Review Article Candida Infections, Causes, Targets, and Resistance Mechanisms ... · 2019. 7. 31. · nate to internal organs. Risk factors for invasive candidiasis include surgery

Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 204237 13 pageshttpdxdoiorg1011552013204237

Review ArticleCandida Infections Causes Targets and ResistanceMechanisms Traditional and Alternative Antifungal Agents

Claudia Spampinato12 and Dariacuteo Leonardi34

1 Departamento de Quımica Biologica Facultad de Ciencias Bioquımicas y Farmaceuticas Universidad Nacional de Rosario (UNR)Suipacha 531 2000 Rosario Argentina

2 Centro de Estudios Fotosinteticos y Bioquımicos (CEFOBI UNR-CONICET) Suipacha 531 2000 Rosario Argentina3Departamento de Tecnologıa Farmaceutica Facultad de Ciencias Bioquımicas y Farmaceuticas Universidad Nacional de Rosario(UNR) Suipacha 531 2000 Rosario Argentina

4 Instituto de Quımica Rosario (IQUIR UNR-CONICET) Suipacha 531 2000 Rosario Argentina

Correspondence should be addressed to Darıo Leonardi leonardiiquir-conicetgovar

Received 8 April 2013 Revised 6 June 2013 Accepted 6 June 2013

Academic Editor Abdelwahab Omri

Copyright copy 2013 C Spampinato and D Leonardi This is an open access article distributed under the Creative CommonsAttribution License which permits unrestricted use distribution and reproduction in any medium provided the original work isproperly cited

The genus Candida includes about 200 different species but only a few species are human opportunistic pathogens and causeinfectionswhen the host becomes debilitated or immunocompromisedCandida infections can be superficial or invasive Superficialinfections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs Howeverinvasive fungal infections are often life-threatening probably due to inefficient diagnostic methods and inappropriate initialantifungal therapies Here we briefly review our current knowledge of pathogenic species of the genus Candida and yeast infectioncauses and then focus on current antifungal drugs and resistance mechanisms An overview of new therapeutic alternatives for thetreatment of Candida infections is also provided

1 Introduction

Candida albicans is the most important fungal opportunisticpathogen It usually resides as a commensal in the gas-trointestinal and genitourinary tracts and in the oral andconjunctival flora [1ndash5] However it causes infection whenthe host becomes debilitated or immunocompromisedTheseinfections can be superficial and affect the skin or mucousmembrane [6] or can invade the bloodstream and dissemi-nate to internal organs Risk factors for invasive candidiasisinclude surgery (especially abdominal surgery) burns long-term stay in an intensive care unit and previous administra-tion of broad-spectrum antibiotics and immunosuppressiveagents [7ndash10] Advances in medical management as anti-neoplasic chemotherapy organ transplantation hemodialy-sis parenteral nutrition and central venous catheters alsocontribute to fungal invasion and colonization [11] OtherCandida species found in healthy individuals include Can-dida glabrata Candida tropicalis Candida parapsilosis and

Candida krusei [12] All five mentioned species cause morethan 90 of invasive infections although the relative preva-lence of the species depends on the geographical locationpatient population and clinical settings [12ndash14] Emergenceof Candida guilliermondii Candida kefyr Candida rugosaCandida dubliniensis and Candida famata as pathogens hasalso been reported worldwide [6 14] In fact the NationalNosocomial Infections Surveillance System (NNISS) reportsCandida species as the fourth most common nosocomialbloodstream pathogen [15] Mortality rates are estimated tobe as high as 45 [16] probably due to inefficient diagnosticmethods and inappropriate initial antifungal therapies [17]

2 Antifungal Drugs in Clinical Treatments

Although the antifungal drugs used in clinical treatmentsappear to be diverse and numerous only few classes of

2 BioMed Research International

Antifungal class Mode of action Drugs

Azoles Inhibitors of lanosterol14-120572-demethylase

MiconazoleEconazoleClotrimazoleKetoconazoleFluconazoleItraconazoleVoriconazolePosaconazole

Echinocandins Inhibitors of(13)-120573-D-glucan synthase

CaspofunginMicafunginAnidulafungin

Polyenes Binding ergosterol NystatinAmphotericin B

Nucleoside analogues Inhibitor of DNARNA synthesis Flucytosine

Allylamines Inhibitors of squalene-epoxidase TerbinafineAmorolfineNaftifine

Thiocarbamates Inhibitors of squalene-epoxidase TolnaftateTolciclate

Antibiotic Interaction with 120573-tubulin Griseofulvin

Nucleoside analoguesInhibitors ofnucleic acid

synthesis

Plasma membraneCell wall

MitosisNuclei

Cytosol

Endoplasmaticreticulum

PolyenesBinding ergosterol

Azolesallylamines and

Inhibitors ofergosterol synthesis

EchinocandinsInhibitors of

120573-glucan synthesisGriseofulvineInhibitor ofmicrotubule

synthesis

thiocarbamates

Figure 1 Primary targets and mode of action of several antifungal agents

antifungal agents are currently available to treat mucosal orsystemic infections with Candida spp (Figure 1) [18ndash20]

21 Azoles Inhibitors of the Lanosterol 14-120572-Demethylase Thelargest family of antifungal drugs is the azole family Azolesdisrupt the cell membrane by inhibiting the activity of thelanosterol 14-120572-demethylase [21] enzyme involved in thebiosynthesis of ergosterol (Figure 1) Ergosterol analogous tocholesterol in animal cells is the largest sterol component of

the fungal cell membrane Since ergosterol and cholesterolhave sufficient structural differences most antifungal agentstargeted to ergosterol binding or biosynthesis does not cross-react with host cells The azole family includes imidazoles(miconazole econazole clotrimazole and ketoconazole) andtriazoles (fluconazole itraconazole and the latest agentvoriconazole (second-generation synthetic triazole deriva-tive of fluconazole) and posaconazole (hydroxylated ana-logue of itraconazole)) [21 22] Many azoles are effective

BioMed Research International 3

Table 1 Administration routes and pharmacokinetic parameters of representative antifungal agents belonging to the major families ofcompounds

Drug family Drug Admroutea

Pharmacokinetic parametersReferencesOral bioavailability

()119862max

b

120583gmLAUCc

mgsdothLProtein

binding ()Half time

(h) Elimination

Azoles

Fluconazole Oral gt90 07 4000 10ndash12 27ndash31 Urine [35 37]Itraconazole Oral gt55 11 292 998 21ndash64 Hepatic [35 37]Voriconazole Oral gt90 46 203 600 6 Renal [35 37 38]Posaconazole Oral gt98 78 170 990 15ndash35 Feces [35 39]

EchinocandinsCaspofungin IV lt5 95ndash121 935ndash1005 960 106 Urine [20 35 40

41]

Micafungin IV lt5 71ndash109 599ndash1113 998 11ndash17 Feces [20 35 4041]

Anidulafungin IV lt5 34ndash75 444ndash1045 840 181ndash256 Feces [20 35 4041]

Polyenes Amphotericin B IV lt5 15ndash21 13ndash17 gt95 68ndash50 Feces [35 42]Nucleosideanalogues Flucytosine Oral 76ndash89 80 62 4 3ndash6 Renal [31 35]aAdm route indicates administration route fluconazole itraconazole and voriconazole can be administered by both intravenous and oral routes IVintravenous b119862max maximal concentration cAUC area under the curve

both for topical use and for the treatment and prophylaxisof invasive fungal infections [22] In this regard these agentshave the approval of the US Food and Drug Administration(FDA) and the European Medicines Agency (EMEA) [23]

22 Echinocandins Inhibitors of the Glucan Synthesis Echi-nocandins (caspofungin micafungin and anidulafungin) arelipopeptidic antifungal agents that inhibit the synthesis offungal wall by noncompetitive blockage of the (13)-120573-D-glucan synthase (Figure 1) This enzyme inhibition leads tothe formation of fungal cell walls with impaired structuralintegrity which finally results in cell vulnerability to osmoticlysis [24] All three agents (caspofungin micafungin andanidulafungin) exhibit concentration-dependent fungicidalactivity against most species of Candida [25 26] and havebeen approved by the regulatory agency FDA for the treat-ment of esophageal and invasive candidiasis including can-didemia [27ndash29]

23 Polyenes Binding Ergosterol Polyenes such as nystatinand amphotericin B (both isolated from Streptomyces spp)bind ergosterol and disrupt the major lipidic component ofthe fungal cell membrane resulting in the production of aque-ous pores (Figure 1) Consequently the cellular permeabilityis altered and leads to the leakage of cytosolic componentsand therefore fungal death [30]

24 Nucleoside Analogues Inhibitors of DNARNA SynthesisFlucytosine is a pyrimidine analogue It is transported intofungal cells by cytosine permeases Then it is deaminated to5-fluorouracil and phosphorylated to 5-fluorodeoxyuridinemonophosphate This fluorinated nucleotide inhibitsthymidylate synthase and thus interferes with DNA synthesis(Figure 1 [31]) The 5-fluorodeoxyuridine monophosphate

can be further phosphorylated and incorporated to RNAthus affecting RNA and protein synthesis (Figure 1 [32])

25 Other Antifungal Agents Allylamines and thiocarba-mates also disrupt the cell membrane by inhibiting thesqualene-epoxidase [33] enzyme involved in the biosynthesisof ergosterol (Figure 1)

Griseofulvin (a tricyclic spirodiketone first isolated fromPenicillium griseofulvum) acts by disrupting spindle and cyto-plasmic microtubule production thereby inhibiting fungalmitosis (Figure 1 [34])

26 Treatment of Systemic Infections The antifungal therapyis driven by whether the agents are being used to treatmucosal or systemic infections Superficial infections can betreated successfully with topical antifungal drugs Systemicinfections can be treated with oral or intravenous (IV)preparations Table 1 shows the pharmacokinetic parametersof the main antifungal agents used for the treatment ofsystemic candidiasis Pharmacokinetic parameters are notalways directly comparable because data derive frommultiplesources and trials [20] However the routes of adminis-tration and excretion are often important considerationsin selecting an appropriate antifungal agent Some drugsare available only as IV preparations (eg caspofunginmicafungin anidulafungin and amphotericin B) only as oralpreparations (eg posaconazole and flucytosine) or can beadministered by both IV and oral routes (eg fluconazoleitraconazole and voriconazole) depending on the drug sol-ubility [35] Since fluconazole and caspofungin are primarilyexcreted into the urine as active forms (Table 1) they areagents of choice for the treatment of urinary tract fungalinfections Unfortunately some of these antifungal drugshave been extensively used and led to an increased selectivepressure and the development of antifungal resistance [36]


Table 2 Resistance mechanisms of major systemic antifungal drugs Antifungal resistance is based on different mechanisms namely (i)reduced drug intracellular accumulation (ii) decreased target affinityprocessivity for the drug and (iii) counteraction of the drug effect

Antifungalclass Genetic basis for resistance Functional basis for resistance

Azoles

Upregulation of CDR1CDR2 andMDR1 by pointmutations in TAC1 andMRR1 transcriptionfactors

(i) Upregulation of drug transporters

Point mutations in ERG11 (ii) Decreased lanosterol 14-120572-demethylase binding affinity for thedrug

Upregulation of ERG11 by gene duplication andtranscription factor regulation (iii) Increased concentration of lanosterol 14-120572-demethylase

Point mutations in ERG3 (iii) Inactivation of C5 sterol desaturase leading to alterations in theergosterol synthetic pathway

Echinocandins Point mutations in FKS1 and FKS2 (ii) Decreased glucan synthase processivity for the drugPolyenes Point mutations in ERG3 and ERG6 (iii) Decreased ergosterol content in cells

Nucleosideanalogues

Point mutations in FCY2 (i) Inactivation of cytosine permease affecting drug uptake

Point mutations in FCY1 (iii) Inactivation of cytosine deaminase leading to alterations in themetabolism of 5-fluorocytosine

Point mutations in FUR1 (iii) Inactivation of uracil phosphoribosyl transferase leading toalterations in the metabolism of 5-fluorocytosine

3 Mechanisms of Resistance againstAntifungal Agents

Antifungal resistance is based on different mechanismsnamely (i) reduced drug intracellular accumulation (ii)decreased target affinityprocessivity for the drug and (iii)counteraction of the drug effect Particularly the mechanismof resistance will be different depending on the mode ofaction of antifungal compounds Cellular and molecularmechanisms supporting resistance against antifungal classesmentioned above have been discussed in detail in previousreviews [43ndash46] Below we briefly summarize the mainobservations (Table 2)

31 Azole Resistance Over the past 10 years fluconazole anditraconazole have been used extensively for chemoprophy-laxis and treatment of systemic fungal infections because oftheir favorable oral bioavailability and safety profiles [84ndash86]Afterwards fluconazole resistance has been described in ahigh percentage of patients [87] In fact azole-resistant Calbicans is frequent inHIV-infected patients with oropharyn-geal candidiasis [88] However resistance is less importantin patients with other diseases such as vaginal candidiasisand candidemia [89] An intrinsically reduced susceptibilityto fluconazole has been also reported for non-albicans speciesof Candida like C glabrata C krusei and C lusitaniae [9091] It appears that variations in the structure of azoles areresponsible for the cross-resistance patterns among Candidaspecies [92ndash94] Several major mechanisms leading to azoleresistance have been elucidated (Table 2 [95]) and detailedbelow

(i) Reduced Drug Intracellular Accumulation A responsiblemechanism for decreasing the intracellular concentration ofazole relies on an upregulation of two principal families of

efflux pumps (reviewed in [96]) These transporters differ inthe source of energy used to pump out the drug and in thespecificity of the azole molecule The Cdr pumps belong tothe superfamily of ATP-binding cassette (ABC) transportersand are able to extrude all azole antifungals These pumpsare encoded by Candida drug resistance 1 and 2 (CDR1 andCDR2) genes in C albicans [96] The other pump is a sec-ondary transporter which utilizes proton gradient as a sourceof energy and is specific for fluconazole This pump belongsto themajor facilitator superfamily (MFS) transporters and isencoded by theMDR1 gene in C albicans [96] UpregulationofCDR1CDR2 andMDR1 arises frommutations inTAC1 andMRR1 transcription factors respectively [97 98] Gain-of-functionmutations generate hyperactive alleles in C albicansand subsequent loss of heterozigocyty (LOH) at theTAC1 andMRR1 loci [99] Other transporter genes have been reportedto be upregulated in azole-resistant C glabrata (CgCDR1CgCDR2 (formerly named PDH1) and CgSNQ2 (anotherABC transporter)) [100ndash102] C dubliniensis (CdCDR1 andCdCDR2) [103] C krusei (ABC1 and 2) [104 105] and Ctropicalis (CDR1-homologue) isolates [44] In C glabrataCgCDR1 CgCDR2 and CgSNQ2 genes are regulated by theCgPDR1 transcription factor [106ndash108]

(ii) Decreased Target Affinity for the Drug The target of azoleantifungals is the lanosterol 14-120572-demethylase encoded by theERG11 gene Several point mutations have been characterizedand associated to azole minimum inhibitory concentration(MIC) increases (reviewed in [95])

(iii) Counteraction of the Drug Effect Two mechanismscontribute to counterbalancing the drug effects The firstsystem involves an upregulation of the ERG11 gene leadingto an intracellular increase of the target protein ERG11overexpression occurs by transcription factor regulation and


gene duplication (reviewed in [95]) The second mechanismalthough very uncommon has been identified in severalclinical isolates ofC albicans [109] Alteration of the late stepsof the biosynthesis of ergosterol through ERG3 inactivationleads to the total inactivation of the C5 sterol desaturase [110]Thus toxic 14120572-methylated sterols are no longer accumulatedand yeast strains produce cell membranes devoid of ergos-terol but containing other sterols [110]

32 Echinocandin Resistance Echinocandin drugs are rec-ommended as the first line for invasive candidiasis Howeverreports of echinocandin resistance in patients with infectionsdue to C albicans C glabrata C tropicalis and C krusei arerising [111ndash116] In fact resistance in C glabrata increasedfrom 49 to 123 between 2001 and 2010 [115] Even moreemergence of coresistance to both echinocandins and azolesin clinical isolates of C glabrata has been reported [115] Inaddition intrinsic echinocandin resistance of C parapsilosisC orthopsilosisCmetapsilosis andC guilliermondiihas beendescribed [117 118]

Secondary resistance to echinocandins is associated withthe following mechanism

(ii) Decreased Target Processivity for the Drug Resistanceis attributed to point mutations in the FKS1 andor FKS2genes (Table 2 [119ndash121]) which encode the (13)-120573-D-glucansynthase complex [121] Mutations in FKS1 did not altersubstrate binding but lowered 119881max values [122]

33 Polyene Resistance Despite more than 30 years of clin-ical use minimal resistance to amphotericin B has beendeveloped However the main problem associated with theprophylactic use of conventional amphotericin B has alwaysbeen due to its well-known side effects and toxicity [123124] Resistance tends to be species dependent C glabrataand C krusei are usually considered to be susceptible toamphotericin B although they show higherMICs to polyenesthan C albicans In this regard higher than usual doses ofamphotericin B have been recommended by the InfectiousDiseases Society of America for treating candidemia causedby C glabrata and C krusei [125] In fact a significantproportion of isolates of C glabrata and C krusei speciesresistant to amphotericin B has been reported [126] Addi-tionally some Candida spp including C lusitaniae and Cguilliermondii besides C glabrata are capable of expressingresistance to amphotericin B [127] It is noteworthy that eventhe antifungal lipopeptide caspofungin led to drug resistancein transplanted patients [112] When resistance to polyenesoccurs it may result from the following mechanism

(iii) Counteraction of the Drug Effect Acquired resistance isprobably due to a decrease or lack of ergosterol content in cellmembranes In factmembranes of polyene-resistantCandidaisolates have relatively low ergosterol content compared tothose of polyene-susceptible isolates These deficiencies areprobably consequences of loss of function mutations in theERG3 or ERG6 genes which encode some of the enzymesinvolved in ergosterol biosynthesis (Table 2 [128ndash130])

34 Flucytosine Resistance Primary resistance to flucytosineremains low (lt2) Secondary resistance relies on inactiva-tion of different enzymes of the pyrimidine pathway (Table 2)as described below

(i) Reduced Drug Intracellular Accumulation Uptake of thedrug is affected by point mutations in the FCY2 gene whichencodes the cytosine permease [46 128]

(iii) Counteraction of the Drug Effect Acquired resistanceto flucytosine also results from point mutations in theFCY1 gene which encodes for the cytosine deaminase orFUR1 gene which encodes for the uracil phosphoribosyltransferase These enzymes catalyze the conversion of 5-fluorocytosine to 5-fluorouracil and 5-fluorouracil to 5-fluorouridine monophosphate respectively The most fre-quently acquired resistance to flucytosine is based on pointmutations in the FUR1 gene Several point mutations havebeen described in C albicans C glabrata and C lusitaniae[46 128 131 132]

The rapid development of antifungal resistance the tox-icity and the variability in available formulations of someagents and the increase in the frequency of non-albicansCandida spp infections support the need for more effectiveand less toxic treatment strategies

4 Need of New Antifungal Agents

Potential pharmacological strategies include the use of (i)new formulations of antifungals such as liposomal ampho-tericin B amphotericin B lipid complex amphotericin Bcolloidal dispersion amphotericin B into a lipid nanosphereformulation itraconazole and 120573-cyclodextrin itraconazoleor (ii) combination therapies of one or more antifungalcompounds for example amphotericin B + flucytosinefluconazole + flucytosine amphotericin B + fluconazolecaspofungin + liposomal amphotericin B and caspofungin +fluconazole

Potential alternative therapies include the use of newactive principles obtained from different general sources asnatural products synthetic agents or polymeric materialsthat have been shown to be active in vitro (Table 3) Amongthe natural products plants contain diverse components thatare important sources of biologically active molecules [50133 134] In fact the activity of plant crude extracts againstdifferent microorganisms has been reported that is strongantifungal activity of somemajor components of essential oils[135 136] In this regard the antibiofilm activity of terpenesand the exceptional efficiency of carvacrol geraniol and thy-mol in the treatment of candidiasis associated with medicaldevices have been demonstrated [137] In another workterpenoids exhibited excellent activity against C albicansyeast and hyphal form growth at concentrations that werenontoxic to HeLa cells [138] Thus terpenoids may be usefulin the near future not only as an antifungal chemotherapeuticagent but also to synergize effects of conventional drugs likefluconazole [138] Other compounds with antimycologicalactivity obtained from plants are saponins alkaloids pep-tides and proteins [47 48] Marine organisms endophytic


Table 3 Some natural products synthetic agents and polymeric materials with reported antifungal activities

Generalsource Specific source Biological active molecules Examples References

Naturalproducts

PlantsEssential oils terpenoidssaponins phenolic compoundsalkaloids peptides proteins

Steroidal saponins sesquiterpenoids [47 48]

Marine organismsAnthracycline-relatedcompounds lipopeptidespentacyclic compounds

Xestodecalactone B seragikinone A [49]

Endophytic fungi Secondary metabolites peptidespyrones cryptocandin pestalopyrone [50]

Microorganisms ofterrestrial environment Lipopeptides terpenoids Echinocandins enfumafungin [50 51]

Syntheticagents

Organically synthesized orderived compounds(not polymeric materials)

Compounds based onNN-dimethylbiguanidecomplexes

Me(NN-dimethylbiguanide)2(CH3COO)2sdotnH2Owhere Me Mn Ni Cu and Zn

[52 53]

Derived compounds fromtraditional antifungal structures Imidazole derivatives amine-derived bis-azoles [54 55]

Synthetic derived peptides Lactoferrin-derived peptides [56]

Derived compounds fromnatural products

Micafungin sodium anidulafungincaspofungin acetate pneumocandin andenfumafungin derivatives

[57 58]

Polymericmaterials Polymeric materials

Polymers with quaternarynitrogen atoms

Polymers containing aromatic or heterocyclicstructures [59]

Cationic conjugated polyelectrolytes [58]Polymers with quaternary nitrogen atomswithin the main chain [60]

Block copolymers containing quaternaryammonium salt [61]

Synthetic peptides synthetic dendrimericpeptides [62 63]

Antifungal peptides mimics

Arylamide and phenylene ethynylenebackbone polymers [64]

Polynorbornene derivatives [65]Polymethacrylate and polymethacrylamideplatforms containing hydrophobic and cationicside chains

[66 67]

Polymers with superficial activity Fluorine-containing polymers [68]

Polymers containing differentcontents of halogens

Chlorine-containing phenyl methacrylatepolymers [69 70]

Polymeric N-halamines [71]

Chelates Polymer-copper(II)-bipyridyl complex [72]N-vinylimidazole copolymerized withphenacyl methacrylate [73]

Imidazole derivative polymers 2-[(5-methylisoxazol-3-yl)amino]-2-oxo-ethylmethacrylate and ethyl methacrylate [71]

Polymers loaded with antifungalcompounds

Organic compounds [74ndash76]Inorganic compounds [77ndash79]

fungi andmicroorganisms of terrestrial environment are alsospecific sources of antifungal compounds although to a lesserextent [50 139] Among them good antimicrobial activi-ties of anthracycline-related compounds peptides pyroneslipopeptides and terpenoids isolated from these specificsources have been reported [49ndash51]

A second general source of antifungal agents comprisesnonpolymeric synthetic agents which can be classified intofour groups (Table 3) The first group includes chemicalsbased on NN-dimethylbiguanide complexes [52] Thesecompounds displayed low cytotoxicity and could be consid-ered as potential broad-spectrum agents [53] The second


group involves derived compounds of traditional antifungalstructures [54 55] where some of them present betterantimicrobial action than the original structures [55 140]The third group is formed by synthetic derived peptidesthat is the ldquohuman lactoferrin derived peptiderdquo which waswell tolerated in preclinical tests and clinical trials [56]Finally the last group includes compounds which are derivedfrom semisynthetic natural products such as compoundsderived from echinocandins micafungin sodium anidu-lafungin caspofungin acetate and pneumocandin Theseagents showed improved properties over the parental com-pounds [50 141] Unfortunately echinocandins derivativesare poorly absorbed when administered orally and thereforeare used only for IV administration A natural antifungalwith comparable activity to that of caspofungin acetateagainst Candida pathogenic fungal strains was isolated [51]The compound named enfumafungin is a new triterpeneglycoside that inhibits the (13)-120573-D-glucan synthase Severalsynthetic products derived from enfumafungin are currentlyunder development in order to optimize in vivo antifungalactivity and oral efficacy [57]

The third general source of antifungal compoundsnamely polymeric materials could be classified into sevengroups (Table 3) (1) Polymers with quaternary nitrogenatoms [60] that can exist in different structures that isaromatic or heterocyclic structures [59] cationic conjugatedpolyelectrolytes [58] quaternary nitrogen atoms within themain chain [60] block copolymers [61] and synthetic anddendrimeric peptides [62 63] All of them were shownto be effective against a variety of microorganisms basedon the exposure of its quaternary ammonium group (2)Mimic antimicrobial peptides among them are arylamideand phenylene ethynylene backbone polymers [64] poly-norbornene derivatives which depending on their structuremay exhibit substantial antimicrobial and low hemolyticactivity [65] and polymethacrylate and polymethacrylamidewith hydrophobic and cationic side chains [66 67] (3)Polymers with antimicrobial activity derived from theirsuperficial activity (surfactants) based on fluorine-containingcompounds [68] (4) Polymers containing different contentsof halogens where the halogen group is the commander ofthe inhibition process such as phenyl methacrylate polymerswith different contents of chlorine [69 70] The halogenmay form a covalent bond to nitrogen yielding polymericN-halamines with a broad-spectrum antimicrobial activitywithout causing environmental concerns [71] (5) Chelatesthe antimicrobial activity of different chelates such as N-vinylimidazole copolymerizedwith phenacylmethacrylate orpoly (13-thiazol-2-yl-carbamoyl) methyl methacrylate withCd(II) Cu(II) or Ni (II) has been analyzed in 2011 by Soykanet al [73] The Ni(II) complexes showed higher activitythan those of Cu(II) and Co(II) ions However all of themexhibited lower activity than fluconazole Another complexcontaining Cu(II) was found to have good antifungal activitydue to electrostatic binding to fungalDNA [72] (6) Imidazolederivatives polymers and copolymers with antimicrobialeffectiveness depending on the polymeric structures [71 142](7) Polymers loaded with antimicrobial organic or inorganiccompounds Antimicrobial organic agents are based on

organic drugs that is chlorhexidine has been incorporatedinto polymeric microparticles and into polymeric hydrogelsto modulate the release of the drug [74 75] Another researchgroup loaded triclosan into polymeric nanoparticles [76]Antimicrobial inorganic agents frequently incorporatemetalsinto polymers such as silver This metal exhibits muchhigher toxicity to microorganisms than to mammalian cellsPolymeric nanotubes [77] and nanofibers [78] with silvernanoparticles have been prepared by chemical oxidationpolymerization of rhodanine Other silver nanocompositeshave been reported in the literature based on different silver-loaded nanoparticles such as silver-zirconium phosphatenanoparticles [79] or silver zeolites [142] Another example ofinorganic compound loaded into polymers is copper Copperparticles are also known for their antimicrobial activityalthough they are relatively less studied than silver [143]

The mentioned agents have been tried in vitro againstCandida however many of them are not used in clinicaltreatments in this regard there are three agents with actualpromise E1210 albaconazole and isavuconazole (Figure 2)

E1210 is a broad-spectrum antifungal agent with a novelmechanism of action based on the inhibition of fungal glyco-sylphosphatidylinositol biosynthesis [144 145] The efficacyof oral E1210 was evaluated in murine models of oropharyn-geal and disseminated candidiasis [80]

Results indicate that E1210 significantly reduced thenumber of viable Candida in the oral cavity in comparison tothat of the control treatment and prolonged survival of miceinfected with Candida spp Therapeutic responses were dosedependent [80] Table 4 shows the major pharmacokineticparameters after administration of E1210 in mice E1210 wasalso highly effective in the treatment of disseminated candidi-asis caused by azole-resistant C albicans or C tropicalis [80]Currently E1210 is in Phase II

Albaconazole is a new oral triazole with broad-spectrumantifungal activity unique pharmacokinetics and excellenttolerability [146] It has been demonstrated that this com-pound was highly effective in vitro against pathogenic yeastsand also in animal models of systemic candidiasis [146]Oral bioavailability was calculated to be 80 in rats and100 in dogs [81] Assays in healthy human volunteersshowed that albaconazole was rapidly absorbed and pre-sented good pharmacokinetic parameters (Table 4) In factthe therapeutic efficacy of a single dose of albaconazole atge40mg was more effective than 150 mg of fluconazole for thetreatment of acute vulvovaginal candidiasis [81] Currentlyalbaconazole is in Phase II In addition low toxicity wasobserved when albaconazole was administered to animalsand human volunteers [82]

Finally isavuconazole (the active metabolite of thewater-soluble prodrug isavuconazonium) is a novel second-generation water-soluble triazole with broad-spectrum anti-fungal activity also against azole-resistant strains Studiescarried out with neutropenic mice of disseminated C trop-icalis or C krusei infections showed that the treatmentsignificantly reduced kidney burden in mice infected with Ctropicalis and both kidney and brain burden in mice infectedwith C krusei [147] This azole is currently under Phase IIItrials in patients with systemic candidiasis Both oral and


NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)

Figure 2 Chemical structures of three agents with actual promise E1210 (a) albaconazole (b) and isavuconazole (c)

Table 4 Pharmacokinetic parameters of some lead drugs

Drug Availableforms Experimental organisms

Pharmacokinetic parametersReferencesOral

bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination

E1210 OralIVa Mice 575 011 05 High 22 nrd [80]

Albaconazole Oral Healthy human volunteers nrd5ndash80

(proportionalto dose)

2ndash4 98 30ndash56 Feces [81 82]

Isavuconazonium Oral Healthy human volunteers Very high103

(100mgdose)

075ndash1 98 56ndash77 Feces [81ndash83]

Isavuconazole IVa Healthy human volunteers nrd145

(100mgdose)


aIV intravenous b119862max maximal concentration c119905max time to reach maximal plasma concentrations after oral administration dnr not reported

intravenous formulations showed favorable pharmacokinetic(Table 4) and pharmacodynamic profiles [82] This drughas the potential to become an important agent for thetreatment of invasive fungal infections principally because ofits relatively broad and potent in vitro antifungal activity itsfavorable pharmacokinetic profile and the absence of severeadverse effects [82 148 149]

5 Conclusions

Although the antifungal drugs used in clinical treatmentsappear to be diverse and numerous only few classes of anti-fungal agents are currently available in oral and intravenous

forms Additionally antifungal resistance based on differentmechanisms continues to grow and evolve and exacerbatethe need of new treatments against Candida infections Inthis regard new formulations of antifungals combinationtherapies and development of new bioactive compoundsmight be useful for a better therapeutic outcome Particularlythere are three compounds in Phase II or III studies withactual promise for the treatment of invasive candidiasis

Acknowledgments

This paper was supported by grants from Agencia Nacionalde Promocion Cientıfica y Tecnologica (ANPCyT) to Claudia


Spampinato (PICT 0458) and Darıo Leonardi (PICT 2643)Consejo Nacional de Investigaciones Cientıficas y Tecnicas(CONICET) to Claudia Spampinato (PIP 0018) and Uni-versidad Nacional de Rosario (UNR) to Claudia Spampinato(BIO 221) and Darıo Leonardi (BIO 328) Both authors aremembers of the Researcher Career of CONICET

References

[1] B E Jackson K RWilhelmus and BMMitchell ldquoGeneticallyregulated filamentation contributes to Candida albicans viru-lence during corneal infectionrdquoMicrobial Pathogenesis vol 42no 2-3 pp 88ndash93 2007

[2] T G Wu B M Mitchell T S Carothers et al ldquoMolecularanalysis of the pediatric ocular surface for fungirdquo Current EyeResearch vol 26 no 1 pp 33ndash36 2003

[3] J M Achkar and B C Fries ldquoCandida infections of thegenitourinary tractrdquo Clinical Microbiology Reviews vol 23 no2 pp 253ndash273 2010

[4] A Rosenbach D Dignard J V Pierce M Whiteway and C AKumamoto ldquoAdaptations of Candida albicans for growth in themammalian intestinal tractrdquo Eukaryotic Cell vol 9 no 7 pp1075ndash1086 2010

[5] J R Naglik D L Moyes B Wachtler and B Hube ldquoCandidaalbicans interactions with epithelial cells and mucosal immu-nityrdquoMicrobes and Infection vol 13 no 12-13 pp 963ndash976 2011

[6] R Lopez-Martınez ldquoCandidosis a new challengerdquo Clinics inDermatology vol 28 pp 178ndash184 2010

[7] D P Kontoyiannis E Mantadakis and G Samonis ldquoSystemicmycoses in the immunocompromised host an update in anti-fungal therapyrdquo Journal of Hospital Infection vol 53 no 4 pp243ndash258 2003

[8] T E Zaoutis J Argon J Chu J A Berlin T J Walsh andC Feudtner ldquoThe epidemiology and attributable outcomes ofcandidemia in adults and children hospitalized in the UnitedStates a propensity analysisrdquoClinical Infectious Diseases vol 41no 9 pp 1232ndash1239 2005

[9] E R M Sydnor and T M Perl ldquoHospital epidemiology andinfection control in acute-care settingsrdquo Clinical MicrobiologyReviews vol 24 no 1 pp 141ndash173 2011

[10] M A Pfaller and D J Diekema ldquoRare and emerging oppor-tunistic fungal pathogens concern for resistance beyond Can-dida albicans and Aspergillus fumigatusrdquo Journal of ClinicalMicrobiology vol 42 no 10 pp 4419ndash4431 2004

[11] MMikulska V del Bono S Ratto and C Viscoli ldquoOccurrencepresentation and treatment of candidemiardquo Expert Review ofClinical Immunology vol 8 pp 755ndash765 2012

[12] D M MacCallum ldquoHosting infection experimental models toassay Candida virulencerdquo International Journal of Microbiologyvol 2012 Article ID 363764 12 pages 2012

[13] M A Pfaller and D J Diekema ldquoEpidemiology of invasivecandidiasis a persistent public health problemrdquo Clinical Micro-biology Reviews vol 20 no 1 pp 133ndash163 2007

[14] M HMiceli J A Dıaz and S A Lee ldquoEmerging opportunisticyeast infectionsrdquoTheLancet Infectious Diseases vol 11 no 2 pp142ndash151 2011

[15] HWisplinghoff T Bischoff S M Tallent H Seifert R PWen-zel and M B Edmond ldquoNosocomial bloodstream infectionsin US hospitals analysis of 24179 cases from a prospectivenationwide surveillance studyrdquo Clinical Infectious Diseases vol39 pp 309ndash317 2004

[16] M-F Cheng Y-L Yang T-J Yao et al ldquoRisk factors forfatal candidemia caused by Candida albicans and non-albicansCandida speciesrdquo BMC Infectious Diseases vol 5 article 222005

[17] MMorrell V J Fraser andM H Kollef ldquoDelaying the empirictreatment of Candida bloodstream infection until positiveblood culture results are obtained a potential risk factor forhospital mortalityrdquo Antimicrobial Agents and Chemotherapyvol 49 no 9 pp 3640ndash3645 2005

[18] B P Mathew and M Nath ldquoRecent approaches to antifungaltherapy for invasive mycosesrdquo ChemMedChem vol 4 no 3 pp310ndash323 2009

[19] M K Kathiravan A B Salake A S Chothe et al ldquoThe biologyand chemistry of antifungal agents a reviewrdquo Bioorganic ampMedicinal Chemistry vol 20 pp 5678ndash5698 2012

[20] D W Denning and W W Hope ldquoTherapy for fungal diseasesopportunities and prioritiesrdquoTrends inMicrobiology vol 18 no5 pp 195ndash204 2010

[21] H Hof ldquoA new broad-spectrum azole antifungalposaconazolemdashmechanisms of action and resistance spectrumof activityrdquoMycoses vol 49 no 1 pp 2ndash6 2006

[22] R Hay ldquoAntifungal drugsrdquo in European Handbook of Dermato-logical Treatments A Katsambas and T Lotti Eds pp 700ndash710Springer Berlin Germany 2003

[23] J F AparicioMVMendes N Anton E Recio and J FMartınldquoPolyenemacrolide antiobiotic biosynthesisrdquoCurrentMedicinalChemistry vol 11 no 12 pp 1645ndash1656 2004

[24] N Grover ldquoEchinocandins a ray of hope in antifungal drugtherapyrdquo Indian Journal of Pharmacology vol 42 no 1 pp 9ndash112010

[25] D Cappelletty and K Eiselstein-McKitrick ldquoThe echinocan-dinsrdquo Pharmacotherapy vol 27 no 3 pp 369ndash388 2007

[26] J A Vazquez ldquoAnidulafungin a new echinocandin with a novelprofilerdquo Clinical Therapeutics vol 27 no 6 pp 657ndash673 2005

[27] L Ostrosky-Zeichner D Kontoyiannis J Raffalli et al ldquoInter-national open-label noncomparative clinical trial of micafun-gin alone and in combination for treatment of newly diagnosedand refractory candidemiardquo European Journal of Clinical Micro-biology and InfectiousDiseases vol 24 no 10 pp 654ndash661 2005

[28] N de Wet A Llanos-Cuentas J Suleiman et al ldquoA ran-domized double-blind parallel-group dose-response studyof micafungin compared with fluconazole for the treatmentof esophageal candidiasis in HIV-positive patientsrdquo ClinicalInfectious Diseases vol 39 no 6 pp 842ndash849 2004

[29] J Mora-Duarte R Betts C Rotstein et al ldquoComparison ofcaspofungin and amphotericin B for invasive candidiasisrdquo TheNew England Journal of Medicine vol 347 no 25 pp 2020ndash2029 2002

[30] D Sanglard and F C Odds ldquoResistance of Candida species toantifungal agents molecular mechanisms and clinical conse-quencesrdquoThe Lancet Infectious Diseases vol 2 no 2 pp 73ndash852002

[31] A Vermes H-J Guchelaar and J Dankert ldquoFlucytosine areview of its pharmacology clinical indications pharmacoki-netics toxicity and drug interactionsrdquo Journal of AntimicrobialChemotherapy vol 46 no 2 pp 171ndash179 2000

[32] J Onishi M Meinz J Thompson et al ldquoDiscovery of novelantifungal (13)-120573-D-glucan synthase inhibitorsrdquo AntimicrobialAgents and Chemotherapy vol 44 no 2 pp 368ndash377 2000

[33] D SanglardACoste and S Ferrari ldquoAntifungal drug resistancemechanisms in fungal pathogens from the perspective of


transcriptional gene regulationrdquo FEMS Yeast Research vol 9no 7 pp 1029ndash1050 2009

[34] I E J A Francois A M Aerts B P A Cammue and KThevissen ldquoCurrently used antimycotics spectrum mode ofaction and resistance occurrencerdquo Current Drug Targets vol 6no 8 pp 895ndash907 2005

[35] E S D Ashley R Lewis J S Lewis C Martin and DAndes ldquoPharmacology of systemic antifungal agentsrdquo ClinicalInfectious Diseases vol 43 no 1 pp S28ndashS39 2006

[36] A Espinel-Ingroff ldquoNovel antifungal agents targets or thera-peutic strategies for the treatment of invasive fungal diseasesa review of the literature (2005ndash2009)rdquo Revista Iberoamericanade Micologia vol 26 no 1 pp 15ndash22 2009

[37] H-P Lipp ldquoClinical pharmacodynamics and pharmacokineticsof the antifungal extended-spectrum triazole posaconazole anoverviewrdquo British Journal of Clinical Pharmacology vol 70 no4 pp 471ndash480 2010

[38] U Theuretzbacher F Ihle and H Derendorf ldquoPharmacoki-neticpharmacodynamic profile of voriconazolerdquo Clinical Phar-macokinetics vol 45 no 7 pp 649ndash663 2006

[39] Y Li U Theuretzbacher C J Clancy M H Nguyen andH Derendorf ldquoPharmacokineticpharmacodynamic profile ofposaconazolerdquoClinical Pharmacokinetics vol 49 no 6 pp 379ndash396 2010

[40] U Theuretzbacher ldquoPharmacokineticspharmacodynamics ofechinocandinsrdquo European Journal of Clinical Microbiology andInfectious Diseases vol 23 no 11 pp 805ndash812 2004

[41] C Wagner W Graninger E Presterl and C Joukhadar ldquoTheechinocandins comparison of their pharmacokinetics phar-macodynamics and clinical applicationsrdquo Pharmacology vol78 no 4 pp 161ndash177 2006

[42] I Bekersky R M Fielding D E Dressler J W Lee DN Buell and T J Walsh ldquoPharmacokinetics excretion andmass balance of liposomal amphotericin B (AmBisome) andamphotericin B deoxycholate in humansrdquo Antimicrobial Agentsand Chemotherapy vol 46 no 3 pp 828ndash833 2002

[43] ZAKanafani and J R Perfect ldquoResistance to antifungal agentsmechanisms and clinical impactrdquo Clinical Infectious Diseasesvol 46 no 1 pp 120ndash128 2008

[44] P Vandeputte S Ferrari and A T Coste ldquoAntifungal resistanceand new strategies to control fungal infectionsrdquo InternationalJournal of Microbiology vol 2012 Article ID 713687 26 pages2012

[45] D S Perlin ldquoAntifungal drug resistance do molecular methodsprovide a way forwardrdquo Current Opinion in Infectious Diseasesvol 22 no 6 pp 568ndash573 2009

[46] J Peman E Canton and A Espinel-Ingroff ldquoAntifungal drugresistance mechanismsrdquo Expert Review of Anti-Infective Ther-apy vol 7 no 4 pp 453ndash460 2009

[47] M J Abad M Ansuategui and P Bermejo ldquoActive antifungalsubstances from natural sourcesrdquo Arkivoc vol 2007 no 7 pp116ndash145 2007

[48] Y-Y Li Z-Y Hu C-H Lu and Y-M Shen ldquoFour newterpenoids fromXylaria sp 101rdquoHelvetica Chimica Acta vol 93no 4 pp 796ndash802 2010

[49] P Bhadury B T Mohammad and P C Wright ldquoThe currentstatus of natural products frommarine fungi and their potentialas anti-infective agentsrdquo Journal of Industrial Microbiology andBiotechnology vol 33 no 5 pp 325ndash337 2006

[50] M Sortino M Derita L Svetaz et al ldquo6 The role of naturalproducts in discovery of new anti-infective agents with empha-sis on antifungal compoundsrdquo in Plant Bioactives and Drug

Discovery Principles Practice and Perspectives V C Filho Edpp 205ndash239 2012

[51] F Pelaez A Cabello G Platas et al ldquoThe discovery ofenfumafungin a novel antifungal compound produced byan endophytic Hormonema species biological activity andtaxonomy of the producing organismsrdquo Systematic and AppliedMicrobiology vol 23 no 3 pp 333ndash343 2000

[52] R Olar M Badea D Marinescu et al ldquoProspects for newantimicrobials based on NN-dimethylbiguanide complexes aseffective agents on both planktonic and adhered microbialstrainsrdquo European Journal of Medicinal Chemistry vol 45 no7 pp 2868ndash2875 2010

[53] R Olar M Badea D Marinescu et al ldquoN N-dimethylbiguanide complexes displaying low cytotoxicityas potential large spectrum antimicrobial agentsrdquo EuropeanJournal of Medicinal Chemistry vol 45 no 7 pp 3027ndash30342010

[54] E B Anderson and T E Long ldquoImidazole- and imidazolium-containing polymers for biology and material science applica-tionsrdquo Polymer vol 51 no 12 pp 2447ndash2454 2010

[55] B Fang C-H Zhou and X-C Rao ldquoSynthesis and biologicalactivities of novel amine-derived bis-azoles as potential antibac-terial and antifungal agentsrdquo European Journal of MedicinalChemistry vol 45 no 9 pp 4388ndash4398 2010

[56] C P J M BrouwerM Rahman andMMWelling ldquoDiscoveryand development of a synthetic peptide derived from lactoferrinfor clinical userdquo Peptides vol 32 no 9 pp 1953ndash1963 2011

[57] B H Heasley G J Pacofsky A Mamai et al ldquoSynthesis andbiological evaluation of antifungal derivatives of enfumafunginas orally bioavailable inhibitors of 120573-1 3-glucan synthaserdquoBioorganicampMedicinal Chemistry Letters vol 22 pp 6811ndash68162012

[58] L D Melo E M Mamizuka and A M Carmona-RibeiroldquoAntimicrobial particles from cationic lipid and polyelec-trolytesrdquo Langmuir vol 26 no 14 pp 12300ndash12306 2010

[59] L M Timofeeva N A Kleshcheva A F Moroz and L VDidenko ldquoSecondary and tertiary polydiallylammonium saltsnovel polymers with high antimicrobial activityrdquo Biomacro-molecules vol 10 no 11 pp 2976ndash2986 2009

[60] I Cakmak Z Ulukanli M Tuzcu S Karabuga and K GenctavldquoSynthesis and characterization of novel antimicrobial cationicpolyelectrolytesrdquo European Polymer Journal vol 40 no 10 pp2373ndash2379 2004

[61] G Sauvet W Fortuniak K Kazmierski and J ChojnowskildquoAmphiphilic block and statistical siloxane copolymers withantimicrobial activityrdquo Journal of Polymer Science A vol 41 no19 pp 2939ndash2948 2003

[62] J Zhu P W Luther Q Leng and A J Mixson ldquoSynthetichistidine-rich peptides inhibit Candida species and other fungiin vitro role of endocytosis and treatment implicationsrdquoAntimicrobial Agents andChemotherapy vol 50 no 8 pp 2797ndash2805 2006

[63] J P Tam Y-A Lu and J-L Yang ldquoAntimicrobial dendrimericpeptidesrdquo European Journal of Biochemistry vol 269 no 3 pp923ndash932 2002

[64] G N Tew D Clements H Tang L Arnt and R W ScottldquoAntimicrobial activity of an abiotic host defense peptidemimicrdquo Biochimica et Biophysica Acta vol 1758 no 9 pp 1387ndash1392 2006

[65] A Som Y Choi and G N Tew ldquoMonovalent salt effects on themembrane activity of antimicrobial polymersrdquoMacromolecularSymposia vol 283-284 no 1 pp 319ndash325 2009


[66] E F Palermo and K Kuroda ldquoChemical structure of cationicgroups in amphiphilic polymethacrylatesmodulates the antimi-crobial and hemolytic activitiesrdquo Biomacromolecules vol 10 no6 pp 1416ndash1428 2009

[67] E F Palermo I Sovadinova and K Kuroda ldquoStructuraldeterminants of antimicrobial activity and biocompatibility inmembrane-disrupting methacrylamide random copolymersrdquoBiomacromolecules vol 10 no 11 pp 3098ndash3107 2009

[68] L Caillier E Taffin de Givenchy R Levy Y VandenbergheS Geribaldi and F Guittard ldquoPolymerizable semi-fluorinatedgemini surfactants designed for antimicrobial materialsrdquo Jour-nal of Colloid and Interface Science vol 332 no 1 pp 201ndash2072009

[69] M B Patel S A Patel A Ray and R M Patel ldquoSynthesis char-acterization and antimicrobial activity of acrylic copolymersrdquoJournal of Applied Polymer Science vol 89 no 4 pp 895ndash9002003

[70] J N Patel M B Dolia K H Patel and R M PatelldquoHomopolymer of 4-chloro-3-methyl phenyl methacrylate andits copolymers with butyl methacrylate synthesis characteri-zation reactivity ratios and antimicrobial activityrdquo Journal ofPolymer Research vol 13 no 3 pp 219ndash228 2006

[71] A Munoz-Bonilla andM Fernandez-Garcıa ldquoPolymeric mate-rials with antimicrobial activityrdquo Progress in Polymer Sciencevol 37 pp 281ndash339 2012

[72] R Senthil Kumar K Sasikala and S Arunachalam ldquoDNAinteraction of some polymer-copper(II) complexes containing221015840-bipyridyl ligand and their antimicrobial activitiesrdquo Journalof Inorganic Biochemistry vol 102 no 2 pp 234ndash241 2008

[73] C Soykan R Coskun and S Kirbag ldquoPoly(crotonic acid-co-2-acrylamido-2-methyl-1-propanesulfonic acid)-metalcomplexes with copper(II) cobalt(II) and nickel(II) synthesischaracterization and antimicrobial activityrdquo European PolymerJournal vol 43 no 9 pp 4028ndash4036 2007

[74] I C Yue J Poff M E Cortes et al ldquoA novel polymericchlorhexidine delivery device for the treatment of periodontaldiseaserdquo Biomaterials vol 25 no 17 pp 3743ndash3750 2004

[75] A S Kiremitci A Ciftci M Ozalp and M GumusdereliogluldquoNovel chlorhexidine releasing system developed from ther-mosensitive vinyl ether-based hydrogelsrdquo Journal of BiomedicalMaterials Research B vol 83 pp 609ndash614 2007

[76] H Zhang D Wang R Butler et al ldquoFormation and enhancedbiocidal activity of water-dispersable organic nanoparticlesrdquoNature Nanotechnology vol 3 no 8 pp 506ndash511 2008

[77] H Kong J Song and J Jang ldquoOne-step preparation of antimi-crobial polyrhodanine nanotubes with silver nanoparticlesrdquoMacromolecular Rapid Communications vol 30 no 15 pp1350ndash1355 2009

[78] H Kong and J Jang ldquoSynthesis and antimicrobial propertiesof novel silverpolyrhodanine nanofibersrdquo Biomacromoleculesvol 9 no 10 pp 2677ndash2681 2008

[79] Y-Y Duan J Jia S-H Wang W Yan L Jin and Z-Y WangldquoPreparation of antimicrobial poly(e-caprolactone) electro-spun nanofibers containing silver-loaded zirconium phosphatenanoparticlesrdquo Journal of Applied Polymer Science vol 106 no2 pp 1208ndash1214 2007

[80] K Hata T Horii M Miyazaki et al ldquoEfficacy of oral E1210a new broad-spectrum antifungal with a novel mechanismof action in murine models of candidiasis aspergillosis andfusariosisrdquo Antimicrobial Agents and Chemotherapy vol 55 no10 pp 4543ndash4551 2011

[81] A C Pasqualotto and D W Denning ldquoNew and emergingtreatments for fungal infectionsrdquo The Journal of AntimicrobialChemotherapy vol 61 pp i19ndashi30 2008

[82] C Girmenia ldquoNew generation azole antifungals in clinicalinvestigationrdquo Expert Opinion on Investigational Drugs vol 18no 9 pp 1279ndash1295 2009

[83] A Schmitt-Hoffmann B Roos M Heep et al ldquoSingle-ascending-dose pharmacokinetics and safety of the novelbroad-spectrum antifungal triazole BAL4815 after intravenousinfusions (50 100 and 200milligrams) andoral administrations(100 200 and 400 milligrams) of its prodrug BAL8557 inhealthy volunteersrdquo Antimicrobial Agents and Chemotherapyvol 50 no 1 pp 279ndash285 2006

[84] J F G M Meis and P E Verweij ldquoCurrent management offungal infectionsrdquo Drugs vol 61 no 1 pp 13ndash25 2001

[85] H L Hoffman E J Ernst and M E Klepser ldquoNovel triazoleantifungal agentsrdquo Expert Opinion on Investigational Drugs vol9 no 3 pp 593ndash605 2000

[86] D M Livermore ldquoThe need for new antibioticsrdquo ClinicalMicrobiology and Infection vol 10 no 4 pp 1ndash9 2004

[87] S W Redding W R Kirkpatrick S Saville et al ldquoMultiplepatterns of resistance to fluconazole inCandida glabrata isolatesfrom a patient with oropharyngeal candidiasis receiving headand neck radiationrdquo Journal of Clinical Microbiology vol 41 no2 pp 619ndash622 2003

[88] D J Skiest J AVazquezGMAnstead et al ldquoPosaconazole forthe treatment of azole-refractory oropharyngeal and esophagealcandidiasis in subjects with HIV infectionrdquo Clinical InfectiousDiseases vol 44 no 4 pp 607ndash614 2007

[89] M Ribeiro C R Paula J R Perfect and G M Cox ldquoPhe-notypic and genotypic evaluation of fluconazole resistance invaginal Candida strains isolated from HIV-infected womenfromBrazilrdquoMedicalMycology vol 43 no 7 pp 647ndash650 2005

[90] J A Vazquez G Peng J O Sabel et al ldquoEvolution of antifungalsusceptibility among Candida species isolates recovered fromhuman immunodeficiency virus-infected women receiving flu-conazole prophylaxisrdquo Clinical Infectious Diseases vol 33 no 7pp 1069ndash1075 2001

[91] A Safdar F van Rhee J P Henslee-Downey S Singhal andJ Mehta ldquoCandida glabrata and Candida krusei fungemiaafter high-risk allogeneic marrow transplantation no adverseeffect of low-dose fluconazole prophylaxis on incidence andoutcomerdquo BoneMarrow Transplantation vol 28 no 9 pp 873ndash878 2001

[92] M Cuenca-Estrella A Gomez-Lopez E Mellado M JBuitrago A Monzon and J L Rodriguez-Tudela ldquoHead-to-head comparison of the activities of currently available antifun-gal agents against 3378 Spanish clinical isolates of yeasts andfilamentous fungirdquo Antimicrobial Agents and Chemotherapyvol 50 no 3 pp 917ndash921 2006

[93] M A Pfaller S A Messer L Boyken et al ldquoUse of fluconazoleas a surrogate marker to predict susceptibility and resistanceto voriconazole among 13338 clinical isolates of Candidaspp tested by clinical and laboratory standards institute-recommended broth microdilution methodsrdquo Journal of Clin-ical Microbiology vol 45 no 1 pp 70ndash75 2007

[94] M A Pfaller S A Messer L Boyken et al ldquoCross-resistancebetween fluconazole and ravuconazole and the use of flu-conazole as a surrogate marker to predict susceptibility andresistance to ravuconazole among 12796 clinical isolates ofCandida spprdquo Journal of Clinical Microbiology vol 42 no 7 pp3137ndash3141 2004


[95] T Noel ldquoThe cellular and molecular defense mechanisms ofthe Candida yeasts against azole antifungal drugsrdquo Journal deMycologie Medicale vol 22 pp 173ndash178 2012

[96] RDCannon E LampingA RHolmes et al ldquoEfflux-mediatedantifungal drug resistancerdquo Clinical Microbiology Reviews vol22 no 2 pp 291ndash321 2009

[97] A T Coste M Karababa F Ischer J Bille and D SanglardldquoTAC1 transcriptional activator of CDR genes is a new tran-scription factor involved in the regulation of Candida albicansABC transporters CDR1 and CDR2rdquo Eukaryotic Cell vol 3 no6 pp 1639ndash1652 2004

[98] A Coste V Turner F Ischer et al ldquoA mutation in TAC1p atranscription factor regulatingCDR1 andCDR2 is coupled withloss of heterozygosity at chromosome 5 to mediate antifungalresistance in Candida albicansrdquo Genetics vol 172 no 4 pp2139ndash2156 2006

[99] A T Coste J Crittin C Bauser B Rohde and D SanglardldquoFunctional analysis of cis-and trans-acting elements of theCandida albicans CDR2promoter with a novel promoterreporter systemrdquo Eukaryotic Cell vol 8 no 8 pp 1250ndash12672009

[100] R Torelli B Posteraro S Ferrari et al ldquoThe ATP-bindingcassette transporter-encoding gene CgSNQ2 is contributing tothe CgPDR1-dependent azole resistance of Candida glabratardquoMolecular Microbiology vol 68 no 1 pp 186ndash201 2008

[101] D Sanglard F Ischer D Calabrese P A Majcherczyk andJ Bille ldquoThe ATP binding cassette transporter gene CgCDR1from Candida glabrata is involved in the resistance of clinicalisolates to azole antifungal agentsrdquo Antimicrobial Agents andChemotherapy vol 43 no 11 pp 2753ndash2765 1999

[102] J E Bennett K Izumikawa and K A Marr ldquoMechanism ofIncreased Fluconazole Resistance in Candida glabrata duringProphylaxisrdquo Antimicrobial Agents and Chemotherapy vol 48no 5 pp 1773ndash1777 2004

[103] G P Moran D Sanglard S M Donnelly D B Shanley D JSullivan and D C Coleman ldquoIdentification and expression ofmultidrug transporters responsible for fluconazole resistance inCandida dubliniensisrdquo Antimicrobial Agents and Chemotherapyvol 42 no 7 pp 1819ndash1830 1998

[104] E Lamping A Ranchod K Nakamura et al ldquoAbc1p is amultidrug efflux transporter that tips the balance in favor ofinnate azole resistance in Candida kruseirdquo Antimicrobial Agentsand Chemotherapy vol 53 no 2 pp 354ndash369 2009

[105] S K Katiyar and T D Edlind ldquoIdentification and expression ofmultidrug resistance-related ABC transporter genes inCandidakruseirdquoMedical Mycology vol 39 no 1 pp 109ndash116 2001

[106] J-P Vermitsky and T D Edlind ldquoAzole resistance in Candidaglabrata coordinate upregulation of multidrug transportersand evidence for a Pdr1-like transcription factorrdquo AntimicrobialAgents and Chemotherapy vol 48 no 10 pp 3773ndash3781 2004

[107] J-P Vermitsky K D Earhart W L Smith R Homayouni T DEdlind and P D Rogers ldquoPdr1 regulatesmultidrug resistance inCandida glabrata gene disruption and genome-wide expressionstudiesrdquo Molecular Microbiology vol 61 no 3 pp 704ndash7222006

[108] H-F Tsai A A Krol K E Sarti and J E Bennett ldquoCandidaglabrata PDR1 a transcriptional regulator of a pleiotropic drugresistance network mediates azole resistance in clinical isolatesand petite mutantsrdquo Antimicrobial Agents and Chemotherapyvol 50 no 4 pp 1384ndash1392 2006

[109] C M Martel J E Parker O Bader et al ldquoIdentification andcharacterization of four azole-resistant erg3mutants ofCandida

albicansrdquo Antimicrobial Agents and Chemotherapy vol 54 no11 pp 4527ndash4533 2010

[110] YMiyazaki A Geber HMiyazaki et al ldquoCloning sequencingexpression and allelic sequence diversity of ERG3 (C-5 steroldesaturase gene) in Candida albicansrdquo Gene vol 236 no 1 pp43ndash51 1999

[111] S Hernandez J L Lopez-Ribot L K Najvar D I McCarthyR Bocanegra and J R Graybill ldquoCaspofungin resistance inCandida albicans correlating clinical outcome with laboratorysusceptibility testing of three isogenic isolates serially obtainedfrom a patient with progressive candida esophagitisrdquo Antimi-crobial Agents and Chemotherapy vol 48 no 4 pp 1382ndash13832004

[112] M Krogh-Madsen M C Arendrup L Heslet and J D Knud-sen ldquoAmphotericin B and caspofungin resistance in Candidaglabrata isolates recovered from a critically ill patientrdquo ClinicalInfectious Diseases vol 42 no 7 pp 938ndash944 2006

[113] M Hakki J F Staab and K A Marr ldquoEmergence of a Candidakrusei isolate with reduced susceptibility to caspofungin duringtherapyrdquo Antimicrobial Agents and Chemotherapy vol 50 no 7pp 2522ndash2524 2006

[114] T Pasquale J R Tomada M Ghannoun J Dipersio and HBonilla ldquoEmergence ofCandida tropicalis resistant to caspofun-ginrdquo Journal of Antimicrobial Chemotherapy vol 61 no 1 p 2192008

[115] B Alexander M Johnson C Pfeiffer et al ldquoIncreasingechinocandin resistance in Candida glabrata clinical failurecorrelates with presence of FKS mutations and elevated min-imum inhibitory concentrationsrdquo Clinical Infectious Diseasesvol 56 pp 1724ndash1732 2013

[116] M A Pfaller M Castanheira S R Lockhart A M Ahlquist SAMesser and RN Jones ldquoFrequency of decreased susceptibil-ity and resistance to echinocandins amongfluconazole-resistantbloodstream isolates of Candida glabratardquo Journal of ClinicalMicrobiology vol 50 no 4 pp 1199ndash1203 2012

[117] G Garcia-Effron S K Katiyar S Park T D Edlind and DS Perlin ldquoA naturally occurring proline-to-alanine amino acidchange in Fks1p in Candida parapsilosis Candida orthopsilosisand Candida metapsilosis accounts for reduced echinocandinsusceptibilityrdquo Antimicrobial Agents and Chemotherapy vol 52no 7 pp 2305ndash2312 2008

[118] E Canton J Peman M Sastre M Romero and A Espinel-Ingroff ldquoKilling kinetics of caspofungin micafungin andamphotericin B against Candida guilliermondiirdquo AntimicrobialAgents and Chemotherapy vol 50 no 8 pp 2829ndash2832 2006

[119] J N Kahn G Garcia-EffronM-J Hsu S Park K AMarr andD S Perlin ldquoAcquired echinocandin resistance in a Candidakrusei isolate due to modification of glucan synthaserdquo Antimi-crobial Agents and Chemotherapy vol 51 no 5 pp 1876ndash18782007

[120] S Park R Kelly J N Kahn et al ldquoSpecific substitutions in theechinocandin target Fks1p account for reduced susceptibility ofrare laboratory and clinical Candida sp isolatesrdquo AntimicrobialAgents and Chemotherapy vol 49 no 8 pp 3264ndash3273 2005

[121] S V Balashov S Park and D S Perlin ldquoAssessing resistanceto the echinocandin antifungal drug caspofungin in Candidaalbicans by profiling mutations in FKS1rdquo Antimicrobial Agentsand Chemotherapy vol 50 no 6 pp 2058ndash2063 2006

[122] G Garcia-Effron S Park and D S Perlin ldquoCorrelatingechinocandinMIC and kinetic inhibition of fks1 mutant glucansynthases for Candida albicans implications for interpretive


breakpointsrdquo Antimicrobial Agents and Chemotherapy vol 53no 1 pp 112ndash122 2009

[123] R Laniado-Laborın andM N Cabrales-Vargas ldquoAmphotericinB side effects and toxicityrdquo Revista Iberoamericana de Micolo-gia vol 26 no 4 pp 223ndash227 2009

[124] D Ellis ldquoAmphotericin B spectrum and resistancerdquo Journal ofAntimicrobial Chemotherapy vol 49 supplement 1 pp 7ndash102002

[125] JH Rex T JWalsh J D Sobel et al ldquoPractice guidelines for thetreatment of candidiasisrdquoClinical InfectiousDiseases vol 30 no4 pp 662ndash678 2000

[126] D P Kontoyiannis and R E Lewis ldquoAntifungal drug resistanceof pathogenic fungirdquo The Lancet vol 359 no 9312 pp 1135ndash1144 2002

[127] P G Pappas J H Rex J D Sobel et al ldquoGuidelines fortreatment of Candidiasisrdquo Clinical Infectious Diseases vol 38no 2 pp 161ndash189 2004

[128] A Espinel-Ingroff ldquoMechanisms of resistance to antifungalagents yeasts and filamentous fungirdquoRevista Iberoamericana deMicologia vol 25 no 2 pp 101ndash106 2008

[129] P Vandeputte G Tronchin T Berges C Hennequin DChabasse and J-P Bouchara ldquoReduced susceptibility topolyenes associated with amissense mutation in the ERG6 genein a clinical isolate of Candida glabrata with pseudohyphalgrowthrdquo Antimicrobial Agents and Chemotherapy vol 51 no 3pp 982ndash990 2007

[130] S L Kelly D C Lamb D E Kelly et al ldquoResistance tofluconazole and cross-resistance to amphotericin B in Candidaalbicans from AIDS patients caused by defective sterol Δ56-desaturationrdquo FEBS Letters vol 400 no 1 pp 80ndash82 1997

[131] F Chapeland-Leclerc J Bouchoux A Goumar C Chastin JVillard and T Noel ldquoInactivation of the FCY2 gene encodingpurine-cytosine permease promotes cross-resistance to flucy-tosine and fluconazole in Candida lusitaniaerdquo AntimicrobialAgents and Chemotherapy vol 49 no 8 pp 3101ndash3108 2005

[132] P Vandeputte L Pineau G Larcher et al ldquoMolecular mecha-nisms of resistance to 5-fluorocytosine in laboratory mutants ofCandida glabratardquoMycopathologia vol 171 no 1 pp 11ndash21 2011

[133] M C T Duarte G M Figueira A Sartoratto V L GRehder and C Delarmelina ldquoAnti-Candida activity of Brazilianmedicinal plantsrdquo Journal of Ethnopharmacology vol 97 no 2pp 305ndash311 2005

[134] M S Butler ldquoThe role of natural product chemistry in drugdiscoveryrdquo Journal of Natural Products vol 67 no 12 pp 2141ndash2153 2004

[135] F Mondello F de Bernardis A Girolamo A Cassone and GSalvatore ldquoIn vivo activity of terpinen-4-ol the main bioactivecomponent ofMelaleuca alternifolia Cheel (tea tree) oil againstazole-susceptible and -resistant human pathogenic Candidaspeciesrdquo BMC Infectious Diseases vol 6 article 158 2006

[136] V Manohar C Ingram J Gray et al ldquoAntifungal activities oforiganum oil against Candida albicansrdquoMolecular and CellularBiochemistry vol 228 no 1-2 pp 111ndash117 2001

[137] S Dalleau E Cateau T Berges J-M Berjeaud and C ImbertldquoIn vitro activity of terpenes against Candida biofilmsrdquo Interna-tional Journal of Antimicrobial Agents vol 31 no 6 pp 572ndash5762008

[138] G B Zore A D Thakre S Jadhav and S M KaruppayilldquoTerpenoids inhibitCandida albicans growth by affectingmem-brane integrity and arrest of cell cyclerdquo Phytomedicine vol 18no 13 pp 1181ndash1190 2011

[139] A A L Gunatilaka ldquoNatural products from plant-associatedmicroorganisms distribution structural diversity bioactivityand implications of their occurrencerdquo Journal of Natural Prod-ucts vol 69 no 3 pp 509ndash526 2006

[140] N G Aher V S Pore N N Mishra et al ldquoSynthesis andantifungal activity of 123-triazole containing fluconazole ana-loguesrdquo Bioorganic and Medicinal Chemistry Letters vol 19 no3 pp 759ndash763 2009

[141] G Kofla and M Ruhnke ldquoPharmacology and metabolism ofanidulafungin caspofungin andmicafungin in the treatment ofinvasive candidosismdashreview of the literaturerdquo European Journalof Medical Research vol 16 no 4 pp 159ndash166 2011

[142] A Fernandez E Soriano P Hernandez-Munoz and R GavaraldquoMigration of antimicrobial silver from composites of polylac-tide with silver zeolitesrdquo Journal of Food Science vol 75 no 3pp E186ndashE193 2010

[143] O Ozay A Akcali M T Otkun C Silan N Aktas and NSahiner ldquoP(4-VP) based nanoparticles and composites withdual action as antimicrobial materialsrdquo Colloids and Surfaces Bvol 79 no 2 pp 460ndash466 2010

[144] N-A Watanabe M Miyazaki T Horii K Sagane K Tsuka-hara and K Hata ldquoE1210 a new broad-spectrum antifungalsuppresses Candida albicans hyphal growth through inhibi-tion of glycosylphosphatidylinositol biosynthesisrdquo Antimicro-bial Agents and Chemotherapy vol 56 no 2 pp 960ndash971 2012

[145] MMiyazaki T Horii K Hata et al ldquoIn vitro activity of E1210 anovel antifungal against clinically important yeasts andmoldsrdquoAntimicrobial Agents and Chemotherapy vol 55 no 10 pp4652ndash4658 2011

[146] J Bartroli andMMerlos ldquoOverview of albaconazolerdquoEuropeanInfectious Disease vol 5 no 2 pp 88ndash91 2011

[147] J Majithiya A Sharp A Parmar D W Denning and P AWarn ldquoEfficacy of isavuconazole voriconazole and fluconazolein temporarily neutropenic murine models of disseminatedCandida tropicalis andCandida kruseirdquo Journal of AntimicrobialChemotherapy vol 63 no 1 pp 161ndash166 2009

[148] F C Odds ldquoDrug evaluation BAL-8557mdasha novel broad-spectrum triazole antifungalrdquo Current Opinion in Investiga-tional Drugs vol 7 no 8 pp 766ndash772 2006

[149] J Livermore andWHope ldquoEvaluation of the pharmacokineticsand clinical utility of isavuconazole for treatment of invasivefungal infectionsrdquo Expert Opinion on Drug Metabolism ampToxicology vol 8 pp 759ndash765 2012

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Anatomy Research International

PeptidesInternational Journal of


Hindawi Publishing Corporation httpwwwhindawicom

International Journal of

Volume 2014

Zoology


Molecular Biology International

GenomicsInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014


BioinformaticsAdvances in

Marine BiologyJournal of



Signal TransductionJournal of


BioMed Research International

Evolutionary BiologyInternational Journal of



Biochemistry Research International

ArchaeaHindawi Publishing Corporationhttpwwwhindawicom Volume 2014


Genetics Research International


Advances in

Virolog y

Hindawi Publishing Corporationhttpwwwhindawicom

Nucleic AcidsJournal of

Volume 2014

Stem CellsInternational



Enzyme Research



Microbiology


Antifungal class Mode of action Drugs

Azoles Inhibitors of lanosterol14-120572-demethylase

MiconazoleEconazoleClotrimazoleKetoconazoleFluconazoleItraconazoleVoriconazolePosaconazole

Echinocandins Inhibitors of(13)-120573-D-glucan synthase

CaspofunginMicafunginAnidulafungin

Polyenes Binding ergosterol NystatinAmphotericin B

Nucleoside analogues Inhibitor of DNARNA synthesis Flucytosine

Allylamines Inhibitors of squalene-epoxidase TerbinafineAmorolfineNaftifine

Thiocarbamates Inhibitors of squalene-epoxidase TolnaftateTolciclate

Antibiotic Interaction with 120573-tubulin Griseofulvin

Nucleoside analoguesInhibitors ofnucleic acid

synthesis

Plasma membraneCell wall

MitosisNuclei

Cytosol

Endoplasmaticreticulum

PolyenesBinding ergosterol

Azolesallylamines and

Inhibitors ofergosterol synthesis

EchinocandinsInhibitors of

120573-glucan synthesisGriseofulvineInhibitor ofmicrotubule

synthesis

thiocarbamates

Figure 1 Primary targets and mode of action of several antifungal agents

antifungal agents are currently available to treat mucosal orsystemic infections with Candida spp (Figure 1) [18ndash20]

21 Azoles Inhibitors of the Lanosterol 14-120572-Demethylase Thelargest family of antifungal drugs is the azole family Azolesdisrupt the cell membrane by inhibiting the activity of thelanosterol 14-120572-demethylase [21] enzyme involved in thebiosynthesis of ergosterol (Figure 1) Ergosterol analogous tocholesterol in animal cells is the largest sterol component of

the fungal cell membrane Since ergosterol and cholesterolhave sufficient structural differences most antifungal agentstargeted to ergosterol binding or biosynthesis does not cross-react with host cells The azole family includes imidazoles(miconazole econazole clotrimazole and ketoconazole) andtriazoles (fluconazole itraconazole and the latest agentvoriconazole (second-generation synthetic triazole deriva-tive of fluconazole) and posaconazole (hydroxylated ana-logue of itraconazole)) [21 22] Many azoles are effective





()119862max

b

120583gmLAUCc

mgsdothLProtein

binding ()Half time

(h) Elimination

Azoles



41]















Azoles







Nucleosideanalogues




























Naturalproducts







Syntheticagents




[52 53]





[57 58]










[66 67]





















NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





()119862max

b

120583gmLAUCc

mgsdothLProtein

binding ()Half time

(h) Elimination

Azoles



41]















Azoles







Nucleosideanalogues




























Naturalproducts







Syntheticagents




[52 53]





[57 58]










[66 67]





















NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Azoles







Nucleosideanalogues




























Naturalproducts







Syntheticagents




[52 53]





[57 58]










[66 67]





















NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


















Naturalproducts







Syntheticagents




[52 53]





[57 58]










[66 67]





















NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




Naturalproducts







Syntheticagents




[52 53]





[57 58]










[66 67]





















NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology











NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology


NH2

O

O

N

N

N

(a)

OOH

ClN

NNN

N

CH3

F

F

(b)

F

FN

N

N

N

N

HOS

(c)





bioavailability()

119862maxb

(120583gmL)119905max

c

(h)

Proteinbinding()

Halftime(h)

Elimination






(100mgdose)



(100mgdose)




5 Conclusions



Acknowledgments




References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



References





































































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology




































































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

































































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology



































































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology





































Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology








Volume 2014

Zoology






















Advances in

Virolog y



Volume 2014




Enzyme Research



Microbiology

Documents

Review Article Candida Infections, Causes, Targets, and Resistance Mechanisms ... · 2019. 7. 31. · nate to internal organs. Risk factors for invasive candidiasis include surgery