Acne vulgaris is a disorder of the pilosebaceous unit caused primarily by increased sebum secretion and follicular plugging. Acne variants can affect people of all age groups, but it is most prevalent in adolescence. Over 90% of males and 80% of females have experienced acne by the age of 21.1 Acne affects approximately 40 to 50 million people in the United States annually at a cost of $2.5 billion.2,3
The psychosocial impact of acne has been well documented. Body image issues associated with acne can result in depression, anxiety, social isolation, and low self-esteem.4 The teenage years in particular are notorious for being socially stressful and challenging; the cosmetic effects of acne can greatly impact an individual's emotional and psychological health at this very crucial point in development.5 When managing with these patients, the nurse practitioner (NP) needs to be considerate of these potential issues. Emotional support and understanding, in addition to medical therapy, are crucial.
Acne treatment should be geared toward the severity and characteristics of the acne lesions. To avoid unnecessary frustration with the regimen, patients should be counseled that response to treatment can take several months.
The pathophysiology of acne vulgaris is complex, with both internal and external triggers (see How acne develops). However, the underlying cause is increased sebum production and abnormal desquamation of epithelial cells.6 One of the initial events in the evolution of acne lesions is the development of the microcomedo, or blockage of the follicular canal. Increased cohesiveness of corneocytes and hyperkeratosis of the follicular lining cause keratin and sebum to accumulate in the follicle. This creates a plug (comedo) above the sebaceous gland duct. As these cells continue to pack into the follicle, the comedo expands behind a small follicular opening to the skin. This results in distension of the follicle and formation of a closed comedone (firm, elevated, white or yellow papule). If the pore begins to dilate at the surface of the skin due to this retention keratosis, an open comedone results (blackhead).6
The closed comedone is the precursor to the inflammatory lesions associated with acne. As the enlarging comedone causes increased force within the follicle, eventual rupture of the comedo wall results in extrusion of keratin and sebum as well as subsequent inflammation of the skin.6,7 (See Comedones of acne.)
Propionibacterium acnes (P. acnes) is the predominant bacteria associated with acne. It is considered part of the normal skin flora and is an inhabitant of the pilosebacous follicle. However, the role of P. acnes in acne vulgaris is significant since the bacteria greatly contributes to the inflammation and irritation associated with acne.6,7
Figure. How acne dev...Image Tools
Hormones play a central role in the stimulation of sebaceous glands and development of acne. Sebaceous gland size and metabolic rate are directly stimulated by dihydrotestosterone, a derivative of testosterone (an androgenic/sex hormone).6 Interestingly, an increase in estrogen will decrease sebum secretion.8
Development of acne often heralds the onset of puberty and increased sex hormone production.9 The severity of the acne generally correlates with the level of sex hormones being secreted (which tends to peak in the mid-teenage years). Females also tend to experience a flare in acne about a week before menstruation.9
At times, acne can be a sign of hyperandrogenism. Female teenagers and adult women presenting with acne should always be asked about irregular menses, hirsutism, or unexplained weight gain. Evaluation for polycystic ovary syndrome may then be necessary. Females with acne resistant to conventional treatment or sudden onset of severe acne may also warrant an endocrine evaluation.9
Other external factors that cause occlusion of the hair follicle can also trigger acne outbreaks. For instance, the use of comedogenic products such as cosmetics and greasy hair products can induce comedones and inflammatory lesions. Furthermore, occlusive garments such as collars, sports bras, hats, helmets, and chin straps can greatly exacerbate acne due to mechanical irritation and occlusion of the follicles.9,10 Overzealous washing practices, especially with the use of exfoliants, also cause mechanical irritation that could exacerbate acne.9
There is a unique form of acne-like eruptions that are associated with certain medications. These eruptions are generally uniformly inflammatory papules, may be found in an atypical distribution, can present at an unusual age of onset, and are often resistant to conventional acne therapy. Examples of these medications include corticosteroids, androgens, anabolic steroids, neuropsychotherapeutic drugs (tricyclic antidepressants, selective serotonin reuptake inhibitors, lithium, antiepilectics), immunomodulators, and chemotherapeutic agents.11
Figure. Comedones of...Image Tools
Acne manifests most commonly in areas of the body that have larger, more numerous sebaceous glands, such as the face, back, chest, and upper arms.6 Acne lesions can be separated into inflammatory and noninflammatory lesions. Inflammatory lesions can appear as pink papules, pustules, or cysts (see Inflammatory lesions). Noninflammatory lesions are closed or open comedones and contain a thick, white material mostly composed of keratin (see Comedonal lesions). Most patients with acne present with a combination of different acne lesions at varying states of formation (see Comedonal and inflammatory lesions). Inflammatory papules, pustules, and cysts often resolve with postinflammatory hyperpigmentation (areas of discoloration) that can last for several weeks to months. Cysts and nodules can result in long-term scarring (see Cystic lesions).
Prior to the initiation of treatment, a thorough history should be performed to rule out other medical issues that can influence the treatment plan. The complex cascade of events leading to acne lesions allows for many different approaches to treatment. Because there are innumerable products on the market claiming to remedy acne outbreaks, choosing the appropriate treatment can be both confusing and daunting. Dermatologists have very personal preferences with their choice of medications, and there is no single way to approach acne treatment (see Approach to acne treatment). Most treatments either work to decrease bacterial load or break down the comedo. Hormonal treatments can also be used in females to decrease androgen levels. In most cases, a multidimensional approach to acne treatment is necessary, since most patients have a combination of inflammatory and noninflammatory lesions. In addition, monotherapy with antibiotics alone often sets the stage for eventual treatment failure with the emergence of antibiotic resistance.
Other issues that contribute to treatment failure include a lack of adherence to medication regimens and overuse of acne products. In an attempt to dry out acne lesions, some patients use too many products or apply excessive amounts of product to the affected area. This causes further irritation and over-drying of the skin. Most acne products can be irritating, so patients need to be instructed on how much product to apply and how often. Many new topical acne medications have been developed recently to increase tolerability without compromising efficacy.
Patient education should also include the importance of washing with mild cleansers and using a noncomedogenic moisturizer in conjunction with topical acne medications to combat or avoid excessive skin irritation. Vigorously scrubbing the skin and using abrasive exfoliants can exacerbate acne by rupturing comedos, leading to the development of inflammatory lesions. Picking and squeezing lesions and overusing cosmetic products should be discouraged. All products used on the skin (makeup, cleansers, and moisturizers) should be noncomedogenic formulations. Patients must also be instructed that response to acne treatment can take several weeks to months, so patience and adherence to the regimen cannot be overemphasized.
Salicylic acid. Salicylic acid is the active ingredient in many over-the-counter (OTC) acne preparations. It is a beta-hydroxy acid that has both comedolytic and anti-inflammatory properties. It is mostly used for mild acne but can be an adjunct to regimens treating more severe acne.12
Sodium sulfacetamide. Sodium sulfacetamide is a topical sulfonamide antibacterial agent that targets P. acnes. It is available in various prescription formulations, such as lotions, creams, foams, and washes. It is often combined with sulfur to treat acne rosacea and seborrheic dermatitis in addition to acne vulgaris.13 Although widely used, data regarding the efficacy of sodium sulfacetamide in the treatment of acne are limited.14
Benzoyl peroxide. Benzoyl peroxide contains potent antibacterial properties, although it has also shown mild comedolytic and anti-inflammatory activity as well.9,15 It is most effective for treatment of inflammatory acne (pink papules, pustules, and cysts).16 There is no evidence of bacterial resistance with the use of benzoyl peroxide at this time. The medication is, therefore, often used in conjunction with topical antibiotics to reduce the chance of resistance.14
One of the main issues with benzoyl peroxide is its potential for irritation. Some patients using benzoyl peroxide formulations will develop mild, transient erythema and xerosis, while others cannot tolerate the medication at all due to severe erythema and vesiculation. Benzoyl peroxide is available both OTC and in prescription preparations. Concentrations range from 2.5% to 10% and can be found as washes, creams, gels, and lotion.17 The choice of strength depends on the area being treated. Benzoyl peroxide in formulations of 5% or less is appropriate for facial acne due to better tolerability at lower concentrations. Stronger concentrations are acceptable options for chest, back, and arms. Benzoyl peroxide is a bleaching agent, so avoid contact with clothing, sheets, or towels.
Topical antibiotics. Inflammatory papules are often treated with topical antibiotics. Erythromycin and clindamycin are the most conventional topical antibiotics prescribed; however, emerging bacterial resistance to both medications mandates the addition of other topical modalities to achieve therapeutic response (benzoyl peroxide or retinoids).18,19 Clindamycin is prescribed more often than erythromycin, as it has maintained better efficacy.20
Oral antibiotics. Oral antibiotics may be warranted in patients with approximately 10 or more inflammatory lesions. They work by reducing the bacteria that trigger the inflammatory response. The most commonly prescribed class of antibiotics for acne is the tetracyclines (tetracycline, doxycycline, minocycline), which have both antibacterial and anti-inflammatory properties.14,21 Sulfamethoxazole/trimethoprim (off-label use for acne) is also effective, but its association with Stevens-Johnson syndrome makes it a less popular choice among clinicians. Oral erythromycin (off-label use) can be used to treat acne; however, bacterial resistance has reduced its efficacy.14 Finally, some clinicians find cephalosporins (cephalexin, cefadroxil) to work well for inflammatory lesions.6
Oral antibiotic therapy should be continued until patients are no longer developing new lesions. This can typically be accomplished within 2 to 5 months of treatment. Occasionally, a patient will not respond to the chosen oral antibiotic and will need to be switched to a different class of antibiotic. Because antibiotic resistance can develop, treatment with antibiotics alone may not result in long-term success. In addition, possible adverse reactions associated with oral antibiotics should be given consideration.
Figure. Approach to ...Image Tools
Topical retinoids. Topical retinoids are considered first-line therapy for acne since they target the microcomedo, the precursor to all acne lesions.18 They normalize follicular desquamation by influencing the turnover and maturation of epithelial cells and reducing follicular plugging.6,22 Retinoids are therefore both comedolytic and anticomedogenic, making them an effective treatment for closed comedones, open comedones, and inflammatory papules. They also aid in penetration of other topical medications, decrease postinflammatory hyperpigmentation, and may have anti-inflammatory properties.9 Retinoids are an important part of acne maintenance, since there is no risk of resistance to the medication with long-term use.18
The most well-known retinoids are tazarotene, tretinoin, and adapalene.17,18 Unfortunately, they are slow to work (8 to 12 weeks) and can potentially cause dryness and irritation, which makes adherence to treatment difficult at times. Strategies to increase tolerability of retinoids include beginning with a lower strength topical formulation and then increasing strength over time, beginning with less frequent applications (Monday, Wednesday, and Friday only) and then increasing days of application, or using a short-contact approach with the medication being washed off a few minutes after application. In addition, patients should be instructed to use a pea-sized amount of medication for the entire face.
Retinoids can increase sensitivity to the sun, so sunscreen use should be encouraged.7 Tazarotene and tretinoin may possibly degrade in sunlight, so the medications should be applied at night. Tazarotene is pregnancy category X, and therefore, contraindicated in pregnancy.
Azelaic acid. Azelaic acid has comedolytic, antibacterial, and anti-inflammatory properties, which make it effective against both mild comedonal and inflammatory acne.23,24 It is generally well tolerated, with some transient tingling on initial application. It also helps decrease erythema and postinflammatory hyperpigmentation.25
Dapsone. A relatively new medication on the market is topical dapsone 5% gel. Dapsone has antimicrobial and anti-inflammatory properties, although the mechanism of action is not well understood.26–28 It is used to treat mild-to-moderate inflammatory acne.29 Studies found efficacy of this medication greater in females; however, there is no contraindication to use in males. The medication causes little to no skin irritation and is a good alternative for benzoyl peroxide sensitive or allergic patients.
Combination therapy. Since successful treatment of acne often necessitates combination therapy, new formulations have been developed. These will not only increase the efficacy of the acne treatment but also boost adherence by simplifying the application regimen.30 Examples of combination medications include erythromycin-benzoyl peroxide gel, clindamycin-benzoyl peroxide gel, adapalene-benzoyl peroxide gel, and clindamycin-tretinoin gel.18 Mild acne lesions may be controlled with just one of these products. Moderate-to-severe acne will most likely need additional topical formulations and oral antibiotic treatment.
Isotretinoin. Isotretinoin is an oral retinoid that is reserved for severely cystic acne or moderate acne that does not respond to more conventional treatment. Its efficacy is well documented.31–33 It works by reducing sebum secretion, follicular plugging, and P. acnes proliferation. The most common adverse reactions are cheilitis and xerosis, which are treated with liberal and frequent emollient applications. Other adverse reactions can include headaches and musculoskeletal discomfort. Monthly lab monitoring of lipids, complete blood cell count, and liver function tests should be performed.14
In 1998, the U.S. FDA warned of possible association of depression, psychosis, suicidal ideation, and suicide with isotretinoin. However, the literature is conflicting, and data have since been published supporting a decrease in depression with isotretinoin treatment of acne.34 The mood swings associated with adolescence and the body image issues associated with severe acne further complicate interpretation of these studies.35
The greatest concern regarding isotretinoin is the teratogenic potential of the medication. It is essential that female patients do not get pregnant while taking isotretinoin. Strict pregnancy prevention policies are now in place through a U.S. FDA mandated registry program called IPLEDGE.14 Sexually active women are required to use two methods of birth control and cannot fill new prescriptions without documented monthly negative pregnancy tests. Before both males and females are able to start treatment with isotretinoin, they are required to read a booklet distributed by the IPLEDGE program that outlines all the possible adverse reactions of the medication, including possible risk of depression and teratogenicity. This booklet includes an informed consent form that must be signed prior to initiation of therapy.
A topic of great controversy in the dermatology community is the suggestion of a possible association between isotretinoin and inflammatory bowel disease (IBD). Case studies in the gastroenterology literature have noted this association. However, according to the American Academy of Dermatology's position statement on the issue:
“Current evidence is insufficient to prove either an association or a causal relationship between isotretinoin use and inflammatory bowel disease (IBD) in the general population. While some recent studies have suggested a relationship, further studies are required to conclusively determine if an association or causal relationship exists and/or whether IBD risk may be linked to the presence of severe acne itself.”36
Of note, some suggest that the link between IBD and isotretinoin is actually due to initial long-term use of the tetracycline class of antibiotics prior to isotretinoin therapy.37 Studies are now evaluating whether there is an association between IBD and the tetracycline class of antibiotics.
Treatment with isotretinoin generally lasts 4 to 7 months. Patients start with a lower dose to avoid severe flares of acne, which can accompany initiation of treatment. Dose increases are weight and treatment response dependent. Most patients on isotretinoin show dramatic improvement with remission of acne for years, if not indefinitely. Occasionally, if teenage patients are treated at a younger age, or if the cumulative dosage prescribed is too conservative, re-treatment with isotretinoin may be necessary.
Hormonal treatment. Hormonal treatment of acne is appropriate for females only. It is geared toward decreasing androgen levels, the hormone implicated in stimulation of the sebaceous follicle. Oral contraceptives work by blocking both adrenal and ovarian production of androgens.7,22 Combination pills with estrogen and progestins that have low androgenic activity should be chosen. Although not FDA approved for the treatment of acne, Spironolactone can also be used to block androgen receptors.6,14,17
Hormonal therapy is particularly useful for females who have premenstrual flares of acne or a diagnosis of polycystic ovary syndrome. Women who present with inflammatory papules of the lower face (especially the jawline) and neck may also benefit from hormonal treatment.
Response to hormonal treatment can take 3 to 6 months and often should be used in conjunction with topical (and possibly oral) acne regimens. Data are conflicting regarding possible decreased efficacy of oral contraceptives when taken with oral antibiotics.38–40 Therefore, precautions should still be taken to avoid pregnancy when taking oral contraceptives and oral antibiotics concomitantly.
Nicotinamide (also known as niacinamide) is a component of the vitamin B complex. It works by inhibiting sebaceous lipogenesis and blocks the inflammation associated with various inflammatory skin conditions, such as acne vulgaris.41 Oral and topical nicotinamide supplementation have been shown to be useful as adjuvant treatment of inflammatory acne.42
Zinc is bacteriostatic against P. acnes and contains anti-inflammatory properties that may be beneficial in the treatment of inflammatory lesions.43 It has shown some success in the reduction of inflammatory lesions.44 However, the literature is still inconclusive regarding its true efficacy.
There is a relatively new dietary supplement on the market that combines nicotinamide, azelaic acid, zinc, pyridoxine, copper, and folic acid. As stated earlier, azelaic acid has antimicrobial activity and aids in normalization of keratinization. A recent study demonstrated that supplementation with the nicotinamide/azelaic acid combination resulted in a visible reduction of inflammatory acne lesions when added to the acne treatment regimen.41
The association between diet and acne still needs to be elucidated. Studies have been done showing a possible link between milk consumption and increased acne lesions, but the data are weak.43,45 Data examining chocolate and fried food as possible triggers to acne are inadequate or conflicting.
There appears to be an association between foods with high glycemic load (refined sugars) and acne. It is proposed that diets with high glycemic index can cause hypersinsulinemia, leading to increased androgen levels and sebum production.3,46
Intralesional corticosteroids. A single injection of triamcinolone acetonide to cystic or large pustular lesions can be used for quick suppression of inflammation.14 This is generally used in conjunction with topical and oral acne treatments as a “quick fix” treatment for painful or cosmetically bothersome lesions. Incorrect injection technique or too much volume can result in skin atrophy at the injection site. This atrophy is temporary, and the depression will resolve in a few months.6
Acne surgery. The term “acne surgery” refers to extracting comedones and draining pustules and cysts.6 Comedones can be easily extracted with the use of a comedone extractor tool or applying pressure around the follicular opening with two cotton-tipped applicators. Pustules can be drained after inserting a 22-gauge needle into the lesion and applying pressure with cotton-tipped applicators. Care must be taken to not cause tissue damage when performing these procedures.
Chemical peels. Superficial chemical peels (salicylic acid, glycolic acid) are comedolytic, exfoliating, and anti-inflammatory. They can also improve postinflammatory hyperpigmentation and skin texture. There are very few clinical trials evaluating the efficacy of superficial chemical peels; however, data show that clinical improvement of acne lesions is evident with increased numbers of chemical peels.47 Most often, chemical peels are used in conjunction with a daily topical regimen.
Laser treatment and phototherapy. The use of lasers and light therapy for the treatment of acne is still in the early stages of development. These treatments either work to decrease levels of P. acnes, decrease sebaceous gland function, or reduce inflammation.48 The long-term safety and efficacy of light-based treatments still need to be clarified.16,18 However, these treatments are potentially helpful for individuals who cannot tolerate other acne regimens or those who have failed conventional therapeutic treatments.48
Resolving acne lesions can leave residual discoloration of the skin, termed “post-inflammatory hyperpigmentation.” These lesions can be pink, tan, or brown macules and are often more apparent in dark-skinned individuals. As mentioned earlier, some of the topical acne formulations help treat postinflammatory hyperpigmentation (retinoids, azelaic acid). However, some patients will have the misconception that their acne is not improving because of this persistent discoloration. Patients need to be informed that this discoloration does not represent active acne and that it will lighten up over time. It may take months for postinflammatory hyperpigmentation to completely resolve.
Acne vulargis is a significant psychological and financial burden for those affected. Although it is most prevalent in adolescence, it can continue late into adulthood. Multiple OTC and prescription medications are available for the treatment of acne, which can be both confusing and overwhelming for patients and practitioners alike. Monotherapy rarely results in satisfactory treatment results. Topical medications are appropriate for mild acne. Oral therapies are often necessary in moderate-to-severe acne cases. Patients need to be aware that response to treatment can take several weeks to months and that both patience and consistency are essential to therapeutic success.
1. Saitta P, Keehan P, Yousif J, Way BV, Grekin S, Brancaccio R. An update on the presence of psychiatric comorbidities in acne patients. Part 1: overview of prevalence. Cutis
. 2011; 88(1):33–40.
2. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol
. 1999; 41(4):577–580.
3. Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol
4. Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol
5. Dalgard F, Gieler U, Holm JØ, Bjertness E, Hausner S. Self-esteem and body satisfaction among late adolescents with acne: results from a population survey. J Am Acad Dermatol
6. Habif TP. Clinical Dermatology: A Color Guide to Diagnosis and Therapy
. 4th ed. Philadelphia: Mosby; 2004:162–194.
7. Bolognia JL, Jorizzo JL, Rapini RP. Dermatology
. 2nd ed. Spain: Mosby; 2008:496–508.
8. Zouboulis CC. Acne and sebaceous gland function. Clin Dermatol
9. James WD, Berger T, Elston D. Andrews' Diseases of the Skin: Clinical Dermatology
. 10th ed. Philadelphia, PA: Saunders; 2006:231–239.
10. Ramanathan S, Herbert AA. Management of acne vulgaris. J Pediatr Health Care
11. Du-Thanh A, Kluger N, Bensalleh H, Guillot B. Drug-induced acneiform eruption. Am J Clin Dermatol
12. Akarsu S, Fetil E, Yücel F, Gül E, Güne_, AT. Efficacy of the addition of salicylic acid to clindamycin and benzoyl peroxide combination for acne vulgaris. J Dermatol
13. Del Rosso JQ. The use of sodium sulfacetamide 10%-sulfur 5% emollient foam in the treatment of acne vulgaris. J Clin Aesthet Dermatol
14. Strauss JS, Krowchuk DP, Lyden JJ, et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol
15. Tanghetti E. The evolution of benzoyl peroxide therapy. Cutis
. 2008;82(suppl 5):5–11.
16. Simonart T. Newer approaches to the treatment of acne vulgaris. Am J Clin Dermatol
17. Tripathi SV, Gustafson CJ, Huang KE, Feldman SR. Side effects of common acne treatments. Expert Opin Drug Saf
18. Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the global alliance to improve outcomes in acne group. J Am Acad Dermatol
. 2009;60(suppl 5):S1–S50.
19. Drucker CR. Update on topical antibiotics in dermatology. Dermatol Ther
21. Maffeis L, Veraldi S. Minocycline in the treatment of acne: latest findings. G Ital Dermatol Venereol
22. Gollnick H, Cunliffe W, Berson D, et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol
. 2003;49(suppl 1):S1–S37.
23. Mastrofrancesco A, Ottaviani M, Aspite N, et al. Azelaic acid modulates the inflammatory response in normal human keratinocytes through PPARgamma activation. Exp Dermato
24. Thiboutot D. Versatility of azelaic acid 15% gel in treatment of inflammatory acne vulgaris. J Drugs Dermatol
25. Kircik LH. Efficacy and safety of azelaic acid (AzA gel) 15% in the treatment of post-inflammatory hyperpigmentation and acne: a 16-week, baseline-controlled study. J Drugs Dermatol
27. Kircik LH. Harnessing the anti-inflammatory effects of topical dapsone for management of acne. J Drugs Dermatol
28. Pickert A, Raimer S. An evaluation of dapsone gel 5% in the treatment of acne vulgaris. Expert Opin Pharmacother
29. Lucky AW, Maloney JM, Roberts J., et al. Dapsone gel 5% for the treatment of acne vulgaris: safety and efficacy of long-term (1 year) treatment. J Drugs Dermatol
30. Ghali F, Kang S, Leyden J, Shalita AR, Thiboutot DM. Changing the face of acne therapy. Cutis
. 2009;83(suppl 2):4–15.
31. Del Rosso JQ. Face to face with oral isotretinoin: a closer look at the spectrum. J Clin Aesthet Dermatol
32. Zaenglein AL, Thiboutot DM. Expert committee recommendations for acne management. Pediatrics
33. Ingram JR, Grindlay DJ, Williams HC. Management of acne vulgaris: an evidence-based update. Clin Exp Dermatol
34. Nevoralova Z, Dvorakova D. Mood changes, depression, and suicide risk during isotretinoin treatment: a prospective study. Int J Dermatol
35. Hodgkiss-Harlow CJ, Eichenfield LF, Dohil MA. Effective monitoring of isotretinoin safety in a pediatric dermatology population: a novel “patient symptom survey” approach. J Am Acad Dermatol
37. Margolis DJ, Fanelli M, Hoffstad O, Lewis JD. Potential association between the oral tetracycline class of antimicrobials used to treat acne and inflammatory bowel disease. Am J Gastroenterol
38. Toh S, Mitchell AA, Anderka M, de Jong-van den Berg LT, Hernández-Díaz S National Birth Defects Prevention Study. Antiobiotics and oral contraceptive failure—a case-crossover study. Contraception
39. Koopmans PC, Bos JH, de Jong van den Berg LT. Are antibiotics related to oral combination contraceptive failures in the Netherlands? A case-crossover study. Pharmacoepidemiol Drug Saf
40. Helms DE, Bredle DL, Zajic J, Jarjoura D, Brodell RT, Krishnarao I. Oral contraceptive failure rates and oral antibiotics. J Am Acad Dermatol
. 1997;36(5 pt 1):705–710.
41. Shalita AR, Falcon RF, Olansky A, et al. Inflammatory acne management with a novel prescription dietary supplement. J Drugs Dermatol
42. Niren NM, Torok HM. The Nicomide Improvement in Clinical Outcomes Study (NICOS): results of an 8-week trial. Cutis
. 2006;77(suppl 1)17–28.
43. Bowe WP, Joshi SS, Shalita AR. Diet and acne. J Am Acad Dermatol
44. Dreno B, Moyse D, Alirezai M, et al. Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology
45. Adebamowo CA, Spiegelman D, Berkey CS., et al. Milk consumption and acne in teenaged boys. J Am Acad Dermatol
46. Veith WB, Silverberg NB. The association of acne vulgaris with diet. Cutis
47. Dréno B, Fischer TC, Perosino E, et al. Expert opinion: efficacy of superficial chemical peels in active acne management—what can we learn from the literature today? Evidence-based recommendations. J Eur Acad Dermatol Venereol
48. Jung JY, Hong JS, Ahn CH, Yoon JY, Kwon HH, Suh DH. Prospective randomized controlled clinical and histopathological study of acne vulgaris treated with dual mode of quasi-long pulse and Q-switched 1064-nm Nd:YAG laser assisted with a topically applied carbon suspension. J Am Acad Dermatol