Novel Antifungal Agents

Dr. Khaled H. Abu-Elteen

Dr. Mawieh A. Hamad

Department of Biological Sciences

Faculty of Science- Hashemite University

Most Important Antifungal Agents

Used in Treatment of Fungal Infections

Griseofulvina 1947

Amphotericin B 1957

Fluocytosine 1971

Miconazole 1978

Ketoconazole 1981

Fluconazole 1989

Itraconazole 1990

Voriconazole

Caspofungin

2003

2003

Polyene Macrolide AntibioticsThe discovery of nystatin (fungicidin) by Rachel Brown and Elizabeth Hazen in the early 1950s had led to the isolation and characterization of

numerous antibiotics. Amphotericin B (fungizone), first isolated in the 1957 from

Streptomyces nodosus, an actinomycete cultured from the soil of the Orinoco Valley in Venezuela,

was the first commercially available systemic antifungal drug; so far, about 200 antifungal

agents of this class exist. However, problems associated with the stability, solubility, toxicity and absorption of most such compounds, cut down the number of polyenes approved for

therapeutic use to only a few.

Polyenes are characterized by a large macrolide ring of carbon atoms closed by the formation of an internal ester of lactone (Figure 1). The macrolide ring contains 12- 37 carbon atoms, the conjugated double bond structure is

contained exclusively within the cyclic lactone. A number of hydroxyl groups (6-14) are distributed along the

macrolide ring on alternate carbon atoms. Amphotericin B has a free carboxyl group and a primary amine group

that confer amphoteric properties on the compound, hence the drug’s name. Being amphoteric, amphotericin

B tends to form channels through the cell membrane causing cell leakage.

HN

NH

O

F

NH2

O

OCH3

OHNH2OH

CH3

CH3

O

HO

H3C OH

COOHOHOOHOH

OH

OHOHO

O

OCH3

OHNH2OH

CH3

CH3

O

HO

H3C OH

COOHOHOOHO

OH

OHOHOH

Nystatin

POLYENES

Amphotericine B

FLUCYTOSINE

Figure 6.1

Although amphotericin B remains the preferred compound for treating systemic mycoses, problems associated with solubility in water, toxicity and ineffectiveness against mold diseases in immunocompromised patients limit its therapeutic potential. Three lipid formulations of amphotericin B (amphotericin B lipid complex, amphotericin B cholesteryl sulfate and liposomal amphotericin B) have been developed and approved for use in the US. These drug delivery systems offer several advantages over conventional amphotericin B. The parent drug can be introduced in much higher doses (up to 10-fold) compared with conventional amphotericin B.

Mechanism of Action of PolyenesPolyene antibiotics increase cell membrane permeability,

which causes leakage of cellular constituents (amino acids, sugars and other metabolites), cell lysis and death. Inhibition of aerobic and anaerobic respiration observed

in cells treated with polyenes is though to be a consequence of leakage of cellular constituents.

Polyenes could also cause oxidative damage to the fungal plasmalemma, which may contribute to the

fungicidal activity of the drug. Inhibition of fungal growth by polyenes depends, to a large extent, on the binding of

the drug to the cell; only cells that bind appreciable amounts of the drug are sensitive. Bacterial cells and

protoplasts do not take up polyenes; therefore, they are resistant to the drug .

Polyene antifungals selectively bind to membrane sterols; ergosterol in fungal cells and cholesterol in mammalian

cells.

The interaction of larger polyenes like amphotericin B with fungal membrane sterols results in the production

of aqueous pores consisting of an annulus of eight amphotericin B molecules linked hydrophobically to membrane sterols (Figure 6.2). This leads to the

formation of pores in which the hydroxyl residues of the polyene face inwards to give an effective pore

diameter of 0.4 to 1.0 nm. Leakage of vital cytoplasmic components and death of the cell follows.

The selective mode of action of polyenes is also related to the differential affinity of different polyenes to membrane sterols on target cells. Amphotericin B

binds with high affinity to ergosterol in fungal cell membrane.

PHARMACOKINETICS PHARMACODYNAMICS

SERUM

LEVELS

TISSUE

LEVELSmetabolism

doseabsorption

elimination

MICKILLING

PAFEPAFSE

high serum

or tissue levels

low orabsentserum

or tissue levels

distribution

TOXICITY EFFICACY RESISTANCE (?)

dose optimisation

PK CORRELATION

(T>MIC AUC/MIC Cmax/MIC)

PD

Sites of action of antifungal agentsSites of action of antifungal agents

Mukherjee PK et al., Clin Microbiol Rev, 2005

Cytoplasm

Lanosterolo Zymosterolo Ergosterolo

FLU inhibits ergosterol biosynthesis , resulting In depletion of this sterol in the cell membrane

(A) Mechanism of azole action (B) Mechanism of polyene

Ergosterolo

Cell wall

Cell membrane

ergosterolofluconazolo

Amphotericin B

Endocellular space

Cytoplasm

Pore/channel formed by AmB results in cell death

(C) Mechanism of 5-fluorocytosine action (D) Mechanism of echinocandin action

Cell membrane

5-FC 5-FC 5-FU

5-FUMP

5-FdUMP

Inhibition of protein synthesis

Inhibition of DNAsynthesis

Cytosinepermease

-(1,3)-D-glucan -(1,6)-D-glucan

Cell wallCell

membrane

cytoplasm

-(1,6)-D-glucan synthase

Candin

Candins inhibitfungal glucan synthase

SQUALENE

Squalene epoxide

LANOSTEROL

14-α-demethyl lanosterol

Zymosterol

Fecosterol

ERGOSTEROL

Squalene epoxidase

Lanosterol 14-α demethylase

ALLYLAMINES:NaftifineTerbinafine

AZOLES:KetoconazoleFluconazoleItraconazoleVoriconazole

POLYENES:Amphotericin BNystatin

Membrane Antifungal Agents

Structural features of Amphotericin B

Hydrophilic stretch

Hydrophobic stretch

Mycosamine ring withCarbohydrate moiety

AMPHOTERICIN B DEOXYCOLATEAMPHOTERICIN B DEOXYCOLATE

Main side effects

Main pharmacokinetic parameters (0.5-1.0 mg/kg)

Nausea and vomitingNausea and vomitingFever, chillsFever, chillsArtralgia, myalgiaArtralgia, myalgiaHeadachesHeadachesThrombophlebitisThrombophlebitis

NephrotoxicityNephrotoxicityHypotensionHypotensionCardiotoxicityCardiotoxicityBronchospasmBronchospasm

Cmax 1.2-2.4 Cmax 1.2-2.4 g/mlg/mlT1/2 initial phase: 24-48 hT1/2 initial phase: 24-48 hT1/2 terminal phase: 15 daysT1/2 terminal phase: 15 days Protein binding: 91 - 95Protein binding: 91 - 95% %

Elimination: biliary-renalElimination: biliary-renal Fu 24 h: 3 - 5Fu 24 h: 3 - 5% % CSF/serum: 2 - 4CSF/serum: 2 - 4% %

Modified from Como and Dismuekes, 1994; Groll et al., 1998

Physicochemical information on the lipid formulations Physicochemical information on the lipid formulations of AmB in comparison to AmB deoxycholateof AmB in comparison to AmB deoxycholate

c-AmB L-AmB Liposomal AmB

ABLC AmB lipid complex

Brand name Fungizone AmBisome Abelcet

Lipids (molar ratio) Deoxycholate HPC/CHOL/DSPG (2:1:0.8)

DMPC/DMPG (7:3)

Mol% AmB 34% 10% 35%

Lipid configuration Micelles Liposomes Lipid-sheets

Diameter (m) < 0.4 0.08 1.6 - 11.0

The first Liposomal formulation of AMB is made up by a mixture of two phospholipid : Dimyristoyl

phosphatidylcholine [ DMPC] and dimyristoyl phosphatidylglycerol [ DMPG] in a 7:3 molar ratio with 5-

10% of the mixture being AMB .

Hartsel S and Bolard J, TiPS, 1996

Mechanisms of actionAmphotericin B (AMB) Amphotericin B lipid

formulations(formation of transmembrane pores)

LDL=low density lipoproteins

cholesterol

ergosterol

lipid peroxidation

AmB-LDLAmB-lipidcomplex

lysosome

endosome

Host cell

Fungal cell

a

FreeAmB

b

d

Slow release of free AmB

c

macrophages

endosome

endosome

parasiteFungal cell

dc

b

a

Fungal cell

Antifungal activity of amphotericin BAntifungal activity of amphotericin B

VERY ACTIVEVERY ACTIVEAVERAGE ACTIVITYAVERAGE ACTIVITY

Candida Candida sppspp

Criptococcus Criptococcus neoformansneoformans

Blastomyces Blastomyces dermatitidisdermatitidis

Histoplasma capsulatumHistoplasma capsulatum

Sporothrix Sporothrix schenckiischenckii

Coccidioides immitisCoccidioides immitis

Paracoccidioides braziliensisParacoccidioides braziliensis

Aspergillus Aspergillus sppspp

Penicillium marneffeiPenicillium marneffei

Candida lusitaniaeCandida lusitaniae

Candida tropicalisCandida tropicalis

Candida parapsilosisCandida parapsilosis

Scedosporium boydiiScedosporium boydii

Fusarium Fusarium sppspp

Malassezia furfurMalassezia furfur

Trichosporon beigeliiTrichosporon beigelii

Physicochemical and pharmacokinetic information on the lipid Physicochemical and pharmacokinetic information on the lipid formulations of AmB in comparison to AmB deoxycholateformulations of AmB in comparison to AmB deoxycholate

AmB L-AmB ABLC

Brand name Fungizone AmBisome Abelcet

Lipids (molar ratio) Deoxycholate HPC/CHOL/DSPG (2:1:0.8)

DMPC/DMPG (7:3)

Mol% AmB 34% 10% 35%

Lipid configuration Micelles SUVs Ribbon-like

Diameter (m) < 0.4 0.08 1.6 - 11.0

Standard dosage (mg AmB/kg) 1 mg/kg 3-5 mg/kg 5 mg/kg

Cmax (relative to AmB) -- Increased Decreased

AUC (relative to AmB) -- Increased Decreased

Vd (relative to AmB) -- Decreased Increased

Cl (relative to AmB) -- Decreased Increased

Relative nephrotoxicity +++ ± ±

Infusion-related toxicity High Mild Moderate

AmB, amphotericin B deoxycholate; L-AmB, liposomal AmB; ABLC, AmB lipid complex; HPC, hydrogenated

phosphatidylcholine; CHOL, cholesterol; DSPG, disteaorylphosphatidylglycerol; DMPC, dimyristoyl phosphatidylcholine; DMPG, dimyristoyl phosphatidylglycerol; SUV, small unilamellar vesicles (liposomes)

Azole derivatives

• FIRST GENERATION

– Ketoconazole

• SECOND GENERATION

– Fluconazole

– Itraconazole

• THIRD GENERATION

– Voriconazole ( most widly used)

– Ravuconazole (BMS-207147)

– Posaconazole (SCH-56592)

R-120758 SYN-2869 T-8581VR-9746 VR-9751 (D0870)

The inhibition of fungal growth by azole derivatives was described in the 1940s and the fungicidal properties of N-

substituted imidazoles were described in the 1960s. Clotrimazole and miconazole have proven very important in combating human fungal infections. More than 40 of the β-

substituted 1-phenethylimidazole derivatives are known to be potent against fungi, dermatophytes and Gram-positive bacteria. Imidazoles and triazoles are available for treatment of systemic fungal infections. Imidazoles are five –membered ring structures

containing two nitrogen atoms with a complex side chain attached to one of the nitrogen atoms. The structure of triazoles

is similar but they contain three nitrogen atoms in the rings (Figure). Imidazoles in clinical use are clotrimazole, miconazole, econazole and ketoconazole. Triazole compounds approved for

clinical use are itraconazole, fluconazole, voriconazole, lanconazole, ravuconazole and posaconazole

Ketoconazolo

Fluconazolo

Voriconazolo

Itraconazolo

Posaconazolo SCH-56592

Derivati azolici

RavuconazoloBMS-207,147

Mechanism of ActionAntifungal activity of azoles is mediated mainly through the

inhibition of a cytochrome P450–dependent enzyme involved in the synthesis of ergosterol. In eukaryotic cells, these are integral components of the smooth endoplasmic reticulum and the inner mitochondrial membrane. They contain an iron protoporphyrin

moiety located at the active site and play a key role in metabolic and detoxification reactions. They interact with sterols, steroids,

bile acids, phenols, alkenes, epoxides, sulfones, and soluble vitamins. Azoles activity is also manifested in inhibiting

cytochrome C oxidative and peroxidative enzymes, influencing cell membrane fatty acids causing leakage of proteins and amino acids, inhibiting catalase systems, decreasing fungal adherence

and inhibiting germ tube and mycelia formation

The principle molecular target of azoles (fluconazole, itraconazole and voriconazole) is a cytochrome P450–Erg 11P

or Cyp 51P according to gene–based nomenclature. Cytochrome P450–Erg 11P catalyses the oxidative removal of

the 14 α-methyl group in lanosterol and/or eburicol by P450 mono–oxygenase activity. As cytochrome P450–Erg 11P

contains an iron protoporphyrin moiety located at the active site, the drug binds to the iron atom via a nitrogen atom in the

imidazole or triazole ring. Inhibition of 14 α–demethylase leads to depletion of ergosterol and accumulation of sterol precursors including 14 α–methylated sterol as shown in figure 6.5. With

ergosterol depleted and replaced by unusual sterols, permeability and fluidity of the fungal cell membrane is altered. Miconazole and ketoconazole can inhibit the ATPase system in the cell membrane of C. albicans and other yeasts, which may account for the rapid collapse of the electrochemical gradient

and the fall in intracellular ATP.

Additionally, at growth inhibitory concentrations, miconazoles and ketoconazoles tend to inhibit the activity of C. albicans

plasma membrane glucan synthase, chitin synthase, adenylcyclase and 5-nucleotidase enzymes.

Incubation of C. albicans and other yeasts at fungistatic concentrations with clotrimazole, miconazole, econazole,

voriconazole, posaconazole or ketoconazole results in extensive changes in the cell envelope especially the plasma

membrane; for example, the appearance of holes in the nuclear membrane. At fungicidal concentrations however, changes in

the membrane are more pronounced and include the disappearance of mitochondrial internal structures and the complete loss of the nuclear membrane. Ketoconazole can

affect the transformation of C. albicans from the budding form to the pseudomycelial form, the prevailing type found in infected

individuals.

Antifungal activity of triazolesAntifungal activity of triazoles

FluconazoleFluconazoleItraconazoleItraconazoleVoriconazoleVoriconazole

Candida albicansCandida albicans

Candida non albicansCandida non albicans

Aspergillus Aspergillus sppspp

Criptococcus neoformansCriptococcus neoformans

Fusarium Fusarium sppspp

Scedosporium Scedosporium sppspp

Blastomyces dermatitidisBlastomyces dermatitidis

Histoplasma capsulatumHistoplasma capsulatum

Sporothrix schenckiiSporothrix schenckii

Coccidioides immitisCoccidioides immitis

Zygomycetes Zygomycetes sppspp

Paracoccidioides braziliensisParacoccidioides braziliensis

Dermatophytes Dermatophytes sppspp

Malassezia furfurMalassezia furfur

+ + ++ + +

*+ +*+ +

--

+ + ++ + +

- -

+ + ++ + +

+ + + +

+ + + +

- / +- / +

+ + + + + +

--

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

**+ +**+ +

+ + ++ + +

+ + ++ + +

+ + + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

- / +- / +

+ + ++ + +

+ + + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + ++ + +

--

+ + ++ + +

--

+ + ++ + +

+ + ++ + +

+ + ++ + +

+ + + very active + + average activity +/- low activity - no activity* except C.krusei and C.glabrata ** +/- for C.krusei

SQUALENE

Squalene epoxide

LANOSTEROL

14-alpha-demethyl lanosterol

Zymosterol

Fecosterol

ERGOSTEROL

Squalene epoxidase

Lanosterol 14-alpha demethylase

ALLYLAMINES:NaftifineTerbinafine

AZOLES:KetoconazoleFluconazoleItraconazoleVoriconazole

POLYENES:Amphotericin BNystatin

Membrane Antifungal Agents

Morpholines

Pharmacokinetic properties of Pharmacokinetic properties of oral azole agentsoral azole agents

--8080 > >1122 - - 44Urinary recoveryUrinary recovery(%) *(%) *

44. . 66 < <33 < <11 - - 22 < <11 - - 22Vd (l/kg)Vd (l/kg)

< <6060 < <7070 > >11 > >1010CSF penetrationCSF penetration(%) (%)

58581111 < <99999999Protein bindingProtein binding(%) (%)

66 - - 992727 - - 37372424 - - 424277 - - 1010t ½ (h)t ½ (h)

11 - - 2222 - - 4444 - - 5511 - - 44TTmaxmax (h) (h)

22 - - 4410.210.20.20.2 - - 0.40.41.51.5 - - 3.13.1Plasma CPlasma Cmax max (mg/l)(mg/l)

9696 < <9090 > >70707575BioavailabilityBioavailability(%) (%)

VoriconazoleVoriconazole

400mg 200mg po400mg 200mg po

FluconazoleFluconazole

200200 mg pomg po

Itraconazole Itraconazole 200 mg po200 mg po

Ketoconazole Ketoconazole 200 mg po200 mg po

DoseDose

*as active drug

Dismukes W.E., CID, 2000

ItraconazoleItraconazole

Combination with cyclodextrine in the oral solutionCombination with cyclodextrine in the oral solution

Bioavailability increased of 30-60% in HIV and/or Bioavailability increased of 30-60% in HIV and/or neutropenic patientsneutropenic patients

IV formulation as a complex with cyclodextrineIV formulation as a complex with cyclodextrine

De Beule K. & Van Gestel J.V., Drugs, 2001

TRIAZOLESTRIAZOLESFluconazoleFluconazoleItraconazoleItraconazole

PK-PD correlation = AUC/MICPK-PD correlation = AUC/MIC

Current data suggest an exposure-dependent Current data suggest an exposure-dependent pharmacodynamicspharmacodynamics

Both compounds may be most effective when Both compounds may be most effective when adequate levels are maintained at target siteadequate levels are maintained at target site

Groll AH et al., 1999, 2001

Side EffectSide Effect

Itraconazolo (n=3446)

Fluconazolo (n=3648)

Dispepsia 0,7 - 2,3% Nausea 2,1%

Dolori addominali 1,2 - 2% Dolori addominali 1,4%

Nausea 1,2 - 1,8% Cefalea 1,2%

Diarrea 0,3 - 1,6% Diarrea 0,8%

Vertigini 0,2 - 1,2% Vomito 0,65%

Cefalea 0,5 - 1% Vertigini 0,5%

Prurito 0,2 - 0,5% Rash-cutanei 0,4%

Prurito 0,3%

Azole derivatives(Ketoconazole, Itraconazole, Fluconazole)

Drug interactions

Decreased absorption of azoleAntacids, H2 antagonists, Omeprazole KETOCONAZOLE

ITRACONAZOLE

Increased metabolism of azoleRifampinPhenytoinCarbamazepine

ALLKETOCONAZOLE, ITRACONAZOLEITRACONAZOLE

Decreased metabolism of other drugsCyclosporineTacrolimusPhenytoinWarfarinSulphonylureasBenzodiazepinesStatinsTerfenadine, LoratadineCisaprideDigoxin

ALLFLUCONAZOLEALLALLALLALLITRACONAZOLEITRACONAZOLEALLITRACONAZOLE

VoriconazoleVoriconazole MetabolismMetabolism

Voriconazole is metabolised Voriconazole is metabolised in vitroin vitro via three via three CYP450 isozymesCYP450 isozymes

CYP2C19CYP2C19

CYP2C9CYP2C9

CYP3A4CYP3A4

In vivoIn vivo the major isozyme is CYP2C19 the major isozyme is CYP2C19

Genetic polymorphism in CYP2C19Genetic polymorphism in CYP2C19

HL Hoffman & R Chris Rathbun, Expert Opin Investig Drugs, 2002FDA - Briefing document for Voriconazole - Pfizer, October 2001courtesy of Dr. N. Wood, Pfizer Central Research

• CYP2C19 genetic polymorphism results in significantinter-subject variation in plasma levels and drugexposure– Poor metabolizers (3-5% Caucasians and Blacks, 15-20%

Asians) have 3-4 fold increase in systemic exposureHeterozygous poor metabolizers have about a 2-foldincrease in exposure

• Genotype, age and gender result in wide inter- subject variability in exposure

Voriconazole metabolism

FlucytosineFlucytosine or 5–fluorocytosine (5-FC) is a synthetic

fluorinated pyrimidine used as an oral antimycotic agent. It was first synthesized in the 1950s as a spin off of work in cytostatic and antineoplastic agents. 5-FC lacks such

activities but it has noticeable antifungal activity. Currently, 5-FC is used as an adjunct to amphotericin B therapy because amphotericin B potentate the uptake of

5-FC through increasing fungal cell membrane permeability. The activity of 5-FC is enhanced when used

in combination with fluconazole against C. neoformans and C. albicans

Mechanism of ActionThe antifungal activity of 5-FC is mediated through one of two mechanisms: (i) disruption of DNA synthesis and /or (ii) alteration of the amino acid pool.

Initially, 5-FC enters susceptible cells by means of cytosine permease, which is usually responsible for the uptake of cytosine, adenine, guanine,

and hypoxanthine. Once inside the cell, 5-FC is converted to 5- fluorouracil (5FU) by cytosine deaminase. Inside target cells, 5-FU is then converted by uridine monophosphate pyrophosphorylase to 5-fluorouridylic acid (FUMP),

which is phosphorylated further and incorporated into RNA resulting in disruption of protein synthesis. Extensive replacement of uracil by 5-FC in fungal RNA can lead to alterations in the amino acid pool. Some 5-FU can be converted to 5-fluorodeoxyuridine monophosphate, which functions as a

potent inhibitor of thymidylate synthase, one of the enzymes involved in DNA synthesis and nuclear division .

Inhibition of DNA synthesis in C. albicans can take place before 5-FU incorporation into RNA or inhibition of protein synthesis. Resistant

strains of C. neoformans incorporate 5-FC into RNA at levels comparable with sensitive strains. This could mean that resistance inhibition of DNA synthesis is more important than the production of

aberrant RNA in mediating the effects of 5-FC. The drug incorporates in large quantities into the 80S ribosomal subunits in C. albicans. The

number of ribosomes synthesized in the presence of high concentrations of 5-FC is greatly reduced.

Morphological and ultrastructural changes that occur in C. albicans cells include increased cell diameter if growing at sub-inhibitory

concentrations of 5-FC

EchinocandinsThe fungal cell wall contains compounds, such as mannan,

chitin, and α– and β-glucans, which are unique to the kingdom Fungi. A number of compounds that have the ability

to affect the cell wall of fungi have been discovered and described over the past 30 years. Of the three groups of

compounds (aculeacins, echinocandins, and papulacandins) that are specific inhibitors of fungal 1-3 β-glucan synthase.

Echinocandins are actively pursued in clinical trials to evaluate their safety, tolerability and efficacy against

candidiasis. Discovered by random screening in the 1970s, echinocandins are fungal secondary metabolites comprising a cyclic hexapeptide core with a lipid side chain responsible

for antifungal activity. A modified form of echinocandin B, cilofungin, was developed to the point of phase 2 trials, but

then abandoned due to increased toxicity. In the late 1990s, three echinocandin compounds (anidulafungin,

caspofungin and micafungin) entered clinical development and evaluation.

Phospholipid bilayerof the fungal cell

membrane

Fungalcell wall

-(1,3)-glucan

-(1,6)-glucan

-(1,3)-glucan synthase Ergosterol

Caspofungin: Mechanism of ActionCaspofungin: Mechanism of Action

Caspofungin specifically inhibits beta (1-3)-D-glucan synthesis, Caspofungin specifically inhibits beta (1-3)-D-glucan synthesis, essential to the essential to the cell-wallcell-wall integrity of many fungi, including integrity of many fungi, including

AspergillusAspergillus and and Candida Candida spp, thereby compromising the integrityspp, thereby compromising the integrity

As a result, the fungal cell wall becomes permeable, and cell lysisAs a result, the fungal cell wall becomes permeable, and cell lysis

Beta (1-3)-D-glucan synthesis does not occur in human cellsBeta (1-3)-D-glucan synthesis does not occur in human cells

Antifungal activity of the echinocandinsAntifungal activity of the echinocandins

HIGHLY ACTIVEHIGHLY ACTIVEVERY ACTIVEVERY ACTIVESOME ACTIVITYSOME ACTIVITYINACTIVEINACTIVE

Candida albicansCandida albicans

Candida glabrataCandida glabrata

Candida tropicalisCandida tropicalis

Candida kruseiCandida krusei

Candida kefyrCandida kefyr

Pneumocystis cariniiPneumocystis carinii**

Candida parapsilosisCandida parapsilosis

Candida gulliermondiiCandida gulliermondii

Aspergillus fumigatusAspergillus fumigatus

Aspergillus flavusAspergillus flavus

Aspergillus terreusAspergillus terreus

Candida lusitaniaeCandida lusitaniae

Coccidioides immitisCoccidioides immitis

Blastomyces dermatididisBlastomyces dermatididis

Scedosporium Scedosporium sppspp

Paecilomyces variotiiPaecilomyces variotii

Histoplasma capsulatumHistoplasma capsulatum

ZygomycetesZygomycetes

Cryptococcus neoformansCryptococcus neoformans

Fusarium Fusarium sppspp

Trichosporon Trichosporon sppspp

* Only active against cyst form, and probably only useful for prophylaxis

Denning DW, Lancet, 2003

CASPOFUNGINCASPOFUNGINPharmacokinetic parameters in healthy adultsPharmacokinetic parameters in healthy adults

VariableVariableParameterParameter

Peak (mg/l)Peak (mg/l)12.112.1

Trough (mg/l)Trough (mg/l)1.31.3

Volume of distribution (l)Volume of distribution (l)9.79.7

AUCAUC0-24h0-24h (mg·h/l) (mg·h/l)93.593.5

Half-life (h)Half-life (h)

PhasePhase

PhasePhase

PhasePhase

1-21-2

9-119-11

40-5040-50

Protein bindingProtein binding(%) (%) 96.596.5

Clearance (ml/min)Clearance (ml/min)1212

Renal clearance (ml/min)Renal clearance (ml/min)0.150.15

Deresinski SC & Stevens DA, CID, 2003

Chitin synthesis is inhibited competitively by polyoxin and nikkomycin, nucleoside–peptide antibiotics produced by soil strains of Streptomycetes. These agents specifically inhibit chitin synthase by acting as mimics or decoys of

the enzyme substrate (uridine diphosphate-N-acetylglucosamine). In vitro susceptibility testing of

nikkomycins X and Z against various fungi show moderate susceptibility of C. albicans and C. neoformans to these compounds. Activity against C. albicans and C. neoformans improves significantly when nikkomycin Z is used in combination with fluconazole and itraconazole

Allylamines and ThiocarbamatesNaftifine and terbinafine are the two major allylamines in

clinical use and tolnaftate is the only thiocarbamate available for use. Naftifine is used as a topical agent while terbinafine is administered orally. These are two synthetic

compounds with a chemical structure similar to naphthalene ring substituted at 1 position with an aliphatic

chain. Both allylamines thiocarbamates function as noncompetitive inhibitors of squalene epoxidase, an

enzyme involved in the conversion of squalene to lanosterol, which is an essential step in the synthesis

fungal cell membrane.

Cell death is dependent on the accumulation of squalene rather than ergosterol deficiency as high levels of

squalene increase membrane permeability leading to disruption of cellular organization. Terbinafine inhibits the growth of dermatophytic fungi in vitro at concentrations of

0.01 µg/ml or lower .