Sarecycline: A Narrow-Spectrum Antibiotic

Susuana Adjei, MD¹; Austinn C. Miller, MD¹; Laurie A. Temiz, BA^1,2; Stephen K. Tyring, MD, PhD, MBA^1,3

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.

---

Abstract:
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

Introduction

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

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

Discussion

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

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

Conclusion

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.

Purchase Article PDF for $1.99