safe; however, 2.5% of patients were found to have persistent elevations in total bilirubin (Table 1).32 In another retrospective study 94,487 acne patients, ages 15–35 years old, researchers found that those who received tetracycline (N=38,603) were approximately 40% more likely to develop new-onset IBD [HR 1.43; 95% CI 1.92–2.02] (Table 1).18
DISCUSSION
Dermatologists play an important role in antibiotic stewardship because dermatologists write the highest number of antibiotic prescriptions per clinician, and oral tetracyclines account for approximately 75% of these antibiotic prescriptions.33 In this review, we summarized the efficacy and safety of oral tetracyclines indicated for acne from large clinical trials and observational studies.
Maintaining diversity of the gut microbiome is important. For example, one benefit of a diverse gut microbiome is the production of short-chain fatty acids (SCFA). SCFA have been found beneficial in metabolism, nutrient absorption, and prevention of carcinogenesis and inflammation in specific cells.33-36 However, the broad-spectrum antimicrobial actions of some oral tetracyclines may be associated with gut dysbiosis.7 Multiple factors can contribute to the adverse effect of gut dysbiosis, which includes mechanism of action, dose, and duration.37 For example, 10μg/ml (~10mg/kg) of doxycycline resulted in major reductions in the concentrations of common gut anaerobic bacteria such as Enterobacteriacea and Bacteroides.38 In comparison, a minimum inhibitory concentration (MIC) of ~32μg/ml (~32mg/kg) of sarecycline was equivalent to a MIC of ~8μg/ml (~8mg/kg) of doxycycline on reducing Enterobacteriacea species by 50%.11 This demonstrates sarecycline’s 16-fold decrease in activity against Enterobacteriacea, a common gut anaerobic bacteria, when compared to doxycycline.11
Prolonged, non-selective antibiotic use can be associated with the development of antibiotic-resistant organisms. Specifically, regarding C. acnes, rates of resistance to antibiotic monotherapy have been increasing from ~20% in the 1960s to ~60% in 2003.39,40 Furthermore, patients found to have C. acnes resistance were less likely to demonstrate clinical improvement.40 Of note, countries that utilize fewer antibiotics typically have lower resistance rates.41 Selective therapies, such as sarecycline, have a low propensity for resistance and can be utilized to help reduce the development of antibiotic resistance.10,11
Unfortunately, the use of broad-spectrum antibiotics to treat acne vulgaris contributes to the erosion of their activity against Gram-negative bacterial infections, for which few effective antibiotics are available. Oral doxycycline, for example, is FDA-approved for several indications, including rickettsial infections, sexually transmitted infections, respiratory tract infections, specific bacterial infections, ophthalmic infections, anthrax, and acne, among others. This raises the question whether its long-term repeated use in acne will compromise its efficacy in treating infectious diseases.
In conclusion, oral tetracyclines remain the mainstay of oral treatment for acne. To minimize adverse effects, recommendations for the use of oral antibiotics in acne include combining oral antibiotic therapies with topical treatments, limiting treatment duration to three to four months at a time, and re-evaluation every six to eight weeks.42 The use of narrow-spectrum antibiotics is one of the main elements of the antibiotic stewardship program.43,44 The primary goal of antibiotic stewardship is to improve patient outcomes while minimizing side effects and preventing drugresistant bacterial infections. Future drug developments in oral antibiotics should continue to focus on selecting highly efficacious agents while minimizing antibiotic resistance and gut dysbiosis.
Maintaining diversity of the gut microbiome is important. For example, one benefit of a diverse gut microbiome is the production of short-chain fatty acids (SCFA). SCFA have been found beneficial in metabolism, nutrient absorption, and prevention of carcinogenesis and inflammation in specific cells.33-36 However, the broad-spectrum antimicrobial actions of some oral tetracyclines may be associated with gut dysbiosis.7 Multiple factors can contribute to the adverse effect of gut dysbiosis, which includes mechanism of action, dose, and duration.37 For example, 10μg/ml (~10mg/kg) of doxycycline resulted in major reductions in the concentrations of common gut anaerobic bacteria such as Enterobacteriacea and Bacteroides.38 In comparison, a minimum inhibitory concentration (MIC) of ~32μg/ml (~32mg/kg) of sarecycline was equivalent to a MIC of ~8μg/ml (~8mg/kg) of doxycycline on reducing Enterobacteriacea species by 50%.11 This demonstrates sarecycline’s 16-fold decrease in activity against Enterobacteriacea, a common gut anaerobic bacteria, when compared to doxycycline.11
Prolonged, non-selective antibiotic use can be associated with the development of antibiotic-resistant organisms. Specifically, regarding C. acnes, rates of resistance to antibiotic monotherapy have been increasing from ~20% in the 1960s to ~60% in 2003.39,40 Furthermore, patients found to have C. acnes resistance were less likely to demonstrate clinical improvement.40 Of note, countries that utilize fewer antibiotics typically have lower resistance rates.41 Selective therapies, such as sarecycline, have a low propensity for resistance and can be utilized to help reduce the development of antibiotic resistance.10,11
Unfortunately, the use of broad-spectrum antibiotics to treat acne vulgaris contributes to the erosion of their activity against Gram-negative bacterial infections, for which few effective antibiotics are available. Oral doxycycline, for example, is FDA-approved for several indications, including rickettsial infections, sexually transmitted infections, respiratory tract infections, specific bacterial infections, ophthalmic infections, anthrax, and acne, among others. This raises the question whether its long-term repeated use in acne will compromise its efficacy in treating infectious diseases.
In conclusion, oral tetracyclines remain the mainstay of oral treatment for acne. To minimize adverse effects, recommendations for the use of oral antibiotics in acne include combining oral antibiotic therapies with topical treatments, limiting treatment duration to three to four months at a time, and re-evaluation every six to eight weeks.42 The use of narrow-spectrum antibiotics is one of the main elements of the antibiotic stewardship program.43,44 The primary goal of antibiotic stewardship is to improve patient outcomes while minimizing side effects and preventing drugresistant bacterial infections. Future drug developments in oral antibiotics should continue to focus on selecting highly efficacious agents while minimizing antibiotic resistance and gut dysbiosis.
DISCLOSURES
AWA has served as a research investigator and/or consultant to AbbVie, Janssen, Lilly, Leo, Novartis, UCB, Ortho Dermatologics, Dermira, KHK, Sanofi, Regeneron, Sun Pharma, BMS, Dermavant, and Modernizing Medicine.
JH declares no conflicts of interest.
LHK has served as either a consultant, speaker, or an investigator for Almirall, Galderma, Epi Health, Mayne Pharma, Novartis, Ortho Dermatologics, Dr Reddys, and Sun Pharma.
JH declares no conflicts of interest.
LHK has served as either a consultant, speaker, or an investigator for Almirall, Galderma, Epi Health, Mayne Pharma, Novartis, Ortho Dermatologics, Dr Reddys, and Sun Pharma.
REFERENCES
1. Collier CN, Harper JC, Cantrell WC, et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol. 2008 Jan 1;58(1):56-9.
2. Rasmussen B, Noller HF, Daubresse G, et al. Molecular basis of tetracycline action: identification of analogs whose primary target is not the bacterial ribosome. Antimicrob Agents Chemother. 1991 Nov 1;35(11):2306-11.
3. Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res. 2011 Feb 1;63(2):130-45.
4. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May 1;74(5):945- 73.
5. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Human gut microbes associated with obesity. Nature. 2006 Dec;444(7122):1022-3.
6. Ahmad OF, Akbar A. Microbiome, antibiotics and irritable bowel syndrome. Br Med Bull. 2016 Dec 1;120(1).
7. Melander RJ, Zurawski DV, Melander C. Narrow-spectrum antibacterial agents. Medchemcomm. 2018;9(1):12-21.
8. 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;17(9):987-96.
9. Leyden JJ, Bruce S, Lee CS, Ling M, Sheth PB, Stewart DM, Werschler WP, Gilbert RD, Kircik L. A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium. J Drugs Dermatol. 2013;12(6):658-63.
2. Rasmussen B, Noller HF, Daubresse G, et al. Molecular basis of tetracycline action: identification of analogs whose primary target is not the bacterial ribosome. Antimicrob Agents Chemother. 1991 Nov 1;35(11):2306-11.
3. Monk E, Shalita A, Siegel DM. Clinical applications of non-antimicrobial tetracyclines in dermatology. Pharmacol Res. 2011 Feb 1;63(2):130-45.
4. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016 May 1;74(5):945- 73.
5. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Human gut microbes associated with obesity. Nature. 2006 Dec;444(7122):1022-3.
6. Ahmad OF, Akbar A. Microbiome, antibiotics and irritable bowel syndrome. Br Med Bull. 2016 Dec 1;120(1).
7. Melander RJ, Zurawski DV, Melander C. Narrow-spectrum antibacterial agents. Medchemcomm. 2018;9(1):12-21.
8. 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;17(9):987-96.
9. Leyden JJ, Bruce S, Lee CS, Ling M, Sheth PB, Stewart DM, Werschler WP, Gilbert RD, Kircik L. A randomized, phase 2, dose-ranging study in the treatment of moderate to severe inflammatory facial acne vulgaris with doxycycline calcium. J Drugs Dermatol. 2013;12(6):658-63.
