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Review

Candida Species Biofilms’ Antifungal Resistance

by
Sónia Silva
*,
Célia F. Rodrigues
,
Daniela Araújo
,
Maria Elisa Rodrigues
and
Mariana Henriques
Centre of Biological Engineering (CEB), University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal
*
Author to whom correspondence should be addressed.
J. Fungi 2017, 3(1), 8; https://doi.org/10.3390/jof3010008
Submission received: 23 December 2016 / Revised: 30 January 2017 / Accepted: 9 February 2017 / Published: 21 February 2017
(This article belongs to the Special Issue Fungal Biofilms)
Browse Figure
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Abstract

:
Candida infections (candidiasis) are the most prevalent opportunistic fungal infection on humans and, as such, a major public health problem. In recent decades, candidiasis has been associated to Candida species other than Candida albicans. Moreover, biofilms have been considered the most prevalent growth form of Candida cells and a strong causative agent of the intensification of antifungal resistance. As yet, no specific resistance factor has been identified as the sole responsible for the increased recalcitrance to antifungal agents exhibited by biofilms. Instead, biofilm antifungal resistance is a complex multifactorial phenomenon, which still remains to be fully elucidated and understood. The different mechanisms, which may be responsible for the intrinsic resistance of Candida species biofilms, include the high density of cells within the biofilm, the growth and nutrient limitation, the effects of the biofilm matrix, the presence of persister cells, the antifungal resistance gene expression and the increase of sterols on the membrane of biofilm cells. Thus, this review intends to provide information on the recent advances about Candida species biofilm antifungal resistance and its implication on intensification of the candidiasis.

1. Introduction

During the last two decades, the occurrence of Candida species infections has been increasing and becoming more difficult to treat due to the growth of immunogenic diseases, the disproportionate use of immunosuppressive drugs, malnutrition, endocrine disorders, the widespread use of indwelling medical devices, broad spectrum antibiotics, aging and an increase in patient’s population [1,2]. A fairly small number of Candida species are pathogenic for humans, causing superficial and deep-seated mycoses, disseminated worldwide [3]. Nonetheless, Candida is becoming a significant clinical problem that has taken the opportunity to create infections, called candidiasis [1,2,3].
Candida albicans continues to be the most prevalent and problematic of all Candida species. However, with the development of molecular identification methods, the number of other Candida species, non-Candida albicans Candida (NCAC) species, identified as implicated in candidiasis, is now superior. This group includes, among others, Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei species [4,5,6]. The pathogenicity of Candida species is attributed to certain virulence factors, such as the ability to evade host defences, adhesion and biofilm formation (on host tissues and or on medical devices), and the production of tissue-damaging hydrolytic enzymes, such as proteases, phospholipases and hemolysins [7]. Biofilms are biological communities with an extraordinary degree of organization, in which Candida cells form structured, coordinated, and functional communities, embedded in a self-secreted extracellular matrix. Biofilm production is also related to a high level of antifungal resistance of the associated microorganisms. Moreover, the ability of Candida species to form drug-resistant biofilms is an important factor in their contribution to human disease [8]. In the widely held view of Candida microbial biofilms [9] sessile cells within biofilms are less susceptible to antifungal agents than planktonic cells [10], since the development of drug resistance has been linked with, for example, an increase in the biofilm maturation process.
Thus, the morbidity and mortality associated with candidiasis is still very high, even using the actual antifungal drugs [8,11]. Annually, 50% of adults and up to 30% of children [11,12] die of candidiasis, most of them related with biofilms. Furthermore, in fact, an estimated 100,000 deaths are caused by biofilm infections and about $6.5 billion are spent per year in the United States (US) in order to treat them. In fact, biofilm infections have been assumed as a serious public health problem with a high economic impact [13,14]. Thus, this review intends to provide information on the recent advances about Candida species biofilm antifungal resistance mechanisms and its implication on intensification of the candidiasis.

2. Candida Biofilms: A Real Problem

2.1. Biofilm Characteristics

The first documented scientific report about a biofilm was written in 1683 by Antoni van Leeuwenhoek in the Royal Society of London [15,16]. Since then, the definition of biofilm has evolved to what is now described as a community of adherent cells enclosed in an exopolysaccharide matrix, with properties distinct from those of free-floating (planktonic) cells [14,17,18,19]. Biofilms are often found attached to solid surfaces, but they can also be formed in liquid–air interfaces. The most common environments colonized by biofilms include aquatic environments, artificial structures, biomaterials, and plant and mammalian tissues. Within these environments, biofilms may be composed of a single-species population or a community derived from multiple species [6,17]. In both cases, biofilms are thought to provide ecologic advantages such as protection from the environment, nutrient availability, metabolic cooperation, and acquisition of new traits [19,20]. Perhaps because of these, biofilms are notoriously difficult to eliminate and are a source of many recalcitrant infections [6]. As such, biofilms are highly relevant to public health. Indeed, the National Institutes of Health signposts that pathogenic biofilms are responsible, directly or indirectly, for over 80% of all microbial infections [13,19,21], which can range from superficial mucosal (75% of women experience a vaginal yeast infection at least once in their lifetime) or dermal infections, to more serious spread infections with high mortality rates (47% in various cases) [13,21].
Candida species biofilms are among the most common in clinical settings, and their main characteristics, which are dependent of the Candida species, can be found in Table 1. Candida commonly adheres to biomedical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations [20,22]. The medical device most commonly infected by Candida biofilms is the central venous catheter (CVC), which is used to administer fluids and nutrients and/or cytotoxic drugs. The infusion fluid itself, or the catheter core, can be contaminated but, more frequently, Candida can have origin on the patient’s skin or on the hands of nursing staff (the distal tip of the catheter can be contaminated at the time of insertion or, instead, organisms can migrate down the catheter wound) [11,22,23,24]. Each year, in the US, more than five million CVCs are placed and, even with new improved clinical security procedures, biofilm infection still occurs in over 50% of these catheters [21]. Recurrently encountered and sometimes difficult to eradicate, superficial Candida infections related with medical devices are much less serious. The most common cases are those related with oral mucosa, e.g., denture stomatitis and silicone rubber voice prostheses [4,25,26]. Non-medical-device-related infections such as Candida endocarditis can result from the formation of biofilms on damaged vascular endothelium of native heart valves in patients with pre-existing cardiac disease [21]. Several authors reported formation of Candida biofilms on different surfaces, which are summarized in Table 2.

2.2. Candida Biofilms and Resistance Mechanisms

The major classes of antifungal drugs used for treatment of Candida species infections are azoles, polyenes, and echinocandins [86,104,105,106,107,108]. Azoles (e.g., fluconazole, voriconazole and posaconazole) possess a fungistatic effect, blocking ergosterol synthesis, targeting the enzyme lanosterol 14α-demethylase (related to the ERG11 gene) and leading to an accumulation of toxic sterol pathway intermediates. Polyenes (e.g., amphotericin B and nystatin) are fungicidal, intercalating into membranes containing ergosterol, creating pores that destroy the proton gradient, which result in the outflow of the cytoplasm and other cell contents. Echinocandins (e.g., caspofungin, micafungin and anidulafungin) are also a fungicidal, targeting the synthesis of 1,3-β-glucan, a component of the Candida species cell wall. It is also important to address that preferably to azoles, the use of echinocandins and polyenes is recommended if the patient had prior azoles exposure and if the infection is markedly severe for patients infected with C. glabrata, which is consider as generally very azole-resistant. Echinocandins are, most frequently and according to the latest guidelines, the first antifungal drug choice in these severe cases of candidemia [109,110]. There is some evidence that suggests that prophylactic use of fluconazole may be advantageous for preterm neonates, transplant recipients, intensive care unit patients, and other high-risk patient populations [111,112,113,114,115,116]. Though, due to some controversies, this is not a standard for all hospitals [21].
Initial studies examined the impact of known mechanisms to play a role in drug resistance during planktonic Candida cells growth [7,117,118,119]. As described, acquired planktonic cell resistance has been linked to increased efflux pump activity, mutations in genes encoding drug target enzymes and alterations in the composition of both the cell membrane and the cell wall [117]. The Candida biofilm resistance phenomenon was for the first time demonstrated in 1995 for C. albicans by Hawser and Douglas (1995) [6]. After that, the ability of Candida species biofilms to survive extraordinarily to high antifungal concentrations has been the subject of numerous investigations for many researchers [7,117,118,120,121]. So, in the last decade, additional investigations began to focus on the role of biofilm-specific traits. These studies have examined the influence of high cell density, growth rate reduction, nutrient limitation, matrix extracellular production, presence of persister cells, gene expression alterations and sterols content increase on Candida membrane cells. The role of these mandatory factors is reviewed below and is schematized on Figure 1.

2.2.1. Impact of Candida Cells Density, Nutrient and Growth Limitation

An important biofilm-specific trait suspected to influence antifungal resistance is the high relative concentration of Candida cells into biofilm communities comparatively to the great majority of planktonic conditions [122,123]. Perumal and Chaffin, (2007) [122] after studying the cells density effect on antifungal treatment, observed that the azole antifungals’ tolerance to planktonic cell cultures was effectively lower when compared to intact and/or disrupt biofilm communities. Candida albicans biofilm formation is associated with the dimorphic switch between yeast and hyphal growth, and biofilms of this species generically have two distinct layers: a thin, basal yeast layer and a thickener compact hyphal layer [4]. In contrast, C. parapsilosis biofilms tend to be thinner, less structured, and consist almost exclusively of aggregates [29,124]. Candida tropicalis biofilms consist of a dense network of yeast cells with evident different filamentous morphologies and C. glabrata biofilms are structured on multilayers of blastospores with high cohesion among them [124]. In general, C. glabrata biofilms possessed higher density of cells comparatively to C. tropicalis and C. parapsilosis biofilms [125], which may be implicated on the usual highest resistance of C. glabrata biofilms to antifungal azoles and/or amphotericin B [7,117,120].
The well-structured biofilms layers open another hypothesis for Candida species antifungal resistance, that is, that cells placed in deeper layers of the biofilm grow slower owing to a lack of nutrients, and are subsequently more resistant to antifungal drugs. There is in fact a lack of work concerning this subject. However, by controlling nutrients in a perused biofilm fermentor, Baillie and Douglas [126,127] were able to compare the antifungal susceptibility of C. albicans biofilms growing at various rates. These authors, in opposition to what was expectable over a wide range of growth rates, verified that biofilm-associated cells exhibited similar levels of resistance to amphotericin B, suggesting that growth rate does not play a significant role in biofilm antifungal resistance. Similarly, C. albicans grown under glucose and iron limitation conditions were shown to both be highly resistant to amphotericin B [127]. Nevertheless, factors including pH, temperature, and oxygen availability are described as possible inductors of biofilm architecture alteration and thus the antifungal sensibility [128,129,130].
The general physiological state of sessile cells has also been reported as implicated in the susceptibility profiles of Candida biofilms. Metabolic activity confirms that cells within biofilms are undergoing mitochondrial respiration during development [5,29,86,123,130].

2.2.2. Contribution of the Extracellular Matrix Production

Extracellular matrix (ECM) is a defining characteristic of all Candida species biofilms, providing the cells protection from hostile factors such as host immunity and antifungal agents [7,131]. In some of the pioneer works, Candida species biofilm’s matrices were shown to increase when biofilms were grown under dynamic flow conditions and their quantity is strongly species- and strains-dependent [6,124,132]. Subsequent work has shown that while ECM hampers diffusion, penetration of antifungal drugs is not thought to play an important role in biofilm resistance [132]. However, more recent studies have provided new insights about the chemical composition of ECM and that it may play a central role in resistance by antifungal agents’ neutralization.
It is important to address that the composition of the Candida biofilm matrices is species-variable. Little is known about matrix composition of NCAC species biofilms, but according to Baillie and Douglas 1998 [126], C. albicans biofilm matrix is mainly composed of carbohydrates, proteins, phosphorus and hexosamines. Silva and colleagues 2009 [124] reported that the ECM of C. parapsilosis contained large amounts of carbohydrates and low levels of proteins. In the same study, C. glabrata biofilm matrices were found to have high levels of both proteins and carbohydrates, while C. tropicalis biofilm matrices had low levels of carbohydrates and proteins compared to the other NCAC species. Recently, Rodrigues et al. (2016) [120] revealed for the first time the presence of β-glucans in the C. glabrata matrices even when treated with amphotericin B. Furthermore, other authors [7] showed that matrix material extracted from biofilms of C. tropicalis and C. albicans contained carbohydrates, proteins, hexosamine, phosphorus and uronic acid. However, the major component quantified in C. tropicalis biofilm matrices was hexosamine (27%). The same authors also reported that these biofilms partially detached after treatment with lipase type VII and chitinase, which is in contrast to biofilms of C. albicans that detached only after treatment with proteinase K, chitinase, DNase I or β-N-aceytyglucosamidase. In Candida species, there is scarce knowledge concerning the contribution of extracellular DNA to biofilm matrix and overall structure [74].
In this sense, studies have been carried out to clarify the involvement of some of the matrix components in Candida biofilm resistance. Martins et al. (2013) [133] highlighted the importance of DNA in C. albicans biofilm formation, integrity and structure and that the addition of DNase improves the efficacy of polyenes and echinocandins, but not to azoles [133].
The major carbohydrate component is β-1,3 glucans, as treatment of C. albicans biofilms with β-1,3 glucanase helps detach biofilms from a substrate [132]. Its contribution is confirmed, where it was shown to increase in C. albicans biofilm cell walls compared to planktonic organisms and was also detected in the surrounding biofilm milieu and as part of the ECM [134]. The involvement in the resistance was realized when it was also shown that biofilm cell walls bound four- to five-fold more azole than equivalent planktonic cells, and culture supernatant bound a quantifiable amount of this antifungal agent. Moreover, β-1,3 glucanase markedly improved the activity of both fluconazole and amphotericin B. The addition of exogenous biofilm ECM and commercial β-1,3 glucan also reduced the activity of fluconazole against planktonic C. albicans in vitro [134]. The group has recently shown that the ECM β-1,3 glucan is synthesized from Fks1 using a defined knockout and over-expressing strain [135]. This study demonstrated that β-1,3 glucan is responsible for sequestering azoles, acting as a sponge and conferring resistance on C. albicans biofilms [135]. Further studies have shown that they are also responsible for sequestering echinocandins, pyrimidines, and polyenes [136]. Subsequent studies have identified a role for the SMI1 in C. albicans, a gene involved in cell-wall glucans, in biofilm ECM production and development of a drug-resistant phenotype, which appears to act through transcription factor Rlmp and glucan synthase Fks1. In addition to Fks1, a zinc-response transcription factor ZAP1 has been shown to be a negative regulator of ECM soluble β-1,3 glucan in both in vitro and in vivo C. albicans biofilm models [137]. Conversely, two glucoamylases, Gca1 and Gca2, are thought to have positive roles in matrix production. A group of alcohol dehydrogenases ADH5, CSH1, and LFD6 also have roles in matrix production, with ADH5 acting positively, and CSH1 and LFD6 acting negatively [138]. It is also present on a number of other Candida species, including C. glabrata, C. parapsilosis and C. tropicalis [7].
Recent studies revealed the involvement of the matrix on C. tropicalis strains on amphotericin B resistance [118]. These studies highlight the incapacity of this traditional antifungal to totally prevent biofilm formation and to eradicate C. tropicalis biofilms. Interestingly, it was observed that amphotericin B led to a significant increase of the biofilm production due to an augment of the total protein and carbohydrate contents of the matrix. Fernandes et al. (2016) [121] revealed recently that voriconazole had no effect on pre-formed C. tropicalis biofilms. Remarkably, an increase in total biomass was observed when pre-formed biofilms were treated with this antifungal agent. This phenomenon is probably due to a response of C. tropicalis biofilm cells to the stress caused by the presence of the agent, which led to an expansion of the biofilm matrices’ production. Fonseca et al. (2014) [117] revealed a phenomenon similar for C. glabrata with an increase of proteins and carbohydrates in the matrices extracted from biofilms treated with fluconazole.

2.2.3. Emergence of Persister Cells

An intriguing development in understanding Candida species biofilm resistance is the presence of persister cells [139]. Persister cells are a subset of cells, dormant variants, which lie deep in a biofilm and exhibit tolerance to multiple antifungal drug classes [140,141]. LaFleur (2006) [140] published the first study in fungi that demonstrated the presence of persister cells in C. albicans biofilms, but not in planktonic populations. In fact, a re-inoculation of cells, which survived from a biofilm treated with amphotericin B, was able to develop a new biofilm also with persister cells. This work suggested that these cells are not mutants but cells phenotype variants of the wild type. The presence of persisters in C. krusei, and C. parapsilosis biofilms treated with amphotericin B, were also described [142]. It was shown that the persister levels of the isolates varied from 0.2% to 9%, and strains isolated from patients with long-term carriage had high levels of persisters, whereas those from transient carriage did not [140]. While the mechanisms of Candida persister cells transition remains unclear, transcriptional analysis of these cells shows differential regulation of genes involved in ergosterol (ERG1 and ERG25) and β-1,6 glucan (SKN1 and KRE1) pathways [143]. Moreover, superoxide dismutases (SOD) were found to be differentially expressed by miconazole-treated sessile C. albicans cells compared to untreated cells. Inhibition of SOD resulted in an 18-fold reduction of the miconazole-tolerant persister cells and increased endogenous reactive oxygen species (ROS) levels in these cells [144]. Bink et al. (2011) [144] also demonstrated that in biofilms from strains lacking sod4/sod5 at least three-fold less miconazole-tolerant persisters were observed, and ROS levels were also increased.

2.2.4. Impact of Sterols Contents and Its Correlation with ERG Genes Expression

Ergosterol is the most prevalent sterol in Candida cells plasma membrane. Moreover, antifungal agents (e.g., azoles and amphotericin B) act as ergosterol synthesis inhibitors by binding to lanosterol demthylase, a specific enzymatic in ergosterol biosynthesis. The observation that Candida mutants with altered ergosterol synthesis show enhanced resistance to azoles and amphotericin B led the investigators to question if Candida biofilm cells may employ similar mechanisms of resistance [145]. Mukerjee and colleagues (2003) [145] showed that, when comparing planktonic cells’ membranes with the membranes of biofilm cells, the latter had a lower concentration of ergosterol, especially during the last steps of biofilm formation. This finding suggests that cells from mature biofilms rely less on ergosterol for maintaining its membrane fluidity and potentially limiting the efficacy of the ergosterol targeting drugs. In fact, several studies have demonstrated alterations in the transcriptional profile of sterol pathway genes in diverse Candida species [139,146]. Candida albicans microarray analysis demonstrated an increase of ERG25 and ERG11 in vitro biofilm growth when compared with its planktonic counterparts [147]. Interestingly, transcriptional analysis of a rat venous catheter biofilm also found increased transcription of ERG25, but not ERG11 [134]. Moreover, the principal drug target, ERG11, can easily develop point mutations or even be over-expressed [148,149].
These results confirm the involvement of the alterations on sterol content in membrane of C. tropicalis cells as in other Candida cells. Candida glabrata is assumed to be the most azole-resistant species of all Candida species [7]. Besides, all the genes involved in the biosynthesis of ergosterol have been described as up-regulated in C. glabrata treated with azoles molecules in planktonic cells [7]. It is believed that the increase of C. glabrata infections is due to its intrinsically low susceptibility to azoles, including the imidazoles and the oral-parenteral triazoles (e.g., fluconazole, voriconazole) [150]. Additionally, it is known that the acquired resistance is resulted of rare mutations that are selected by drug pressure [151]. All the genes involved in the biosynthesis of ergosterol are expected to be up-regulated in the presence of azole molecules. Nevertheless, ERG genes are the ones more focused on in studies. Between them are ERG1, ERG3, ERG6, ERG7, ERG9, and especially ERG11. ERG11 is noticeably more referred as the central point on the increase of ergosterol production, in response to the azole attack to the C. glabrata cell membrane, which has great ease to acquire azole resistance [151,152].
Induction of ergosterol genes has also been described in C. dubliniensis, where incubation with fluconazole and formation of biofilm was coupled with up-regulation of the ERG3 and ERG25 [153]. Moreover, up-regulation of genes involved with ergosterol biosynthesis has been described in C. parapsilosis biofilms [154], which are also resistant to azole antifungal therapy [155]. Regarding C. tropicalis, recently Fernandes and colleagues (2016) [121] demonstrated that, similar to C. albicans, voriconazole-resistant cells presented an increased on expression of ERG genes.

2.2.5. Over-Expression of Other Antifungal Targets

Many cases of drug resistance are linked to the increase of efflux pumps in Candida cells membrane and the consequent reduction of the drug accumulation within the cells [156]. In C. albicans, efflux pumps have been described as playing an important role in azole resistance, but not in resistance to amphotericin B and echinocandins [157,158,159,160,161].
The ATP binding cassette transporters (CDR1 and CDR2) and major facilitator transporter (MDR1) are typically expressed at low levels in the absence of antifungal exposure [160]. The finding that azole-resistant clinical isolates often show constitutive over-expression of these pumps prompted investigators to postulate that the biofilm drug resistance phenotype may be related to increased efflux pump activity [159,162,163,164,165]. Ramage and colleagues (2009) [166] demonstrated that transcription of both MDR1 and CDR1 was more abundant in C. albicans biofilms than planktonic cultures of the same age. In opposition, some authors investigated the role of these efflux pumps by deletion of their genes and observed that, during the planktonic growth, these mutants displayed hypersensitivity to fluconazole. However, this phenotype was not observed when these same mutants were grown as biofilms, suggesting that the efflux pumps do not contribute significantly to drug resistance during the mature biofilm stage [131]. Mukherjee et al. (2011) [145] examined the role of efflux pumps in antifungal resistance throughout the biofilm process. The researchers included early, intermediate and mature C. albicans biofilms with planktonic growth comparisons. Similar to the prior investigation, single, double and triple mutants of the three main efflux genes were no more susceptible to fluconazole treatment during mature biofilm growth than the parent strains; however, in the early phase, double and triple efflux pump mutants had significantly increased azole susceptibility when compared with the parent strains. This suggests that the efflux pumps contribute to resistance during the early biofilm developmental phase, and that the pumps may function in a cooperative manner. This theory of time-specific efflux pump functionality was further supported by transcriptional analysis, showing higher expression of efflux pump genes after 12 h biofilm formation when compared with mature, 48 h biofilm formation [145]. This is collective evidence that Candida efflux pumps likely contribute to drug resistance during the early phase of biofilm growth, while their role in resistance in mature biofilms appears to be minimal at most. Investigations of C. glabrata and C. tropicalis biofilms have also shown up-regulation of efflux pumps [166,167]. Fonseca et al. (2016) [117] evaluated the expression of C. glabrata ABC (ATP-binding cassette) transporters (CDR1, SNQ2 and PDR1) in presence of fluconazole, and observed that, in addition to high amounts, the matrix produced an over-expression of these efflux pumps.
This data supports the hypothesis that efflux pumps are an important—but not exclusive—determinant of fungal biofilm resistance to antifungal drugs. Their primary role may be for homeostasis within complex environments to protect themselves from acute toxicity, but within clinical environments, exposure to azoles drugs may enhance the levels of efflux pump expression, therefore either contributing towards or inducing clinical resistance.

3. Conclusions

Reducing the incidence of biofilm-related candidiasis in hospitals is a requirement in the search for optimized patient care. However, the high degree of resistance of biofilm-associated Candida cells hinders rapid development toward highly efficacious therapies. Recent efforts of various excellent research groups tremendously broadened our knowledge on the complex mechanisms underlying biofilm resistance. According to the authors, the presence of matrix material is the most important biofilm resistance mechanism. However, several other important mechanisms such as cell density, differential regulation of drug targets, up-regulation of drug efflux pumps in developing biofilms, the presence of persisters into biofilms, up-regulation of different pathways and possibly yet-undefined mechanisms can further increase resistance to a maximum level. The elucidation of these resistance mechanisms provides a promising step toward the development of optimal therapies.

Acknowledgments

The authors acknowledge the Fundação para a Ciência e Tecnologia (FCT), Portugal, for supporting Maria Elisa Rodrigues (SFRH/BPD/95401/2013) and Célia F. Rodrigues (SFRH/BD/93078/2013). This study was also supported by the Programa Operacional, Fatores de competitividade—COMPETE and by national funds through FCT—Fundação para a Ciência e a Tecnologia under the scope of the projects FCT PTDC/EBB-EBI/120495/2010 and RECI/EBB-EBI/0179/2012 (FCOM-01-0124-FEDER-027462).

Author Contributions

All authors contributed to the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Li, L.; Redding, S.; Dongari-Bagtzoglou, A. Candida glabrata: An emerging oral opportunistic pathogen. J. Dent. Res. 2007, 86, 204–215. [Google Scholar] [CrossRef] [PubMed]
  2. Garcia-Cuesta, C.; Sarrion-Perez, M.G.; Bagan, J.V. Current treatment of oral candidiasis: A literature review. J. Clin. Exp. Dent. 2014, 6, 576–582. [Google Scholar] [CrossRef] [PubMed]
  3. Douglas, L.J. Candida biofilms and their role in infection. Trends Microbiol. 2003, 11, 30–36. [Google Scholar] [CrossRef]
  4. Donlan, R.M.; Costerton, J.W. Biofilms: Survival Mechanisms of Clinically Relevant Microorganisms. Clin. Microbiol. Rev. 2002, 15, 167–193. [Google Scholar] [CrossRef] [PubMed]
  5. Chandra, J.; Mukherjee, P. Candida Biofilms: Development, Architecture, and Resistance. Microbiol. Spectr. 2015, 3, 157–176. [Google Scholar] [CrossRef] [PubMed]
  6. Hawser, S.P.; Douglas, L.J. Resistance of Candida albicans biofilms to antifungal agents in vitro. Antimicrob. Agents Chemother. 1995, 39, 2128–2131. [Google Scholar] [CrossRef] [PubMed]
  7. Silva, S.; Negri, M.; Henriques, M.; Oliveira, R.; Williams, D.; Azeredo, J. Candida glabrata, Candida parapsilosis and Candida tropicalis: Biology, epidemiology, pathogenicity and antifungal resistance. FEMS Microbiol. Rev. 2012, 36, 288–305. [Google Scholar] [CrossRef] [PubMed]
  8. Rodrigues, C.F.; Silva, S.; Henriques, M. Candida glabrata: A review of its features and resistance. Eur. J. Clin. Microbiol. Infect. Dis. 2014, 33, 673–688. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Rajendran, R.; Robertson, D.P.; Hodge, P.J.; Lappin, D.F.; Ramage, G. Hydrolytic enzyme production is associated with Candida albicans biofilm formation from patients with type 1 diabetes. Mycopathologia 2010, 170, 229–235. [Google Scholar] [CrossRef] [PubMed]
  10. Kuhn, D.M.; Ghannoum, M.A. Candida biofilms: Antifungal resistance and emerging therapeutic options. Curr. Opin. Investig. Drugs 2004, 5, 186–197. [Google Scholar] [PubMed]
  11. Negri, M.; Silva, S.; Henriques, M.; Oliveira, R. Insights into Candida tropicalis nosocomial infections and virulence factors. Eur. J. Clin. Microbiol. Infect. Dis. 2012, 31, 1399–1412. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  12. Pfaller, M.A.; Jones, R.N.; Messer, S.A.; Edmond, M.B.; Wenzel, R.P. National surveillance of nosocomial blood stream infection due to Candida albicans: Frequency of occurrence and antifungal susceptibility in the SCOPE Program. Diagn. Microbiol. Infect. Dis. 1998, 31, 327–332. [Google Scholar] [CrossRef]
  13. Gulati, M.; Nobile, C.J. Candida albicans biofilms: Development, regulation, and molecular mechanisms. Microbes Infect. 2016, 18, 310–321. [Google Scholar] [CrossRef] [PubMed]
  14. Nobile, C.J.; Johnson, A.D. Candida albicans Biofilms and Human Disease. Annu. Rev. Microbiol. 2015, 69, 71–92. [Google Scholar] [CrossRef] [PubMed]
  15. Gulati, M.; Nobile, C.J. Candida albicans biofilms: Development, regulation, and molecular mechanisms. Microbes Infect. 2015, 18, 310–321. [Google Scholar] [CrossRef] [PubMed]
  16. Jana, J.; Susanne, S.; James Thomas, W. Medical Biofilms Detection, Prevention, and Control; John Wiley & Sons, Ltd.: Chichester, UK, 2003. [Google Scholar]
  17. Kolter, R.; Greenberg, E.P. Microbial sciences: The superficial life of microbes. Nature 2006, 441, 300–302. [Google Scholar] [CrossRef] [PubMed]
  18. López, D.; Vlamakis, H.; Kolter, R. Biofilms. Cold Spring Harbor Perspect. Biol. 2010, 2, 1–12. [Google Scholar] [CrossRef] [PubMed]
  19. Taff, H.T.; Mitchell, K.F.; Edward, J.A.; Andes, D.R. Mechanisms of Candida biofilm drug resistance. Future Microbiol. 2013, 8, 1325–1337. [Google Scholar] [CrossRef] [PubMed]
  20. Nett, J.E.; Brooks, E.G.; Cabezas-Olcoz, J.; Sanchez, H.; Zarnowski, R.; Marchillo, K.; Andes, D.R. Rat indwelling urinary catheter model of Candida albicans biofilm infection. Infect. Immun. 2014, 82, 4931–4940. [Google Scholar] [CrossRef] [PubMed]
  21. Fox, E.P.; Singh-babak, S.D.; Hartooni, N.; Nobile, C.J. Biofilms and Antifungal Resistance. In Antifungals: From Genomics to Resistance and the Development of Novel Agents; Caister Academic Press: Poole, UK, 2015; pp. 71–90. [Google Scholar]
  22. Johnson, C.C.; Yu, A.; Lee, H.; Fidel, P.L.; Noverr, M.C. Development of a contemporary animal model of Candida albicans-associated denture stomatitis using a novel intraoral denture system. Infect. Immun. 2012, 80, 1736–1743. [Google Scholar] [CrossRef] [PubMed]
  23. Ivor, D.B.; Sanley, J.R.; Adolph, W.K.; Lawrence, J.K. Torulopsis glabrata fungemia—A clinical pathological study. Medicine 1979, 58, 430–440. [Google Scholar]
  24. Heffner, D.K.; Franklin, W.A. Endocarditis caused by Torulopsis glabrata. Am. J. Clin. Pathol. 1978, 70, 420–423. [Google Scholar] [CrossRef]
  25. Budtz-Jorgensen, E. Candida-associated denture stomatitis and angular cheilitis. Oral Candidosis. 1990, 156–183. [Google Scholar]
  26. Van Der Mei, H.C.; Free, R.H.; Elving, G.J.; Van Weissenbruch, R.; Albers, F.W.J.; Busscher, H.J. Effect of probiotic bacteria on prevalence of yeasts in oropharyngeal biofilms on silicone rubber voice prostheses in vitro. J. Med. Microbiol. 2000, 49, 713–718. [Google Scholar] [CrossRef] [PubMed]
  27. Uppuluri, P.; Chaturvedi, A.K.; Srinivasan, A.; Banerjee, M.; Ramasubramaniam, A.; Köhler, J.; Kadosh, D.; Lopez-Ribot, J. Dispersion as an important step in the Candida albicans biofilm developmental cycle. PLoS Pathog. 2010, 6, e1000828. [Google Scholar] [CrossRef] [PubMed]
  28. Tumbarello, M.; Fiori, B.; Trecarichi, E.M.; Posteraro, P.; Losito, A.; De Luca, A.; Sanguinetti, M.; Fadda, G.; Cauda, R.; Posterano, B. Risk factors and outcomes of candidemia caused by biofilm-forming isolates in a tertiary care hospital. PLoS ONE 2012, 7, 1–9. [Google Scholar] [CrossRef]
  29. Kuhn, D.M.; George, T.; Chandra, J.; Mukherjee, P.K.; Ghannoum, M.A. Antifungal susceptibility of Candida biofilms: Unique efficacy of Amphotericin B lipid formulations and echinocandins. Society 2002, 46, 1773–1780. [Google Scholar] [CrossRef]
  30. Taff, H.T.; Nett, J.E.; Andes, D.R. Comparative analysis of Candida biofilm quantitation assays. Med. Mycol. 2012, 50, 214–218. [Google Scholar] [CrossRef] [PubMed]
  31. Pannausorn, S.; Fernandez, V.; Römling, F. Prevalence of biofilm formation in clinical isolates of Candida species causing bloodstream infection. Mycoses 2012, 56, 264–272. [Google Scholar] [CrossRef]
  32. Valdivieso, M.; Luna, M.; Bodey, G.P.; Rodriguez, V.; Groschel, D. Fungemia due to Torulopsis glabrata in the compromised host. Cancer 1976, 38, 1750–1756. [Google Scholar] [CrossRef]
  33. Goodman, J.S.; Seibert, D.G.; Reahl, G.E.; Geckler, R.W. Fungal infection of prosthetic joints: A report of two cases. J. Rheumatol. 1983, 10, 494–495. [Google Scholar] [PubMed]
  34. Cecchin, E.; De Marchi, S.; Panarello, G.; Franceschin, A.; Chiaradia, V.; Santini, G.; Tesio, F. Torulopsis glabrata Peritonitis Complicating Continuous Ambulatory Peritoneal Dialysis: Successful Management With Oral 5-Fluorocytosine. Am. J. Kidney Dis. 1984, 4, 280–284. [Google Scholar] [CrossRef]
  35. Paige, C.; Pinson, C.W.; Antonovic, R.; Strausbaugh, L.J. Catheter-related thrombophlebitis of the superior vena cava caused by Candida glabrata. West. J. Med. 1987, 147, 333–335. [Google Scholar] [PubMed]
  36. Komshian, S.V.; Uwaydah, A.K.; Sobel, J.D.; Crane, L.R. Fungemia Caused by Candida Species and Torulopsis glabrata in the hospitalized patient: frequency, characteristics, and evaluation of factors influencing outcome. Clin. Infect. Dis. 1989, 11, 379–390. [Google Scholar] [CrossRef]
  37. Walter, E.B.; Gingras, J.L.; McKinney, R.E. Systemic Torulopsis glabrata infection in a neonate. South. Med. J. 1990, 83, 837–838. [Google Scholar] [CrossRef] [PubMed]
  38. Fortún, J.; Martín-Dávila, P.; Gómez-García de la Pedrosa, E.; Pintado, V.; Cobo, J.; Fresco, G.; Meije, Y.; Ros, L.; Alvarez, M.E.; Luengo, J.; et al. Emerging trends in candidemia: A higher incidence but a similar outcome. J. Infect. 2012, 65, 64–70. [Google Scholar] [CrossRef] [PubMed]
  39. Ding, C.; Vidanes, G.M.; Maguire, S.L.; Guida, A.; Synnott, J.; Andes, D.; Butler, G. Conserved and divergent roles of Bcr1 and CFEM proteins in Candida parapsilosis and Candida albicans. PLoS ONE 2011, 6. [Google Scholar] [CrossRef] [PubMed]
  40. Mohan, P.; Holland, L.; Butler, G.; Gacser, A.; Bliss, J.M. Candida parapsilosis is a significant neonatal pathogen: A systematic review and meta-analysis. Pediatr. Infect. Dis. J. 2013, 32, 206–216. [Google Scholar]
  41. Wada, M.; Baba, H.; Imura, S. Prosthetic knee Candida parapsilosis infection. J. Arthroplast. 1998, 13, 479–482. [Google Scholar] [CrossRef]
  42. Fox, P.M.; Lee, G.K. Tissue expander with acellular dermal matrix for breast reconstruction infected by an unusual pathogen: Candida parapsilosis. J. Plast. Reconstr. Aesthet. Surg. 2012, 65, e286–e289. [Google Scholar] [CrossRef] [PubMed]
  43. Younkin, S.; Evarts, C.M.; Steigbigel, R.T. Candida parapsilosis infection of a total hip-joint replacement: Successful reimplantation after treatment with amphotericin B and 5-fluorocytosine. A case report. J. Bone Jt. Surg. Am. 1984, 66, 142–143. [Google Scholar] [CrossRef] [PubMed]
  44. Mansur, A.J.; Safi, J.; Markus, M.R.P.; Aiello, V.D.; Grinberg, M.; Pomerantzeff, P. Late failure of surgical treatment for bioprosthetic valve endocarditis due to Candida tropicalis. Clin. Infect. Dis. 1996, 22, 380–381. [Google Scholar] [CrossRef] [PubMed]
  45. Thomas, B.; Thomas, F.F. Oral biofilm-associated diseases: Trends and implications for quality of life, systemic health and expenditures. Periodontol 2000 2011, 55, 87–103. [Google Scholar]
  46. Rautemaa, R.; Ramage, G. Oral candidosis-clinical challenges of a biofilm disease. Crit. Rev. Microbiol. 2011, 37, 328–336. [Google Scholar] [CrossRef] [PubMed]
  47. Dongari-Bagtzoglou, A.; Kashleva, H.; Dwivedi, P.; Diaz, P.; Vasilakos, J. Characterization of mucosal Candida albicans biofilms. PLoS ONE 2009, 4. [Google Scholar] [CrossRef] [PubMed]
  48. Ramage, G.; Tomsett, K.; Wickes, B.L.; López-Ribot, J.L.; Redding, S. Denture stomatitis: A role for Candida biofilms. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2004, 98, 53–59. [Google Scholar] [CrossRef]
  49. Sardi, J.C.O.; Duque, C.; Mariano, F.S.; Peixoto, I.T.; Höfling, J.; Gonçalves, R. Candida spp. in periodontal disease: A brief review. J. Oral Sci. 2010, 52, 177–185. [Google Scholar] [CrossRef] [PubMed]
  50. Carvalho, F.G.; Silva, D.S.; Hebling, J.; Spolidorio, L.C.; Spolidorio, D.M. Presence of mutans Streptococci and Candida spp. in dental plaque/dentine of carious teeth and early childhood caries. Arch. Oral Biol. 2006, 51, 1024–1028. [Google Scholar] [CrossRef] [PubMed]
  51. Gündüz Arslan, S.; Akpolat, N.; Kama, J.D.; Özer, T.; Hamamci, O. One-year follow-up of the effect of fixed orthodontic treatment on colonization by oral Candida. J. Oral Pathol. Med. 2008, 37, 26–29. [Google Scholar] [CrossRef] [PubMed]
  52. Canabarro, A.; Valle, C.; Farias, M.R.; Santos, F.B.; Lazera, M.; Wanke, B. Association of subgingival colonization of Candida albicans and other yeasts with severity of chronic periodontitis. J. Periodontal Res. 2012, 48, 428–432. [Google Scholar] [CrossRef] [PubMed]
  53. Bamford, C.V.; D’Mello, A.; Nobbs, A.H.; Dutton, L.C.; Vickerman, M.M.; Jenkinson, H.F. Streptococcus gordonii modulates Candida albicans biofilm formation through intergeneric communication. Infect. Immun. 2009, 77, 3696–3704. [Google Scholar] [CrossRef] [PubMed]
  54. Silverman, R.J.; Nobbs, A.H.; Vickerman, M.M.; Barbour, M.E.; Jenkinson, H.F. Interaction of Candida albicans cell wall Als3 protein with Streptococcus gordonii SspB adhesin promotes development of mixed-species communities. Infect. Immun. 2010, 78, 4644–4652. [Google Scholar] [CrossRef] [PubMed]
  55. Coulthwaite, L.; Verran, J. Potential pathogenic aspects of denture plaque. Br. J. Biomed. Sci. 2007, 64, 180–189. [Google Scholar] [CrossRef] [PubMed]
  56. Nett, J.E.; Marchillo, K.; Spiegel, C.A.; Andes, D.R. Development and validation of an in vivo Candida albicans biofilm denture model. Infect. Immun. 2010, 78, 3650–3659. [Google Scholar] [CrossRef] [PubMed]
  57. Pereira-Cenci, T.; Del Bel Cury, A.A.; Crielaard, W.; Ten Cate, J.M. Development of Candida-associated denture stomatitis: New insights. J. Appl. Oral Sci. 2008, 16, 86–94. [Google Scholar] [CrossRef] [PubMed]
  58. Ramage, G.; Coco, B.; Sherry, L.; Bagg, J.; Lappin, D.F. In Vitro Candida albicans Biofilm Induced Proteinase Activity and SAP8 expression correlates with in vivo denture stomatitis severity. Mycopathologia 2012, 174, 11–19. [Google Scholar] [CrossRef] [PubMed]
  59. Macfarlane, S. Microbial biofilm communities in the gastrointestinal tract. J. Clin. Gastroenterol. 2008, 42, S142–S143. [Google Scholar] [CrossRef] [PubMed]
  60. Trevisani, L.; Sartori, S.; Rossi, M.R.; Bovolenta, R.; Scoponi, M.; Gullini, S.; Abbasciano, V. Degradation of polyurethane gastrostomy devices: What is the role of fungal colonization? Dig. Dis. Sci. 2005, 50, 463–469. [Google Scholar] [CrossRef] [PubMed]
  61. Gottlieb, K.; Leya, J.; Kruss, D.M.; Mobarhan, S.; Iber, F.L. Intraluminal fungal colonization of gastrostomy tubes. Gastrointest. Endosc. 1993, 39, 413–415. [Google Scholar] [CrossRef]
  62. Klaerner, H.G.; Uknis, M.E.; Acton, R.D.; Dahlberg, P.S.; Carlone-Jambor, C.; Dunn, D.L. Candida albicans and Escherichia coli are synergistic pathogens during experimental microbial peritonitis. J. Surg. Res. 1997, 70, 161–165. [Google Scholar] [CrossRef] [PubMed]
  63. Bandara, H.M.H.N.; Yau, J.Y.Y.; Watt, R.M.; Jin, L.J.; Samaranayake, L.P. Escherichia coli and its lipopolysaccharide modulate in vitro Candida biofilm formation. J. Med. Microbiol. 2009, 58, 1623–1631. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Mason, K.L.; Downward, J.R.E.; Mason, K.D.; Falkowski, N.R.; Eaton, K.A.; Kao, J.Y.; Young, V.B.; Huffnagle, G.B. Candida albicans and bacterial microbiota interactions in the cecum during recolonization following broad-spectrum antibiotic therapy. Infect. Immun. 2012, 80, 3371–3380. [Google Scholar] [CrossRef] [PubMed]
  65. Gajer, P.; Brotman, R.M.; Bai, G.; Sakamoto, J.; Schütte, U.M.; Zhong, X.; Koenig, S.S.; Ma, Z.; Zhou, X.; Abdo, Z.; et al. Temporal dynamics of the human vaginal microbiota. Sci. Transl. Med. 2012, 4, 132–152. [Google Scholar] [CrossRef] [PubMed]
  66. Chiocchio, V.; Matković, L. Determination of ergosterol in cellular fungi by HPLC. A modified technique. J. Argentine Chem. Soc. 2011, 98, 10–15. [Google Scholar]
  67. Kauffman, C.A.; Fisher, J.F.; Sobel, J.D.; Newman, C.A. Candida urinary tract infections—Diagnosis. Clin. Infect. Dis. 2011, 52, 452–456. [Google Scholar] [CrossRef] [PubMed]
  68. Sobel, J.D.; Fisher, J.F.; Kauffman, C.A.; Newman, C.A. Candida urinary tract infections—Epidemiology. Clin. Infect. Dis. 2011, 52, 433–436. [Google Scholar] [CrossRef] [PubMed]
  69. Reid, G.; Denstedt, J.D.; Kang, Y.S.; Lam, D.; Nause, C. Microbial adhesion and biofilm formation on ureteral stents in vitro and in vivo. J. Urol. 1992, 148, 1592–1594. [Google Scholar] [PubMed]
  70. Harriott, M.M.; Lilly, E.A.; Rodriguez, T.E.; Fidel, P.L.; Noverr, M.C. Candida albicans forms biofilms on the vaginal mucosa. Microbiology 2010, 156, 3635–3644. [Google Scholar] [CrossRef] [PubMed]
  71. Yang, S.P.; Chen, Y.Y.; Hsu, H.S.; Wang, F.D.; Chen, L.Y.; Fung, C.P. A risk factor analysis of healthcare-associated fungal infections in an intensive care unit: A retrospective cohort study. BMC Infect. Dis. 2013, 13, 10. [Google Scholar] [CrossRef] [PubMed]
  72. Chassot, F.; Negri, M.F.N.; Svidzinski, A.E.; Donatti, L.; Peralta, R.; Svidzinski, T.; Consolaro, M. Can intrauterine contraceptive devices be a Candida albicans reservoir? Contraception 2008, 77, 355–359. [Google Scholar] [CrossRef] [PubMed]
  73. Foreman, A.; Jervis-Bardy, J.; Wormald, P.J. Do biofilms contribute to the initiation and recalcitrance of chronic rhinosinusitis? Laryngoscope 2011, 121, 1085–1091. [Google Scholar] [CrossRef] [PubMed]
  74. Keir, J.; Pedelty, L.; Swift, A.C. Biofilms in chronic rhinosinusitis: Systematic review and suggestions for future research. J. Laryngol. Otol. 2011, 125, 331–337. [Google Scholar] [CrossRef] [PubMed]
  75. Ebbens, F.A.; Georgalas, C.; Fokkens, W.J. The mold conundrum in chronic hyperplastic sinusitis. Curr. Allergy Asthma Rep. 2009, 9, 114–120. [Google Scholar] [CrossRef] [PubMed]
  76. Ebbens, F.A.; Georgalas, C.; Fokkens, W.J. Fungus as the cause of chronic rhinosinusitis: The case remains unproven. Curr. Opin. Otolaryngol. Head Neck Surg. 2009, 17, 43–49. [Google Scholar] [CrossRef] [PubMed]
  77. Grosjean, P.; Weber, R. Fungus balls of the paranasal sinuses: A review. Eur. Arch. Oto Rhino Laryngol. 2007, 264, 461–470. [Google Scholar] [CrossRef] [PubMed]
  78. Karkas, A.; Rtail, R.; Reyt, E.; Timi, N.; Righini, C.A. Sphenoid sinus fungus ball. Eur. Arch. Otorhinolaryngol. 2012, 270, 893–898. [Google Scholar] [CrossRef] [PubMed]
  79. Harding, M.W.; Marques, L.L.R.; Howard, R.J.; Olson, M.E. Can filamentous fungi form biofilms? Trends Microbiol. 2009, 17, 475–480. [Google Scholar] [CrossRef] [PubMed]
  80. Mowat, E.; Williams, C.; Jones, B.; McChlery, S.; Ramage, G. The characteristics of Aspergillus fumigatus mycetoma development: Is this a biofilm? Med. Mycol. 2009, 47, S120–S126. [Google Scholar] [CrossRef] [PubMed]
  81. Buijssen, K.J.D.A.; van der Laan, B.F.A.M.; van der Mei, H.C.; Atema-Smit, J.; van der Huijssen, P.; Busscher, H.J.; Harmsen, H. Composition and architecture of biofilms on used voice prostheses. Head Neck 2012, 34, 863–871. [Google Scholar] [CrossRef] [PubMed]
  82. Ell, S.R. Candida ‘the cancer of silastic’. J. Laryngol. Otol. 1996, 110, 240–242. [Google Scholar] [CrossRef] [PubMed]
  83. Holmes, A.R.; van der Wielen, P.; Cannon, R.D.; Ruske, D.; Dawes, P. Candida albicans binds to saliva proteins selectively adsorbed to silicone. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endodontol. 2006, 102, 488–494. [Google Scholar] [CrossRef] [PubMed]
  84. Marie-Soleil, D.; Williamson, D.R.; Albert, M.; Perreault, M.M.; Jiang, X.; Day, A.G.; Heyland, D.K. Impact of Candida species on clinical outcomes in patients with suspected ventilatorassociated pneumonia. Can. Respir. J. 2011, 18, 131–136. [Google Scholar]
  85. Hamet, M.; Pavon, A.; Dalle, F.; Pechinot, A.; Prin, S.; Quenot, J.P.; Charles, P.E. Candida spp. airway colonization could promote antibiotic-resistant bacteria selection in patients with suspected ventilator-associated pneumonia. Intensive Care Med. 2012, 38, 1272–1279. [Google Scholar] [CrossRef] [PubMed]
  86. Gutiérrez-Correa, M.; Ludena, Y.; Ramage, G.; Villena, G.K. Recent advances on filamentous fungal biofilms for industrial uses. Appl. Biochem. Biotechnol. 2012, 167, 1235–1253. [Google Scholar] [CrossRef] [PubMed]
  87. Singh, P.K.; Schaefer, A.L.; Parsek, M.R.; Moninger, T.O.; Welsh, M.J.; Greenberg, E.P. Quorum-sensing signals indicate that cystic fibrosis lungs are infectedwith bacterial biofilms. Nature 2000, 407, 762–764. [Google Scholar] [CrossRef] [PubMed]
  88. Ramage, G.; Rajendran, R.; Gutierrez-Correa, M.; Jones, B.; Williams, C. Aspergillus biofilms: Clinical and industrial significance. FEMS Microbiol. Lett. 2011, 324, 89–97. [Google Scholar] [CrossRef] [PubMed]
  89. Mowat, E.; Lang, S.; Williams, C.; McCulloch, E.; Jones, B.; Ramage, G. Phase-dependent antifungal activity against Aspergillus fumigatus developing multicellular filamentous biofilms. J. Antimicrob. Chemother. 2008, 62, 1281–1284. [Google Scholar] [CrossRef] [PubMed]
  90. Seidler, M.J.; Salvenmoser, S.; Müller, F.M.C. Aspergillus fumigatus forms biofilms with reduced antifungal drug susceptibility on bronchial epithelial cells. Antimicrob. Agents Chemother. 2008, 52, 4130–4136. [Google Scholar] [CrossRef] [PubMed]
  91. Chotirmall, S.H.; O’Donoghue, E.; Bennett, K.; Gunaratnam, C.; O’Neil, S.; McElvaney, N.G. Sputum Candida albicans presages FEV decline and hospital-treated exacerbations in cystic fibrosis. Chest 2010, 138, 1186–1195. [Google Scholar] [CrossRef] [PubMed]
  92. Delhaes, L.; Monchy, S.; Fréalle, E.; Hubans, C.; Salleron, J.; Leroy, S.; Prevotat, A.; Wallet, F.; Wallaert, B.; Dei-Cas, E.; et al. The airway microbiota in cystic fibrosis: A complex fungal and bacterial community—Implications for therapeutic management. PLoS ONE 2012, 7, 1–14. [Google Scholar] [CrossRef] [PubMed]
  93. Cugini, C.; Calfee, M.W.; Farrow, J.M.; Morales, D.K.; Pesci, E.C.; Hogan, D. Farnesol, a common sesquiterpene, inhibits PQS production in Pseudomonas aeruginosa. Mol. Microbiol. 2007, 65, 896–906. [Google Scholar] [CrossRef] [PubMed]
  94. Gibson, J.; Sood, A.; Hogan, D.A. Pseudomonas aeruginosa-Candida albicans interactions: Localization and fungal toxicity of a phenazine derivative. Appl. Environ. Microbiol. 2009, 75, 504–513. [Google Scholar] [CrossRef] [PubMed]
  95. Morales, D.K.; Jacobs, N.J.; Rajamani, S.; Krishnamurthy, M.; Cubillos-Ruiz, J.R.; Hogan, D. Antifungal mechanisms by which a novel Pseudomonas aeruginosa phenazine toxin kills Candida albicans in biofilms. Mol. Microbiol. 2010, 78, 1379–1392. [Google Scholar] [CrossRef] [PubMed]
  96. Hogan, D.; Vik, A.; Kolter, R. A Pseudomonas aeruginosa quorum-sensing molecule influences Candida albicans morphology. Mol. Microbiol. 2004, 54, 1212–1223. [Google Scholar] [CrossRef] [PubMed]
  97. Peters, B.M.; Jabra-Rizk, M.A.; O’May, G.A.; William Costerton, J.; Shirtliff, M.E. Polymicrobial interactions: Impact on pathogenesis and human disease. Clin. Microbiol. Rev. 2012, 25, 193–213. [Google Scholar] [CrossRef] [PubMed]
  98. Sibley, C.D.; Duan, K.; Fischer, C.; Parkins, M.D.; Storey, D.G.; Rabin, H.R.; Surette, M.G. Discerning the complexity of community interactions using a Drosophila model of polymicrobial infections. PLoS Pathog. 2008, 4, e1000184. [Google Scholar] [CrossRef] [PubMed]
  99. Sibley, C.D.; Parkins, M.D.; Rabin, H.R.; Duan, K.; Norgaard, J.C.; Surette, M.G. A polymicrobial perspective of pulmonary infections exposes an enigmatic pathogen in cystic fibrosis patients. Proc. Natl. Acad. Sci. USA 2008, 105, 15070–15075. [Google Scholar] [CrossRef] [PubMed]
  100. Seth, A.K.; Geringer, M.R.; Hong, S.J.; Leung, K.P.; Mustoe, T.A.; Galiano, R.D. In vivo modeling of biofilm-infected wounds: A review. J. Surg. Res. 2012, 178, 330–338. [Google Scholar] [CrossRef] [PubMed]
  101. Branski, L.K.; Al-Mousawi, A.; Rivero, H.; Jeschke, M.G.; Sanford, A.P.; Herndon, D.N. Emerging infections in burns. Surg. Infect. 2009, 10, 389–397. [Google Scholar] [CrossRef] [PubMed]
  102. Coco, B.J.; Bagg, J.; Cross, L.J.; Jose, A.; Cross, J.; Ramage, G. Mixed Candida albicans and Candida glabrata populations associated with the pathogenesis of denture stomatitis. Oral Microbiol. Immunol. 2008, 23, 377–383. [Google Scholar] [CrossRef] [PubMed]
  103. Harriott, M.M.; Noverr, M.C. Candida albicans and Staphylococcus aureus form polymicrobial biofilms: Effects on antimicrobial resistance. Antimicrob. Agents Chemother. 2009, 53, 3914–3922. [Google Scholar] [CrossRef] [PubMed]
  104. Arendrup, M.C. Epidemiology of invasive candidiasis. Curr. Opin. Crit. Care 2010, 16, 445–452. [Google Scholar] [CrossRef] [PubMed]
  105. Mikolajewska, A.; Schwartz, S.; Ruhnke, M. Antifungal treatment strategies in patients with haematological diseases or cancer: From prophylaxis to empirical, pre-emptive and targeted therapy. Mycoses 2012, 55, 2–16. [Google Scholar] [CrossRef] [PubMed]
  106. Chen, S.C.-A.; Slavin, M.A.; Sorrell, T.C. Echinocandin antifungal drugs in fungal infections: A comparison. Drugs 2011, 71, 11–41. [Google Scholar] [CrossRef] [PubMed]
  107. Cowen, L.E. The evolution of fungal drug resistance: Modulating the trajectory from genotype to phenotype. Nat. Rev. Microbiol. 2008, 6, 187–198. [Google Scholar] [CrossRef] [PubMed]
  108. Jabra-Rizk, M.A.; Falkler, W.A.; Meiller, T.F. Fungal Biofilms and Drug Resistance. Emerg. Infect. Dis. 2004, 10, 14–19. [Google Scholar] [CrossRef] [PubMed]
  109. White, T.C.; Marr, K.A. Clinical, Cellular, and Molecular Factors That Contribute to Antifungal Drug Resistance. Clin. Microbiol. Rev. 1998, 11, 382–402. [Google Scholar] [PubMed]
  110. Pappas, P.G.; Kauffman, C.A.; Andes, D.R.; Clancy, C.J.; Marr, K.A.; Ostrosky-Zeichner, L.; Reboli, A.C.; Schuster, M.G.; Vazquez, J.A.; Walsh, T.J.; et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2015, 62, e1–e50. [Google Scholar] [CrossRef] [PubMed]
  111. Ullmann, A.J.; Akova, M.; Herbrecht, R.; Viscoli, C.; Arendrup, M.C.; Arikan-Akdagli, S.; Bassetti, M.; Bille, J.; Calandra, T.; Castagnola, E.; et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: Adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clin. Microbiol. Infect. 2012, 18, 53–67. [Google Scholar] [CrossRef] [PubMed]
  112. Rex, J.H.; Sobel, J.D. Prophylactic antifungal therapy in the intensive care unit. Clin. Infect. Dis. 2001, 32, 1191–1200. [Google Scholar] [PubMed]
  113. Manzoni, P. Prophylactic fluconazole is effective in preventing fungal colonization and fungal systemic infections in preterm neonates: A single-center, 6-year, retrospective cohort study. Pediatrics 2006, 117, e22–e32. [Google Scholar] [CrossRef] [PubMed]
  114. Lipsett, P.A. Clinical trials of antifungal prophylaxis among patients in surgical intensive care units: Concepts and considerations. Clin. Infect. Dis. 2004, 39, S193–S199. [Google Scholar] [CrossRef] [PubMed]
  115. Ho, K.M.; Lipman, J.; Dobb, G.J.; Webb, S.A. The use of prophylactic fluconazole in immunocompetent high-risk surgical patients: A meta-analysis. Clin. Infect. Dis. 2006, 9, R710–R717. [Google Scholar]
  116. Blumberg, H.M.; Jarvis, W.R.; Soucie, J.M.; Edwards, J.E.; Patterson, J.E.; Pfaller, M.A.; Rangel-Frausto, M.S.; Rinaldi, M.G.; Saiman, L.; Wiblin, T.; et al. Risk factors for candidal bloodstream infections in surgical intensive care unit patients: The NEMIS prospective multicenter study. Clin. Infect. Dis. 2001, 33, 177–186. [Google Scholar] [CrossRef] [PubMed]
  117. Fonseca, E.; Silva, S.; Rodrigues, C.F.; Alves, C.T.; Azeredo, J.; Henriques, M. Effects of fluconazole on Candida glabrata biofilms and its relationship with ABC transporter gene expression. Biofouling 2014, 30, 447–457. [Google Scholar] [CrossRef] [PubMed]
  118. Fernandes, T.; Silva, S.; Henriques, M. Candida tropicalis biofilm’s matrix-involvement on its resistance to amphotericin B. Diagn. Microbiol. Infect. Dis. 2015, 83, 165–169. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Posteraro, B.; Vella, A.; De Carolis, E.; Sanguinetti, M. Molecular detection of resistance to azole components. Methods Mol. Biol. 2017, 1508, 423–435. [Google Scholar] [PubMed]
  120. Rodrigues, C.F.; Silva, S.; Azeredo, J.; Henriques, M. Candida glabrata’s recurrent infections: Biofilm formation during Amphotericin B treatment. Lett. Appl. Microbiol. 2016, 63, 77–81. [Google Scholar] [CrossRef] [PubMed]
  121. Fernandes, T.; Silva, S.; Henriques, M. Effect of voriconazole on Candida tropicalis biofilms: Relation with ERG genes expression. Mycopathologia 2016, 181, 643–651. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Perumal, P.; Mekala, S.; Chaffin, W.L. Role for cell density in antifungal drug resistance in Candida albicans biofilms. Antimicrob. Agents Chemother. 2007, 51, 2454–2463. [Google Scholar] [CrossRef] [PubMed]
  123. Seneviratne, C.J.; Jin, L.; Samaranayake, L.P. Biofilm lifestyle of Candida: A mini review. Oral Dis. 2008, 14, 582–590. [Google Scholar] [CrossRef] [PubMed]
  124. Silva, S.; Henriques, M.; Martins, A.; Oliveira, R.; Williams, D.; Azeredo, J. Biofilms of non-Candida albicans Candida species: Quantification, structure and matrix composition. Med. Mycol. 2009, 47, 681–689. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Silva, S.; Henriques, M.; Oliveira, R.; Williams, D.; Azeredo, J. In vitro biofilm activity of non-Candida albicans Candida species. Curr. Microbiol. 2010, 61, 534–540. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Baillie, G.S.; Douglas, L.J. Effect of growth rate on resistance of Candida albicans biofilms to antifungal agents. Antimicrob. Agents Chemother. 1998, 42, 1900–1905. [Google Scholar] [PubMed]
  127. Baillie, G.S.; Douglas, L.J. Iron-limited biofilms of Candida albicans and their susceptibility to Amphotericin B. Antimicrob. Agents Chemother. 1998, 42, 2146–2149. [Google Scholar] [PubMed]
  128. Dumitru, R.; Hornby, J.M.; Kenneth, W.; Nickerson, K.W. Defined anaerobic growth medium for studying Candida albicans basic biology and resistance to eight antifungal drugs. Antimicrob. Agents Chemother. 2004, 48, 2350–2354. [Google Scholar] [CrossRef] [PubMed]
  129. Kucharíková, S.; Tournu, H.; Lagrou, K.; van Dijck, P.; Bujdakova, H. Detailed comparison of Candida albicans and Candida glabrata biofilms under different conditions and their susceptibility to caspofungin and anidulafungin. J. Med. Microbiol. 2011, 60, 1261–1269. [Google Scholar] [CrossRef] [PubMed]
  130. Pettit, R.K.; Repp, K.K.; Hazen, K.C. Temperature affects the susceptibility of Cryptococcus neoformans biofilms to antifungal agents. Med. Mycol. 2010, 48, 421–426. [Google Scholar] [CrossRef] [PubMed]
  131. Ramage, G.; VandeWalle, K.; Wickes, B.L.; López-Ribot, J.L. Standardized method for in vitro antifungal susceptibility testing of Candida albicans biofilms. Antimicrob. Agents Chemother. 2001, 45, 2475–2479. [Google Scholar] [CrossRef] [PubMed]
  132. Al-fattani, M.A.; Douglas, L.J. Penetration of Candida biofilms by antifungal agents. Antimicrob. Agents Chemother. 2004, 48, 3291–3297. [Google Scholar] [CrossRef] [PubMed]
  133. Martins, M.; Henriques, M.; Lopez-Ribot, J.L.; Oliveira, R. Addition of DNase improves the in vitro activity of antifungal drugs against Candida albicans biofilms. Mycoses 2012, 55, 80–85. [Google Scholar] [CrossRef] [PubMed]
  134. Nett, J.; Lincoln, L.; Marchillo, K.; Massey, R.; Holoyda, K.; Hoff, B.; VanHandel, M.; Andes, D. Putative role of β-1,3 glucans in Candida albicans biofilm resistance. Antimicrob. Agents Chemother. 2007, 51, 510–520. [Google Scholar] [CrossRef] [PubMed]
  135. Nett, J.E.; Sanchez, H.; Cain, M.T.; Andes, D.R. Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J. Infect. Dis. 2010, 202, 171–175. [Google Scholar] [CrossRef] [PubMed]
  136. Nett, J.E.; Crawford, K.; Marchillo, K.; Andes, D.R. Role of Fks1p and matrix glucan in Candida albicans biofilm resistance to an echinocandin, pyrimidine, and polyene. Antimicrob. Agents Chemother. 2010, 54, 3505–3508. [Google Scholar] [CrossRef] [PubMed]
  137. Nett, J.E.; Sanchez, H.; Cain, M.T.; Ross, K.M.; Andes, D.R. Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation. Eukaryot. Cell 2011, 10, 1660–1669. [Google Scholar] [CrossRef] [PubMed]
  138. Nobile, C.J.; Nett, J.E.; Hernday, A.D.; Homann, O.R.; Deneault, J.-S.; Nantel, A.; Andes, D.R.; Johnson, A.D.; Mitchell, A.P. Biofilm matrix regulation by Candida albicans Zap1. PLoS Biol. 2009, 7. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  139. Lewis, K. Persister Cells. Annu. Rev. Microbiol. 2010, 64, 357–372. [Google Scholar] [CrossRef] [PubMed]
  140. LaFleur, M.D.; Kumamoto, C.A.; Lewis, K. Candida albicans biofilms produce antifungal-tolerant persister cells. Antimicrob. Agents Chemother. 2006, 50, 3839–3846. [Google Scholar] [CrossRef] [PubMed]
  141. Lewis, K. Multidrug tolerance of biofilms and persister cells. Curr. Top. Microbiol. Immunol. 2008, 322, 107–131. [Google Scholar] [PubMed]
  142. Al-Dhaheri, R.S.; Douglas, L.J. Absence of amphotericin B-tolerant persister cells in biofilms of some Candida species. Antimicrob. Agents Chemother. 2008, 52, 1884–1887. [Google Scholar] [CrossRef] [PubMed]
  143. Knot, P.D.; Suci, P.A.; Miller, R.L.; Nelson, R.D.; Tyler, B.J. A small subpopulation of blastospores in Candida albicans biofilms exhibit resistance to amphotericin B associated with differential regulation of ergosterol and β-1,6-glucan pathway genes. Antimicrob. Agents Chemother. 2006, 50, 3708–3716. [Google Scholar]
  144. Bink, A.; Vandenbosch, D.; Coenye, T.; Nelis, H.; Cammue, B.P.A.; Thevissen, K. Superoxide dismutases are involved in Candida albicans biofilm persistence against miconazole. Antimicrob. Agents Chemother. 2011, 55, 4033–4037. [Google Scholar] [CrossRef] [PubMed]
  145. Mukherjee, P.K.; Chandra, J.; Kuhn, D.M.; Ghannoum, M.A. Mechanism of fluconazole resistance in Candida albicans biofilms: Phase-specific role of efflux pumps and membrane sterols. Infect. Immun. 2003, 71, 4333–4340. [Google Scholar] [CrossRef] [PubMed]
  146. Finkel, J.S.; Mitchell, A.P. Genetic control of Candida albicans biofilm development. Nat. Rev. Microbiol. 2011, 9, 109–118. [Google Scholar] [CrossRef] [PubMed]
  147. Nett, J.; Lincoln, L.; Marchillo, K.; Andes, D. β-1,3 Glucan as a test for central venous catheter biofilm infection. J. Infect. Dis. 2007, 195, 1705–1712. [Google Scholar] [CrossRef] [PubMed]
  148. Cannon, R.D.; Lamping, E.; Holmes, A.R.; Niimi, K.; Tanabe, K.; Niimi, M.; Monk, B.C. Candida albicans drug resistance—Another way to cope with stress. Microbiology 2007, 153, 3211–3217. [Google Scholar] [CrossRef] [PubMed]
  149. White, T.C. Increased mRNA levels of ERG16, CDR, and MDR1 correlate, with increases in azole resistance in Candida albicans isolates from a patient infected with human immunodeficiency virus. Antimicrob. Agents Chemother. 1997, 41, 1482–1487. [Google Scholar] [PubMed]
  150. Tscherner, M.; Schwarzmüller, T.; Kuchler, K. Pathogenesis and antifungal drug resistance of the human fungal pathogen Candida glabrata. Pharmaceuticals 2011, 4, 169–186. [Google Scholar] [CrossRef]
  151. Akins, R.A. An update on antifungal targets and mechanisms of resistance in Candida albicans. Med. Mycol. 2005, 43, 285–318. [Google Scholar] [CrossRef] [PubMed]
  152. Henry, K.W.; Nickels, J.T.; Edlind, T.D. Upregulation of ERG genes in Candida species by azoles and other sterol biosynthesis inhibitors. Antimicrob. Agents Chemother. 2000, 44, 2693–2700. [Google Scholar] [CrossRef] [PubMed]
  153. Borecká-Melkusová, S.; Moran, G.P.; Sullivan, D.J.; Kucharíková, S.; Chrovát, D.; Bujdáková, H. The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida dubliniensis biofilms exposed to fluconazole. Mycoses 2009, 52, 118–128. [Google Scholar] [CrossRef] [PubMed]
  154. Rossignol, T.; Ding, C.; Guida, A.; D’Enfert, C.; Higgins, D.G.; Butler, G. Correlation between biofilm formation and the hypoxic response in Candida parapsilosis. Eukaryot. Cell 2009, 8, 550–559. [Google Scholar] [CrossRef] [PubMed]
  155. Katragkou, A.; Chatzimoschou, A.; Simitsopoulou, M.; Dalakiouridou, M.; Diza-Mataftsi, E.; Tsantali, C.; Roilides, E. Differential activities of newer antifungal agents against Candida albicans and Candida parapsilosis biofilms. Antimicrob. Agents Chemother. 2008, 52, 357–360. [Google Scholar] [CrossRef] [PubMed]
  156. Morschhäuser, J. The genetic basis of fluconazole resistance development in Candida albicans. Biochim. Biophys. Acta Mol. Basis Dis. 2002, 1587, 240–248. [Google Scholar] [CrossRef]
  157. Shapiro, R.S.; Robbins, N.; Cowen, L.E. Regulatory circuitry governing fungal development, drug resistance, and disease. Microbiol. Mol. Biol. Rev. 2011, 75, 213–267. [Google Scholar] [CrossRef] [PubMed]
  158. Bachmann, S.P.; Patterson, T.F.; López-Ribot, J.L. In vitro activity of caspofungin (MK-0991) against Candida albicans clinical isolates displaying different mechanisms of azole resistance. J. Clin. Microbiol. 2002, 40, 2228–2230. [Google Scholar] [CrossRef] [PubMed]
  159. Schubert, S.; Barker, K.S.; Znaidi, S.; Schneider, S.; Dierolf, F.; Dunkel, N.; Aïd, M.; Boucher, G.; Rogers, P.D.; Raymond, M.; et al. Regulation of efflux pump expression and drug resistance by the transcription factors Mrr1, Upc2, and Cap1 in Candida albicans. Antimicrob. Agents Chemother. 2011, 55, 2212–2223. [Google Scholar] [CrossRef] [PubMed]
  160. Niimi, K.; Maki, K.; Ikeda, F.; Holmes, A.R.; Lamping, E.; Niimi, M.; Monk, B.C.; Cannon, R.D. Overexpression of Candida albicans CDR1, CDR2, or MDR1 Does Not Produce Significant Changes in Echinocandin Susceptibility. Antimicrob. Agents Chemother. 2006, 50, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
  161. Silver, P.M.; Oliver, B.G.; White, T.C. Characterization of caspofungin susceptibilities by broth and agar in Candida albicans clinical isolates with characterized mechanisms of azole resistance. Med. Mycol. 2008, 46, 231–239. [Google Scholar] [CrossRef] [PubMed]
  162. Sanglard, D.; Kuchler, K.; Ischer, F.; Pagani, J.L.; Monod, M.; Bille, J. Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters. Antimicro. Agents Chemother. 1995, 39, 2378–2386. [Google Scholar] [CrossRef]
  163. Albertson, G.D.; Niimi, M.; Cannon, R.D.; Jenkinson, H.F. Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance. Antimicrob. Agents Chemother. 1996, 40, 2835–2841. [Google Scholar] [PubMed]
  164. Coste, A.; Turner, V.; Ischer, F.; Diogo, D.; Bougnoux, M.-E.; d’Enfert, C.; Berman, J.; Sanglard, D. A mutation in Tac1p, a transcription factor regulating CDR1 and CDR2, is coupled with loss of heterozygosity at chromosome 5 to mediate antifungal resistance in Candida albicans. Genetics 2006, 172, 2139–2156. [Google Scholar] [CrossRef] [PubMed]
  165. Dunkel, N.; Blass, J.; Rogers, P.D.; Morschhäuser, J. Mutations in the multidrug resistance regulator MRR1, followed by loss of heterozygosity, are the main cause of MDR1 overexpression in fluconazole-resistant Candida albicans strains. Mol. Microbiol. 2008, 69, 827–840. [Google Scholar] [CrossRef] [PubMed]
  166. Ramage, G.; Rajendran, R.; Sherry, L.; Williams, C. Fungal biofilm resistance. Int. J. Microbiol. 2012, 2012, 528521. [Google Scholar] [CrossRef] [PubMed]
  167. Bizerra, F.C.; Nakamura, C.V.; De Poersch, C.; Svidzinski, T.; Quesada, R.; Goldenberg, S.; Krieger, M.; Yamada-Ogatta, S. Characteristics of biofilm formation by Candida tropicalis and antifungal resistance. FEMS Yeast Res. 2008, 8, 442–450. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. General scheme of the mechanisms described as involved on Candida species biofilm resistance.
Figure 1. General scheme of the mechanisms described as involved on Candida species biofilm resistance.
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Table
Table 1. Characteristics of the most common Candida species biofilms.
Table 1. Characteristics of the most common Candida species biofilms.
Candida SpeciesBiofilm Forming CapacityBiofilm CharacteristicsRefs.
Candida albicans+++++Basal blastospore layer with a dense overlying matrix composed of exopolysaccharides and hyphae.[27,28]
Candida dubliniensis++/+++Chains of cells with thin extracellular matrix material.[29,30]
Hhigh variability among clinical isolates.
Candida glabrata++/+++Forms considerably less biofilm than C. albicans.[6,28]
High in both protein and carbohydrate content.
Candida krusei++++Thick multilayered biofilm of pseudohyphal forms embedded within the polymer matrix.[31]
Candida parapsilosis+++Clumped blastospores and less volume.[23,27,28,30,32]
Large amounts of carbohydrate with less protein.
High variability among clinical isolates.
Candida tropicalis+++Chains of cells with thin, but large, amounts of extracellular matrix material.[24,28]
Low amounts of carbohydrate and protein.
+++ Normal to high; ++++ High; +++++ Very high biofilm formers.
Table
Table 2. Localization, condition/disease and most common species found on several Candida biofilms.
Table 2. Localization, condition/disease and most common species found on several Candida biofilms.
BiofilmCondition/DiseaseMost Common Candida SpeciesRefs.
Medical DevicesEndocarditisCandida albicans[14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33]
Total parenteral nutrition Candida glabrata
Prosthetic jointsCandida tropicalis
Peritoneal dialysis Candida parapsilosis
Cannulation
Ventriculoperitoneal shunts
Prosthetic knees
Hip joints
Breast implants
Bioprosthetic heart valves
Catheter-related disease: urinary catheter, central venous catheter, intravenous catheter
OralCariesCandida albicans[10,24,33,34,35,36,37,38,39,40,41,42,43,44,45,46]
Periodontal diseaseCandida glabrata
Endodontic infectionCandida dubliniensis Candida tropicalis
Several mucosal infectionsCandida krusei
Candida parapsilosis
Gastrointestinal (GI) and Urinary TractFeeding tubes for enteral nutritionCandida albicans[47,48,49,50,51,52,53,54,55,56,57,58,59]
Ulcerative colitisCandida tropicalis
GI candidiasis
Pyelonephritis
Cystitis
Prostatitis
Intrauterine contraceptives
Upper AirwaysRhinosinusitisCandida albicans[60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85]
Ventilator-associatedCandida glabrata
PneumoniaCandida krusei
Lower AirwaysCystic FibrosisCandida albicans[86,87,88,89,90,91,92,93,94,95,96,97,98,99]
Allergic bronchopulmonary diseases
WoundsDiabetic foot ulcerCandida albicans[100,101,102,103]
Non-healing surgical woundsCandida glabrata
Chronic wound infections
Pressure ulcers
Venous leg ulcers

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Silva, S.; Rodrigues, C.F.; Araújo, D.; Rodrigues, M.E.; Henriques, M. Candida Species Biofilms’ Antifungal Resistance. J. Fungi 2017, 3, 8. https://doi.org/10.3390/jof3010008

AMA Style

Silva S, Rodrigues CF, Araújo D, Rodrigues ME, Henriques M. Candida Species Biofilms’ Antifungal Resistance. Journal of Fungi. 2017; 3(1):8. https://doi.org/10.3390/jof3010008

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Silva, Sónia, Célia F. Rodrigues, Daniela Araújo, Maria Elisa Rodrigues, and Mariana Henriques. 2017. "Candida Species Biofilms’ Antifungal Resistance" Journal of Fungi 3, no. 1: 8. https://doi.org/10.3390/jof3010008

APA Style

Silva, S., Rodrigues, C. F., Araújo, D., Rodrigues, M. E., & Henriques, M. (2017). Candida Species Biofilms’ Antifungal Resistance. Journal of Fungi, 3(1), 8. https://doi.org/10.3390/jof3010008

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