Acne, the Skin Microbiome, and Antibiotic Treatment

Haoxiang Xu; Huiying Li

Disclosures

Am J Clin Dermatol. 2019;20(3):335-344. 

In This Article

Antibiotics in Acne Treatment

Bacterial factors and inflammation are both thought to contribute to acne pathogenesis. Although acne is not a typical infectious disease, the use of antibiotics has been the mainstay in acne treatment for over 40 years. Topical antibiotics are largely used for their bactericidal effects against P. acnes. Oral antibiotics have anti-inflammatory effects in addition to antimicrobial effects, which target both P. acnes and host immune response.[4,75,76]

Based on several treatment guidelines and expert consensus documents, macrolides, clindamycin, and tetracyclines are recommended as the first-line therapy in the acute inflammatory phase of acne.[77–82] Erythromycin, clarithromycin, roxithromycin, and azithromycin are macrolides. Clindamycin belongs to lincosamides. Tetracyclines for acne treatment mainly include tetracycline, doxycycline, and minocycline. The effects of macrolides, clindamycin, and tetracyclines on the skin microbiome, including the target bacterium P. acnes and other non-target bacteria, and the associated issue of antibiotic resistance are discussed in Sects. 3.1–3.3. Several other antibiotics, such as trimethoprim–sulfamethoxazole, levofloxacin, rifampin, dapsone, and metronidazole, may also be used in acne treatment. However, current data on the effects of these antibiotics are limited in scope and quality. Additional studies are needed to address multiple knowledge gaps regarding these antibiotics.

Influence of Antibiotic use on P. acnes

Effect of Macrolides and Clindamycin. Erythromycin and clindamycin have been widely used in the last 40 years in acne treatment, and are still frequently prescribed by physicians. Long-term use of oral macrolides for acne treatment facilitates the increase of macrolide-resistant P. acnes strains.[83] In recent years, increasing levels of resistance of P. acnes to macrolides and clindamycin have been reported in several regions of the world.[83] In some countries, the resistance of P. acnes to erythromycin is over 50%,[83,84] and the resistance to azithromycin reaches 82–100%.[85,86] Similarly, the resistance of P. acnes to clindamycin increased from 4% in 1999 to 90.4% in 2016.[85,87] There was a high proportion (52%) of acne patients who carried at least one P. acnes strain resistant to clindamycin.[88] When topical clindamycin was administered for 16 weeks for acne treatment, the amount of resistant P. acnes was increased by 16 times from the baseline.[89] After antibiotic treatment is ended, tolerant P. acnes strains may remain on the skin for a considerably long period of time, and the presence of resistant P. acnes strains manifests as a re-occurrence of acne.[4] Furthermore, when patients are treated again with antibiotics, the efficacy of such drugs is reduced or voided.[4,90]

Different P. acnes strains exhibit a varying degree of antibiotic resistance. Based on multiple recent studies of P. acnes isolates collected from different geographic areas including Italy, Sweden, UK, Australia, USA,[10,47,51,91] Denmark,[88] and Greece,[92] RT4 and RT5 strains, which are mostly clonal complex 3 (CC3) strains and some CC18 strains based on MLST,[51,88] accounted for 85–95% of the antibiotic-resistant strains.[47,51,91,92] The underlying molecular mechanisms for resistance include point mutations G2057A, A2058G, and A2059G in the domain V of 23S rRNA, as well as the presence of erm(X) gene.[92–96] It is common that resistance to erythromycin correlates with resistance to clindamycin.[93] Cross-resistance to erythromycin and clindamycin of P. acnes isolates from acne patients varies from 11.6 to 100%, as reported in different studies.[51,97–100]

To reduce the emergence of antibiotic resistance, it is currently recommended that topical antibiotics be used in combination with benzoyl peroxide (BPO) or retinoid in acne treatment.[83] Studies have shown that combining clindamycin with BPO or retinoid for topical application not only significantly reduced the total number of P. acnes on the skin, but also lowered antibiotic resistance of P. acnes to erythromycin and clindamycin.[101]

Effect of Tetracyclines. Tetracyclines are another class of antibiotics frequently used for treating moderate to severe acne. Although this group of antibiotics is still largely active against the majority of P. acnes isolates, antibiotic resistance is rising and needs the attention of the medical field. The rate of resistance to tetracycline differed from 2 to 30% in studies from different geographic regions in recent years.[86,97,99,101] In parallel, resistance to doxycycline among isolated P. acnes strains varied between 2 and 44.2%.[85,86,97,101] The combined resistance to tetracycline and doxycycline ranged from 1.2 to 100% in different groups of patients.[99,102] In contrast to this high resistance rate to tetracycline and doxycycline, a lower resistance rate to minocycline (< 2%) was observed in Europe, Latin America, Northern America, and parts of Asia. This makes minocycline the most effective agent in the tetracycline class for acne treatment.[85,92,97] The resistance mechanism against tetracyclines is a G1058C mutation in P. acnes 16S rRNA gene.[96] Additionally, an amino acid substitution in the ribosomal S10 protein contributes to reduced doxycycline susceptibility.[103]

Influence of Antibiotic Use on Other Skin Bacteria

Effect of Macrolides and Clindamycin. The use of macrolides and clindamycin in acne treatment results in resistance in other skin bacteria in addition to P. acnes. At least 30% of S. epidermidis isolates from acne patients were resistant to erythromycin, roxithromycin, and clindamycin.[104] Harkaway et al.[105] reported that after 12-week treatment with topical erythromycin alone, erythromycin-tolerant S. epidermidis became predominant on the skin surface, and the relative abundance of S. aureus at nostrils rose from 15 to 40%. Similarly, Mills et al.[106] reported that in acne treatment with topical erythromycin, the proportion of patients with erythromycin-tolerant staphylococci on the face was 87% at baseline, and increased to 98% at week 12 of treatment. Furthermore, the proportion of patients with resistant staphylococci was only slightly reduced 12 weeks after drug withdrawal. The average density of tolerant bacteria at non-treated sites, such as the back, increased at the end of the treatment. Transmission of such bacteria to different sites may cause serious consequences.[106] Like macrolides, clindamycin exerts selection pressure on both P. acnes and staphylococci. The study by Nakase et al.,[95] which analyzed the correlation of antimicrobial resistance between P. acnes and S. epidermidis, reported that clindamycin-resistant S. epidermidis strains were isolated from more than 80% of the patients who also carried clindamycin-resistant P. acnes.

Effect of Tetracyclines. There are few established data on the effect of tetracyclines on the skin bacteria besides P. acnes. Doxycycline 40 mg modified release has been used for the treatment of inflammatory lesions in moderate and severe acne. Limited evidence suggested that this dose showed no effect on the normal skin flora as well as the rate of antibiotic resistance while being effective in reducing acne lesions.[76,107]

Lymecyclin and sarecycline are new members of tetracyclines in acne therapy. A recent study based on 16S rRNA sequencing demonstrated that at 6 weeks after lymecyclin treatment, the relative abundance of Propionibacterium on the cheeks of patients decreased, but the relative abundances of Streptococcus, Staphylococcus, Micrococcus, and Corynebacterium increased. Changes in this microbial community after drug withdrawal were not investigated.[108] Sarecycline (two phase III clinical trials completed in 2017) has a narrow antibacterial spectrum relative to other tetracyclines. It might have less selective pressure on enteric Gram-negative bacteria, but there are no data available on its influence on the skin microbiome.[109]

Applications of Antibiotics in Acne Treatment

The growing prevalence of antibiotic resistance in P. acnes and other skin commensal bacteria is becoming increasingly alarming. For mild-to-moderate acne, topical antibiotic monotherapy is not recommended. Topical retinoid, BPO, or a combination therapy (topical retinoid + BPO, topical antibiotic + BPO, topical retinoid + topical antibiotic + BPO) is recommended.[110] For moderate-to-severe acne, the recommended first-line treatment is oral antibiotics combined with BPO and/or a topical retinoid. Oral antibiotic monotherapy is not recommended.[111] To reduce antibiotic-resistant microorganisms on the skin, as alternative treatments, BPO can be used for at least 5–7 days between antibiotic courses.[5] Oral contraceptives or anti-androgens may be another alternative for some female patients. To obtain better clinical efficacy and reduce antibiotic resistance, information on past exposure to macrolides or clindamycin should suggest avoidance of prescription of these antibiotics. Given that some acne patients are colonized by antibiotic-resistant P. acnes strains, Sinnott et al.[112] recommended that swabbing, culturing, and testing for resistant strains may be one way to help avoid long-term use of ineffective antibiotics.

The recommended minimum course of acne treatment with oral antibiotics is 6–8 weeks. Oral antibiotics may continue to be used after taking effect, but should not be used for longer than 12 weeks.[83,113] However, it is reported that in practice, 17.5% of antibiotic treatment courses last ≥ 6 months and 7% of the treatments last over 9 months, with an average treatment time of 125–129 days.[114,115] The long-term use of antibiotics may significantly alter the skin microbiome and increase drug resistance. Future longitudinal studies of long-term use of antibiotics may shed light on its effect on the composition and dynamics of the microbiome.[83]

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