¹Faculty of Medicine, University of Western Ontario, London, ON, Canada
²Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada
³Division of Dermatology, Department of Medicine, University of Toronto, ON, Canada
⁴Women’s College Research Institute, Women’s College Hospital, Toronto, ON, Canada
⁵Sunnybrook Health Sciences Centre, Toronto, ON, Canada
⁶Probity Medical Research, Waterloo, ON, Canada
⁷Dermatology Research Institute, Calgary, AB, Canada
⁸Skin Health & Wellness Centre, Calgary, AB, Canada
⁹Section of Community Pediatrics, Department of Pediatrics, University of Calgary, Calgary, AB, Canada
¹⁰Section of Pediatric Rheumatology, Department of Pediatrics, University of Calgary, Calgary, AB, Canada

Conflict of interest:
Abrahim Abduelmula has no relevant disclosures. Brian D. Rankin has no relevant disclosures. Jensen Yeung has been an advisor, consultant, speaker, and/or investigator for AbbVie, Allergan, Amgen, Astellas, Boehringer Ingelheim, Celgene, Centocor, Coherus, Dermira, Eli Lilly, Forward, Galderma, GSK, Janssen, LEO Pharma, Medimmune, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sun Pharma, Takeda, UCB, Valeant, and Xenon. Vimal H. Prajapati has been an advisor, consultant, speaker, and/or investigator for AbbVie, Actelion, Amgen, AnaptysBio, Aralez, Arcutis, Arena, Aspen, Bausch Health, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cipher, Concert, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Homeocan, Incyte, Janssen, LEO Pharma, Medexus, Nimbus Lakshmi, Novartis, Pediapharm, Pfizer, Regeneron, Reistone, Sanofi Genzyme, Sun Pharma, Tribute, UCB, and Valeant.

Funding sources: None.

Abstract:
Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disease. Targeted treatment options remain limited. Tralokinumab (Adtralza^®) is a promising, new systemic therapy that inhibits interleukin-13. It was recently approved by Health Canada and the US FDA for the treatment of moderate-to-severe AD in adults and may be used alone or with topical corticosteroids. Herein, we review the efficacy and safety of tralokinumab in adults, as demonstrated in clinical trials.

Keywords:
Adtralza^®, tralokinumab, immunomodulator, therapeutics, biologic, atopic dermatitis, eczema, clinical trial

Introduction

Atopic dermatitis (AD) is a common, chronic, recurrent, immune-mediated inflammatory skin disorder affecting between 5-10% of adults, with moderate-to-severe disease accounting for approximately 20-30% of cases.^1,2 This condition can have a significant negative impact on psychosocial well-being, health-related quality of life (QoL), and work/school productivity. In addition, uncontrolled AD is associated with a substantial financial burden on the patient and their family as well as the health care system.³

Topical therapies are employed as first-line treatment for the majority of AD cases, but lack of response can necessitate the use of phototherapy and/or systemic therapies. With respect to systemic therapies, recent advances have led to the development of new targeted treatments, of which four are now approved by Health Canada and the US FDA for moderate-to-severe AD. This includes two biologics (dupilumab [Dupixent^®], an interleukin (IL)-4/IL-13 inhibitor, and tralokinumab [Adtralza^®], an IL-13 inhibitor) and two small molecules (upadacitinib [Rinvoq^®] and abrocitinib [Cibinqo^®], both selective Janus kinase 1 [JAK1] inhibitors).

Background

Tralokinumab is a fully human immunoglobulin G4 (IgG4) monoclonal antibody that binds with high affinity to IL-13, thereby blocking its interaction with the IL-13Rα1/IL-4Rα1 heterodimer and IL-13Rα2 homodimer receptor complexes and subsequently leading to downstream STAT-6 inhibition.⁴ The latter results in reduced inflammation, improved skin barrier function (reductions in epidermal thickness and increased epithelial barrier integrity), as well as restoration of the microbiome (a near 10-fold reduction in Staphylococcus aureus colonization of the skin).^4,5

Tralokinumab may be given alone or in combination with a topical corticosteroid (TCS).^6,7 It was approved by both Health Canada and the US FDA in 2021 for the treatment of moderate-to-severe AD in adult patients whose disease is not adequately controlled with prescription topical therapies or when those prescription topical therapies are not advisable.⁶ Available as a single-use prefilled syringe containing 150 mg of tralokinumab in 1 mL solution (150 mg/mL), tralokinumab is administered as a subcutaneous (SC) injection.⁶ The recommended dosage for adult patients is an initial 600 mg loading dose followed by 300 mg maintenance doses every other week (Q2W). According to the product monograph, the prescriber may choose to administer tralokinumab every fourth week (Q4W) in adult patients who achieve clear or almost clear skin after 16 weeks of treatment; however, there is an increased probability that maintenance efficacy may be decreased with Q4W dosing.⁶

Non-medicinal ingredients of the product include acetic acid, polysorbate 80, sodium acetate trihydrate, sodium chloride, and water. No published data is currently available for its use in pediatric or pregnant patients, and, as such, tralokinumab has not been approved for utilization in children/adolescents (<18 years of age), nor is it recommended for pregnant women.⁶

Supporting Evidence from Clinical Trials (Figures 1-5)

Results from Pivotal Phase 3 Monotherapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=802) with moderate-to-severe AD (ECZTRA 1), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=603) versus placebo (n=199) was evaluated.⁸ At week 16: the primary endpoint of an Investigator Global Assessment (IGA) score of clear or almost clear (IGA 0/1) was achieved by 15.8% and 7.1% of patients treated with tralokinumab and placebo, respectively (p<0.002) (Figure 1); an improvement of ≥75% and ≥90% in the Eczema Area and Severity Index (EASI75 and EASI90, respectively) was achieved by 25.0% and 14.5% of patients treated with tralokinumab versus 12.7% and 4.1% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus Numerical Rating Scale (NRS) improved by 20.0% with tralokinumab versus 10.3% with placebo (p=0.002); and there was a reduction in Dermatology Life Quality Index (DLQI) scores by 7.1 with tralokinumab and 5.0 with placebo, respectively (p=0.002) (Figure 3). Safety evaluation revealed similar adverse event (AE) profiles between the tralokinumab and placebo groups, with the majority of treatment-emergent AEs (TEAEs) being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included viral upper respiratory tract infection (URTI) (23.1%), conjunctivitis (10.0%), and eczema herpeticum (0.5%). One case of conjunctivitis led to treatment discontinuation. No injection-site reactions (ISRs) were observed in either treatment group.⁸

In another phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=794) with moderate-to-severe AD (ECZTRA 2), the efficacy and safety of tralokinumab 300 mg SC Q2W (n=593) versus placebo (n=201) was evaluated.⁸ At week 16: the primary endpoint of IGA 0/1 was achieved by 22.2% and 10.9% of patients treated with tralokinumab and placebo, respectively (p<0.001) (Figure 1); EASI75 and EASI90 were achieved by 33.2% and 18.3% of patients treated with tralokinumab versus 11.4% and 5.5% of patients treated with placebo (p<0.001 and p<0.05, respectively) (Figure 2); pruritus NRS improved by 25.0% with tralokinumab versus 9.5% with placebo (p<0.001); and there was a reduction in DLQI by 8.8 with tralokinumab and 4.9 with placebo, respectively (p<0.001) (Figure 3). Safety evaluation revealed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being mild and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (8.3%), conjunctivitis (5.2%), and eczema herpeticum (0.3%). No cases of conjunctivitis led to discontinuation. In addition, no ISRs were observed in either treatment group.⁸

By week 52, IGA 0/1 responses achieved at week 16 with tralokinumab Q2W were maintained, without any rescue therapy (including TCS), by 51% (ECZTRA 1) and 59% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 47% (ECZTRA 1) and 25% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.60 and p=0.004, respectively) (Figure 4). In addition, by week 52, EASI75 responses achieved at week 16 with tralokinumab Q2W were maintained by 60% (ECZTRA 1) and 56% (ECZTRA 2) of patients who continued to receive tralokinumab Q2W versus 33% (ECZTRA 1) and 21% (ECZTRA 2) of patients who were rerandomized from tralokinumab Q2W to placebo (p=0.056 and p<0.001, respectively) (Figure 5).⁸ A subset of patients following week 16 were downdosed from Q2W to Q4W dosing of tralokinumab. By week 52, 39% (ECZTRA 1) and 45% (ECZTRA 2) of patients maintained their week 16 IGA 0/1 responses despite being switched from Q2W to Q4W dosing (Figure 4). In addition, by week 52, 49% (ECZTRA 1) and 51% (ECZTRA 2) of patients maintained their week 16 EASI75 responses despite being switched from Q2W to Q4W dosing (Figure 5).

Results from Pivotal Phase 3 Combination Therapy Studies

In a phase 3 multicenter, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=380) with moderate-to-severe AD (ECZTRA 3), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=253) versus placebo + TCS (n=127) was evaluated. The TCS utilized was mometasone furoate 0.1% cream. At week 16: the primary endpoint of IGA 0/1 was achieved by 38.9% and 26.2% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.015) (Figure 1); EASI75 and EASI90 were achieved by 56.0% and 32.9% of patients treated with tralokinumab + TCS versus 35.7% and 21.4% of patients treated with placebo + TCS (p<0.001 and p<0.022, respectively) (Figure 2); pruritus NRS improved by 45.5% with tralokinumab + TCS versus 34.1% with placebo + TCS (p=0.037); and there was a reduction in DLQI by 11.7 with tralokinumab + TCS and 8.8 with placebo + TCS, respectively (p<0.001) (Figure 3). By week 32, in patients receiving tralokinumab Q2W + TCS, 89.6% and 92.5% maintained their week 16 IGA 0/1 and EASI75 responses, respectively (Figure 4 and 5, respectively). A subset of patients following week 16 were downdosed from tralokinumab Q2W to Q4W dosing. At week 32, 77.6% and 90.8% of patients maintained their week 16 IGA 0/1 and EASI75 responses, respectively, despite being switched from Q2W to Q4W dosing (Figure 4 and 5, respectively).⁹ Safety evaluation revealed similar AE profiles between the tralokinumab + TCS and placebo + TCS groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab + TCS included URTI (19.4%), conjunctivitis (13.1%), and eczema herpeticum (0.4%). Six patients permanently discontinued treatment with tralokinumab due to non-serious AEs, one of which was conjunctivitis.⁹ No ISRs were observed in either treatment group.

In another phase 3 multicenter, parallel, randomized, double-blind, placebo-controlled clinical trial of adult patients (n=277) with moderate-to-severe AD (ECZTRA 7), the efficacy and safety of tralokinumab 300 mg SC Q2W + TCS (n=140) versus placebo + TCS (n=137) was evaluated. The TCS utilized was mometasone furoate 0.1% cream.¹⁰ At week 16: the primary endpoint of EASI75 was achieved by 64.2% and 50.5% of patients treated with tralokinumab + TCS and placebo + TCS, respectively (p=0.018) (Figure 2); EASI90 was achieved by 41.1% of patients treated with tralokinumab + TCS versus 29.3% of patients treated with placebo + TCS (p<0.001) (Figure 2); pruritus NRS was reduced by 4 with tralokinumab + TCS versus 3.1 with placebo + TCS (p<0.001); and there was a reduction in DLQI by 11.2 with tralokinumab + TCS and 9.6 with placebo + TCS, respectively (p=0.009) (Figure 3). By week 26, in patients receiving tralokinumab + TCS, 68.8% achieved EASI75 and 48.6% achieved EASI90, compared with 55.3% and 36.4% for placebo + TCS (p=0.014 and p=0.027, respectively) (Figure 5). Safety evaluation once again showed similar AE profiles between the tralokinumab and placebo groups, with the majority of TEAEs being non-serious and self-limiting in nature. The most observed TEAEs with tralokinumab included URTI (26.8%), conjunctivitis (9.4%), and eczema herpeticum (0.7%). One patient permanently discontinued treatment with tralokinumab due to an AE that was not deemed serious.¹⁰ No ISRs were observed in either treatment group.

Summary of Results from Pivotal Phase 3 Monotherapy and Combination Therapy Study Results and Additional Analyses

In summary, tralokinumab was more effective than placebo in both monotherapy and combination therapy studies, with tralokinumab demonstrating greater efficacy than placebo for patients with moderate-to-severe AD across all phase 3 clinical trials. Interestingly, rates of eczema herpeticum were higher in the placebo groups as opposed to the tralokinumab groups.^8-10 An additional pooled analysis (n=1605) of five completed double-blind, randomized, placebo-controlled, phase 2 and 3 clinical trials of tralokinumab in adult patients with moderateto- severe AD examined the rates of conjunctivitis within these studies; it was found that tralokinumab had a slightly higher incidence of conjunctivitis (7.5%) in comparison to placebo (3.2%), with the majority of cases being mild-to-moderate in severity and 75% of events resolving before the treatment period was over in both groups.¹¹

Tralokinumab was also shown to have a significant impact on health-related QoL in a phase 2b randomized, double-blind, placebo-controlled clinical trial involving adult patients (n=204) with moderate-to-severe AD. At week 6, a 5.4-point reduction in DLQI was observed with tralokinumab monotherapy, while a 2.3-point reduction in DLQI was observed with placebo (p=0.05). At week 16, a 6.8-point reduction in DLQI was observed with tralokinumab monotherapy, while a 3.5-point reduction in DLQI was observed with placebo (p=0.006) (Figure 3).¹²

Tralokinumab may also help resolve other IL-13-associated skin abnormalities. In a phase 2 randomized, double-blind, placebo-controlled study (n=204), adult patients with moderate-to-severe AD treated with tralokinumab had lower rates of Staphylococcus aureus colonization, fewer skin infections requiring systemic antimicrobial therapy, and a lower frequency of eczema herpeticum when compared to placebo groups.⁷ In another phase 2, 30-week, double-blind, randomized, placebo-controlled clinical trial (n=215), it was shown that tralokinumab did not impair vaccine-induced immune responses in adult patients receiving tetanus-diphtheria-pertussis (Tdap) or meningococcal vaccines.¹³

Special Populations

Tralokinumab has not been approved for utilization in children/ adolescents (<18 years of age), although a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial in adolescent patients (12-17 years of age) with moderate-to-severe AD is still ongoing.¹⁴ Tralokinumab is currently not recommended in pregnant or breastfeeding women. It remains unknown if the drug is excreted in breast milk. There were no differences in terms of efficacy or safety with use in elderly patients (≥65 years of age).⁶

Table 1. Summary of the efficacy and quality of life data for tralokinumab from pivotal phase 2 and 3 clinical trials in adult patients with moderate-to-severe AD

Counselling: Practical Tips to Optimize Administration

Tralokinumab is administered as an SC injection. Optimal anatomic sites for the SC injection include the lower limb (specifically thigh) or trunk (specifically abdomen, excluding a 5 cm radius around the navel); the upper limb (specifically lateral upper arm) may also be used if another individual can administer the medication. Multiple doses should be delivered in the same anatomic site but at different points within that anatomic site. Doses should be rotated to different anatomic sites with each subsequent set of SC injections. Tralokinumab should not be injected into tender or damaged skin. If a patient and/or a caregiver wishes to administer the SC injection, proper training should be provided. If a dose is missed, the missed dose should be administered as soon as possible and the scheduled dosing regimen continued.⁶

Conclusion

Tralokinumab is an effective and safe treatment for adult patients with moderate-to-severe AD. It may be used alone or in combination with TCS. This biologic can be considered first-line treatment after failure of or intolerance to topical therapies, and, as such, represents an important tool in our therapeutic armamentarium.

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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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