Download Antibiotic Resistance in Acne Treatment

Volume 17 • Number 9 • October 2012
Indexed by the US National Library of Medicine and PubMed
Antibiotic Resistance in Acne Treatment
Shannon Humphrey, MD, FRCPC, FAAD
Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
ABSTRACT
Propionibacterium acnes (P. acnes) is an anaerobic bacteria implicated in the pathogenesis of acne. The last 30 years have
witnessed an alarming increase in resistance to antibiotics commonly employed to treat acne. Antibiotic resistance in acne represents
a significant international public health concern because resistance can occur in more pathogenic bacteria than P. acnes, and an
increase in pathogenic P. acnes has been reported. Current treatment guidelines offer strategies to limit the potential for resistance
while achieving optimal outcome in the management of inflammatory and non-inflammatory acne.
Key words: acne vulgaris, antibacterial agents, antibiotic resistance, benzoyl peroxide, topical combination therapy
Antibiotic Resistance in Acne Therapy
Propionibacterium acnes (P. acnes) is an anaerobic bacteria
implicated in the pathogenesis of acne vulgaris. There are four
primary pathogenic factors: excess sebum production, bacterial
colonization, inflammation, and abnormal keratinization. 1
Treatment targets as many pathogenic factors as possible and
may include a combination of topical and systemic agents.
Although current acne guidelines discourage the use of antibiotics
as prolonged monotherapy,1 about 5 million prescriptions for
oral antibiotics are written each year for the treatment of acne.2
Antibiotics demonstrate anti-inflammatory and antimicrobial
effects and work on two levels: to decrease the presence of
P. acnes – a resident of the normal microflora found in abnormally
high numbers in the sebaceous follicles of patients with acne and
a primary factor in the development of inflammatory acne3 – and
to inhibit the production of P. acnes-associated inflammatory
mediators.4 Indeed, topical and oral antibiotics have been the
mainstay of acne treatment for over 50 years.
In 1976, there was no evidence of antibiotic-resistant
propionibacteria on the skin of over 1000 patients with acne.5 By
1979, Crawford and colleagues had detected the first indication of
resistance to topical erythromycin and clindamycin,6 which was
followed by the emergence of tetracycline-resistant P. acnes in the
early eighties.7 Since then, the incidence of antibiotic resistance
in acne has continued to rise across the globe, from 20% in 1978
to 72.5% in 1995,8 with combined resistance to erythromycin
and clindamycin more prevalent than resistance to tetracycline.9
Evidence suggests that it is the use of topical erythromycin and
clindamycin – the most commonly used topical antibiotics in
acne – that has contributed to the gradual increase in resistance
over the last 20 years.7,8,10-12 In fact, resistant P. acnes strains have
been shown to emerge after only 8 weeks of topical antibiotic
monotherapy, with the number of resistant strains increasing
progressively over subsequent weeks.13
Evidence of Clinical Relevance
Acne does not represent a typical bacterial infection, in
which antibiotic resistance directly correlates to treatment
failure, because antibiotics demonstrate both antibacterial
and anti-inflammatory effects, and P. acnes – existing in the
microaerophilic or anaerobic and lipid-rich environment of the
pilosebaceous follicle – cannot easily be cultured. However, it is
logical to assume that resistance manifests with a reduced clinical
response, and this theory is substantiated by the results of several
investigations linking resistant strains to higher counts of P. acnes
and therapeutic failure.7,10,14,15 A systematic review of 50 clinical
trials using topical antibiotics between 1974 and 2003 paints a
startling picture: a significant decrease in the efficacy of topical
erythromycin on inflammatory and non-inflammatory lesions
over time (Figure 1).16
The question remains: what does it matter? While it is true that
that the prevalence of life-threatening infections caused by
P. acnes has greatly increased in the last twenty-odd years,17 most
often in the post-surgical setting in patients with significant
medical comorbidities,18 acute propionibacterial infections
are never treated with acne medication. Furthermore, it would
seem that antibiotic-resistant acne puts neither patients nor the
community at risk for resistant propionibacterial infections.
Resistance in Pathogenic Organisms
Prolonged regimens using either topical or oral antibiotics for
the treatment of acne have resulted in selection pressure or the
transfer of resistant genes to potentially pathogenic bacteria,
such as certain strains of staphylococci or streptococci,4,6 and it
is these resistant organisms that could present clinical challenges.
ALSO IN THIS ISSUE: Device-Based Therapies for Onychomycosis Treatment (page 4) & Update on Drugs (page 10)
The implications are potentially serious. S. epidermidis has
been found to be pathogenic in certain patients, predominantly
those with indwelling catheters, surgical patients, or premature
infants.23-25 More ominously, CNS has been shown to transfer
resistance to the more pathogenic S. aureus, 26 which tends
to thrive and disseminate more widely in conjunction with
topical antibiotic therapy. In a 24-week randomized trial of
2% erythromycin gel versus its vehicle, antibiotic therapy led to
an increase from 15% to 40% in erythromycin-resistant S. aureus
carriage rates in the nose, and resistance increased significantly
and substantially in the treated group versus patients receiving
vehicle (63% vs. 37%) by the end of the treatment period.22
For all the potentially pathogenic organisms that develop
resistance to anti-acne antibiotics, the question remains: does
it really matter? Physicians are unlikely to treat S. epidermidis
or group A streptococcus with acne medication. However,
consider this: first-line systemic agents for community-acquired
methecillin-resistant S. aureus (MRSA) include minocycline
and trimethoprim-sulfamethoxazole, both of which are used
for the treatment of acne. Thus far, resistance to minocycline is
not common; the same cannot be said about trimethoprim.27
As multi-drug-resistant organisms emerge, therapeutic options
continue to shrink.
Antibiotic Resistance in Acne Treatment: Evidence of Clinical Relevance
Figure 1: Impact on acne: efficacy of topical erythromycin
over time (empty circles: studies evaluating treatment
efficacy after 8 weeks; asterisks: studies evaluating treatment
efficacy after 12 weeks).
Figure from Simonart T, Dramaix M., Treatment of acne with topical
antibiotics: lessons from clinical studies. Br J Dermatol. 2005 Aug;153(2):page
399, Figure 1. Reprinted with permission from John Wiley and Sons.
Levy and colleagues investigated the effects of topical and/or oral
antibiotics on the oropharyngeal flora in patients with acne.19
Patients treated with any antibiotic exhibited a 3-fold greater risk
of group A streptococcus colonization by Streptococcus pyogenes
(S. pyogenes) compared to patients not using antibiotic therapy.
Eighty-five percent of S. pyogenes cultures from those using
antibiotics were resistant to at least one tetracycline antibiotic,
compared to 20% from those not using antibiotics.
A subgroup analysis of topical versus oral antibiotics found
similar prevalence rates, indicating that topical antibiotics have
an impact on distant flora and resistance patterns by direct
inoculation or systemic absorption. Like their oral counterparts,
topical antibiotics may alter the microbial equilibrium through
selective elimination of certain bacteria, allowing species like
S. pyogenes, which would normally be held in check, to flourish.19
Studies have clearly demonstrated that the use of topical
erythromycin increases counts of resistant coagulase-negative
staphylococci (CNS) on both local and distant anatomical
sites.20-22 Harkaway and colleagues demonstrated aerobic flora
dominated by Staphylococcus epidermidis (S. epidermidis)
completely resistant to erythromycin and partially resistant to
clindamycin and tetracycline after 12 weeks of treatment.20 Vowels
and colleagues found that the prevalence and density of resistant
organisms persisted and did not return to baseline values until
6 weeks after discontinuation of topical antibiotic therapy.21
2
• Reduced clinical response to antibiotic therapy
• Potential increase in pathogenicity of P. acnes
• Transfer of resistance to more pathogenic organisms
Strategies to Limit Resistance
Since prescribing practice patterns directly influence the rates of
P. acnes resistance in the population (i.e., the levels of resistance
correlate to the levels of antibiotic use), and since selection
pressure may affect more pathogenic bacteria than P. acnes, it
makes sense to implement strategies and guidelines to limit
antibiotic resistance.1 The Global Alliance to Improve Outcomes
in Acne guidelines recommend the combination of a topical
retinoid plus an antimicrobial agent as first-line therapy for most
patients with acne.1 When antibiotics are indicated, the guidelines
recommend strategies to limit resistance, including the use of
oral antibiotics only in moderate and moderately severe cases of
acne, and the necessary addition of benzoyl peroxide (BPO) and a
topical retinoid to regimens using topical antibiotics in mild-tomoderate cases.
Strategies to Limit Antibiotic Resistance in Acne
•
•
•
•
•
Avoid topical or oral antibiotics as monotherapy or maintenance therapy
Limit duration of antibiotic use and assess response at 6 to 12 weeks
Use concomitant BPO (leave-on or wash)
Avoid simultaneous use of oral and topical antibiotics without BPO
Use topical retinoid +/- BPO as maintenance in lieu of antibiotics
Evidence suggests that BPO, alone or in combination with a topical
retinoid, may serve as an effective and well tolerated option for
treating acne in patients with resistant P. acnes, while minimizing
the development of further antibiotic resistance. Topical retinoids
exhibit both anti-inflammatory and anticomedonal activities11
and are highly effective in reducing both inflammatory and non-
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
inflammatory lesions.28,29 BPO is a broad-spectrum antibacterial
agent that comes in many formulations and works through the
interaction of oxidized intermediates with various constituents of
microbial cells.30 Despite its widespread use, bacterial resistance
has not been reported.
Leave-on products containing BPO not only suppress
existing insensitive strains, but also reduce the emergence
of erythromycin- and clindamycin-resistant strains during
antibiotic therapy.13,15,30-35 Moreover, the concomitant use of
BPO with a topical antibiotic is highly effective in reducing the
colony counts of cutaneous P. acnes.20,33,36 Even simple washes
containing BPO effectively reduce P. acnes,11,37 including resistant
populations.39 Leyden and colleagues assessed the effectiveness
of a gel combination treatment containing 0.1% adapalene and
2.5% BPO in healthy patients with high P. acnes populations
resistant to erythromycin, tetracycline and clindamycin, and
found a significant reduction in resistant strains by week 4.12
Indeed, therapy with a combination of adapalene and BPO
eradicated some resistant strains entirely in some patients.
Subantimicrobial Dosing
There is some evidence that subantimicrobial doses of antibiotics
may reduce inflammation and provide immunomodulatory
effects without risk of any resistance. Doxycycline is a secondgeneration tetracycline class antibiotic normally used at a dose
of 100 mg to 200 mg/day in the treatment of acne. Skidmore
randomized 51 patients with moderate acne to twice daily
20 mg doses of doxycycline or placebo for 6 months.39 Active
treatment significantly reduced the number of inflammatory
and non-inflammatory lesions by more than 50% and led to
a greater overall improvement compared to placebo, with no
change in number or severity of resistant pathogens or evidence
of antimicrobial effect on the skin flora. Toossi and colleagues
compared subantimicrobial doses (20 mg twice daily) with
antimicrobial doses (100 mg daily) in a prospective, double-blind,
randomized controlled trial of 100 patients with moderate facial
acne.40 Both treatments significantly decreased inflammatory
lesion counts; subantimicrobial dosing led to an 84% and 90%
reduction in the number of papules and pustules, respectively.
Although more rigorous trials designed to study the impact on
follicular and cutaneous microflora and resistance patterns are
warranted, these early results are promising and may represent a
future possibility for the management of acne vulgaris.
Conclusion
Although antibiotics play an important role in acne management,
the increase in P. acnes resistance should be cause for concern
and serve as the impetus for change in prescribing patterns
and treatment algorithms. Not only are resistant strains linked
to lack or worsening of clinical response to treatment, but the
pathogenicity of P. acnes has increased over recent years, and
most importantly prolonged regimens of antibiotic therapy have
led to the transfer of resistance among non-targeted pathogenic
bacteria. Limiting the frequency and duration of antibiotic use
and adding the topical antimicrobial agent BPO will minimize
the development of resistance while maintaining efficacy in the
treatment of inflammatory and non-inflammatory acne lesions.
References
1. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of
acne: an update from the Global Alliance to Improve Outcomes in Acne group.
J Am Acad Dermatol. 2009 May;60(5 Suppl):S1-50.
2. Stern RS. Medication and medical service utilization for acne 1995-1998. J Am
Acad Dermatol. 2000 Dec;43(6):1042-8.
3. Webster GF. Acne vulgaris. BMJ. 2002 Aug 31;325(7362):475-9.
4. Leyden JJ, Del Rosso JQ, Webster GF. Clinical considerations in the treatment
of acne vulgaris and other inflammatory skin disorders: focus on antibiotic
resistance. Cutis. 2007 Jun;79(6 Supp™l):9-25.
5. Leyden JJ. Antibiotic resistant acne. Cutis. 1976 Mar;17(3):593-606.
6. Crawford WW, Crawford IP, Stoughton RB, et al. Laboratory induction and
clinical occurrence of combined clindamycin and erythromycin resistance in
Corynebacterium acnes. J Invest Dermatol. 1979 Apr;72(4):187-90.
7. Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance
to antibiotics in acne patients. J Am Acad Dermatol. 1983 Jan;8(1):41-5.
8. Cooper AJ. Systematic review of Propionibacterium acnes resistance to
systemic antibiotics. Med J Aust. 1998 Sep 7;169(5):259-61.
9. Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from
Europe. Br J Dermatol. 2003 Mar;148(3):467-78.
10. Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria
in antibiotic treated acne patients: association with therapeutic failure. Br J
Dermatol. 1989 Jul;121(1):51-7.
11. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from
a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol. 2003
Jul;49(1 Suppl):S1-37.
12. Leyden JJ, Preston N, Osborn C, et al. In-vivo effectiveness of adapalene
0.1%/benzoyl peroxide 2.5% gel on antibiotic-sensitive and resistant
Propionibacterium acnes. J Clin Aesthet Dermatol. 2011 May;4(5):22-6.
13. Cunliffe WJ, Holland KT, Bojar R, et al. A randomized, double-blind comparison
of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching
clindamycin gel with respect to microbiologic activity and clinical efficacy in
the topical treatment of acne vulgaris. Clin Ther. 2002 Jul;24(7):1117-33.
14. Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide
problem. Dermatology. 2003;206(1):54-6.
15. Ozolins M, Eady EA, Avery AJ, et al. Comparison of five antimicrobial
regimens for treatment of mild to moderate inflammatory facial acne
vulgaris in the community: randomised controlled trial. Lancet. 2004 Dec
18-31;364(9452):2188-95.
16. Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons
from clinical studies. Br J Dermatol. 2005 Aug;153(2):395-403.
17. Jakab E, Zbinden R, Gubler J, et al. Severe infections caused by
Propionibacterium acnes: an underestimated pathogen in late postoperative
infections. Yale J Biol Med. 1996 Nov-Dec;69(6):477-82.
18. Oprica C, Nord CE. European surveillance study on the antibiotic susceptibility
of Propionibacterium acnes. Clin Microbiol Infect. 2005 Mar;11(3):204-13.
19. Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal
flora in patients with acne. Arch Dermatol. 2003 Apr;139(4):467-71.
20. Harkaway KS, McGinley KJ, Foglia AN, et al. Antibiotic resistance
patterns in coagulase-negative staphylococci after treatment with topical
erythromycin, benzoyl peroxide, and combination therapy. Br J Dermatol. 1992
Jun;126(6):586-90.
21. Vowels BR, Feingold DS, Sloughfy C, et al. Effects of topical erythromycin on
ecology of aerobic cutaneous bacterial flora. Antimicrob Agents Chemother.
1996 Nov;40(11):2598-604.
22. Mills O, Jr., Thornsberry C, Cardin CW, et al. Bacterial resistance and
therapeutic outcome following three months of topical acne therapy with 2%
erythromycin gel versus its vehicle. Acta Derm Venereol. 2002;82(4):260-5.
23. Lowy FD, Hammer SM. Staphylococcus epidermidis infections. Ann Intern
Med. 1983 Dec;99(6):834-9.
24. Gemmell CG. Coagulase-negative staphylococci. Med Microbiol. 1986
Dec;22(4):285-95.
25. Stillman RI, Wenzel RP, Donowitz LC. Emergence of coagulase negative
staphylococci as major nosocomial bloodstream pathogens. Infect Control.
1987 Mar;8(3):108-12.
26. Naidoo J, Noble WC. Skin as a source of transferable antibiotic resistance in
coagulase-negative staphylococci. Zentralblatt Bakt Suppl. 1987;16:225-34.
27. Eady EA, Jones CE, Gardner KJ, et al. Tetracycline-resistant propionibacteria
from acne patients are cross-resistant to doxycycline, but sensitive to
minocycline. Br J Dermatol. 1993 May;128(5):556-60.
Continued on page 9
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
3
Device-Based Therapies
for Onychomycosis Treatment
Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC1,2 and Fiona Simpson, HBSc2
Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
2
Mediprobe Research Inc., London, ON, Canada
1
ABSTRACT
Device-based therapies are promising alternatives for the treatment of onychomycosis because they can mitigate some of the negative
factors associated with treatment failure. There are four categories of device-based treatments: laser devices, photodynamic therapy,
iontophoresis, and ultrasound. These therapeutic modalities are noninvasive procedures that are carried out by medical professionals,
reduce the need for long-term patient adherence, and avoid adverse reactions associated with conventional systemic antifungal
therapies.
Key words: antifungal, iontophoresis, laser devices, nails, onychomycosis, photodynamic therapy, ultrasound
Introduction
Onychomycosis is a common nail disorder that faces significant
barriers to successful treatment. Etiologically, fungal pathogens
such dermatophyte fungi, yeasts, and non-dermatophyte molds
invade and colonize the nail plate, bed, and matrix creating an
entrenched infection.1-10 The prevalence of onychomycosis is
estimated at 2-8% of the global population. A number of medical
conditions can also confer an increased risk of co-morbid
onychomycosis infection including diabetes,11 peripheral vascular
disease,11 HIV,12 immunosupression,13,14 obesity,15 smoking,11
and increased age.14 Many individuals have sustained infections
persisting for months or years and, hence, they may not be
motivated to initiate or complete therapy due to a perception that
their condition is untreatable.
Onychomycosis has traditionally been treated by oral and
topical antifungals16 that often yield low to moderate efficacy.
Even when pharmacotherapy initially results in a mycological
cure, the relapse and/or reinfection rate ranges between
16-25%.17,18 Successful treatment for onychomycosis requires
antifungal drugs to penetrate the nail plate and nail bed, but
incomplete dissemination to the lesion is a problem for both
oral and topical agents. Antifungal drugs may be associated
with adverse events that can cause patients to discontinue
treatment and therapy may be complicated with the presence
of a co-morbid condition.19,20 Additionally, the extended course
of treatment may discourage patient compliance, which poses a
significant detriment to effective therapy. Thus, these factors can
contribute to the suboptimal delivery of conventional therapy for
onychomycosis.
Device-based therapies are promising solutions for the
treatment of onychomycosis because they can mitigate some of
the negative factors that contribute to treatment failure. There
are four categories of device-based treatments: laser devices,
photodynamic therapy, iontophoresis and ultrasound. Each
of these techniques is a noninvasive procedure conducted by
a medical professional, which reduces the need for long-term
4
patient compliance. Photodynamic therapy, iontophoresis and
ultrasound are used in combination with local pharmacological
agents, thereby avoiding adverse effects associated with systemic
antifungal therapy.
Laser Therapy
Laser treatment of onychomycosis infections uses the principle
of selective photothermolysis.21,22 Laser therapy is intended to
exploit the differences in laser energy absorption and thermal
conductivity between the fungal infection and the surrounding
tissue. The absorption of light energy by the fungi results in the
conversion of the energy into heat or mechanical energy.21,22
Fungi are heat sensitive above 55°C, so absorption of laser energy
that results in sustained photothermal heating of the mycelium
(10+ minutes) is likely to result in fungicidal effects.23,24 However,
heating dermal tissue to temperatures above 40°C results in pain
and necrosis; therefore, the laser energy format must either be
pulsed to allow the dissipation of heat by the tissue through its
superior thermal conduction or delivered at a moderate energetic
level to prevent tissue damage. The exact mechanism of laser
therapy is still under investigation, but it may combine direct
fungicidal effects of the laser with induced modifications in the
immune system or changes in the local microenvironment.
Laser therapy for onychomycosis is currently being studied
in vitro and in vivo. In addition, at the time of this writing, the
following lasers have been granted FDA marketing approval
for the treatment of onychomycosis: PinPointe™ FootLaser™
(PinPointe USA, Inc.),25 Cutera GenesisPlus™ (Cutera, Inc.),26
Q-Clear™ (Light Age, Inc.),27 CoolTouch VARIA™ (CoolTouch,
Inc.),28 and JOULE ClearSense™ (Sciton, Inc.).29 The parameters
of lasers that have been FDA cleared or tested and supported by
publications for onychomycosis are summarized in Table 1. It is
important to note that regulatory clearance of device systems are
made on the basis of “substantial equivalence” to the technical
specifications of pre-existing devices approved for marketing for
onychomycosis, not on the basis of clinical trials data, so these
systems cannot be directly compared to pharmacologic therapies.
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
4
Solid State Lasers
Solid state lasers use a solid crystal rod and they include many of
the common commercial lasers such as the neodymium-doped
yttrium aluminum garnet (Nd:YAG) and titanium sapphire
(Ti:Sapphire) lasers. Solid state lasers may be built for use as
continuous lasers or as pulsed lasers with pulse durations in
the millisecond, microsecond, nanosecond, or femtosecond
ranges. The maximum pulse energy increases as the pulse length
decreases, so different pulse formats may result in greater nonspecific heating of the nail plate, or require longer treatment
lengths to produce a fungicidal effect. The lasers that have been
approved for the treatment of onychomycosis in North America
have all been Nd:YAG lasers.
cooling.31 The nail plate was treated in a spiral pattern. A 2 minute
wait period was observed before repeating the laser treatment.31
Participants received 4 treatments at 1 week intervals and they
were followed after therapy from 12-30+ months. A completely
clear nail plate was achieved by 93.5% of participants.32 The
Fotona Dynamis™ family of laser systems has the same technical
parameters as the laser used in the studies described above and
has received marketing clearance in Europe.
Short Pulse Laser Systems
The first two lasers that were sanctioned by the FDA for the
treatment of onychomycosis (PinPointe™ FootLaser™ and
Cutera GenesisPlus™) are both flashlamp pumped short pulse
Nd:YAG 1064 nm lasers.25,26 The CoolTouch VARIA™ laser is the
most recent addition to this class of devices.28 These lasers emit
100-3000 μs pulses with an energy fluence of 25.5 J/cm2 for a
1 mm spot size.25,26,28 The PinPointe™ FootLaser™ was used
in an initial phase I/II clinical trial.33 Seventeen participants
demonstrating great toenails afflicted with onychomycosis
were enrolled and randomized into treated (n=11) or untreated
(n=6) groups. Participants received a single treatment and were
followed-up at 3 and 6 months. At the 6 month time period, 11 of
14 treated toes showed improvement in clear linear nail growth.
Clinicaltrials.gov reports that a phase III clinical trial for the
PinPointe™ laser (NCT00935649) was completed on November
29, 2010, but the data from this study remains unpublished. 34
Cutera has released a white paper on the GenesisPlus™ laser35 that
reported a 70% improvement rate in the 7 participants treated
Long Pulse Laser Systems
Long pulse Nd:YAG lasers have received CE Marking in Europe
(the mandatory conformity designation for marketed products
in the European Economic Area), but they have not yet been
approved to treat onychomycosis in North America.30 The pulse
duration for these lasers is in the millisecond range. These lasers
can cause a high degree of non-specific heating and may need to
be operated in the presence of a dedicated cooling system. The
largest study of millisecond Nd:YAG lasers was conducted using
the Fotona Dualis SP™ laser on 162 participants in Serbia.31,32
Fungal infections in both fingernails and toenails were identified
by potassium hydroxide (KOH) microscopy.31 Participants were
treated with a 30-40 J/cm2 energy fluence with a spot size of
4 mm and a pulse duration of 35 ms in the presence of cold air
Laser System
Type of Laser
Wavelength
(nm)
Energy
Fluence
(J/cm2)
Spot
Size
(mm)
Pulse
Length
Pulse
Frequency
(Hz)
International
Approvals for
Onychomycosis
Dualis SP™, Fotona
PinPointe™ FootLaser™,
Nuvolase
GenesisPlus™, Cutera
VARIA™, CoolTouch
LightPod® Neo™,
Aerolase
JOULE ClearSense™,
Sciton
Q-Clear™, Light Age
Q-switched Nd:YAG
laser, Surgical Laser
Technology
CoolTouch CT3 Plus™,
CoolTouch
Mira® 900,
Coherent Laser Group
Noveon®, Nomir
Medical Technologies
V-Raser®,
ConBio/Cynosure
Long pulse Nd:YAG
Short pulse Nd:YAG
1064
1064
35-40
25.5
4
2.5
35 ms
100-3000 µs
1
1
Short pulse Nd:YAG
Short pulse Nd:YAG
Short pulse Nd:YAG
1064
1064
1064
16
223
5
2
300 µs
600 µs
650 µs
2
-
EU
US, Canada, EU,
Australia
US, Canada, EU
US, EU
-
Short pulse Nd:YAG
1064
13
-
0.3-200 ms
6
US
Q-switched Nd:YAG
Q-switched Nd:YAG
1064
532, 1064
4-12
2-10
2.5-6
2
3-10 ns
-
1-5
10
US
-
Short pulse Nd:YAG
1320
-
2-10
450 µs
-
EU
Modelocked
Ti:Sapphire
Diode
800
0.120.45
15
200 fs
76 MHz
-
870, 930
1031 to
1033 m-2 s-1
212/424
-
-
EU
Diode
980
-
-
-
-
-
Table 1: Laser device systems
(-) = data unavailable; EU = European Union; US = United States
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
5
with 2 sessions of laser therapy. The JOULE ClearSense™ laser
was tested in an initial trial of 21 patients.36 Onychomycosis was
confirmed by culture and periodic-acid schiff (PAS) microscopy.
Patients were treated 4 times, at 1 week intervals with a pulse
length of 0.3 ms, an energy fluence of 13 J/cm2, and a repetition
rate of 6 Hz. Follow-up mycological culture was negative in 95%
of patients.36 Clinical trials data for the CoolTouch™ laser has not
yet been released.
An additional clinical study was published by Hochman et
al. using a short pulse Nd:YAG laser system that has not been
FDA cleared for onychomycosis.37 This study confirmed active
fungal infections in toenails and fingernails by culture or PAS
stain. Participants were treated with a 223 J/cm2 energy fluence
with a 2 mm spot size for ≤45 seconds. Each subject received
2-3 treatments spaced at least 3 weeks apart. Antifungal cream
was used daily where anatomically possible during this study. The
efficacy of treatment was followed for between 4-6 months after
therapy. Treatment resulted in negative mycological culture in
7 of 8 participants.
CoolTouch, Inc. is also conducting a clinical trial with a 1320 nm
Nd:YAG laser (NCT01498393).38 The CoolTouch CT3 Plus™ with
the CoolBreeze Zoom handpiece can be operated in short pulse
(450 μs) or continuous mode.39 The handpiece has a pre-set
temperature threshold that employs a cryogen cooling system.40
Duration of the trial is 6 months and the inclusion criteria require
patients to have a fungal infection on both great toenails.
Q-switched Laser Systems
Q-switched lasers have a pulse duration in the nanosecond range
and they emit the highest peak power per pulse of all the Nd:YAG
lasers. In vitro, an energy fluence of 4 J/cm2 optimally inhibited
Trichophyton rubrum (T. rubrum) colony growth.41 The Light Age
Q-Clear™ is a FDA-cleared Q-switched Nd:YAG 1064 nm laser.27
The FDA 510(k) summary for this laser device states that “Light
Age, Inc.’s study of 100 randomized subjects of both genders,
including Caucasian, Asian, African American, and Latino, has
demonstrated substantially effective clearance of dystrophic
toenails having a clinically apparent diagnosis of onychomycosis.
Statistical analysis of results indicates significant apparent
clearing in 95% of the subjects with an average clearance of
affected areas of 56 ± 7% at 98% level of confidence.”27
Modelocked Laser Systems
A modelocked femtosecond pulsed Ti:Sapphire laser tuned to
800 nm was used in an in vitro study on T. rubrum.42 Nail
clippings were obtained from participants with onychomycosis
and the fungal infection was confirmed by culture (n=99). The
cultures were irradiated with a Ti:Sapphire laser that was pumped
by a solid-state laser, which emitted 200 fs pulses at a frequency of
76 MHz through a variety of numerical apertures from 0.12 to
0.45. Treatment with energy above 7x1031 photons m-2 s-1 resulted
in a 100% fungicidal effect.
Near Infrared Diode Lasers
Diode lasers use semiconductors for the optical gain medium as
an alternative to solid crystals. The diode lasers that are currently
under investigation for onychomycosis operate at near infrared
wavelengths. The Noveon® laser (Nomir Medical Technologies)
is an 870 nm and 930 nm dual wavelength diode laser.43
In vitro studies have shown that 870 nm and 930 nm wavelengths
6
photoinactivate T. rubrum and Candida albicans, and have a
minimal negative effect on cultured fibroblasts.44 Preliminary
trials for the Noveon® laser have been conducted.42 Distal and
lateral subungual onychomycosis was confirmed by culture or
PAS stain and each participant received 4 treatments on days
1, 14, 42 and 120. Each treatment comprised 4 minutes of dual
wavelength therapy, followed by 2 minutes of 930 nm treatment.
At 180 days, the participants showed an 85% improvement of
infection in 26 toes treated.43 The status of the phase II and II/III
trials for the Noveon® laser in onychomycosis (NCT00771732 and
NCT00776464) remains unknown.45,46
ConBio Inc. has registered a single assignment, open label
clinical trial (NCT01452490) for a near infrared diode laser.47
The V-Raser® laser is a 980 nm near infrared diode laser that has
previously been marketed for the removal of vascular lesions. The
study aims to enroll 50 participants at two podiatric practices in
the United States. Participants will receive 4 laser treatments at
6 week intervals.47
Photodynamic Therapy
Photodynamic therapy (PDT) uses visible spectrum light
to activate a topically applied photosensitizing agent, which
generates reactive oxygen species that initiate apoptosis.
Photodynamic therapy was originally optimized for actinic
keratosis, but photosensitizers can also be absorbed by fungi.48,49
The effects of various photosensitizing agents have been
studied in vitro and in vivo. These include 5-aminolevulinic
acid (ALA), methyl aminolevulinate (MAL), and 5,10,15-tris
(4-methylpyridiuium)-20-phenyl-[21H,23H]-porphine
trichloride (Sylsens B).
Heme Biosynthesis Intermediates - ALA and MAL
ALA and its methyl ester MAL are heme precursors. They
cause a build-up of protoporphyrin IX (PpIX), which is a
photodynamically active molecule. In the presence of the correct
spectrum of light, PpIX generates reactive oxygen species that
initiate apoptosis.50 Both of these drugs are commercially available
for the treatment of actinic keratosis. Several studies have
tested these formulations in small studies on participants with
onychomycosis (Table 2).51-54 These studies are heterogeneous,
preventing any form of direct comparison; however, these
investigations have shown promising initial results, but their
small sample sizes (n<30) limit our ability to draw conclusions
on the efficacy of this mode of therapy. The protocols developed
for these studies indicate that the nail plate should be pre-treated
with urea ointment to soften the nail plate prior to application of
the photosensitizer.
Non-Heme Porphyrins - Sylsens B
Sylsens B is a non-heme porphyrin that has been used for
in vitro studies on T. rubrum. PDT with Sylsens B is fungicidal
in T. rubrum suspensions of both hyphae and microconidia at
concentrations above 10 µM.49,55,56 PDT with Sylsens B is also
fungicidal when T. rubrum is adhered to keratinized structures.57
In vitro experiments determined that ultraviolet-A (UVA-1)
light is fungicidal in commercial strains and clinical isolates of
T. rubrum, so it was an ideal excitatory light source for PDT.58
The clinically isolated strain required a higher dose of Syslens B
(9 µM) than the commercial strain (1 µM) using a UVA-1 energy
fluence of 18 J/cm2.58 Sylsens B has not yet been tested in vivo.
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
Study Parameters
Number of Patients
Age
Diagnosis of Infection
Type of Infection
Pre-treatment
Length of Pretreatment
Photosensitizer
Length of Treatment
Irradiation Source
Length of Irradiation
Number of Treatments
Treatment Interval
Follow-up Period
Mycological Cure Rate
Complete Cure Rate
Watanabe et al.
200851
Piraccini et al.
200852
Sotiriou et al.
201053
Gilaberte et al.
201154
2
31-80
KOH microscopy and
culture
-
1
78
KOH microscopy and
culture
T. rubrum
30
41-81, mean 59.6
Microscopy and
culture
-
20% urea ointment
10 hours
20% MAL
5 hours
630 nm laser 100 J/cm2
1
N/A
6 months
100%
100%
40% urea ointment
7 days
16% MAL
3 hours
630 nm 36 J/cm2
7 min 24 sec
2
15 days
24 months
100%
0%
20% urea ointment
10 consecutive nights
20% ALA
3 hours
570-670 nm 40 J/cm2
3
2 weeks
18 months
43%
36.6%
2
44-60
Confirmed, technique
unspecified
Fusarium oxysporum,
Aspergillus terreus
40% urea ointment
12 hours
16% MAL
4 hours
635 nm 37 J/cm2
3
2 weeks
6 months
100%
100%
Table 2: In vivo studies of ALA and MAL PDT
(-) = data unavailable
Iontophoresis
Iontophoresis is a technique that uses a low level electrical current
to increase the transport of drugs across semi-permeable barriers.
The limitation of many topical treatments for onychomycosis is
their inability to fully penetrate the nail plate.59 This technique
may be more successful in incorporating the drug into the nail
plate and passing it through the plate to ensure that it penetrates
the nail bed and matrix. Iontophoresis is currently being
optimized for terbinafine, because it has the highest antifungal
effect on dermatophytes in vitro.60 There are two iontophoresis
devices currently in clinical trials.
Iontophoresis increases the amount of terbinafine accumulated in
the nail plate over the uptake from a passive source.61-67 The nail
plate then acts as a reservoir of terbinafine that is then released
into the nail bed and matrix over 60-70 days. 62-65,67 The drug
uptake during iontophoresis can be enhanced after removal of the
dorsal layer of the nail plate, or in the presence of keratolysis.64
The devices by NB Therapeutics were effective at targeting the
nail plate exclusively and both the nail plate and surrounding
skin.63 The iontophretic device (Electrokinetic Transungual
System) by Transport Pharmaceuticals was registered in a
phase I clinical trial (NCT00768768) that has since been
completed, but the data remains unpublished.68 A phase II clinical
trial is also ongoing in North America (NCT01484145).69
The Power Paper iontophoretic patch device was used in a single
preliminary trial of 38 participants.61 Infections were confirmed
by both KOH examination and mycological culture. The
participants were randomized into two groups for the treatment
of a single great toenail. The first group received terbinafine
iontophoresis with a current density of 100 µA/cm2. The second
was treated with the terbinafine gel patch without iontophoresis.
The participants wore the patch overnight, every day for 4 weeks.
After the initial visit, two further iontophoresis treatments were
conducted. Follow-up occurred at 8 weeks and 12 weeks. At the
final follow-up, 84% of participants demonstrated a mycological
cure confirmed by KOH microscopy.
Ultrasound Drug Delivery System
The most recent development in device-based treatments for
onychomycosis is an ultrasound mediated nail drug delivery
system.70 This system has been tested in a canine nail model. The
intent was to determine which period of 1.5 W/cm2 ultrasound
treatment increased the nail uptake of a blue dye. Findings
showed that the 120 second period was the most effective,
increasing dye permeability by 1.5 fold. Further studies will be
required to determine if this technique is suitable for existing
antifungal drugs.
Conclusion
Device-based therapies for onychomycosis show promise in
initial clinical studies involving lasers, photodynamic therapy,
iontophoresis, and ultrasound-based therapy. Device-based
treatments may be advantageous because they are conducted in
the clinic and only require short-term patient compliance. These
modalities also have the potential to reduce adverse events caused
by antifungal drugs, as they are highly localized treatments.
Devices may also be alternatives for patients whose susceptibility
to onychomycosis infection arises from a co-morbidity, as
these therapies do not interact with the drugs involved in the
management of such conditions.65, 66 In order to substantiate the
efficacy of device-based therapies for onychomycosis, randomized
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012
7
controlled trials with mycological evaluation and long-term
follow-up are required. We believe this therapeutic area will
continue to expand and hope that broader clinical investigations
will result in new options for practitioners.
28.
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• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 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
Name/Company
Delayed-release
prednisone tablets
Rayos®
Horizon Pharma, Inc.
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
Lidocaine topical 5%
patch
Watson Pharmaceuticals
The FDA has approved an abbreviated new drug application
(ANDA) in August 2012 for lidocaine topical 5% patch.
Treatment is indicated for the relief of pain associated with
post herpetic neuralgia (innovator brand Lidoderm®, Endo
Health Solutions Inc.).
Clobetasol propionate
0.05% shampoo
Perrigo Company
The FDA approved an ANDA in August 2012 for clobetasol
propionate shampoo 0.05%, which is indicated for the
treatment of moderate to severe scalp psoriasis (innovator
brand Clobex® Shampoo, Galderma).
University of Manchester, Manchester, UK
University of Toronto, Toronto, Canada
Mark Lebwohl, MD
Mt. Sinai Medical Center, New York, USA
James J. Leydon, MD
University of Pennsylvania, Philadelphia, USA
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
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
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.
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10
The US FDA approved a delayed-release corticosteroid
in July 2012 indicated as an anti-inflammatory or
immunosuppressive agent to treat a wide spectrum of
diseases including rheumatoid arthritis, psoriatic arthritis,
polymyalgia rheumatica, ankylosing spondylitis, asthma, and
chronic obstructive pulmonary disease (COPD). The delayedrelease tablet formulation will be available in 1 mg, 2 mg,
and 5 mg strengths.
Imiquimod 3.75% cream The European Commission (EC) granted marketing
Zyclara®
authorization to this immune response modifier in August
Meda AB
2012 for the topical treatment of actinic keratosis. This
approval is valid in all European Union countries.
Christopher E.M. Griffiths, MD
Aditya K. Gupta, MD, PhD
Approval Dates/Comments
Drug News
Apremilast (CC-10004), an orally administered phosphodiesterase-4 inhibitor, has been
under active investigation for the treatment of psoriasis, psoriatic arthritis (PsA) and
other chronic inflammatory diseases. Apremilast appears to dose dependently inhibit
tumor necrosis factor-alpha (TNF-α) production. In September 2012, a press release by
Celgene International reported that three pivotal phase III, randomized, placebo-controlled
studies (PALACE-1, 2 & 3) including approximately 1,500 patients, achieved statistical
significance and clinically meaningful improvements for the primary endpoint, as well
as other measures of signs and symptoms and physical function for patients receiving
apremilast 20 mg or 30 mg twice-daily. Among PsA patients, statistically significant
response of ACR20 (a measure of success in reducing symptoms) was shown at week 16,
which was maintained through week 24. Studies are ongoing through to week 52. Based on
the combined PALACE-1, 2 & 3 studies for PsA, a new drug application (NDA) is expected
to be filed with the FDA in the first quarter of 2013. A combined marketing authorization
application (MAA) submission for PsA and moderate to severe psoriasis in Europe is also
planned for the second half of 2013.
More information is available at:
http://ir.celgene.com/phoenix.zhtml?c=111960&p=irol-newsArticle&ID=1732178&highlight=
In September 2012, the FDA issued a warning to consumers regarding the potential for
serious skin injuries resulting from the use of over-the-counter pain relieving products
(including creams, lotions, ointments, and patches) applied to the skin to alleviate
mild muscle and joint pain. Although reported cases are rare, the injuries ranged
from mild to severe chemical burns caused by the active ingredients menthol, methyl
salicylate, or capsaicin (brand-names include Bengay®, Capzasin®, Flexall®, Icy Hot®,
and Mentholatum®). Adverse effects included burns at the application site after single
administration, with severe burning or blistering developing within 24 hours, and some
cases requiring hospitalization. A higher incidence of severe burns was associated with the
use of a menthol or menthol/methyl salicylate combination product. Products containing
higher concentrations of menthol and methyl salicylate (>3% menthol or 10% methyl
salicylate) posed the greatest risk and few of the cases involved capsaicin.
More information is available at:
http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm318674.htm?source=govdelivery
• Editor: Dr. Stuart Maddin • Volume 17, Number 9 • October 2012