Which drugs?. Mode of action of antifungals ergosterol polyenes e.g. amphotericin B polyenes azoles...

Which drugs?

Mode of action of antifungals

ergosterolergosterolergosterolergosterol

polyenespolyenese.g. amphotericin Be.g. amphotericin Bpolyenespolyenese.g. amphotericin Be.g. amphotericin B

azolesazolese.g. fluconazolee.g. fluconazoleazolesazolese.g. fluconazolee.g. fluconazole

nucleosidesnucleosidese.g. 5-flucytosinee.g. 5-flucytosinenucleosidesnucleosidese.g. 5-flucytosinee.g. 5-flucytosine

squalenessqualenessqualenessqualenes

lanosterollanosterollanosterollanosterol

KK++

Mg Mg 2+2+

KK++

Mg Mg 2+2+

allylaminesallylaminese.g. terbinafinee.g. terbinafineallylaminesallylaminese.g. terbinafinee.g. terbinafine

acetyl-Co-Aacetyl-Co-Aacetyl-Co-Aacetyl-Co-A

echinocandinsechinocandinse.g. caspofungine.g. caspofunginechinocandinsechinocandinse.g. caspofungine.g. caspofungin

nikkomycinsnikkomycinsnikkomycinsnikkomycins

nucleic acid synthesisnucleic acid synthesisnucleic acid synthesisnucleic acid synthesis

glucan synthesisglucan synthesisglucan synthesisglucan synthesis

chitin synthesischitin synthesischitin synthesischitin synthesis

Therapeutic window of antifungal agents




chitin synthesischitin synthesischitin synthesischitin synthesis


cholesterolcholesterolcholesterolcholesterol

protein synthesisprotein synthesisprotein synthesisprotein synthesis protein synthesisprotein synthesisprotein synthesisprotein synthesis

mannan synthesismannan synthesismannan synthesismannan synthesis

humanhumanhumanhuman fungusfungusfungusfungus

AmBisome

Related azole antifungal agents (1)

Echinocandins

Comparative spectrum of activity in-vitro

FungusFungus AMBAMB FCZFCZ ITZITZ VCZVCZ PCZPCZ RCZRCZ CFCFMFMF AFAF

Candida albicansCandida albicans

Candida tropicalisCandida tropicalis

Candida parapsilosisCandida parapsilosis

Candida kruseiCandida krusei

Candida glabrataCandida glabrataCryptococcus neoformansCryptococcus neoformans Histoplasma capsulatumHistoplasma capsulatum Blastomyces dermatitidisBlastomyces dermatitidis Coccidiodes immitisCoccidiodes immitis Paracoccidiodes brasiliensisParacoccidiodes brasiliensis Pneumocystis cariniiPneumocystis carinii

Aspergillus fumigatusAspergillus fumigatus Mucor sppMucor spp

RhizopusRhizopus spp spp

FusariumFusarium spp spp









FusariumFusarium spp spp azolesazoles candinscandins



















FusariumFusarium spp spp azolesazoles candinscandins

Pneumocystis cariniiPneumocystis carinii




















Cryptococcus neoformansCryptococcus neoformans

azolesazoles candinscandins

Mode of action of antifungals


polyenespolyenese.g. amphotericin Be.g. amphotericin Bpolyenespolyenese.g. amphotericin Be.g. amphotericin B

azolesazolese.g. fluconazolee.g. fluconazoleazolesazolese.g. fluconazolee.g. fluconazole

squalenessqualenessqualenessqualenes

lanosterollanosterollanosterollanosterol

KK++

Mg Mg 2+2+

KK++

Mg Mg 2+2+

acetyl-Co-Aacetyl-Co-Aacetyl-Co-Aacetyl-Co-A

echinocandinsechinocandinse.g. caspofungine.g. caspofunginechinocandinsechinocandinse.g. caspofungine.g. caspofungin


Available broad-spectrum drugs

polyenespolyenespolyenespolyenes

azolesazolesazolesazoles

echinocandinsechinocandinsechinocandinsechinocandins

caspofungincaspofunginamphotericin Bamphotericin B

AmBisomeAmBisome

AbelcetAbelcet

Amphocil/AmphotecAmphocil/Amphotec

itraconazoleitraconazole

voriconazolevoriconazole

How good is the evidence?

Prophylaxis

-7 0 7 14 21 28 35 42 49 56 63-14

0.1

1

10

Days after transplant

Gra

nulo

cyte

s (lo

g 10x1

09/l)

0

Allogeneic HSCT recipient

treatment

Disease likelihood

ProphylaxisProphylaxis

remoteremote

3636

3737

3838

3939

4040

4141

Tem

pera

ture

(°C

)T

empe

ratu

re (

°C)

Prophylaxis

•most often initiated when a patient falls into a risk group

–expected to develop prolonged, profound neutropenia

–measurable risk of developing invasive fungal infection

High-risk but no evidenceHigh-risk but no evidence

Prophylaxis - candidosis

Candida parapsilosisCandida albicans


Candida albicansCandida tropicalis


Candida albicansCandida glabrataCandida krusei


YeastYeastYeastYeast

FluconazoleFluconazole

Effective & safeEffective & safe

Fluconazole - HSCT recipients

356356

171799

171777

FluconazoleFluconazole placeboplacebo

332277

Invasive candidiasisInvasive candidiasis2%2% 15%15%

101011

111166

Empirical antifungalEmpirical antifungal56%56% 66%66%

5555

4466

Death - all causesDeath - all causes31%31% 26%26%

Goodman et al. N Eng J Med. 1992 326 845

400 mg/d400 mg/d

Slavin et al. J. Infect. Dis. 1995;171 1545

Fluconazole - HSCT recipients

301301

151522

141499


1111

2277

Invasive diseaseInvasive disease7%7% 18%18%

5588

8822


2200

3311


400 mg/d400 mg/d

Fluconazole - neutropenic patients

274274

141411

131333


553322


8800

6677


22 88Death - fungalDeath - fungal1%1% 6%6%

Rotstein et al 1999 Clin Infect Dis 28 331

400 mg/d400 mg/d

Winston et al. Ann Intern Med 1993. 118 495

Fluconazole - neutropenic patients

256256

121233

131322


551100


7799

9977


2266

2244


400 mg/d400 mg/d







YeastYeastYeastYeast


not provennot proven

Prophylaxis - candidosis

405405

202011

202044

itraconazoleitraconazole placeboplacebo

55 99Invasive diseaseInvasive disease3%3% 5%5%

4422

5599


11 55Death - fungalDeath - fungal1%1% 3%3%

Itraconazole- neutropenic patients

Menichetti et al.. Clin Infect Dis 1999;28 250

MouldsMouldsMouldsMoulds

Aspergillus fumigatusAspergillus fumigatus

amphotericin Bamphotericin Binhalationinhalation

Prophylaxis - aspergillosis

Amphotericin B inhalation study of prophylaxis

222277

111155

nilnil

1100

1111

aspergillosisaspergillosis4%4% 7%7%

7733

6622


3300

1155


Schwartz et al. Blood. 93. 1999 pp. 3654-3661

MouldsMouldsMouldsMoulds

Aspergillus fumigatusAspergillus fumigatus


Prophylaxis - aspergillosis

Itraconazole study of prophylaxis

557557

282811

272766

itraconazoleitraconazole amphotericin B poamphotericin B po

55 99aspergillosisaspergillosis2%2% 3%3%

111144

131322


1188

2233


Harrassou et al. Antimicrob Ag Chemother. 44. 2000 1887


140140

7711

6677

itraconazoleitraconazole FluconazoleFluconazole

33 88aspergillosisaspergillosis4%4% 12%12%

2222

3344


3322

2288





Time to development of invasive fungal infection - all Time to development of invasive fungal infection - all patientspatients



Time to development of invasive fungal infection - GVHDTime to development of invasive fungal infection - GVHD

Which drugs?. Mode of action of antifungals ergosterol polyenes e.g. amphotericin B polyenes azoles...

Documents

Transcript of Which drugs?. Mode of action of antifungals ergosterol polyenes e.g. amphotericin B polyenes azoles...