The prevalence of antimicrobial-resistant Propionibacterium acnes strains isolated from acne patients has been increasing in Japan. Here, to estimate the current resistance rate, we tested antimicrobial susceptibility among P. acnes from acne patients having visited a specialized dermatology clinic between 2013 and 2015. Rates of resistance to macrolides and clindamycin were 44.3 (31/70) and 38.6% (27/70), respectively. erm(X), which confers high-level clindamycin resistance (minimum inhibitory concentration ≥256 μg/mL), was detected in six isolates, whereas no resistance determinants were identified in eight strains showing high-level resistance to clindamycin. Using single-locus sequence typing, the P. acnes isolates were classified into five clades (A, E, F, H and K), with all high-level clindamycin-resistant strains lacking known clindamycin resistance determinants being grouped together (in clade F). P. acnes isolates from patients previously treated with macrolides and clindamycin showed a macrolide resistance rate (55.3%) significantly higher than that of those from patients not having received these treatments (21.7%, P < 0.05). Furthermore, strains of clade F, which were very rarely isolated from healthy individuals, were more frequently recovered from patients with severe acne (40.0%) than those with mild acne (23.3%). Our data showed an increase in macrolide-resistant P. acnes prevalence in Japan due to the use of antimicrobial agents for acne treatment. Furthermore, we identified strains of specific phylogenetic groups frequently associated with severe acne patients.

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Antimicrobial-resistant Cutibacterium acnes strains have emerged and disseminated throughout the world. The 23S rRNA mutation and erm(X) gene are known as the major resistance determinants of macrolides and clindamycin in C. acnes. We isolated eight high-level macrolide-clindamycin-resistant C. acnes strains with no known resistance determinants, such as 23S rRNA mutation and erm(X), from different acne patients in 2008 between 2013 and 2015. The aim of this study was to identify the novel mechanisms of resistance in C. acnes. Whole-genome sequencing revealed the existence of a plasmid DNA, denoted pTZC1 (length, 31,440 bp), carrying the novel macrolide-clindamycin resistance gene erm(50) and tetracycline resistance gene tet(W). pTZC1 was detected in all C. acnes isolates (eight strains) exhibiting high-level macrolide-clindamycin resistance, with no known resistance determinants (MIC of clarithromycin, ≥256 μg/ml; clindamycin, ≥256 μg/ml). Transconjugation experiments demonstrated that the pTZC1 was horizontally transferred among C. acnes strains and conferred resistance to macrolides, clindamycin, and tetracyclines. Our data showed, for the first time, the existence of a transferable multidrug-resistant plasmid in C. acnes. Increased prevalence of this plasmid will be a great threat to antimicrobial therapy for acne vulgaris.

Use of antimicrobials for acne treatment is correlated with an increased occurrence of antimicrobial‐resistant Cutibacterium acnes. To clarify the role of antimicrobial use on the resistance and to investigate the characteristics of resistant strains, we conducted a multicenter study in dermatological clinics frequently visited by new patients with acne vulgaris. We collected specimens in 264 acne patients and tested 164 C. acnes strains isolated from 164 patients visiting 13 dermatological clinics. Antimicrobial susceptibility testing showed that the rates of resistance for tetracyclines, macrolides and clindamycin were significantly higher in C. acnes strains isolated from patients using antimicrobials for acne treatment than patients not using them. In particular, clindamycin‐resistant strains were frequently isolated from patients with older median age (≥24 years) and severe/moderate acne. After investigating the resistance mechanism of 15 high‐level clindamycin‐resistant strains, the transposable clindamycin resistance genes, erm(X) or erm(50), were detected in 14 strains. Using single‐locus sequence typing for C. acnes, the strains with erm(X) or multidrug resistance plasmid pTZC1 coding erm(50) and tetracycline resistance gene tet(W) were classified into clade F, which were specifically isolated from Japanese patients with acne, except for one strain. Our data showed that patients’ information, such as antimicrobial use, age and acne severity, are valuable in estimating whether a patient carries antimicrobial‐resistant C. acnes. Additionally, our results suggest that the clade F strains have a high risk of acquiring multidrug resistance.

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The prevalence of antimicrobial-resistant Cutibacterium acnes is an important concern for the antimicrobial treatment of acne vulgaris. We hypothesized that antimicrobial treatment regimens for acne vulgaris would change following the revisions in the Japanese acne treatment guidelines, which added a statement regarding appropriate antimicrobial usage. Here, we studied the changes in antimicrobial use and antimicrobial-resistant C. acnes isolated from acne patients. A total of 127 C. acnes isolates collected from 212 patients with acne between 2013 and 2018 were used. Roxithromycin and clindamycin resistance rates were approximately 50% and 40%, respectively. In contrast, the prevalence of low doxycycline-susceptible strains (minimum inhibitory concentration [MIC] ≥8 μg/ mL) in 2018 (17.4%) was 5.6-fold higher than that in 2013 (3.1%). Although the number of patients with severe and moderate acne did not change, the number of patients with a history of oral tetracycline use increased. The incidence of low doxycycline-susceptible strains was high in patients with a history of oral tetracycline use. The prevalence of strains with a 16S rRNA mutation, which confers reduced susceptibility to tetracyclines, increased by 8.6-fold (12.1%) from 2016 to 2018 in comparison with the previously revised guidelines (1.4%). Furthermore, the prevalence of low susceptibility strains with two resistance factors, 16S rRNA mutation and ribosomal S10 protein substitution, also increased. Approximately 10% of strains had the exogenous resistance gene, tet(W) (2013 to 2015, 10.1%; 2016 to 2018, 8.6%), and these strains showed different susceptibility to doxycycline dependent on the expression of tet(W) (MIC range 0.5-8 μg/mL).Our data show that the antimicrobial resistance pattern in C. acnes changes according to the trend of antimicrobial usage for acne treatment. Therefore, we should pay heed to the rapid dissemination of tetracycline resistance in C. acnes owing to acquisition of 16S rRNA mutation and tet(W).

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Macrolide-resistant Propionibacterium acnes are frequently isolated from patients with acne vulgaris, and the most resistant isolates (>90% resistance) have the 23S rRNA mutation. An increase in resistant P. acnes with this mutation is thought to be caused by the inappropriate use of antimicrobials. Therefore, we studied the mutation frequency of macrolide resistance in P. acnes in vitro. When P. acnes mutants were exposed to clarithromycin after being incubated in broth without antimicrobials, resistant mutants with the 23S rRNA mutation were not isolated. However, the mutants were obtained at the frequency of 10 after being pre-incubated with 0.03 μg/mL of antimicrobials. This is the estimated epidermal concentration of clarithromycin after p.o. administration. The resistant mutants had the 23S rRNA mutations A2058G, A2059G and C2611G. When pre-incubated with clarithromycin, C2611G mutants which showed resistance to clarithromycin were obtained 32.1% more often than pre-incubated with clindamycin (P < 0.01). By contrast, when pre-incubated with clindamycin, A2058G mutants, which show high-level resistance to both clarithromycin and clindamycin, were more frequently obtained than pre-incubated with clarithromycin (87.5%, P < 0.01). No difference in the isolation rate of A2059G mutants, which show high-level resistance to macrolides but low-level resistance to clindamycin, was found with either treatment. These results indicate the possibility that long-term use of oral macrolides for acne treatment facilitate the increase of macrolide-resistant P. acnes.