Future directions for anti-biofilm therapeutics targeting Candida
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Review
Future directions for
anti-biofilm therapeutics
targeting Candida
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
Expert Rev. Anti Infect. Ther. 12(3), 375–382 (2014)
Jeniel E Nett While proliferating in its most common mode of growth, a biofilm, Candida spp. exhibit
Department of Medicine, Department
increased resistance to available antifungal agents. These adherent communities are difficult
of Medical Microbiology and to eradicate and often responsible for treatment failures. New therapies are urgently needed
Immunology, University of Wisconsin, to treat a variety of Candida biofilm infections in the medical setting. This review discusses
4153 Microbial Sciences Building,
the medical relevance of Candida biofilms, the drug resistance associated with this mode of
1550 Linden Drive, Madison, WI
53705, USA growth, and approaches to combat these resilient infections.
Tel.: +1 608 262 7494
Fax: +1 608 263 4464 KEYWORDS: amphotericin B • antifungal • azole • biofilm • Candida • echinocandin • lock therapy • matrix
jenett@medicine.wisc.edu • resistance
therapies, these infections are notoriously diffi-
For personal use only.
Role of biofilm in Candida infection cult to treat. Most often, cure of biofilm infec-
Many fungal and bacterial pathogens thrive as tions requires removal of the infected
biofilms, causing infections in a variety of clini- device [11]. This is reflected in current guide-
cal and environmental niches [1,2]. As a biofilm, lines that recommend removal of Candida-
a microbial population demonstrates properties infected medical devices as treatment of the
distinct from non-biofilm, free-floating cells. infection [12]. However, procedural risk to the
These cohesive communities of organisms are patient may be significant, especially in the
adherent to a surface and surrounded by an setting of permanent devices, such as pace-
extracellular, polymeric matrix. They resist host makers or hemodialysis access devices.
defenses and may be extraordinarily tolerant to
antimicrobials, withstanding anti-infectives at Efficacy of available antifungal therapies
concentrations many times greater than those The majority of medically important Candida
needed to eradicate non-biofilm cells [1,3]. The spp. have now been shown to generate biofilms,
importance of biofilms has been increasingly including C. albicans, C. dubliniensis, C. glab-
evident with the widespread use of medical rata, C. krusei, C. tropicalis and C. parapsilosis
devices, as nearly all device-associated infections [6,13]. Candida biofilms exhibit resistance to
involve the biofilm mode of growth [2,4]. agents from all available, commonly used anti-
Vulnerable devices are diverse and include cath- fungal drug classes, including the azoles (flucon-
eters, implants, pacemakers, artificial heart azole, itraconazole, voriconazole, posaconazole),
valves and CNS shunts [2,5]. the echinocandins (caspofungin, micafungin,
Infection by Candida, the most common anidulafungin), the amphotericin B formula-
hospital-acquired fungal pathogen, frequently tions and flucytosine [14–19]. These antifungal
involves biofilm growth [5,6]. This organism drugs have diverse mechanisms of action. The
has a propensity to adhere to the surface of azole drugs and amphotericin B formulations
catheters and other commonly used medical interfere with cell membrane ergosterol, while
devices (FIGURE 1). In the hospital setting where the echinocandins inhibit cell wall b-1,3 glucan
medical device use is commonplace, Candida synthesis and flucytosine, a pyrimidine analog,
is the fourth most common cause of blood- inhibits nucleic acid synthesis. [20]. The biofilm-
stream infection and the third most common associated drug-resistant phenotype has been
cause of urinary tract infection [7–10]. Exhibit- replicated and studied using numerous in vitro
ing increased resistance to available antifungal models of biofilm infections [11,12,21–24]. In vivo
informahealthcare.com 10.1586/14787210.2014.885838 2014 Informa UK Ltd ISSN 1478-7210 375Review Nett
collectively promote resistance to anti-infectives during biofilm
growth. There appears to be interplay between several resistance
mechanisms, which vary during the phases of biofilm growth.
Also, there is diversity among the biofilm cells in these heteroge-
neous structures. For example, subpopulations of Candida within
biofilms are highly resistant to amphotericin B [33,34]. Upon drug
treatment, these ‘persisters’ are proposed to act as a reservoir,
allowing the biofilm to repopulate. An example of a phase-
specific mechanism of resistance is the alteration of efflux pump
activity. Upon transitioning to the biofilm lifestyle, the activity
of C. albicans efflux pumps increases, ultimately lowering the
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
intracellular azole drug concentrations and promoting resis-
tance [18,31]. The contribution of the mechanism appears to be
greatest early in biofilm formation, likely due to the lower cell
density [37]. Other mechanisms are more specific to mature bio-
10 µm
film formation. For example, later in biofilm development, the
Figure 1. Candida albicans biofilm infection of rat venous
increased cell density and extracellular matrix promotes resistance
catheter. C. albicans was instilled in the lumen of a jugular to amphotericin B, azoles and echinocandins [3,35–40]. In addition,
venous catheter, allowed to dwell for 6 h, and then flushed. the altered ergosterol content found in mature biofilm cells is
After a growth period of 24 h, the catheter was harvested, fixed hypothesized to influence drug resistance during the later growth
and dehydrated. Catheter segments were imaged by scanning phase [18].
electron microscopy on a JEOL JSM-6100 at 10 kV (2000). The
biofilm is composed of both yeast and hyphae encased in an
The presence of an adhesive extracellular matrix, one of
extracellular matrix. the unique and defining biofilm traits, has been linked to
the multidrug-resistant phenotype observed for biofilms formed
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studies using rat or rabbit models of vascular catheter infection by many Candida spp., including C. albicans, C. parapsilosis,
show Candida biofilms can withstand fluconazole concentrations C. tropicalis, C. glabrata and C. krusei [3,35,36,38–40]. This mecha-
up to 1000-fold higher than the minimal inhibitory concentra- nism has been shown to play a key role in biofilm resistance to
tion (MIC) for planktonic organisms [25,26]. Clinically, outcomes amphotericin B, echinocandin drugs, flucytosine and fluconazole
of patients with invasive candidiasis are improved when infected [40–43]. Several components of the extracellular matrix have been
medical devices are removed, signifying that antifungal therapy linked to biofilm resistance. The b-1,3 glucan content of the bio-
alone is not adequate for treatment of Candida biofilm infection. film matrix correlates the antifungal-resistant phenotype and this
Although resistance has been described for commonly used substance has been shown to be a key factor in the binding or
antifungals, the degree of drug resistance associated with biofilm sequestering of both fluconazole and amphotericin B [43,44]. More
growth appears to vary quite significantly among the drugs. Stud- recently, the importance of C. albicans eDNA has been recog-
ies examining the impact of fluconazole, the most commonly nized. Interestingly, this substance is critical for biofilm resistance
used azole drug, demonstrate that biofilms are tolerant to con- to echinocandins and amphotericin B, but does not appear to
centrations up to 2000-fold above the MIC of planktonic contribute greatly to azole resistance [42]. While the importance of
cells [18,27]. Comparatively, the antifungals with the most activity the biofilm matrix in biofilm drug resistance has become increas-
against biofilms are the liposomal formulation of amphotericin B ing appreciated, how the individual components cooperate to pro-
and agents in the echinocandin drug class, which have been duce this characteristic remains unclear, and may vary for the
shown to be active at concentrations 2- to 25-fold above their individual drugs.
planktonic MICs [28]. As might be expected by this observation, As Candida transitions to the biofilm lifestyle, cellular
the mechanism of biofilm drug resistance is a complex phenome- stress responses become activated. These pathways contribute
non that varies by drug class. These investigations have included to the ability of Candida biofilms to resistant environmental
diverse in vivo and in vitro experimental systems, which differ insults, including antifungal therapy. Pathways shown to
with regard to substrate, flow, media and environmental condi- contribute to azole resistance in Candida biofilms involve
tions. The degree of biofilm resistance has been shown to vary the mitogen-activated protein kinase, calcineurin and heat
among the in vitro and in vivo models employed [29]. Studies shock protein 90 (Hsp90p) [32,45–47]. These resistance path-
have also found considerable variation in drug resistance among ways have been of great interest, as there are pharmaceutical
biofilms formed by different Candida species and strains [30]. agents that target calcineurin and Hsp90, which will be dis-
cussed below [45,47,48].
Mechanisms of Candida biofilm resistance
Identification of the mechanisms underlying the resistance of Strategies to combat Candida biofilms infections
Candida biofilms to antifungals has been of great interest [18,31–36]. As the available antifungal agents have minimal activity against
Studies to date support a model in which multiple factors biofilm infections, innovative approaches have been undertaken
376 Expert Rev. Anti Infect. Ther. 12(3), (2014)Future directions for anti-biofilm therapeutics targeting Candida Review
to eradicate these infections (FIGURE 2). One Enhance antifungal activity Local/lock therapy
of the strategies to optimize the efficacy – Inhibition of stress responses – Antifungals
of antifungals is delivery of high drug – Prostaglandin inhibition – Antiseptics
concentrations, most often by direct – Matrix degradation
administration, such as lock therapy for – Quorum sensing disruption
an infected catheter [26,49–51]. Other inves- Novel compounds
tigations have examined the impact of – Natural products
targeting a variety of pathways involved – Pharmaceutical
in biofilm growth, including the stress
responses, quorum sensing, extracellular
matrix production and prostaglandin
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
synthesis [45,47,48,52–54]. Disruption of these
processes can greatly enhance the activity
of antifungals during combination ther- Figure 2. Anti-biofilm strategies.
apy. Lastly, screens of pharmaceutical and
natural products have yielded promising compounds with excel- hydrazide, this compound forms a fungicidal gel. The product
lent anti-biofilm activity [55–57]. was well-tolerated in animals and has potential for future diverse
uses in the local treatment of Candida biofilm infection. Possible
High-dose therapy with available antifungals applications include the treatment of vascular catheter, bone, joint
While biofilms are capable of withstanding antifungals at the and abdominal infections involving Candida biofilms.
concentrations safely achievable in patients, they are susceptible No controlled trials have examined the efficacy of antifungal
to higher concentrations of a subset of these drugs, including lock therapy for patients with fungal biofilm infections and
amphotericin B and the echinocandins [28]. The toxicity of data are limited to few case reports [51]. Lock therapy regimens
amphotericin B formulations limits their use at higher doses. used in patients primarily have included high doses of ampho-
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Although azoles are relatively well-tolerated, Candida biofilms tericin B formulations or ethanol. Although several case reports
are tolerant to exceedingly high concentrations of these describe high salvage rates, there is a concern for the possibility
drugs [40–43]. Of the available antifungals, the echinocandins of publication bias. A randomized controlled trial is needed to
appear to have the most utility for biofilm treatment when determine if the lock therapies are effective, and if so, for
administered systemically. Clinically, higher doses of these which patient population. As lock therapy is delivered to the
drugs have been used for treatment of biofilm infection, such luminal surface only, biofilm infections involving the catheter
as endocarditis [12]. However, even with the higher doses, bio- tip or outer surface would likely have a higher failure rate.
films often persist and physical removal of biofilm is ultimately Also, if there is a concern for disseminated infection, concomi-
required for cure [11,12]. tant systemic antifungal therapy may be required. In addition,
there is the possibility that the use of an antifungal lock may
Anti-infective lock therapy promote development of resistance. Therefore, the use of anti-
Lock therapy, the prolonged instillation of drug into the cathe- septics or non-antifungal agents is of interest. In vitro, EDTA,
ter lumen, allows delivery of high-dose therapy while avoiding ethanol and high-dose minocycline (3 mg/ml) appear to be
systemic toxicity. By directly administering drug to the infected promising lock agents for treatment of Candida biofilms [61–63].
site, local antifungal concentrations may safely reach 1000-fold
higher than those achieved with systemic therapy [51]. Based on Exploiting combination therapy
in vitro models, the antifungals anticipated to have the greatest One approach to increase the efficacy of antifungal therapies is
anti-biofilm activity when administered in lock therapy are to combine synergistic agents. This strategy has been shown to
drugs in the echinocandin class and two amphotericin B for- be successful for several drug classes for the treatment of
mulations, liposomal amphotericin B and amphotericin B lipid Candida biofilms. Some of the most effective studies have
complex [28,58]. In animal vascular catheter infection models, included agents targeting stress responses activated during bio-
lock therapies with high doses of these agents (liposomal film growth [45,47]. Uppuluri et al. identified calcineurin as a key
amphotericin B 10 mg/ml, liposomal amphotericin B and regulator of C. albicans biofilm drug resistance [47]. The addition
amphotericin B lipid complex 5 mg/ml and caspofungin of inhibitors of calcineurin (cyclosporine A or tacrolimus) ren-
6.67 mg/ml) successfully eradicated C. albicans biofilms [26,49–51]. dered in vitro biofilms susceptible to fluconazole. This synergy
However, consistent with in vitro data, azole therapy (flucona- was recapitulated in vivo using combination lock therapy in a
zole 10 mg/ml) and low-dose echinocandin (0.25 mg/ml) were rat catheter biofilm infection model. Calcineurin inhibitors have
much less effective as lock therapy for treatment of the animal since been shown to exhibit synergy with both an echinocandin
catheter infections [26,59]. Hudson et al. described an innovative (caspofungin) and amphotericin B [48]. The clinical availability
amphotericin B formulation, a dextran-aldehyde-amphotericin of calcineurin inhibitors makes this combination therapy appeal-
B conjugate [60]. When mixed with carboxymethlcellulose- ing. However, the immunosuppressive effects of these drugs
informahealthcare.com 377Review Nett
would likely preclude systemic administration and may limit In a non-biofilm murine candidiasis model, administration of
their utility to lock therapy. Combination therapy also looks farnesol was protective [69]. However, studies have not examined
promising for agents targeting Hsp90p, a molecular chaperone farnesol for treatment of biofilm infections in animal models.
governing Candida biofilm resistance [45]. Combination therapy There is a concern that disruption of quorum sensing may pro-
with an Hsp90 inhibitor, geldanamycin, potentiated the activity voke dispersion, the process of releasing cells from the biofilm,
of fluconazole against C. albicans biofilms. ultimately leading to disseminated disease [68]. Further studies of
The use of NSAIDs in combination with antifungal therapy biofilms would be valuable to access the utility of targeting this
shows potential for treatment of biofilm infections [52]. Medica- quorum sensing pathway for Candida biofilm treatment.
tions in this drug class inhibit cyclooxygenases involved in the
biosynthesis of mammalian prostaglandins. They are currently Targeting extracellular matrix
used for treatment of a variety of pain and inflammatory con- One unique characteristic of biofilms, the presence of an extra-
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
ditions. Interest for combination therapy arose from the discov- cellular matrix, contributes greatly to the antifungal resistance.
ery that several NSAIDs impair the ability of C. albicans to The matrix elements specifically linked to this resistance,
produce filaments and form biofilms in vitro [64,65]. One of the eDNA and b-1,3 glucan, are potential targets for anti-biofilm
most potent inhibitors, aspirin, was even effective in eliminat- therapies [40–43]. When these components are disrupted by tar-
ing established biofilms. This activity has been linked to inhibi- geted enzymatic digestion, the efficacy of antifungals is greatly
tion of fungal prostaglandin E2 production [64]. Bink et al. enhanced. For example, digestion of b-1,3 glucan potentiated
explored the utility of NSAID-based combination therapy by fluconazole activity while degradation of eDNA enhanced
testing the impact of combining an NSAID (diclofenac) with amphotericin B activity in vitro [25,35,42]. The utility of targeted
an echinocandin (caspofungin) [52]. In vitro, diclofenac acted enzyme degradation would likely be limited to local therapy.
synergistically with caspofungin and was most efficacious if An example that supports the feasibility of this approach is dor-
administered during biofilm formation. In a subcutaneous nase alfa (Pulmozyme), a clinically available inhaled enzymatic
device-associated biofilm model, treatment with diclofenac treatment that targets the eDNA of bacterial biofilms in
markedly enhanced the activity of caspofungin. This finding is patients with cystic fibrosis and chronic pulmonary infec-
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exciting as NSAIDs are pharmaceutically available agents with tions [70]. Another potential approach would be to identify
established safety profiles. However, further studies are needed inhibitors of the pathways known to regulate biofilm matrix
to determine the feasibility of this type of treatment regimen production and delivery [44,71,72].
for patients. It is unclear if initiating the combination therapy
in the setting of an established biofilm infection, as would be Natural products
done clinically, would show this degree of efficacy. Many natural products are active against biofilms formed by a
To identify novel agents effective against C. albicans bio- variety of Candida spp. [73]. Compounds in investigation
films, LaFleur et al. screened compounds for synergistic activity include peptides, oils, plant extracts and polyphenols from
of azoles [55]. They discovered that 2-adamantanamine, the teas [56,57,74–80]. Although the results of these studies appear
structural analog of the antiviral amantadine, potentiated the promising, the toxicities of many of the compounds have not
activity of the azole, miconazole. The specific fungal target of been established and the tolerable dose in patients is unknown.
2-adamantanamine is unknown, but it is thought to inhibit a One of the more well-studied compounds is carbohydrate-
component of the ergosterol pathway upstream of the azole tar- derived fulvic acid (CHD-FA), a heat stable, cationic, colloidal
get, a-14 lanosterol demethylase. The safety profile of 2-ada- material [56]. CHD-FA is active against Candida biofilms as
mantanamine has not been established. If the profile is similar well as bacterial biofilms formed by oral bacteria that often
to the antiviral amantadine, therapeutic systemic levels may be accompany Candida in polymicrobial oral biofilm infec-
achievable [55]. tions [56,81]. CHD-FA appears to non-specifically disrupt the
fungal cell membrane and retains activity against many drug-
Disrupting quorum sensing resistant Candida strains. As it is relatively inexpensive and
As Candida cells proliferate, they communicate through quo- exhibits broad-spectrum anti-biofilm activity, it may be well
rum sensing, a process of sensing cell density [66]. One of these suited for use as an oral antiseptic. The efficacy of CHD-FA
secreted molecules, farnesol, is an isoprenoid that inhibits the has not been established in vivo, but the compound appears to
yeast-to-hyphae transition as well as the initiation of biofilm. be non-toxic in an epithelial cell line and a rat model [81].
At physiologic concentrations, this quorum sensing molecule To identify natural products with antifungal activity,
does not appear to impact cells that have already begun to fila- Coleman et al. screened compounds using a high-throughput
ment or biofilms that have become established [67]. However, at Caenorhabditis elegans assay [57]. This innovative approach con-
farnesol concentrations exceeding physiologic conditions, bio- currently assesses toxicity and treatment efficacy. With this
films are degraded [68]. This observation suggests a potential screen, they identified 12 saponins with antifungal activity, sev-
use of farnesol, or a compound targeting this pathway, in the eral of which were active against C. albicans biofilms at concen-
treatment of biofilm infections. In vitro data suggest that farne- trations without apparent toxicity. These compounds are
sol treatment may even enhance the activity of azoles [53,54]. proposed to target fungal ergosterol and form pores in the
378 Expert Rev. Anti Infect. Ther. 12(3), (2014)Future directions for anti-biofilm therapeutics targeting Candida Review
Candida membrane. With a mechanism of action distinct from small nidus of infection may blossom to severe, recurrent infec-
available drug classes, these compounds have the potential to tion. To achieve this degree of activity, several strategies may
have activity against resistant organisms or act synergistically be considered for design of new drugs. One approach is to
with other antifungals. identify compounds with exquisite anti-Candida and anti-
biofilm activity, effective against even the most resistant sub-
Expert commentary & five-year view population of biofilm cells. Another approach is to uncover
It is becoming increasingly clear that Candida cells of a biofilm agents that disrupt biofilm processes, allowing traditional anti-
vary greatly from their free-floating counterparts. Therapies fungals to attack biofilms when used on combination. Still
that inhibit planktonic Candida often have little impact on bio- another approach is to identify drugs that disrupt biofilm in a
films. Given the high prevalence of biofilm infection, the devel- manner that allows the immune system to take hold, ultimately
opment of anti-Candida therapies should focus on this mode completely clearing the infection. As our understanding of Can-
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
of growth. Models of Candida biofilms are critical for discovery dida biofilms continues to grow, it will be fascinating to see
of new antifungals and for investigating their efficacy. The how this information is applied to discovery of anti-biofilm
development of high-throughput models is necessary for eco- drugs.
nomically testing large libraries of molecules for anti-biofilm
activity. One such model is the biofilm chip, which consists of Financial & competing interests disclosure
nano-biofilms on a high-density microarray platform [82]. The author’s research is supported by a Burroughs Wellcome Fund Career
A number of animal models with Candida biofilm infections Award for Medical Scientists. The authors have no other relevant affilia-
closely mimicking patient infections will be of great value for tions or financial involvement with any organization or entity with a
examination of treatment efficacy [22,26,83–86]. financial interest in or financial conflict with the subject matter or materi-
To be the most useful medically, new antifungals would ide- als discussed in the manuscript apart from those disclosed.
ally be capable of completely eradicating a biofilm, as just a No writing assistance was utilized in the production of this manuscript.
Key issues
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• Candida, one of the most common fungal pathogens, frequently grows as a biofilm adherent to a medical device or other surface.
• Candida biofilms exhibit increased resistance to antimicrobial therapies, including all available antifungal agents.
• The drug resistance of Candida biofilms is multifactorial. Contributing mechanisms include the presence of an extracellular matrix,
increased activity of efflux pumps, increased cell density and induction of stress responses.
• Animal studies show that high doses of antifungals, such as liposomal amphotericin B and echinocandins, have anti-biofilm activity
when delivered locally as catheter lock therapy.
• Therapies targeting the fungal stress responses (calcineurin, heat shock protein 90) can augment the action of antifungal drugs.
• Natural products, such as carbohydrate-derived fulvic acid and saponins, are promising compounds for treatment of Candida biofilms.
• A combination of high-throughput screens and animal models of Candida biofilm infection will be important for identifying and testing
novel antifungals.
References 6. Douglas LJ. Medical importance of biofilms 10. Pfaller MA, Diekema DJ. Epidemiology of
in Candida infections. Rev Iberoam Micol invasive candidiasis: a persistent public
1. O’Toole GA. To build a biofilm.
2002;19(3):139-43 health problem. Clin Microbiol Rev 2007;
J Bacteriol 2003;185(9):2687-9
7. Groeger JS, Lucas AB, Thaler HT, et al. 20(1):133-63
2. Donlan RM. Biofilms and device-associated
Infectious morbidity associated with 11. Andes DR, Safdar N, Baddley JW, et al.
infections. Emerg Infect Dis 2001;7(2):
long-term use of venous access devices in Impact of treatment strategy on outcomes
277-81
patients with cancer. Ann Intern Med 1993; in patients with candidemia and other forms
3. Hawser SP, Baillie GS, Douglas LJ. 119(12):1168-74 of invasive candidiasis: a patient-level
Production of extracellular matrix by quantitative review of randomized trials.
8. Richards MJ, Edwards JR, Culver DH,
Candida albicans biofilms. J Med Microbiol Clin Infect Dis 2012;54(8):1110-22
Gaynes RP. Nosocomial infections in
1998;47(3):253-6
medical intensive care units in the United 12. Pappas PG, Kauffman CA, Andes D, et al.
4. Passerini L, Lam K, Costerton JW, States. National Nosocomial Infections Clinical practice guidelines for the
King EG. Biofilms on indwelling vascular Surveillance System. Crit Care Med 1999; management of candidiasis: 2009 update by
catheters. Crit Care Med 1992;20(5):665-73 27(5):887-92 the Infectious Diseases Society of America.
5. Kojic EM, Darouiche RO. Candida 9. Edmond MB, Wallace SE, McClish DK, Clin Infect Dis 2009;48(5):503-35
infections of medical devices. Clin et al. Nosocomial bloodstream infections in 13. Shin JH, Kee SJ, Shin MG, et al. Biofilm
Microbiol Rev 2004;17(2):255-67 United States hospitals: a three-year analysis. production by isolates of Candida species
Clin Infect Dis 1999;29(2):239-44 recovered from nonneutropenic patients:
informahealthcare.com 379Review Nett
comparison of bloodstream isolates with 26. Schinabeck MK, Long LA, Hossain MA, Candida albicans biofilms. Antimicrob
isolates from other sources. J Clin Microbiol et al. Rabbit model of Candida albicans Agents Chemother 2007;51(7):2454-63
2002;40(4):1244-8 biofilm infection: liposomal amphotericin B 38. Al-Fattani MA, Douglas LJ. Penetration of
14. Baillie GS, Douglas LJ. Effect of growth antifungal lock therapy. Antimicrob Agents Candida biofilms by antifungal agents.
rate on resistance of Candida albicans Chemother 2004;48(5):1727-32 Antimicrob Agents Chemother 2004;48(9):
biofilms to antifungal agents. Antimicrob 27. Ramage G, Vande Walle K, Wickes BL, 3291-7
Agents Chemother 1998;42(8):1900-5 Lopez-Ribot JL. Standardized method for 39. Baillie GS, Douglas LJ. Matrix polymers of
15. Chandra J, Kuhn DM, Mukherjee PK, in vitro antifungal susceptibility testing of Candida biofilms and their possible role in
et al. Biofilm formation by the fungal Candida albicans biofilms. Antimicrob biofilm resistance to antifungal agents.
pathogen Candida albicans: development, Agents Chemother 2001;45(9):2475-9 J Antimicrob Chemother 2000;46(3):
architecture, and drug resistance. J Bacteriol 28. Kuhn DM, George T, Chandra J, et al. 397-403
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
2001;183(18):5385-94 Antifungal susceptibility of Candida 40. Samaranayake YH, Ye J, Yau JY, et al. In
16. Hawser SP, Douglas LJ. Biofilm formation biofilms: unique efficacy of amphotericin B vitro method to study antifungal perfusion
by Candida species on the surface of lipid formulations and echinocandins. in Candida biofilms. J Clin Microbiol
catheter materials in vitro. Infect Immun Antimicrob Agents Chemother 2002;46(6): 2005;43(2):818-25
1994;62(3):915-21 1773-80
41. Nett JE, Crawford K, Marchillo K,
17. Lewis RE, Kontoyiannis DP, Darouiche RO, 29. Ramage G, Rajendran R, Sherry L, Andes DR. Role of Fks1p and matrix
et al. Antifungal activity of amphotericin B, Williams C. Fungal biofilm resistance. Int J glucan in Candida albicans biofilm
fluconazole, and voriconazole in an in vitro Microbiol 2012;2012:528521 resistance to an echinocandin, pyrimidine,
model of Candida catheter-related 30. Fiori B, Posteraro B, Torelli R, et al. In and polyene. Antimicrob Agents Chemother
bloodstream infection. Antimicrob Agents vitro activities of anidulafungin and other 2010;54(8):3505-8
Chemother 2002;46(11):3499-505 antifungal agents against biofilms formed by 42. Martins M, Henriques M, Lopez-Ribot JL,
18. Mukherjee PK, Chandra J, Kuhn DM, clinical isolates of different Candida and Oliveira R. Addition of DNase improves
Ghannoum MA. Mechanism of fluconazole Aspergillus species. Antimicrob Agents the in vitro activity of antifungal drugs
resistance in Candida albicans biofilms: Chemother 2011;55(6):3031-5 against Candida albicans biofilms. Mycoses
phase-specific role of efflux pumps and Ramage G, Bachmann S, Patterson TF, 2012;55(1):80-5
For personal use only.
31.
membrane sterols. Infect Immun 2003; et al. Investigation of multidrug efflux 43. Vediyappan G, Rossignol T, d’Enfert C.
71(8):4333-40 pumps in relation to fluconazole resistance Interaction of Candida albicans biofilms
19. Ramage G, VandeWalle K, Bachmann SP, in Candida albicans biofilms. J Antimicrob with antifungals: transcriptional response
et al. In vitro pharmacodynamic properties Chemother 2002;49(6):973-80 and binding of antifungals to beta-glucans.
of three antifungal agents against preformed 32. Kumamoto CA. A contact-activated kinase Antimicrob Agents Chemother 2010;54(5):
Candida albicans biofilms determined by signals Candida albicans invasive growth 2096-111
time-kill studies. Antimicrob Agents and biofilm development. Proc Natl Acad 44. Nett JE, Sanchez H, Cain MT, Andes DR.
Chemother 2002;46(11):3634-6 Sci USA 2005;102(15):5576-81 Genetic basis of Candida biofilm resistance
20. Dodds Ashley ES, Lewis R, Lewis JS, et al. 33. Khot PD, Suci PA, Miller RL, et al. due to drug-sequestering matrix glucan.
Pharmacology of systemic antifungal agents. A small subpopulation of blastospores in J Infect Dis 2010;202(1):171-5
Clin Infect Dis 2006;43(S1):S28-39 Candida albicans biofilms exhibit resistance 45. Robbins N, Uppuluri P, Nett J, et al.
21. Hawser SP, Douglas LJ. Resistance of to amphotericin B associated with Hsp90 governs dispersion and drug
Candida albicans biofilms to antifungal differential regulation of ergosterol and resistance of fungal biofilms. PLoS Pathog
agents in vitro. Antimicrob Agents beta-1,6-glucan pathway genes. Antimicrob 2011;7(9):e1002257
Chemother 1995;39(9):2128-31 Agents Chemother 2006;50(11):3708-16
46. Chen YL, Brand A, Morrison EL, et al.
22. Andes D, Nett J, Oschel P, et al. 34. LaFleur MD, Kumamoto CA, Lewis K. Calcineurin controls drug tolerance, hyphal
Development and characterization of an Candida albicans biofilms produce growth, and virulence in Candida
in vivo central venous catheter Candida antifungal-tolerant persister cells. dubliniensis. Eukaryot Cell 2011;10(6):
albicans biofilm model. Infect Immun 2004; Antimicrob Agents Chemother 2006;50(11): 803-19
72(10):6023-31 3839-46
47. Uppuluri P, Nett J, Heitman J, Andes D.
23. Ramage G, Vandewalle K, Wickes BL, 35. Al-Fattani MA, Douglas LJ. Biofilm matrix Synergistic effect of calcineurin inhibitors
Lopez-Ribot JL. Characteristics of biofilm of Candida albicans and Candida tropicalis: and fluconazole against Candida albicans
formation by Candida albicans. Rev chemical composition and role in drug biofilms. Antimicrob Agents Chemother
Iberoam Micol 2001;18(4):163-70 resistance. J Med Microbiol 2006;55(Pt 8): 2008;52(3):1127-32
999-1008
24. Chandra J, Mukherjee PK, Leidich SD, 48. Shinde RB, Chauhan NM, Raut JS,
et al. Antifungal resistance of candidal 36. Mitchell KF, Taff HT, Cuevas MA, et al. Karuppayil SM. Sensitization of Candida
biofilms formed on denture acrylic in vitro. Role of matrix beta-1,3 glucan in antifungal albicans biofilms to various antifungal drugs
J Dent Res 2001;80(3):903-8 resistance of non-albicans Candida Biofilms. by cyclosporine A. Ann Clin Microbiol
Antimicrob Agents Chemother 2013;57(4): Antimicrob 2012;11:27
25. Nett J, Lincoln L, Marchillo K, et al.
1918-20
Putative role of beta-1,3 glucans in Candida 49. Mukherjee PK, Long L, Kim HG,
albicans biofilm resistance. Antimicrob 37. Perumal P, Mekala S, Chaffin WL. Role for Ghannoum MA. Amphotericin B lipid
Agents Chemother 2007;51(2):510-20 cell density in antifungal drug resistance in complex is efficacious in the treatment of
Candida albicans biofilms using a model of
380 Expert Rev. Anti Infect. Ther. 12(3), (2014)Future directions for anti-biofilm therapeutics targeting Candida Review
catheter-associated Candida biofilms. Int J eradicates organisms embedded in biofilm. pathogenicity, biofilm formation, natural
Antimicrob Agents 2009;33(2):149-53 Antimicrob Agents Chemother 2007;51(1): antifungal products and new therapeutic
50. Shuford JA, Rouse MS, Piper KE, et al. 78-83 options. J Med Microbiol 2013;62(Pt 1):
Evaluation of caspofungin and amphotericin 62. Sherertz RJ, Boger MS, Collins CA, et al. 10-24
B deoxycholate against Candida albicans Comparative in vitro efficacies of various 74. Rossignol T, Kelly B, Dobson C,
biofilms in an experimental intravascular catheter lock solutions. Antimicrob Agents d’Enfert C. Endocytosis-mediated vacuolar
catheter infection model. J Infect Dis 2006; Chemother 2006;50(5):1865-8 accumulation of the human ApoE
194(5):710-13 63. Raad I, Chatzinikolaou I, Chaiban G, et al. apolipoprotein-derived ApoEdpL-W
51. Walraven CJ, Lee SA. Antifungal lock In vitro and ex vivo activities of minocycline antimicrobial peptide contributes to its
therapy. Antimicrob Agents Chemother and EDTA against microorganisms antifungal activity in Candida albicans.
2013;57(1):1-8 embedded in biofilm on catheter surfaces. Antimicrob Agents Chemother 2011;55(10):
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
Antimicrob Agents Chemother 2003;47(11): 4670-81
52. Bink A, Kucharikova S, Neirinck B, et al.
The nonsteroidal antiinflammatory drug 3580-5 75. Mandal SM. A novel hydroxyproline rich
diclofenac potentiates the in vivo activity of 64. Alem MA, Douglas LJ. Prostaglandin glycopeptide from pericarp of Datura
caspofungin against Candida albicans production during growth of Candida stramonium: proficiently eradicate
biofilms. J Infect Dis 2012;206(11):1790-7 albicans biofilms. J Med Microbiol 2005; the biofilm of antifungals resistant
54(Pt 11):1001-5 Candida albicans. Biopolymers 2012;
53. Yu LH, Wei X, Ma M, et al. Possible
98(4):332-7
inhibitory molecular mechanism of farnesol 65. Ghalehnoo ZR, Rashki A, Najimi M,
on the development of fluconazole resistance Dominguez A. The role of diclofenac 76. Pires RH, Lucarini R, Mendes-Giannini MJ.
in Candida albicans biofilm. Antimicrob sodium in the dimorphic transition in Effect of usnic acid on Candida orthopsilosis
Agents Chemother 2012;56(2):770-5 Candida albicans. Microb Pathog 2010; and C. parapsilosis. Antimicrob Agents
48(3-4):110-15 Chemother 2012;56(1):595-7
54. Sharma M, Prasad R. The quorum-sensing
molecule farnesol is a modulator of drug 66. Hornby JM, Jensen EC, Lisec AD, et al. 77. Pires RH, Montanari LB, Martins CH,
efflux mediated by ABC multidrug Quorum sensing in the dimorphic fungus et al. Anticandidal efficacy of cinnamon oil
transporters and synergizes with drugs in Candida albicans is mediated by farnesol. against planktonic and biofilm cultures of
Candida albicans. Antimicrob Agents Appl Environ Microbiol 2001;67(7): Candida parapsilosis and Candida
For personal use only.
Chemother 2011;55(10):4834-43 2982-92 orthopsilosis. Mycopathologia 2011;172(6):
453-64
55. Lafleur MD, Sun L, Lister I, et al. 67. Ramage G, Saville SP, Wickes BL,
Potentiation of azole antifungals by Lopez-Ribot JL. Inhibition of Candida 78. Evensen NA, Braun PC. The effects of tea
2-adamantanamine. Antimicrob Agents albicans biofilm formation by farnesol, a polyphenols on Candida albicans: inhibition
Chemother 2013;57(8):3585-92 quorum-sensing molecule. Appl Environ of biofilm formation and proteasome
Microbiol 2002;68(11):5459-63 inactivation. Can J Microbiol 2009;55(9):
56. Sherry L, Jose A, Murray C, et al.
1033-9
Carbohydrate Derived Fulvic Acid: an in 68. Uppuluri P, Chaturvedi AK, Srinivasan A,
vitro Investigation of a Novel Membrane et al. Dispersion as an important step in 79. Alviano WS, Mendonca-Filho RR,
Active Antiseptic Agent Against Candida the Candida albicans biofilm Alviano DS, et al. Antimicrobial activity of
albicans Biofilms. Front Microbiol developmental cycle. PLoS Pathog 2010; Croton cajucara Benth linalool-rich essential
2012;3:116 6(3):e1000828 oil on artificial biofilms and planktonic
microorganisms. Oral Microbiol Immunol
57. Coleman JJ, Okoli I, Tegos GP, et al. 69. Martins M, Lazzell AL, Lopez-Ribot JL,
2005;20(2):101-5
Characterization of plant-derived saponin et al. Effect of exogenous administration of
natural products against Candida albicans. Candida albicans autoregulatory alcohols in 80. Shuford JA, Steckelberg JM, Patel R. Effects
ACS Chem Biol 2010;5(3):321-32 a murine model of hematogenously of fresh garlic extract on Candida albicans
disseminated candidiasis. J Basic Microbiol biofilms. Antimicrob Agents Chemother
58. Bachmann SP, VandeWalle K, Ramage G,
2012;52(4):487-91 2005;49(1):473
et al. In vitro activity of caspofungin against
Candida albicans biofilms. Antimicrob 70. Frederiksen B, Pressler T, Hansen A, et al. 81. Sherry L, Millhouse E, Lappin DF, et al.
Agents Chemother 2002;46(11):3591-6 Effect of aerosolized rhDNase (Pulmozyme) Investigating the biological properties of
on pulmonary colonization in patients with carbohydrate derived fulvic acid (CHD-FA)
59. Lazzell AL, Chaturvedi AK, Pierce CG,
cystic fibrosis. Acta Paediatr 2006;95(9): as a potential novel therapy for the
et al. Treatment and prevention of Candida
1070-4 management of oral biofilm infections.
albicans biofilms with caspofungin in a
BMC Oral Health 2013;13:47
novel central venous catheter murine model 71. Taff HT, Nett JE, Zarnowski R, et al.
of candidiasis. J Antimicrob Chemother A Candida biofilm-induced pathway for 82. Srinivasan A, Uppuluri P, Lopez-Ribot J,
2009;64(3):567-70 matrix glucan delivery: implications for drug Ramasubramanian AK. Development of a
resistance. PLoS Pathog 2012;8(8): high-throughput Candida albicans biofilm
60. Hudson SP, Langer R, Fink GR,
e1002848 chip. PLoS ONE 2011;6(4):e19036
Kohane DS. Injectable in situ cross-linking
hydrogels for local antifungal therapy. 72. Nobile CJ, Nett JE, Hernday AD, et al. 83. Nett JE, Marchillo K, Spiegel CA,
Biomaterials 2010;31(6):1444-52 Biofilm matrix regulation by Candida Andes DR. Development and validation
albicans Zap1. PLoS Biol 2009;7(6): of an in vivo Candida albicans biofilm
61. Raad I, Hanna H, Dvorak T, et al. Optimal
e1000133 denture model. Infect Immun 2010;
antimicrobial catheter lock solution, using
78(9):3650-9
different combinations of minocycline, 73. Sardi JC, Scorzoni L, Bernardi T, et al.
EDTA, and 25-percent ethanol, rapidly Candida species: current epidemiology,
informahealthcare.com 381Review Nett
84. Johnson CC, Yu A, Lee H, et al. 85. Wang X, Fries BC. A murine model for pathogen-host interactions during Candida
Development of a contemporary animal catheter-associated candiduria. J Med albicans biofilm formation using in vivo
model of Candida albicans-associated Microbiol 2011;60(Pt 10):1523-9 bioluminescence. Cell Microbiol 2013. [Epub
denture stomatitis using a novel intraoral 86. Vande Velde G, Kucharikova S, Schrevens S, ahead of print]
denture system. Infect Immun 2012;80(5): et al. Towards non-invasive monitoring of
1736-43
Expert Review of Anti-infective Therapy Downloaded from informahealthcare.com by Ms. Stephanie Harris on 06/23/14
For personal use only.
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