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 .