Pediatric-Acne

Pediatric Acne: Putting Best Practices into Actual Practice

By Lawrence F. Eichenfield, MD

Restaurants do it all of the time—something changes and the restaurant must understand the change, adapt to it, and make changes to its system. Changes may seem unimportant—a decrease in local foot traffic, changes in customer preferences for certain foods—but they can impact business. When the change is well managed, the restaurant recognizes it and responds accordingly. If it does this well, the consumer experience remains optimal, the restaurant retains or expands its business, costs are controlled, and outcomes remain favorable.

Why don’t we do this in healthcare? Specifically, why don’t we do this in the field of pediatric acne?

 

Here’s what has changed:

A great deal has been elucidated recently about the preadolescent acne microbiome. Preadolescents with acne tend to be colonized with a greater diversity of cutaneous bacteria than control patients; in particular, Streptococcus species are more prevalent. See Figure 1.

 

Pediatric-Acne

Figure 1. Preadolescent microbiome for acne for healthy controls, acne patients treated with benzoyl peroxide (BP), and those treated with tretinoin. Note that 1 and 2 indicate first visit and pretreatment while 2 indicates the second visit.1

 

In a study of girls between the ages of 7 and 12 with at least six acneiform lesions performed by Ahluwalia et al, patients were treated with benzoyl peroxide (BP) 4% for six weeks (range four to 8 weeks). They were administered a swab to assess the microbiome at week 0 and then at the end of their treatment. This study found that patients with more acneiform lesions were significantly more likely to have more P. acnes bacteria and there were trends toward decreased S. mitis and increased S. epidermis.  This has led to the intriguing observation that P. acnes seems to create a hostile environment for certain pathogens—but allows Staphylococcal strains like S. epidermis to flourish.1 This seems to suggest that early preadolescent acne may involve a shift from a dominant S. mitis in the microbiome to a dominant P. acnes, which is then accompanied by more acne lesions.

Another change has been the switch of BP from a prescription medication to an over-the-counter (OTC) product, as well as the introduction of OTC retinoids (adapalene). OTC products are a cornerstone of acne treatment, but patients seem somewhat less consistent at acquiring OTC products as compared to prescriptions.. In a cohort study of 84 patients (ages 12 to 45) seen in a dermatology clinic for acne, patients were contacted by phone two weeks after their appointment. All patients had been counseled by the dermatologist to purchase an OTC BP product as part of their treatment. Only 20% of the patients remembered what OTC product was recommended and about a third (36%) did not purchase any OTC products, although 93% picked up their prescriptions. Of the 64% of patients who reported that they did buy an OTC acne product as recommended, only 32% of these products contained BP.2

 

Here’s what we can do:

Knowing more about the microbiome, better and more targeted medications can be developed. The antimicrobial effects of BP have been shown to be equivocal.1 Nevertheless, BP is a key part of acne treatment.  BP is now available OTC and patients must be educated that it is an important element in acne treatment and that they must read labels or follow instructions to be sure to get the right OTC product. Some ideas to improve this situation are samples for patients to take home and handouts or other printed materials with product images so the patient purchases the right OTC product.

Pediatric acne guidelines are in place.3 There is a large body of evidence in the medical literature about how to treat pediatric acne. However, in medicine, there is often a time lag between the validation of medical evidence (including published clinical trials and updated guidelines) and their implementation. For example, it took over 15 years for the use of beta-blockade following myocardial infarction to translate into practice as a standard of care for the average heart attack survivor.

Pediatricians are on the frontlines of caring for pediatric acne. While patients can be referred to a dermatologist, it may be more efficient and convenient for patients if the pediatrician could manage these cases efficiently. To that end, these pearls are offered.

  • Pediatricians and the clinicians who work with them should be trained with respect to the guidelines on pediatric acne
  • Training materials for patients should be developed—it would be ideal if these could be ordered via electronic medical records
  • In particular, training materials should offer images of OTC products, if recommended, to assure patients select the right medications

References

  1. Coughlin CC, Swink SM, Horwinski J, et al. The preadolescent acne microbiome: A prospective, randomized, pilot study investigating characterization and effects of acne therapy. Pediatric dermatology. 2017;34(6):661-664.
  2. Huyler AH, Zaenglein AL. Adherence to over-the-counter benzoyl peroxide in patients with acne. Journal of the American Academy of Dermatology. 2017;77(4):763-764.
  3. Eichenfield LF, Krakowski AC, Piggott C, et al. Evidence-based recommendations for the diagnosis and treatment of pediatric acne. Pediatrics. 2013;131 Suppl 3:S163-186.

Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea

Concurrent administration of ivermectin 1% cream with brimonidine 0.33% gel improves efficacy and tolerability in treatment of moderate-to-severe rosacea

Presenters: Gold LS1, Papp K2, Lynde C3, Lain E4, Gooderham M5, Johnson S6, Kerrouche N7, Schäfer G8

Affiliations: 1Department of Dermatology, Henry Ford Medical Center, Detroit, MI; 2K. Papp Clinical Research, Probity Medical Research, Waterloo, ON, Canada; 3Lynde Institute for Dermatology, Markham, ON, Canada; 4Austin Institute for Clinical Research, Pflugerville, TX; 5SKiN Centre for Dermatology, Probity Medical Research and Queen’s University Peterborough, ON, Canada; 6Johnson Dermatology, Fort Smith, AR; 7Galderma R&D, Sophia Antipolis, Biot, France, 8Galderma International, Paris, France

Background/Objective: Multiple studies have demonstrated the efficacy of ivermectin 1% (IVM) cream (inflammatory lesions) and brimonidine 0.33% (BR) gel (persistent erythema). This prospective study evaluated the efficacy and safety of IVM and BR versus their vehicles in moderate-to-severe rosacea.

Methods: This was a multicenter, randomized, double-blind, vehicle-controlled study in moderate-to-severe rosacea (Investigator Global Assessment [IGA] ?3). The study comprised three arms. The two active treatment arms were: 1) once-daily BR (morning) and IVM (evening) for 12 weeks (IVM+BR/12W; n=49); or 2) Once-daily BR vehicle for four weeks, followed by once-daily BR for eight weeks (morning), and once-daily IVM for 12 weeks (evening; IVM+BR/8W; n=46). The the vehicle arm stipulated once-daily BR vehicle (morning) and IVM vehicle (evening), 12 weeks (n=95). A general skin care regimen (cleanser/moisturizer/sunscreen) was provided/recommended. IGA (0–4), Clinician’s Erythema Assessment (CEA; 0–4), percent change from baseline inflammatory lesion count (ILC), percentage of subjects with 10- percent IL reduction, subject global rosacea improvement, and facial appearance questionnaire. Adverse events (AEs) were monitored throughout the study.

Results: The total IVM and BR population showed superior efficacy (Week 12, Hour 3; IGA success [clear/almost clear]) versus vehicle (55.8% vs. 36.8%, p=0.007); IVM and BR/12W showed better efficacy versus vehicle (61.2% vs. 36.8%, p=0.003) than IVM and BR/8W (50% vs. 36.8%, p=0.135). At Week 12, success increased for IVM and BR/12W (32.7%, Hour 0 [pre-BR application]; 61.2%, Hour 3 [post-BR application) and IVM and BR/8W (28.3%, Hour 0; 50%, Hour 3). CEA and median percent change in ILC improved with IVM and BR/12W and IVM and BR/8W vs vehicle (p<0.01). IVM and BR/12W trended toward higher efficacy. Eight treatment-related AEs in six subjects (3.2%) were reported (including treatment-related worsening of rosacea: 1 with IVM and BR, 3 with vehicle).

Conclusion: Administration of IVM cream with BR gel demonstrated good efficacy and safety. Early introduction of BR (Day 1; with a complete daily skin care regimen) might benefit efficacy and accelerate treatment success without impairing tolerability.

Funding: This analysis was funded by Galderma R&D. G. Schäfer and N. Kerrouche are employees of Galderma.

Adapalene 0.3% / benzoyl peroxide 2.5% gel plus oral doxycycline is an effective and safe option for oral isotretinoin candidates with severe inflammatory acne (non-nodulocystic/nonconglobate)

Adapalene 0.3% / benzoyl peroxide 2.5% gel plus oral doxycycline is an effective and safe option for oral isotretinoin candidates with severe inflammatory acne (non-nodulocystic/nonconglobate)

Presenters: Del Rosso J1, Gold LS2, Johnson SM3, Rueda MJ4, Baldwin H5, Lain EL6, Landis M7, Rendon M8, Tanghetti E9, Thiboutot D10, Weiss J11

Affiliations: 1Thomas Dermatology, Las Vegas, N; 2Henry Ford Medical Center, Deptartment of Dermatology, Detroit, MI; 3Johnson Dermatology, Fort Smith, AR; 4Galderma Laboratories, L.P., Fort Worth, TX; 5The Acne Treatment and Research Center, Morristown, NJ; 6Austin Institute for Clinical Research, Pflugerville, TX; 7Forefront Dermatology, Jeffersonville, IN; 8Rendon Center for Dermatology and Aesthetic Medicine, Boca Raton, FL; 9Center for Dermatology and Laser Surgery, Sacramento, CA; 10The Pennsylvania State University College of Medicine, Hershey, PA; 11Gwinnett Dermatology, Snellville, GA

Background/Objective: Acne treatment guidelines suggest combined topical therapy with oral antibiotics or oral isotretinoin (OI) as first-line treatments for severe acne. This study tested the efficacy and safety of a daily regimen of 0.3% adapalene/benzoyl peroxide (ABPO) gel and oral doxycycline 200mg (DOX, two 50mg delayed-release tablets twice-daily) in severe (non-nodulocystic, nonconglobate) inflammatory acne.

Methods: This was a Phase IV, 12-week, single-arm, open-label, multicenter investigational study. Men and women aged 12 years or older with severe inflammatory acne (IGA 4, n=186) and considered OI candidates by the investigator were enrolled. OI candidacy was reevaluated at each study visit. Efficacy endpoints included inflammatory lesion (IL) reduction (Week 12), IGA success (Weeks 4, 8, and 12), percent-reduction in lesions (Weeks 4, 8, and 12), and subject questionnaires (Week 12). Safety assessments included adverse events (AEs) and tolerability.

Results: Mean IL counts were significantly reduced (standard deviation [SD]; baseline, 44.8 (21.73); Week 12, 14.8 (16.11); mean percent-reduction, 66.2% [30.47]; P<.0001). By Week 12, 37.1 percent of subjects achieved IGA Success (n=69, P<0.0001). Most subjects self-reported at least moderate improvement in acne (90.2%) and were “Satisfied” or “Very Satisfied” with the study treatment overall (83.2%). Nearly half (41.9%) of the subjects were no longer considered OI candidates at Week 4. At 12 weeks, just 19.9 percent were still considered OI candidates. Twenty-seven (15.4%) AE were considered to have a reasonable possibility of being treatment-related (gastrointestinal disorders were the most common; n=7, 4.0%). Only four subjects discontinued due to an adverse event, (“skin burning sensation”; 1 mild, 2 moderate, 1 severe; all were considered “possibly related”).

Conclusion: 0.3% A/BPO plus DOX is an effective and safe treatment option for severe inflammatory acne (non-nodulocystic, nonconglobate) before starting OI treatment or as an alternative when OI cannot be used.

Funding/disclosures: This study was sponsored by Galderma Laboratories, L.P. Galderma is the maker of Epiduo Forte Gel. Dr. Rueda is an employee of Galderma. All other authors are advisors or investigators for Galderma.

Efficacy and safety of omalizumab in Japanese and Korean patients with chronic idiopathic/spontaneous urticaria (CIU/CSU): results from the Phase III POLARIS study

Efficacy and safety of omalizumab in Japanese and Korean patients with chronic idiopathic/spontaneous urticaria (CIU/CSU): results from the Phase III POLARIS study

Presenters: Hide M1, Park HS 2, Igarashi A3, Ye YM2, Kim TB4, Yagami A5, Roh JY6, Lee JH7, Fukunaga A8, Khalil S9

Affiliations: 1Department of Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan; 2Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea; 3Department of Dermatology, NTT Medical Center Tokyo, Tokyo, Japan; 4Department of Allergy and Clinical Immunology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea; 5Department of Allergology, Fujita Health University Second Educational Hospital, Nagoya, Japan; 6Department of Dermatology, Gachon University Gil Medical Center, Incheon, Korea; 7Department of Internal Medicine, Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea; 8Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan; 9Novartis Pharma AG, Basel, Switzerland

Background/Objective: To date, the effect of omalizumab treatment on CIU/CSU has not been extensively assessed in an Asian population. POLARIS represents the first randomized, double-blind, placebo-controlled clinical trial of omalizumab for CIU/CSU in an Eastern Asian population.

Methods: Efficacy and safety of omalizumab as add-on therapy for treatment of CIU/CSU were evaluated in patients aged 12 to 75 years who were refractory to approved doses of nonsedating H1 antihistamines. This 26-week study comprised a two-week screening, 12-week randomized treatment, and 12-week follow up epochs. Patients (n=218) were randomized 1:1:1 to omalizumab 300mg, 150mg, or placebo by subcutaneous injection every four weeks. Primary outcome was changed from baseline (BL) to Week 12 (W12) in weekly itch severity score (ISS7). Secondary endpoints included change from BL in weekly urticaria activity score (UAS7) and weekly number of hives score (HSS7), proportion of patients achieving a UAS7 score between 0 and 6, and change in the Dermatology Life Quality Index (DLQI). Safety was assessed through the summary of adverse events (AEs).

Results: Most disease characteristics were well balanced across treatment arms. At W12, statistically significant decreases were observed from BL in ISS7 with omalizumab versus placebo (mean changes -10.22 and -8.80 for omalizumab 300mg and 150mg; p<0.001 and p=0.006 vs. placebo [-6.51], respectively). The corresponding mean changes from BL in UAS7 were -22.44 and -18.79 (p<0.001 and p=0.007 vs. placebo [?13.90], respectively). At W12, the proportions of patients treated with omalizumab 300mg or 150mg who achieved UAS7 scores of 6 or less were 57.5 percent and 42.9 percent (p<0.001 and p=0.002 vs. placebo [18.9%]), and for UAS7=0 were 35.6 percent and 18.6 percent (p<0.001 and p=0.013 vs. placebo [4.1%]), respectively. Mean changes in HSS7 at W12 were -12.17 and -10.04 with omalizumab 300mg and 150mg (p<0.001 and p=0.016 vs. placebo [-7.41]), respectively. Mean DLQI changes at W12 from BL were -8.4 and -7.2 with omalizumab 300mg and 150mg (p<0.001 and p=0.011 vs. placebo [-5.3]), respectively. Overall incidence of AEs was similar across treatment arms (54.8%, 57.7%, and 55.4% of subjects with omalizumab 300mg, 150mg, and placebo, respectively). Nasopharyngitis was the most frequently reported AE with all treatments.

Conclusion: POLARIS demonstrated that omalizumab treatment results in significant clinical benefits with no new safety concerns in patients with H1 antihistamine-refractory CIU/CSU in Japan and Korea.

An open-label study evaluating the quality of life, long-term efficacy, and safety of lidose-isotretinoin (ABSORICA®) capsules administered without food in patients with severe recalcitrant nodular acne: interim analysis of 20-week active treatment period

An open-label study evaluating the quality of life, long-term efficacy, and safety of lidose-isotretinoin (ABSORICA®) capsules administered without food in patients with severe recalcitrant nodular acne: interim analysis of 20-week active treatment period

Presenters: Zaenglein A1, Del Rosso J2

Affiliations: 1Department of Dermatology, Pennsylvania State University, Hershey, PA; 2JDR Dermatology Research/Thomas Dermatology, Las Vegas, NV

Background/Objective: Severe acne is known to have a significant adverse effect on self-esteem and quality of life (QoL). Effective treatment of acne with isotretinoin can subsequently improve the patient’s QoL. The timing of QoL improvement over the course of treatment with lidose-isotretinoin has not been established. Isotretinoin products must be taken with a high-fat meal to achieve optimal absorption. Fasted plasma levels of isotretinoin can be nearly 60-percent lower than fed levels. Nonadherence with the food intake requirements can potentially compromise the long-term efficacy of isotretinoin. Absorption of lidose-isotretinoin is less dependent on the amount and/or type of food intake, and it can be taken without meals while still providing a reliable isotretinoin blood concentration. In this study, we evaluated the efficacy and safety of lidose-isotretinoin taken without food by patients with severe recalcitrant nodular acne, as well as assessed their quality of life. Primary objective during the 20-week active treatment period (ATP) was to evaluate the QoL of patients taking lidose-isotretinoin twice daily (bid) without food. Secondary objectives during the ATP were to evaluate the efficacy and safety of lidose-isotretinoin taken twice-daily without food.

Methods: This was a Phase IV, multicenter, single-arm, open-label study conducted in the United States in patients with severe recalcitrant nodular acne (NCT02457520) consisting of two phases: a 20-week (5-month) open-label ATP and a 104-week post-treatment period. Patients were included in the study if they were 12 to 45 years of age with recalcitrant acne severe enough for isotretinoin treatment, including five or more facial nodules. Included patients had no prior exposure to systemic isotretinoin or other systemic retinoid and weighed between 40kg and 110kg. Women included in the study could not be pregnant or breastfeeding; women of childbearing potential had to use two forms of effective contraception simultaneously for one month before the trial, during the trial, and for one month after stopping study medication, or commit to continuous abstinence from heterosexual intercourse.

Dosing during the 20-week ATP to attain target cumulative dose of 120mg to 150mg per kilogram of weight was 0.5mg/kg per day divided into two daily doses for four weeks, followed by 1.0 mg/kg per day divided into two daily doses for 16 weeks. Study medication was taken without food (1 hour before or at least 2 hours after ingestion of food or beverages other than water). Primary efficacy endpoint was the change from baseline to the end of treatment (EOT) in the Acne-QoL score, assessed on a graded scale (overall and by domain). Domains included self-perception, role-social, role-emotional, and acne symptoms. Secondary efficacy endpoints included monthly change from baseline in Acne-QoL scores (overall and by domain) and lesion counts during the ATP and change from baseline to EOT in Investigator’s Global Assessment (IGA) scores. Efficacy evaluation was conducted using the intent-to-treat (ITT) population. Overall Acne-QoL score, each domain score, and the changes from baseline for these scores were summarized using descriptive statistics. Differences between baseline and postbaseline values were analyzed using paired t-tests. Descriptive statistics are provided for mean percentage change from baseline value for inflammatory, noninflammatory, and total lesion counts. Differences between baseline and postbaseline values were analyzed using paired t-tests. Descriptive statistics are provided for IGA observed values.

Results: A total of 201 patients (mean age: 18.7 [range: 12–45] years) were enrolled in the study at 21 sites. Eighty-five percent (n=170/201) of patients completed the 20-week ATP. There was a significant increase in standard deviation (SD) Acne-QoL from baseline to EOT (61.4 [28.4] vs. 99.0 [19.8], P<0.0001). All four domains (self-perception, role-social, role-emotional, acne symptoms) were significantly improved over the course of treatment, with positive improvements beginning at Week 4. Mean (SD) percentage change in inflammatory (-87.2 [22.5]) and noninflammatory lesion (-83.2 [30.3]) counts from baseline to EOT were significant (P<0.0001).

Mean IGA scores improved from baseline by approximately 3.0 points at EOT. A total of 286 adverse events (AEs) was reported in 60.2 percent of patients (121/201). The most common AEs were dry skin (10.9%), dry lips (10.4%), and cheilitis (9.0%)

A total of 166 treatment-related AEs was reported in 46.3 percent of patients (93/201). Twelve severe AEs were reported; five were considered to be treatment-related (nausea [n=2], increased blood cholesterol [n=1], liver function test abnormal [n=1], and headache [n=1]). Psychiatric AEs occurred in 17 patients (8.5%). The psychiatric events reported were depression (4.0%), insomnia (1.0%), and anxiety (1.0%). Abnormal laboratory results occurred in 11 patients (5.5%), including increases in blood triglycerides (3.5%), alanine aminotransferase (1.5%), aspartate aminotransferase (1.5%), and blood cholesterol (1.5%). One serious AE was reported: diabetes mellitus on Study Day 127, severe in intensity and unlikely related to study treatment. Eight patients discontinued the study due to AE (psychiatric events [n=5] and abnormalities in laboratory test results [n=3]). Six additional patients had study drug withdrawn for an AE (psychiatric events [n=4], migraine [n=1], and diabetes mellitus [n=1]).

Conclusion: Twice-daily use of lidose-containing isotretinoin taken without food improved QoL over the 20-week treatment period, with improvement seen as early as Week 4. Clinical efficacy was also demonstrated. AEs were generally consistent with the known safety profile for isotretinoin.

Funding/Disclosures: This study was funded by Sun Pharmaceutical Industries, Inc. Andrea Zaenglein has served as a consultant for Ranbaxy/Sun Pharmaceutical Industries, Inc. James Del Rosso has served as a consultant, speaker, and research investigator for Sun Pharmaceutical Industries, Inc.

Oxymetazoline Hydrochloride 1% Cream for Rosacea

Oxymetazoline hydrochloride (HCl) cream, 1% (RHOFADE), an alpha-1A-adrenoceptor agonist and a partial agonist at the alpha-2 receptor, was approved in January of 2017 and is indicated for the treatment of persistent facial erythema associated with rosacea in adults. Nasal sprays containing a lower concentration of oxymetazoline HCl have been used off-label to treat rosacea for many years, and oxymetazoline hydrochloride (HCl) cream, 1% is the first approved treatment using this compound (Smith, 2017).

In two clinical trials, once-daily application of oxymetazoline hydrochloride (HCl) cream, 1% reduced persistent facial erythema associated with rosacea through 12 hours.  After 29 days of treatment, patients achieving clinical success at 12 hours were 15% vs 6% for placebo in one study and 12% vs 6% in the second trial (RHOFADE PI, 2017).

Oxymetazoline HCl cream, 1% is not the first adrenergic agent approved for the treatment of rosacea. Brimonidine topical gel, 0.33% (MIRVASO) is an alpha-adrenergic agonist indicated for the topical treatment of persistent facial erythema of rosacea in adults that has been available since 2013 (MIRVASO PI, 2016).

Which of these two preparations is a better choice for your patient?  There is no head-to-head comparison of these treatments, so it is hard to know. Combined assessment of results from different studies (for example, with network meta-analyses) has now become a fairly common approach for comparing treatments that have never been tested vs each other, but that has not been accomplished for these drugs.  A look at the labels for the two agents suggests that effect sizes for oxymetazoline HCl cream, 1% and bromocriptine gel, 0.33% are very similar, but that application site erythema may occur more often with bromocriptine gel, 0.33% than with oxymetazoline HCl cream, 1% (RHOFADE PI, 2017; MIRVASO PI, 2016).


References

MIRVASO (brimonidine) topical gel. 2016. Available at: http://www.galdermausa.com/PI/MirvasoPI.pdf

RHOFADE (oxymetazoline hydrochloride) cream, for topical use. 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208552s000lbl.pdf

New Drugs and Therapies for 2016: Rosacea

Drs. Neal Bhatia and Ted Rosen

Part 5 of an 8-part series on the large number of new topical and systemic medications that have become available or moved closer to approval in the last 12 months.

Brimonidine 3.3% gel

Rosacea is a chronic relapsing disease of the facial skin, characterized by recurrent episodes of facial flushing, persistent erythema, telangiectasia, papules, and pustules. At present, there is no effective treatment in primary care for the symptoms of flushing and erythema, and management generally consists of lifestyle advice and off-label use of drugs, such as propranolol or clonidine, which may cause significant side effects.

Brimonidine tartrate is a highly selective a2 adrenergic receptor agonist, with potent vasoconstrictive and vasostabilizing activity. Facial application of brimonidine tartrate reduces erythema through direct cutaneous vasoconstriction. Brimonidine tartrate gel (Mirvaso®) was recently approved for the symptomatic treatment of facial erythema of rosacea in adults. It is an aqueous gel that is applied to the face once every 24 hours, at any time that is suitable for the patient, for as long as facial erythema is present. Approval of Mirvaso was based on results from two randomized, vehicle-controlled phase III trials that included 553 patients. The primary efficacy end point was the ‘success rate’, defined as a 2-grade improvement on both the Clinician’s Erythema Assessment (CEA) and Patient’s Self‑Assessment (PSA) over 12 hours on days 1, 15 and 29. Results from these studies indicated that once-daily brimonidine 3.3% gel had a good safety profile and provides significantly greater efficacy vs vehicle gel for the treatment of moderate to severe erythema of rosacea.

Acne: Clinical Pearls

James Treat, MD

5 things to remember about treating acne in pediatric patients:

  • Children who develop acne between the ages of 1 and 7 should have an endocrine workup
  • When needed oral erythromicin can be used off-label as a systemic antibiotic in children under 8.
  • Neonatal acne is in part caused by malassezia yeasts.
  • Pre-adolescent acne can be treated similarly to adolescent acne except that doxycycline should not be used in children under 9 or those who have not developed their secondary teeth
  • Isotretinoin MUST be given with food

Antibiotic Stewardship and Isotretinoin

Presented by Guy Webster, MD, PhD

Written by Judy Seraphine, MSc

In this presentation at Maui Derm 2015, Dr Webster discusses the proper use of antibiotics, i.e., “antibiotic stewardship” and how the use of isotretinoin can help us avoid the use of antibiotics.

Dr Webster states that the philosophy of antibiotic use used to be “bacteria are bad, kill them all.” The yang of that philosophy, which we are beginning to appreciate more, is that bacteria are really a part of our personal ecosystem, whether on the skin or in the gut, and that if we mess with our own personal ecosystem, we may cause problems. There’s reasonable data showing that antibiotic use among children at a young age can lead to increased weight gain as they get older due to changes in their flora that become stable.

Remember that antimicrobials are in many soaps and personal products. In fact, 75% of adults have detectable levels of antimicrobials. Topical antibiotics are available over-the-counter and are not regulated (e.g., polymyxin, neomycin, bacitracin). Dr Webster feels that the big problem with antibiotic usage is in farming. The concept here is that antibiotics promote animal growth. The United States uses 29 tons of agricultural antibiotics per year. Resistant strains, as well as antibiotics themselves, can get into wastewater from livestock and poultry farms leading to a potentially altered microbial ecosystem as well as causing disease.

MRSA has also been seen in animals. Strain ST398 was a sensitive Euro human strain that crossed into animals. The use of tetracycline to increase hog weight gave birth to resistant ST398 variants, including MRSA. This strain is now recovered from human infection as well as supermarket beef and pork (30%) and shopping cart handles (10%). There is a clear crossover from the farm to the community. (Nature 499:398, 2013) Data suggest that 30% of farm workers using tetracycline feed have tetracycline-resistant MRSA nasal colonization. On the contrary, only 2% of workers from antibiotic-free farms carry nasal MRSA.

Dr Webster asks us to think about this question—in the face of ongoing agricultural abuses, will what we do with the use of antibiotics make a difference?

The dermatology specialty has a long history of profligate antibiotic usage and until recently, most dermatologists were not study-driven as many diseases are too rare to easily study. We also know that many diseases are said to respond to antibiotics; however, they are not infections (e.g. acne, rosacea, eczema, hidradinitis, bullous pemphigoid).

How do we decide how/when to use a long-term antibiotic?

Long-term antibiotic use is defensible when you are treating a real disease that could harm the patient and clearly responds to antibiotics, and there is nothing more sensible, safe, and/or affordable.

Granuloma annulare (GA) is a great example. There are case reports published in several journals supporting the long-term use of antibiotics for GA; however, recent studies have shown little benefit and this is probably something that we, as dermatologists, should stop doing.

Doxycycline is clearly effective for the treatment of mild-to-moderate bullous pemphigoid. It has demonstrated superior safety as compared to prednisone and may be given for years.

Reasonable evidence and randomized controlled trials support the use of doxycycline and minocycline for the treatment of acne. The use of cephalexin, azithromycin, penicillin, ampicillin, ciprofloxacin, and TMP/SXT is only supported by anecdote or smaller studies. While many dermatologists prefer personal experience over data, Dr Webster believes that we need to shift away from this and use what has shown to be effective in studies.

The duration of oral antibiotics for the treatment of acne has not been widely studied. Recent guidelines suggest that it should be limited to three to six months. A retrospective cohort study, published in 2014, found that the mean duration of use was 129 days and among the 31,634 courses, 57.8% did not use concomitant retinoid therapy. Although the duration of antibiotic usage is decreasing compared with previous data, some patients are still receiving them for longer periods than they probably need; thus increasing exposure and cost.

Data show that the use of topical retinoid plus an antibiotic is effective for the treatment of acne and after three months, if patients are on the topical retinoid alone, they tend to do as well as those patients who are on combination therapy or an antibiotic alone. The key is to utilize the retinoid from the beginning.

One concern for all clinicians is the development of resistant strains with the use of long-term antibiotics. Unlike the current beliefs about the long-term use of antimicrobial agents, one study found that the prolonged use of tetracycline antibiotics commonly used for acne treatment lowered the prevalence of colonization by S aureus and did not increase resistance to the tetracycline antibiotics. (Antibiotics, Acne, and Staphylococcus aureus Colonization Matthew Fanelli, MD, Eli Kupperman, BA, Ebbing Lautenbach, MD, MPH, Paul H. Edelstein, MD, and David J. Margolis, MD, PhD)

Minimizing Antibiotic Use

Besides giving an antibiotic with a retinoid, you need to consider patient fears, common sense, cost and adverse events. The UK is very concerned about resistance and they tend to use isotretinoin much faster.

Clinical Pearls

  • No topical monotherapy
    • Add benzoyl peroxide to minimize resistance
  • Oral antibiotics should be given with a topical retinoid
    • Allows for discontinuation of antibiotic after three months in most
  • Earlier switch to isotretinoin or spironolactone when antibiotic + retinoid fails

Isotretinoin Issues

Isotretinoin has been used for many years and, in fact, the longer we use it, the safer we have deemed it to be. Isotretinoin resistance can develop from inadequate dosing, virilization, being taken on an empty stomach, young patients with bad disease, and competing medications. Data show that a meal high in fat increases the absorption of isotretinoin.

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Common adverse events (AEs) among patients taking isotretinoin include dry skin, dry lips, high triglycerides and acne flares. Uncommon AEs include elevated CK and elevated AST and ALT. Patients may also experience dry eyes, decreased night vision, depression, and acne fulminans, i.e., an eruption of bad acne in a patient who may have had relatively trivial acne.

Isotretinoin-induced acne fulminans is uncommon, but devastating. It is most often seen early in the treatment of patients, usually on too high of a dose, with moderate-to-severe chest acne. If someone presents with a few nodules on their chest, Dr Webster will often start them at 20mg/day of isotretinoin along with one month of prednisone 20mg/day.

Isotretinoin and bowel disease has become a worry. There have been scattered reports of patients flaring as well as scattered reports of safe usage. Retrospective studies have shown no link or a very weak link between IBD flares and isotretinoin usage. There may; however, be a link between acne and IBD and antibiotics and IBD. (J. Invest Derm 2012, doi:10.1038/jid.2012.387)

 Many small studies, although not all adequate, have been conducted looking at the association between isotretinoin and bone mineral density (BMD). A recent study using DEXA found that there was no change from the beginning to the end of isotretinoin treatment in patients’ BMD.

Regarding depression, studies have shown that there are no differences in depression among teens taking isotretinoin versus antibiotics and that there is no greater risk of suicide in isotretinoin versus non-isotretinoin. But, there are always case reports where someone is on the drug and gets depressed, goes off the drug and gets better, then goes back on and gets depressed again. Those outliers probably have something real going on. Studies have been conducted looking at patients with bipolar disease. If you have a known bipolar teen whom you are looking to put on isotretinoin, you may want to consult with the psychiatrist.

 

 

 

 

 

 

 

Out of the Box: Clinical Pearls for Acne and Rosacea

Linda Stein Gold, MD

  • Optimal antibiotic dosing and duration is not clear based on the literature. Data suggests that minocycline efficacy is not increased by increasing dose, only adverse effects are increased.
  • There appears to be a dose response curve for doxycycline.
  • “Short contact” benzoyl peroxide is appears to be more efficacious for decreasing p acnes on the trunk than benzoyl peroxide “wash”.
  • Diet does seem to influence acne. Low glycemic index diets and avoidance of skim milk may improve acne.
  • The current fad of coconut oil has no scientific studies in acne showing efficacy.  In-vitro and animal studies suggest an effect on inflammation and p. acnes.