Antifungal Agent from Merck Research LaboratoriesAntifungal Agent from Merck Research Laboratories

CaspofunginCaspofungin

Discovery and Development of a Novel, PotentDiscovery and Development of a Novel, Potent

Mortality Rates of Candida and Aspergillus InfectionsMortality Rates of Candida and Aspergillus Infections

*In transplant recipients.Edmond MB Clin Infect Dis 1999;29:239–244; Paterson DL Medicine 1999;78(2):123–138.

Aspergillus up to 90%*Candida 40%

Mortality

Current Options in Antifungal TherapyCurrent Options in Antifungal TherapyDisadvantagesDrug Advantages

Fungizone™Fungizone™ Active against Candida, AspergillusActive against Candida, Aspergillus

NephrotoxicityPotential for toxicityNephrotoxicityPotential for toxicity

Lipid formulationLipid formulation Active against Candida, Aspergillus, CryptococcusNephrotoxicity is lower than with conventional amphotericin B

Active against Candida, Aspergillus, CryptococcusNephrotoxicity is lower than with conventional amphotericin B

FluconazoleFluconazole Active against Candida, CryptococcusActive against Candida, Cryptococcus

Ineffective against AspergillusPotential resistance developmentIneffective against AspergillusPotential resistance development

ItraconazoleItraconazole Active against Candida, Aspergillus, CryptococcusActive against Candida, Aspergillus, Cryptococcus

Potent inhibitor of cytochrome P450 3A4 system – may cause serious cardiovascular events in combination with certain drugs, contraindicated in severe renal dysfunction. Idiosyncratic hepatitis and hepatotoxicity, resistance observed

Potent inhibitor of cytochrome P450 3A4 system – may cause serious cardiovascular events in combination with certain drugs, contraindicated in severe renal dysfunction. Idiosyncratic hepatitis and hepatotoxicity, resistance observed

FlucytosineFlucytosine Selective toxicitySelective toxicity Weak activity against Candida, CryptococcusRapid resistance developmentWeak activity against Candida, CryptococcusRapid resistance development

Amphotericin BAmphotericin B

AzolesAzoles

Nucleoside analogNucleoside analog

Andriole VT J Antimicrob Chemother 1999;44:151–162; Groll AH Adv Pharmacol 1998;44:343-500; Onishi J Antimicrob Agents Chemother 2000;44:368–377; Stone EA Clin Ther 2002;24(3):351-377; Sporanox™ (Itraconazole) Injection Prescribing Information; Fluconazole Prescribing Information.

NephrotoxicityPotential for toxicityRates of acute infusion-related reactions do not differ substantially from those observed with conventional amphotericin B

NephrotoxicityPotential for toxicityRates of acute infusion-related reactions do not differ substantially from those observed with conventional amphotericin B

Antifungal Screening: History of the EchinocandinsAntifungal Screening: History of the Echinocandins

Limited antifungal spectrum, low water solubility, poor oral bioavailability, hemolytic

Potent in vitro and in vivo activityagainst Candida with low toxicity

Identified by severalpharmaceutical companies

Cyclic hexapeptides, N-acylated with afatty acid side chain

Isolated in 1974, from Aspergillus species

Groll AH Adv Pharmacol 1998;44:343–500; Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001; Onishi J Antimicrob Agents Chemother 2000;44(2):368–377; Tkacz JS Emerging Targets in Antibacterial and Antifungal Chemotherapy 1992:495–523; Debono M Annu Rev Microbiol 1994;48:471–497; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332.

Screening for Natural ProductsScreening for Natural Products

Identify a Therapeutic Target

Develop Assays that Look for Biological Activity Against Target

Test Fungal, Bacterial, Plant, or Other Extracts for Desired Biological Activity

Purify and Identify Lead Compound(s)

Produce Quantities for Clinical Trials

Medicinal Chemistryto Optimize Compound

Characteristics

Additionalin vitro Testing

In vivoTesting

Discovery of Antifungal ActivityDiscovery of Antifungal Activity

In vitro activity against Candida was observedin a fermentation extract of Glarea lozoyensis In vitro activity against Candida was observedin a fermentation extract of Glarea lozoyensis

Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

A Novel Glucan Synthesis Inhibitor(L-688786)A Novel Glucan Synthesis Inhibitor(L-688786)

OHOH

NN

HNHN

OHOHHNHNOO

HOHO

CH3CH3

OHOH

OO

NHNH

HOHO

NN

HOHOH2NH2N

OO

HOHO

OHOH

OO

OO

OO

OO

HOHO

OO

HNHN

HNHN

Groll AH Adv Pharmacol 1998;44:343–500.

L-688786 – Stepping Up ProductionL-688786 – Stepping Up Production

Chemical ModificationsChemical Modifications

• Water soluble

• Improved potency

• Expanded spectrum

• Favorablepharmacokinetics

• Water soluble

• Improved potency

• Expanded spectrum

• Favorablepharmacokinetics

Synthesizing Caspofungin (L-743872) from L-688786Synthesizing Caspofungin (L-743872) from L-688786

HOHO

HOHO

H3NH3N

glutamineglutamine

HOHO

HOHO

OO HNHN

HNHN

NHNH

OO

OO

OO

OONN

HNHN

HOHOOO

HOHO OHOHOO

OHOH

CH3CH3

OHOH

NHNHH3NH3N

HNHN

hemiaminalhemiaminal

H2NOCH2NOC

NN

• 2 CH3COOH• 2 CH3COOH

Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332; Groll AH Adv Pharmacol 1998;44:343–500; Powles MA Antimicrob Agents Chemother 1998;42(8):1985–1989; Debono M Annu Rev Microbiol 1994;48:471–497; Stone EA Clin Ther 2002;24(3):351–377.

Compound NomenclatureCompound Nomenclature

Inhibitor Class: glucan synthesis inhibitor

Generic Class: lipopeptide

Structural Class: echinocandin

Semisynthetic derivative of: L-688786 (Pneumocandin BO)

Produced by: Glarea lozoyensis

Merck L#: L-743872

Merck MK#: MK-0991

Generic Name: caspofungin acetate

Trade Name: CANCIDAS™

Inhibitor Class: glucan synthesis inhibitor

Generic Class: lipopeptide

Structural Class: echinocandin

Semisynthetic derivative of: L-688786 (Pneumocandin BO)

Produced by: Glarea lozoyensis

Merck L#: L-743872

Merck MK#: MK-0991

Generic Name: caspofungin acetate

Trade Name: CANCIDAS™

Georgopapadakou NH Exp Opin Invest Drugs 2001;10(2):269–280; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332; Data on file, MSD.CANCIDAS (caspofungin acetate) is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

(1,3)-D-glucan: Integral Part of Fungal Cell Wall (1,3)-D-glucan: Integral Part of Fungal Cell Wall

• Fungal specific, not found in mammalian cells

• Important cell wall component of many fungal species:

– Candida species mostly -1,3 & -1,6 (~40–60%)

– Aspergillus species (hyphae mostly -1,3)

– Pneumocystis carinii (cyst form)

• C. neoformans mostly -1,3 and -1,3 (~30–50%)

• Fungal specific, not found in mammalian cells

• Important cell wall component of many fungal species:

– Candida species mostly -1,3 & -1,6 (~40–60%)

– Aspergillus species (hyphae mostly -1,3)

– Pneumocystis carinii (cyst form)

• C. neoformans mostly -1,3 and -1,3 (~30–50%)

Data on file, MSD; Debono M Annu Rev Microbiol 1994;48:471–497; Tkacz JS Emerging Targets in Antibacterial and Antifungal Chemotherapy 1992:495–523; Maertens J Current Medicinal Chemistry–Anti-Infective Agents 2002;1(1); Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Phospholipid bilayerof the fungal cell

membrane

Fungalcell wall

(1,3)-glucan

(1,6)-glucan

(1,3)-glucan synthase Ergosterol

Fungal Cell WallFungal Cell Wall

Kartsonis NA. Presented at the 12th European Congress of Clinical Microbiology and Infectious Diseases. April 24–27, 2002.

Glucan Synthesis and Its InhibitionGlucan Synthesis and Its Inhibition

Caspofungin: Preclinical In Vitro DataCaspofungin: Preclinical In Vitro Data

Caspofungin In Vitro Spectrum of ActivityCaspofungin In Vitro Spectrum of Activity

Candida species Histoplasma capsulatum Cryptococcus neoformans

Aspergillus species Coccidiodes imitis Fusarium species

Saccharomyces cerevisiae Paracoccidiodes species Trichosporon species

Alternaria species Blastomyces dermatitidis Rhizopus species

Curvularia species Sporothrix schenckii Trichophyton species

Fonseca pedrosoi Phiolophora species Scedosporium species

Pneumocystis carinii** Epidermophyton species Pseudallescheria boydii

Candida species Histoplasma capsulatum Cryptococcus neoformans

Aspergillus species Coccidiodes imitis Fusarium species

Saccharomyces cerevisiae Paracoccidiodes species Trichosporon species

Alternaria species Blastomyces dermatitidis Rhizopus species

Curvularia species Sporothrix schenckii Trichophyton species

Fonseca pedrosoi Phiolophora species Scedosporium species

Pneumocystis carinii** Epidermophyton species Pseudallescheria boydii

Potent(0.03–2.0 g/mL)

Potent(0.03–2.0 g/mL)

Minimum Inhibitory Concentrations* (g/mL)Minimum Inhibitory Concentrations* (g/mL)

*Data derived from MRL, National Fungus Testing Laboratory and National Mycology Reference Laboratory**Based on in vivo dataBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Intermediate(2.0–16.0 g/mL)

Intermediate(2.0–16.0 g/mL)

Weak(16.0–>64.0 g/mL)

Weak(16.0–>64.0 g/mL)

Glucan Synthesis Inhibition vs. MIC ValueGlucan Synthesis Inhibition vs. MIC Value

Candida albicans (MY1028) 0.6 0.125

Aspergillus fumigatus (MF4839) 9.6 0.125

Candida albicans (MY1028) 0.6 0.125

Aspergillus fumigatus (MF4839) 9.6 0.125

Glucan SynthesisIC50 (nM)

Glucan SynthesisIC50 (nM)

Mean MICµg/mL ± SE Mean MIC

µg/mL ± SE

Data on file, MSD.

In Vitro SusceptibilityIn Vitro Susceptibility

C. albicans 0.12 0.25 0.50

Candida spp. (non-albicans) 0.50 0.50 16.0

Aspergillus spp. 0.38 0.43 >64.0

Cryptococcus neoformans 16.0 0.50 0.50

C. albicans 0.12 0.25 0.50

Candida spp. (non-albicans) 0.50 0.50 16.0

Aspergillus spp. 0.38 0.43 >64.0

Cryptococcus neoformans 16.0 0.50 0.50

CaspofunginCaspofungin AmBAmB FluconazoleFluconazole

MIC90 (g/mL)MIC90 (g/mL)

Minimum Inhibitory ConcentrationsMinimum Inhibitory Concentrations

AmB = Amphotericin B Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Fluconazole-Susceptible and -Resistant Candida albicansFluconazole-Susceptible and -Resistant Candida albicans

0.05–0.8 0.400.01–0.8 0.200.04–>40 0.640.08–10 2.5

0.1–0.8 0.400.02–0.4 0.200.08–1.25 0.6420–80 80

0.05–0.8 0.400.01–0.8 0.200.04–>40 0.640.08–10 2.5

0.1–0.8 0.400.02–0.4 0.200.08–1.25 0.6420–80 80

RangeRange MIC90MIC90

MIC (g/mL)MIC (g/mL)

CaspofunginAmphotericin BFlucytosineFluconazole

CaspofunginAmphotericin BFlucytosineFluconazole

CaspofunginAmphotericin BFlucytosineFluconazole

CaspofunginAmphotericin BFlucytosineFluconazole

C. albicans (40)Susceptible

C. albicans (10)Resistant

C. albicans (40)Susceptible

C. albicans (10)Resistant

Vazquez JA Antimicrob Agents Chemother 1997;41(7):1612–1614.

Antifungal Agent

Antifungal Agent

Organism(no. of isolates)

Organism(no. of isolates)

Drug Combination StudiesDrug Combination Studies

Candida albicans

Cryptococcus neoformans

Aspergillus fumigatus

Candida albicans

Cryptococcus neoformans

Aspergillus fumigatus

FIC* (μg/ml)MK-0991 Plus Amphotericin B

FIC* (μg/ml)MK-0991 Plus Amphotericin B

0.82

0.50

0.45

0.82

0.50

0.45

*≤0.5 = Synergistic ≤4.0 = Additive-to-indifferent ≥4.0 = AntagonisticBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Fungus(n=2)

Fungus(n=2)

Caspofungin: Genetics Show Target Is Essential in CandidaCaspofungin: Genetics Show Target Is Essential in Candida

URA3URA3

Step 1

Or

Select for FOA resistance

URA3URA3

URA3URA3 FKS1FKS1FKS1FKS1FKS1FKS1

Genetics Prove Caspofungin Target Is Essential in CandidaGenetics Prove Caspofungin Target Is Essential in Candida

URA3URA3

URA3URA3

If CaFKS1 is not

essential:

If CaFKS1 is essential:

No functionalFKS1 remains

Always retaina functionalcopy of FKS1

Result: Candida (1,3)-D-glucan synthase is essentialResult: Candida (1,3)-D-glucan synthase is essential

Step 2

URA3URA3 FKS1FKS1FKS1FKS1FKS1FKS1

Colony Forming Unit QuantitationColony Forming Unit Quantitation

10 Colony Forming Units

4 Colony Forming Units

1 Colony Forming Unit

1 Colony Forming Unit

Candida spp. and Other Yeasts Aspergillus spp.

Evaluation of Caspofungin Effect Against Aspergillus spp. In Vitro Using Vital Dyes Evaluation of Caspofungin Effect Against Aspergillus spp. In Vitro Using Vital Dyes

Alive Fluorescent Non-fluorescent

Dead Non-fluorescent Fluorescent

Alive Fluorescent Non-fluorescent

Dead Non-fluorescent Fluorescent

Status of CellStatus of CellViable Stain

(CFDA)Viable Stain

(CFDA)Non-viable Stain

(DiBAC4[3])Non-viable Stain

(DiBAC4[3])

Data on file, MSD.

Viable Stain — Caspofungin Halts Growth of Aspergillus fumigatusViable Stain — Caspofungin Halts Growth of Aspergillus fumigatus

Amphotericin B0.15 µg/mL

Caspofungin0.30 µg/mL

Itraconazole2.5 µg/mLControl

Data on file, MSD; Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.

Non-viable Stain — Cellular Lysis in Aspergillus fumigatus ConfirmedNon-viable Stain — Cellular Lysis in Aspergillus fumigatus Confirmed

Amphotericin B0.15 µg/mL

Caspofungin0.30 µg/mL

Itraconazole2.5 µg/mLControl

Data on file, MSD; Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.

Effects of Caspofungin on Aspergillus fumigatusEffects of Caspofungin on Aspergillus fumigatus

Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.

Caspofungin: Preclinical In Vivo DataCaspofungin: Preclinical In Vivo Data

In Vivo Efficacy of Caspofungin & Amphotericin B Against Candida Species in MiceIn Vivo Efficacy of Caspofungin & Amphotericin B Against Candida Species in Mice

Candida albicans 0.02 0.03

Candida glabrata 0.06 0.17

Candida lusitaniae 0.16 0.11

Candida tropicalis 0.05 0.24

Candida albicans 0.02 0.03

Candida glabrata 0.06 0.17

Candida lusitaniae 0.16 0.11

Candida tropicalis 0.05 0.24

CaspofunginCaspofungin

ED (Effective Dose)90

(mg/kg/dose)ED (Effective Dose)90

(mg/kg/dose)

IsolateIsolate

Data on file, MSD; Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001; Abruzzo GK Antimicrob Agents Chemother 1997;41(11):2333–2338.

Amphotericin BAmphotericin B

Caspofungin, AmB* or FCZ** in DBA/2 Mice vs. Disseminated Renal Candidiasis after Delayed TreatmentCaspofungin, AmB* or FCZ** in DBA/2 Mice vs. Disseminated Renal Candidiasis after Delayed Treatment

Days After ChallengeDays After ChallengeChallenge I.V.Challenge I.V.

20

33

44

55

66

77

88

22 44 66 88 1010 1212 1414 1616 1818

Log

CF

U C

. alb

ican

s/g

kid

ney

sL

og C

FU

C. a

lbic

ans/

g k

idn

eys

DoseI.V. q.d. x 4

Fluconazole @ 10 mg/kg0% SterilizationVehicle Control

AmB* @ 0.5 mg/kg40% SterilizationCaspofungin @ 0.38mg/kg60% Sterilization

*AmB = Amphotericin B**FCZ = FluconazoleBartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Caspofungin vs. AmB in Chronic Pancytopenic Mouse Model of Disseminated Aspergillosis

Dosing

Per

cen

t S

urv

ival

Per

cen

t S

urv

ival

2020

4040

6060

8080

100100

00 55 1010 1515 2020 2525

Days PostinfectionDays Postinfection

Day +28Day +28Day –3Day –3Immunosuppression with CyclophosphamideImmunosuppression with Cyclophosphamide

1 mg/kg

0.25 mg/kg

1 mg/kg

0.25 mg/kg

Sham-Rx

Caspofungin

AmB

Data on file, MSD.

Disseminated Candidiasis in Chronically Pancytopenic Mice: Survival

Dosing

Per

cen

t S

urv

ival

Per

cen

t S

urv

ival

00

2020

3030

4040

5050

6060

7070

8080

9090

100100

00 44 88 1212 1616 2020 2424

1 mg/kg

0.25 mg/kg

Days After ChallengeDays After Challenge

1 mg/kg

0.25 mg/kg

Sham-Rx

Day +28Day +28Day –3Day –3Immunosuppression with CyclophosphamideImmunosuppression with Cyclophosphamide

Caspofungin

AmB

1010

2828

80 mg/kg

20 mg/kg

Fluconazole

Data on file, MSD.

Disseminated Candidiasis in Chronically Pancytopenic Mice: Tissue Burden and SterilizationDisseminated Candidiasis in Chronically Pancytopenic Mice: Tissue Burden and Sterilization

Caspofungin 1 mg/kg 4.84 100 0.25 mg/kg 3.13 40

Amphotericin B 1 mg/kg 3.52 80 0.25 mg/kg 2.49 50

Fluconazole 80 mg/kg -0.92 205

20 mg/kg +0.75 01

Caspofungin 1 mg/kg 4.84 100 0.25 mg/kg 3.13 40

Amphotericin B 1 mg/kg 3.52 80 0.25 mg/kg 2.49 50

Fluconazole 80 mg/kg -0.92 205

20 mg/kg +0.75 01

Log10 CFU Reduction

Log10 CFU Reduction

% Kidney Tissue Sterilization

% Kidney Tissue Sterilization

Kidney Burden Reduction fromControl at Day 28*

Kidney Burden Reduction fromControl at Day 28*

* Mice were challenged IV with C. albicans MY1055 at 5.6 104 CFU/mouse and 1.22 105 CFU/mouse. Kidneys aseptically collected at Days 14 and 28 after challenge. Mean log10 CFU/g at time points after challenge for paired kidneys. Ten mice per group unless indicated by superscript number.Data on file, MSD.

P. carinii Cyst Clearance in Mice with CaspofunginP. carinii Cyst Clearance in Mice with Caspofungin

Control

TMP-SMZ*

MK-0991

90% Reduction

99% Reduction

77

66

55

44

3300 22 44 66 88 1010 1212 1414 1616

Log

10 M

ean

Num

ber

of

Cys

ts/L

ung

Log

10 M

ean

Num

ber

of

Cys

ts/L

ung

Days of TreatmentDays of Treatment

*TMP-SMZ = Trimethoprim-sulfamethoxazole.Powles MA Antimicrob Agents Chemother 1998;42(8):1985–1989.

Preclinical Microbiology SummaryPreclinical Microbiology Summary

• Spectrum of activity includes Candida albicans,non-albicans Candida spp., and Aspergillus spp.

• Caspofungin is fungicidal for Candida spp. based on in vitro and in vivo studies

• Caspofungin demonstrates clear activity againstAspergillus spp.

– In vitro• Kills cells with active cell wall synthesis• Effects are consistent with the mechanism of action

– In vivo, there is a sustained activity in severely immunosuppressed mice with disseminated aspergillosis

• Spectrum of activity includes Candida albicans,non-albicans Candida spp., and Aspergillus spp.

• Caspofungin is fungicidal for Candida spp. based on in vitro and in vivo studies

• Caspofungin demonstrates clear activity againstAspergillus spp.

– In vitro• Kills cells with active cell wall synthesis• Effects are consistent with the mechanism of action

– In vivo, there is a sustained activity in severely immunosuppressed mice with disseminated aspergillosis

Data on file, MSD; Maertens J Current Medicinal Chemistry–Anti-Infective Agents 2002;1(1); Bowman JC Antimicrob Agents Chemother 2002;46(9):3001–3012.

Additional In Vivo StudiesAdditional In Vivo Studies

• Reduction of infections in CD4+ deficient micewith chronic oropharyngeal and gastrointestinal mucosal candidiasis

• Effective prophylactic and therapeutic treatment of immunocompromised rats with pulmonary aspergillosis

• Limited role in the treatment of Histoplasma capsulatum

• No activity against Cryptococcus neoformans

• Reduction of infections in CD4+ deficient micewith chronic oropharyngeal and gastrointestinal mucosal candidiasis

• Effective prophylactic and therapeutic treatment of immunocompromised rats with pulmonary aspergillosis

• Limited role in the treatment of Histoplasma capsulatum

• No activity against Cryptococcus neoformans

Flattery AM Antimicrob Agents Chemother 1996:40(7):1604–1609; Data on file, MSD; Stone EA Clin Ther 2002;24(3):351–377.

Comparative Pharmacokinetics:Caspofungin Single IV DoseComparative Pharmacokinetics:Caspofungin Single IV Dose

100100

1010

11

0.10.100 44 88 1212 1616 2020 2424

Mea

n P

lasm

a C

once

ntra

tion

(

g/m

l)M

ean

Pla

sma

Con

cent

rati

on

(g/

ml)

Time (Hours)Time (Hours)

C. albicans MIC90

Candida spp., A. fumigatus MIC90

0.5 mg/kg

0.75 mg/kg

1 mg/kg

Mouse 7.6Rat 6.1Rhesus 5.0Chimpanzee 5.2Human 10.0

Species T1/2 hrs

Bartizal K. Presented at Antibacterial & Antifungal Drug Discovery & Development Summit. March 2001.

Merck Antifungal Caspofungin (MK-0991)Preclinical SummaryMerck Antifungal Caspofungin (MK-0991)Preclinical Summary• Water soluble (1,3)-D-glucan synthesis inhibitor:

– 0.6 nM–Candida– 9.6 nM–Aspergillus

• Relevant spectrum: – Candida & Aspergillus

• Fungicidal against C. albicans• Low resistance induction potential• Effective vs. FCZ*, AmB**, 5FC***

resistors • No antagonism

– In combination with AmB** or FCZ*• Excellent animal efficacy:

– Candida, Aspergillus• Pharmacokinetics supports

once-daily dosing

• Water soluble (1,3)-D-glucan synthesis inhibitor:

– 0.6 nM–Candida– 9.6 nM–Aspergillus

• Relevant spectrum: – Candida & Aspergillus

• Fungicidal against C. albicans• Low resistance induction potential• Effective vs. FCZ*, AmB**, 5FC***

resistors • No antagonism

– In combination with AmB** or FCZ*• Excellent animal efficacy:

– Candida, Aspergillus• Pharmacokinetics supports

once-daily dosing

OHOH

NN

NHNH

HNHN

OHOHHNHNOO

NHNH

CH3CH3

OHOH

OO

HNHN

NHNH

HOHO

NN

HOHO

HOHOOO

HOHO

OHOH

OO

OO

OO

OO

H2NH2N

H2NH2N

·2CH3CO2H·2CH3CO2H

CH3CH3CH3

CH3

H3CH3C

*FCZ = fluconazole **AmB = amphotericin B***5FC = flucytosineData on file, MSD; Franzot SP Antimicrob Agents Chemother 1997;41(2):331–336; Bartizal K Antimicrob Agents Chemother 1997;41(11):2326–2332.