;14(4):380-5.
43. Harriott MM, Lilly EA, Rodriguez TE, et al. Candida albicans forms biofilms on
the vaginal mucosa. Microbiology. 2010 Dec;156(Pt 12):3635-44.
44. Dongari-Bagtzoglou A, Kashleva H, Dwivedi P, et al. Characterization of
mucosal Candida albicans biofilms. PLoS One. 2009;4(11):e7967.
45. Dwivedi P, Thompson A, Xie Z, et al. Role of Bcr1-activated genes Hwp1 and
Hyr1 in Candida albicans oral mucosal biofilms and neutrophil evasion. PLoS
One. 2011;6(1):e16218.
46. Nett JE, Marchillo K, Spiegel CA, et al. Development and validation of an
in vivo Candida albicans biofilm denture model. Infect Immun. 2010 Sep;
78(9):3650-9.
47. Williams DW, Kuriyama T, Silva S, et al. Candida biofilms and oral candidosis:
treatment and prevention. Periodontol 2000. 2011 Feb;55(1):250-65.
48. Hawser SP, Douglas LJ. Resistance of Candida albicans biofilms to antifungal
agents in vitro. Antimicrob Agents Chemother. 1995 Sep;39(9):2128-31.
49. LaFleur MD, Kumamoto CA, Lewis K. Candida albicans biofilms produce
antifungal-tolerant persister cells. Antimicrob Agents Chemother. 2006 Nov;
50(11):3839-46.
50. Vediyappan G, Rossignol T, d’Enfert C. Interaction of Candida albicans
biofilms with antifungals: transcriptional response and binding of antifungals
to beta-glucans. Antimicrob Agents Chemother. 2010 May;54(5):2096-111.
51. Kuhn DM, George T, Chandra J, et al. Antifungal susceptibility of Candida
biofilms: unique efficacy of amphotericin B lipid formulations and
echinocandins. Antimicrob Agents Chemother. 2002 Jun;46(6):1773-80.
52. Traboulsi RS, Mukherjee PK, Chandra J, et al. Gentian violet exhibits activity
against biofilms formed by oral Candida isolates obtained from HIV-infected
patients. Antimicrob Agents Chemother. 2011 Jun;55(6):3043-5.
53. Tournu H, Van Dijck P. Candida biofilms and the host: models and new
concepts for eradication. Int J Microbiol. 2012;2012:845352.
54. Narins RS, Coleman WP, 3rd, Glogau RG. Recommendations and treatment
options for nodules and other filler complications. Dermatol Surg. 2009 Oct;
35(Suppl 2):1667-71.
55. Bjarnsholt T, Tolker-Nielsen T, Givskov M, et al. Detection of bacteria by
fluorescence in situ hybridization in culture-negative soft tissue filler lesions.
Dermatol Surg. 2009 Oct;35(Suppl 2):1620-4.
56. Akiyama H, Morizane S, Yamasaki O, et al. Assessment of Streptococcus
pyogenes microcolony formation in infected skin by confocal laser scanning
microscopy. J Dermatol Sci. 2003 Sep;32(3):193-9.
57. Yamasaki O, Akiyama H, Toi Y, et al. A combination of roxithromycin
and imipenem as an antimicrobial strategy against biofilms formed by
Staphylococcus aureus. J Antimicrob Chemother. 2001 Oct;48(4):573-7.
58. Mowad CM, McGinley KJ, Foglia A, et al. The role of extracellular polysaccharide
substance produced by Staphylococcus epidermidis in miliaria. J Am Acad
Dermatol. 1995 Nov;33(5 Pt 1):729-33.
59. Burkhart CN, Burkhart CG, Gupta AK. Dermatophytoma: recalcitrance to
treatment because of existence of fungal biofilm. J Am Acad Dermatol. 2002
Oct;47(4):629-31.
Free app available for iPad, iPhone and iPod touch
Content & instructions can be found at:
http://www.skintherapyletter.com/ipad/about.html
http://www.skintherapyletter.com/ipad/support.html
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
5
A Look at Epidermal Barrier Function in
Atopic Dermatitis: Physiologic Lipid Replacement
and the Role of Ceramides
Dušan Sajić, MD, PhD; Rachel Asiniwasis, MD; Sandy Skotnicki-Grant, MD, FRCPC
Division of Dermatology, University of Toronto Dermatology, Toronto, ON
Bay Dermatology Centre, Toronto, ON
ABSTRACT
This review summarizes and discusses the role and efficacy of moisturizers, particularly the more recently introduced ceramide-based
formulations, in the skin care regimen of patients with both active and quiescent atopic dermatitis (AD). It is now well established
that a complex interplay of environmental and genetic factors are responsible for disease onset and chronicity. Indeed, several novel
genetic mechanisms have been recently discovered to be associated with AD pathogenesis. Moreover, it is increasingly recognized
that the epidermal barrier plays a critical role in the initiation, perpetuation, and exacerbation of AD. The skin of patients with
AD harbors several defects in epidermal barrier function, including filaggrin and ceramides. An improved understanding of these
etiopathogenic factors has led to the development of topical ceramide-dominant moisturizers to replace the deficient molecules
and re-establish the integrity of barrier defenses. Some of these products have demonstrated efficacy in the treatment of adult and
childhood AD that are similar to mid-potency topical steroids. More importantly, they have been shown to be safe with very few
associated side-effects. We recommend the addition of such new agents as both the first step of treatment and in the maintenance of
clinically quiescent skin of patients with AD.
Key words: atopic dermatitis, ceramides, eczema, emollients, epidermal barrier, lipids, transepidermal water loss
Introduction
Atopic dermatitis (AD) is a chronic, inflammatory, pruritic
skin disease of increasing prevalence (affecting 15-30% of
children and 2-10% of adults).1 AD is considered by many
to be the first step in the “atopic march” that can progress to
include asthma and allergic rhinitis, as well as be a precursor
to, rather than a consequence of, food allergies.1 The precise
sequence of biochemical events leading to the development of
AD has still not been fully elucidated, but most experts agree
that it involves a complex interplay of environmental and genetic
factors that induce derangements in the structure and function
of the epidermal barrier and immune system. Diagnosis can
be challenging, as the variability of clinical presentation can be
confounding. Morphology alone cannot reliably confirm the
diagnosis and the spectrum of features associated with AD must
be considered. While several sets of diagnostic criteria for AD
have been proposed and validated, the traditionally used being
that of Hanifin and Rajka, full agreement amongst clinicians and
uniformity of criteria are still lacking.2
Epidermal Barrier Dysfunction
Traditionally, it was thought that the primary pathogenic
mechanism of atopic dermatitis was initiated by immune
dysfunction leading to a Th2 cytokine imbalance, increased
inflammation, and secondary disruption of the epidermal
barrier.1,3 However, accumulating evidence suggests that rather
than merely having a bystander effect, a primary defect in the
stratum corneum plays a major role in driving the pathogenesis
of atopic dermatitis that leads to sustained cytokine release,
6
recruitment of pro-inflammatory molecules, and stimulation
of a Th2 response.3,4 Moreover, further barrier disruption in
the chronic stages of AD, through mechanical scratching, not
only perpetuates but alters the response to a mostly Th1 type.5
In addition, while several other cytokines and T cell subsets
like IL-31 and Th2,6 respectively, have recently been identified
within the skin of patients with AD, the role of the skin barrier
influencing their expression remains unclear.7
AD has been separated into two different subtypes, i.e., intrinsic
and extrinsic, which were derived on the basis of the extrinsic
subtype stemming from allergic sensitization to an external
antigen with subsequent allergen specific IgE production, and the
intrinsic variant describes patients with all clinical features of AD,
but no detectable allergen specific IgE. However, these subtypes
may actually represent different stages of evolution based on the
relative degree of sensitization. Under this view, AD in infancy
is thought to begin as “intrinsic” or non-atopic dermatitis, and
over time it progresses to “true” atopy in the majority of cases
via allergen exposure through what is now being more widely
recognized as a primarily defective epidermal barrier function.1,2
It is well established that the first line of defense within the
epidermal barrier is the stratum corneum, which serves
several fundamental roles in maintaining protection from the
environment as well as preventing water loss. This “outside-in”
theory views a primary defect in the stratum corneum as a
key condition that drives the inflammatory cascade of AD,
predisposing to increased transepidermal water loss (TEWL),
penetration of irritants, allergens, secondary infection, and
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
6
increased inflammation.8 Several lines of evidence demonstrate
the capacity of the cutaneous barrier to initiate and perpetuate
AD including observations that:
1. the defects in the barrier result in elevated pH that activates
proteases capable of directly inducing a Th2 inflammatory
response,9
2. the severity of the barrier defect parallels AD severity,10,11
3. the barrier defect persists longer than both the clinical lesions
and the underlying inflammation,11
4. several genetic disorders with skin lesions similar to AD
implicate abnormal gene coding that affect the epidermal
barrier, and lastly,12
5. therapeutic strategies aimed at repairing the epidermal
barrier, as further discussed below, also ameliorates both the
inflammation and the clinically involved skin.13
Morphological Changes in Epidermal Lipids in AD
The stratum corneum represents a multicellular vertically stacked
layer of cells embedded within a hydrophobic extracellular
matrix. This matrix is derived from the secretion of lipid
precursors and lipid hydrolases, both of which are secreted from
lamellar bodies in the stratum granulosum. These hydrolases
cleave the precursors to form essential and non-essential fatty
acids, cholesterol, and at least 10 different ceramides, which
self-organize into multilayered lamellar bilayers between the
corneocytes (“bricks”), resulting in the formation of watertight
“mortar”, thus, maintaining skin hydration.12 In physiological
balance, the approximate proportions of the lipid component are
predominantly composed of 50% ceramides, 25% cholesterol, and
10-20% free fatty acids.8 In atopic dermatitis, there is a decrease in
all three key lipids, especially ceramides, which are found in both
lesional and non-lesional skin.1 A lipid imbalance and inadequate
amounts of ceramides contribute to defective formation of the
corneocyte lipid envelope and lipid mortar, which correlates with
increased TEWL and enhanced barrier permeability.
Filaggrin Mutations and Exogenous Factors in AD
Contribute to Epidermal Barrier Dysfunction
There has been a large focus on the role of genetic abnormalities
leading to defects in key structural components of the
epidermal barrier. Perhaps the best example of this is a loss of
function mutation in the filaggrin gene, which encodes for the
filament aggregating protein (FLG), found in up to 60% of AD
patients.12 While there are various other candidate genes that lead
to increased susceptibility, including KLK7, SPINK5, and CSTA,
FLG remains by far the most prominent.14 Although filaggrin
is certainly one of the most important single genes involved
in AD susceptibility, inherent redundancy in the epidermal
differentiation complex with several other similar genes may
mitigate the negative effect of filaggrin mutations and explain
the incomplete penetrance in AD. As such, patients carrying a
mutation in the FLG gene display a wide spectrum of disease,
ranging from mildly dry skin to more severe manifestations of
ichthyosis vulgaris.15 Moreover, since only 44% of AD patients
carry the heterozygous mutation and 76% of homozygous or
compound heterozygous FLG mutation carrying patients suffer
from AD,16 this further implicates the role of other genes and the
environment in disease pathogenesis. Nevertheless, complete
absence of FLG, either as a homozygous mutation or a compound
heterozygote mutation, clearly disrupts the epidermal barrier, as
all of these patients to date have been shown to present with a
clinical picture of ichthyosis vulgaris.17,18
Filaggrin normally assists in cytoskeletal aggregation and
formation of the cornified cell envelope (CCE), providing
additional strength and structure. It is required for normal
lamellar body formation and content secretion. Furthermore,
as corneocytes mature and start losing water, FLG dissociates
from the CCE and is processed into acidic metabolites acting
as osmolytes that help to retain hydration and keep the pH
below the threshold required for the activation of Th2-inducing
endogenous serine proteases. 9 Therefore, a FLG mutation
contributes to a disrupted epidermal barrier, increased water
loss, and inflammation. There are also many exogenous factors
that can exacerbate barrier dysfunction, specifically soaps and
surfactants in detergents that accelerate corneocyte and lipid
degradation. Several antigens, including those from cockroaches,
Staphylococcus aureus, dust mites, and scabies induce endogenous
proteolytic activity, cleaving corneodesmosomal proteins and
filaggrin, thus contributing further to the cycle of inflammation
and pruritus.1
Lipid Replacement Therapy in AD
Traditionally viewed as an immunological disorder, therapies
for AD have included topical steroids and immunomodulators,
and sometimes more aggressive immunosuppressives that do
not target the underlying structural barrier abnormalities.4,19 As
well, most conventional moisturizers do not address this
underlying lipid deficiency. With an improved understanding
of AD etiopathogenesis, a new nonpharmacologic approach
has emerged aimed at barrier repair involving the delivery of
balanced proportions of stratum corneum specific lipids to assist
in correcting this epidermal barrier dysfunction.
With accumulating evidence supporting barrier defect-initiated
disease pathogenesis and its effects on both triggering and
perpetuating AD, it is not surprising that emollients, ointments
and oils thought to prevent epidermal water loss and inhibit
sensitizing exogenous peptides from traversing the compromised
barrier, have become the first-line/adjunctive therapy in patients
with AD. While the use of sophisticated moisturizers has been
shown to confer protective effects on the skin barrier by delaying
onset and decreasing AD severity and flares,1 it is not appropriate
to generalize this benefit to all moisturizers, as they not only differ
widely in their compositions, but are classified into subcategories
based on the therapeutic properties of their key ingredients,
e.g., occlusives, humectants, emollients (e.g., intercellular lipids),
or some combination of the three. Within the intercellular lipids
category, moisturizers contain a variable mix of ceramides,
cholesterol, and free fatty acids.
One of the most promising barrier repair methods have been
ceramide-dominant physiological lipid-based barrier repair
topical emulsions. In contrast to traditional moisturizers, these
formulations focus on physiologic lipid replacement therapy,
particularly ceramides, to restore normal balance of the epidermal
barrier. In comparison with other emollients (e.g., petrolatum)
that form a more superficial occlusive barrier, ceramide-dominant
moisturizers are thought to permeate the stratum corneum and
are synthesized in the keratinocytes, processed in lamellar bodies,
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
7
and secreted back into the stratum corneum to become a part of
the dermal matrix.8,20
Interestingly, while cholesterol, ceramides, and fatty acids are
all required for repair, individually they encumber rather than
facilitate barrier recovery.21 Moreover, incomplete mixtures can
also result in suboptimal recovery,22 underlining the importance
of proper physiological ratios of individual components to achieve
maximal efficacy. Ceramide-based emulsions, such as EpiCeram®
and TriCeram®, contain the physiological 3:1:1 molar ratio of
ceramides, cholesterols, and free fatty acids, which emulates
the endogenous composition of the stratum corneum and has
been shown to repair its integrity and function.21 While several
reports have shown that the 3:1:1 ratio seems to be important in
barrier repair,21-24 it appears that the “3” does not necessarily need
to be a ceramide, as both three-fold higher ratios of a fatty acid
or cholesterol rather than a ceramide can significantly improve
barrier function when compared to vehicle alone. 23 Moreover,
while both TriCeram® and EpiCeram® contain 2.1% of ceramides,
one study showed that a dilution of 1:9 also has significant effects
on barrier repair.21 In addition to assisting in restoration of the
lipid defect in AD, these products also help to normalize the pH
of the skin, which itself is separately associated with a decrease in
epidermal barrier integrity, increased inflammation, and reduced
antimicrobial defenses.25,26
Although most of the early studies compared the efficacy of the
three component mixtures to vehicle alone, several recent reports
have shown that some ceramide-dominant formulations can, on
their own, induce improvements comparable to topical steroids
in the treatment of mild to moderate disease.19,27 Therefore,
avoiding associated adverse effects from corticosteroid treatment
and certain dosing restrictions, as therapy is suitable for patients
of all ages and may be used on sensitive skin sites (e.g., face and
intertriginous areas), which are prone to steroid-induced atrophy.
Another ceramide-based barrier repair cream is CeraVe™, the first
over-the-counter (OTC) product featuring multilamellar vesicular
emulsions (MVEs), which are similar to liposomes, but facilitate
a slow 24-hour controlled, time-released delivery of the contents.
This delivery advance offers once-daily application, thereby
encouraging adherence to a simplified regimen of moisturizer
use. While no standalone trials have been conducted with
MVEs, the combination of MVEs with topical fluocinonide 0.05%
has recently been shown to reduce disease duration and time to
clearance when compared with the same corticosteroid alone,
resulting in accelerated skin barrier recovery.28
Natural vs. Synthetic Ceramides
As previously discussed, ceramides are the main components of
the multilayered lamellar bilayers between the corneocytes and,
thus, a key factor in water retention and overall integrity of the
barrier. Chemically, they are amide-linked free fatty acids with
long-chain amino alcohol sphingoid bases, which are amidelinked to hydroxylated, x-hydroxylated or nonhydroxylated fatty
acids, and shown to also have functions in apoptosis, cell growth,
senescence, and cell cycle control.29 Clinically, while many other
moisturizers are important in providing short-term relief from
dryness in AD, long-term benefits can only be derived through
restoring adequate ceramide levels. While replacement with
natural ceramides seems to represent the most logical step in the
8
correction of the barrier, there are three important considerations
connected with the use of “natural” ceramides. Firstly, there is a
high cost associated with nature-identical, synthetic ceramides
(e.g., $2,000-$10,000/kg).30 Secondly, inexpensive naturally
occurring ceramides are typically extracted from bovine central
nervous system, which raises concerns about bovine spongiform
encephalopathy (‘mad cow disease’). Thirdly, excess intracellular
ceramides can be linked with significant toxicity and lead to cell
growth retardation and apoptosis.20,30 Synthetic ceramides are
capable of overcoming most of these obstacles and are currently
being explored as potential alternatives to natural ceramides.
Kang et al. showed that application of 1% K6PC-9p (a synthetic
ceramide derivative of PC-9S) resulted in similar improvement of
tetradecanoylphorbol acetate (TPA)-induced skin inflammation,
when compared to 0.1% hydrocortisone.31 Moreover, application
of a ceramide complex (pseudoceramides and eucalyptus leaf
extract) resulted in not only improved TEWL and erythema
gradings of treated AD patients when compared to vehicle
control, but also increased levels of endogenous stratum
corneum ceramides.32 Another study investigated a synthetic
pseudoceramide and eucalyptus leaf extract formulation in
patients with mild to severe AD. 33 This double-blind, within
subject vehicle-controlled study of patients with AD lesions on the
arms and legs assessed TEWL, global assessment, and erythema.
A significant differential benefit for the ceramide complex over
vehicle was shown. Additionally, the findings demonstrated that
this ceramide complex of pseudoceramides appears to work
similar to the endogenous ceramindes found in the skin.
Other Non-steroidal Barrier Repair Products
While ceramide-based moisturizers clearly appear to be
superior to most non-ceramide OTC moisturizers, it should
be noted that a recent trial showed the use of a glycyrrhetinic
acid-containing barrier repair cream (Atopiclair®) resulted
in improvement of mild to moderate AD in children that was
equivalent to EpiCeram®.34 Similar findings were seen in another
recent study that demonstrated non-superiority of topical
pimecrolimus when compared to a number of different OTC
creams (collectively regarded as one group),25 suggesting that
correction of numerous epidermal barrier derangements may
be an effective way of controlling AD. As well, a multicenter,
observational, uncontrolled study of 2456 AD patients aged 2-70
years showed that regular use of a barrier cream containing
lipids and N-palmitoylethanolamine (MimyX®) significantly
reduced AD skin symptoms (e.g., erythema, pruritus, excoriation,
scaling, lichenification, and dryness), sleep disturbance, and
topical steroid use.35 Eletone® is another FDA-cleared 510(k)
prescription medical device moisturizer that helps to improve
stratum corneum impairment and restore barrier integrity.
The product contains 70% oil dispersed in 30% water, but it
uses a proprietary reverse emulsion technology that produces
a formulary consistency of a cream with occlusive properties of
an ointment, resulting in enhanced cosmetic acceptability. In a
study assessing the use of twice-daily Eletone® in 133 pediatric
patients with mild to moderate AD, at 4 weeks 54% of patients
experienced improvement in pruritus and average body surface
area involvement decreased by 43.6%. 36 Whether such treatments
lead to an indirect restoration of ceramide levels remains
unknown and warrants further investigation. • Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
Conclusion
AD follows a chronic relapsing course, as such, in addition
to pharmacologic intervention, it is essential to maintain
hydration and barrier function of the skin with daily regimented
moisturizer use. Ceramide-based moisturizers have been shown
to be beneficial in reducing TEWL, improving barrier function,
and maintaining hydration of the stratum corneum, and thus,
can be a useful component in AD management. Adequate
moisturization reduces the need for drug treatments, as well as
limits the severity and frequency of eczematous flares. Indeed,
more studies are showing that correction of the skin barrier
defects through emollient therapy inhibits downstream drivers
of the inflammatory response, thereby providing the rationale
for prophylactic and continuous use. Furthermore, the ceramidebased barrier repair emulsions have an excellent safety profile,
without significant adverse events other than occasional transient
tingling upon application, and thus, can be safely used in patients
of all ages and on sensitive skin regions, including the face and
intertriginous areas. Additional research is warranted and
will lead to a better understanding of the optimal formulary
compositions as well as development of a better treatment ladder
for varying severities of AD. Also, long-term studies would be
helpful in establishing whether lipid barrier replacement therapy
reduces bacterial colonization or prevents progression of the
atopic march.
References
1. Danby S, Cork MJ. A new understanding of atopic dermatitis: the role
of epidermal barrier dysfunction and subclinical inflammation. J Clin
Dermatol. 2010;1:33-46.
2. Bos JD, Brenninkmeijer EE, Schram ME, et al. Atopic eczema or atopiform
dermatitis. Exp Dermatol. 2010 Apr;19(4):325-31.
3. Elias PM, Schmuth M. Abnormal skin barrier in the etiopathogenesis of atopic
dermatitis. Curr Allergy Asthma Rep. 2009 Jul;9(4):265-72.
4. Elias PM. An Appropriate response to the black-box warning: corrective,
barrier repair therapy in atopic dermatitis. Clin Med Dermatol. 2009 Feb
9;2:1-3.
5. Matsushima H, Hayashi S, Shimada S. Skin scratching switches immune
responses from Th2 to Th1 type in epicutaneously immunized mice. J
Dermatol Sci. 2003 Sep;32(3):223-30.
6. Jin H, He R, Oyoshi M, et al. Animal models of atopic dermatitis. J Invest
Dermatol. 2009 Jan;129(1):31-40.
7. Szegedi K, Kremer AE, Kezic S, et al. Increased frequencies of IL-31 producing
T cells are found in chronic atopic dermatitis skin. Exper Dermatol. 2012 Jun;
21(6):431-6.
8. Sugarman JL. The epidermal barrier in atopic dermatitis. Semin Cutan Med
Surg. 2008 Jun;27(2):108-14.
9. Briot A, Deraison C, Lacroix M, et al. Kallikrein 5 induces atopic dermatitis-like
lesions through PAR2-mediated thymic stromal lymphopoietin expression in
Netherton syndrome. J Exp Med. 2009 May 11;206(5):1135-47.
10. Sugarman JL, Fluhr JW, Fowler AJ, et al. The objective severity assessment
of atopic dermatitis score: an objective measure using permeability barrier
function and stratum corneum hydration with computer-assisted estimates
for extent of disease. Arch Dermatol. 2003 Nov;139(11):1417-22.
11. Seidenari S, Giusti G. Objective assessment of the skin of children affected by
atopic dermatitis: a study of pH, capacitance and TEWL in eczematous and
clinically uninvolved skin. Acta Derm Venereol. 1995 Nov;75(6):429-33.
12. Elias PM, Wakefield JS. Therapeutic implications of a barrier-based
pathogenesis of atopic dermatitis. Clin Rev Allergy Immunol. 2011 Dec;
41(3):282-95.
13. Elias PM, Wood LC, Feingold KR. Epidermal pathogenesis of inflammatory
dermatoses. Am J Contact Dermat. 1999 Sep;10(3):119-26.
14. Cork MJ, Danby SG, Vasilopoulos Y, et al. Epidermal barrier dysfunction in
atopic dermatitis. J Invest Dermatol. 2009 Aug;129(8):1892-908.
15. Heimall J, Spergel JM. Filaggrin mutations and atopy: consequences for future
therapeutics. Expert Rev Clin Immunol. 2012 Feb;8(2):189-97.
16. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function
variants of the epidermal barrier protein filaggrin are a major predisposing
factor for atopic dermatitis. Nat Genet. 2006 Apr;38(4):441-6.
17. Smith FJ, Irvine AD, Terron-Kwiatkowski A, et al. Loss-of-function mutations
in the gene encoding filaggrin cause ichthyosis vulgaris. Nat Genet. 2006
Mar;38(3):337-42.
18. Hu Z, Xiong Z, Xu X, et al. Loss-of-function mutations in filaggrin gene
associate with psoriasis vulgaris in Chinese population. Hum Genet. 2012 Jul;
131(7):1269-74.
19. Kircik LH, Del Rosso JQ, Aversa D. Evaluating clinical use of a ceramidedominant, physiologic lipid-based topical emulsion for atopic dermatitis. J
Clin Aesthet Dermatol. 2011 Mar;4(3):34-40.
20. Anderson PC, Dinulos JG. Are the new moisturizers more effective? Curr Opin
Pediatr. 2009 Aug;21(4):486-90.
21. Man MQ, Feingold KR, Elias PM. Exogenous lipids influence permeability
barrier recovery in acetone-treated murine skin. Arch Dermatol. 1993 Jun;
129(6):728-38.
22. Man MQ, Brown BE, Wu-Pong S, et al. Exogenous nonphysiologic vs
physiologic lipids. Divergent mechanisms for correction of permeability
barrier dysfunction. Arch Dermatol. 1995 Jul;131(7):809-16.
23. Man MM, Feingold KR, Thornfeldt CR, et al. Optimization of physiological
lipid mixtures for barrier repair. J Invest Dermatol. 1996 May;106(5):1096-101.
24. Yang L, Mao-Qiang M, Taljebini M, et al. Topical stratum corneum lipids
accelerate barrier repair after tape stripping, solvent treatment and some but
not all types of detergent treatment. Br J Dermatol. 1995 Nov;133(5):679-85.
25. Emer JJ, Frankel A, Sohn A, et al. A bilateral comparison study of pimecrolimus
cream 1% and a topical medical device cream in the treatment of patients with
atopic dermatitis. J Drugs Dermatol. 2011 Jul;10(7):735-43.
26. Elias PM, Choi EH. Interactions among stratum corneum defensive functions.
Exp Dermatol. 2005 Oct;14(10):719-26.
27. Sugarman JL, Parish LC. Efficacy of a lipid-based barrier repair formulation
in moderate-to-severe pediatric atopic dermatitis. J Drugs Dermatol. 2009
Dec;8(12):1106-11.
28. Draelos ZD. The effect of ceramide-containing skin care products on eczema
resolution duration. Cutis. 2008 Jan;81(1):87-91.
29. Sawai H, Domae N, Okazaki T. Current status and perspectives in ceramidetargeting molecular medicine. Curr Pharm Des. 2005;11(19):2479-87.
30. Uchida Y, Holleran WM, Elias PM. On the effects of topical synthetic
pseudoceramides: comparison of possible keratinocyte toxicities provoked by
the pseudoceramides, PC104 and BIO391, and natural ceramides. J Dermatol
Sci. 2008 Jul;51(1):37-43.
31. Kang JS, Yoon WK, Youm JK, et al. Inhibition of atopic dermatitis-like skin
lesions by topical application of a novel ceramide derivative, K6PC-9p, in NC/
Nga mice. Exp Dermatol. 2008 Nov;17(11):958-64.
32. Ishikawa J, Shimotoyodome Y, Chen S, et al. Eucalyptus increases ceramide
levels in keratinocytes and improves stratum corneum function. Int J Cosmet
Sci. 2012 Feb;34(1):17-22.
33. Ishida K, Takahashi A, Koutatsu B, et al. The ability of ceramide complex to
reduce erythema and enhance barrier function of atopic skin. Poster #5433
presented at: American Academy of Dermatology 70th Annual Meeting. San
Diego, CA. March 16-20, 2012.
34. Miller DW, Koch SB, Yentzer BA, et al. An over-the-counter moisturizer is
as clinically effective as, and more cost-effective than, prescription barrier
creams in the treatment of children with mild-to-moderate atopic dermatitis:
a randomized, controlled trial. J Drugs Dermatol. 2011 May;10(5):531-7.
35. Eberlein B, Eicke C, Reinhardt HW, et al. Adjuvant treatment of atopic eczema:
assessment of an emollient containing N-palmitoylethanolamine (ATOPA
study). J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.
36. Abramovits W, Alvarez-Connelly E, Breneman D, et al. A double-blind,
randomized, vehicle-controlled trial to determine the efficacy and safety of
hydrocortisone butyrate 0.1% lipocream in the treatment of mild to moderate
atopic dermatitis in pediatric subjects. Poster presented at: 25th Anniversary
Fall Clinical Dermatology Conference. Las Vegas, NV. October 6-9, 2006.
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012
9
Update on Drugs
EDITOR-IN-CHIEF
Stuart Maddin, MD
University of British Columbia, Vancouver, Canada
ASSOCIATE EDITORS
Hugo Degreef, MD, PhD
Catholic University, Leuven, Belgium
Jason Rivers, MD
University of British Columbia, Vancouver, Canada
EDITORIAL ADVISORY BOARD
Murad Alam, MD
Northwestern University Medical School, Chicago, USA
Kenneth A. Arndt, MD
Beth Israel Hospital
Harvard Medical School, Boston, USA
Wilma Fowler Bergfeld, MD
Cleveland Clinic, Cleveland, USA
Jan D. Bos, MD
University of Amsterdam, Amsterdam, Holland
Alastair Carruthers, MD
University of British Columbia, Vancouver, Canada
Bryce Cowan, MD, PhD
University of British Columbia, Vancouver, Canada
Jeffrey S. Dover, MD
Yale University School of Medicine, New Haven, USA
Dartmouth Medical School, Hanover, USA
Boni E. Elewski, MD
University of Alabama, Birmingham, USA
Barbara A. Gilchrest, MD
Boston University School of Medicine, Boston, USA
Christopher E.M. Griffiths, MD
University of Manchester, Manchester, UK
Aditya K. Gupta, MD, PhD
University of Toronto, Toronto, Canada
Mark Lebwohl, MD
Mt. Sinai Medical Center, New York, USA
James J. Leydon, MD
University of Pennsylvania, Philadelphia, USA
Name/Company
CIP-Isotretinoin
The US FDA has approved this novel formulation of isotretinoin
Absorica™
in May 2012 for the treatment of severe recalcitrant nodular
Cipher Pharmaceuticals acne. According to the manufacturer, CIP-isotretinoin is based
on the patented oral Lidose® drug delivery system, which
offers precise, consistent, and uniform dosage delivery with an
absorption characteristic that is stable with or without food
when compared with traditional generic isotretinoin. A major
challenge for existing isotretinoin products is patient adherence,
as the active ingredient should be taken with a high-fat meal
to ensure consistent absorption. Currently available generic
isotretinoin products have an estimated 65% variability in
absorption depending on dietary intake, resulting in inconsistent
dosing and pharmacokinetic implications, which is of particular
concern in teenaged patients. Hence, CIP-istotretinoin was
designed to maintain steady drug absorption throughout the
typical 3- to 5-month course of treatment. Product launch in
the US is expected in Q4 2012 and it is currently under Health
Canada review.
Tazarotene 0.1% foam
Fabior™
Stiefel Laboratories
FDA approval was granted to a novel retinoid formulation in
May 2012 for the topical treatment of acne vulgaris. Therapy
is indicated for acne patients ≥12 years of age. The approval
of tazarotene foam was based on two multicenter, randomized,
double-blind, vehicle-controlled pivotal Phase 3 studies. The
most common side-effects were application site reactions, such
as irritation, dryness, erythema, and exfoliation.
Butoconazole nitrate
2% vaginal cream
Perrigo Company
The FDA approved an abbreviated new drug application for
this antifungal agent in May 2012, which is indicated for the
local treatment of vulvovaginal candidiasis (infections cause
by Candida). It is the generic equivalent of innovator brand
Gynazole-1® (KV Pharmaceuticals).
Andrew N. Lin, MD
University of Alberta, Edmonton, Canada
Harvey Lui, MD
University of British Columbia, Vancouver, Canada
Howard I. Maibach, MD
University of California Hospital, San Francisco, USA
Jose Mascaro, MD, MS
University of Barcelona, Barcelona, Spain
Larry E. Millikan, MD
Tulane University Medical Center, New Orleans, USA
Jean Paul Ortonne, MD
Centre Hospitalier Universitaire de Nice, Nice, France
Jaggi Rao, MD
University of Alberta, Edmonton, Canada
Ted Rosen, MD
Device News
Baylor College of Medicine, Houston, USA
Alan R. Shalita, MD
SUNY Health Sciences Center, Brooklyn, USA
Wolfram Sterry, MD
Humboldt University, Berlin, Germany
Richard Thomas, MD
University of British Columbia, Vancouver, Canada
Stephen K. Tyring, MD, PhD
University of Texas Health Science Center, Houston, USA
John Voorhees, MD
University of Michigan, Ann Arbor, USA
Multisource
radiofrequency
aesthetic device
Glow by EndyMed™
EndyMed Medical Ltd
Eclipse Aesthetics
The FDA cleared this aesthetic device in May 2012 for the
reduction of mild to moderate facial wrinkles and fractional
radiofrequency (RF) skin resurfacing. Two versions are
available: one with a non-ablative multisource RF dermal
heating handpiece and the other with a multisource fractional
RF skin resurfacing (FSR) handpiece. This system utilizes
3DEEP™ technology, a multisource, phase-controlled RF energy
source and advanced software to control the phase of the energy
flowing between the handpiece electrodes.
Low-level laser for
circumferential upper
arm reduction
Zerona®
Erchonia Medical
The FDA granted 510(k) clearance to market this bodycontouring laser treatment in June 2012 for the non-invasive
reduction of arm circumference by emitting low-level (or
cold) output energy that does not generate a thermal effect on
body tissues. The device is a monochromactic semiconductor
diode laser that emits 5 independent 635 nm divergent beams.
A blinded and controlled clinical study showed that Zerona®
laser demonstrated a statistically significant difference in
circumference reduction, which was sustained 7.6 months
post-treatment, as compared with a placebo laser. Subjects who
received Zerona® laser therapy experienced approximately 4 cm
reduction in the circumference of their arms without dieting,
exercising or nutritional supplementation.
Guy Webster, MD
Jefferson Medical College, Philadelphia, USA
Klaus Wolff, MD
University of Vienna, Vienna, Austria
Skin Therapy Letter © (ISSN 1201–5989) Copyright 2012 by
SkinCareGuide.com Ltd. Skin Therapy Letter © is published 10 times
annually by SkinCareGuide.com Ltd, 1004 – 750 West Pender, Vancouver,
British Columbia, Canada, V6C 2T8. All rights reserved. Reproduction in
whole or in part by any process is strictly forbidden without prior consent of
the publisher in writing. While every effort is made to see that no inaccurate
or misleading data, opinion, or statement appears in the Skin Therapy
Letter ©, the Publishers and Editorial Board wish to make it clear that the
data and opinions appearing in the articles herein are the responsibility
of the contributor. Accordingly, the Publishers, the Editorial Committee
and their respective employees, officers, and agents accept no liability
whatsoever for the consequences of any such inaccurate or misleading
data, opinion, or statement. While every effort is made to ensure that drug
doses and other quantities are presented accurately, readers are advised
that new methods and ­techniques involving drug usage, and described
herein, should only be followed in conjunction with the drug manufacturer’s
own published literature. Printed on acid-free paper effective with Volume
1, Issue 1, 1995.
Subscription Information. Annual subscription: Canadian $94 individual; $171 institutional (plus GST); US $66 individual; $121 institutional. Outside North America: US$88 individual; $143 institutional.
We sell reprints in bulk (100 copies or more of the same article). For
individual reprints, we sell photocopies of the articles. The cost is $20
to fax and $15 to mail. Prepayment is required. Student rates available
upon request. For inquiries: [email protected]
10
Approval Dates/Comments
• Editor: Dr. Stuart Maddin • Volume 17, Number 7 • July-August 2012