Antibiotics for acne
Acne vulgaris (commonly known as acne) is a common chronic skin disease that occurs in hair follicles and often involves inflammation. About 85% of adolescents and young adults are affected by this condition, while moderate to severe acne accounts for 15-20%. According to data from the 2013 Global Burden of Disease Study, acne accounts for 0.29% of all skin conditions and contributes 1.79% to the global burden of disease. Acne is the second most common skin disease after dermatitis.
Four factors are thought to be involved in acne: excessive secretion of sebum, abnormal proliferation and differentiation of keratinocytes in hair follicles, bacterial colonization, and host inflammation. The skin microbiome in the hair follicle is made up of a diverse group of microbes. Among them, Propionibacterium acnes (P. acnes) and Malassezia spp. have been implicated in the development of acne through their effects on sebum secretion, acne formation, and inflammatory response. Antibiotics targeting P. acnes have been the mainstay of acne treatment for the past four decades. The worldwide increase in antibiotic resistance due to frequent and prolonged use of antibiotics has raised significant concerns about how the symbiotic skin microbiome and its protective effects on the skin are affected. A better understanding of the relationship between acne, skin microbiota, and antibiotic treatment may provide new insights into the treatment of the disease.
Skin microbiome and acne
Bacteria are the most important members of the skin microbiome, and more than 40 bacterial genera have been identified on human skin. The proportion of these bacteria in each community varies by individual, body part, and skin microenvironment. Propionibacterium, staphylococcus , corynebacterium and gram-negative bacteria predominate in sebum region, moist skin and dry skin, respectively. The balance of the skin microbiome and its interactions with the host influence the state of skin health and disease.
Propionibacterium acnes and acne
P. acnes was first discovered by Unna in 1896 and isolated from acne lesions by Sabouraud in 1897, leading to speculation about its involvement in the pathogenesis of acne. Of the follicular sebaceous gland units in which acne occurs, P. acnes is the most common and abundant strain, accounting for about 90% of the microbiome. Several mechanisms by which P. acnes are involved in the pathogenesis of acne include altered sebaceous gland activity, acne formation, and host inflammation.
Increased sebum secretion: P. acnes uses skin lipids as metabolic substrates in the hair follicle sebum gland unit to promote its own growth, while further increasing sebum secretion by enhancing diacylglyceryl acyltransferase activity, exacerbating hypersebum caused by androgens.
Promote acne formation: P. acnes breaks down triglycerides secreted by sebaceous glands, releases free fatty acids, and catalyzes the oxidation of squalene to oxidized squalene. These products promote excessive proliferation of keratinocytes and retention in hair follicle ducts, forming pimples. P. acnes can also form biofilm, increase the adhesion of keratinocytes, activate IGF-1/IGF-1 receptor signaling pathway, and up-regulate the expression of filagmin, thus affecting the proliferation and differentiation of keratinocytes and promoting the formation of acne.
Inducing/aggravating inflammation: P. acnes binds to TLR-2 and TLR-4 on the surface of keratinocytes and induces monocytes and other cells to produce a variety of cytokines and peptides, such as IL-1α, IL-1β, IL-6, IL-8, IL-12, TNF-α, interferon, chemokines, and β-defencins, triggering or exacerbating inflammatory responses. P. acnes also activates the complement pathway, forming C3a and C5a, increasing vascular permeability and leukocyte chemotaxis. In addition, P. acnes stimulated the secretion of transforming growth factor-β, IL-1β and IL-6 by sebaceous cells, promoted the transformation of T cells to Th17 cells, and activated the NLRP3 inflammatome to further release IL-1β, IL-8 and TNF-α, which directly damaged hair follicles, sebaceous glands and dermal extracellular matrix, and aggravated inflammation.
Malassezia and acne
Malassezia spp. is thought to induce acne. Malassezia is the most abundant fungus on the skin, co-existing with propionibacterium acnes and other bacterial species. In a study by Hu et al., acne lesions were significantly reduced after treatment with antifungal drugs. The authors suggest that Malassezia, rather than P. acnes, may be the cause of refractory acne. The results of several other studies support this hypothesis. Song et al. and Numata et al. reported that Malassezia spp. could be isolated from young acne patients. Akaza et al. showed that the lipase activity of Malassezia was ~ 100 times that of P. acnes. Malazzia can also hydrolyze triglycerides in sebum to produce free fatty acids, which may affect the abnormal keratosis of hair follicle ductus, chemotaxis polymorphonuclear neutrophils, and promote the secretion of pro-inflammatory factors by keratinocytes and monocytes. The role of Malassezia in the pathogenesis of acne remains to be further studied.
Antibiotics in acne treatment
Both bacterial factors and inflammation are thought to be involved in the pathogenesis of acne. Although acne is not a typical infectious disease, the use of antibiotics has been the mainstay of acne treatment for more than 40 years. Topical antibiotics are mainly used for the bactericidal effect on P. acnes. In addition to antibacterial effects, oral antibiotics also have anti-inflammatory effects, and their targets include P. acnes and the host immune response.
Macrolides, clindamycin and tetracycline are used as first-line treatment for acute inflammation of acne. Erythromycin, clarithromycin, roxithromycin and azithromycin are macrolide antibiotics. Clindamycin belongs to the lincoamide group. The tetracycline class of drugs used for acne treatment mainly includes tetracycline, doxycycline and minocycline. Several other antibiotics, such as trimethoprim-sulfamethoxazole, levofloxacin, rifampicin, dapsone, metronidazole, etc., can also be used in the treatment of acne. However, current data on the effects of these antibiotics are limited in scope and quality, and more research is needed.
Antibiotics for acne at BOC Sciences
Antibiotic production services at BOC Sciences
Macrolides and clindamycin for acne
Erythromycin and clindamycin have been widely used in the treatment of acne for the past 40 years and are still frequently prescribed by doctors. Long-term oral treatment of acne with macrolide antibiotics was beneficial to the increase of macrolide antibiotic-resistant P. acnes strains. Resistance of P. acnes to macrolide antibiotics and clindamycin has been increasing in several parts of the world in recent years. In some countries, the resistance rate of P. acnes to erythromycin exceeds 50%, and the resistance rate of P. acnes to azithromycin reaches 82-100%. Similarly, the rate of resistance of P. acnes to clindamycin increased from 4% in 1999 to 90.4% in 2016. A higher proportion (52%) of acne patients carried at least one strain of P. acnes resistant to clindamycin.
Different P. acnes strains showed different degree of antibiotic resistance. Potential molecular mechanisms of resistance include point mutations G2057A, A2058G, and A2059G in the V region of 23S rRNA, as well as the presence of the erm (X) gene. The use of macrolides and clindamycin in acne treatment has led to the development of resistance in skin bacteria other than P. acnes. At least 30% of S. epidermidis isolates in acne patients were resistant to erythromycin, roxithromycin, and clindamycin.
To reduce the emergence of antibiotic resistance, topical antibiotics in combination with benzoyl peroxide (BPO) or retinoic acid are currently recommended for acne treatment. Studies have shown that local application of clindamycin in combination with BPO or retinoic acid not only significantly reduced the total number of P. acnes on the skin, but also reduced the resistance of P. acnes to erythromycin and clindamycin.
Tetracycline for acne
The tetracycline group still has great activity against most P. acnes isolates, but antibiotic resistance is on the rise and needs to be paid attention to by the medical community. In recent years, the drug resistance rate of tetracycline from different regions varied greatly, ranging from 2% to 30%. At the same time, the resistance rate of P. acnes to doxycycline ranged from 2% to 44.2%. The combined drug resistance rate of tetracycline and doxycycline in different groups ranged from 1.2 to 100 %. In contrast to the high rates of resistance to tetracycline and doxycycline, the rates of resistance to minocycline were lower (< 2%) in Europe, Latin America, North America, and parts of Asia. This makes minocycline the most effective drug in the tetracycline family for treating acne. The mechanism of resistance to tetracycline antibiotics was the mutation of P. acnes 16S rRNA gene G1058C. In addition, amino acid replacement of the ribosome S10 protein helps to reduce doxycycline sensitivity.
Lymecyclin and sarecycline are new members of the tetracycline family in acne treatment. A recent study based on 16S rRNA sequencing showed that after 6 weeks of lycidycline treatment, the relative abundance of propionibacterium on the cheeks of patients decreased, but that of streptococcus, staphylococcus, micrococcus, and corynebacterium increased. Sericycline (two phase III clinical trials completed in 2017) has a narrower antibacterial profile than other tetracycline antibiotics.
Chemical structure of sarecycline hydrochloride.
Minocycline for acne
Minocycline has become one of the commonly used antibiotics in the treatment of moderate and severe acne because of its good anti-propionibacterium acnes activity and significant anti-inflammatory effect. However, there are some adverse reactions of oral minocycline, which limits the application of minocycline. 4% FMX101 is a novel topical antibiotic formulation for the treatment of moderate to severe acne. It is formed from lipophile minocycline dissolved in an oily foam matrix. The preparation quickly dissolves in sebum upon contact with the skin and promotes the entry of minocycline into the sebaceous unit of the hair follicle, acting both antibacterial and anti-inflammatory while reducing systemic absorption. FMX101 was approved by the FDA in 2019 for use in patients older than 9 years of age with moderate to severe acne.
Conclusion and prospect
Given the rapid emergence of antibiotic resistance worldwide, and given the impact of antibiotic use on the human microbiome, the clinical practice of alternative antibiotic prescriptions to treat microbiome related diseases becomes critical. A recently published study suggests that preventing acne by targeting Christie Atkins-Munch-Petersen (CAMP) factors as antigens is a potential vaccine approach. Meanwhile, other studies have shown that microbiome-based treatments may alter the balance among microbiome members, affecting the function of immune cells and preventing disease while restoring a healthy microbiome. In one such study, Nakatsuji et al. showed that reintroduction of an antimicrobial peptide-producing coagulase negative Staphylococcus (CoNS) strain into patients with atopic dermatitis reduced the colonization of Staphylococcus aureus on the skin. The study demonstrates how symbiotic skin bacteria defend against pathogens and suggests that correcting microbiome dysregulation could be used to treat or improve certain conditions. Future research on how to maintain the balance of the symbiotic microbiome while effectively reducing the burden of pathogenic microorganisms and inflammation may become a potential new therapy.
Reference
- Xu, H., Li, H. Acne, the skin microbiome, and antibiotic treatment. American Journal of Clinical Dermatology. 2019, 20(3): 335-344.
