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General review

Propionibacterium acnes, an emerging pathogen: From acne to implant-infections, from phylotype to resistance
Propionibacterium acnes, un pathogne mergent : de lacn aux infections sur matriel, du phylotype la rsistance G.G. Aubin a,b , M.E. Portillo c , A. Trampuz d , S. Corvec a,,b
Service de Bactriologie-Hygine, Institut de biologie des hpitaux de Nantes, CHU de Nantes, 9, quai Moncousu, 44093 Nantes cedex 01, France b EA3826 Thrapeutiques cliniques et exprimentales des infections, Universit de Nantes, facult de mdecine, 44000 Nantes, France c Microbiology Laboratory, Laboratori de Referncia de Catalunya, Carrer de la Selva, 10, Edici Inblau A. Parc de Negocis Mas Blau, 08820 El Prat de Llobregat, Barcelona, Spain d Charit - University Medicine Free and Humboldt-University of Berlin Charitplatz, 1D-10117 Berlin, Germany Received 28 June 2013; received in revised form 24 December 2013; accepted 12 February 2014
a

Abstract Propionibacterium acnes colonizes the lipid-rich sebaceous glands of the skin. This preferential anaerobic bacterium is easily identied if cultures are prolonged. It is involved in the inammation process of acne, but until recently, it was neglected in other clinical presentations. Despite a reported low virulence, the new genomic, transcriptomic, and phylogenetic studies have allowed better understanding of this pathogens importance that causes many chronic and recurrent infections, including orthopedic and cardiac prosthetic, and breast or eye implant-infections. These infections, facilitated by the ability of P. acnes to produce a biolm, require using anti-biolm active antibiotics such as rifampicin. The antibiogram of P. acnes is not systematically performed in microbiology laboratories because of its susceptibility to a wide range of antibiotics. However, in the last 10 years, the rate of antibiotic-resistant bacteria has increased, especially for macrolides and tetracyclines. Recently, rpoB gene mutations conferring resistance to rifampicin have been also reported. Thus in case of a biolm growth mode, the therapeutic strategy should be discussed, according to the resistance phylotype and phenotype so as to optimize the treatment of these severe infections. 2014 Published by Elsevier Masson SAS.
Keywords: Acne; Prosthesis or device-related infections; Phylotype; Antibiotic resistance

Rsum Propionibacterium acnes colonise lenvironnement riche en lipides des glandes pilo-sbacs de la peau. Lidentication de ce micro-organisme anarobie prfrentiel est favorise par la prolongation des cultures. Cette bactrie est implique dans les processus inammatoires de lacn et tait jusqu rcemment nglige dans dautres situations cliniques. Malgr une faible virulence rapporte, les nouvelles tudes gnomiques, phylogntiques et transcriptomiques ont permis de mieux comprendre limportance de ce pathogne lorigine de nombreuses infections chroniques et rcidivantes notamment celles lies aux prothses orthopdiques, cardiaques, mammaires et implants oculaires. Ces infections, facilites par la capacit de P. acnes produire un biolm, ncessitent dutiliser des antibiotiques ayant une activit anti-biolm comme la rifampicine. En raison de sa sensibilit de nombreux antibiotiques, lantibiogramme de P. acnes nest pas ralis de manire systmatique dans les laboratoires de Microbiologie. Cependant, depuis 10 ans, la proportion de bactries rsistantes aux antibiotiques a augment, notamment vis--vis des macrolides et des ttracyclines. Par ailleurs, des mutations dans le gne rpoB confrant la rsistance la rifampicine ont t rapportes rcemment. Dans ce contexte et en prsence de biolm, la stratgie thrapeutique doit tre discute, en fonction du phylotype et du phnotype de rsistance, an doptimiser le traitement de ces infections graves. 2014 Publi e par Elsevier Masson SAS.
Mots cls : Acn ; Prothse ; Phylotype ; Rsistance aux antibiotiques

Corresponding author. E-mail address: stephane.corvec@chu-nantes.fr (S. Corvec).

0399-077X/$ see front matter 2014 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.medmal.2014.02.004

Please cite this article in press as: Aubin GG, et al. Propionibacterium acnes, an emerging pathogen: From acne to implant-infections, from phylotype to resistance. Med Mal Infect (2014), http://dx.doi.org/10.1016/j.medmal.2014.02.004

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G.G. Aubin et al. / Mdecine et maladies infectieuses xxx (2014) xxxxxx Table 1 Identication criteria for Propionibacterium acnes species. Critres didentication lespce Propionibacterium acnes. Identication criteria for Propionibacterium acnes species Gram staining Cultures features Gram-positive bacilli Slow growth in anaerobic conditions, aerotolerant Growth on blood agar and sometimes better on chocolate agar from deep samples Possibility of bread dumpling in case of Schaedler broth growth Catalase positive Indole positive in 70% Nitrate reductase positive Metronidazole resistant Fosfomycin resistant

1. Introduction Historically, the bacillus of acne was rst described by Unna in 1896, when working on histological sections of blackheads. This bacillus morphologically resembling a corynebacterium was rst classied in the genus Corynebacterium in 1923. It was subsequently transferred to the genus Propionibacterium, in 1933, because of its relationship to oxygen and the nature of its catabolic process [1]. Propionibacterium acnes is an important part of the normal ora of human skin, living in and around sweat glands and sebaceous glands. Furthermore, some species of the genus Propionibacterium are able to synthesize propionic acid. They are used in the production of various compounds in the industrial manufacturing of probiotics or cheese [2]. The pathogenicity of P. acnes has long been restricted to skin conditions. Its isolation from other anatomical sites or deep microbiological samples has often been considered as contamination. Although described as a commensal bacterium with a low pathogenicity, its involvement has been reported in many clinical entities: chronic prostatitis [3], synovitisacnepustulosishyperostosisosteitis syndrome (SAPHO) [4], or sarcoidosis [5]. More recently, this microorganism has been considered as responsible for various types of infections associated with breast implants [6], cerebrospinal uid shunts [7], cardiovascular devices [8], ocular implants [9], or osteosynthesis and joint prosthesis [10]. The development of various typing techniques allowed rst, to link sub-populations of P. acnes to a specic disease and, secondly, to determine the predominant clones [11,12]. In case of P. acnes infections, the use of antibiotics has sometimes led to the emergence of resistance favored by prolonged administration and/or probabilistic treatment, by poor compliance, responsible for subdosing, or when the treatment was not associated with topical based retinoids in teenagers [13,14]. However, the resistance of P. acnes seems to be limited to some families. The objective of this study was: to review the signicance of P. acnes in clinical practice; to discuss the molecular aspects of the phylogeny and molecular typing; to describe the new trends of emergent resistance in P. acnes strains, and their underlying molecular mechanisms; to consider potential new therapeutic strategies for deep infections. 2. Microbiology of P. acnes P. acnes is an anaerobic bacterium, aerotolerant, diphtheroid, Gram-positive bacillus (Table 1). Its natural habitats are the sebaceous follicles of human skin, conjunctiva, oral cavity, intestinal tract, and the external auditory canal [15]. P. acnes tolerates oxygen for several hours, is able to survive in anaerobic conditions up to 8 months in vitro, and can also survive for long period in human tissues with low oxidation potential [16]. In addition, this

Biochemical tests

Susceptibility test

bacterium can resist to phagocytosis and persist in macrophages [17]. Growth appears to be slow and sometimes unpredictable in aerobic condition. In case of severe or deep infections, the suspicion of P. acnes requires extended anaerobic incubation for 14 days. Seeding a Schaedler or thioglycolate broth is sometimes recommended to increase the sensitivity of the examination. In addition, any suspicion of bacterial growth (dumpling bread aspect for example) in broth should lead to re-inoculation on agar [18]. Finally, a culture positive for P. acnes should be analyzed with caution. If the growth is only observed in broth, or in only one of several per-operative clinical samples, additional arguments supporting infection (clinical and histopathological criteria) will be needed to determine if P. acnes is a pathogen or a contaminant [18]. Obsolete tests (serological agglutination and carbohydrate analysis of the cell wall) were used to classify strains of P. acnes in 3 different phenotypes (type I, II, and III). The distinction between types IA, IB, IC, II, and III are now based on the sequence analysis of 2 genes: recA gene, a non- ribosomal gene, and tly gene, a housekeeping gene encoding a hemolysin/cytotoxin [11]. Biolm formation is an important virulence factor, especially responsible for nosocomial infections. Innovative techniques such as whole genome sequencing, high throughput sequencing, and molecular typing, have identied 3 groups of genes encoding adhesins and enzymes involved in the biosynthesis of extracellular polysaccharide. This element, essential in the production of biolm, contributes to the persistence of P. acnes in the body [19]. 3. A supercial infection: acne vulgaris Acne is a skin disease that usually affects young adults. Nearly 80% of teenagers have presented with acne. The causes of acne vary according to psychological, chemical, and cutaneous genetic factors related to hormonal changes [20]. The inammatory condition is related to a gland dysfunction or chronic inammation of pilosebaceous units, characterized by an increased secretion of sebum, a hyperproliferation of the epidermis and hair follicles, and microbial growth of P. acnes [15]. If you need to learn more about acne, inammation, or

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interactions with immunity, the authors of references [15,20,21], and [21b] present these aspects in more details. 4. P. acnes infections without implant Numerous authors have reported the potential role of P. acnes during infection without carriage of any medical devices. Recently, its likely involvement in prostatitis was reported. However, due to possible contamination of the sample, it was recommended to identify the pathogen in various biological tissues by different methods. It can be difcult to incriminate P. acnes, in case of low inoculum, heterogeneous distribution of the bacteria in the sample, and also because of a multifactorial histological inammation of the gland. Nevertheless, its presence was clearly reported in the tissues of patients with prostate cancer complicated by prostatitis [3]. The involvement of a low virulence microorganism such as P. acnes was also mentioned in the diagnosis of SAPHO syndrome (pustulo-hyperostotic psoriatic spondylitis). P. acnes may interact with the immune system, causing inammation and triggering chronic osteitis, even after removal of material [4]. Finally, although the causes of sarcoidosis remain unknown, the involvement of P. acnes was suggested in this disease because of its signicant presence in culture from lymph nodes of patients. The mechanisms of granuloma formation and immunomodulation by P. acnes have not been elucidated yet. It seems that the concentration P. acnes DNA in alveolar liquid is signicantly higher in these patients [5]. 5. P. acnes prosthesis and implant-related infections 5.1. Osteo-articular prosthesis infections The complex pathogenesis of bone and joint infections (BJI) is explained by the growth of microorganisms in biolms and micro-colonies, making it difcult to diagnose, eradicate, and treat such kind of infections [22]. Staphylococci are involved in 50 to 60% of the cases in these infections [18]. The rate of P. acnes involvement is estimated at 10%, but it is probably underestimated [18,22]. P. acnes is usually the cause of delayed infections occurring 3 to 24 months or more after prosthesis placement. P. acnes is frequently associated with shoulder prosthesis infections because of its more common ecological niche (sebaceous follicles) [10]. The authors of a study reported that P. acnes was isolated only in male patients, suggesting that host factors may predispose to this type of infection. Furthermore, if type I P. acnes strains are predominant, type IB strains seem more common than type IA in prosthetic infections [12]. Usually, a 2-stage replacement is performed, but more and more frequently, a short interval between explantation and re-implantation of the prosthesis is used, especially if P. acnes strain remains rifampin susceptible [23]. Torpid and chronic infections considered as low-grade infections are difcult to distinguish from aseptic prosthetic dysfunction, presenting only with early prosthetic loosening, persistent pain, but sometimes without clinical signs. Several authors have suggested that aseptic loosening

of prosthesis in the absence of clinical and microbiological arguments could be related to a low-grade infection [24,25]. There is currently no ideal biomarker for the diagnosis and monitoring of bone sepsis; and a normal value of C-reactive protein (CRP), cannot rule out infection [21]. During P. acnes infection, the leukocyte count in the synovial uid or histology of peri-prosthetic tissue can sometimes remain normal, reecting a weak virulence or a low inoculum. However, the formation of a stula, with or without purulent discharge, is a good argument for a BJI [18,22,26]. The current diagnostic methods have limited sensitivity, with 10 to 20% false negative cultures. The widespread use of automated bead mill processing and the inoculation of crushed samples into blood culture bottles should reduce the rate of false negatives [18]. New molecular techniques have been developed to increase the sensitivity of BJI detection (especially in case of late antibiotic treatment interruption). The use of degenerate primers (targeting the 16S ribosomal DNA) does not always allow detecting this pathogen (personal data). Finally, some commercial kits include specic primers for the detection of P. acnes [24]. 5.2. Spine prosthesis infections The rate of infection after spinal surgery remains low, 0.2%, but can increase to 12% in case of instrumentation [27]. These infections can be divided in early (rst month after surgery) or late infections. Although P. acnes and S. epidermidis are the most common bacterial etiologies of late postoperative infections [28], P. acnes is also found in 10 to 40% of early postoperative infections [27,28]. The clinical manifestations are usually nonspecic. Fever is rarely reported and biological markers of inammation are not reliable, especially in case of torpid infections [28]. The infection is usually conrmed by imaging and microbiological cultures. The pathogen can be isolated using culture of biopsy or tissue in contact with device [18]. However, Sampedro et al. recently demonstrated that the prosthesis sonicate uid culture was more sensitive than tissue culture in contact with the material. [28] The therapeutic management of this type of infection remains controversial and depends on the level of consolidation, withdrawal, or prosthesis retention associated with a more or less prolonged antibiotic treatment [26,27]. 5.3. Cardiac device-related infections P. acnes infective endocarditis (IE) are rare, although the prevalence is probably under evaluated due to diagnostic difculties [8]. These infections usually occur on a prosthetic heart valve or pacemaker. The skin is the most common portal of entry in case of surgery or in case of bacteremia [8]. Less than 50 to 60 cases of P. acnes IE on replacement heart valve, usually aortic, have been reported [30]. The diagnosis of endocarditis using Duke criteria remains often difcult and performed too late, because of non-specic symptoms and slow growth. The consequences of this disease are signicant: valvular destruction and dysfunction leading to heart failure. The death rate remains high (1527%) despite appropriate antibiotic therapy and surgery to

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change the valve, [30]. Future research on the involvement of P. acnes in sepsis on stents is also needed. 5.4. Neurosurgical shunt infections P. acnes is increasingly isolated in neurosurgical infections of external ventricular shunts. These infections are a severe complication leading to a signicantly increased mortality and morbidity [31]. The infection rate ranges from 1.5 to 38%. These early and late infections (more or less 1 year after surgery) are caused by bacteria of the human skin ora, related to contamination during surgery. Late infections are less frequent (< 1% per year), and usually associated with peritonitis, or hematogenous spread from a secondary focus [32]. The infections of external ventricular drains range from 5 to 20%. Factors associated with an increased risk of infection are intraventricular or subarachnoid hemorrhage, and a skull fracture with leakage of cerebrospinal uid (CSF). The authors of a recent study, reported that most of the isolated microorganisms were coagulase-negative staphylococci (63%) and P. acnes (15%) [32]. P. acnes infections are mainly related to an inoculation from the skin during surgery, but symptoms can occur weeks, months, or even years after the implantation or handling of materials [32] Neurosurgical device infection is diagnosed by a body of evidence including the clinical evaluation and microbiological analysis of CSF. The distinction between infection and contamination/colonization remains difcult if there is no fever. P. acnes infections are usually asymptomatic with normal serum CRP levels. Patients have a low initial WBC count with minor changes in CSF glucose and protein levels [32]. CSF culture remains a valuable tool for the diagnosis of shunt-associated infections. Allergic reactions to materials can mimic an infectious presentation. The most effective treatment for P. acnes infection in neurosurgery is prosthesis removal and implementing a temporary external ventricular drainage or ventricular punctures (if necessary) accompanied by penicillin G in high doses. Sparing the distal part of the material often leads to a relapse of the infection [31,32]. 5.5. Breast implant-infections Breast implants are increasingly used after mastectomy for cosmetic or reconstructive reasons. Infection after breast surgery occurs in 1% to 2.5% of cases and up to 35% for reconstruction after mastectomy [33]. These infections are usually related to the commensal skin ora, including Staphylococcus aureus, coagulase-negative staphylococci, Arcanobacterium spp., or anaerobic bacteria. Acute infections associated with breast implants usually occur during the rst month after implantation and are often associated with fever, acute pain, and marked erythema of the breast. In some cases, P. acnes alone or in combination with a staphylococcus can be involved. Late infections are rare. Risk factors for infection of breast implants are breast reconstruction after mastectomy and radiotherapy. The surgical removal of the implant is mandatory in most cases [34]. Biolm growth of P. acnes on the surface of the prosthesis can cause a persistent inammation of the surrounding tissue, leading to the

formation of capsular brosis and subsequent retraction. A signicant correlation between the degree of capsular contracture and the presence of biolm on implants has been demonstrated, especially after sonication [10,34]. 5.6. Intraocular lens infections Infectious endophthalmitis is the most serious complication of intraocular surgery. The incidence of infection after cataract surgery and lens implantation in the posterior chamber is low, less than 0.5% [9]. Bacteria may form a biolm on the surface of intraocular lenses. Postoperative endophthalmitis can be classied into acute and delayed infections. Acute infections usually occur a few days after surgery (involving mostly S. aureus, Streptococcus spp., coagulase-negative staphylococci), but delayed infection may appear up to several years after surgery and will mainly implicate microorganisms with low virulence such as P. acnes, Actinomyces spp., and Corynebacterium spp. The diagnosis is based on ocular symptoms, as well as the microscopic and microbiological intraocular sample examinations. The most typical manifestation of postoperative endophthalmitis is white patches on the lens capsule or intraocular lens associated with recurrent intraocular infection. The cultures of vitreous uid does not always allow detecting the causative pathogens because of a low inoculum and low volume of sample. The new molecular diagnostic techniques may be more effective, even if they are not always used or available [35]. 6. Pathogenic role of P. acnes 6.1. Whole genome sequencing and putative virulence factors P. acnes was considered as a ubiquitous and usual commensal of the human skin. The bacterium was recognized as contaminant without virulence factors, but recent evidence has revealed some features of P. acnes leading to consider it as a potentially opportunistic pathogen. Various genomes were completely sequenced and P. acnes was shown to express various kinds of proteins such as cytotoxic proteins, enzymes allowing oxidative phosphorylation, anaerobic respiration, or markers responsible for the protection of the cell from the toxic effects of reduced oxygen level. Putative hemolysins or cytotoxins (CAMP factors, hemolysin III), enzymes putatively involved in degrading host tissue or molecules (GehA lipase, lysophospholipase, hyaluronate lyase, endoglycoceramidase, etc.) were also detected; they are likely implicated in the pathogenesis of various diseases listed above [36]. Moreover, like several other bacteria, P. acnes carries components on its surface acting as antigens, which can trigger or mediate an inammatory process or which can exhibit cell-adherent properties (dermatan-sulphate adhesion, thrombospondin type 3 repeat protein). In both cases, these proteins interact with the host. Thus, some proteins could be involved in inammation or granuloma (skin, sarcoidosis) but might be essential for the adherence to skin tissue or medical devices

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and probably for the development of a biolm matrix, as we suggested for implant-related infections [37]. P. acnes can modify its metabolism, and adapt its surface structure to environmental challenges, especially immunological response, inammation, presence or lack of oxygen. Therefore, it might contribute to damaging human tissues depending on the number and type of proteins implicated [3638]. These are new elements helping to understand P. acnes pathogenesis and why this bacterium or some clones are now considered as emerging. 6.2. Host interactions and P. acnes invasion The proteomic identication of proteins secreted by P. acnes associated with new molecular typing method on commensal and pathogenic strains has allowed a better understanding of host interactions [3941]. P. acnes secretome harbors various proteins likely to play a role in host tissue damage, degradation, and inammation. According to the phylotype (see below), the strain behavior seems to change due to specic host-tissue interacting identied proteins. Thus, recent data suggests the role of P. acnes in both innate (activation of Toll-like receptors resulting in the release of pro-inammatory proteins) and acquired immunity [21b]. The severity of acne depends partly on the strain implicated but also on the host, related to considerable potential variation in the immunogenic surface components. Fassi Fehri et al. reported the prevalence of P. acnes in prostatitis and its inammatory and transforming activity on prostate epithelial cells, suggesting that it could be a contributing factor to the initiation or progression of prostate cancer [42]. Active secretion of cytokines by infected cells, such as Il-6 or Il-8, was observed. The host response was likely mediated by the transcriptional factors NF-kB and STAT3, which were both activated during P. acnes infection. Similarly, differences in P. acnes strains involved in sarcoidosis revealed differences in the bacterial antigens and host interactions leading to various stimulation proles. The cell-invasiveness of P. acnes and the close correlation of cell-invasiveness to the genotype of 2 invasion-associated P. acnes genes (mce and P60 genes) were highlighted. Interestingly, serotype II strains were non-invasive compared with serotype I strains. The prominent trigger factor gene polymorphism was clearly correlated with invasiveness, with a deletion of 15 amino acid residues in invasive strains [43]. Furthers studies are needed to increase our understanding of P. acnes pathogenesis, especially in device-related infections. 7. Innovative aspects of molecular typing and phylogeny Johnson and Cummins had identied 2 groups of P. acnes, based on serological agglutination tests or analysis of the components of the bacterial cell wall [11]. Improving typing methods, including PCR and sequencing, allowed to better understanding the phylogeny of this pathogen. The sequence analysis of recA gene conrmed it belonged to 2 phylogenetically distinct lineages of types I and II. The association of some strains to specic clinical presentations was also demonstrated [12].

Later, McDowell et al. reported 5 main phylogenetically distinct groups: IA, IB, IC, II and III [11]. Molecular typing methods are used routinely to search for a possible genetic link or clonal relationship among isolates from case clusters in a single location and in a short period. Techniques such as pulsed-eld gel electrophoresis (PFGE), rep-PCR, or multi-locus sequence typing (MLST) have been used to identify a possible cluster (Table 2). PFGE is a robust method but technically difcult, especially during the extraction stage which requires the use of mutanolysin. Digestion of genomic DNA can be performed with 2 types of restriction enzymes (SpeI and NotI) [44]. Oprica et al., in a European study, reported no relationship between the distribution of clones and the type of infection. However, 38% of isolates from blood cultures and 60% of isolates from skin or soft tissue infections belonged to the same clone [45]. Similarly, several clones from patients with deep infections after cardiac surgery were identied [46]. The easy implementation of and the reduced cost of sequencing have led to an increasingly frequent use of MLST. It does not serve the same purpose as PFGE. It allows analyzing the phylogenetic evolution of many clones of the concerned species. There are 2 MLST schemes for P. acnes: 1 in Aarhus with 9 genes located on the bacterial chromosome; and 1 in Belfast targeting 35% of the genes. Only the recA gene is common to both. The recent comparison of both strategies emphasized that the Aarhus MLST scheme (http://pacnes.mlst.net/) had a signicantly higher discriminatory power [47]. More large studies including isolates from many anatomical sites should allow better understanding on one hand, the distribution of phylotypes according to infection and, on the other hand, to better dene commensal or pathogenic clinical strain features. Indeed, according to the Aarhus scheme, acne strains belong most frequently to CC3, CC31, and often CC18, especially the epidemic clone ST18. Conversely, opportunistic infection strains belonged to CC43 or CC53/60, whereas prostatic strains were reported in various singletons such as ST36, ST38, ST61, ST79 to ST83. The recent semi-automated technique, rep-PCR (DiversiLab, bioMrieux, France technology) allows rapid typing of isolates. However, initial studies prove that this new technology is less discriminating than MLST. Various sequence types (ST) can be found in the same phylogenetic branches with the same band prole, using rep-PCR. However, this technique could allow for a rapid screening of many clones in epidemiological studies. Therefore, MLST remains contributive featuring a more detailed analysis of the population heterogeneity and identication of specic subtypes among P. acnes isolates [48]. The correlation with PFGE results remains to be established on a collection of commensal and pathogenic strains large enough to conclude on the effectiveness of these technologies and on the epidemiological answers they provide. 8. Antimicrobial activity on P. acnes Some antibiotics should be tested to adapt treatment because of the prevalence of antibiotic resistance in P. acnes:

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Table 2 Molecular typing and phylogenetic analysis of Propionibacterium acnes isolates. Typages molculaires et analyses phylogntiques des isolats de Propionibacterium acnes. Methods used Phylotype determination Pulsed-eld gel electrophoresis Multi-Locus Sequence Typing Aarhus scheme: cel (Transcription regulator CelR) coa (O-succinylbenzoate-CoA synthase) fba (Fructose bisphosphate aldolase) gms (Glutamyl-tRNA synthetase) lac (L-lactate dehydrogenase) oxc (Cytochrome c oxidase subunit II) pak (Pantothenate kinase) recA (Recombinase A) zno (Zn-dependent alcohol dehydrogenase) Belfast scheme: aroE (Shikimate 5-dehydrogenase) atpD (ATP synthase beta chain) gmk (Guanylate kinase) guaA (GMP synthase) lepA (GTP-binding protein) recA (Recombinase A) sodA (Superoxide dismutase) Target genes recA (Recombinase A) tly (Hemolysin/cytotoxin) Techniques PCR and sequencing DNA extraction, Restriction (SpeI or NotI) and migration PCR and sequencing References 11 4546

4748

tetracycline, erythromycin, clindamycin, and cotrimoxazole [49] (Table 3). Furthermore, other antibiotics should be tested for severe infections, to optimize treatment and obtain a synergistic effect against P. acnes: penicillin, cephalosporins, vancomycin, quinolones, rifampicin, and the new antibiotics such as linezolid, daptomycin, and tigecycline, to which P. acnes is usually susceptible. Aminoglycosides are not active against clinical strains of P. acnes. Moreover, its natural resistance to fosfomycin and metronidazole allows conrming the identication of P. acnes.

9. Susceptibility testing methods 9.1. Minimal inhibitory concentration (MIC) determination The MIC is determined by the dilution technique using Brucella agar supplemented with 5% debrinated sterile horse blood, vitamin K, and hemin. A nal inoculum of 105 CFU per spot is used [50]. The plates are incubated anaerobically for 48 to 72 h at 37 C. Strains of P. acnes ATCC6919 and ATCC11827 are used as quality controls [45]. The E-test technique uses an inoculum of McFarland 1 in the same anaerobic conditions. The MIC is determined after 48 or 72 h of incubation at 37 C. A good correlation between both techniques has been reported. 9.2. Minimal bactericidal concentration (MBC) determination There is little data on the determination of the MBC for P. acnes. The authors of a recent study, reported that the MIC and MBC were determined by the broth dilution method. An inoculum of 106 CFU/mL was used [50]. 9.3. Minimal biolm eradication concentration (MBEC) determination Various in vitro methods have been described to assess the activity of antibiotics on bacterial biolm. Most methods are based on a static analysis microplate assay. Biolms are formed in the wells of polystyrene, and the quantication of biolm

Table 3 Antibiotics to be tested and resistance mechanisms described. Antibiotiques tester et mcanismes de rsistance dcrits. Antibiotic family -lactams Fluoroquinolones Glycopeptides Lipopeptides Macrolides Resistance mechanism Unknown Unknown Unknown Unknown Mutations in the 23S RNA gene or acquired ermX transposon Mutations in the 16S RNA gene Unknown Mutations in the rpoB gene Unknown References 5255

Tetracyclines Cotrimoxazole Rifampicin Linezolide

54 54 23

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is achieved by various methods: crystal violet, resazurin, etc. [29]. However, these assays have not been widely used for slowgrowing bacteria and anaerobes such as P. acnes, maybe because of problems of reproducibility and intra-experimental variations already in the biolm formation phase, as shown for the use of crystal violet to stain P. acnes biolm. The effect of antibiotics on a 72 h mature biolm formed on glass beads was evaluated [50]. Factors such as the biomaterial used, the incubation time, the duration of biolm formation (early or mature), are important parameters to determine the minimum biolm eradication concentration. Therefore, each laboratory must be aware of the limitations and performance of the method used to determine the activity of antibiotics on the biolm. Recently, the ability of P. acnes to form biolms on orthopedic biomaterials and its susceptibility to various antibiotics were also measured [52].

erythromycin resistance: blood (31.4%), meningitis (21 4%), abdominal infections (18.2%), and lung and pleural uids (16.7%); clindamycin resistance: meningitis (21.4%), prosthesis (20%) and blood (20%). Resistance to tetracycline was associated with strains isolated from tissue, bile, bones, skin, and blood. 10.3. Molecular mechanisms of antimicrobial resistance 10.3.1. Macrolides The most common mechanism of macrolide resistance is associated with point mutations among the 3 genes encoding the V domain of the peptidyl transferase loop of 23S rRNA [52]. In 2002, the Tn5432 transposon carrying the erm(X) resistance gene was identied [55]. Ross et al. dened four groups: Group I is the most common (80%). It is linked to a mutation at position 2058 (Escherichia coli numbering), conferring highlevel resistance to erythromycin (512 to 2048 mg/L) and variable resistance to clindamycin (4512 mg/L) [53,54]. Group III (9.8%) in which resistance is due to a mutation at position 2057 (E. coli numbering), conferring low-level resistance to erythromycin (12 mg/L) with susceptibility to other macrolides. Group IV (10%) in which a mutation at position 2059 (E. coli numbering) confers resistance to erythromycin (> 2048 mg/L) and to other macrolides, except for telithromycin. One strain classied in group I had mutations at positions 2058 and 2059 [53,54]. Finally, group II contrasts with previously documented phenotypes. Indeed, the resistance determinant, erm(X), is located on the composite transposon Tn5432. It accounts for less than 10% of erythromycin resistance [55]. This mechanism provides a high-level of resistance and it is detected by PCR. A high-level correlation was observed between the phenotypic classes, the cross-resistance prole, and molecular detection [54,55]. However, another mechanism may be involved, such as mutations in ribosomal proteins L4 and L22, the transition at position 2611 in domain V of 23S rRNA, or deletion in domain II of 23S rRNA [55]. These mechanisms are rare. 10.3.2. Tetracyclines A mutation in the gene encoding 16S rRNA is usually implicated in resistance to tetracycline. This change in position 1058 (E. coli numbering), provides variable resistance to tetracycline, doxycycline, and minocycline (MIC = 32 mg/L) [54]. 10.3.3. Rifampicin P. acnes had been considered as susceptible to rifampicin until recently. This antibiotic is the gold-standard treatment for infections related to medical devices, because of a biolm [23]. Resistance to rifampicin has been reported in several bacterial species, such as Staphylococcus aureus, E. coli, Streptococcus pyogenes, and Mycobacterium tuberculosis [23]. Resistance is usually due to point mutations in the rpoB gene. Substitutions occur in the conserved domains: group I (507-533 amino acids),

10. Antimicrobial resistance and its molecular background 10.1. Emergence of antimicrobial resistance The prevalence of resistance has continued to increase since the rst description of a P. acnes resistant strain in 1979 [13,51]. Various factors are involved in the development of resistance: the inoculum, the antibiotic level (selection pressure), the acquisition of resistance in the normal ora [52], a high rate of sebum excretion [51], the duration of treatment, the consecutive use of various antibiotics and poor patient compliance, especially in case of prolonged treatment for deep infections on material. Antibiotic resistance is either acquired (genetic exchange between strains) or linked to chromosomal mutations. Nostrils could also be an important reservoir of resistant P. acnes strains [53]. However, P. acnes has reduced genetic adaptability, allowing the medical community to use antibiotics effectively [52,53]. Conversely to other Gram-positive bacteria (staphylococci, in particular), P. acnes rarely develops resistance to antibiotics by acquiring mobile genetic elements such as plasmids [54].

10.2. Epidemiology of antimicrobial resistance The rate of patients carrying P. acnes strains resistant to one or more antibiotics has increased steadily from 34.5% in 1991 to 64% in 1997. It decreased to 50.5% in 1999, and increased to 55.5% in 2000. Resistance to erythromycin was the most common, frequently associated with resistance to clindamycin. Resistance to tetracycline was less common [54]. 684 strains of P. acnes were isolated from various sources (brain abscess, cerebrospinal uid, synovial uid, skin, blood, bone biopsy, valve) in the last 8 years in our hospital; 22 were resistant to clindamycin (3.2%) and 5 to rifampicin (0.7%). the Task Force on Antimicrobial Resistance of anaerobic bacteria ESCMID Group published a report in 2005, on clinical resistance with a breakdown by type of sample:

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group II (563-572 amino acids), and group III (amino acids 684690), according to E. coli numbering. Three mutations were detected in the region or cluster I rpoB gene. Two mutations, His437Tyr and Ser442Leu confer high-level resistance, while mutation Leu444Ser position confers a low-level of resistance. Two mutations Ile483Val and Ser485Leu, in region 2, confer low-level resistance [23]. No clinical isolate has been reported resistant to rifampicin so far, although 1 strain was reported by Zappe et al. with a MIC of 0.5 mg/L [56]. Rifampicin resistance should continue to be monitored. It may have important consequences in the therapeutic management of device-related infections [10,22,23,26]. 10.3.4. Cotrimoxazole Resistance of P. acnes strains to trimethoprim was reported in the early 1990s. The authors of a study including 171 isolates of P. acnes, reported that 16.4% were resistant to trimethoprim. Various types of molecular mechanisms may be described: changes in permeability or efux pumps, new pathways, and target changes. The molecular mechanism involved in this resistance has not been elucidated yet [54]. The Task Force on Antimicrobial Resistance ESCMID anaerobic bacteria (ESGARAB) determined the prole of antibiotic susceptibility of 304 P. acnes strains isolated in various types of systemic infections. There was 2.6% of the isolates that was resistant to tetracycline, 15.1% to clindamycin, and 17.1% to erythromycin [45,51] with considerable differences among European countries. No resistance to penicillin, vancomycin, linezolid, or daptomycin was reported, unlike in other Gram-positive bacteria. 10.3.5. P. acnes, biolms, and antimicrobial resistance P. acnes is present in a biolm with reduced metabolic activity in medical device-related infections. Systemic antibiotic therapy usually fails because of dual resistance to antibiotics and phagocytosis. Holmberg et al. recently demonstrated the importance of biolm formation in deep P. acnes infections [57]. Once the bacteria detach from the biolm, they become susceptible, suggesting antimicrobial resistance is due to tolerance in biolm, and not to mechanisms such as mutations or inactivating enzymes. Rifampicin, a small molecule that can easily penetrate the exopolysaccharide matrix, has an excellent activity against biolm, including staphylococcus [23]. Its activity against P. acnes within a biolm was recently demonstrated in vitro and in vivo [50]. Combinations with linezolid or daptomycin improve the in vitro and in vivo activity, respectively [50]. Penicillin G also had a good activity in vitro [50,51] and remains to be assessed in vivo, although it is considered as a rstline treatment in the new U.S. guidelines. Little data is available on the risk of selection of resistant bacteria within the biolm, compared with staphylococci, and studies are needed to better understand its physiopathology. 11. Treatment The treatment of severe infections caused by P. acnes includes a combination of antibiotics, administrated intravenously

initially, and usually associated with optimal surgery (e.g., removal of the device and/or debridement of the surgical site). Penicillin G and ceftriaxone are still considered as rstline antibiotics for severe infections [58], vancomycin and daptomycin are considered as alternatives in case of allergy to -lactams or resistance (not reported yet). Clindamycin, tetracycline, and levooxacin, all available per os, are also alternative treatment or may be used for prolonged treatment [58]. Rifampicin and daptomycin should also be considered as active antimicrobial agents, including against P. acnes biolm [50]. More studies are needed to validate the effectiveness of some combinations, especially in case of polymicrobial infections. Removal of the device is usually sufcient to reduce the inoculum causing chronic infection involving this bacterium with pro-inammatory and biolmogenic properties. 12. Conclusion P. acnes was often ignored but has been reported as involved in various clinical presentations, including deep and severe device-related infections. The modern and innovative diagnostic tools available allow identifying it more easily, especially if the microbiologist extends the culture time. Sonication of prosthetic devices could help improve the diagnosis of infections on foreign material, especially for orthopedic prosthesis, breast implants, or intra-cardiac devices. The adaptation of molecular methods, or specic multiplex PCR (automated or not) should also increase the sensitivity of P. acnes detection. The authors of recent genomic and proteomic studies on the pathogenic role of P. acnes in several diseases have explained why this bacterium is emerging. More research is needed to improve our knowledge. Why are diseases due to P. acnes? What bacterial factors, or which clone are responsible for these diseases? Furthermore, P. acnes may be resistant to some antibiotic families, such as macrolides. This was proven recently for rifampicin. Today, the phylotype, the antibiotype, and molecular typing allow better understanding of the evolution and phylogenetic relationships between a type of infection and specic P. acnes strains. However, more research is needed to better understand the emergence of resistance (uoroquinolones) and the adaptation of some pathovars to specic clinical settings. Disclosure of interest The authors declare that they have no conicts of interest concerning this article. References
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