Systemic Therapies for the Treatment of Acne

When treatment for acne requires more than topical therapies, systemic treatments may be warranted. John S. Barbieri, MD, discussed with Dermatology Advisor some of the most common mechanisms of acne and how best to address them.

Disease severity is a primary consideration in the choice of treatment for acne. Topical therapies are usually the first choices for mild to moderate acne, but severe acne often involves multiple mechanisms, making it more difficult to treat.1,2 “For patients with acne that does not improve with topical treatments or who have more moderate to severe acne characterized by inflammatory bumps, cysts, and nodules, systemic treatments may be necessary,” John S. Barbieri, MD, a practicing dermatologist and epidemiologist in Philadelphia, Pennsylvania, and coauthor of a number of acne studies, told Dermatology Advisor. Factors such as hormonal status, adherence to topical treatment, and patient preference for an oral therapy may also figure into the decision to initiate a systemic treatment regimen.

Four pathogenic mechanisms for acne have been identified1,2:

1) Hormone imbalances, with increased androgen production resulting in overproduction of sebum

2) Keratinization of skin follicles producing blockages

3) Bacterial colonization of Propionibacterium acnes (P acnes)

4) Inflammatory-mediated responses within the skin

Systemic therapies all produce more serious adverse effects than topical therapies, which can become a major issue during longer durations of treatment. “Besides isotretinoin (which results in a durable remission), all treatments for acne only work while you are using them,” explained Dr Barbieri. “Since acne often persists into young adulthood, most patients will require treatment for months to years (for instance, 40% and 20% of men report acne in their 20s and 30s, respectively, and 50% and 35% of women report acne in their 20s and 30s, respectively),” he said.3

Several classes of agents are currently used as systemic therapy for acne, including antibiotics, retinoids, oral contraceptives, and corticosteroids.1,2,4 Zinc sulfate, ibuprofen, and clofazimine may also be effective.1 These drugs work through different mechanisms, and none has proven to be the ideal therapy for all patients.

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Antibiotics are the most commonly used systemic treatments for moderate to severe acne that is inflammatory or has become widespread.2 The most commonly used classes of antibiotics include macrolides, fluoroquinolones, tetracycline, and co-trimoxazole.1

Antibiotics are effective at suppressing the further colonization of P acnes, but their use has diminished in recent years as a result of the high profile of potentially severe adverse effects and the potential for antibiotic resistance.1,4 Despite being given in low doses for the treatment of acne, antibiotic treatment often continues long-term, contributing to the disruption of bacterial flora and causing bacterial resistance affecting multiple organisms.4 Barbieri et al4 also noted an increased risk for cancer associated specifically with tetracycline therapy, and a range of upper respiratory infections and pharyngitis associated with many antimicrobial agents. Less serious adverse effects are still troubling to patients, and include photosensitivity with doxycycline and eosinophilia, vestibular disturbances, and benign intracranial hypertension with minocycline and gastrointestinal symptoms with both.2,5 For those reasons, other classes of agents are preferred when systemic therapy is indicated.


Spironolactone, a synthetic 17-lactone steroid, is a hormonal therapy that blocks androgenic receptor activity when given at higher doses, which in turn inhibits sebum production.4 It is considered safe and effective for the treatment of severe acne. “For both men and women, hormones play a key role in the development of acne, which is why acne starts in puberty, when hormone levels increase,” Dr Barbieri said. “These hormones lead to increased oil production in the skin, resulting in the development of acne. Spironolactone works by decreasing oil production in the skin, which is how it is effective for acne. We recently conducted a study suggesting it may be a preferable option compared to oral antibiotics for treatment of acne in women,” he added.6

Adverse effects of spironolactone include menstrual irregularities, breast tenderness, dizziness, nausea, headache, polyuria, and fatigue.4 Spironolactone is designated pregnancy category C, meaning women should be counseled to avoid pregnancy while receiving this drug.4 Because of its potassium-sparing effects, it carries risks for hyperkalemia in patients with renal insufficiency and heart failure when given at the highest doses of 200 mg/day.4

Oral Contraceptives

Oral contraceptives modify the normal hormonal balance in women of childbearing age by adding estrogen and progestin to every menstrual cycle.4 This mechanism also serves to prevent normal binding of circulating testosterone to the androgen receptor. The resulting increase in testosterone levels by an average of 40% to 50% also suppresses normal production of sebum.4

“Combined oral contraceptives are a great treatment option for women with acne,” reported Dr Barbieri. “There is even some evidence that they may be as effective as oral antibiotics. Patients should discuss with their doctor whether they are a candidate for treatment with a combined oral contraceptive, but these medications are generally quite safe in healthy young women,” he said.

Use of oral contraceptives presents a risk for venous thromboembolism, myocardial infarction, and stroke, while reducing lifetime risks for pelvic inflammatory disease and ovarian, colorectal, and endometrial cancers.7


Isotretinoin is an oral retinoid that is widely considered the most effective systemic therapy for acne. Harris and Cooper2 wrote in their 2017 review that, “Its efficacy is due to the fact that it targets all four known components involved in the development of acne,” making it the only therapy that offers the possibility of remission. Dr Barbieri noted that, “Additionally, for patients with scarring acne, systemic treatments such as isotretinoin are often used to reduce the risk of future scarring.” 

Starting doses of isotretinoin range from 0.2 mg/day for milder acne up 0.5 mg/day for severe acne, which can be titrated up to 1 mg/day as tolerated.4 Higher doses are more likely to produce durable remission, while also increasing the incidence of adverse effects (mucotaneous[ALH1]  dryness, ocular complications, and myalgias).4

The conclusion that “[m]ore efficient and safer treatment options are needed for the treatment of acne”1 speaks to the growing interest in complementary and alternative medicines to treat acne. Current therapeutic strategies need to target multiple disease mechanisms and patient comfort levels, while reducing risks to adverse effects and antibiotic resistance.1,2,4

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1. Fox L, Csongradi C, Aucamp M, du Plessis J, Gerber M. Treatment modalities for acne. Molecules 2016;21(8):1063.

2. Harris VR, Cooper AJ. Modern management of acne. Med J Aust. 2017;206(1):41-45.

3. Collier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008;58(1):56-59.

4. Barbieri JS, Spaccarelli N, Margolis DJ, James WD. Approaches to limit systemic antibiotic use in acne: Systemic alternatives, emerging topical therapies, dietary modification, and laser and light-based treatments. J Am Acad Dermatol. 2019;80(2):538-549.

5. Park H, Skopit S. Safety considerations and monitoring in patients treated with systemic medications for acne. Dermatol Clin. 2016;34(2):185-193.

6. Barbieri JS, Choi JK, Mitra N, Margolis DJ. Frequency of treatment switching for spironolactone compared to oral tetracycline-class antibiotics for women with acne: a retrospective cohort study 2010-2016. J Drugs Dermatol. 2018;17(6):632-638.

7. Harper JC. Use of Oral contraceptives for management of acne vulgaris: practical considerations in real world practice. Dermatol Clin. 2016;34(2):159-165.