Development Of Acne Lesions Research Articles

Characterization of the forehead skin microbiome in the early phase of acne.

The skin microbiota is known to be imbalanced in acne vulgaris, but the changes occurring during the early stages of acne onset remain poorly described. To characterize the skin microbiome of subclinical stages of acne in adults and adolescents. The composition and diversity of the microbiota from non-lesional skin on the forehead of subjects with mild-to-moderate acne were compared to the ones from non-acne subjects. Analyses of skin swab samples were performed using high-throughput sequencing of the V1-V3 regions of the bacterial 16S ribosomal RNA gene, the tuf gene fragment of Staphylococcus species and the internal transcribed spacer (ITS1) region of the fungal rRNA gene to determine the relative abundance, alpha-diversity and beta-diversity of bacteria and fungi. Compared with non-acne subjects, acne subjects had a higher abundance of Cutibacterium (72.4% vs. 57.8%) and lower abundances of Corynebacterium (2.8% vs. 4.8%) and Streptococcus (1.4% vs. 3.2%). Bacterial alpha- and beta-diversity indices also differed significantly between the two groups, reflecting differences in richness, evenness, abundance and phylogenetic distance between bacterial populations. Differences were also observed at the level of Staphylococcus species: S. capitis was predominant in skin samples from non-acne subjects (46.7%), whereas S. epidermidis was the most abundant Staphylococcus species in non-lesional forehead skin areas of acne subjects (44.2%). Conversely, no significant between-group differences were found for fungi, with Malasseziales being the predominant order in both subject groups. Dysbiosis was observed very early in subclinical acne stages of the forehead skin, with the overall abundance, richness and evenness of the bacterial population being lower in acne than in non-acne skin samples. Dysbiosis was also found at the level of Staphylococcus species. The development of acne lesions could therefore be prevented by using a skin care product that rebalances facial skin microbiota at very early stages.

Role of Oral Retinoids in Treatment of Acne Vulgaris With a Bioinformatics-Based Perspective of Personalized Medicine.

Acne vulgaris is a skin condition characterized by the inflammation or hyperactivity of sebaceous glands on the skin, which results in the creation of comedones, lesions, nodules, and perifollicular hyperkeratinization. Increased sebum production, follicular blockage, and bacterial colonization may contribute to the disease etiology. Environmental factors, hormonal imbalance, and genetic predisposition can alter the severity of the disease. Its mental and monetary effects can be problematic for the society. In this study, we examined the role of isotretinoin in the treatment of acne vulgaris based on evidence from prior research. This review literature study compiled publications on the treatment of acne vulgaris from 1985 to 2022 based on PubMed and Google Scholar publications. Additional bioinformatics analyses were accompanied by GeneCards, STRING model, and DrugBank databases. These complementary analyses were designed to obtain a better perspective of personalized medicine which is highly required for dose-precise administrations of acne vulgaris treatment. Isotretinoin has been recognized as an effective treatment for acne vulgaris, particularly in cases that have been resistant to previous medications or have resulted in scarring, according to gathered data. Oral isotretinoin inhibits the proliferation of Propionibacterium acne, a critical factor in the development of acne lesions; also, it has been shown to be effective in reducing the number of Propionibacterium-resistant patients and regulating sebum production and reducing sebaceous gland size more effectively than other treatment options resulting in general improvements in skin clarity and acne severity and reduce inflammatory in 90% of patients. In addition to its efficacy, the majority of patients have shown that oral isotretinoin is well tolerated. This review highlights the use of oral retinoids, particularly isotretinoin, as an effective and well-tolerated treatment option for acne vulgaris. It has been proven that oral isotretinoin is useful for achieving long-lasting remission in patients with severe or resistant instances. Despite the fact that oral isotretinoin is related to a number of potential harmful effects, skin dryness was the most common side effect reported by patients that can be managed with the aid of suitable monitoring and drug administration against specific genes identified by genotyping of the susceptible variants of genes involved in TGFβ signaling pathway.

Metabolic and Dietary Factors in Acne Vulgaris and Evaluation of the Acne Vulgaris Treatment with Oral Contraceptive-Based Therapies in Young Adult Women.

The etiopathogenesis of acne is complex, as several endo- and exogenous factors that affect the sebaceous-hair unit are involved in the development of acne lesions. The main aim of the study was to evaluate selected metabolic parameters before treatment. Another goal of the study was to determine the correlation between selected metabolic and dietary parameters and the severity of acne before treatment. The third objective was to assess the severity of acne before and after treatment, considering the type of treatment used. The final objective was to assess the relationship between the difference in acne severity before and after treatment, considering the type of treatment used and factors of dairy or sweets intake. 168 women participated in the study. The patients belonged to two groups: the study group (99 patients with acne vulgaris) and the control group (69 patients without skin lesions). The study group was divided into subgroups according to the treatment used: contraceptive preparation, contraceptive preparation and cyproterone acetate, and contraceptive preparation and isotretinoin preparation. We found that LDL levels and consumption of sweets correlated with acne severity. The mainstay of acne treatment is contraceptive treatment (ethinylestradiol and drospirenone). The effectiveness of the three contraceptive-based treatments was confirmed by observing the severity of acne. There were no significant correlations between the difference in acne severity before and after treatment with the three treatments and factors of dairy or sweet consumption.

The Role of Skin Immune System in Acne.

Acne vulgaris is a skin disease that often occurs in adolescence and in young adulthood. The main pathogenic factors are hyperkeratinization, obstruction of sebaceous glands, stimulation of sebaceous gland secretion by androgens, and bacterial colonization of sebaceous units by Cutibacterium acnes, which promotes inflammation. Little is known about the role of skin immune cells in the development of acne lesions. The aim of the study was to try to understand the role of skin immune cells in the course of acne. Recent studies have shown that there are at least four major pathways by which Cutibacterium acnes interacts with the innate immune system to induce inflammation: through TLRs, activating inflammasomes, inducing the production of matrix metalloproteinases (MMPs), and stimulating antimicrobial peptide (AMP) activity. Cells of adaptive immune response, mainly Th1 and Th17 lymphocytes, also play an important role in the pathogenesis of acne. It is worth emphasizing that understanding the role of the skin’s immune cells in the pathogenesis of acne may, in the future, contribute to the application of modern therapeutic strategies that would avoid addiction to antibiotics, which would alleviate the spectrum of resistance that is now evident and a current threat.

Endocrine Disrupting Chemicals, Hormone Receptors, and Acne Vulgaris: A Connecting Hypothesis.

The relationship between endocrine disrupting chemicals (EDCs) and the pathogenesis of acne vulgaris has yet to be explored in the literature. Acne vulgaris is a chronic inflammatory skin disease of the pilosebaceous unit. The pathogenesis of acne involves several hormonal pathways, including androgens, insulin-like growth factor 1(IGF-1), estrogens, and corticosteroids. EDCs influence these pathways primarily through two mechanisms: altering endogenous hormone levels and interfering with hormone receptor function. This review article describes the mechanistic links between EDCs and the development of acne lesions. Highlighted is the contributory role of androgen receptor ligands, such as bisphenol A (BPA) and mono-2-ethylhexyl Phthalate (MEHP), via upregulation of lipogenic genes and resultant exacerbation of cholesterol synthesis. Additionally discussed is the protective role of phytoestrogen EDCs in counteracting androgen-induced sebocyte maturation through attenuation of PPARy transcriptional activity (i.e., resveratrol) and restoration of estrogen-regulated TGF-B expression in skin cells (i.e., genistein). Examination of the relationship between EDCs and acne vulgaris may inform adjunctive avenues of treatment such as limiting environmental exposures, and increasing low-glycemic, plant-rich foods in the diet. With a better understanding of the cumulative role that EDCs play in acne, clinicians can be better equipped to treat and ultimately improve the lives of their patients.

Ferredoxin reductase regulates proliferation, differentiation, cell cycle and lipogenesis but not apoptosis in SZ95 sebocytes

Ferredoxin reductase (FDXR), a mitochondrial membrane-associated flavoprotein, is essential for electron transfer and modulates p53-dependent apoptosis in cancer cells.FDXR may be implicated in epidermal and sebocytic differentiation, but its explicit function in sebocytes remains to be elucidated. In the present study, immunohistochemistry revealed that FDXR expression was increased in sebaceous cells of acne lesions. FDXR, PPARγ, LXRα/β, SREBP1 and Sox9 expression was incremental during sebocyte differentiation. FDXR overexpression induced by Ad-GFP-FDXR infection enhanced differentiation, reactive oxygen species (ROS), lipogenesis and PPARγ expression, and consequnently inhibited proliferation in SZ95 sebocytes. Flow cytometry showed that FDXR overexpression induced significant blockade of G2/M phase but had no effect on sub-G1 (apoptotic) sebocytes. Insulin-like growth factor-1 (IGF-1)-induced FDXR and PPARγ expression and lipogenesis were abolished by pretreatment with PI3K inhibitor LY294002. These results suggest that FDXR overexpression might promote differentiation and lipogenesis via ROS production and suppress proliferation via G2/S blockade in SZ95 sebocytes. IGF-1 could facilitate differentiation and lipogenesis through PI3K/Akt/FDXR pathway. FDXR could serve as a potential marker of advanced sebaceous differentiation, and its overexpression may be involved in the development of acne lesions.

Noninflammatory comedones have greater diversity in microbiome and are more prone to biofilm formation than inflammatory lesions of acne vulgaris.

The ability of Cutibacterium acnes strains to form biofilms has been correlated with their virulence. This study examined biofilm and skin microbiota in acne patients in order to understand their role in the development of acne lesions. Thin sections of punch biopsy specimens of (i) uninflamed comedones, (ii) inflammatory lesions, and (iii) uninvolved adjacent skin of acne patients were examined. Epiflourescence and confocal laser scanning microscopy were used for biofilm detection, and pyrosequencing with taxonomic classification of 16s rRNA gene amplicons was used for microbiota analysis. Of the 39 skin specimens from patients with mild-moderate acne (n=13) that were studied, nine (23%) contained biofilm. Among these specimens, biofilm was most frequently detected in comedones (55.6%) and less frequently in inflammatory papules (22.2%) and uninvolved skin (22.2%). Comedones demonstrated the highest mean alpha diversity of all the lesion subtypes. The relative abundance of Staphylococcus was significantly higher in comedones (11.400%±12.242%) compared to uninvolved skin (0.073%±0.185%, P=0.024). The microenvironment of the comedone differs from that of inflammatory lesions and unaffected skin. The increased frequency of biofilm in comedones may account for the lack of host inflammatory response to these lesions.

Endocrinology and immunology of acne: Two sides of the same coin.

Current experimental research on acne pathophysiology has revealed a more complicated background than the classically reported four-factor aetiology. Cells of the pilosebaceous unit, which represent the template for the development of acne lesions, seem to be parallelly affected by endocrinological/metabolic factors as well as inflammatory/immunological ones that cooperate in sebocyte differentiation and lipogenesis. Indeed, the unique programme of sebocyte terminal differentiation and death, the so called holocrine secretion, is influenced by inflammatory and metabolic (lipid) signalling with common denominator the selective regulation of peroxisome proliferator-activated receptors. Autophagy provides substrates for energy generation and biosynthesis of new cell structure proteins contributing to the normally increased sebaceous gland metabolic functions, which are also regulated by extracellular calcium signalling, essential lipids and hormones. The ultimate differentiation product of human sebocytes, sebum, co-regulates the inflammatory sebocyte status. Sebum composition is controlled among others by Propionibacterium acnes and other bacteria, sexual hormones, neuropeptides, endogenous opioids and environmental agents, which may function as endocrine disruptors. Diet may also be an important source of substrates for the synthesis of pro-inflammatory and anti-inflammatory sebaceous lipids. Sebum changes might induce inflammation and initiate underlying immune mechanisms leading to acne lesions. Current new therapeutic efforts on acne concentrate on anti-inflammatory/immunologically active concepts, which are able to regulate sebaceous lipogenesis. At last, current molecular studies based on published molecular data sets confirmed the major role of inflammation in acne development.

Modulation of skin androgenesis and sebum production by a dermocosmetic formulation.

Excessive androgenesis in the skin promotes sebaceous hyperproduction which is the onset of acne vulgaris pathogenesis. Free fatty acids and lipid accumulation in the glandular infundibulum culminates in microbiota imbalance, triggering inflammatory response and follicular hyperkeratinization. The purpose of this work was to present an alternative cosmetic treatment for acne skin care, focusing on the prevention of sebaceous gland dysregulation. Insulin-stimulated human sebocytes were treated with noncytotoxic concentrations of a DTRW cosmetic formulation. After 6days of incubation, cell lysates were collected for testosterone, 5α-reductase, and dyhidrotestosterone (DHT) quantitation. In parallel, cells were stained with Oil Red O to measure sebum production. Human sebocytes were incubated with insulin to mimic a seborrheic microenvironment with overproduction of intracellular lipids and fatty acids. Concomitant incubation of cell cultures with DRTW was able to promote a 52.97% reduction in intracellular lipid content. The anti-androgenic properties of DRTW had been proved by the reductions of testosterone (↓59.90%), 5α reductase (↓59.34%), and DHT (↓55.98%) levels in sebocyte cultures also stimulated with insulin. The results indicate a promising action of DRTW cosmetic formulation in preventing the development of acne lesions by mechanisms involving the modulation of cutaneous androgenesis and consequently the control of sebum overproduction, considered one of the leading causes of acne.

Assessment of Serum Level of lipocalin2 in Patients with Acne Vulgaris

Acne vulgaris(AV) is a chronic disease of the pilosebaceous unit which is most common during adolescence. Four factors are believed to play a key role in the development of acne lesions: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by Propionibacterium acnes,and the release of inflammatory mediators into the skin. Evaluation of serum levels of lipocalin2(LCN2) in acne vulgaris patients.Serum LCN2 concentrations were measured in 30 patients with AV and 30 healthy controls using enzyme-linked immunosorbent assay (ELISA).Serum levels of LCN2 in patients with AV were found to be higher than in healthy controls (p < 0.001). Increased serum LCN2 probably reflect the role of LCN2 in the pathogenesis of AV.

Licochalcone A attenuates acne symptoms mediated by suppression of NLRP3 inflammasome.

Activation of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome by Propionibacterium acnes (P.acnes) is critical for inducing inflammation and aggravating the development of acne lesions. We searched for available small-molecule inhibitors of the NLRP3 inflammasome that could be topically administered for the treatment of acne. We found that licochalcone A, a chalconoid isolated from the root of Glycyrrhiza inflate, was an effective inhibitor for P.acnes-induced NLRP3 inflammasome activation. Licochalcone A blocked P.acnes-induced production of caspase-1(p10) and IL-1β in primary mouse macrophages and human SZ95 sebocytes, indicating the suppression of NLRP3 inflammasome. Licochalcone A suppressed P.acnes-induced ASC speck formation and mitochondrial reactive oxygen species. Topical application of licochalcone A to mouse ear skin attenuated P.acnes-induced skin inflammation as shown by histological assessment, ear thickness measurement, and inflammatory gene expression. Licochalcone A reduced caspase-1 activity and IL-1β production in mouse ear injected with P.acnes. This study demonstrated that licochalcone A is effective in the control of P.acnes-induced skin inflammation as an efficient inhibitor for NLRP3 inflammasome. Our study provides a new paradigm for the development of anti-acne therapy via targeting NLRP3 inflammasome.

Confocal microscopy in adult women with acne.

Acne is an inflammatory disease of the pilosebaceous follicle, affecting 41-54% of adult women, with a particular form that involves the mandible. We characterized infundibulum morphology in two groups of adult women using reflectance confocal microscopy. First, we investigated acne visually "healthy zones" on the forehead in 15 adult women with diffuse acne and compared with acne-free controls. We then compared healthy forehead and affected mandibular zone in 15 acne patients with mandibular involvement. Exposed results had a P<0.05. Seven hundred and ninety-one follicles were observed on apparently healthy skin of 15 adult women with acne, with a larger diameter, thicker (68%), and hyper keratinized (65%) follicle border, and more keratin plugs (44%) than in controls. In the second group of 15 adult women with mandibular acne, we compared 569 follicles in the mandibular zone and 475 on forehead. In the mandibular area, follicles were significantly larger, thicker (76%), more hyper keratinized (72%), with more keratin plugs (47%) and increased inflammation (23%) compared with the forehead area. In the mandibular area, 0.2% of follicles showed isolated inflammation without hyper keratinization, and 15.3% had both thickened borders with an onion-like appearance and keratin plugs associated with inflammation. Hyper keratinization was higher in healthy skin of adult women with acne compared with controls, confirming that microcomedo is crucial in the development of acne lesions. We also demonstrate that the repartition of comedones and microcomedones is inhomogeneous with a great number in the mandibular area where acne lesions are located.

OCT-based label-free in vivo lymphangiography within human skin and areola.

Due to the limitations of current imaging techniques, visualization of lymphatic capillaries within tissue in vivo has been challenging. Here, we present a label-free high resolution optical coherence tomography (OCT) based lymphangiography (OLAG) within human skin in vivo. OLAG enables rapid (~seconds) mapping of lymphatic networks, along with blood vessel networks, over 8 mm x 8 mm of human skin and 5 mm x 5 mm of human areola. Moreover, lymphatic system’s response to inflammation within human skin is monitored throughout an acne lesion development over 7 days. The demonstrated results promise OLAG as a revolutionary tool in the clinical research and treatment of patients with pathologic conditions such as cancer, diabetes, and autoimmune diseases.

In vivo tissue injury mapping using optical coherence tomography based methods.

An injury causes changes in the optical attenuation coefficient (OAC) of a light beam traveling inside a tissue. We report a method called tissue injury mapping (TIM), which utilizes a noninvasive in vivo optical coherence tomography approach to generate an OAC and microvascular map of the injured tissue. Using TIM, the infarct region development in a mouse cerebral cortex during a stroke is visualized. Moreover, we demonstrate the changes in human facial skin structure and microvasculature during an acne lesion development from initiation to scarring. The results indicate that TIM may be used to aid in the characterization and the treatment of various diseases by enabling a high-resolution detection of tissue structural and microvascular changes.

From new findings in acne pathogenesis to new approaches in treatment.

Acne is a chronic disease of the pilosebaceous unit which is most common during adolescence. Four factors are believed to play a key role in the development of acne lesions: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by Propionibacterium acnes, and the release of inflammatory mediators into the skin. Consequently, in order to effectively and rapidly reduce acne lesions, treatments need to address as many of these underlying factors as possible. Currently, about half of patients have poor adherence to acne treatments. To overcome this limitation, treatments need to be developed which are well tolerated by patients, and easy for them to use, handle and apply. Topical monotherapies for acne such as retinoids and antimicrobials by themselves have a restricted range of actions against the pathogenic factors of acne. Instead, the Global Alliance to Improve Outcomes in Acne Group recommends combination therapy with a topical retinoid and an antimicrobial agent as the preferred approach for almost all acne patients. The principal advantage of such combinations is that they target more of the underlying pathogenic factors of acne than individual monotherapies and this results in faster and more complete clearing of acne lesions. Fixed-dose combinations are also more convenient than applying two medications separately, which leads to improved adherence with the regimen. By normalizing desquamation, the retinoid component of these combinations allows entry of the antimicrobial agent into the pilosebaceous unit resulting in faster clearance of P.acnes. In conclusion, topical retinoid/antimicrobial fixed-dose combinations represent a rational approach for the treatment of acne. They should be considered as the cornerstone of acne management and should be used much more in the future.

Sebum Secretion of the Trunk and the Development of Truncal Acne in Women: Do Truncal Acne and Sebum Affect Each Other?

Background: There are few published data on truncal acne because most studies have focused on facial acne. Aims: The objective of this study was to investigate truncal sebum secretion levels in patients with acne vulgaris and to evaluate the relationship between sebum secretion and the development of acne lesions. Methods: The sebum casual levels at five different facial sites and ten truncal sites were measured in 35 Korean females with acne using a Sebumeter®. We performed an analysis of the correlation between sebum excretion and acne lesion number. Results: We found that all of the truncal sites analyzed had lower sebum secretion levels than the facial sites. There was no significant correlation between sebum secretion and acne lesions on the trunk. Conclusion: Pathogenic factors other than sebum may have a predominant role in the development of truncal acne.

High resolution imaging of acne lesion development and scarring in human facial skin using OCT-based microangiography.

Acne is a common skin disease that often leads to scarring. Collagen and other tissue damage from the inflammation of acne give rise to permanent skin texture and microvascular changes. In this study, we demonstrate the capabilities of optical coherence tomography-based microangiography in detecting high-resolution, three-dimensional structural, and microvascular features of in vivo human facial skin during acne lesion initiation and scar development. A real time swept source optical coherence tomography system is used in this study to acquire volumetric images of human skin. The system operates on a central wavelength of 1,310 nm with an A-line rate of 100 kHz, and with an extended imaging range (∼12 mm in air). The system uses a handheld imaging probe to image acne lesion on a facial skin of a volunteer. We utilize optical microangiography (OMAG) technique to evaluate the changes in microvasculature and tissue structure. Thanks to the high sensitivity of OMAG, we are able to image microvasculature up to capillary level and visualize the remodeled vessels around the acne lesion. Moreover, vascular density change derived from OMAG measurement is provided as an alternative biomarker for the assessment of human skin diseases. In contrast to other techniques like histology or microscopy, our technique made it possible to image 3D tissue structure and microvasculature up to 1.5 mm depth in vivo without the need of exogenous contrast agents. The presented results are promising to facilitate clinical trials aiming to treat acne lesion scarring, as well as other prevalent skin diseases, by detecting cutaneous blood flow and structural changes within human skin in vivo.

Acne vulgaris

Acne vulgaris is worldwide the most common skin disease. Acne is an inflammatory disorder in whose emergence androgens, PPAR ligands, the IGF-1 signaling pathway, regulating neuropeptides and environmental factors are probably involved. These factors interrupt the natural cycling process in the sebaceous gland follicle and support the transition of microcomedones to comedones and inflammatory lesions. Proinflammatory lipids and cytokines are mediators for the development of acne lesions. Bacterial antigens can potentate the inflammatory phenomena. Acne is predominantly treated with combination therapy. Selecting a treatment regimen depends on the exact classification of acne type and severity. The development of scars is the main criterion for the choice of systemic therapy. Retinoids for mild comedonal acne and the combination of retinoids with antibiotics and/or benzoyl peroxide for mild to moderate papulopustular acne are the drugs of first choice for topical treatment. The use of topical antibiotics is not recommended any more because of the development of resistant bacterial strains. Systemic antibiotics, in combination with topical retinoids and/or benzoyl peroxide, for moderate papular/nodular acne and isotretinoin for severe nodular/conglobate acne are the columns of systemic acne treatment. Systemic anti-androgens are used in women against moderate papulopustular acne. Due to advances in the understanding of the underlying inflammatory mechanisms in recent years the development of new therapeutic agents with good efficacy and better side effect profile should be expected in the future.

Acne is an inflammatory disease and alterations of sebum composition initiate acne lesions

Hyperseborrhoea has been considered as a major aetiopathogenetic factor of acne. However, changes in sebaceous gland activity not only correlate with seborrhoea but also with alterations in sebum fatty acid composition. Current findings indicate that sebum lipid fractions with proinflammatory properties and inflammatory tissue cascades are associated in the process of the development of acne lesions. The oxidant/antioxidant ratio of the skin surface lipids and alterations of lipid composition are the main players in the induction of acne inflammation. Nutrition may influence the development of seborrhoea, the fractions of sebum lipids and acne. Acne is an inflammatory disease probably triggered, among others, by proinflammatory sebum lipid fractions.

Propionibacterium acnes: an update on its role in the pathogenesis of acne

In recent years, significant progress has been made in the understanding of the pathophysiological mechanisms of acne and the role of Propionibacterium acnes. With this review, the authors aim to provide an update on the current understanding of the role of P.acnes in the development of acne lesions and analysing the potential implications for future treatments. A total of 188 articles published between January 1980 and March 2013 were searched using key words such as acne, P.acnes, microbiology, Corynebacterium acnes, acne vulgaris, pathogenesis, antibiotic, vaccination and a combination of those key words. From those articles, 77 were analysed in depth. Recent data confirm that P.acnes has a strong proinflammatory activity and targets molecules involved in the innate cutaneous immunity, keratinocytes and sebaceous glands of the pilosebaceous follicle and leads to the development of comedones. Furthermore, the profile of its different strains may differ between healthy subjects and acne patients. The better understanding of the role of P.acnes may allow for new perspectives in the treatment of acne. Novel therapies should target molecules implicated in the activation of innate immunity, including toll-like receptors, protease-activated receptors and topical antimicrobial peptides; the latter may be an alternative to topical antibiotics and thus a solution for limiting bacterial resistance induced by topical macrolides. Vaccines may also be promising. However, the most appropriate candidate remains to be selected.