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Médecine et maladies infectieuses 44 (2014) 241–250

General review

Propionibacterium acnes, an emerging pathogen: From acne toimplant-infections, from phylotype to resistance

Propionibacterium acnes, un pathogène émergent : de l’acné aux infections sur matériel, duphylotype à la résistance

G.G. Aubin a,b, M.E. Portillo c, A. Trampuz d, S. Corvec a,∗,b

a Service de Bactériologie-Hygiène, Institut de biologie des hôpitaux de Nantes, CHU de Nantes, 9, quai Moncousu, 44093 Nantes cedex 01, Franceb EA3826 Thérapeutiques cliniques et expérimentales des infections, Université de Nantes, faculté de médecine, 44000 Nantes, France

c Microbiology Laboratory, Laboratori de Referència de Catalunya, Carrer de la Selva, 10, Edifici Inblau A. Parc de Negocis Mas Blau, 08820 El Prat deLlobregat, Barcelona, Spain

d Charité - University Medicine Free and Humboldt-University of Berlin Charitéplatz, 1D-10117 Berlin, Germany

Received 28 June 2013; received in revised form 24 December 2013; accepted 12 February 2014Available online 20 March 2014

bstract

Propionibacterium acnes colonizes the lipid-rich sebaceous glands of the skin. This preferential anaerobic bacterium is easily identified ifultures are prolonged. It is involved in the inflammation process of acne, but until recently, it was neglected in other clinical presentations.espite a reported low virulence, the new genomic, transcriptomic, and phylogenetic studies have allowed better understanding of this pathogen’s

mportance that causes many chronic and recurrent infections, including orthopedic and cardiac prosthetic, and breast or eye implant-infections.hese infections, facilitated by the ability of P. acnes to produce a biofilm, require using anti-biofilm active antibiotics such as rifampicin. Thentibiogram of P. acnes is not systematically performed in microbiology laboratories because of its susceptibility to a wide range of antibiotics.owever, in the last 10 years, the rate of antibiotic-resistant bacteria has increased, especially for macrolides and tetracyclines. Recently, rpoBene mutations conferring resistance to rifampicin have been also reported. Thus in case of a biofilm growth mode, the therapeutic strategy shoulde discussed, according to the resistance phylotype and phenotype so as to optimize the treatment of these severe infections.

2014 Elsevier Masson SAS. All rights reserved.

eywords: Acne; Prosthesis or device-related infections; Phylotype; Antibiotic resistance

ésumé

Propionibacterium acnes colonise l’environnement riche en lipides des glandes pilo-sébacés de la peau. L’identification de ce micro-organismenaérobie préférentiel est favorisée par la prolongation des cultures. Cette bactérie est impliquée dans les processus inflammatoires de l’acné ettait jusqu’à récemment négligée dans d’autres situations cliniques. Malgré une faible virulence rapportée, les nouvelles études génomiques, phy-ogénétiques et transcriptomiques ont permis de mieux comprendre l’importance de ce pathogène à l’origine de nombreuses infections chroniquest récidivantes notamment celles liées aux prothèses orthopédiques, cardiaques, mammaires et implants oculaires. Ces infections, facilitées para capacité de P. acnes à produire un biofilm, nécessitent d’utiliser des antibiotiques ayant une activité anti-biofilm comme la rifampicine. Enaison de sa sensibilité à de nombreux antibiotiques, l’antibiogramme de P. acnes n’est pas réalisé de manière systématique dans les laboratoires de

icrobiologie. Cependant, depuis 10 ans, la proportion de bactéries résistantes aux antibiotiques a augmenté, notamment vis-à-vis des macrolidest des tétracyclines. Par ailleurs, des mutations dans le gène rpoB conférant la résistance à la rifampicine ont été rapportées récemment. Danse contexte et en présence de biofilm, la stratégie thérapeutique doit être discutée, en fonction du phylotype et du phénotype de résistance, afin

’optimiser le traitement de ces infections graves.

2014 Elsevier Masson SAS. Tous droits réservés.

ots clés : Acné ; Prothèse ; Phylotype ; Résistance aux antibiotiques

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

399-077X/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved.ttp://dx.doi.org/10.1016/j.medmal.2014.02.004

2 ladies infectieuses 44 (2014) 241–250

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Table 1Identification criteria for Propionibacterium acnes species.Critères d’identification à l’espèce Propionibacterium acnes.

Identification criteria for Propionibacteriumacnes species

Gram staining Gram-positive bacilliCultures features Slow growth in anaerobic conditions,

aerotolerantGrowth on blood agar and sometimes better onchocolate agar from deep samplesPossibility of bread dumpling in case ofSchaedler broth growth

Biochemical tests Catalase positiveIndole positive in 70%Nitrate reductase positive

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. Introduction

Historically, the “bacillus of acne” was first describedy Unna in 1896, when working on histological sectionsf blackheads. This bacillus morphologically resembling aorynebacterium was first classified in the genus Corynebac-erium in 1923. It was subsequently transferred to the genusropionibacterium, in 1933, because of its relationship toxygen and the nature of its catabolic process [1]. Propionibac-erium acnes is an important part of the normal flora of humankin, living in and around sweat glands and sebaceous glands.urthermore, some species of the genus Propionibacterium areble to synthesize propionic acid. They are used in the produc-ion of various compounds in the industrial manufacturing ofrobiotics or cheese [2].

The pathogenicity of P. acnes has long been restrictedo skin conditions. Its isolation from other anatomical sitesr deep microbiological samples has often been consid-red as contamination. Although described as a commensalacterium with a low pathogenicity, its involvement haseen reported in many clinical entities: chronic prostatitis3], synovitis–acne–pustulosis–hyperostosis–osteitis syndromeSAPHO) [4], or sarcoidosis [5]. More recently, this microor-anism has been considered as responsible for various typesf infections associated with breast implants [6], cerebrospinaluid shunts [7], cardiovascular devices [8], ocular implants [9],r osteosynthesis and joint prosthesis [10].

The development of various typing techniques allowed first,o link sub-populations of P. acnes to a specific disease and,econdly, to determine the predominant clones [11,12].

In case of P. acnes infections, the use of antibiotics has some-imes led to the emergence of resistance favored by prolongeddministration and/or probabilistic treatment, by poor compli-nce, responsible for subdosing, or when the treatment was notssociated with topical based retinoids in teenagers [13,14].owever, the resistance of P. acnes seems to be limited to some

amilies.The objective of this study was:

to review the significance of P. acnes in clinical practice; to discuss the molecular aspects of the phylogeny and molec-

ular 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 infec-

tions.

. Microbiology of P. acnes

P. acnes is an anaerobic bacterium, aerotolerant, diphtheroid,ram-positive bacillus (Table 1). Its natural habitats are the seba-

eous follicles of human skin, conjunctiva, oral cavity, intestinal

ract, and the external auditory canal [15]. P. acnes tolerates oxy-en for several hours, is able to survive in anaerobic conditionsp to 8 months in vitro, and can also survive for long period inuman tissues with low oxidation potential [16]. In addition, this

cae[

usceptibility test Metronidazole resistantFosfomycin resistant

acterium can resist to phagocytosis and persist in macrophages17]. Growth appears to be slow and sometimes unpredictable inerobic condition. In case of severe or deep infections, the sus-icion of P. acnes requires extended anaerobic incubation for 14ays. Seeding a Schaedler or thioglycolate broth is sometimesecommended to increase the sensitivity of the examination. Inddition, any suspicion of bacterial growth (“dumpling bread”spect for example) in broth should lead to re-inoculation ongar [18]. Finally, a culture positive for P. acnes should be ana-yzed with caution. If the growth is only observed in broth, orn only one of several per-operative clinical samples, additionalrguments supporting infection (clinical and histopathologicalriteria) will be needed to determine if P. acnes is a pathogen or

contaminant [18].Obsolete tests (serological agglutination and carbohydrate

nalysis of the cell wall) were used to classify strains of P. acnesn 3 different phenotypes (type I, II, and III). The distinc-ion between types IA, IB, IC, II, and III are now based onhe sequence analysis of 2 genes: recA gene, a non- ribo-omal gene, and tly gene, a housekeeping gene encoding aemolysin/cytotoxin [11]. Biofilm formation is an importantirulence factor, especially responsible for nosocomial infec-ions. Innovative techniques such as whole genome sequencing,igh throughput sequencing, and molecular typing, have identi-ed 3 groups of genes encoding adhesins and enzymes involved

n the biosynthesis of extracellular polysaccharide. This ele-ent, essential in the production of biofilm, contributes to the

ersistence of P. acnes in the body [19].

. A superficial infection: acne vulgaris

Acne is a skin disease that usually affects young adults.early 80% of teenagers have presented with acne. The causesf acne vary according to psychological, chemical, and cuta-eous genetic factors related to hormonal changes [20]. Thenflammatory condition is related to a gland dysfunction or

hronic inflammation of pilosebaceous units, characterized byn increased secretion of sebum, a hyperproliferation of thepidermis and hair follicles, and microbial growth of P. acnes15]. If you need to learn more about acne, inflammation, or

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nteractions with immunity, the authors of references [15,20,21],nd [21b] present these aspects in more details.

. P. acnes infections without implant

Numerous authors have reported the potential role of P. acnesuring infection without carriage of any medical devices.ecently, its likely involvement in prostatitis was reported.owever, due to possible contamination of the sample, it was

ecommended to identify the pathogen in various biologicalissues by different methods. It can be difficult to incriminate. acnes, in case of low inoculum, heterogeneous distributionf the bacteria in the sample, and also because of a multifac-orial histological inflammation of the gland. Nevertheless, itsresence was clearly reported in the tissues of patients withrostate cancer complicated by prostatitis [3].

The involvement of a low virulence microorganism such as. acnes was also mentioned in the diagnosis of SAPHO syn-rome (pustulo-hyperostotic psoriatic spondylitis). P. acnes maynteract with the immune system, causing inflammation andriggering chronic osteitis, even after removal of material [4].inally, although the causes of sarcoidosis remain unknown, the

nvolvement of P. acnes was suggested in this disease because ofts significant presence in culture from lymph nodes of patients.he mechanisms of granuloma formation and immunomodula-

ion by P. acnes have not been elucidated yet. It seems that theoncentration P. acnes DNA in alveolar liquid is significantlyigher in these patients [5].

. P. acnes prosthesis and implant-related infections

.1. Osteo-articular prosthesis infections

The complex pathogenesis of bone and joint infections (BJI)s explained by the growth of microorganisms in biofilms and

icro-colonies, making it difficult to diagnose, eradicate, andreat such kind of infections [22]. Staphylococci are involvedn 50 to 60% of the cases in these infections [18]. The ratef P. acnes involvement is estimated at 10%, but it is probablynderestimated [18,22]. P. acnes is usually the cause of delayednfections occurring 3 to 24 months or more after prosthe-is placement. P. acnes is frequently associated with shoulderrosthesis infections because of its more common ecologi-al niche (sebaceous follicles) [10]. The authors of a studyeported that P. acnes was isolated only in male patients,uggesting that host factors may predispose to this type ofnfection. Furthermore, if type I P. acnes strains are predom-nant, type IB strains seem more common than type IA inrosthetic infections [12]. Usually, a 2-stage replacement iserformed, but more and more frequently, a short intervaletween explantation and re-implantation of the prosthesiss used, especially if P. acnes strain remains rifampin sus-eptible [23]. Torpid and chronic infections considered as

ow-grade infections are difficult to distinguish from asepticrosthetic dysfunction, presenting only with early prostheticoosening, persistent pain, but sometimes without clinicaligns. Several authors have suggested that aseptic loosening

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s infectieuses 44 (2014) 241–250 243

f prosthesis in the absence of clinical and microbiological argu-ents could be related to a low-grade infection [24,25]. There

s currently no ideal biomarker for the diagnosis and monitor-ng of bone sepsis; and a normal value of C-reactive proteinCRP), cannot rule out infection [21]. During P. acnes infec-ion, the leukocyte count in the synovial fluid or histology oferi-prosthetic tissue can sometimes remain normal, reflecting

weak virulence or a low inoculum. However, the formationf a fistula, with or without purulent discharge, is a good argu-ent for a BJI [18,22,26]. The current diagnostic methods have

imited sensitivity, with 10 to 20% false negative cultures. Theidespread use of automated bead mill processing and the inoc-lation of crushed samples into blood culture bottles shouldeduce the rate of false negatives [18]. New molecular techniquesave been developed to increase the sensitivity of BJI detectionespecially in case of late antibiotic treatment interruption). These of degenerate primers (targeting the 16S ribosomal DNA)oes not always allow detecting this pathogen (personal data).inally, some commercial kits include specific primers for theetection of P. acnes [24].

.2. Spine prosthesis infections

The rate of infection after spinal surgery remains low, 0.2%,ut can increase to 12% in case of instrumentation [27]. Thesenfections can be divided in early (first month after surgery) orate infections. Although P. acnes and S. epidermidis are the mostommon bacterial etiologies of late postoperative infections28], P. acnes is also found in 10 to 40% of early postoperativenfections [27,28]. The clinical manifestations are usually non-pecific. Fever is rarely reported and biological markers ofnflammation are not reliable, especially in case of torpid infec-ions [28]. The infection is usually confirmed by imaging and

icrobiological cultures. The pathogen can be isolated usingulture of biopsy or tissue in contact with device [18]. How-ver, Sampedro et al. recently demonstrated that the prosthesisonicate fluid culture was more sensitive than tissue culture inontact with the material. [28] The therapeutic managementf this type of infection remains controversial and depends onhe level of consolidation, withdrawal, or prosthesis retentionssociated with a more or less prolonged antibiotic treatment26,27].

.3. Cardiac device-related infections

P. acnes infective endocarditis (IE) are rare, although therevalence is probably under evaluated due to diagnostic dif-culties [8]. These infections usually occur on a prosthetic heartalve or pacemaker. The skin is the most common portal of entryn case of surgery or in case of bacteremia [8]. Less than 50 to 60ases of P. acnes IE on replacement heart valve, usually aortic,ave been reported [30]. The diagnosis of endocarditis usinguke criteria remains often difficult and performed too late,

ecause of non-specific symptoms and slow growth. The conse-uences of this disease are significant: valvular destruction andysfunction leading to heart failure. The death rate remains high15–27%) despite appropriate antibiotic therapy and surgery to

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hange the valve, [30]. Future research on the involvement of. acnes in sepsis on stents is also needed.

.4. Neurosurgical shunt infections

P. acnes is increasingly isolated in neurosurgical infectionsf external ventricular shunts. These infections are a severeomplication leading to a significantly increased mortality andorbidity [31]. The infection rate ranges from 1.5 to 38%.hese early and late infections (more or less 1 year afterurgery) are caused by bacteria of the human skin flora, relatedo contamination during surgery. Late infections are less fre-uent (< 1% per year), and usually associated with peritonitis,r hematogenous spread from a secondary focus [32]. Thenfections of external ventricular drains range from 5 to 20%.actors associated with an increased risk of infection are intra-entricular or subarachnoid hemorrhage, and a skull fractureith leakage of cerebrospinal fluid (CSF). The authors of a

ecent study, reported that most of the isolated microorganismsere coagulase-negative staphylococci (63%) and P. acnes

15%) [32]. P. acnes infections are mainly related to an ino-ulation from the skin during surgery, but symptoms can occureeks, months, or even years after the implantation or handlingf materials [32] Neurosurgical device infection is diagnosedy a body of evidence including the clinical evaluation andicrobiological analysis of CSF. The distinction between infec-

ion and contamination/colonization remains difficult if theres no fever. P. acnes infections are usually asymptomatic withormal serum CRP levels. Patients have a low initial WBCount with minor changes in CSF glucose and protein levels32]. CSF culture remains a valuable tool for the diagnosis ofhunt-associated infections. Allergic reactions to materials canimic an infectious presentation. The most effective treatment

or P. acnes infection in neurosurgery is prosthesis removal andmplementing a temporary external ventricular drainage or ven-ricular punctures (if necessary) accompanied by penicillin G inigh doses. Sparing the distal part of the material often leads to

relapse of the infection [31,32].

.5. Breast implant-infections

Breast implants are increasingly used after mastectomy forosmetic or reconstructive reasons. Infection after breast surgeryccurs in 1% to 2.5% of cases and up to 35% for recon-truction after mastectomy [33]. These infections are usuallyelated to the commensal skin flora, including Staphylococ-us aureus, coagulase-negative staphylococci, Arcanobacteriumpp., or anaerobic bacteria. Acute infections associated withreast implants usually occur during the first month after implan-ation and are often associated with fever, acute pain, and markedrythema of the breast. In some cases, P. acnes alone or in com-ination with a staphylococcus can be involved. Late infectionsre rare. Risk factors for infection of breast implants are breast

econstruction after mastectomy and radiotherapy. The surgicalemoval of the implant is mandatory in most cases [34]. Biofilmrowth of P. acnes on the surface of the prosthesis can cause aersistent inflammation of the surrounding tissue, leading to the

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ormation of capsular fibrosis and subsequent retraction. A sig-ificant correlation between the degree of capsular contracturend the presence of biofilm on implants has been demonstrated,specially after sonication [10,34].

.6. Intraocular lens infections

Infectious endophthalmitis is the most serious complicationf intraocular surgery. The incidence of infection after cataracturgery and lens implantation in the posterior chamber is low,ess than 0.5% [9]. Bacteria may form a biofilm on the surface ofntraocular lenses. Postoperative endophthalmitis can be classi-ed into acute and delayed infections. Acute infections usuallyccur a few days after surgery (involving mostly S. aureus, Strep-ococcus spp., coagulase-negative staphylococci), but delayednfection may appear up to several years after surgery and will

ainly implicate microorganisms with low virulence such as. acnes, Actinomyces spp., and Corynebacterium spp. The diag-osis is based on ocular symptoms, as well as the microscopicnd microbiological intraocular sample examinations. The mostypical manifestation of postoperative endophthalmitis is whiteatches on the lens capsule or intraocular lens associated withecurrent intraocular infection. The cultures of vitreous fluidoes not always allow detecting the causative pathogens becausef a low inoculum and low volume of sample. The new moleculariagnostic techniques may be more effective, even if they are notlways used or available [35].

. Pathogenic role of P. acnes

.1. Whole genome sequencing and putative virulenceactors

P. acnes was considered as a ubiquitous and usual commen-al of the human skin. The bacterium was recognized asontaminant without virulence factors, but recent evidence hasevealed some features of P. acnes leading to consider it as aotentially opportunistic pathogen. Various genomes were com-letely sequenced and P. acnes was shown to express variousinds of proteins such as cytotoxic proteins, enzymes allowingxidative phosphorylation, anaerobic respiration, or markersesponsible for the protection of the cell from the toxic effectsf reduced oxygen level. Putative hemolysins or cytotoxinsCAMP factors, hemolysin III), enzymes putatively involvedn degrading host tissue or molecules (GehA lipase, lysophos-holipase, hyaluronate lyase, endoglycoceramidase, etc.) werelso detected; they are likely implicated in the pathogenesis ofarious diseases listed above [36].

Moreover, like several other bacteria, P. acnes carries com-onents on its surface acting as antigens, which can triggerr mediate an inflammatory process or which can exhibitell-adherent properties (dermatan-sulphate adhesion, throm-

ospondin type 3 repeat protein). In both cases, these proteinsnteract with the host. Thus, some proteins could be involvedn inflammation or granuloma (skin, sarcoidosis) but might bessential for the adherence to skin tissue or medical devices

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nd probably for the development of a biofilm matrix, as weuggested for implant-related infections [37].

P. acnes can modify its metabolism, and adapt its surfacetructure to environmental challenges, especially immuno-ogical response, inflammation, presence or lack of oxygen.herefore, it might contribute to damaging human tissuesepending on the number and type of proteins implicated36–38].

These are new elements helping to understand P. acnesathogenesis and why this bacterium or some clones are nowonsidered as emerging.

.2. Host interactions and P. acnes invasion

The proteomic identification of proteins secreted by P. acnesssociated with new molecular typing method on commensalnd pathogenic strains has allowed a better understanding ofost interactions [39–41]. P. acnes secretome harbors variousroteins likely to play a role in host tissue damage, degrada-ion, and inflammation. According to the phylotype (see below),he strain behavior seems to change due to specific host-tissuenteracting identified proteins. Thus, recent data suggests theole of P. acnes in both innate (activation of Toll-like recep-ors resulting in the release of pro-inflammatory proteins) andcquired immunity [21b]. The severity of acne depends partlyn the strain implicated but also on the host, related to consider-ble potential variation in the immunogenic surface components.assi Fehri et al. reported the prevalence of P. acnes in prostati-

is and its inflammatory and transforming activity on prostatepithelial cells, suggesting that it could be a contributing factoro the initiation or progression of prostate cancer [42]. Activeecretion of cytokines by infected cells, such as Il-6 or Il-8,as observed. The host response was likely mediated by the

ranscriptional factors NF-kB and STAT3, which were both acti-ated during P. acnes infection. Similarly, differences in P. acnestrains involved in sarcoidosis revealed differences in the bacte-ial antigens and host interactions leading to various stimulationrofiles. The cell-invasiveness of P. acnes and the close correla-ion of cell-invasiveness to the genotype of 2 invasion-associated. acnes genes (mce and P60 genes) were highlighted. Inter-stingly, serotype II strains were non-invasive compared witherotype I strains. The prominent trigger factor gene polymor-hism was clearly correlated with invasiveness, with a deletionf 15 amino acid residues in invasive strains [43].

Furthers studies are needed to increase our understanding of. acnes pathogenesis, especially in device-related infections.

. Innovative aspects of molecular typing and phylogeny

Johnson and Cummins had identified 2 groups of P. acnes,ased on serological agglutination tests or analysis of the compo-ents of the bacterial cell wall [11]. Improving typing methods,ncluding PCR and sequencing, allowed to better understand-

ng the phylogeny of this pathogen. The sequence analysis ofecA gene confirmed it belonged to 2 phylogenetically dis-inct lineages of types I and II. The association of some strainso specific clinical presentations was also demonstrated [12].

8

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s infectieuses 44 (2014) 241–250 245

ater, McDowell et al. reported 5 main phylogenetically distinctroups: IA, IB, IC, II and III [11].

Molecular typing methods are used routinely to search for aossible genetic link or clonal relationship among isolates fromase clusters in a single location and in a short period. Techniquesuch as pulsed-field gel electrophoresis (PFGE), rep-PCR, orulti-locus sequence typing (MLST) have been used to identify

possible cluster (Table 2).PFGE is a robust method but technically difficult, espe-

ially during the extraction stage which requires the use ofutanolysin. Digestion of genomic DNA can be performed with

types of restriction enzymes (SpeI and NotI) [44]. Oprica et al.,n a European study, reported no relationship between the dis-ribution of clones and the type of infection. However, 38% ofsolates from blood cultures and 60% of isolates from skin oroft tissue infections belonged to the same clone [45]. Similarly,everal clones from patients with deep infections after cardiacurgery were identified [46].

The easy implementation of and the reduced cost ofequencing have led to an increasingly frequent use of MLST. Itoes not serve the same purpose as PFGE. It allows analyzing thehylogenetic evolution of many clones of the concerned species.here are 2 MLST schemes for P. acnes: 1 in Aarhus with 9enes located on the bacterial chromosome; and 1 in Belfastargeting 35% of the genes. Only the recA gene is commono both. The recent comparison of both strategies emphasizedhat the Aarhus MLST scheme (http://pacnes.mlst.net/) had aignificantly higher discriminatory power [47]. More large stud-es including isolates from many anatomical sites should allowetter understanding on one hand, the distribution of phylo-ypes according to infection and, on the other hand, to betterefine commensal or pathogenic clinical strain features. Indeed,ccording to the Aarhus scheme, acne strains belong mostrequently to CC3, CC31, and often CC18, especially the epi-emic clone ST18. Conversely, opportunistic infection strainselonged to CC43 or CC53/60, whereas prostatic strains wereeported in various singletons such as ST36, ST38, ST61, ST79o ST83.

The recent semi-automated technique, rep-PCR (DiversiLab,ioMérieux, France technology) allows rapid typing of isolates.owever, initial studies prove that this new technology is lessiscriminating than MLST. Various sequence types (ST) can beound in the same phylogenetic branches with the same bandrofile, using rep-PCR. However, this technique could allowor a rapid screening of many clones in epidemiological studies.herefore, MLST remains contributive featuring a more detailednalysis of the population heterogeneity and identification ofpecific subtypes among P. acnes isolates [48]. The correlationith PFGE results remains to be established on a collection of

ommensal and pathogenic strains large enough to conclude onhe effectiveness of these technologies and on the epidemiolog-cal answers they provide.

. Antimicrobial activity on P. acnes

Some antibiotics should be tested to adapt treatmentecause of the prevalence of antibiotic resistance in P. acnes:

246 G.G. Aubin et al. / Médecine et maladies infectieuses 44 (2014) 241–250

Table 2Molecular typing and phylogenetic analysis of Propionibacterium acnes isolates.Typages moléculaires et analyses phylogénétiques des isolats de Propionibacterium acnes.

Methods used Target genes Techniques References

Phylotype determination recA (Recombinase A)tly (Hemolysin/cytotoxin)

PCR and sequencing 11

Pulsed-field gelelectrophoresis

DNA extraction,Restriction (SpeI or NotI)and migration

45–46

Multi-Locus SequenceTyping

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)

PCR and sequencing 47–48

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etracycline, erythromycin, clindamycin, and cotrimoxazole49] (Table 3). Furthermore, other antibiotics should be tested forevere infections, to optimize treatment and obtain a synergisticffect against P. acnes: penicillin, cephalosporins, vancomycin,uinolones, rifampicin, and the “new” antibiotics such as line-olid, daptomycin, and tigecycline, to which P. acnes is usuallyusceptible. Aminoglycosides are not active against clinicaltrains of P. acnes. Moreover, its natural resistance to fos-omycin and metronidazole allows confirming the identification

f P. acnes.

able 3ntibiotics to be tested and resistance mechanisms described.ntibiotiques à tester et mécanismes de résistance décrits.

ntibiotic family Resistancemechanism

References

-lactams Unknown –luoroquinolones Unknown –lycopeptides Unknown –ipopeptides Unknown –acrolides Mutations in the

23S RNA gene oracquired ermXtransposon

52–55

etracyclines Mutations in the16S RNA gene

54

otrimoxazole Unknown 54ifampicin Mutations in the rpoB

gene23

inezolide Unknown –

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. Susceptibility testing methods

.1. Minimal inhibitory concentration (MIC) determination

The MIC is determined by the dilution technique usingrucella agar supplemented with 5% defibrinated sterile horselood, vitamin K, and hemin. A final inoculum of 105 CFU perpot is used [50]. The plates are incubated anaerobically for 48o 72 h at 37 ◦C. Strains of P. acnes ATCC6919 and ATCC11827re used as quality controls [45].

The E-test technique uses an inoculum of McFarland 1 in theame anaerobic conditions. The MIC is determined after 48 or2 h of incubation at 37 ◦C. A good correlation between bothechniques has been reported.

.2. Minimal bactericidal concentration (MBC)etermination

There is little data on the determination of the MBC for. acnes. The authors of a recent study, reported that the MICnd MBC were determined by the broth dilution method. Annoculum of 106 CFU/mL was used [50].

.3. Minimal biofilm eradication concentration (MBEC)etermination

Various in vitro methods have been described to assess thectivity of antibiotics on bacterial biofilm. Most methods areased on a static analysis microplate assay. Biofilms are formedn the wells of polystyrene, and the quantification of biofilm

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s achieved by various methods: crystal violet, resazurin, etc.29]. However, these assays have not been widely used for slow-rowing bacteria and anaerobes such as P. acnes, maybe becausef problems of reproducibility and intra-experimental variationslready in the biofilm formation phase, as shown for the use ofrystal violet to stain P. acnes biofilm.

The effect of antibiotics on a 72 h mature biofilm formed onlass beads was evaluated [50]. Factors such as the biomate-ial used, the incubation time, the duration of biofilm formationearly or mature), are important parameters to determine theinimum biofilm eradication concentration. Therefore, each

aboratory must be aware of the limitations and performancef the method used to determine the activity of antibiotics onhe biofilm. Recently, the ability of P. acnes to form biofilmsn orthopedic biomaterials and its susceptibility to variousntibiotics were also measured [52].

0. Antimicrobial resistance and its molecularackground

0.1. Emergence of antimicrobial resistance

The prevalence of resistance has continued to increase sincehe first description of a P. acnes resistant strain in 1979 [13,51].arious factors are involved in the development of resistance:

he inoculum, the antibiotic level (selection pressure), the acqui-ition of resistance in the normal flora [52], a high rate of sebumxcretion [51], the duration of treatment, the consecutive usef various antibiotics and poor patient compliance, especiallyn case of prolonged treatment for deep infections on mate-ial. Antibiotic resistance is either acquired (genetic exchangeetween strains) or linked to chromosomal mutations. Nostrilsould also be an important reservoir of resistant P. acnes strains53].

However, P. acnes has reduced genetic adaptability, allowinghe medical community to use antibiotics effectively [52,53].onversely to other Gram-positive bacteria (staphylococci, inarticular), P. acnes rarely develops resistance to antibiotics bycquiring mobile genetic elements such as plasmids [54].

0.2. Epidemiology of antimicrobial resistance

The rate of patients carrying P. acnes strains resistant to oner more antibiotics has increased steadily from 34.5% in 1991o 64% in 1997. It decreased to 50.5% in 1999, and increasedo 55.5% in 2000. Resistance to erythromycin was the mostommon, frequently associated with resistance to clindamycin.esistance to tetracycline was less common [54]. 684 strains of. acnes were isolated from various sources (brain abscess, cere-rospinal fluid, synovial fluid, skin, blood, bone biopsy, valve) inhe last 8 years in our hospital; 22 were resistant to clindamycin3.2%) and 5 to rifampicin (0.7%). the Task Force on Antimicro-

ial Resistance of anaerobic bacteria ESCMID Group published

report in 2005, on clinical resistance with a breakdown by typef sample:

spuo

s infectieuses 44 (2014) 241–250 247

erythromycin resistance: blood (31.4%), meningitis (21 4%),abdominal infections (18.2%), and lung and pleural fluids(16.7%);

clindamycin resistance: meningitis (21.4%), prosthesis (20%)and blood (20%).

Resistance to tetracycline was associated with strains isolatedrom tissue, bile, bones, skin, and blood.

0.3. Molecular mechanisms of antimicrobial resistance

0.3.1. MacrolidesThe most common mechanism of macrolide resistance is

ssociated with point mutations among the 3 genes encodinghe V domain of the peptidyl transferase loop of 23S rRNA [52].n 2002, the Tn5432 transposon carrying the erm(X) resistanceene was identified [55]. Ross et al. defined four groups:

Group I is the most common (80%). It is linked to a mutationt position 2058 (Escherichia coli numbering), conferring high-evel resistance to erythromycin (512 to 2048 mg/L) and variableesistance to clindamycin (4–512 mg/L) [53,54].

Group III (9.8%) in which resistance is due to a mutation atosition 2057 (E. coli numbering), conferring low-level resis-ance to erythromycin (1–2 mg/L) with susceptibility to other

acrolides.Group IV (10%) in which a mutation at position 2059 (E. coli

umbering) confers resistance to erythromycin (> 2048 mg/L)nd to other macrolides, except for telithromycin. One strainlassified in group I had mutations at positions 2058 and 205953,54].

Finally, group II contrasts with previously documentedhenotypes. Indeed, the resistance determinant, erm(X), isocated on the composite transposon Tn5432. It accounts foress than 10% of erythromycin resistance [55]. This mechanismrovides a high-level of resistance and it is detected by PCR.

high-level correlation was observed between the phenotypiclasses, the cross-resistance profile, and molecular detection54,55]. However, another mechanism may be involved, suchs mutations in ribosomal proteins L4 and L22, the transition atosition 2611 in domain V of 23S rRNA, or deletion in domainI of 23S rRNA [55]. These mechanisms are rare.

0.3.2. TetracyclinesA mutation in the gene encoding 16S rRNA is usually impli-

ated in resistance to tetracycline. This change in position 1058E. coli numbering), provides variable resistance to tetracycline,oxycycline, and minocycline (MIC = 32 mg/L) [54].

0.3.3. RifampicinP. acnes had been considered as susceptible to rifampicin

ntil recently. This antibiotic is the gold-standard treatment fornfections related to medical devices, because of a biofilm [23].esistance to rifampicin has been reported in several bacterial

pecies, such as Staphylococcus aureus, E. coli, Streptococcusyogenes, and Mycobacterium tuberculosis [23]. Resistance issually due to point mutations in the rpoB gene. Substitutionsccur in the conserved domains: group I (507-533 amino acids),

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roup II (563-572 amino acids), and group III (amino acids 684-90), according to E. coli numbering. Three mutations wereetected in the region or “cluster” I rpoB gene. Two mutations,is437Tyr and Ser442Leu confer high-level resistance, whileutation Leu444Ser position confers a low-level of resistance.wo mutations Ile483Val and Ser485Leu, in region 2, confer

ow-level resistance [23]. No clinical isolate has been reportedesistant to rifampicin so far, although 1 strain was reported byappe et al. with a MIC of 0.5 mg/L [56]. Rifampicin resis-

ance should continue to be monitored. It may have importantonsequences in the therapeutic management of device-relatednfections [10,22,23,26].

0.3.4. CotrimoxazoleResistance of P. acnes strains to trimethoprim was reported

n the early 1990s. The authors of a study including 171 isolatesf P. acnes, reported that 16.4% were resistant to trimetho-rim. Various types of molecular mechanisms may be described:hanges in permeability or efflux pumps, new pathways, andarget changes. The molecular mechanism involved in this resis-ance has not been elucidated yet [54].

The Task Force on Antimicrobial Resistance ESCMIDnaerobic bacteria (ESGARAB) determined the profile of antibi-tic susceptibility of 304 P. acnes strains isolated in variousypes of systemic infections. There was 2.6% of the isolateshat was resistant to tetracycline, 15.1% to clindamycin, and7.1% to erythromycin [45,51] with considerable differencesmong European countries. No resistance to penicillin, van-omycin, linezolid, or daptomycin was reported, unlike in otherram-positive bacteria.

0.3.5. P. acnes, biofilms, and antimicrobial resistanceP. acnes is present in a biofilm with reduced metabolic activity

n medical device-related infections. Systemic antibiotic therapysually fails because of dual resistance to antibiotics and phago-ytosis. Holmberg et al. recently demonstrated the importancef biofilm formation in deep P. acnes infections [57]. Oncehe bacteria detach from the biofilm, they become suscepti-le, suggesting antimicrobial resistance is due to tolerance iniofilm, and not to mechanisms such as mutations or inacti-ating enzymes. Rifampicin, a small molecule that can easilyenetrate the exopolysaccharide matrix, has an excellent activitygainst biofilm, including staphylococcus [23]. Its activitygainst P. acnes within a biofilm was recently demonstratedn vitro and in vivo [50]. Combinations with linezolid or dap-omycin improve the in vitro and in vivo activity, respectively50]. Penicillin G also had a good activity in vitro [50,51] andemains to be assessed in vivo, although it is considered as a first-ine treatment in the new U.S. guidelines. Little data is availablen the risk of selection of resistant bacteria within the biofilm,ompared with staphylococci, and studies are needed to betternderstand its physiopathology.

1. Treatment

The treatment of severe infections caused by P. acnes includes combination of antibiotics, administrated intravenously

s infectieuses 44 (2014) 241–250

nitially, and usually associated with optimal surgery (e.g.,emoval of the device and/or debridement of the surgicalite). Penicillin G and ceftriaxone are still considered as first-ine antibiotics for severe infections [58], vancomycin andaptomycin are considered as alternatives in case of allergyo �-lactams or resistance (not reported yet). Clindamycin,etracycline, and levofloxacin, all available per os, are also alter-ative treatment or may be used for prolonged treatment [58].ifampicin and daptomycin should also be considered as activentimicrobial agents, including against P. acnes biofilm [50].ore studies are needed to validate the effectiveness of some

ombinations, especially in case of polymicrobial infections.emoval of the device is usually sufficient to reduce the inocu-

um causing chronic infection involving this bacterium withro-inflammatory and biofilmogenic properties.

2. Conclusion

P. acnes was often ignored but has been reported as involvedn various clinical presentations, including deep and severeevice-related infections. The modern and innovative diagnos-ic tools available allow identifying it more easily, especially ifhe microbiologist extends the culture time. Sonication of pros-hetic devices could help improve the diagnosis of infectionsn foreign material, especially for orthopedic prosthesis, breastmplants, or intra-cardiac devices. The adaptation of molecular

ethods, or specific multiplex PCR (automated or not) shouldlso increase the sensitivity of P. acnes detection. The authors ofecent genomic and proteomic studies on the pathogenic role of. acnes in several diseases have explained why this bacterium ismerging. More research is needed to improve our knowledge.hy are diseases due to P. acnes? What bacterial factors, orhich clone are responsible for these diseases?Furthermore, P. acnes may be resistant to some antibiotic

amilies, such as macrolides. This was proven recently forifampicin. Today, the phylotype, the antibiotype, and molecularyping allow better understanding of the evolution and phylo-enetic relationships between a type of infection and specific. acnes strains. However, more research is needed to betternderstand the emergence of resistance (fluoroquinolones) andhe adaptation of some pathovars to specific clinical settings.

isclosure of interest

The authors declare that they have no conflicts of interestoncerning this article.

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