Antibiotic Resistance in Acne Treatment

Transcription

1 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 acne 3 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)

2 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 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. 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 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 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 Antibiotic Resistance in Acne Treatment: Evidence of Clinical Relevance 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 activities 11 and are highly effective in reducing both inflammatory and non- 2 Editor: Dr. Stuart Maddin Volume 17, Number 9 October 2012

3 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 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 May;60(5 Suppl):S Stern RS. Medication and medical service utilization for acne J Am Acad Dermatol Dec;43(6): Webster GF. Acne vulgaris. BMJ Aug 31;325(7362): 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 Jun;79(6 Supp l): Leyden JJ. Antibiotic resistant acne. Cutis Mar;17(3): 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 Apr;72(4): Leyden JJ, McGinley KJ, Cavalieri S, et al. Propionibacterium acnes resistance to antibiotics in acne patients. J Am Acad Dermatol Jan;8(1): Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust Sep 7;169(5): Ross JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol Mar;148(3): Eady EA, Cove JH, Holland KT, et al. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol Jul;121(1): 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 Jul;49(1 Suppl):S 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 May;4(5): 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 Jul;24(7): Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology. 2003;206(1): 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 Dec 18-31;364(9452): Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol Aug;153(2): 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 Nov-Dec;69(6): Oprica C, Nord CE. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes. Clin Microbiol Infect Mar;11(3): Levy RM, Huang EY, Roling D, et al. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol Apr;139(4): 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 Jun;126(6): Vowels BR, Feingold DS, Sloughfy C, et al. Effects of topical erythromycin on ecology of aerobic cutaneous bacterial flora. Antimicrob Agents Chemother Nov;40(11): 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): Lowy FD, Hammer SM. Staphylococcus epidermidis infections. Ann Intern Med Dec;99(6): Gemmell CG. Coagulase-negative staphylococci. Med Microbiol Dec;22(4): Stillman RI, Wenzel RP, Donowitz LC. Emergence of coagulase negative staphylococci as major nosocomial bloodstream pathogens. Infect Control Mar;8(3): Naidoo J, Noble WC. Skin as a source of transferable antibiotic resistance in coagulase-negative staphylococci. Zentralblatt Bakt Suppl. 1987;16: 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 May;128(5): Continued on page 9 Editor: Dr. Stuart Maddin Volume 17, Number 9 October

4 Device-Based Therapies for Onychomycosis Treatment Aditya K. Gupta, MD, PhD, MBA, FAAD, FRCPC 1,2 and Fiona Simpson, HBSc 2 1 Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada 2 Mediprobe Research Inc., London, ON, Canada 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 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 antifungals 16 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 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. 4 Editor: Dr. Stuart Maddin Volume 17, Number 9 October

5 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. 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 J/cm 2 energy fluence with a spot size of 4 mm and a pulse duration of 35 ms in the presence of cold air 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 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 μs pulses with an energy fluence of 25.5 J/cm 2 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 (NCT ) was completed on November 29, 2010, but the data from this study remains unpublished. 34 Cutera has released a white paper on the GenesisPlus laser 35 that reported a 70% improvement rate in the 7 participants treated Laser System Type of Laser Wavelength (nm) Energy Fluence (J/cm 2 ) Spot Size (mm) Pulse Length Pulse Frequency (Hz) International Approvals for Onychomycosis Dualis SP, Fotona Long pulse Nd:YAG ms 1 EU PinPointe FootLaser, Nuvolase Short pulse Nd:YAG µs 1 US, Canada, EU, Australia GenesisPlus, Cutera Short pulse Nd:YAG µs 2 US, Canada, EU VARIA, CoolTouch Short pulse Nd:YAG µs - US, EU LightPod Neo, Aerolase JOULE ClearSense, Sciton Short pulse Nd:YAG µs - - Short pulse Nd:YAG ms 6 US Q-Clear, Light Age Q-switched Nd:YAG ns 1-5 US 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 Q-switched Nd:YAG 532, Short pulse Nd:YAG µs - EU Modelocked Ti:Sapphire Table 1: Laser device systems (-) = data unavailable; EU = European Union; US = United States to m -2 s fs 76 MHz - Diode 870, / EU Diode Editor: Dr. Stuart Maddin Volume 17, Number 9 October

6 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/cm 2, 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/cm 2 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 (NCT ). 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/cm 2 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 Treatment with energy above 7x10 31 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 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 (NCT and NCT ) remains unknown. 45,46 ConBio Inc. has registered a single assignment, open label clinical trial (NCT ) 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) 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/cm Sylsens B has not yet been tested in vivo. 6 Editor: Dr. Stuart Maddin Volume 17, Number 9 October 2012

7 Study Parameters Watanabe et al. Piraccini et al. Sotiriou et al. Gilaberte et al Number of Patients Age , mean Diagnosis of Infection KOH microscopy and culture KOH microscopy and culture Microscopy and culture Confirmed, technique unspecified Type of Infection - T. rubrum - Fusarium oxysporum, Aspergillus terreus Pre-treatment 20% urea ointment 40% urea ointment 20% urea ointment 40% urea ointment Length of Pretreatment 10 hours 7 days 10 consecutive nights 12 hours Photosensitizer 20% MAL 16% MAL 20% ALA 16% MAL Length of Treatment 5 hours 3 hours 3 hours 4 hours Irradiation Source 630 nm laser 100 J/cm nm 36 J/cm nm 40 J/cm nm 37 J/cm 2 Length of Irradiation - 7 min 24 sec - - Number of Treatments Treatment Interval N/A 15 days 2 weeks 2 weeks Follow-up Period 6 months 24 months 18 months 6 months Mycological Cure Rate 100% 100% 43% 100% Complete Cure Rate 100% 0% 36.6% 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 The nail plate then acts as a reservoir of terbinafine that is then released into the nail bed and matrix over days ,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 (NCT ) that has since been completed, but the data remains unpublished. 68 A phase II clinical trial is also ongoing in North America (NCT ). 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/cm 2. 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/cm 2 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

8 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. References 1. Gupta AK, Drummond-Main C, Cooper EA, et al. Systematic review of nondermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology, and treatment. J Am Acad Dermatol Mar;66(3): Niewerth M, Korting HC. Management of onychomycoses. Drugs Aug;58(2): Vander Straten MR, Hossain MA, Ghannoum MA. Cutaneous infections dermatophytosis, onychomycosis, and tinea versicolor. Infect Dis Clin North Am Mar;17(1): Treating toenail fungus. Consum Rep Jul;75(7): Effendy I, Lecha M, Feuilhade de Chauvin M, et al. Epidemiology and clinical classification of onychomycosis. J Eur Acad Dermatol Venereol Sep;19(Suppl 1): Finch JJ, Warshaw EM. Toenail onychomycosis: current and future treatment options. Dermatol Ther Jan-Feb;20(1): Foster KW, Ghannoum MA, Elewski BE. Epidemiologic surveillance of cutaneous fungal infection in the United States from 1999 to J Am Acad Dermatol May;50(5): Gupta AK, Ricci MJ. Diagnosing onychomycosis. Dermatol Clin Jul;24(3): Loo DS. Onychomycosis in the elderly: drug treatment options. Drugs Aging. 2007;24(4): Seebacher C, Brasch J, Abeck D, et al. Onychomycosis. Mycoses Jul;50(4): Gupta AK, Gupta MA, Summerbell RC, et al. The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease. J Eur Acad Dermatol Venereol Nov;14(6): Gupta AK, Taborda P, Taborda V, et al. Epidemiology and prevalence of onychomycosis in HIV-positive individuals. Int J Dermatol Oct;39(10): Gulec AT, Demirbilek M, Seckin D, et al. Superficial fungal infections in 102 renal transplant recipients: a case-control study. J Am Acad Dermatol Aug;49(2): Baran R. The nail in the elderly. Clin Dermatol Jan-Feb;29(1): Döner N, Yaşar Ş, Ekmekçi TR. Evaluation of obesity-associated dermatoses in obese and overweight individuals. Turkderm. 2011;45(3): Gupta AK, Uro M, Cooper EA. Onychomycosis therapy: past, present, future. J Drugs Dermatol Sep;9(9): Piraccini BM, Sisti A, Tosti A. Long-term follow-up of toenail onychomycosis caused by dermatophytes after successful treatment with systemic antifungal agents. J Am Acad Dermatol Mar;62(3): Scher RK, Baran R. Onychomycosis in clinical practice: factors contributing to recurrence. Br J Dermatol Sep;149 Suppl 65: Hughes CA, Foisy M, Tseng A. Interactions between antifungal and antiretroviral agents. Expert Opin Drug Saf Sep;9(5): Nyilasi I, Kocsube S, Krizsan K, et al. In vitro synergistic interactions of the effects of various statins and azoles against some clinically important fungi. FEMS Microbiol Lett Jun;307(2): Anderson RR, Parrish JA. Selective photothermolysis: precise microsurgery by selective absorption of pulsed radiation. Science Apr 29;220(4596): Altshuler GB, Anderson RR, Manstein D, et al. Extended theory of selective photothermolysis. Lasers Surg Med. 2001;29(5): Hashimoto T, Blumenthal HJ. Survival and resistance of Trichophyton mentagrophytes arthrospores. Appl Environ Microbiol Feb;35(2): Bergman A, Casadevall A. Mammalian endothermy optimally restricts fungi and metabolic costs. MBio. 2010;1(5). 25. US FDA Medical Device 510(k) Clearances. 510(k) number: K Decision date: October 15, PinPointe FootLaser, PinPointe USA, Inc. Available at: pdf. Accessed: September 5, US FDA Medical Device 510(k) Clearances. 510(k) number: K Decision date: April 5, Cutera GenesisPlus Laser System, Cutera, Inc. Available at: Accessed: September 5, US FDA Medical Device 510(k) Clearances. 510(k) number: K Decision date: September 15, Q-Clear, Light Age, Inc. Available at: Accessed September 5, US FDA Medical Device 510(k) Clearances. 510(k) number: K Decision date: November 1, CoolTouch VARIA, New Star Lasers, Inc. Available at: Accessed September 5, US FDA Medical Device 510(k) Clearances. 510(k) number: K Decision date: Decmber 7, Joule ClearSense, Sciton Inc. Available at: Accessed: September 5, Fotona Inc. Available at: Accessed: September 5, Kozarev J, Vizintin Z. Novel laser therapy in treatment of onychomycosis. J Laser Health Acad. 2010;1: Kozarev J. Summary: ClearSteps laser onychomycosis treatment: assessment of efficacy 12 months after treatment and beyond. J Laser Health Acad. 2011;2011(1):S Harris D, McDowell B, Strisower J. Laser treatment for toenail fungus. Proc of SPIE Feb 19; 7161:7161M PathoLase, Inc. Multi-center trial: evaluation of PinPointe FootLaser treatment for infected toenails (onychomycosis). In: ClinicalTrials.gov, Identifier: NCT Last updated November 29, Available at: clinicaltrials.gov/ct2/show/nct ?term=onychomycosis+lase r&rank=4. Accessed: September 5, Weiss D. 3 month clinical results using sub-millisecond 1064nm Nd:YAG laser for the treatment of onychomycosis Available at: cutera.com/en-intl/technology/ndyag-laser/genesis-plus/white%20 Paper_Dr%20Weiss.pdf. Accessed: September 5, Waibel J. Introducing the Sciton ClearSense accessory featuring the ClearToe treatment for onychomycosis (for non-u.s. customers). Webinar archives. August 26, Available at: Accessed: September 5, Hochman LG. Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd:YAG 1064-nm laser. J Cosmet Laser Ther Feb;13(1): University of California, Irvine. A randomized, placebo-controlled study of the 1320 nm Nd:YAG laser for improving the appearance of onychomycosis. In: ClinicalTrials.gov, Identifier: NCT Last updated December 22, Available at: Accessed: September 5, CoolTouch, Inc. CoolTouch CT3Plus laser specifications. Available at: Accessed: September 5, CoolTouch, Inc. CoolBreeze Features. Available at: com/coolbreeze_laser_features.aspx. Accessed September 5, Vural E, Winfield HL, Shingleton AW, et al. The effects of laser irradiation on Trichophyton rubrum growth. Lasers Med Sci Oct;23(4): Manevitch Z, Lev D, Hochberg M, et al. Direct antifungal effect of femtosecond laser on Trichophyton rubrum onychomycosis. Photochem Photobiol Mar-Apr;86(2): Landsman AS, Robbins AH, Angelini PF, et al. Treatment of mild, moderate, and severe onychomycosis using 870- and 930-nm light exposure. J Am Podiatr Med Assoc May-Jun;100(3): Bornstein E, Hermans W, Gridley S, et al. Near-infrared photoinactivation of bacteria and fungi at physiologic temperatures. Photochem Photobiol Nov-Dec;85(6): Nomir Medical Technologies. Non-randomized open label study to treat 4 toes at a time to eliminate onychomycosis using the Noveon laser. In: ClinicalTrials.gov, Identifier: NCT Last update: October 20, Available at: Accessed: September 5, Nomir Medical Technologies. Noveon laser treatment of onychomycosis: a device performance clinical study. In: ClinicalTrials.gov, Identifier: NCT Last updated October 10, Available at: clinicaltrials.gov/ct2/show/nct Accessed: September 5, ConBio, a Cynosure Company. Study of the V-Raser diode laser system in the treatment of onychomycosis. In: ClinicalTrials.gov, Identifier: NCT Last updated October 12, Available at: show/nct Accessed: September 5, Harris F, Pierpoint L. Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. Med Res Rev Jul Editor: Dr. Stuart Maddin Volume 17, Number 9 October 2012

9 49. Smijs TG, van der Haas RN, Lugtenburg J, et al. Photodynamic treatment of the dermatophyte Trichophyton rubrum and its microconidia with porphyrin photosensitizers. Photochem Photobiol Sep-Oct;80(2): Heinemann IU, Jahn M, Jahn D. The biochemistry of heme biosynthesis. Arch Biochem Biophys Jun 15;474(2): Watanabe D, Kawamura C, Masuda Y, et al. Successful treatment of toenail onychomycosis with photodynamic therapy. Arch Dermatol Jan;144(1): Piraccini BM, Rech G, Tosti A. Photodynamic therapy of onychomycosis caused by Trichophyton rubrum. J Am Acad Dermatol Nov;59(5 Suppl):S Sotiriou E, Koussidou-Eremonti T, Chaidemenos G, et al. Photodynamic therapy for distal and lateral subungual toenail onychomycosis caused by Trichophyton rubrum: Preliminary results of a single-centre open trial. Acta Derm Venereol Mar;90(2): Gilaberte Y, Aspiroz C, Martes MP, et al. Treatment of refractory fingernail onychomycosis caused by nondermatophyte molds with methylaminolevulinate photodynamic therapy. J Am Acad Dermatol Sep;65(3): Smijs TG, Schuitmaker HJ. Photodynamic inactivation of the dermatophyte Trichophyton rubrum. Photochem Photobiol May;77(5): Smijs TG, Bouwstra JA, Talebi M, et al. Investigation of conditions involved in the susceptibility of the dermatophyte Trichophyton rubrum to photodynamic treatment. J Antimicrob Chemother Oct;60(4): Smijs TG, Bouwstra JA, Schuitmaker HJ, et al. A novel ex vivo skin model to study the susceptibility of the dermatophyte Trichophyton rubrum to photodynamic treatment in different growth phases. J Antimicrob Chemother Mar;59(3): Smijs TG, Pavel S, Talebi M, et al. Preclinical studies with 5,10,15-Tris(4- methylpyridinium)-20-phenyl-[21h,23h]-porphine trichloride for the photodynamic treatment of superficial mycoses caused by Trichophyton rubrum. Photochem Photobiol May-Jun;85(3): Murdan S. Enhancing the nail permeability of topically applied drugs. Expert Opin Drug Deliv Nov;5(11): Barsness M, Davis SP, Etheredge R, et al. Studies in drug transport vs. current in iontophoretic onychomycosis treatment. Conf Proc IEEE Eng Med Biol Soc. 2009;2009: Amichai B, Nitzan B, Mosckovitz R, et al. Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. Br J Dermatol Jan;162(1): Nair AB, Kim HD, Chakraborty B, et al. Ungual and trans-ungual iontophoretic delivery of terbinafine for the treatment of onychomycosis. J Pharm Sci Nov;98(11): Nair AB, Kim HD, Davis SP, et al. An ex vivo toe model used to assess applicators for the iontophoretic ungual delivery of terbinafine. Pharm Res Sep;26(9): Nair AB, Sammeta SM, Kim HD, et al. Alteration of the diffusional barrier property of the nail leads to greater terbinafine drug loading and permeation. Int J Pharm Jun 22;375(1-2): Nair AB, Vaka SR, Sammeta SM, et al. Trans-ungual iontophoretic delivery of terbinafine. J Pharm Sci May;98(5): Amichai B, Mosckovitz R, Trau H, et al. Iontophoretic terbinafine HCL 1.0% delivery across porcine and human nails. Mycopathologia May;169(5): Nair AB, Vaka SR, Murthy SN. Transungual delivery of terbinafine by iontophoresis in onychomycotic nails. Drug Dev Ind Pharm Oct; 37(10): Transport Pharmaceuticals. A study of skin/nail sensation and the pharmacokinetics of the uptake of terbinafine in the great toe nail and systemically following treatment with the electrokinetic transungual system (ETS)-terbinafine gel in healthy normal voluneteers. In: ClinicalTrials.gov, Identifier: NCT Last updated March 10, Available at: clinicaltrials.gov/ct2/show/nct Accessed: September 5, Nitric BioTherapeutics, Inc. An unblinded clinical trial to evaluate the deposition of terbinafine in the nail bed after iontophoretic application of ETS terbinafine gel in subjects with distal subungual onychomycosis in the great toenail. In: ClinicalTrials.gov, Identifier: NCT Last updated August 8, Available from: Accessed: September Mididoddi P, Upadhye S, Church C, et al. Influence of etching and ultrasound on the permeability of ciclopirox through the human nail. Presentation at: American Association of Pharmaceutical Scientists Annual Meeting and Exposition. San Antonio, TX. October 28-November 2, Available for ipad, iphone and ipod touch Content & instructions can be found at: Antibiotic Resistance in Acne Treatment - references continued from page Thiboutot DM, Shalita AR, Yamauchi PS, et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigatorblind follow-up of a recent combination study. Arch Dermatol May;142(5): Leyden J, Thiboutot DM, Shalita AR, et al. Comparison of tazarotene and minocycline maintenance therapies in acne vulgaris: a multicenter, doubleblind, randomized, parallel-group study. Arch Dermatol May;142(5): Eady EA, Farmery MR, Ross JI, et al. Effects of benzoyl peroxide and erythromycin alone and in combination against antibiotic-sensitive and -resistant skin bacteria from acne patients. Br J Dermatol Sep;131(3): Bojar RA, Cunliffe WJ, Holland KT. The short-term treatment of acne vulgaris with benzoyl peroxide: effects on the surface and follicular cutaneous microflora. Br J Dermatol Feb;132(2): Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment with a combination of benzoyl peroxide and erythromycin on skin carriage of erythromycin-resistant propionibacteria. Br J Dermatol Jan;134(1): Lookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol Oct;37(4): Leyden J, Levy S. The development of antibiotic resistance in Propionibacterium acnes. Cutis Feb;67(2 Suppl): Thiboutot D. Acne: J Am Acad Dermatol Jul;47(1): Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol. 2001;15 Suppl 3: Gans EH, Kligman AM. Comparative efficacy of clindamycin and benzoyl peroxide for in vivo suppression of Propionibacterium acnes. J Dermatolog Treat Sep;13(3): Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propionibacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis Dec;82(6): Skidmore R, Kovach R, Walker C, et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol Apr;139(4): Toossi P, Farshchian M, Malekzad F, et al. Subantimicrobial-dose doxycycline in the treatment of moderate facial acne. J Drugs Dermatol Dec;7(12): Editor: Dr. Stuart Maddin Volume 17, Number 9 October

10 EDITOR-IN-CHIEF Stuart Maddin, MD ASSOCIATE EDITORS Hugo Degreef, MD, PhD Catholic University, Leuven, Belgium Jason Rivers, MD 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 Bryce Cowan, MD, PhD 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 Andrew N. Lin, MD University of Alberta, Edmonton, Canada Harvey Lui, MD 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 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 ) Copyright 2012 by SkinCareGuide.com Ltd. Skin Therapy Letter is published 10 times annually by SkinCareGuide.com Ltd, 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, 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: info@skintherapyletter.com Name/Company Delayed-release prednisone tablets Rayos Horizon Pharma, Inc. Imiquimod 3.75% cream Zyclara Meda AB Lidocaine topical 5% patch Watson Pharmaceuticals Clobetasol propionate 0.05% shampoo Perrigo Company Update on Drugs Approval Dates/Comments 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. The European Commission (EC) granted marketing authorization to this immune response modifier in August 2012 for the topical treatment of actinic keratosis. This approval is valid in all European Union countries. 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.). 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). 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 A combined marketing authorization application (MAA) submission for PsA and moderate to severe psoriasis in Europe is also planned for the second half of More information is available at: 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: 10 Editor: Dr. Stuart Maddin Volume 17, Number 9 October 2012