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
ergosterolergosterolergosterolergosterol
nucleic acid synthesisnucleic acid synthesisnucleic acid synthesisnucleic acid synthesis
glucan synthesisglucan synthesisglucan synthesisglucan synthesis
chitin synthesischitin synthesischitin synthesischitin synthesis
nucleic acid synthesisnucleic acid synthesisnucleic acid synthesisnucleic acid 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)
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
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 azolesazoles candinscandins
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
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 azolesazoles candinscandins
Pneumocystis cariniiPneumocystis carinii
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
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
Cryptococcus neoformansCryptococcus neoformans
azolesazoles candinscandins
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
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
glucan synthesisglucan synthesisglucan synthesisglucan synthesis
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 parapsilosisCandida albicans
Candida albicansCandida tropicalis
Candida albicansCandida tropicalis
Candida albicansCandida glabrataCandida krusei
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
FluconazoleFluconazole placeboplacebo
1111
2277
Invasive diseaseInvasive disease7%7% 18%18%
5588
8822
Empirical antifungalEmpirical antifungal38%38% 55%55%
2200
3311
Death - all causesDeath - all causes13%13% 21%21%
400 mg/d400 mg/d
Fluconazole - neutropenic patients
274274
141411
131333
FluconazoleFluconazole placeboplacebo
553322
Invasive diseaseInvasive disease6%6% 24%24%
8800
6677
Empirical antifungalEmpirical antifungal57%57% 50%50%
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
FluconazoleFluconazole placeboplacebo
551100
Invasive diseaseInvasive disease4%4% 8%8%
7799
9977
Empirical antifungalEmpirical antifungal64%64% 74%74%
2266
2244
Death - all causesDeath - all causes21%21% 18%18%
400 mg/d400 mg/d
Candida parapsilosisCandida albicans
Candida parapsilosisCandida albicans
Candida albicansCandida tropicalis
Candida albicansCandida tropicalis
Candida albicansCandida glabrataCandida krusei
Candida albicansCandida glabrataCandida krusei
YeastYeastYeastYeast
itraconazoleitraconazole
not provennot proven
Prophylaxis - candidosis
405405
202011
202044
itraconazoleitraconazole placeboplacebo
55 99Invasive diseaseInvasive disease3%3% 5%5%
4422
5599
Empirical antifungalEmpirical antifungal21%21% 29%29%
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
Empirical antifungalEmpirical antifungal32%32% 40%40%
3300
1155
Death - all causesDeath - all causes13%13% 10%10%
Schwartz et al. Blood. 93. 1999 pp. 3654-3661
MouldsMouldsMouldsMoulds
Aspergillus fumigatusAspergillus fumigatus
itraconazoleitraconazole
Prophylaxis - aspergillosis
Itraconazole study of prophylaxis
557557
282811
272766
itraconazoleitraconazole amphotericin B poamphotericin B po
55 99aspergillosisaspergillosis2%2% 3%3%
111144
131322
Empirical antifungalEmpirical antifungal41%41% 48%48%
1188
2233
Death - all causesDeath - all causes6%6% 8%8%
Harrassou et al. Antimicrob Ag Chemother. 44. 2000 1887
Itraconazole study of prophylaxis
140140
7711
6677
itraconazoleitraconazole FluconazoleFluconazole
33 88aspergillosisaspergillosis4%4% 12%12%
2222
3344
Empirical antifungalEmpirical antifungal31%31% 51%51%
3322
2288
Death - all causesDeath - all causes45%45% 42%42%
Winston et al. Ann Intern Med 2003. 138 705
Itraconazole study of prophylaxis
Winston et al. Ann Intern Med 2003. 138 705
Time to development of invasive fungal infection - all Time to development of invasive fungal infection - all patientspatients
Itraconazole study of prophylaxis
Winston et al. Ann Intern Med 2003. 138 705
Time to development of invasive fungal infection - GVHDTime to development of invasive fungal infection - GVHD