Abstract
Fungal biofilms are an important clinical problem. A number of factors including the increasing use of indwelling medical devices wider prescription of broad spectrum antibiotics and an aging and more immuno-compromised patient population has combined to create an opportunity for yeasts and moulds to cause infection. It is also becoming increasingly clear that for a number of serious infections the development of a fungal biofilm is important in the pathophysiology of the infection.
This chapter will discuss the importance of fungal biofilms in different anatomical areas, will try to provide insights into how fungal biofilm infection should be diagnosed and treated and provide an explanation as to why biofilms may be difficult to treat effectively with routine antifungal regimens.
Finally it will discuss how our current level of knowledge of the development and biology of fungal biofilms may, in future, lead to a wider choice of therapeutic interventions.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- Candida Species
- Bacterial Vaginosis
- Ventilator Associate Pneumonia
- Liposomal Amphotericin
- Allergic Bronchopulmonary Aspergillosis
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
1 Introduction
Fungal biofilms are an important clinical problem. The widespread use indwelling medical devices, broad spectrum antibiotics and an aging and more immuno-compromised patient population has created an opportunity for yeasts and moulds to form infections in the form of biofilms. This chapter will discuss the diversity and importance of fungal biofilms in different anatomical areas, provide insights into the management of fungal biofilm infection, explain why biofilms may be difficult to treat with antifungal therapy, and discuss how our current level of knowledge may lead to different treatment interventions.
A biofilm is composed of microorganisms attached to surfaces or one another and enclosed within an extrapolymeric matrix. The biofilm mode of growth is the preferred form of growth of microorganisms and account for up to 65 % of all clinical infections. This mode of growth gives the organism a number of advantages including high level antimicrobial resistance which may cause problems for the clinician attempting to treat such infections (Donlan and Costerton 2002). Over recent years there has been a growing appreciation that pathogenic fungal species both have the ability to form biofilms and that these biofilms may impact clinical practice (Ramage et al. 2009; Sayed et al. 2012; Fanning and Mitchell 2012).
Fungi can be broadly divided into yeasts and moulds and in terms of the number of infections, Candida albicans, a normal commensal of human mucosal surfaces and opportunistic pathogen in immunocompromised patients, is the most clinically important of fungi species in terms of the production of clinically relevant biofilms. This dimorphic fungus exists in both yeast and hyphae forms which results in a structurally complex biofilm. This begins with yeast cells attaching to a relevant surface using defined adhesins, such as the agglutinin-like sequence protein Als3p and the GPI anchored cell wall protein Eap1p (Zhao et al. 2006; Li et al. 2007). The next step is the formation of a microcolony with yeast cells undergoing morphological switching to pseudo- and true-hyphae under the regulatory control of Efg1p (Ramage et al. 2002) which results in the rapid formation of a meshwork of hyphae interspersed with budding yeast cells. As the biofilm matures it becomes enclosed in a glucan rich polymeric matrix (Nett et al. 2010a) which provides protection from host defences and treatment with antifungal agents. Within the biofilm there are a range of niches and in hypoxic areas, Tye7p controlled up-regulation of glycolytic genes, which influence filamentation, occurs (Bonhomme et al. 2011). Flow of fluids across the surface of the biofilm may then result in the dispersion of daughter cells which attach to a new substrate and the cycle starts again (Uppuluri et al. 2010). This entire process is controlled by transcription factors, such as Bcr1p, Ace2p, Efg1p and Zap1p, which are involved in precisely regulated molecular pathways (Zhao et al. 2006; Finkel and Mitchell 2011; Nobile and Mitchell 2006; Fanning et al. 2012).
From a clinical point of view it is important as an understanding the basis of adherence, proliferation, maturation and dispersal both forms the basis for all other pathogenic fungal biofilm studies and signposts important potential new targets for clinical interventions in these infections. This chapter will review fungal biofilms and their clinical importance, discuss why these infections may be so difficult to treat, and provide evidence for potential novel strategies to improve clinical management.
2 Where May Fungal Biofilms Be Important?
2.1 Oral Cavity
The oral cavity represents one of the major portals of entry for microorganisms, and is a site in which the presence of multispecies microbial biofilms has been widely studied both in the presence and absence of foreign materials (Jakubovics 2010). Within the oral cavity, caries, periodontal disease, endodontic infection and mucosal infections all involve microbial biofilms (Beikler and Flemmig 2011) and Candida species are the important fungal pathogen (Rautemaa and Ramage 2011). The oral cavity is a good environment for biofilm growth for a variety of fungal species. In a study of 20 healthy individuals Fungal microbiome analysis of the oral cavity, using a pyrosequencing approach, identified 74 culturable and 11 non-culturable fungal (Ghannoum et al. 2010). Candida species were shown to be the most prominent genera in this group (75 %), followed by Cladosporium (65 %), Aureobasidium (50 %), Saccharomycetales (50 %), Aspergillus (35 %), Fusarium (30 %), and Cryptococcus (20 %). Overall 101 species were present and each individual had from 9 to 23 different fungal species. While these results demonstrate the potential diversity of fungi in the mouth there remains the possibility that DNA from these fungal species was ingested or inhaled.
Nevertheless, yeasts clearly exist within the oral cavity and form biofilms. Oral candidosis, best defined fungal biofilm infections of both soft and hard tissue in the mouth forms complex biofilms in association with host components and bacteria (Rautemaa and Ramage 2011; Dongari-Bagtzoglou et al. 2009). Candida species have been isolated from periodontal pockets, orthodontic appliances, enamel, dentures and mucosal surfaces (Dongari-Bagtzoglou et al. 2009; Ramage et al. 2004; Sardi et al. 2010; de Carvalho et al. 2006; Arslan et al. 2008). Where Candida species are isolated from subgingival mixed species biofilms in patients with severe chronic periodontitis (Canabarro et al. 2012) there is a clear correlation between disease severity and both the quantity and species of yeast cells isolated with C. albicans being found in high numbers from those with moderate and severe chronic periodontitis. However a causal relationship has yet to be demonstrated and the presence of Candida species may simply represent poor oral health.
Interestingly there seems to be a relationship between Yeasts and other bacteria in oral biofilms. Another metagenomic analysis of elderly patients showed that increased candidal load favoured the presence of oral streptococci (Bamford et al. 2009) a potential mechanism for this has been suggested in mixed C. albicans and Streptococcus gordonii mixed biofilms where growth is enhanced through specific cell-cell interactions involving both Als3p and the surface protein adhesion SspB (Silverman et al. 2010). In addition these physical interactions chemical interactions have also been shown to influence biofilm formation (Bamford et al. 2009). Complex biofilms are a key mode of survival within the oral cavity and this process may influence both oral and systemic health (Coulthwaite and Verran 2007).
When foreign materials such as dentures are present in the mouth biofilms are also important in the causation of denture stomatitis (Nett et al. 2010b). This is characterized by Candida species forming on a denture prosthesis (Pereira-Cenci et al. 2008) usually associated with the upper fitting denture, where the biofilm forms on the surface adjacent to the oral mucosa (Ramage et al. 2004). C. albicans is the most frequently isolated yeast from the denture, but Candida glabrata, Candida dubliniensis, Candida tropicalis, Candida krusei and a range of other Candida species have been isolated (Coco et al. 2008; Williams et al. 2011). The level of inflammation of the palate ranges from localised areas of erythema to diffuse areas of severe erythema (Newton 1962). In this condition again the species of yeast present seems to be important in that those with severe inflammation preferentially cultured C. albicans (Coco et al. 2008). Further in vitro analysis of these strains showed a positive correlation between the severity of disease and secreted aspartyl proteinase (Sap) release and expression when the organism was grown as a biofilm (Ramage et al. 2012), which has also been shown with strains isolated from type 1 diabetes patients (Rajendran et al. 2010). These proteolytic enzymes have been shown to be present in various in vivo studies (Naglik et al. 2003, 2004, 2006) but it is not possible to attribute a causal role as no single Sap plays a predominant role in mucosal invasion (Lermann and Morschhauser 2008; Naglik et al. 2008). It is possible however to suggest that Sap proteins play a role in proteolytic cleavage of the mucin Msb2, which activates the Cek1 MAPK pathway and induce filamentation (Puri et al. 2012) which is known to play a key role biofilm development and stabilisation (Ramage et al. 2002) which suggest a physical and regulatory role for proteolytic enzymes in C. albicans biofilm production.
It is clear that there is interaction between yeasts and bacteria, however synergistic interactions between different Candida species within a biofilm have also been proposed as a pathogenic mechanism. Coco et al (Coco et al. 2008) showed that C. glabrata and C. albicans are often co-isolated from patients, particularly those with severe inflammation. He suggested that as C. glabrata does not produce hyphae and therefore forms relatively structurally poor and unstable biofilms, that it was possible, in mixed yeast biofilms, that C. glabrata was using C. albicans as a structural scaffold to gain entry to the host. This has now been confirmed in another study where C. albicans appears to assist the invasive capacity of C. glabrata within an in vitro reconstituted epithelial biofilm model (Silva et al. 2011). Further studies using in vivo models to investigate the pathogenesis of denture stomatitis would be useful in this context (Nett et al. 2010b).
2.2 Upper Airways
Sinusitis (or rhinosinusitis) is defined as an inflammation of the mucous membrane lining the paranasal sinuses. It may be acute or chronic however subacute, and acute exacerbation of chronic diseases have also been described and as all types have similar symptoms it is often clinically difficult to distinguish these. Around 90 % of adults have had some symptoms of sinusitis at some time. There is a growing appreciation that chronic rhinosinusitis is typified by biofilm growth (Foreman et al. 2011; Keir et al. 2011; Ebbens et al. 2009a). While there is increasing evidence for the role of bacterial biofilms in this infection, there role of fungi remains controversial (Ebbens et al. 2009b). Paranasal sinus fungus balls have been described (Grosjean and Weber 2007; Karkas et al. 2012), which share some of the features of fungal biofilms (Harding et al. 2009; Mowat et al. 2009). In a recent study of 118 patients with chronic sinusitis, nasal discharge, headache and visual disturbance, over a 14 year period 23.7 % had a sphenoidal fungus ball in which Aspergillus fumigatus and Aspergillus nidulans hyphae were observed microscopically (Karkas et al. 2012). Other fungi have also been implicated including Schizophyllum commune (Chowdhary et al. 2013; Sa et al. 2012), Trichos-poron inkin (Janagond et al. 2012), Mucorales (Mignogna et al. 2011), and Fusarium (Rombaux et al. 1996). In terms of infections associated with foreign bodies A. fumigatus infection within the maxillary sinus associated with a zygomatic implant has been reported (Sato et al. 2010). Experimental studies have shown that A. fumigatus biofilms form in a primary human sinonasal epithelial model (Singhal et al. 2011) and in a sheep model of induced sinus biofilms A. fumigatus readily forms biofilms often associated with Staphylococcus aureus (Boase et al. 2011). These data suggest that fungal biofilms, alone or more likely in mixed species biofilms with other organisms, may play a role in sinus infection however there is little evidence to support the role of fungi in other upper airway biofilm infections such as otitis media (Bakaletz 2007; Martin et al. 2005; Yao and Messner 2001).
When foreign bodies are present, such as head and neck related prostheses polymicrobial biofilms containing Candida species have been reported (Ariani et al. 2012). Biofilms including C. albicans and C. glabrata, have also been extensively described in voice prosthesis biofilms (Buijssen et al. 2012; Ell 1996) where they have been shown to bind to salivary proteins (Holmes et al. 2006), and are often found co-aggregated with bacterial species (Kania et al. 2010). Clinically they restrict airflow (Elving et al. 2001), impede speech, swallowing and respiration (Sayed et al. 2012). Other fungal species such as Fusarium solani species complex (Honraet et al. 2005) and Cryptococcus neoformans (Bauters et al. 2001) have also been described.
The finding of fungal biofilms on speech prostheses may also be of relevance in terms of the pathophysiology of Ventilator associated pneumonia (VAP). Studies have shown that the isolation of Candida species isolated alone or in combination from respiratory secretions in those with suspected VAP are associated with increased mortality compared to those with only bacteria isolated, an unadjusted odds ration of 2.9 (Delisle et al. 2011). In addition Candida colonisation has been associated with an increased risk of isolation of multi-drug resistant bacteria (Hamet et al. 2012). The mechanisms for this are unclear but it is possible that yeasts form the basis of multi-species biofilms which effect the pathogenicity of other yeasts or bacteria contained in the biofilm. It is also possible that the incidence of fungi within these VAP samples may be due to previous treatment with broad-spectrum antibiotics, but in VAP following cardiac surgery 30.19 % of patients were culture positive for fungi, including C. albicans (16.97 %), Pneumocystis jirovecii (3.77 %), C. glabrata, Candida sake, C. krusei, Geotrichum capitatum and Cryptococcus humicola, (1.89 % each) (Serban et al. 2010).
Care bundles which include measures that may reduce or prevent the growth of biofilms such as oral decontamination with chlorhexidine, have dramatically reduced the rates of VAP in the intensive care setting (Stonecypher 2010; Caserta et al. 2012).
2.3 Lower Airways
Lower respiratory tract infection may be due to biofilm infection, the archetype of which is Pseudomonas aeruginosa in cystic fibrosis patients (Singh et al. 2000). It is also now recognised however that fungal biofilms present in the lung may also contribute to infection.
Filamentous fungi, mainly A. fumigatus, may cause a spectrum of respiratory disease including from a discrete lesion in a pre-existing cavity, aspergilloma, wheezing mediated by an immune response, allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) (Denning 1998). A bronchopulmonary lavage (BAL) of these individuals often reveals the presence of numerous intertwined hyphae in the form of a complex multicellular structure when examined histologically (Jayshree et al. 2006), this is indicative of a biofilm phenotype (Harding et al. 2009; Mowat et al. 2009). The recently described Aspergillus bronchitis may also be biofilm associated and is characterized by bronchial casts containing mycelia forming compact masses (Young et al. 1970). It is clear that Aspergillus species form medically important biofilms (Gutierrez-Correa et al. 2012; Ramage et al. 2011) and understanding their clinical role in is crucial, as with all biofilms, these structures are highly resistant to antifungal therapy (Mowat et al. 2008; Seidler et al. 2008).
A number of fungal species including Aspergillus spp., Scedosporium spp. and Exophiala spp. have been isolated from different cohorts of CF patients (Blyth et al. 2010; Cimon et al. 2000; Kondori et al. 2011). Given the ubiquitous nature of moulds within the environment, and with thousands of conidia being inhaled every day (Richardson 2009), it is unsurprising that pathogenic fungi can adhere, colonise and form complex multispecies biofilms in lungs with abnormal clearance mechanisms such as CF however their pathogenic role has not yet been fully elucidated. A number of recent studies have reported that lung function declines more rapidly in patients co-infected with A. fumigatus and P. aeruginosa when compared to single-species infection (Amin et al. 2010; Gangell et al. 2011), this has also been reported with Candida species and P. aeruginosa (Chotirmall et al. 2010). Evidence is therefore increasing for the improved clinical management of these patients (Delhaes et al. 2012).
There is a suggestion that interactions in mixed eukaryotic prokaryotic biofilms (polymicrobial infections) in the CF lung may lead to adverse clinical outcomes (Leclair and Hogan 2010). It has been shown that P. aeruginosa is able to both form biofilms and kill C. albicans in the hyphal form but not the yeast form (Hogan and Kolter 2002) possibly through the release of a phenazine toxin (Gibson et al. 2009; Morales et al. 2010). Pseudomonas has also been shown to inhibit the morphological transition of yeast through a 3-oxo-C12 homoserine lactone (Hogan et al. 2004) which has also been demonstrated in studies of A. fumigatus biofilms (Mowat et al. 2010). Further evidence of eukaryotic/prokaryotic interaction comes from the fact that the release of farnesol, a quorum sensing molecule of C. albicans impacts by inhibiting its quinolone signalling and subsequent pyocyanin production in P. aeurginosa (Cugini et al. 2007). These studies highlight potential battles going on within a polymicrobial environment such as the CF lung, which plays a crucial role in the overall pathogenesis of disease (Peters et al. 2012) exemplified by studies in a Drosophila model of polymicrobial infection in which microorganisms from CF showed a different outcome depending on the presence or absence of P. aeruginosa (Sibley et al. 2008a, b).
3 Gastrointestinal and Urinary Tract
The mucosa of the gastrointestinal (GI) tract is heavily laden with bacterial microbiota, growing as healthy biofilm communities (Macfarlane and Dillon 2007). Clinically they present a problem, for example when they are located in the stomach of those with percutaneous endoscopy gastronomy (PEG) feeding tubes for enteral nutrition, or in the large intestines in diseases such as ulcerative colitis (Macfarlane 2008). C. albicans and C. tropicalis have been shown to colonise these PEG tubes and contribute to degradation of the polyurethane (Trevisani et al. 2005; Gottlieb et al. 1993). Clinically this may lead to diarrhoea, or possibly cause translocation of microbes across the epithelial barrier, leading to sepsis.
Candida spp. colonisation of the GI tract is common, accounting for 30–80 % in normal healthy adults (Damman et al. 2012). Chronic colonisation may lead to GI candidisasis, which in immunocompromised individuals may lead to systemic candidiasis. Whilst little direct work has focussed on fungal biofilm in the GI tract per se, this environment is largely a polymicrobial biofilm, and interactions between yeasts and bacteria are likely to exist and play a role in health and disease. In fact, it has been suggested that Candida colonization may enhance inflammation in the GI tract (Kumamoto 2011). Investigations of Escherichia coli and C. albicans co-infection have reported synergistic virulence when grown together (Klaerner et al. 1997). Interestingly, in vitro studies have revealed dynamic population changes of these two organisms within biofilms, with a proposed role for lipopolysaccharide (LPS) modulation of C. albicans (Bandara et al. 2009). Recently, experimental murine studies have reported that C. albicans are able to modulate the bacterial microbiota composition of non-pathogenic species following antibiotic exposure (Mason et al. 2012), suggesting that in health there is a bidirectional relationship between bacteria and C. albicans, rather than simply competitive inhibition by bacteria.
The urinary tract is also a polymicrobial environment, with a diverse metagenome present that is capable of preventing bacterial vaginosis, yeast infections, sexually transmitted disease and urinary tract infections (Ma et al. 2012). High acidity from lactic acid bacterial metabolism is a key mediator of selective inhibition of other species (Gajer et al. 2012). Therefore, control of candidal biofilms may be best achieved through competitive inhibition by bacterial flora, such as lactobacilli, though no definitive studies have focussed in this area yet (McMillan et al. 2011). Nonetheless, it is suggested that 75 % of woman experience vulvovaginal candidiasis at some point in their life, suggesting that Candida species are important in this body site. Candida species have been associated with pyelonephritis, cystitis and prostatitis (Kauffman et al. 2011; Sobel et al. 2011). Candida biofilms have been detected on ureteral stents and have been shown to grow in this lifestyle on experimentally on vaginal mucosa (Reid et al. 1992; Harriott et al. 2010). Urinary catheters are also a significant risk factor in intensive care units for healthcare associated fungal infections (Yang et al. 2013). Moreover, they are commonly detected on intrauterine contraceptives (Chassot et al. 2008). Whilst relatively rare, reports of an aspergilloma also occurs within the urinary tract (Lee 2010; Muller et al. 2011).
3.1 Wounds
Non-healing wounds, such as diabetic foot ulcers (Seth et al. 2012) represent a significant clinical burden to patients, and are associated with the presence of microbial biofilms. S. aureus and P. aeruginosa are often isolated together in these patients and have been shown to have a non-random association within the wound site (Fazli et al. 2009). Evidence is emerging that pathogenic fungal species may play a role in these infections (Branski et al. 2009).
Wounds acquired in combat situations especially with persistent evidence of wound necrosis often contain fungi with mould isolates found in 83 % of cases (Mucorales, n = 16; Aspergillus spp., n = 16; Fusarium spp., n = 9), commonly with multiple mould species among infected wounds (28 %). Clinical outcomes included three related deaths (8.1 %), frequent debridements and amputation revisions (58 %) (Warkentien et al. 2012).
A metagenomic approach to venous leg ulcers reveals that C. albicans, C. glabrata and Aspergillus species are present, but intriguingly the authors report that individuals seem to have unique microbial profiles (Wolcott et al. 2009). A further retrospective molecular analysis of 915 chronic wound infections, pressure ulcers, diabetic foot ulcers, non-healing surgical wounds and venous leg ulcers, showed that 208 (23 %) of these contained pathogenic fungi (Dowd et al. 2011). Yeasts were the most abundant fungi (Candida spp.), but Aureobasidium, Cladosporium, Curvularia, Engodontium, Malessezia, Trichto-phyton, and Ulocladium were also. Overall, fungal species represented over 50 % of the microbial burden in the majority of specimens examined but direct evidence that the fungi were present as biofilms is lacking.
There is a potentially interesting interaction between Staphylococcus and Candida. In the studies above there was a negative association however previous studies have shown a positive biofilm relationship between these organisms, with S. aureus using C. albicans hyphal biofilms as a scaffold through Als3p, in an analogous way to S. gordonni and C. glabrata (Silverman et al. 2010; Coco et al. 2008; Harriott and Noverr 2009). Synergistic interaction between these two organisms has been described with respect to mortality in a murine intraperitoneal model (Carlson 1982) which may be due to S. aureus upregulating lactate dehydrogenase (Peters et al. 2010).
3.2 Medical Devices
Broad-spectrum antibiotics, parenteral nutrition, immuno-suppression due to chemotherapy and radiotherapy, and disruption of mucosal barriers due to surgery, are among the most important predisposing factors for invasive fungal infection (Odds 1988). Candida species predominate and are the fourth most common cause of bloodstream infection in patients requiring intensive care and the most common etiologic agent of fungal related biofilm infection.
Indwelling medical devices, such as intravascular catheters, become colonized with Candida spp. allowing the development of adherent biofilm structures from which cells can then detach and cause an acute fungemia and/or disseminated infection. Experimental studies have reported that cells detaching from the biofilm have a greater association with cytotoxicity and mortality than equivalent planktonic yeasts (Uppuluri et al. 2010). Investigations have therefore begun to investigate whether the biofilm phenotype does play a defined clinical role. In an initial retrospective investigation using multivariate analysis to analyse the risk factors associated with patients with candidaemia it was reported that inadequate antifungal therapy (OR 2.35, P = 0.03), APACHE III scores (OR 1.03, P < 0.001) and biofilm formation (OR 2.33, P = 0.007) were independent predictors of mortality (Tumbarello et al. 2007). Analysis of mortality with biofilm forming ability demonstrated that both C. albicans (P < 0.001) and C. parapsilosis (P = 0.007) correlated with increased mortality. In a subsequent prospective case-control study by the same group it was shown that Candida bloodstream infections caused by biofilm forming isolates could be independently predicted by the presence of central venous catheters, urinary catheters, total parenteral nutrition and diabetes mellitus (Tumbarello et al. 2012). The hospital length of stay and cost of antifungal therapy were also greater in those with biofilm forming isolates, and these patients had a greater risk of hospital mortality (OR 1.77). However in these studies biofilm formation was defined by XTT and spectrophotometric transmittance, rather than a biofilm biomass and/or dry weight (Taff et al. 2012; Kuhn et al. 2003) which may bias the data towards non-albicans species, such as C. glabrata, which do not form hyphae (Kuhn et al. 2002a). In fact, it was reported in this study that C. albicans biofilm production was significantly less frequent (26.2 % n = 122) than non-albicans species (61.1 % n = 85) (p < 0.001) (Tumbarello et al. 2012), an observation also reported elsewhere (Pannanusorn et al. 2012).
One of the first documented episodes of biofilm related disease associated with C. glabrata was in terminally ill patients with intravenous catheters (Valdivieso et al. 1976). Interestingly, although the patients ultimately died, the candidaemia was treated by the removal of the catheter, a practice reported elsewhere in the same era (Berkowitz et al. 1979). Historically, biofilm associations have also been reported in patients with endocarditis (Heffner and Franklin 1978), prosthetic joints (Goodman et al. 1983), peritoneal dialysis (Cecchin et al. 1984), venous catheters (Paige et al. 1987), cannulation (Komshian et al. 1989), ventriculoperitoneal shunts (Walter et al. 1990), in addition to other indwelling devices. Not surprisingly, the presence of an indwelling catheter was a defined risk factor for the development of C. glabrata candidaemia (Fortun et al. 2012).
C. parapsilosis is another important species of Candida that has been shown to play an important clinical role in biofilm infections. Biofilm development by these organisms is similar to C. albicans, sharing the key transcriptional biofilm regulator Bcr1 (Ding et al. 2011). Indwelling catheters in the neonates patient group are an important risk factor for this organism (Pammi et al. 2013). However, prosthetic knees, hip joints and breast implants have also been implicated (Wada et al. 1998; Fox and Lee 2012; Younkin et al. 1984), in addition to a substantial literature on its role on endocarditis of bioprosthetic valves (Wallner et al. 2012; Garzoni et al. 2007). C. tropicalis has also received attention in relation to biofilm formation in vitro and in vivo, having been shown to be important in bioprosthetic heart valves and catheter related disease (Mansur et al. 1996; Negri et al. 2012).
Other yeasts and filamentous fungi biofilm related infections have also been increasingly described, including Aspergillus (Escande et al. 2011), Cryptococcus (Walsh et al. 1986), Coccidioides (Davis et al. 2002), Zygomycetes (Singh et al. 2011), Blastoschizomyces (D’Antonio et al. 2004), Malassezia (Cannizzo et al. 2007). Aspergillus species have been reported to cause serious biomaterial related biofilm infections, involving catheters, joint replacements, cardiac pace makers, heart valves, and breast augmentation implants (Escande et al. 2011; Langer et al. 2003; Rosenblatt and Pollock 1997; Jeloka et al. 2011; Golmia et al. 2011). C. neoformans has been shown to colonize and subsequently form biofilms (Ajesh and Sreejith 2012), cardiac valves (Banerjee et al. 1997), peritoneal dialysis fistulas (Braun et al. 1994), ventricular shunts (Walsh et al. 1986), and prosthetic hip joints (Johannsson and Callaghan 2009). Malassezia pachydermatis has been isolated from patients undergoing parenteral nutrition and upon catheters (Cannizzo et al. 2007; Curvale-Fauchet et al. 2004), Blastoschizomyces capitatus has been associated with catheter-related fungemia (D’Antonio et al. 2004), and recurrent meningitis has been associated with a Coccidioides immitis biofilm at the tip of a ventriculo-peritoneal shunt tubing (Davis et al. 2002). Finally, Trichosporon species can cause biofilm-related infections (Agirbasli et al. 2008; Di Bonaventura et al. 2006; Pini et al. 2005), including cardiac grafts (Krzossok et al. 2004), catheters (Ruan et al. 2009), and breast implants (Reddy et al. 2002).
Fungal biofilms are also associated with building fabrics and hospital infrastructure (Richardson 2009; Short et al. 2011; Siqueira et al. 2011; Anaissie et al. 2002).
3.3 Clinical Management
It is clear from the literature that a wide variety of fungi have the capacity to form biofilms on a range of anatomically diverse sites. Arguably the most important reason for their clinical importance is our inability to manage these infections effectively, leading to unacceptably high rates of morbidity and mortality. The following section discusses conventional and novel methods for effective clinical management of fungal biofilms.
4 Conventional Antifungal Approaches
Undoubtedly the most effective and logical way of dealing with clinically important fungal biofilms is to either inhibit their development, use mechanical force to disrupt them or simply remove and replace an implicated medical device. The European Society for Clinical Microbiology and Infectious Disease (ESCMID) have recently produced guidelines discussing the role of catheter associated infection and their clinical management (Cornely et al. 2012). The guidelines indicate that where possible the catheter should be removed. This is supported by clinical data, such as a prospective randomized trial comparing fluconazole to amphotericin B deoxycholate, where removal of a catheter within the first 24 h of candidaemia resulted in a shorter duration of candidaemia (Rex et al. 1995). Conversely, when comparing echinocandins to liposomal amphotericin B the removal of the catheter showed no improved time to mycological eradication, possibly due to the effectiveness of both antifungal agents against biofilms (Nucci et al. 2010). A recent meta-analysis from seven prospective randomized clinical trials has provided some clarity to this, reporting that removal of central venous catheter is associated with decreased mortality (OR, 0.50, 95 % Cl, 0.35–0.72, p = 0.0001) (Andes et al. 2012).
Where removal of the catheter is not possible, the use of antifungal therapy should be considered, though unlike bacterial biofilm infections, there are currently no guidelines for treating C. albicans associated biomaterial infections with chemotherapeutic agents (O’Grady et al. 2011). However, limited evidence exists for in situ use of antifungal lock therapy (ALT) in fungi. A recent review has highlighted a limited number of case studies that advocate the potential for ALT where clinically appropriate (Walraven and Lee 2013). This small analysis reported 11 studies (20 cases) where C. albicans was the most frequently treated (n = 9), followed by C. parapsilosis (n = 5), C. glabrata (n = 4), C. tropicalis (n = 1), C. guillermondii (n = 1), C. lipolytica (n = 1), Rhodoturula (n = 1) and Malassesia furfur (n = 1). Amphotericin B deoxycholate was used most frequently, and was effective in 76.9 % of cases (Arnow and Kushner 1991; Johnson et al. 1994; Krzywda et al. 1995; Benoit et al. 1995; Viale et al. 2001; Angel-Moreno et al. 2005; Wu and Lee 2007). Liposomal amphotericin B was also effective in 60 % (three of five cases) (Castagnola et al. 2005; Buckler et al. 2008). Caspofungin was used, but only once and was effective against C. lipolytica (Ozdemir et al. 2011). In one case ethanol was used as the solitary ALT solution rather than antifungals, which was shown to be effective (Blackwood et al. 2011). ALT was most commonly used for 14 days when negative blood cultures were observed. These studies collectively provide evidence to demonstrate that antifungal ALT for biofilm associated infections is worth considering, with emphasis on using either echinocandins, liposomal amphotericin B or amphotericin B lipid complexes (Cornely et al. 2012), this recommendation relates to evidence from early in vitro studies, where these compounds were shown to be highly effective against C. albicans biofilms (Bachmann et al. 2002; Kuhn et al. 2002b). More recently, a number of important studies have been conducted in vitro with various Candida species to test the potential in ALT, which have compared a range of antifungal compounds (Walraven and Lee 2013). In these models, caspofungin and micafungin has been shown to have excellent activity, though complete eradication of the biofilm was not demonstrated (Cateau et al. 2008, 2011). Time-dependant killing analysis has recently reported that liposomal formulations of amphotericin B kill significantly quicker than echinocandins (Ramage et al. 2013). Rather oddly, in an independent in vitro ALT study it was reported that azoles (itraconazole, voriconazole and fluconazole) were more effective than both caspofungin and amphotericin B (Ko et al. 2010). This study highlights how biofilm study design can negatively impact interpretation of data during in vitro studies, as it is universally accepted that azoles have little effect on mature fungal biofilms in vitro (Ramage et al. 2013), and in vivo (Andes et al. 2004; Kucharikova et al. 2010).
Animal studies have shown that C. albicans biofilms in implanted catheters respond to both caspofungin and amphotericin B formulations (Lazzell et al. 2009; Schinabeck et al. 2004; Mukherjee et al. 2009). Fluconazole (10 mg/ml) on the other hand was unable to salvage any treated catheters, whereas liposomal amphotericin B (10 mg/ml) led to a 100 % success rate (Schinabeck et al. 2004). Finally, comparison of amphotericin B deoxycholate (3.33 mg/ml) with caspofungin (6.67 mg/ml) produced a 81.3 and 100 % catheter salvage success rate, respectively (Shuford et al. 2006).
This has important implications for other fungal biofilm infections, particularly those associated with indwelling devices or on anatomically ‘hard-to-reach locations’, such as heart valves and orthopaedic joints (Falcone et al. 2009; Dutronc et al. 2010). For Candida endocarditis retrospective data suggest that combined antifungal treatment with surgery gives the best outcomes, with prosthetic valve infections having poorer outcomes than native valve infection (Falcone et al. 2009). Prognosis is poor, with 1-year mortality greater than 50 %, combined with substantial relapse rates (Ellis et al. 2001). Valve replacement should be performed as soon as possible, though if prevented liposomal amphotericin B and caspofungin can be used (Boland et al. 2011). There is however an account of successfully treating A. fumigatus prosthetic valve endocarditis with oral voriconazole (Reis et al. 2005). Less evidence is available for the treatment of infected hip joints, though it has been reported that voriconazole and amphotericin B have been used together in bone cement to treat a C. albicans infected hip (Deelstra et al. 2013). Amphotericin B and fluconazole have also been used to treat a C. neoformans infection of a prosthetic hip joint, but this was unsuccessful due to poor penetration through the biofilm (Johannsson and Callaghan 2009). There are suggestions however that fluconazole may have a role in the treatment of candidal prosthetic joint infection (Kelesidis and Tsiodras 2010).
Wound fungal biofilms are managed with surgical debridement (Warkentien et al. 2012). In severe wounds, such as those occurring from combat trauma, liposomal amphotericin B, voriconazole and posaconazole have been used, often as combinational therapy, although the clinical outcomes were variable. Nevertheless, it has been reported that in the management of a case of fungal osteomyelitis combined use of voriconazole and terbinafine along with surgical debridement was able to successfully control a Scedosporium inflatum infection and salvage the limb (Cetrulo et al. 2012).
These studies suggest that wound fungal biofilms may have a different structural composition, as they respond to azoles more effectively than other fungal biofilms. Many of these infections are polymicrobial, and undergo repeated debridement with topical antiseptics. Moreover, wound dressings containing antimicrobial molecules are used, so it is not surprising that fungal wound biofilms respond to azole therapy in this context.
5 Concluding Remarks
From review of the available literature it is evident that fungal biofilms do play a significant role in clinical medicine. Over 20 different genera of fungi have been implicated in some way of another in clinical biofilm infections, most notably the Candida genera. Fungi have been demonstrated to form biofilms on both hard and soft tissue, and upon implanted medical devices. Diagnosing the presence of a fungal biofilm is difficult, with reliance on clinical skill and judgement, along with some key mycological considerations. Removal and replacement of medical devices, or surgical debridement of soft tissue, where appropriate, represents the first line in clinical management, followed by antifungal management. Treatment outcomes vary to conventional antifungal agents, which are largely dictated on by the accessibility of the infection site. Liposomal formulations of amphotericin B and echinocandin antifungal agents show the greatest efficacy against fungal biofilms, whereas azoles are highly ineffective against mature biofilms. Developing methods to augment antifungal activity have been demonstrated experimentally, such as matrix degrading molecules, natural products and microbially derived molecules. Moreover, our knowledge of the how adaptive resistance within the biofilm has revealed therapeutic targets, potentially through the pharmacological depletion of specific molecules involved in these processes. Collectively, these approaches provide a viable platform to successfully manage fungal biofilms of clinical importance. However further consideration needs to be given to how interactions between prokaryote and eukaryote in polymicrobial biofilm infections impact clinical management.
References
Agirbasli H, Bilgen H, Ozcan SK, Otlu B, Sinik G et al (2008) Two possible cases of Trichosporon infections in bone-marrow-transplanted children: the first case of T. japonicum isolated from clinical specimens. Jpn J Infect Dis 61:130–132
Ajesh K, Sreejith K (2012) Cryptococcus laurentii biofilms: structure, development and antifungal drug resistance. Mycopathologia 174:409–419
Amin R, Dupuis A, Aaron SD, Ratjen F (2010) The effect of chronic infection with Aspergillus fumigatus on lung function and hospitalization in patients with cystic fibrosis. Chest 137:171–176
Anaissie EJ, Stratton SL, Dignani MC, Lee CK, Mahfouz TH et al (2002) Cleaning patient shower facilities: a novel approach to reducing patient exposure to aerosolized Aspergillus species and other opportunistic molds. Clin Infect Dis 35:E86–E88
Andes D, Nett J, Oschel P, Albrecht R, Marchillo K et al (2004) Development and characterization of an in vivo central venous catheter Candida albicans biofilm model. Infect Immun 72:6023–6031
Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC et al (2012) Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis 54:1110–1122
Angel-Moreno A, Boronat M, Bolanos M, Carrillo A, Gonzalez S et al (2005) Candida glabrata fungemia cured by antibiotic-lock therapy: case report and short review. J Infect 51:e85–e87
Ariani N, Vissink A, van Oort RP, Kusdhany L, Djais A et al (2012) Microbial biofilms on facial prostheses. Biofouling 28:583–591
Arnow PM, Kushner R (1991) Malassezia furfur catheter infection cured with antibiotic lock therapy. Am J Med 90:128–130
Arslan SG, Akpolat N, Kama JD, Ozer T, Hamamci O (2008) One-year follow-up of the effect of fixed orthodontic treatment on colonization by oral Candida. J Oral Pathol Med 37:26–29
Bachmann SP, VandeWalle K, Ramage G, Patterson TF, Wickes BL et al (2002) In vitro activity of caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 46:3591–3596
Bakaletz LO (2007) Bacterial biofilms in otitis media: evidence and relevance. Pediatr Infect Dis J 26:S17–S19
Bamford CV, d’Mello A, Nobbs AH, Dutton LC, Vickerman MM et al (2009) Streptococcus gordonii modulates Candida albicans biofilm formation through intergeneric communication. Infect Immun 77:3696–3704
Bandara HM, Yau JY, Watt RM, Jin LJ, Samaranayake LP (2009) Escherichia coli and its lipopolysaccharide modulate in vitro Candida biofilm formation. J Med Microbiol 58:1623–1631
Banerjee U, Gupta K, Venugopal P (1997) A case of prosthetic valve endocarditis caused by Cryptococcus neoformans var. neoformans. J Med Vet Mycol 35:139–141
Bauters TG, Moerman M, Pini G, Vermeersch H, Nelis HJ (2001) Colonization of a voice prosthesis by Cryptococcus neoformans. Med Mycol 39:379–381
Beikler T, Flemmig TF (2011) Oral biofilm-associated diseases: trends and implications for quality of life, systemic health and expenditures. Periodontol 2000 55:87–103
Benoit JL, Carandang G, Sitrin M, Arnow PM (1995) Intraluminal antibiotic treatment of central venous catheter infections in patients receiving parenteral nutrition at home. Clin Infect Dis 21:1286–1288
Berkowitz ID, Robboy SJ, Karchmer AW, Kunz LJ (1979) Torulopsis glabrata fungemia – a clinical pathological study. Medicine (Baltimore) 58:430–440
Blackwood RA, Klein KC, Micel LN, Willers ML, Mody RJ et al (2011) Ethanol locks therapy for resolution of fungal catheter infections. Pediatr Infect Dis J 30:1105–1107
Blyth CC, Middleton PG, Harun A, Sorrell TC, Meyer W et al (2010) Clinical associations and prevalence of Scedosporium spp. in Australian cystic fibrosis patients: identification of novel risk factors? Med Mycol 48(Suppl 1):S37–S44
Boase S, Valentine R, Singhal D, Tan LW, Wormald PJ (2011) A sheep model to investigate the role of fungal biofilms in sinusitis: fungal and bacterial synergy. Int Forum Allergy Rhinol 1:340–347
Boland JM, Chung HH, Robberts FJ, Wilson WR, Steckelberg JM et al (2011) Fungal prosthetic valve endocarditis: Mayo Clinic experience with a clinicopathological analysis. Mycoses 54:354–360
Bonhomme J, Chauvel M, Goyard S, Roux P, Rossignol T et al (2011) Contribution of the glycolytic flux and hypoxia adaptation to efficient biofilm formation by Candida albicans. Mol Microbiol 80:995–1013
Branski LK, Al-Mousawi A, Rivero H, Jeschke MG, Sanford AP et al (2009) Emerging infections in burns. Surg Infect (Larchmt) 10:389–397
Braun DK, Janssen DA, Marcus JR, Kauffman CA (1994) Cryptococcal infection of a prosthetic dialysis fistula. Am J Kidney Dis 24:864–867
Buckler BS, Sams RN, Goei VL, Krishnan KR, Bemis MJ et al (2008) Treatment of central venous catheter fungal infection using liposomal amphotericin-B lock therapy. Pediatr Infect Dis J 27:762–764
Buijssen KJ, van der Laan BF, van der Mei HC, Atema-Smit J, van den Huijssen P et al (2012) Composition and architecture of biofilms on used voice prostheses. Head Neck 34:863–871
Canabarro A, Valle C, Farias MR, Santos FB, Lazera M et al (2012) Association of subgingival colonization of Candida albicans and other yeasts with severity of chronic periodontitis. J Periodontal Res 48:428–432
Cannizzo FT, Eraso E, Ezkurra PA, Villar-Vidal M, Bollo E et al (2007) Biofilm development by clinical isolates of Malassezia pachydermatis. Med Mycol 45:357–361
Carlson E (1982) Synergistic effect of Candida albicans and Staphylococcus aureus on mouse mortality. Infect Immun 38:921–924
Caserta RA, Marra AR, Durao MS, Silva CV, Pavao Dos Santos OF et al (2012) A program for sustained improvement in preventing ventilator associated pneumonia in an intensive care setting. BMC Infect Dis 12:234
Castagnola E, Marazzi MG, Tacchella A, Giacchino R (2005) Broviac catheter-related candidemia. Pediatr Infect Dis J 24:747
Cateau E, Rodier MH, Imbert C (2008) In vitro efficacies of caspofungin or micafungin catheter lock solutions on Candida albicans biofilm growth. J Antimicrob Chemother 62:153–155
Cateau E, Berjeaud JM, Imbert C (2011) Possible role of azole and echinocandin lock solutions in the control of Candida biofilms associated with silicone. Int J Antimicrob Agents 37:380–384
Cecchin E, De Marchi S, Panarello G, Franceschin A, Chiaradia V et al (1984) Torulopsis glabrata peritonitis complicating continuous ambulatory peritoneal dialysis: successful management with oral 5-fluorocytosine. Am J Kidney Dis 4:280–284
Cetrulo CL Jr, Leto Barone AA, Jordan K, Chang DS, Louie K et al (2012) A multi-disciplinary approach to the management of fungal osteomyelitis: current concepts in post-traumatic lower extremity reconstruction: a case report. Microsurgery 32:144–147
Chassot F, Negri MF, Svidzinski AE, Donatti L, Peralta RM et al (2008) Can intrauterine contraceptive devices be a Candida albicans reservoir? Contraception 77:355–359
Chotirmall SH, O’Donoghue E, Bennett K, Gunaratnam C, O’Neill SJ et al (2010) Sputum Candida albicans presages FEV decline and hospital-treated exacerbations in cystic fibrosis. Chest 138:1186–1195
Chowdhary A, Randhawa HS, Gaur SN, Agarwal K, Kathuria S et al (2013) Schizophyllum commune as an emerging fungal pathogen: a review and report of two cases. Mycoses 56:1–10
Cimon B, Carrere J, Vinatier JF, Chazalette JP, Chabasse D et al (2000) Clinical significance of Scedosporium apiospermum in patients with cystic fibrosis. Eur J Clin Microbiol Infect Dis 19:53–56
Coco BJ, Bagg J, Cross LJ, Jose A, Cross J et al (2008) Mixed Candida albicans and Candida glabrata populations associated with the pathogenesis of denture stomatitis. Oral Microbiol Immunol 23:377–383
Cornely OA, Bassetti M, Calandra T, Garbino J, Kullberg BJ et al (2012) ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect 18(Suppl 7):19–37
Coulthwaite L, Verran J (2007) Potential pathogenic aspects of denture plaque. Br J Biomed Sci 64:180–189
Cugini C, Calfee MW, Farrow JM 3rd, Morales DK, Pesci EC et al (2007) Farnesol, a common sesquiterpene, inhibits PQS production in Pseudomonas aeruginosa. Mol Microbiol 65:896–906
Curvale-Fauchet N, Botterel F, Legrand P, Guillot J, Bretagne S (2004) Frequency of intravascular catheter colonization by Malassezia spp. in adult patients. Mycoses 47:491–494
D’Antonio D, Parruti G, Pontieri E, Di Bonaventura G, Manzoli L et al (2004) Slime production by clinical isolates of Blastoschizomyces capitatus from patients with hematological malignancies and catheter-related fungemia. Eur J Clin Microbiol Infect Dis 23:787–789
Damman CJ, Miller SI, Surawicz CM, Zisman TL (2012) The microbiome and inflammatory bowel disease: is there a therapeutic role for fecal microbiota transplantation? Am J Gastroenterol 107:1452–1459
Davis LE, Cook G, Costerton JW (2002) Biofilm on ventriculo-peritoneal shunt tubing as a cause of treatment failure in coccidioidal meningitis. Emerg Infect Dis 8:376–379
de Carvalho FG, Silva DS, Hebling J, Spolidorio LC, Spolidorio DM (2006) Presence of mutans streptococci and Candida spp. in dental plaque/dentine of carious teeth and early childhood caries. Arch Oral Biol 51:1024–1028
Deelstra JJ, Neut D, Jutte PC (2013) Successful treatment of Candida albicans-infected total hip prosthesis with staged procedure using an antifungal-loaded cement spacer. J Arthroplasty 28(374):e375–e378
Delhaes L, Monchy S, Frealle E, Hubans C, Salleron J et al (2012) The airway microbiota in cystic fibrosis: a complex fungal and bacterial community – implications for therapeutic management. PLoS One 7:e36313
Delisle MS, Williamson DR, Albert M, Perreault MM, Jiang X et al (2011) Impact of Candida species on clinical outcomes in patients with suspected ventilator-associated pneumonia. Can Respir J 18:131–136
Denning DW (1998) Invasive aspergillosis. Clin Infect Dis 26:781–803, quiz 804–785
Di Bonaventura G, Pompilio A, Picciani C, Iezzi M, D’Antonio D et al (2006) Biofilm formation by the emerging fungal pathogen Trichosporon asahii: development, architecture, and antifungal resistance. Antimicrob Agents Chemother 50:3269–3276
Ding C, Vidanes GM, Maguire SL, Guida A, Synnott JM et al (2011) Conserved and divergent roles of Bcr1 and CFEM proteins in Candida parapsilosis and Candida albicans. PLoS One 6:e28151
Dongari-Bagtzoglou A, Kashleva H, Dwivedi P, Diaz P, Vasilakos J (2009) Characterization of mucosal Candida albicans biofilms. PLoS One 4:e7967
Donlan RM, Costerton JW (2002) Biofilms: survival mechanisms of clinically relevant microorganisms. Clin Microbiol Rev 15:167–193
Dowd SE, Delton Hanson J, Rees E, Wolcott RD, Zischau AM et al (2011) Survey of fungi and yeast in polymicrobial infections in chronic wounds. J Wound Care 20:40–47
Dutronc H, Dauchy FA, Cazanave C, Rougie C, Lafarie-Castet S et al (2010) Candida prosthetic infections: case series and literature review. Scand J Infect Dis 42:890–895
Ebbens FA, Georgalas C, Fokkens WJ (2009a) Fungus as the cause of chronic rhinosinusitis: the case remains unproven. Curr Opin Otolaryngol Head Neck Surg 17:43–49
Ebbens FA, Georgalas C, Fokkens WJ (2009b) The mold conundrum in chronic hyperplastic sinusitis. Curr Allergy Asthma Rep 9:114–120
Ell SR (1996) Candida ‘the cancer of silastic’. J Laryngol Otol 110:240–242
Ellis ME, Al-Abdely H, Sandridge A, Greer W, Ventura W (2001) Fungal endocarditis: evidence in the world literature, 1965–1995. Clin Infect Dis 32:50–62
Elving GJ, van Der Mei HC, Busscher HJ, van Weissenbruch R, Albers FW (2001) Air-flow resistances of silicone rubber voice prostheses after formation of bacterial and fungal biofilms. J Biomed Mater Res 58:421–426
Escande W, Fayad G, Modine T, Verbrugge E, Koussa M et al (2011) Culture of a prosthetic valve excised for streptococcal endocarditis positive for Aspergillus fumigatus 20 years after previous a fumigatus endocarditis. Ann Thorac Surg 91:e92–e93
Falcone M, Barzaghi N, Carosi G, Grossi P, Minoli L et al (2009) Candida infective endocarditis: report of 15 cases from a prospective multicenter study. Medicine (Baltimore) 88:160–168
Fanning S, Mitchell AP (2012) Fungal biofilms. PLoS Pathog 8:e1002585
Fanning S, Xu W, Solis N, Woolford CA, Filler SG et al (2012) Divergent targets of Candida albicans biofilm regulator Bcr1 in vitro and in vivo. Eukaryot Cell 11:896–904
Fazli M, Bjarnsholt T, Kirketerp-Moller K, Jorgensen B, Andersen AS et al (2009) Nonrandom distribution of Pseudomonas aeruginosa and Staphylococcus aureus in chronic wounds. J Clin Microbiol 47:4084–4089
Finkel JS, Mitchell AP (2011) Genetic control of Candida albicans biofilm development. Nat Rev Microbiol 9:109–118
Foreman A, Jervis-Bardy J, Wormald PJ (2011) Do biofilms contribute to the initiation and recalcitrance of chronic rhinosinusitis? Laryngoscope 121:1085–1091
Fortun J, Martin-Davila P, Gomez-Garcia de la Pedrosa E, Pintado V, Cobo J et al (2012) Emerging trends in candidemia: a higher incidence but a similar outcome. J Infect 65:64–70
Fox PM, Lee GK (2012) Tissue expander with acellular dermal matrix for breast reconstruction infected by an unusual pathogen: Candida parapsilosis. J Plast Reconstr Aesthet Surg 65:e286–e289
Gajer P, Brotman RM, Bai G, Sakamoto J, Schutte UM et al (2012) Temporal dynamics of the human vaginal microbiota. Sci Transl Med 4:132ra152
Gangell C, Gard S, Douglas T, Park J, de Klerk N et al (2011) Inflammatory responses to individual microorganisms in the lungs of children with cystic fibrosis. Clin Infect Dis 53:425–432
Garzoni C, Nobre VA, Garbino J (2007) Candida parapsilosis endocarditis: a comparative review of the literature. Eur J Clin Microbiol Infect Dis 26:915–926
Ghannoum MA, Jurevic RJ, Mukherjee PK, Cui F, Sikaroodi M et al (2010) Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog 6:e1000713
Gibson J, Sood A, Hogan DA (2009) Pseudomonas aeruginosa-Candida albicans interactions: localization and fungal toxicity of a phenazine derivative. Appl Environ Microbiol 75:504–513
Golmia R, Bello I, Marra A, Hamerschlak N, Osawa A et al (2011) Aspergillus fumigatus joint infection: a review. Semin Arthritis Rheum 40:580–584
Goodman JS, Seibert DG, Reahl GE Jr, Geckler RW (1983) Fungal infection of prosthetic joints: a report of two cases. J Rheumatol 10:494–495
Gottlieb K, Leya J, Kruss DM, Mobarhan S, Iber FL (1993) Intraluminal fungal colonization of gastrostomy tubes. Gastrointest Endosc 39:413–415
Grosjean P, Weber R (2007) Fungus balls of the paranasal sinuses: a review. Eur Arch Otorhinolaryngol 264:461–470
Gutierrez-Correa M, Ludena Y, Ramage G, Villena GK (2012) Recent advances on filamentous fungal biofilms for industrial uses. Appl Biochem Biotechnol 167:1235–1253
Hamet M, Pavon A, Dalle F, Pechinot A, Prin S et al (2012) Candida spp. airway colonization could promote antibiotic-resistant bacteria selection in patients with suspected ventilator-associated pneumonia. Intensive Care Med 38:1272–1279
Harding MW, Marques LL, Howard RJ, Olson ME (2009) Can filamentous fungi form biofilms? Trends Microbiol 17:475–480
Harriott MM, Noverr MC (2009) Candida albicans and Staphylococcus aureus form polymicrobial biofilms: effects on antimicrobial resistance. Antimicrob Agents Chemother 53:3914–3922
Harriott MM, Lilly EA, Rodriguez TE, Fidel PL Jr, Noverr MC (2010) Candida albicans forms biofilms on the vaginal mucosa. Microbiology 156:3635–3644
Heffner DK, Franklin WA (1978) Endocarditis caused by Torulopsis glabrata. Am J Clin Pathol 70:420–423
Hogan DA, Kolter R (2002) Pseudomonas-Candida interactions: an ecological role for virulence factors. Science 296:2229–2232
Hogan DA, Vik A, Kolter R (2004) A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol Microbiol 54:1212–1223
Holmes AR, van der Wielen P, Cannon RD, Ruske D, Dawes P (2006) Candida albicans binds to saliva proteins selectively adsorbed to silicone. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102:488–494
Honraet K, De Vos MM, Summerbell RC, van Kempen I, De Saeger S et al (2005) Recurrent colonization of successively implanted tracheoesophageal vocal prostheses by a member of the Fusarium solani species complex. J Clin Microbiol 43:770–777
Jakubovics NS (2010) Talk of the town: interspecies communication in oral biofilms. Mol Oral Microbiol 25:4–14
Janagond A, Krishnan KM, Kindo AJ, Sumathi G (2012) Trichosporon inkin, an unusual agent of fungal sinusitis: a report from south India. Indian J Med Microbiol 30:229–232
Jayshree RS, Shafiulla M, George J, David JK, Bapsy PP et al (2006) Microscopic, cultural and molecular evidence of disseminated invasive aspergillosis involving the lungs and the gastrointestinal tract. J Med Microbiol 55:961–964
Jeloka TK, Shrividya S, Wagholikar G (2011) Catheter outflow obstruction due to an aspergilloma. Perit Dial Int 31:211–212
Johannsson B, Callaghan JJ (2009) Prosthetic hip infection due to Cryptococcus neoformans: case report. Diagn Microbiol Infect Dis 64:76–79
Johnson DC, Johnson FL, Goldman S (1994) Preliminary results treating persistent central venous catheter infections with the antibiotic lock technique in pediatric patients. Pediatr Infect Dis J 13:930–931
Kania RE, Lamers GE, van de Laar N, Dijkhuizen M, Lagendijk E et al (2010) Biofilms on tracheoesophageal voice prostheses: a confocal laser scanning microscopy demonstration of mixed bacterial and yeast biofilms. Biofouling 26:519–526
Karkas A, Rtail R, Reyt E, Timi N, Righini CA (2012) Sphenoid sinus fungus ball. Eur Arch Otorhinolaryngol 270:893–898
Kauffman CA, Fisher JF, Sobel JD, Newman CA (2011) Candida urinary tract infections – diagnosis. Clin Infect Dis 52(Suppl 6):S452–S456
Keir J, Pedelty L, Swift AC (2011) Biofilms in chronic rhinosinusitis: systematic review and suggestions for future research. J Laryngol Otol 125:331–337
Kelesidis T, Tsiodras S (2010) Candida albicans prosthetic hip infection in elderly patients: is fluconazole monotherapy an option? Scand J Infect Dis 42:12–21
Klaerner HG, Uknis ME, Acton RD, Dahlberg PS, Carlone-Jambor C et al (1997) Candida albicans and Escherichia coli are synergistic pathogens during experimental microbial peritonitis. J Surg Res 70:161–165
Ko KS, Lee JY, Song JH, Peck KR (2010) In vitro evaluation of antibiotic lock technique for the treatment of Candida albicans, C. glabrata, and C. tropicalis biofilms. J Korean Med Sci 25:1722–1726
Komshian SV, Uwaydah AK, Sobel JD, Crane LR (1989) Fungemia caused by Candida species and Torulopsis glabrata in the hospitalized patient: frequency, characteristics, and evaluation of factors influencing outcome. Rev Infect Dis 11:379–390
Kondori N, Gilljam M, Lindblad A, Jonsson B, Moore ER et al (2011) High rate of Exophiala dermatitidis recovery in the airways of patients with cystic fibrosis is associated with pancreatic insufficiency. J Clin Microbiol 49:1004–1009
Krzossok S, Birck R, Henke S, Hof H, van der Woude FJ et al (2004) Trichosporon asahii infection of a dialysis PTFE arteriovenous graft. Clin Nephrol 62:66–68
Krzywda EA, Andris DA, Edmiston CE Jr, Quebbeman EJ (1995) Treatment of Hickman catheter sepsis using antibiotic lock technique. Infect Control Hosp Epidemiol 16:596–598
Kucharikova S, Tournu H, Holtappels M, Van Dijck P, Lagrou K (2010) In vivo efficacy of anidulafungin against mature Candida albicans biofilms in a novel rat model of catheter-associated Candidiasis. Antimicrob Agents Chemother 54:4474–4475
Kuhn DM, Chandra J, Mukherjee PK, Ghannoum MA (2002a) Comparison of biofilms formed by Candida albicans and Candida parapsilosis on bioprosthetic surfaces. Infect Immun 70:878–888
Kuhn DM, George T, Chandra J, Mukherjee PK, Ghannoum MA (2002b) Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother 46:1773–1780
Kuhn DM, Balkis M, Chandra J, Mukherjee PK, Ghannoum MA (2003) Uses and limitations of the XTT assay in studies of Candida growth and metabolism. J Clin Microbiol 41:506–508
Kumamoto CA (2011) Inflammation and gastrointestinal Candida colonization. Curr Opin Microbiol 14:386–391
Langer P, Kassim RA, Macari GS, Saleh KJ (2003) Aspergillus infection after total knee arthroplasty. Am J Orthop 32:402–404
Lazzell AL, Chaturvedi AK, Pierce CG, Prasad D, Uppuluri P et al (2009) Treatment and prevention of Candida albicans biofilms with caspofungin in a novel central venous catheter murine model of candidiasis. J Antimicrob Chemother 64:567–570
Leclair LW, Hogan DA (2010) Mixed bacterial-fungal infections in the CF respiratory tract. Med Mycol 48(Suppl 1):S125–S132
Lee SW (2010) An Aspergilloma mistaken for a pelviureteral stone on nonenhanced CT: a fungal bezoar causing ureteral obstruction. Korean J Urol 51:216–218
Lermann U, Morschhauser J (2008) Secreted aspartic proteases are not required for invasion of reconstituted human epithelia by Candida albicans. Microbiology 154:3281–3295
Li F, Svarovsky MJ, Karlsson AJ, Wagner JP, Marchillo K et al (2007) Eap1p, an adhesin that mediates Candida albicans biofilm formation in vitro and in vivo. Eukaryot Cell 6:931–939
Ma B, Forney LJ, Ravel J (2012) Vaginal microbiome: rethinking health and disease. Annu Rev Microbiol 66:371–389
Macfarlane S (2008) Microbial biofilm communities in the gastrointestinal tract. J Clin Gastroenterol 42(Suppl 3 Pt 1):S142–S143
Macfarlane S, Dillon JF (2007) Microbial biofilms in the human gastrointestinal tract. J Appl Microbiol 102:1187–1196
Mansur AJ, Safi J Jr, Markus MR, Aiello VD, Grinberg M et al (1996) Late failure of surgical treatment for bioprosthetic valve endocarditis due to Candida tropicalis. Clin Infect Dis 22:380–381
Martin TJ, Kerschner JE, Flanary VA (2005) Fungal causes of otitis externa and tympanostomy tube otorrhea. Int J Pediatr Otorhinolaryngol 69:1503–1508
Mason KL, Erb Downward JR, Mason KD, Falkowski NR, Eaton KA et al (2012) Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect Immun 80:3371–3380
McMillan A, Dell M, Zellar MP, Cribby S, Martz S et al (2011) Disruption of urogenital biofilms by lactobacilli. Colloids Surf B Biointerfaces 86:58–64
Mignogna MD, Fortuna G, Leuci S, Adamo D, Ruoppo E et al (2011) Mucormycosis in immunocompetent patients: a case-series of patients with maxillary sinus involvement and a critical review of the literature. Int J Infect Dis 15:e533–e540
Morales DK, Jacobs NJ, Rajamani S, Krishnamurthy M, Cubillos-Ruiz JR et al (2010) Antifungal mechanisms by which a novel Pseudomonas aeruginosa phenazine toxin kills Candida albicans in biofilms. Mol Microbiol 78:1379–1392
Mowat E, Lang S, Williams C, McCulloch E, Jones B et al (2008) Phase-dependent antifungal activity against Aspergillus fumigatus developing multicellular filamentous biofilms. J Antimicrob Chemother 62:1281–1284
Mowat E, Williams C, Jones B, McChlery S, Ramage G (2009) The characteristics of Aspergillus fumigatus mycetoma development: is this a biofilm? Med Mycol 47(Suppl 1):S120–6
Mowat E, Rajendran R, Williams C, McCulloch E, Jones B et al (2010) Pseudomonas aeruginosa and their small diffusible extracellular molecules inhibit Aspergillus fumigatus biofilm formation. FEMS Microbiol Lett 313:96–102
Mukherjee PK, Long L, Kim HG, Ghannoum MA (2009) Amphotericin B lipid complex is efficacious in the treatment of Candida albicans biofilms using a model of catheter-associated Candida biofilms. Int J Antimicrob Agents 33:149–153
Muller FM, Seidler M, Beauvais A (2011) Aspergillus fumigatus biofilms in the clinical setting. Med Mycol 49(Suppl 1):S96–S100
Naglik JR, Challacombe SJ, Hube B (2003) Candida albicans secreted aspartyl proteinases in virulence and pathogenesis. Microbiol Mol Biol Rev 67:400–428, Table of contents
Naglik J, Albrecht A, Bader O, Hube B (2004) Candida albicans proteinases and host/pathogen interactions. Cell Microbiol 6:915–926
Naglik JR, Fostira F, Ruprai J, Staab JF, Challacombe SJ et al (2006) Candida albicans HWP1 gene expression and host antibody responses in colonization and disease. J Med Microbiol 55:1323–1327
Naglik JR, Moyes D, Makwana J, Kanzaria P, Tsichlaki E et al (2008) Quantitative expression of the Candida albicans secreted aspartyl proteinase gene family in human oral and vaginal candidiasis. Microbiology 154:3266–3280
Negri M, Silva S, Henriques M, Oliveira R (2012) Insights into Candida tropicalis nosocomial infections and virulence factors. Eur J Clin Microbiol Infect Dis 31:1399–1412
Nett JE, Sanchez H, Cain MT, Andes DR (2010a) Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J Infect Dis 202:171–175
Nett JE, Marchillo K, Spiegel CA, Andes DR (2010b) Development and validation of an in vivo Candida albicans biofilm denture model. Infect Immun 78:3650–3659
Newton A (1962) Denture sore mouth. A possible aetiology. Br Dent J 112:357–360
Nobile CJ, Mitchell AP (2006) Genetics and genomics of Candida albicans biofilm formation. Cell Microbiol 8:1382–1391
Nucci M, Anaissie E, Betts RF, Dupont BF, Wu C et al (2010) Early removal of central venous catheter in patients with candidemia does not improve outcome: analysis of 842 patients from 2 randomized clinical trials. Clin Infect Dis 51:295–303
O’Grady NP, Alexander M, Burns LA, Dellinger EP, Garland J et al (2011) Guidelines for the prevention of intravascular catheter-related infections. Clin Infect Dis 52:e162–e193
Odds F (1988) Candida and candidosis. Bailliere Tindall, London
Ozdemir H, Karbuz A, Ciftci E, Dincaslan HU, Ince E et al (2011) Successful treatment of central venous catheter infection due to Candida lipolytica by caspofungin-lock therapy. Mycoses 54:e647–e649
Paige C, Pinson CW, Antonovic R, Strausbaugh LJ (1987) Catheter-related thrombophlebitis of the superior vena cava caused by Candida glabrata. West J Med 147:333–335
Pammi M, Holland L, Butler G, Gacser A, Bliss JM (2013) Candida parapsilosis is a significant neonatal pathogen: a systematic review and meta-analysis. Pediatr Infect Dis J 32:e206–e216
Pannanusorn S, Fernandez V, Romling U (2012) Prevalence of biofilm formation in clinical isolates of Candida species causing bloodstream infection. Mycoses 56:264–272
Pereira-Cenci T, Del Bel Cury AA, Crielaard W, Ten Cate JM (2008) Development of Candida-associated denture stomatitis: new insights. J Appl Oral Sci 16:86–94
Peters BM, Jabra-Rizk MA, Scheper MA, Leid JG, Costerton JW et al (2010) Microbial interactions and differential protein expression in Staphylococcus aureus -Candida albicans dual-species biofilms. FEMS Immunol Med Microbiol 59:493–503
Peters BM, Jabra-Rizk MA, O’May GA, Costerton JW, Shirtliff ME (2012) Polymicrobial interactions: impact on pathogenesis and human disease. Clin Microbiol Rev 25:193–213
Pini G, Faggi E, Donato R, Fanci R (2005) Isolation of Trichosporon in a hematology ward. Mycoses 48:45–49
Puri S, Kumar R, Chadha S, Tati S, Conti HR et al (2012) Secreted aspartic protease cleavage of Candida albicans Msb2 activates Cek1 MAPK signaling affecting biofilm formation and oropharyngeal candidiasis. PLoS One 7:e46020
Rajendran R, Robertson DP, Hodge PJ, Lappin DF, Ramage G (2010) Hydrolytic enzyme production is associated with Candida albicans biofilm formation from patients with type 1 diabetes. Mycopathologia 170:229–235
Ramage G, VandeWalle K, Lopez-Ribot JL, Wickes BL (2002) The filamentation pathway controlled by the Efg1 regulator protein is required for normal biofilm formation and development in Candida albicans. FEMS Microbiol Lett 214:95–100
Ramage G, Tomsett K, Wickes BL, Lopez-Ribot JL, Redding SW (2004) Denture stomatitis: a role for Candida biofilms. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 98:53–59
Ramage G, Mowat E, Jones B, Williams C, Lopez-Ribot J (2009) Our current understanding of fungal biofilms. Crit Rev Microbiol 35:340–355
Ramage G, Rajendran R, Gutierrez-Correa M, Jones B, Williams C (2011) Aspergillus biofilms: clinical and industrial significance. FEMS Microbiol Lett 324:89–97
Ramage G, Coco B, Sherry L, Bagg J, Lappin DF (2012) In vitro Candida albicans biofilm induced proteinase activity and SAP8 expression correlates with in vivo denture stomatitis severity. Mycopathologia 174:11–19
Ramage G, Jose A, Sherry L, Lappin DF, Jones B et al (2013) Liposomal formulations of amphotericin B displays rapid dose dependant activity against Candida albicans biofilms. Antimicrob Agents Chemother 57:2369–2371
Rautemaa R, Ramage G (2011) Oral candidosis–clinical challenges of a biofilm disease. Crit Rev Microbiol 37:328–336
Reddy BT, Torres HA, Kontoyiannis DP (2002) Breast implant infection caused by Trichosporon beigelii. Scand J Infect Dis 34:143–144
Reid G, Denstedt JD, Kang YS, Lam D, Nause C (1992) Microbial adhesion and biofilm formation on ureteral stents in vitro and in vivo. J Urol 148:1592–1594
Reis LJ, Barton TD, Pochettino A, Velazquez O, McGarvey M et al (2005) Successful treatment of Aspergillus prosthetic valve endocarditis with oral voriconazole. Clin Infect Dis 41:752–753
Rex JH, Bennett JE, Sugar AM, Pappas PG, Serody J et al (1995) Intravascular catheter exchange and duration of candidemia. NIAID Mycoses Study Group and the Candidemia Study Group. Clin Infect Dis 21:994–996
Richardson M (2009) The ecology of the zygomycetes and its impact on environmental exposure. Clin Microbiol Infect 15(Suppl 5):2–9
Rombaux P, Eloy P, Bertrand B, Delos M, Doyen C (1996) Lethal disseminated Fusarium infection with sinus involvement in the immunocompromised host: case report and review of the literature. Rhinology 34:237–241
Rosenblatt WB, Pollock A (1997) Aspergillus flavus cultured from a saline-filled implant. Plast Reconstr Surg 99:1470–1472
Ruan SY, Chien JY, Hsueh PR (2009) Invasive trichosporonosis caused by Trichosporon asahii and other unusual Trichosporon species at a medical center in Taiwan. Clin Infect Dis 49:e11–e17
Sa HS, Ko KS, Woo KI, Peck KR, Kim YD (2012) A case of sino-orbital infection caused by the Schizophyllum commune. Diagn Microbiol Infect Dis 73:376–377
Sardi JC, Duque C, Mariano FS, Peixoto IT, Hofling JF et al (2010) Candida spp. in periodontal disease: a brief review. J Oral Sci 52:177–185
Sato FR, Sawazaki R, Berretta D, Moreira RW, Vargas PA et al (2010) Aspergillosis of the maxillary sinus associated with a zygomatic implant. J Am Dent Assoc 141:1231–1235
Sayed SI, Datta S, Deore N, Kazi RA, Jagade MV (2012) Prevention of voice prosthesis biofilms: current scenario and future trends in prolonging prosthesis lifetime. J Indian Med Assoc 110:175–178, 180
Schinabeck MK, Long LA, Hossain MA, Chandra J, Mukherjee PK et al (2004) Rabbit model of Candida albicans biofilm infection: liposomal amphotericin B antifungal lock therapy. Antimicrob Agents Chemother 48:1727–1732
Seidler MJ, Salvenmoser S, Muller FM (2008) Aspergillus fumigatus forms biofilms with reduced antifungal drug susceptibility on bronchial epithelial cells. Antimicrob Agents Chemother 52:4130–4136
Serban RI, Dan M, Panzaru CV, Anghel D, Dascalescu D et al (2010) Fungi as emergent etiologic agents in ventilator-associated pneumonia after cardiac surgery. Rev Med Chir Soc Med Nat Iasi 114:1077–1082
Seth AK, Geringer MR, Hong SJ, Leung KP, Mustoe TA et al (2012) In vivo modeling of biofilm-infected wounds: a review. J Surg Res 178:330–338
Short DP, O’Donnell K, Zhang N, Juba JH, Geiser DM (2011) Widespread occurrence of diverse human pathogenic types of the fungus Fusarium detected in plumbing drains. J Clin Microbiol 49:4264–4272
Shuford JA, Rouse MS, Piper KE, Steckelberg JM, Patel R (2006) Evaluation of caspofungin and amphotericin B deoxycholate against Candida albicans biofilms in an experimental intravascular catheter infection model. J Infect Dis 194:710–713
Sibley CD, Duan K, Fischer C, Parkins MD, Storey DG et al (2008a) Discerning the complexity of community interactions using a Drosophila model of polymicrobial infections. PLoS Pathog 4:e1000184
Sibley CD, Parkins MD, Rabin HR, Duan K, Norgaard JC et al (2008b) A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients. Proc Natl Acad Sci U S A 105:15070–15075
Silva S, Henriques M, Hayes A, Oliveira R, Azeredo J et al (2011) Candida glabrata and Candida albicans co-infection of an in vitro oral epithelium. J Oral Pathol Med 40:421–427
Silverman RJ, Nobbs AH, Vickerman MM, Barbour ME, Jenkinson HF (2010) Interaction of Candida albicans cell wall Als3 protein with Streptococcus gordonii SspB adhesin promotes development of mixed-species communities. Infect Immun 78:4644–4652
Singh PK, Schaefer AL, Parsek MR, Moninger TO, Welsh MJ et al (2000) Quorum-sensing signals indicate that cystic fibrosis lungs are infected with bacterial biofilms. Nature 407:762–764
Singh R, Shivaprakash MR, Chakrabarti A (2011) Biofilm formation by zygomycetes: quantification, structure and matrix composition. Microbiology 157:2611–2618
Singhal D, Baker L, Wormald PJ, Tan L (2011) Aspergillus fumigatus biofilm on primary human sinonasal epithelial culture. Am J Rhinol Allergy 25:219–225
Siqueira VM, Oliveira HM, Santos C, Paterson RR, Gusmao NB et al (2011) Filamentous fungi in drinking water, particularly in relation to biofilm formation. Int J Environ Res Public Health 8:456–469
Sobel JD, Fisher JF, Kauffman CA, Newman CA (2011) Candida urinary tract infections – epidemiology. Clin Infect Dis 52(Suppl 6):S433–S436
Stonecypher K (2010) Ventilator-associated pneumonia: the importance of oral care in intubated adults. Crit Care Nurs Q 33:339–347
Taff HT, Nett JE, Andes DR (2012) Comparative analysis of Candida biofilm quantitation assays. Med Mycol 50:214–218
Trevisani L, Sartori S, Rossi MR, Bovolenta R, Scoponi M et al (2005) Degradation of polyurethane gastrostomy devices: what is the role of fungal colonization? Dig Dis Sci 50:463–469
Tumbarello M, Posteraro B, Trecarichi EM, Fiori B, Rossi M et al (2007) Biofilm production by Candida species and inadequate antifungal therapy as predictors of mortality for patients with candidemia. J Clin Microbiol 45:1843–1850
Tumbarello M, Fiori B, Trecarichi EM, Posteraro P, Losito AR et al (2012) Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS One 7:e33705
Uppuluri P, Chaturvedi AK, Srinivasan A, Banerjee M, Ramasubramaniam AK et al (2010) Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog 6:e1000828
Valdivieso M, Luna M, Bodey GP, Rodriguez V, Groschel D (1976) Fungemia due to Torulopsis glabrata in the compromised host. Cancer 38:1750–1756
Viale P, Petrosillo N, Signorini L, Puoti M, Carosi G (2001) Should lock therapy always be avoided for central venous catheter-associated fungal bloodstream infections? Clin Infect Dis 33:1947–1948, Author reply 1949–1951
Wada M, Baba H, Imura S (1998) Prosthetic knee Candida parapsilosis infection. J Arthroplasty 13:479–482
Wallner M, Steyer G, Krause R, Gstettner C, von Lewinski D (2012) Fungal endocarditis of a bioprosthetic aortic valve: pharmacological treatment of a Candida parapsilosis endocarditis. Herz 38:431–434
Walraven CJ, Lee SA (2013) Antifungal lock therapy. Antimicrob Agents Chemother 57:1–8
Walsh TJ, Schlegel R, Moody MM, Costerton JW, Salcman M (1986) Ventriculoatrial shunt infection due to Cryptococcus neoformans: an ultrastructural and quantitative microbiological study. Neurosurgery 18:373–375
Walter EB Jr, Gingras JL, McKinney RE Jr (1990) Systemic Torulopsis glabrata infection in a neonate. South Med J 83:837–838
Warkentien T, Rodriguez C, Lloyd B, Wells J, Weintrob A et al (2012) Invasive mold infections following combat-related injuries. Clin Infect Dis 55:1441–1449
Williams DW, Kuriyama T, Silva S, Malic S, Lewis MA (2011) Candida biofilms and oral candidosis: treatment and prevention. Periodontol 2000 55:250–265
Wolcott RD, Gontcharova V, Sun Y, Dowd SE (2009) Evaluation of the bacterial diversity among and within individual venous leg ulcers using bacterial tag-encoded FLX and titanium amplicon pyrosequencing and metagenomic approaches. BMC Microbiol 9:226
Wu CY, Lee PI (2007) Antibiotic-lock therapy and erythromycin for treatment of catheter-related Candida parapsilosis and Staphylococcus aureus infections. J Antimicrob Chemother 60:706–707
Yang SP, Chen YY, Hsu HS, Wang FD, Chen LY et al (2013) A risk factor analysis of healthcare-associated fungal infections in an intensive care unit: a retrospective cohort study. BMC Infect Dis 13:10
Yao M, Messner AH (2001) Fungal malignant otitis externa due to Scedosporium apiospermum. Ann Otol Rhinol Laryngol 110:377–380
Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita VT (1970) Aspergillosis. The spectrum of the disease in 98 patients. Medicine (Baltimore) 49:147–173
Younkin S, Evarts CM, Steigbigel RT (1984) Candida parapsilosis infection of a total hip-joint replacement: successful reimplantation after treatment with amphotericin B and 5-fluorocytosine. A case report. J Bone Joint Surg Am 66:142–143
Zhao X, Daniels KJ, Oh SH, Green CB, Yeater KM et al (2006) Candida albicans Als3p is required for wild-type biofilm formation on silicone elastomer surfaces. Microbiology 152:2287–2299
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Williams, C., Ramage, G. (2015). Fungal Biofilms in Human Disease. In: Donelli, G. (eds) Biofilm-based Healthcare-associated Infections. Advances in Experimental Medicine and Biology, vol 831. Springer, Cham. https://doi.org/10.1007/978-3-319-09782-4_2
Download citation
DOI: https://doi.org/10.1007/978-3-319-09782-4_2
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-09781-7
Online ISBN: 978-3-319-09782-4
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)