Cutibacterium

Orla-Jensen, 1909.

After its discovery in a patient with "acne vulgaris", Propionibacterium acnes, now called Cutibacterium acnes, underwent a series of taxonomic changes. It was successively placed in the genus Bacillus and then in the genus Corynebacterium. Later, this microorganism was shown to be more closely related to members of the genus Propionibacterium because, like other species of this genus, it ferments lactose to propionic acid in an anaerobic atmosphere. Recently, a major taxonomic revision has been proposed that places all Propionibacterium species from the skin microbiome into a new genus. Consequently, Propionibacterium is replaced by Cutibacterium (C.) e.g. C. avidum, C. acnes, C. granulosum and the recently discovered species C. namnetense and C. humerusii. The pathogenicity of these species has often been ignored, their existence considered as contamination in cultures.

The genus Cutibacterium is a coryneform, gram-positive, pleomorphic, rarely branching anaerobic rod bacterium. The genus consists of species that produce propionic acid during the fermentation process (Whitman WB et al. 2012). The genus belongs to the class Actinobacteria of the order Propionibacteriales (Patrick S et al. 2012).

Species of human medical interest in the genus Propionibacterium (Cutibacterium) are:

Cutibacterium acnes (three subspecies are proposed for C. acnes with respect to different phylotypes and based on phenotypic characteristics (Dekio I et al. 2015, McDowell A et al. 2016).

• Phylotype I: C. acnes subsp. acnes
• Phylotype II: C. acnes subsp. defendens
• Phylotype III: C. acnes subsp. elongatum

Cutibacterium avidum (genetic analyses suggest the existence of 2 subtypes in C. avidum strains).

Cutibacterium granulosum

Cutibacterium namnetense

Cutibacterium humerusii

The species Cutibacterium avidum was often considered a contaminant in cultures in the past. It was considered apathogenic. In the 1970s, C. avidum was used as an adjuvant in antitumor therapies or as an immunostimulant (Azuma I et al. 1976). Its ecological niche is clearly distinguished from other members of this genus by a specific tropism for moist areas (sweat gland regions) of the skin ((McGinley KJ et al. 1978)).

C. avidum is also detected in the intestines of chickens (Poultry Microbiota). Despite its low incidence in human infections to date, numerous associated or invasive infections have been reported: bone infections, infective endocarditis (IE), chest infections, abdominal infections, prostate infections and splenic and skin abscesses have been described, sometimes with significant collateral damage to the patient (di Summa PG et al. 2015). Most positive specimens were obtained from blood cultures as well as valve, bone, tissue, and deep perioperative specimens, often from immunocompromised patients.

Later, the key role of Cutibacterium species, especially C. avidum, in modulating the immune response was demonstrated. They are involved in nonspecific antibacterial, antiviral, or antitumor responses (Ko HL et al. 1995).

Microbiota: Anaerobic diphtheroid bacteria are typical inhabitants of human sebaceous follicles and are involved in the pathogenicity of acne or other skin diseases. After proliferation in the lumen, they migrate from the follicles across the sebaceous skin surface and form dense populations in sebum-rich skin areas (Barnard E et al. 2016). The three most widespread species-C. avidum, C. acnes, and C. granulosum-are found on the skin surfaces of both healthy individuals and acne patients. Their distribution and prevalence are related to the skin region studied, the age of the patient, and the presence of skin lesions (papules, pustules, and nodules). Meanwhile, the ecological niche of C. avidum has also been better analyzed. C. avidum tends to reside in regions with eccrine sweat glands (Nordstrom NK et al. 1984). It is most commonly detected in moist areas (nares, axilla, groin, and rectum, which include areas colonized with enteric Gram-negative bacteria, suggesting an intestinal reservoir), compared with distribution for C. granulosum and C. acnes in sebaceous gland-rich areas. Indeed, other Cutibacterium species, particularly C. acnes and C. granulosum, require skin surface lipids to proliferate. They are involved in acne vulgaris, whereas C. avidum is rarely or generally not associated with acne (Nordstrom NK et al. 1984, Jahns AC et al. 2015). Humidity appears to play a critical role in the ecology of C. avidum (McGinley KJ et al. 1978). The prevalence of C. avidum recovery increases with age and is associated with the onset of puberty. This bacterium is detected much less frequently in young females or males between the ages of 5 and 10 years (5% and 4.5%, respectively), whereas female and male teenagers (15- to 16-year-olds) are 45% and 58% colonized, respectively. Females tend to be colonized earlier in life than males. It is suggested that increasing axillary moisture with age and availability of nutrients may act as key points in the colonization process. This finding represents a possible explanation for the major routes of contamination during breast abscess (Panagea S et al. (2005).

Genetic and genomic analyses: Although propionic acid-producing bacteria were first described by Freudrenreich and Orla-Jensen at the beginning of the last century (1906), DNA analogies were studied in the 1970s to classify Cutibacterium species. Using single-cell locus sequence typing (SLST), it is now possible to precisely differentiate P. acnes/C. acnes subpopulations (Scholz CFP et al. 2014). Phylogenetic analysis confirms a close relationship between C. avidum and C. acnes, whereas C. granulosum is more distant. Using orthologous average nucleotide identity (OrthoANI) analysis, a closer relationship was found between C. acnes, C. namnetense and C. humerusii. In contrast, C. avidum represents a different branch of the dendrogram. The same observation applies to the C. granulosum genome, which is significantly smaller (about 400 kb smaller) than the genomes of C. avidum and C. acnes (Mak TN et al. 2013).

Virulence factors: Very few data on virulence factors are available for C. avidum strains. Nevertheless, C. avidum is capable of producing several biologically active substances, including enzymes that degrade mucopolysaccharides, such as hyaluronidase and neuraminidase (Fujimura S et al. 1982). Propionicins and bacteriocins are also produced by C. avidum strains, some of which are capable of inhibiting all C. acnes or C. granulosum strains tested (Fujimura S et al 1982).

Lipase: The extracellular enzyme triacylglycerol lipase is produced by most Cutibacterium species. Lipase, encoded by the gehA gene, has a crucial influence by hydrolyzing sebum triglycerides, which partly explains acne pathogenesis. The release of irritating free fatty acids within pilosebaceous follicles may explain the inflammation seen in acne. While C. acnes and, to a lesser extent, C. granulosum are clearly involved in acne, the role of C. avidum remains unclear.

Hyaluronidase an extracellular enzyme involved in bacterial pathogenesis. The three major Cutibacterium species derived from the skin can produce hyaluronidase. Although C. acnes strains are the most active (68.8%), with clearly measurable hyaluronidase activity, C. avidum (45%) and C. granulosum (33.3%) strains are also positive, despite much lower activity (Höffler U 1979).

Haemolysin: C. avidum is capable of producing haemolysin. Different hemolysins have also been described for C. acnes (Valanne S et al 2005).

Biofilm formation: Biofilm formation has been well studied and characterized for different clinical strains of Cutibacterium species, especially C. acnes (Aubin GG et al. 2014). Evidence shows that various C. acnes strains can form early or mature biofilms on diverse surfaces (Holmberg A et al. (2009). An analogous capability for biofilm formation and biofilm maturation is also present for C. avidum strains.

Other virulence factors for Cutibacterium species include gelatinase, DNase, lecithinase and a weak phosphatase.

Host-bacterium interaction: In C. acnes, activation of the innate immune system occurs at least in part via TLR2 as well as the NLRP3 inflammasome (Lheure C et al. 2016). Therefore, it is considered likely that C. avidum also interacts with these receptors. The mitogenic activity of bacterial cells or cell wall fractions prepared from various Cutibacterium species, including C. avidum, provide evidence that they act as mitogens on both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells). This mitogenic potential appears to be dose-dependent. In severe acne patients, significantly higher antibody titers against the acidic polysaccharide fraction are found than in healthy patients. These antibodies may cross-react with C. avidum serotype I or II. It is likely that these external bacterial components are involved in the inflammation of acne (Dalen A et al.1980). The key role played by propionibacteria in modulating the immune response has been reported on the basis of different approaches. The three major species, including C. avidum have been described as immunomodifiers that stimulate various cell subsets involved in nonspecific antibacterial, antiviral, and antitumor resistance. The higher activity for C. avidum was confirmed to parallel antitumor activity (Cummins CS et al. 1977). Cutibacterium species can stimulate the reticuloendothelial system but also trigger immune cell modifications, in particular macrophage activation, natural killer cell activation and interferon induction. Thus, C. avidum proved to be a potent and sometimes excellent stimulator of the macrophage-monocyte system and an inducer of endogenous interferons (Markowska-Daniel I et al. 1993). The bacterium also appears to be able to act as an adjuvant in vaccines.

C. Acnes is the most common skin germ in humans. Up to 100,000 germs per cm2 can be found, especially in the crypts of the skin where they escape disinfectants. Cutibacterium spp. are involved in the pathogenesis of acne , but they are not the trigger.

Cutibacterium spp. have been detected in sinusitites. Furthermore, Cutibacterium spp have been detected in infected joint prostheses using the MALDI-TOF detection method(Peel TN et al. 2015).

Breast infections: Aesthetic (reduction mammoplasty) or reconstructive breast implant surgeries after carcinoma are potentially prone to infections, especially S. aureus, anaerobes, and Cutibacterium infections, despite the increase in standardized preventive measures. A first case of breast infection due to C. avidum was reported by Panagea et al. in 2005 after breast reduction surgery (Panagea S et al. 2005). Several studies showed predisposing conditions or risk factors for the occurrence of Cutibacterium infection.

Abdominal infections: Acute abdominal infections are usually caused by Enterobacteriaceae, Enterococci and anaerobes, such as Bacteroides fragilis but also by C.avium (Janvier F et al. 2013).

Splenic abscesses: C. avidum was first described as a causative agent of splenic abscess in 1986 (169). This disease remains rare and mainly involves S. aureus or Enterobacteriaceae. C. acnes has also been described as a potential causative agent (Gangahar DM et al. 1981). Skin abscesses: Only one case of skin abscess without risk factors in a young, immunocompetent patient has been reported, notably without prior surgery.

Infectiveendocarditis: There have been several reports of infective endocarditis (IE) due to C. avidum and c. acnes (Gangahar DM et al. 1981). Although these Cutibacterium infections, are rare, they represent a serious medical entity, and DNA sequencing of the valves (with careful sample handling) identifies Cutibacterium spp. as the cause of aortic endocarditis in most cases, whereas these cases would otherwise have been classified as culture negative.

Bone and joint infections: Because of its conventional niche, C. acnes is an uncommon player in bone and joint infections before C. avidum, especially in hip prostheses. Nevertheless, high BMI with skin folds may be infected with this uncommon bacterium due to the growth and development of C. avidum near the surgical wound.

Acne lesions: C. avidum has been detected less frequently. However, its occurrence has been reported in combination with C. acnes and C. granulosum. In fact, as previously suspected, C. avidum is more commonly detected in moist areas of the body.

Antimicrobial resistance developments: Studies on the antimicrobial susceptibility of Cutibacterium avidum and related species, especially C. acnes, C. granulosum, and Corynebacterium minutissimum, have existed since 1976 (Hoeffler U et al. (1976). Known erythromycin resistances are usually due to methylation of the 23S ribosomal subunit (mutation in the 23S rRNA gene, usually at position 2058 or 2059). Remarkably, no other acquired resistance developments were observed even in larger studies (Höffler U et al. 1980). However, for most C. avidum strains, natural resistance to metronidazole and colistin exists. To limit the occurrence of antibiotic resistance due to the selection of resistant mutants, various alternative "nonantibiotic" treatments for acne have been proposed. Regardless of the frequency of use, tetracyclines remain active against Cutibacterium species (less than 10% to 15% resistance) (Dumont-Wallon G et al 2010). Even in the acne setting, low-dose tetracyclines are still used for their anti-inflammatory properties, but clinical strains of C. avidum (of various origins) remain sensitive to this family.

To date, there is no gold standard regarding the treatment of Cutibacterium infections. Various strategies have been developed, and the proposed therapeutic approaches are usually based on tradition and guided by personal and professional experience. As first-line therapy, penicillin at a dosage of 20 to 24 million units i.v. daily is recommended. As second-line therapy, clindamycin at a dosage of 600 to 900 mg i.v. every 8 h or vancomycin at a dosage of 15 mg/kg body weight i.v. every 12 h. The recommended duration of therapy is 4 to 6 weeks.

Interestingly, various expert groups usually recommend prolonged treatment with different antibiotics, especially combinations with rifampin (Sendi P et al. 2012), which has excellent bone distribution and diffusion through biofilms, together with a fluoroquinolone, amoxicillin or clindamycin. In the case of abscesses, initial surgery with excellent debridement should be performed, and a course of 2 to 4 weeks seems to be associated with a favorable outcome.

Rifampin, amoxicillin, ceftriaxone, levofloxacin and gfls. moxifloxacin as well as daptomycin or linezolid (in case of mixed infections with multidrug-resistant coagulase-negative staphylococci) in different combinations for 3 months are drugs of choice to eliminate Cutibacterium biofilm or device-related infections.

1. Aubin GG et al. (2014) Propionibacterium acnes, an emerging pathogen: from acne to implant infections, from phylotype to resistance. Med Mal Infect 44:241-250.
2. Azuma I et al (1976) Mitogenic activity of the cell walls of mycobacteria, nocardia, corynebacteria and anaerobic coryneforms. Jpn J Microbiol 20:263-271.
3. Banzon JM et al (2017) Propionibacterium acnes endocarditis: a case series. Clin Microbiol Infect 23:396-399.
4. Barnard E et al (2016) The balance of metagenomic elements shapes the skin microbiome in acne and health. Sci Rep 6:39491.
5. Dekio I et al. (2015) Dissecting the taxonomic heterogeneity within Propionibacterium acnes: proposal for Propionibacterium acnes subsp. acnes subsp. nov. and Propionibacterium acnes subsp. elongatum subsp. nov. Int J Syst Evol Microbiol 65:4776-4787.
6. di Summa PG et al. (2015) Propionibacterium avidum infection following breast reduction: high morbidity from a low-virulence pathogen. J Surg Case Rep 2015:rjv002.
7. Dumont-Wallon G et al (2010) Bacterial resistance in French acne patients. Int J Dermatol 49:283-288.
8. Fujimura S et al (1982) Hemolysin of Propionibacterium avidum. Zentralbl Bacteriol Microbiol Hyg A 252:108-115.
9. Gangahar DM et al (1981) Intrasplenic abscess: two case reports and review of the literature. Am Surg 47:488-491.
10. Hoeffler U et al (1976). Antimicrobiol susceptibility of Propinibacterium acnes and related microbial species. Antimicrob Agents Chemother 10:387-394.
11. Höffler U (1979) Production of hyaluronidase by propionibacteria from different origins. Zentralbl Bakteriol Orig A 245:123-129.
12. Höffler U et al (1980) Susceptibility of cutaneous Propionibacteria to newer antibiotics. Chemotherapy 26:7-11.
13. Holmberg A et al. (2009) Biofilm formation by Propionibacterium acnes is a characteristic of invasive isolates. Clin Microbiol Infect 15:787-795.
14. Jahns AC et al (2015) Propionibacterium species and follicular keratinocyte activation in acneic and normal skin. Br J Dermatol 172:981-987.
15. Janvier F et al. (2013) Abdominal wall and intra-peritoneal abscess by Propionibacterium avidum as a complication of abdominal parietoplasty. Pathol Biol (Paris) 61:223-225.
16. Ko HL et al (1978) Propionicins, bacteriocins produced by Propionibacterium avidum. Zentralbl Bakteriol Orig A 241:325-328.
17. Ko HL et al (1995) Influence of Propionibacterium avidum KP-40 on the proliferation, maturation, emigration and activity of thymocytes and monocytes. Zentralbl Bakteriol Int J Med Microbiol 282:86-91.
18. Lheure C et al (2016) TLR-2 recognizes Propionibacterium acnes CAMP factor 1 from highly inflammatory strains. PLoS One 11:e0167237.
19. Lomholt HB et al (2014). Clonality and anatomic distribution on the skin of antibiotic resistant and sensitive Propionibacterium acnes. Acta Derm Venereol 94:534-538.
20. Mak TN et al. (2013) Comparative genomics reveals distinct host-interacting traits of three major human-associated propionibacteria. BMC Genomics 14:640. doi:10.1186/1471-2164-14-640.
21. McDowell A et al. (2016) Proposal to reclassify Propionibacterium acnes type I as Propionibacterium acnes subsp. acnes subsp. nov. and Propionibacterium acnes type II as Propionibacterium acnes subsp. defendens subsp. nov. Int J Syst Evol Microbiol 66:5358-5365. 2nd ed. Springer-Verlag, New York pp 1138-1156.
22. McGinley KJ et al (1978) Regional variations of cutaneous propionibacteria. Appl Environ Microbiol 35:62-66.
23. Nordstrom NK et al (1984). Colonization of the axilla by Propionibacterium avidum in relation to age. Appl Environ Microbiol 47:1360-1362.
24. Orla-Jensen S (1909). The main lineages of the natural bacterial system. Zentralbl Bakteriol Parasiten u. Infektionskrankh 2:305-346.
25. Panagea S et al. (2005) Breast abscess caused by Propionibacterium avidum following breast reduction surgery: case report and review of the literature. J Infect 51:e253-e255.
26. Patrick S et al (2012) Genus I. Propionibacterium. In Whitman WB, Goodfellow M, K̈ampfer P, Busse H-J, Trujillo ME, Ludwig W, Suzuki K-I, Parte A (ed), Bergey's manual of systematic bacteriology,
27. Peel TN et al. (2015) Matrix-assisted laser desorption ionization time of flight mass spectrometry and diagnostic testing for prosthetic joint infection in the clinical microbiology laboratory. Diagn Microbiol Infect Dis 81:163-168.
28. Sendi P et al. (2012) Antimicrobial treatment concepts for orthopaedic device-related infection. Clin Microbiol Infect 18:1176-1184.
29. Whitman WB et al (2012) (ed). The Actinobacteria. Bergey's manual of systematic bacteriology, 2nd ed, vol 5. Springer-Verlag, New York.