Susuana Adjei, MD1; Austinn C. Miller, MD1; Laurie A. Temiz, BA1,2; Stephen K. Tyring, MD, PhD, MBA1,3

1Center for Clinical Studies, Webster, TX, USA
2Meharry Medical College, Nashville, TX, USA
3Department of Dermatology, University of Texas Health Science Center, Houston, TX, USA

Conflict of interest:
Susuana Adjei, Austinn Miller and Laurie Temiz have no conflicts of interest to disclose. Stephen Tyring was a principal investigator for the Almirall PROSES clinical trial.

Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile.

Key Words:
sarecycline, tetracyclines, moderate-to-severe acne, antimicrobial resistance, adverse effects


To date, one of the first-line classes of oral antibiotic treatments for moderate-to-severe acne has been tetracycline-class antibiotics due to their anti-inflammatory effects, antimicrobial activity, bioavailability, and lipophilicity.1 The pathogenesis of acne vulgaris is multifaceted with key factors being abnormal follicular keratinization, Cutibacterium acnes (C. acnes) proliferation/ colonization, and increased sebum production.2 Inflammation also ensues with the expression and upregulation of inflammatory factors/cells such as CD3+, CD4+ T cells, interleukin-1, integrins, toll-like receptors, and macrophages.2

Various methods for grading acne severity have been debated. Consensus remains elusive, as acne assessment must account for a spectrum of factors such as the number, location, type of lesions, associated scarring, and psychosocial influences.1,3 In fact, the established scoring tools Global Acne Grading System (GAGS) and Investigator Global Assessment (IGA), which are widely used in clinical trials, FDA efficacy endpoints, and patient care, do not account for all the associated factors in acne assessment.3

Moderate-to-severe acne classically presents with inflamed papules, pustules, and occasional nodules with lesions commonly affecting the face, chest, and back.4,5 Oral antibiotics are a mainstay of treatment (Table 1).1 Tetracyclines, specifically doxycycline and minocycline, are broad-spectrum antibiotics widely used for acne treatment as they limit inflammation by inhibition of protein synthesis and proliferation of C. acnes.6 However, because of their broad-spectrum activity, tetracyclines not only contribute to the emergence of bacterial resistance, but also disrupt the gut and skin normal microflora, resulting in dysbiosis.7,8 Dysbiosis of the gut has been linked to inflammatory bowel disease. Doxycycline has shown to be associated with 2.25-fold increase in the risk of developing Crohn’s disease.9

Table 1

Name Mechanism of Action Coverage Safety Profile Strength of Recommendation Additional Comments
Sarecycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria; extends to mRNA and increases inhibitory effect Narrow-spectrum; clinically relevant gram-positive bacteria
  • GI disturbance (<5%)
  • Vestibular effects (<1%)
  • Photosensitivity (<1%)\
  • Vulvovaginal candidiasis (0.3-1.1%)
  • Least likely to cause GI upset
  • Less likely to induce bacteria resistance
Minocycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance (1.5-25%)
  • Vestibular toxicity (~10%)
  • CNS problems (~17%)
  • Vulvovaginal candidiasis
  • Blue/grey skin pigmentation
  • Rare but serious autoimmune disease
  • Most lipophilic among tetracyclines
  • Can cause minocycline-related autoimmune disorders
Doxycycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance (10-25%)
  • Photosensitivity (15-30.5%)
  • Vulvovaginal candidiasis
  • Most likely to cause photosensitivity and GI problems when compared to the rest of the tetracyclines
Tetracycline Bacteriostatic; inhibits 30S ribosomal subunit of bacteria Broad-spectrum; gram-positive, gram-negative, and atypical bacteria
  • GI disturbance
  • Vulvovaginal candidiasis
  • Fixed drug eruptions
  • Dizziness
  • Tooth discoloration
  • Must be taken on an empty stomach
TMP-SMX Bactericidal due to synergy; TMP: folic acid analog that inhibits the enzyme dihydrofolate reductase SMX: blocks bacterial synthesis of folic acid Gram-positive, and gram-negative bacteria, fungi, protozoa
  • Hyperkalemia
  • Renal insufficiency
  • Stevens-Johnson syndrome/ toxic epidermal necrolysis
  • Adverse effects are mostly due to sulfonamides
TMP Bacteriostatic; folic acid analog that inhibits the enzyme dihydrofolate reductase Gram-positive, and gram-negative bacteria, fungi, protozoa
  • Drug eruption
Erythromycin Bacteriostatic; inhibits 50S ribosomal subunit of bacteria Anaerobic and aerobic grampositive cocci
  • GI disturbance
  • QT prolongation
  • High resistance rate
Azithromycin Bacteriostatic; inhibits 50S ribosomal subunit of bacteria Anaerobic and aerobic grampositive cocci
  • GI disturbance
  • Dosed intermittently due to long half-life
Table 1. Oral antibiotics available for moderate-to-severe acne treatment.1,24,25
CNS = central nervous system; GI = gastrointestinal; TMP-SMX = trimethoprim-sulfamethoxazole
Strength of recommendation: A = based on consistent and good quality patient-oriented evidence; B = based on inconsistent, limited quality patient-oriented evidence.

In 2018, a new tetracycline derivative, sarecycline, was US FDA-approved for the treatment of inflammatory lesions of non-nodular, moderate-to-severe acne vulgaris in patients aged 9 years and older.10 This once-daily 1.5 mg/kg antibiotic exhibits a better tolerability and efficacy profile as a result of its narrow-spectrum coverage against C. acnes and clinically-relevant gram-positive bacteria with little activity against gram-negative bacteria commonly found in the human gut.10 In vitro studies by Zhanel et al. showed that all tetracyclines had similar activity against C. acnes, even isolates highly resistant against erythromycin ranging at minimum inhibitory concentration (MIC) of 0.5 μg/mL to 32 μg/mL.6 Activity against methicillin-susceptible and resistant isolates of Staphylococcus aureus (including MRSA) revealed a MIC90 of all tetracyclines, including sarecycline, to be 0.5 μg/mL.6 Compared to doxycycline and minocycline, sarecycline had little or no activity against gram-negative enteric bacilli with MIC50 at 32 μg/mL (16-fold less than doxycycline and minocycline).6


Efficacy of Sarecycline

Leyden et al. compared dose ranges of sarecycline versus placebo in a 12-week phase 2 clinical trial with 285 patients. The subjects ranged from ages 12-45 years old with moderate-to-severe acne and were randomized to receive sarecycline dosed at 0.75 mg/kg, 1.5 mg/kg or 3.0 mg/kg, or placebo.10 Reductions of 52.7% and 51.8% in inflammatory lesions were reported in the 1.5mg/kg and 3.0mg/kg treatment groups, respectively, as compared to 38.3% for placebo. These results suggest no difference in efficacy for doses of 1.5 mg/kg and 3.0 mg/kg.10

In two identical 12-week phase 3 trials (SC1401 and SC1402), a total of 2002 subjects aged 9-45 years with moderate-to-severe acne were randomized 1:1 to receive sarecycline or placebo. As early as 3 weeks, there was a mean percentage reduction in inflammatory lesions of -49.9% to -51.8% in the sarecycline group versus -35.1% to -35.4% in the placebo group.11,12 In addition, there was significant improvement in truncal and chest acne by 12 weeks, which was observed as early as 3 weeks.11,12 In non-inflammatory facial acne, Moore et al. revealed a larger mean change from baseline in subjects using sarecycline versus placebo at week 12.12 IGA also improved in truncal acne by 2 points (and clear or almost clear) at week 12 in subjects on sarecycline that had an IGA of more than 2 at baseline.12,13

In a pilot study of 100 patients, sarecycline demonstrated significant efficacy in papulopustular rosacea, reducing not only lesion counts, but also erythema.14 Additionally, one case report showed the effectiveness of sarecycline in periorificial dermatitis.15

Mechanism of Action

Tetracyclines share a common four ring naphthacene core but differ by a variety of structures attached to the carbon groups.16 Sarecycline has a 7-[[methoxy(methyl)amino]methyl] group attached to the C7 position. It binds to the A site codon of tRNA, blocking protein synthesis and inhibiting bacterial growth (Figure 1).16,17 Unlike other tetracyclines, sarecycline extends to mRNA due to its long C7 moiety and allows for direct interaction with the mRNA channel.16 This increases its stabilization, leading to better inhibitory activity by blocking tRNA accommodation and mRNA translation.17,18

Figure of the mechanism of action of sarecycline.
Figure 1. The mechanism of action of sarecycline.
Like other tetracyclines, sarecycline binds to the 30S subunit of rRNA, preventing tRNA from binding to the A site codon. Sarecycline also has a large C7 group that interacts with the mRNA channel, further stabilizing the drug on the ribosome. Modified from: Graber, EM. Treating acne with the tetracycline class of antibiotics: A review. Dermatological Reviews. 2021.9 Severity score: 0 = absent; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

Antibacterial Resistance

Antimicrobial resistance complicates the prolonged use of antibiotics, in general. Due to its narrow-spectrum coverage, sarecycline is less likely to induce resistance.6 C. acnes displayed low propensity for the development of resistance to sarecycline with spontaneous mutation frequency of 10-10 at 4-8 times the MIC.6 Bacteria confer resistance to tetracyclines by forming efflux pumps and acquiring Tet proteins that bind to the A site codon of the tRNA, releasing the bacteria from the antibiotics.16,19 The acquisition of combined Tet(K) and Tet(M) genes among S. aureus strains confers resistance against tetracyclines.6 Compared to the other agents in its drug class, sarecycline has shown superiority in its activity against these tetracyclineresistant S. aureus strains against Tet(K) at MIC ranging from 0.12-0.5 g/mL as compared to 16-65 g/mL with the other tetracyclines.6 Due to its narrow-spectrum activity, sarecycline is expected to yield lower rates of antimicrobial resistance; however, it has not been found to be statistically significant when compared to other tetracyclines.6 Zhanel et al. noted that sarecycline’s propensity to lead to C. acnes mutations was not found to be significantly different from minocycline.6

Safety Profile

The broad-spectrum activity of minocycline and doxycycline elicits common adverse effects such as gastrointestinal symptoms, photosensitivity, dizziness, microbial resistance, and tinnitus.1,19-21 Data has shown that, thus far, the most common adverse effect associated with sarecycline is nausea at an incidence of ≥1%.10 Moore et al. reported that treatment-emergent adverse events were similar in both the sarecycline and placebo groups, the most common being nausea.12 A phase 1 randomized, double-blinded, placebo-controlled study was conducted to assess phototoxicity in 18 healthy adult males with Fitzpatrick skin types I, II, and III on 240 mg sarecycline.22 There was no significant dermal response to ultraviolet light exposure. Photosensitivity reactions were uncommon and limited to mild erythema.22 Dizziness was experienced by <1% of patients receiving sarecycline, and no vertigo or tinnitus was reported.23 Sarecycline is less likely to penetrate the blood-brain barrier, which may explain the very low rates of vestibular adverse events observed in the clinical trials.23


Sarecycline is a novel antibiotic that has shown significant promise in acne treatment due to its narrow-spectrum activity and weight-based dosing. The advantages of this new systemic therapy include improved tolerability, reduced drug resistance and potentially longer-lasting efficacy. There remain more avenues to explore including sarecycline’s utility in treating other cutaneous infections and inflammatory dermatoses.


  1. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May;74(5):945-73 e33.

  2. Tanghetti EA. The role of inflammation in the pathology of acne. J Clin Aesthet Dermatol. 2013 Sep;6(9):27-35.

  3. Alsulaimani H, Kokandi A, Khawandanh S, et al. Severity of acne vulgaris: comparison of two assessment methods. Clin Cosmet Investig Dermatol. 2020 Sep;28;13:711-6.

  4. Purdy S, de Berker D. Acne vulgaris. BMJ Clin Evid. 2011 Jan 5;2011.

  5. Kraft J, Freiman A. Management of acne. CMAJ. 2011 Apr 19;183(7):E430-5.

  6. Zhanel G, Critchley I, Lin LY, et at. Microbiological profile of sarecycline, a novel targeted spectrum tetracycline for the treatment of acne vulgaris. Antimicrob Agents Chemother. 2019 Jan;63(1).

  7. Thompson KG, Rainer BM, Antonescu C, et al. Minocycline and its impact on microbial dysbiosis in the skin and gastrointestinal tract of acne patients. Ann Dermatol. 2020 Feb;32(1):21-30.

  8. Grada A, Bunick CG. Spectrum of antibiotic activity and its relevance to the microbiome. JAMA Netw Open. 2021 Apr 1;4(4):e215357.

  9. Graber EM. Treating acne with the tetracycline class of antibiotics: a review. Dermatol Rev. 2021 Dec;2(6):321-30. Available at: Accessed March 27, 2022.

  10. Leyden JJ, Sniukiene V, Berk DR, et al. Efficacy and safety of sarecycline, a novel, once-daily, narrow spectrum antibiotic for the treatment of moderate to severe facial acne vulgaris: results of a phase 2, dose-ranging study. J Drugs Dermatol. 2018 Mar 1;17(3):333-8.

  11. SEYSARA® (sarecycline) tablets for oral use [prescribing information]. Revised June 2020. Almirall, LLC, Exton, PA. Available at: https://www.accessdata.fda. gov/drugsatfda_docs/label/2020/209521s007lbl.pdf. Accessed March 27, 2022.

  12. Moore A, Green LJ, Bruce S, et al. Once-daily oral sarecycline 1.5 mg/kg/day is effective for moderate to severe acne vulgaris: results from two identically designed, phase 3, randomized, double-blind clinical trials. J Drugs Dermatol. 2018 Sep 1;17(9):987-96.

  13. Del Rosso JQ, Stein Gold L, Baldwin H, et al. Management of truncal acne with oral sarecycline: pooled results from two phase-3 clinical trials. J Drugs Dermatol. 2021 Jun 1;20(6):634-40.

  14. Rosso JQ, Draelos ZD, Effron C, et al. Oral sarecycline for treatment of papulopustular rosacea: results of a pilot study of effectiveness and safety. J Drugs Dermatol. 2021 Apr 1;20(4):426-31.

  15. Graber E, Kay CR. Successful treatment of periorificial dermatitis with novel narrow spectrum sarecycline. J Drugs Dermatol. 2021 Jan 1;20(1):98-100.

  16. Batool Z, Lomakin IB, Polikanov YS, et al. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20530-7.

  17. Deeks ED. Sarecycline: first global approval. Drugs. 2019 Feb;79(3):325-9.

  18. Bunick CG, Keri J, Tanaka SK, et al. Antibacterial mechanisms and efficacy of sarecycline in animal models of infection and inflammation. Antibiotics (Basel). 2021 Apr 15;10(4).

  19. Connell SR, Tracz DM, Nierhaus KH, et al. Ribosomal protection proteins and their mechanism of tetracycline resistance. Antimicrob Agents Chemother. 2003 Dec;47(12):3675-81.

  20. Kircik LH. Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol. 2010 Nov;9(11):1407-11.

  21. Ochsendorf F. Minocycline in acne vulgaris: benefits and risks. Am J Clin Dermatol. 2010;11(5):327-41.

  22. Pariser DM, Green LJ, Lain EL, et al. Safety and tolerability of sarecycline for the treatment of acne vulgaris: results from a phase III, multicenter, open-label study and a phase I phototoxicity study. J Clin Aesthet Dermatol. 2019 Nov;12(11):E53-E62.

  23. Moore AY, Del Rosso J, Johnson JL, et al. Sarecycline: a review of preclinical and clinical evidence. Clin Cosmet Investig Dermatol. 2020 Aug;13:553-60.

  24. Tan HH. Antibacterial therapy for acne: a guide to selection and use of systemic agents. Am J Clin Dermatol. 2003;4(5):307-14.

  25. Armstrong AW, Hekmatjah J, Kircik LH. Oral tetracyclines and acne: a systematic review for dermatologists. J Drugs Dermatol. 2020 Nov 1;19(11):s6- s13.

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