¹Center for Clinical Studies Webster, TX, USA
²Meharry Medical College, Nashville, TN, USA
³Texas A&M University College of Medicine, Temple, TX, USA
⁴University of Texas Health Science Center, Department of Dermatology, Houston, TX, USA

Conflict of interest: All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand how dermatologists can combat this issue.

Keywords: antibiotic resistance, dermatology, antibiotic, antimicrobial, infection, acne, rosacea, hidradenitis suppurativa, folliculitis decalvans, bullous pemphigoid, CARP

Introduction

There are many reasons for the development of antibiotic resistant bacteria. Aside from rampant use in agriculture settings, poor antibiotic stewardship among physicians is a major contributor. Dermatologists play an essential role in this process given the significant incidence of inflammatory dermatoses, as well as skin and soft tissue infections (SSTIs) treated with antibiotics. Furthermore, dermatologists have a higher rate of prescribing antibiotics compared to other specialists.¹ Therefore, it is crucial for dermatologists to understand strategies to combat bacterial resistance and reduce its global burden.

Combating Antibiotic Resistance in Dermatology

Molecular resistance is perpetuated through poor antibiotic stewardship. Commonly, this stems from unclear instructions on self-administration of antibiotics, use of sub-antimicrobial dosing, prescription of antibiotics for minor bacterial infections, use of antibacterial drugs for non-bacterial infections, and use of broad-spectrum antibiotics for narrow-spectrum indications.²

General methods for diminishing risk of antibiotic resistance include detailed history and physical, diagnostic laboratory and culture studies, close monitoring of clinical response, appropriate directed-therapy when the causative organism is identified, relevant empiric treatment based on local antimicrobial susceptibilities within the community, and continuing therapy for the appropriate duration.³ All of these general precautions, as well as discontinuing of antibiotics when deemed unnecessary, will aid to reduce the rate of antibiotic resistance.³

In the United States, individuals with acne vulgaris and rosacea account for 20% of the patients prescribed antimicrobials in dermatology.⁴ SSTIs account for a significant amount of the remaining portion. Specific strategies can be utilized to combat emerging resistance in the treatment of acne vulgaris, rosacea, hidradenitis suppurativa (HS), folliculitis decalvans (FD), bullous pemphigoid (BP), and confluent and reticulated papillomatosis (CARP) and SSTIs.

Acne Vulgaris

Antibiotic monotherapy is not recommended for acne vulgaris treatment. Both topical and systemic monotherapy may induce resistance among Cutibacterium acnes (C. acnes) and other organisms that comprise the commensal and transient flora.⁵ The American Academy of Dermatology (AAD) guidelines recommend coadministration of benzoyl peroxide, a topical bactericidal agent not reported to cause resistance, together with both topical and oral antibiotics.^6,7 Added to topical antibiotics, benzoyl peroxide may prevent the formation of resistance and increase treatment efficacy.⁶ Only indirect evidence supports the ability of benzoyl peroxide to limit resistance when used with oral antibiotics.^6,8 Additionally, the AAD recommends using the shortest possible courses, limiting antibiotic use to 3-4 months.⁷

Low-dose or “sub-antimicrobial” doses of doxycycline have been used in rosacea and acne vulgaris, with the intention to only derive benefits from the anti-inflammatory properties of the antibiotic.^2,9,10 However, contrary to the common belief, recent studies demonstrated that low-dose antibiotic exposure leads to the development of high-level resistance.^2,9,11

A unique method being utilized to bypass bacterial resistance in acne is the development of narrow spectrum drugs such as the new tetracycline, sarecycline. Sarecycline is a US FDA approved therapy specifically designed to treat moderate-severe acne and is the only antibiotic with a low resistance claim in its label.² It is narrow spectrum with coverage limited to clinically relevant gram-positive organisms, including C. acnes. Its structural design involves an elongated C7 moiety that extends into the 30S ribosome and directly interferes with mRNA unlike typical tetracyclines.² This newer design allows for stronger binding and increased inhibitory effects.

Rosacea

The large body of evidence supporting an inflammatory pathogenesis of rosacea not triggered by a bacterial etiology has led to rosacea management guidelines that support avoidance of antibiotics whenever possible.⁵ This includes the papulopustular subtype. Antibiotics should only be used after failure of topical and oral anti-inflammatory therapy.¹² Like acne, if antibiotics are used, the course should be as short as possible with treatment for no longer than 2 months.¹²

Hidradenitis Suppurativa (HS)

Given that topical clindamycin and oral tetracycline are firstline therapies for HS, it is not surprising that a high percentage of HS patients harbor lincosamide and tetracycline resistant bacteria.¹³ Therefore, it is recommended that antibiotics be used as adjunctive therapy with other management options, including chlorhexidine or benzoyl peroxide wash, adalimumab, smoking cessation, weight loss, and other non-antimicrobial treatments.^13,14

Folliculitis Decalvans (FD)

A small study of patients with FD who received one or more courses of antibiotic therapy demonstrated a third of patients harbored antibiotic resistant Staphylococcus aureus (S. aureus).¹⁵ The resistance rates in FD patients were significantly higher than the community reference values.¹⁵

Given FD is thought to stem from S. aureus, antibiotic therapy will likely remain the gold standard for exacerbations.¹⁵ However, treatments should be based on bacterial culture/sensitivities, with the aim to transition to nonantibiotic medical therapies (isotretinoin/dapsone/photodynamic therapy) or destructive therapies (laser hair removal/surgery) to suppress inflammation and address hair follicle structural abnormalities and biofilm formation to induce long-term remission.^15,16

Bullous Pemphigoid (BP)

Although topical and systemic steroids are considered the first-line treatment for BP, the substantial morbidity and mortality associated with these regimens presents a therapeutic challenge. Inasmuch, other treatment options are being sought. Among the plethora of agents trialed have been antibiotics, most notably tetracyclines given their anti-inflammatory properties. While some trials have concluded that systemic tetracyclines are effective in BP treatment, they are inferior in recovery rate when compared to systemic steroids.¹⁷ Moreover, those with milder BP and shorter courses of tetracyclines tend to achieve a lower proportion of remission than those with severe disease, indicating that disease severity and the potential need for prolonged treatment should to be taken into account before initiation.¹⁸ Therefore, judicious consideration is needed before placing patients on antibiotics for BP treatment. In general, tetracyclines may be appropriate in older patients with comorbidities that contraindicate systemic steroid use.¹⁸

Confluent and Reticulated Papillomatosis (CARP)

Oral tetracyclines are the most commonly cited monotherapy for CARP; minocycline is utilized most frequently, but other antibiotics used include amoxicillin and azithromycin.¹⁹ Evidence suggests dysfunctional keratinization as a cause of CARP, and this is supported by successful treatment with both topical and oral retinoids.²¹ Efficacy of this treatment is attributed to the anti-inflammatory and immunomodulating properties of retinoids and normalization of keratinization.²⁰ Advantages of retinoid therapy include higher patient compliance and decreased side effects.²⁰ Other treatment options that have demonstrated clinical effects include topical vitamin D derivatives.¹⁹

Skin and Soft Tissue Infections (SSTIs)

Resistance has emerged against many commonly used topical and oral antibiotics for SSTIs. This is likely a result of overuse and misuse.

Topical

Prophylactic use of topical antibiotics after surgical procedures is often unnecessary. A meta-analysis based on data pooled from four studies failed to demonstrate a statistically significant difference between application of topical antibiotics versus topical petrolatum/paraffin in preventing post-surgical infections after low risk office-based dermatologic procedures.^5,22 Low risk procedures include those with clean and clean-contaminated wounds, and following procedures in patients that are immunocompetent and not at high risk of infection, surgeries performed in regions above the knee, and surgeries not involving the groin, ears, or mucosal region of the nose or mouth.⁵ In cases where risk of post-operative infection is high, it is a better choice to utilize oral antibiotic prophylaxis, as topical therapy alone is not as likely to provide adequate prevention of infection.^5,23

Other prophylactic uses of topical antibiotics, such as with atopic dermatitis (AD), have not demonstrated efficacy either. When a cutaneous infection is present, antibiotic therapy is therapeutically beneficial in AD.¹⁸ However, chronic topical or oral antibiotic therapy is not advised to manage or suppress AD in the absence of a true skin infection, and it serves only to promote antibiotic resistance.¹⁸

Another factor to keep in mind is that topical antibiotic therapy is capable of inducing antibiotic resistance beyond areas of application.⁵ Topical erythromycin used on the face induced resistant C. acnes and staphylococci on the back and anterior nares where it was not applied.²⁴ Similar results have been demonstrated with other bacteria such as streptococci.⁵

Mupirocin resistance has reached up to 80% among bacterial strains such as S. aureus in certain communities with heavy usage.^13,25 Low resistance alternatives are fusidic acid and topical pleuromutilins.¹³ Moreover, regular local antiseptic treatment including octenidine or polyhexanide is broadly efficacious and confers a significantly lower risk of resistance relative to topical antibiotics.²⁶

Systemic

Prophylactic oral antibiotics are rarely appropriate for routine dermatologic surgery and are not indicated for patients who have prosthetic joints or vascular grafts.²³ It is recommended only for a small group of patients that have abnormal cardiac valves, and then only with surgery involving clearly infected skin or soft-tissue.²³

Controlled trials indicate that antimicrobial agents are unhelpful in treating cutaneous abscesses, inflamed epidermal cysts, uninfected atopic eczema, and cutaneous ulcers caused by venous insufficiency or diabetes in the absence of significant contiguous soft-tissue inflammation.²³

Between 5-10% of the North American population is classified as beta-lactam allergic.²⁷ However, only 10% of these can be confirmed by allergy diagnostics.²⁷ A false beta-lactam allergy diagnosis may lead to inappropriate use of broad spectrum antibiotics. Common reasons for a false beta-lactam allergy include misinterpretation of known predictable side effects, misinterpretation of infection-induced urticaria or viral exanthema as an immediate type drug reaction or drug exanthema; interpreting non-specific symptoms as an allergy, and considering known reactions in the family as signs of personal allergy.²⁷ To verify a true beta-lactam allergy, risk stratification of all patients should be performed. Patients with a questionable allergy may be excluded based on history alone.²⁷ Patients with an incomplete history or mild reaction may be tested on a case-by-case basis.²⁷ Patients with a medical history strongly suggesting a true allergy should undergo formal testing through a skin test (skin prick, intradermal/patch), lab test (specific immunoglobulin E, basophil activation test), and/or oral provocation test with fractionated administration of beta-lactam.²⁷

Future Directions

To confront the challenge of resistance, modification of existing antibiotics to improve potency and efficacy is underway.¹³ Additionally, development of new narrow spectrum agents with novel mechanisms of action is being pursued.¹³ Given that drug development is a slow process, it cannot keep up with the spread of resistant bacteria. Therefore, alternative methods are under investigation.

One promising avenue is modulation of the skin microbiome.¹³ Abnormalities in the skin microbiome have been observed in patients with acne.^13,28 Treatment with isotretinoin in these patients restored microbiomes to normal.²⁸ Thus, infectious and inflammatory dermatoses may respond to direct manipulation of the skin microbiome via live biotherapeutic products or transplantation of human skin microbiota.¹³ Recent trials have already demonstrated success in treating AD with skin microbiota transplantation.²⁹

Another alternative gaining traction is phage therapy, which uses bacteriophages to infect and lyse bacteria.^13,30 Recent studies have reported successful use of personalized bacteriophage therapy in patients with multidrug-resistant infections.³¹

Further strategies include implementation of electroporation, antimicrobial peptides, photodynamic therapy (PDT), photothermal therapy, nitrous oxide-releasing nanoparticles, cannabidiol, or combinations of these options.³² PDT is a therapeutic option for cutaneous infections immune to antibiotics. PDT use in acne results in reduced follicular obstruction and lower sebum excretion.³² At higher doses, it can destroy sebaceous glands.³² For cutaneous leishmaniasis and warts, PDT has demonstrated clearance rates of up to 100%.³² PDT has also been initiated as a treatment option for onychomycosis.³² Transdermal iontophoresis has been coupled with PDT to increase its effectiveness.³² It uses small electrical currents to permit controlled drug delivery and use of smaller drug concentrations.³² Its use has demonstrated broad spectrum antimicrobial efficacy against bacteria, fungi, and viruses.

Conclusion

Correct and appropriate use of antibiotics will help to preserve their utility in the face of increasing antibiotic resistance; however, greater awareness of the etiologies of resistance and how to combat each is required among prescribing providers.

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

Conflict of interest:
All authors have no conflicts of interest.

Abstract:
Virtually any antibiotic can be used in dermatology given the broad range of conditions treated. With the widespread use of antibiotics and the rapid emergence of resistant organisms, it is important to understand the mechanisms at play that contribute to resistance.

Key Words:
antibiotic resistance, dermatology, mechanisms of resistance, antibiotic, antimicrobial, infection

Introduction

The advent of antibiotics is arguably one of the greatest achievements in history, permitting survival among many with infections who would have previously died without intervention. Amid the fields in which the use of antibiotics is particularly widespread lies dermatology. A spectrum of inflammatory and infectious dermatologic conditions have been treated with antibiotics since their inception. The continued success of any therapeutic agent is compromised by the potential development of tolerance or resistance to that compound over time.¹ In the case of antibiotics, resistance among bacteria has become a serious issue and has been named one of the greatest threats to human health.² The number of infections caused by multidrug-resistant bacteria is increasing, and the specter of untreatable infections is now a reality.² As this number increases, new antibiotic developments cannot match the pace.²

While many factors contribute to the development of resistance, its basis stems from bacterial alterations at the molecular level. Therefore, it is important for dermatologists to understand the mechanisms at play.

Brief Review of Antibiotics in Dermatology and Mechanism of Action

Many antibiotics are utilized in dermatology. Countless isolates of bacteria may cause skin and soft tissue infections (SSTIs) resulting in a wide variety of clinical presentations. Most commonly, superficial cutaneous infections and pyodermas are caused by Staphylococcus aureus (S. aureus) resulting in impetigo, ecthyma, folliculitis, intertrigo, and paronychia. However, other bacterial organisms may also be responsible. Deeper infections like cellulitis, erysipelas, and necrotizing fasciitis are also classically caused by S. aureus or Streptococcus pyogenes, but are also commonly caused by a variety of other gram-positive and negative organisms. Antibiotics may also be used for anti-inflammatory effects, such as with the treatment of acne vulgaris, rosacea, folliculitis decalvans, and hidradenitis suppurativa.

Given the wide variety of conditions treated with antibiotics, nearly the entire gamut may be utilized by dermatologists at some point in time. Understanding the antibiotic mechanism of action is key to understanding mechanisms of resistance (Figure 1, Table 1).

Mechanisms of Resistance

Mechanisms by which bacteria evade antibiotic destruction vary in complexity. The most basic method involves mutations in the bacterial target gene, creating a mutant target protein that prevents interaction with the antibiotic, rendering it ineffective.² Given the intrinsic error prone process of DNA replication/ repair, this type of resistance is inevitable as mutations are bound to occur.³ Resistance may also occur through acquisition of genes encoding proteins that reduce antibiotic binding to molecular targets.² Bacteria can produce enzymes capable of manipulating molecular targets and blocking antibiotics from binding.² In addition to modifying the molecular target, bacteria can also reduce the concentration of antibiotics through chemical or enzymatic modification.² Finally, if an antibiotic target comprises an entity other than a single gene product, resistance to these drugs is attained via retrieval of pre-existing diversity in cell structures and altering their biosynthesis through global cell adaptations.^2,3

Modification of Antibacterial Target

Bacteria are capable of modifying any protein that an antibiotic might target.⁴ Among the most popular antibiotic protein targets is the bacterial ribosome, a complex protein producing machine.⁵ Bacterial ribosomes consist of dozens of proteins that are arranged into large (50S) and small (30S) subunits.⁶ Each subunit is associated with specialized ribosomal RNA (50S – 23S, 5S; 30S – 16S). Ribosomes produce proteins through translation – a three-step process: initiation, elongation, and termination.

By targeting ribosomal proteins, antibiotics block protein synthesis in bacteria thus halting proliferation. To survive, bacteria have evolved mechanisms to elude antibiotic protein targeting.

Target Protection

Target protection is a phenomenon whereby a resistance protein physically associates with an antibiotic target to rescue it from antibiotic-mediated inhibition.⁵ Target protection is an important mode of bacterial resistance to many antibiotics used in dermatology, especially against tetracyclines.⁷

To disrupt tetracycline action, bacteria deploy ribosomal protection proteins (RPPs) Tet(O) and Tet(M).⁵ Both of the RPPs are hydrolases that become active in a tetracycline dependent manner. When tetracycline interacts with its ribosomal target, it induces changes in the cellular environment that results in increased affinity of the RPPs to the antibiotic-30S structure.⁵ The RPPs then hydrolyze antibiotic-30S bonds, dislodging the tetracycline, which permits normal protein synthesis to resume.⁵

Target Site Modification

By design, antibiotics are selective of target structures. When target structures are modified, chemical properties are altered which change antibiotic target affinity.² For organisms to survive with resistance, these modifications must result in a loss of target affinity while still maintaining adequate function of normal activities. Most often, this is accomplished by point mutations in genes encoding target sites, enzymatic alterations of binding sites, and replacement or bypass of target sites.²

Mutations of Target Site

Mutations of the 16S portion of the 30S ribosomal subunit target site are the most common form of resistance to aminoglycosides.⁸ Macrolides are also resisted via target site mutations. The 23S portions of the 50S ribosomal subunit targeted by macrolides can undergo multiple viable mutations.³ Quinolone resistance can occur through target mutation.⁹ Quinolone resistance determining regions (QRDR) are target gene sequences susceptible to viable mutations that decrease quinolone target affinity.¹⁰ Specifically, substitutions in the gyrA and gyrB sequences affect DNA gyrase, while substitutions in parC and parE affect topoisomerase IV.¹⁰

Enzymatic Alteration of Target Site

Many different enzymes play a role in antibiotic resistance. One method by which enzymes contribute is through modification of the target site, which results in decreased antibiotic affinity similar to target site mutations. Methylation of strategic nucleotides in the antibiotic binding site weakens antibiotic binding via steric clashes with the modified nucleotide.¹¹ Since some antibiotics share partially overlapping binding sites, methylation of a single nucleotide can result in resistance to multiple antibiotic classes.¹¹

Enzymatic methylation of the ribosome confers resistance to many antibiotics that target the 23S portion of the 50S subunit. Moreover, a specific family of genes encoding for enzymatic methylation may confer resistance against multiple antibiotics that share the same ribosomal binding region.¹² For example, the erythromycin ribosomal methylation (erm) gene confers cross resistance to macrolides, lincosamides, and streptogramin B which all bind the same ribosomal site.² This gene is commonly found in gram-positive cocci and is shared among bacteria via plasmids and transposons. The cfr gene functions similarly to erm, producing a methylation enzyme that provides resistance among gram-positive and gram-negative organisms to oxazolidinones, pleuromutilins, and streptogramin A.^2,12

Bypass or Replacement of Target Site

Bypassing of target sites occurs when the target site is changed so that the antibiotic is rendered useless. It may occur through several mechanisms.² A popular example of resistance to beta (β)-lactams is seen with the mecA gene in Staphylococcus aureus.^2,13 This gene results in replacement of normal penicillin-binding proteins (PBPs) with PBP2a that has a low affinity for β-lactams. Its induction occurs in the presence of β-lactams.^2,13

Antibiotic Alteration

One method of resistance that bacteria can employ is antibiotic alteration. This is done through enzymatic modification or degradation.^2,14 Inactivating modifications interfere with antibiotic-target site binding and include acetylation, phosphorylation, glycosylation, and hydroxylation.^2,14 Enzymatic degradation results in the destruction of antibiotics.²

Aminoglycosides are subject to modification through aminoglycoside modifying enzymes (AMEs).^2,14 AMEs consists of acetyltransferases, adenyl transferases, and phosphotransferases.² β-lactams are subject to degradation via β-lactamases.¹⁵ In gram-negative bacteria, β-lactamase enzymes that hydrolyze the amide bond of the four-membered β-lactam ring are the primary resistance mechanism, rendering β-lactams useless.¹⁵ β-lactamases can be encoded intrinsically (chromosomal) or disseminating on mobile genetic elements like plasmids across opportunistic pathogens.¹⁵ In the more recent past, β-lactamases have extended beyond penicillins and cephalosporins to carbapenems.¹⁵ Macrolide resistant bacteria have developed enzymes, such as erythromycin esterases, that cleave essential ester bonds and thus disrupt macrolide structure.¹⁶ The genes encoding these enzymes are found on mobile genetic elements, establishing the potential for widespread resistance.¹⁶

Membrane Permeability Variation

Antibiotic resistance can be mediated by changes to the cell membrane permeability.¹⁷ This can be done through alteration in lipid, porin, and transporter structures such as efflux pumps.²

To gain entry into the bacterial cells, antibiotics like β-lactams cross the lipid bilayer of the cell membrane via porins, whereas other lipophilic antibiotics such as macrolides traverse the bilayer via diffusion.³ Alterations to porins or lipid structure result in permeability changes that potentiate resistance. Some gram-negative bacteria intrinsically express full length lipopolysaccharide that prevent diffusion of lipophilic antibiotics.¹⁸

Porin mediated resistance is achieved through decreasing the rate of antibiotic entry.² Loss of porin function can be acquired via changes in OmpF porin protein resulting in replacement/loss of major porins and reduced permeability.¹⁹

Efflux pumps extrude toxic compounds out of bacterial cells, including antibiotics.² A variety of efflux pumps exist and are seen in both gram-positive and gram-negative organisms.¹⁷ In clinically important bacteria, such as multidrug-resistant (<MDR) Mycobacterium tuberculosis, methicillin-resistant S. aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa, efflux pumps have critical roles in ensuring bacterial survival and evolution into resistant strains.¹⁷

Global Cell Adaptations

Instead of a specific change in one cellular process, some bacteria have developed resistance to antibiotics via global cell adaptations. Through years of evolution, bacteria have developed sophisticated mechanisms to cope with environmental stressors and pressures in order to survive hostile environments.² This involves very complex mechanisms to avoid the disruption of vital cellular processes such as cell wall synthesis and membrane homeostasis.² The two main examples of global cell adaptation resistance occur with lipopeptides and glycopeptides.²

Lipopeptides have a multifaceted mechanism of action that results in disruption of cell membrane homeostasis.²⁰ Activity correlates with the levels of calcium and phosphatidylglycerol in the membrane.²⁰ Resistance can be accomplished in some organisms via alteration in cell membrane charge and downregulation of phosphatidylglycerol.²⁰

Glycopeptides are susceptible to resistance via multiple adaptations observed with S. aureus including increased fructose utilization, increased fatty acid metabolism, decreased glutamate availability, and increased expression of cell wall synthesis genes.² These global adaptations result in reduced autolytic activity, a thickened cell wall, and an increased amount of free D-Ala-D-Ala, all of which reduce effective activity of glycopeptides.²

Conclusion

Awareness of the molecular mechanisms of antibiotic resistance among bacteria is necessary to understand the etiology of antibiotic resistance in dermatology at the most basic level.

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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

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.

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