given the high prevalence of candida as a harmless commensal in humans , it is not surprising that no single primary virulence factor has been identified with the organism . however , a number of putative virulence factors ( table 3 ) have been proposed that in the event of host debilitation contribute to tissue damage and persistence of the organism within the host . putative virulence factors of candida albicans 
  cell surface hydrophobicity non - specific adherence expression of cell surface adhesins secreted aspartyl proteinase production binding of complement antigenic modification secretory iga destruction hydrolytic enzyme production promotes invasion of oral epithelium host cell and extracellular matrix damage the ability of candida to adhere to host surfaces is a prerequisite for both successful commensal carriage as well as persistence during active infection . within the oral cavity , removal of loosely attached candida by the physical flushing action of salivary flow or the process of sloughing off of epithelial cells from mucosal surfaces an enhanced ability to overcome these removal mechanisms can therefore be regarded as a virulence attribute . adherence of candida to human epithelial cells is initiated through weak and reversible interactions involving hydrophobic and electrostatic forces ( 50 ) . the nature of these forces are in part governed by the local environment in the oral cavity ; however , studies have shown that strain variation does occur in terms of cell surface hydrophobicity that may give certain isolates greater pathogenic potential ( 51 ) . specific adhesion between candida and receptors on host tissues results in a stronger covalent attachment . candida genes of the als ( agglutinin - like sequence ) family ( 52 ) and also hwp1 ( hyphal wall protein ) ( 53 ) encodes for cell wall associated glycoproteins that promote adhesion of c. albicans to epithelial surfaces . in addition , specific interaction of candida with oral bacteria has also been demonstrated that could encourage biofilm formation on dentures and in dental plaque ( 54 ) . biofilms can be defined as microbial communities that are often ( but not necessarily ) attached to a solid surface ; invariably the biofilm microorganisms are encased within an extracellular polysaccharide matrix that has been generated by the organisms themselves . candida species are adept at forming biofilms ( 55 , 56 ) and this has been linked to both increased expression of virulence factors ( 57 ) as well as reduced susceptibility to antimicrobial agents ( 58 ) . candida biofilms in human disease are widely recognised and occur on tissue surfaces as well as the biomaterials of medical devices . candida biofilms on artificial voice box prostheses have been identified as a major cause of their failure . urinary tract infections caused by candida biofilms in catheterised patients are recognised , whilst biofilms at other sites including on prosthetic heart valves , intravascular catheters , and replacement joints have also been linked with infection ( 59 ) . candidal biofilms in haemodialysis and peritoneal dialysis catheters are a common occurrence and associated with an infection rate of up to 20% in patients undergoing treatment ( 55 ) . in terms of oral candidosis , biofilms on an oral prosthesis , most commonly a denture , are a major predisposing factor to chronic oral candidosis . candida readily adhere to the polymethylacrylate material of dentures , and also exploit micro fissures and cracks within the material to facilitate retention ( 60 ) . biofilm formation on denture surfaces is further promoted by poor oral hygiene and retention of dentures in the mouth whilst sleeping . several candida species are described as polymorphogenic ( 61 ) and whilst in nutrient rich culture media at 37c , yeast growth would appear to be prevalent , filamentous growth can occur and indeed is frequently seen in clinical situations . both c. albicans and candida dubliniensis are species associated with the generation of true hyphae ( 62 ) . true hyphae are distinct from pseudohyphae ( which are effectively elongated yeast cells ) , as the former lack constriction at yeast / hyphal junctions and also possess septa within the filaments ( fig . the pathogenic significance of being able to produce hyphae could relate to the greater resistance of hyphae to phagocytosis compared with yeast , enhanced adherence to host surfaces , and the ability of hyphae to invade epithelial layers resulting in tissue damage ( fig . hyphal production is also linked with enhanced expression of several putative virulence genes , some of which are not involved in the morphogenic process itself ( 63 ) . it should be noted that both filamentous and yeast forms are encountered in the oral cavity of healthy individuals , highlighting the importance of host factors in controlling candida and the fact that no single predominant virulence factor is associated with the organism ( 64 ) . calcofluor white stained candida albicans showing true hyphae ( * ) and pseudohyphae ( + ) . a phenomenon referred to as  high frequency phenotypic switching is evident in vitro for certain strains of c. albicans when cultured on appropriate agar media . colonies generated by isolates that are  high frequency switchers exhibit variation in terms of colour , shape , and translucency . the cause of these colony switch variants relates to cell morphology and differential gene expression by the variants ( 56 , 61 ) . the so - called white - opaque switching is associated with mating in c. albicans as well as the up - regulation of biofilm genes ( 65 , 66 ) . high frequency switching strains have been proposed to have greater virulence , as replication of this property in vivo might aid in evading recognition by adaptive immune responses as well as promoting biofilm formation . candida produces several extracellular enzymes that could have a locally damaging effect on host structures ( 67 ) . significant attention has been given to the secreted aspartyl proteinases ( saps ) of candida . c. albicans possesses at least 10 different genes that encode for saps , and the resulting proteins are in turn designated saps 110 . saps 18 are released extracellularly , whilst saps 9 and 10 are thought to be membrane bound . sap enzymes belong to the same class of proteinases as the hiv aspartyl proteinase as well as human pepsin and renin . all candida saps are inhibited by the agent pepstatin a. candida saps have optimal activity at acidic ph ( ph 27 activity range ) , although distinct differences in ph optima are evident with saps 13 being most active at the lower end of the ph scale and saps 46 at higher ph . this heterogeneity in activity optima of the saps could benefit candida in its survival under different environmental conditions . of the candida saps , it has been shown that sap 2 is induced when c. albicans is cultured in media containing proteins as the only nitrogen source ( 68 ) . sap 1 and sap 3 are specifically expressed during switching of c. albicans , whilst saps 46 are involved in promoting hyphal growth ( 69 ) . c. albicans proteinases have keratinolytic activity that can both serve to facilitate initial penetration of keratinised cells as well as providing a valuable source of nitrogen during colonisation ( 70 , 71 ) . in terms of virulence , sap activity can therefore directly induce damage to host cells , facilitate hyphal growth for invasion of tissue , increase adherence following exposure of receptor sites , and also degrade host immunoglobulins and other defence proteins ( 55 , 7275 ) . another group of hydrolytic enzymes produced by candida species are the phospholipases ( pls ) and seven distinct encoding genes have been identified in c. albicans . these genes have been given the designations pla , plb1 , plb2 , plc1 , plc2 , plc3 , and pld1 ( 76 ) . through the hydrolysis of ester linkages of phospholipids , pls can effectively degrade the membrane of host cells leading to cell lysis and death . by this process , both adherence of candida to receptor sites and its subsequent penetration of damaged tissue can be facilitated . the role of extracellular lipase and esterase production by candida in pathogenic processes is less well understood ( 77 ) . both lipases and esterases share the ability to hydrolyse the ester bonds in glycerides , although the latter only act on soluble substrate molecules . a total of 10 candida lipase ( lip110 ) genes have been identified in c. albicans and sequence - related genes found in c. tropicalis , c. parapsilosis , and c. krusei ( 78 ) . lipases of c. albicans have recently been shown to exhibit cytotoxic effects on host cells ( 79 ) and lip gene expression detected in oral candidosis ( 80 ) . haemolysins are substances that lyse red blood cells and their production by candida is considered an important attribute in promoting survival within the host through an increased ability to sequester iron . luo et al . ( 81 ) demonstrated - and -haemolysis by clinical isolates of c. albicans , c. dubliniensis , c. kefyr , c. krusei , c. zeylanoides , c. glabrata , c. tropicalis , and c. lusitaniae . candida haemolysin production positively correlates with glucose concentration and that this could be a predisposing factor in candidosis of poorly controlled diabetics where higher blood and salivary glucose levels occurs ( 76 , 82 ) . immunocompetent individuals rarely suffer from oral candidosis even when candida is present in the oral cavity . prevention of mucosal infection by candida is mediated primarily by the functions of the innate immune response . in particular , neutrophils and macrophages professional phagocytes recognise candida through pattern recognition receptors ( prrs ) , which interact with specific molecules ( pathogen - associated molecular patterns ; pamps ) exposed on the surface of candida ( 83 ) . following recognition , these cells release cytokines and chemokines to further modulate the immune response . dendritic cells ( dcs ) are professional antigen presenting cells that provide a sentinel role in mucosal tissue . following phagocytosis , dcs migrate to the lymph nodes where the candida antigen is processed and presented on the surface of the dc to nave cd4 t - cells ( 8488 ) . interaction between dcs and t - cells cause the latter to differentiate into mature effective t - cells ( 89 ) . the type of t - cell generated is thought to be under direction of the dc and examples of effective t - cells include t - helper 1 ( th1 ) , t - helper 2 ( th2 ) , t - helper 17 ( th17 ) , and regulatory t - cells ( tregs ) . previously it was generally accepted that a th1 elicited response was a protective one , whilst th2 responses were implicated in infection . more recently , evidence suggests that a th17 response is predominant in protection of mucosal surfaces ( 90 ) . a priority in the treatment of oral candidosis is the alleviation of any identifiable predisposing factor . acquiring a thorough medical history is , therefore , an essential component in the management process . an example of this are the recommendations made to patients suffering from chronic erythematous candidosis in order to improve oral hygiene through adequate denture cleansing . such recommendations would include the regular and frequent use of a denture cleanser with anti - candidal properties such as 1% sodium hypochlorite preparations , together with the removal of dentures overnight . chlorhexidine ( 0.2% ) should be used if the denture has metal components since hypochlorite will otherwise cause discolouration . however , it should also be noted that discolouration of teeth and mucosal surfaces have been reported with the use of chlorhexidine ( 91 ) . certain predisposing factors are , however , more difficult if not impossible to eradicate such as where there is an underlying disease ( e.g. leukaemia or aids ) . in these cases , targeted antifungal therapy , as discussed later , plays an important role in the management strategy . both the physical and chemical reduction of candida load in the oral cavity can be achieved by good oral hygiene practices including tooth brushing and the use of antimicrobial mouthwashes . manual tooth brushing is limited to accessible oral surfaces , although powered or electrical tooth brushing may be more effective as cavitation within surrounding fluids could disrupt candida biofilms at otherwise inaccessible sites ( 92 ) . several mouthwashes exhibit anti - candidal activity including triclosan , chlorhexidine gluconate , and essential oil formulations . the latter tend to contain natural plant extracts such as thymol , eucalyptol , and bioflavanoids and these can have a direct anti - candidal activity in vitro through cell membrane disruption and enzyme inhibition ( 93 , 94 ) . the reason for this relates to the relatively recent recognition of the significance of human fungal infections and also the fact that fungal organisms are eukaryotic and share many features with mammalian cells making selection of suitable targets for antifungal agents problematic . classification of antifungal agents is based on the target of activity , and in the treatment of candidosis the two classes most commonly used are the polyenes and the azoles ( table 4 ) . antifungals used in the management of candidosis abbreviations : cec , chronic erythematous candidosis ; pmc , pseudomembranous candidosis ; aec , acute erythematous candidosis ; chc , chronic erythematous candidosis . polyenes include the drugs amphotericin b and nystatin and their mode of action is through direct binding to the sterol ergosterol found within fungal cell membranes . polyene binding to ergosterol induces leakage of cytoplasmic contents leading to fungal cell death ( 95 ) . the equivalent mammalian sterol is cholesterol , which has a lower binding affinity for polyenes and this makes host cells less susceptible to their toxic effects . nevertheless , at higher therapeutic concentrations polyenes do exhibit a degree of toxicity in humans . the use of polyenes is limited further as they are poorly absorbed through the gut and , therefore , topical application in the form of lozenges and oral suspensions are the principle means of administration in oral infection . polyenes are frequently used in the treatment of chronic erythematous candidosis , and oral suspension of amphotericin b may be employed in treating refractory oral candidosis frequently seen in hiv - infected and aids patients . the mechanism of action is by inhibiting the enzyme lanosterol demethylase that is a cytochrome p-450 3-a dependent enzyme involved in the synthesis of ergosterol . subsequent depletion of ergosterol in the fungal cell results in inhibition of fungal growth and impairment of membrane permeability . since azoles are fungistatic , complete resolution of the infection will be aided by simultaneously addressing predisposing host factors . the two most frequently administered azole antifungals in the treatment of oral candidosis are fluconazole and itraconazole and these drugs have the advantage of being readily absorbed through the gut with the result that oral administration is an effective means of delivery ( 97 ) . furthermore , fluconazole is secreted in high levels in saliva making the agent particularly suitable for treating oral infection ( 98 ) . unfortunately , in recent years candida resistance to azole antifungals has been detected and this can arise through several mechanisms including the over production of the lanosterol demethylase enzyme , an alteration in the demethylase enzyme structure that makes it less susceptible to azole inhibition , the use of multi - drug transporter pumps to remove azoles from the cell , and the incorporation of alternative sterols to ergosterol within the cell membrane ( 99 ) . several ncac species are inherently more resistant to azoles than other species . for example , 35% and 75% of c. glabrata and c. krusei isolates exhibit resistance to fluconazole and this could be a reason why the prevalence of certain ncac species in human disease has increased in recent years ( 29 , 100 ) . as the need to expand antifungal options increases , newer azole drugs such as itraconazole have been used in the treatment of oral candidosis , whilst others including voriconazole and pozoconazole are alternatives for invasive infections by candida . recently , the echinocandin class of antifungals have emerged as alternatives to the azoles and polyenes ( 101 ) . echinocandins act through inhibition of the d - glucan synthase , which is an enzyme required for the synthesis of the fungal cell wall . whilst echinocandins such as caspofungin , micafungin , and anidulafungin are fungicidal against candida , their use is somewhat limited by their large molecular size that dictates the need for intravenous administration . candida biofilms exhibit significantly higher tolerance to both antimicrobial mouthwashes and also traditional antifungal agents . as a consequence , alternative strategies these have included the modification of biomaterials such as those used in denture prosthesis to inhibit adherence of candida . examples include the use of coatings with silanes , chlorhexidine , histatins , antifungals , as well as the incorporation of surface - modifying groups ( 102105 ) . alternative strategies could exploit quorum - sensing agents to promote biofilm disruption with the agent farnesol already having been shown to induce instability in candida biofilms ( 106 ) . other possible strategies could involve the use of probiotics ( 107 ) , which would induce an added microbiological pressure on candida within the oral cavity and may also promote local immune function . the potential benefits of probiotics in the management of candida biofilms have already been reported for indwelling voice box prostheses ( 108 ) , as well as in lowering the candida prevalence in the oral cavity ( 109 ) . whilst candida species are frequent members of the commensal oral microflora of humans , they are opportunistic pathogens that under conditions of host debilitation can cause a spectrum of oral infection . oral candidoses have been recognised throughout recorded history , although most attention has been given to the infections in the last few decades when the incidence increased greatly with the advent and escalation of the aids epidemic . c. albicans is the species most frequently implicated in oral candidosis , although other species are increasingly being encountered . putative virulence factors of candida include the ability to adhere to host surfaces , produce filamentous growth forms , and release hydrolytic enzymes capable of inducing damage to host cells . effective management of oral candidosis demands correction of any identified predisposing factor together with the administration of appropriate antifungal agents . given the increasing incidence of ncac species in oral infection and the development of resistance against some of the traditionally used antifungals , there is a constant need for research into new and effective agents to treat oral candidosis . there is no conflict of interest in the present study for any of the authors .
oral infections caused by yeast of the genus candida and particularly candida albicans ( oral candidoses ) have been recognised throughout recorded history . however , since the 1980s a clear surge of interest and associated research into these infections have occurred . 
 this has largely been due to an increased incidence of oral candidosis over this period , primarily because of the escalation in hiv - infection and the aids epidemic . 
 in addition , changes in medical practice leading to a greater use of invasive clinical procedures and a more widespread use of immunosuppressive therapies have also contributed to the problem . whilst oral candidosis has previously been considered to be a disease mainly of the elderly and very young , its occurrence throughout the general population is now recognised . 
 candida are true 
 opportunistic pathogens and only instigate oral infection when there is an underlying predisposing condition in the host . 
 treatment of these infections has continued ( and in some regards continues ) to be problematic because of the potential toxicity of traditional antifungal agents against host cells . 
 the problem has been compounded by the emergence of candida species other than c. albicans that have inherent resistance against traditional antifungals . 
 the aim of this review is to give the reader a contemporary overview of oral candidosis , the organisms involved , and the management strategies that are currently employed or could be utilised in the future .