antifungal treatment: past and present malcolm richardson phd, fibiol, frcpath university of...
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Antifungal treatment:
Past and Present
Malcolm RichardsonPhD, FIBiol, FRCPathUniversity of Helsinki
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Introduction
The global and local incidence of systemic fungal infection
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Trends in the Incidence ofDocumented Fungal Infections
198
0
198
1
198
2
198
3
198
4
198
5
198
6
198
7
198
8
198
9
199
0
0
1
2
3
4
5
6
7
%
USA
GERMANY
Adapted data from Beck-Sague J Infect Dis 1993 and Groll et al. J Infect 1996
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Incidence of Invasive Mycotic Infectionsin a General Population 1992-1993
No. of cases per million per year
No. of cases per million per year
CANDIDA species albicans non-albicans
CRYPTOCOCCUS
ASPERGILLUS
Agents of ZYGOMYCOSIS
MALASSEZIA FURFUR
733736
66
12
1.7
<1
Case-fatality for first episode
Case-fatality for first episode
34%38%30%
13%
23%
30%
—
Rees JR et al. Clin Infect Dis 1998
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Focus on invasive aspergillosis
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Days after transplantDays after transplant
1010 2020 3030 4040 5050 6060 7070 8080 9090 100100 110110 120120 130130 140140 150150 160160 170170180180 >180>180
Cas
esC
ases
2020
1818
1616
1414
1212
1010
88
66
44
22
00
Wald et al. J Infect Dis 1997;175:1459
Aspergillus: Time to diagnosis of aspergillosis after BMT
NeutropeniaNeutropenia Graft versus host diseaseGraft versus host disease
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Late onset of IA in BMT patients at a university hospital
• 93 allogeneic and 149 autologous pts• 20 month period• 0% IA autologous• 15.1% allogeneic: overall incidence 5.8%• Median time to occurrence: 92 days• No de novo cases prior to engraftment• Survival 100 days from diagnosis 29%• Conclusions
– shift towards late occurrence – outpatient environment surveillance
Grow et al., BMT 2002; 29: 15-19
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Invasive fungal infections in pediatric bone marrow transplant recipients:
single center experience of 10 years• 148 BMT• 12/73 (16%) infection: allogeneic• 6/75 (8%) infection: autologous• 15/18 died, in 12 IFI as cause of death• 48 suspected infections• allogeneics: severe GVHD major risk factor• steroid dose associated with IFI
Hovi et al. Bone Marrow Transplantation 2000; 26: 999-1004.
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Mortality of Proven and Probable Aspergillus Infections in Bone Marrow Transplantation
0 10 20 30 40 50 60 70 80 90 100
CONNEALLYB.M.T. 1990
DENNINGR.I.D. 1990
HERTENSTEINAnn. Hemat. 1994
MEYERSSem. Oncol. 1990n = 1500
n = 303
n = 2121
n = 123
Case mortality rate
Fo
ur
dif
fere
nt
stu
die
s o
f B
MT
rec
ipie
nts
ev
alu
ated
fo
r A
sper
gill
us
infe
ctio
ns
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Risk periods for mycosis following HSCT
Gra
nu
locy
tes
(log
Gra
nu
locy
tes
(log 101
0 1
x 1
0 1
x 1
066 /L
)/L
)
0.10.1
11
1010
3636
3737
3838
3939
4040
4141
Te
mp
era
ture
°C
Te
mp
era
ture
°C
DaysDays MonthsMonths
-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010
WeeksWeeksTransplantTransplant
ENGRAFTMENTENGRAFTMENTENGRAFTMENTENGRAFTMENTPRE-PRE-TRANSPLANTTRANSPLANTPRE-PRE-TRANSPLANTTRANSPLANT
EARLY POST-EARLY POST-ENGRAFTMENTENGRAFTMENTEARLY POST-EARLY POST-
ENGRAFTMENTENGRAFTMENTLATE LATE POSTENGRAFTMENT -POSTENGRAFTMENT -LATE LATE POSTENGRAFTMENT -POSTENGRAFTMENT -
Stem cellsStem cells acute GvHDacute GvHD low IgGlow IgG
neutropenianeutropenianeutropenianeutropenia corticosteroidscorticosteroidscorticosteroidscorticosteroids
chronic GvHDchronic GvHD
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Assessment of risks following HSCT
Gra
nu
locy
tes
(log
Gra
nu
locy
tes
(log 101
0 1
x 1
0 1
x 1
066 /L
)/L
)
0.10.1
11
1010
3636
3737
3838
3939
4040
4141
Te
mp
era
ture
°C
Te
mp
era
ture
°C
DaysDays MonthsMonths
-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010
WeeksWeeksTransplantTransplant
ENGRAFTMENTENGRAFTMENTENGRAFTMENTENGRAFTMENTPRE-PRE-TRANSPLANTTRANSPLANTPRE-PRE-TRANSPLANTTRANSPLANT
EARLY POST-EARLY POST-ENGRAFTMENTENGRAFTMENTEARLY POST-EARLY POST-
ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENT
treatment
Disease likelihood
ProphylaxisProphylaxis
remoteremote
High riskHost factorsHigh riskHost factors
EmpiricalEmpirical
possiblepossible
Persistent feverMucositis
Persistent feverMucositis
Pre-emptivePre-emptive
Probable diseaseProbable disease
Clinicalfeatures Clinical
features
Mycologicalevidence features
Mycologicalevidence features
SpecificSpecific
provenproven
Tissueevidence
Tissueevidence
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Diagnosis of invasive aspergillosis
Urgent need for early and sensitive diagnosis
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Growth of Aspergillus
1-2 mm per hour1-2 mm per hour
EORTC EORTC IFICGIFICG
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Diagnosis of aspergillosis
Infectious Disease PhysicianInfectious Disease Physician
ClinicianClinician MicrobiologistMicrobiologist
Pharmaceutical IndustryPharmaceutical Industry
PathologistPathologist
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Clinician’s response to laboratory diagnosis
What’s the point? A positive result will only confirm my hunch and a negative result will not make me change the treatment I’m going to give anyway.
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Clinical haste
answeranswer
MicrobiologyMicrobiology
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Rx within 96h - 3 complete resolution - 3 partial response
Rx delayed >2w - 11/11 died
- 7 diagnosed at PM
Why do we need new diagnostic methods?
Early initiation of therapy critical
Aisner et al Ann Intern Med 1977; 86: 539-43
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1970Clinical diagnosis of IA not made in 68% with evidence at autopsy
Young, Medicine 1970; 49: 147-173
199668% patients with autopsy proven IA
received no treatmentGroll, J. Infect 1996; 33: 23-32
Little progress in Little progress in diagnosisdiagnosis of invasive aspergillosis of invasive aspergillosis
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Clinical manifestations arenon-specific
Conventional diagnostic tests insensitive, positive late in
infection
Inability to perform invasive diagnostic procedures
Why the lack of progress?
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New approaches to diagnosis
Nucleic acid amplification
Radiology Serology
Non-culture
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Diagnosis: Chest CT scan – air crescent sign
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Diagnosis: Chest CT scan – halo sign
© Fungal Research Trust
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HRCT Scans
Halo sign Air crescent sign
Kuhlman 1987 Chest 92: 95-99; Caillot 2001 J Clin Oncol 19: 253-9Kuhlman 1987 Chest 92: 95-99; Caillot 2001 J Clin Oncol 19: 253-9
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Non-culture approaches to fungal Non-culture approaches to fungal diagnosisdiagnosis
Cell wall components
Cytoplasmic antigens
Metabolites
Genomic DNA sequences
Candida Aspergillus Detection
Mannans1,3--D-glucanschitin
EnolaseHSP-90
arabinitol
C-14 lanosterol demethylaseChitin synthaseActinAspartate proteinaseRibosomal RNA genes
Galactomannan1,3--D-glucanschitin
D-mannitol
C-14-lanosterol demethylaseAlkaline proteaseMitochondrial DNAHSP-90Ribosomal RNA genes
LAELISARIAAmebocyte lysate assaySpectrophotometry
PCR
GLCMass spectroscopy
ELISAImmunoblot
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Rat Rat monoclonal monoclonal antibody EB-antibody EB-A2A2+ peroxidase+ peroxidase
Sandwich ELISA for Aspergillus galactomannan
11 22 33 44
Rat Rat monoclonal monoclonal antibody EB-antibody EB-A2A2
GalactomannanGalactomannan ChromogeChromogenn
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GM screening: prospective validationGM screening: prospective validation
prospective screening 2x/Week
191 haematology pts (362 episodes)
itraconazole or low dose AmB prophylaxis
Platelia Aspergillus ELISA (BioRad)
Positive cutoff > 1.0
2 consecutive positive results required
Maertens, Blood 2001;97:1604-10
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Positivity preceded:
antifungals in 18/29 by 6d (1-27d)[coincided with 4]
sampling day of first positive culture in 27/29 by 10.5d (1-100d) development of new pul. infiltrates in 19/28 by 5d (1-27d) definitive diagnosis in 29/30 by 17 d (2-110d)
Biopsy proven Probable NoIA (30) IFI (3) IA (9) IA (264)
Positive 30 0 5 5
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all 24 patients with persisting/rising titres died
6 patients cleared GM - 4 survived & 2 died
antigen titres may correspond with clinical outcome could reduce antifungal use from 43% - 12% - but lack of species specificity a concern
Maertens, Blood 2001;97:1604-10Maertens, Blood 2001;97:1604-10
Sensitivity 89.7% Specificity 98.1%PPV 87.5% NPV 98.4%
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Micro-arrays: The New Direction....
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Diagnosis tomorrow
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Diagnosis tomorrow
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Defining systemic fungal infection
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Defining systemic fungalinfectious disease
Host factor
Clinical Clinical featurefeature
MycologyMycology
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Definite invasive fungal disease
Host factor
Clinical Clinical featuresfeatures
MycologyMycologyTissueTissue++ ++ ++
Invasive Fungal Infections Cooperative Group
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Histopathological evidence of IA
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Probable invasive fungal infective disease
Host factor
Clinical Clinical featuresfeatures
MycologyMycology++ ++
Invasive Fungal Infections Cooperative Group
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Possible invasive fungal disease
Host factor
Clinical Clinical featuresfeatures
MycologyMycology++ OROR
Invasive Fungal Infections Cooperative Group
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Mycology
MycologyMycology
Culture of mould from aspirate, BAL or sputum Culture of mould from aspirate, BAL or sputum
Mould seen in sinus Mould seen in sinus aspirateaspirate
AspergillusAspergillus antigen in BAL, CSF antigen in BAL, CSF or bloodor blood
Fungal elements seen in sterile Fungal elements seen in sterile body fluidsbody fluids
Invasive Fungal Infections Cooperative Group
PCR in BAL, CSF or PCR in BAL, CSF or bloodblood
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Host factors
Host factor
NeutropeniaNeutropeniaNeutropeniaNeutropenia
>4 days >4 days unexplained fever unexplained fever despite broad despite broad spectrum spectrum antibioticsantibiotics
>4 days >4 days unexplained fever unexplained fever despite broad despite broad spectrum spectrum antibioticsantibiotics
Graft versus host Graft versus host diseasedisease
Graft versus host Graft versus host diseasedisease
>3 weeks >3 weeks corticosteroidscorticosteroids
>3 weeks >3 weeks corticosteroidscorticosteroids
<36°C or >38°C and: <36°C or >38°C and: • prior mycosisprior mycosis• AIDSAIDS• immunosuppressivesimmunosuppressives• >10 days neutropenia>10 days neutropenia
<36°C or >38°C and: <36°C or >38°C and: • prior mycosisprior mycosis• AIDSAIDS• immunosuppressivesimmunosuppressives• >10 days neutropenia>10 days neutropenia
Invasive Fungal Infections Cooperative Group
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When to treat?
FUO
New pulmonary infiltrates
Antigenaemia
Culture
DNA-
aemia
Antibody
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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
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Mode of action of antifungals
ergosterolergosterolergosterolergosterol
polyenespolyeneseg amphotericin Beg amphotericin Bpolyenespolyeneseg amphotericin Beg amphotericin B
azolesazoleseg fluconazoleeg fluconazoleazolesazoleseg fluconazoleeg fluconazole
squalenessqualenessqualenessqualenes
lanosterollanosterollanosterollanosterol
KK++
Mg Mg 2+2+
KK++
Mg Mg 2+2+
allylaminesallylamineseg terbinafineeg terbinafineallylaminesallylamineseg terbinafineeg terbinafine
acetyl-Co-Aacetyl-Co-Aacetyl-Co-Aacetyl-Co-Anucleosidesnucleosideseg 5-flucytosineeg 5-flucytosinenucleosidesnucleosideseg 5-flucytosineeg 5-flucytosine
nucleic acid synthesisnucleic acid synthesisnucleic acid synthesisnucleic acid synthesis
pneumocandinspneumocandinseg caspofungineg caspofunginpneumocandinspneumocandinseg caspofungineg caspofungin
glucan synthesisglucan synthesisglucan synthesisglucan synthesis
nikkomycinsnikkomycinsnikkomycinsnikkomycinschitin synthesischitin synthesischitin synthesischitin synthesis
azasordarinsazasordarinsazasordarinsazasordarinsprotein synthesisprotein synthesisprotein synthesisprotein synthesis
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ravuconazoleravuconazoleanidulafunginanidulafungin
posaconazoleposaconazole
micafunginmicafungin
CaspofunginCaspofungin
Adapted from Rex & Edwards, 1997
Licensed antifungal agents: the pace quickens
1010
2020
19501950 19601960 19701970 19801980 19901990 20002000
voriconazolevoriconazoleNyotranNyotran
AmBisomeAmBisome
AmphotecAmphotec
AbelcetAbelcet
itraconazoleitraconazole
GriseofulvinGriseofulvin
fluconazolefluconazole
Amphotericin BAmphotericin B
NystatinNystatin
ketoconazoleketoconazolemiconazolemiconazole
5-flucytosine5-flucytosine
terbinafineterbinafine
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• Fungus AMB FCZ ITZ CZ PCZ RCZ CF MF AF
• Candida albicans• Candida tropicalis • Candida parapsilosis• Candida krusei• Candida glabrata• Cryptococcus neoformans • Histoplasma capsulatum • Blastomyces dermatitidis • Coccidiodes immitis • Paracoccidiodes brasiliensis • Pneumocystis carinii• Aspergillus fumigatus • Mucor spp• Rhizopus spp• Fusarium spp •
•
• Fungus AMB FCZ ITZ CZ PCZ RCZ CF MF AF
• Candida albicans• Candida tropicalis • Candida parapsilosis• Candida krusei• Candida glabrata• Cryptococcus neoformans • Histoplasma capsulatum • Blastomyces dermatitidis • Coccidiodes immitis • Paracoccidiodes brasiliensis • Pneumocystis carinii• Aspergillus fumigatus • Mucor spp• Rhizopus spp• Fusarium spp •
•
Comparative spectrum of activity
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Antifungal strategies
• Prophylaxis
• Pre-emptive use
• Early empiric use
• Targeted treatment
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Prophylaxis: Key issues 1
• Which patients should benefit from prophylaxis?
• What is the best drug and what is the appropriate dose?
• What is the impact of prophylaxis on clinical practice re the use of empirical amphotericin B/AmBisome?
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Prophylaxis: Key issues 2
• Is prior prophylaxis a risk factor for subsequent IFI caused by resistant pathogens?
• What is the approach for those patients with a previously documented fungal infection who need to undergo BMT?
• What is the indication for growth factors?
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Prophylactic Therapy
• Data on the efficacy of prophylaxis are
not definitive.
• There is no clear benefit of prophylaxis in many cases.
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IDSA practice guidelinesCandidosis
• Prophylaxis – neutropenic patients
• fluconazole 400 mg/d
• amphotericin B 10-20 mg/d
• AmBisome 1 mg/kg/d
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Prophylaxis – Current situation
• Fluconazole: 200-400 mg daily• Itraconazole (capsules, oral solution): 400
mg/day• Low-dose amphotericin B: 0.1 to 0.25
mg/kg/day• Amphotericin B solution, sprays or inhalants• AmBisome: 2 mg/kg, 3 x weekly• Full dose AmBisome to protect patients with
previous aspergillosis
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Fluconazole for prophylaxis against rectal colonisation in the very LBWN
• fluconazole 6 mg/kg or placebo• rectal colonisation
– C. albicans most common species– 15.1% FLU– 46% placebo
• BUT: no difference in rate of invasive candidosis
• Kicklighter et al. Pediatrics 2001; 107: 293-298
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Fluconazole for prophylaxis against rectal colonisation in the very LBWN
• fluconazole 6 mg/kg or placebo• rectal colonisation
– C. albicans most common species– 15.1% FLU– 46% placebo
• BUT: no difference in rate of invasive candidosis
• Kicklighter et al. Pediatrics 2001; 107: 293-298
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Effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in BMT recipients with
special attention to hepatic candidiasis• Autopsy study: 355 patients• 50% prophylaxis: 400 mg/kg• 40% fungal infection (any site)• Decrease in Candida infections: 27% to 8%• Increase in Aspergillus infections: 18%-
29%• Fungal liver infection: 9%• Conclusions:
– significant reduction in Candida– increase in aspergillosis
van Burk Medicine (Baltimore) 1998; 77: 246-254
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Fluconazole prophylaxis prevents intra-abdominal candidiasis in high risk surgical
patients• 49 patients: recurrent gastrointestinal perforations or
anastomatic leakages• Fluconazole 400 mg/day intervention, or placebo 15 days• Primary end-point: intra abdominal Candida infection• Colonisation:
– 15% fluconazole group– 62% placebo group
• Infection:– 2/23 fluconazole– 7/20 placebo
• 87% C. albicans• All strains susceptible to fluconazole
Eggimann et al. Crit Care Med 1999; 27: 1066-1072
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Adverse consequences of azole prophylaxis
• Increase in bacteraemia• Greater use of amphotericin B• No impact on survival• Advere effect on neutrophil recovery• Higher rate of GvHD• Increased mortality• Risk of hepatitis• Emergence and colonisation by FLU-resistant
strains
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Conclusions - Fluconazole
• Fluconazole prophylaxis is a double-edged sword
• Use should not be trivalized• Fluconazole attractive:
– low toxicity– proven efficacy in systemic candidosis
• Selection of fluconazole-resistant isolates and species will occur if used broadly and injudiciously
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Conclusions - Itraconazole
• Oral solution potentially useful where Aspergillus anticipated: risk assessment
• Steady state rapidly achieved• Topical effect – benefit in OPC• Breakthrough infections associated with
plasma levels <0.25 mg/l• Cross-resistance to ITR 30% of 96 FLU-
resistant Candida isolates• No ITR resistance in FLU-sensitive isolates
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Empirical antifungal therapyThe concept
• In high-risk IC patients with persisting or relapsing infectious symptoms, the probability of developing invasive fungal disease is 20-40%
• The mortality of established fungal disease remains high (40-80%)
• Diagnostic sensitivity and specificity is poor
Early empiric antifungal treatment with amphotericin B (and others) is recommended
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Implementation of empirical amphotericin B
• PUO unresponsive to antibacterials
• Pulmonary infiltrates unresponsive to antibacterials
• Mucosal candidosis
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Empiric AMB
• Ampho lite = 0.1 mg/kg/d
• Ampho regular = 0.5-0.8 mg/kg/d
• Ampho super = 1-2 mg/kg/d
• Ampho mega = 3-5 mg/kg/d or higher
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Empirical antifungal therapy:Questions asked
• Optimal timing
• Optimal dosage
• Optimal agent
• Optimal spectum
• Optimal cost/benefit ratio
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Empirical therapyFAQs
• Does empirical therapy reduce the incidence of systemic mycoses?
• Does empirical therapy improve the prognosis of systemic mycoses?
• What are the practical guidelines for implementation?
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IDSA practice guidelinesCandidosis
• Empirical therapy for neutropenic patients with prolonged PUO
• amphotericin B 0.5-0.7 mg/kg/d
• AmBisome 3-5 mg/kg/d
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THE IDEAL EMPIRICAL/PREEMPTIVE STRATEGY
USE ONLY safe and effective antifungal drugs with spectrum adapted to
local ecology and optimally adjusted dosage; booster host defense (CSF) first
INCLUDE ONLY, BUT QUICKLY patients with high probability of fungal disease , belonging to a
well defined high risk category EXCLUDE CERTAINLY
patients with low risk profile or unlikely to have fungal disease RELY EXCLUSIVELY ON
optimal batteries of clinical, radiologic and laboratory tests AVOID ALWAYS
indiscriminate primary prophylaxis ADOPT
early pre-emptive strategy, secondary prophylaxisHEM/90593M
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Why do we still use empirical antifungal therapy?
• Assumptions:
– Established invasive infections carry excessive mortality rates
– Prophylactic strategies are inefficient– Colonization and disease form an obligatory continuum– Newer diagnostic tools yield « too little, too late »– The « hard » data from the published randomized studies
are reliable and form « proof of principle »
• Emotions and traditionsHEM/20283M
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• Broad spectrum of activity (yeasts and filamentous fungi)
• Rapidly and highly fungicidal, stable to resistance
• Potent in vivo activity (even in neutropenia)
• Both oral and parenteral formulations
• Low toxicity, minimal drug-drug interactions
• Good pharmacokinetics (AUC)
• Good penetration into all tissue compartments
• Cost effective
The ideal antifungal agent
HEM/00223M
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Large studies on empirical antifungal therapy in refractory neutropenic fever
Year N Agents
Viscoli 1996 112 AmphoB vs Fluco
Prentice 1997 338 AmphoB vs Ambisome
Malik 1998 106 AmphoB vs Fluco
White 1998 213 AmphoB vs ABCD
Walsh 1999 687 AmphoB vs Ambisome
Winston 2000 317 AmphoB vs Fluco
Wingard 2000 244 Ambisome vs ABLC
Boogaerts 2001 384 AmphoB vs Itraco
Walsh 2002 849 Ambisome vs Vorico
HEM/20281M
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Response rates(%) in large studies on empirical antifungal therapy in neutropenic
fever (%)
AmphoB
Ambi Fluco Itraco Vorico ABLC/ABCD
Viscoli 50 - 52 - - -
Prentice 46 64 - - - -
Malik 46 - 56 - - -
White 43 - - - - 50
Walsh 49 50 - - - -
Winston 67 - 68 - - -
Wingard - - - - - 40/33
Boogaerts 38 - - 47 - -
Walsh - 31 - - 26 -HEM/20282M
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Success if all of the following occurred:– survival for 7 days post study drug– resolution of fever during neutropenic period– resolution of microbiologically confirmed study
entry Fungal infection.– no proven or presumed emergent F.I. on study drug
therapy or within 7 days after last dose of study drug– study drug was not prematurely discontinued due to
toxicity or lack of efficacy.
Composite endpoint
HEM/80688M
Large studies on empirical antifungal therapy
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Population– Patients with haematologic malignancies
neutropenic (<0.5 x 109 ANC/l) fever of unknown origin (>38° C)3 - 7 days broadspectrum antibiotics
Objectives– Compare efficacy and safety – Empirical therapy
IV itra (7 to 14 days) Itra oral solution (14 days) IV ampho B (28 days)
– Blood levels of itraconazoleHEM/80675M
Empirical Itraconazole verus AmphoB
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Empirical Itraconazole versus AmphoB
Efficacy analysis
p=0.156 p<0.001 p=0.055
0.047/0.052
2-sided 1-sided superiority equivalence test
Itra n (%)
Ampho n (%)
Response 88 (48) 70 (37)
Composite endpoint
99 (53) 83 (46)
HEM/80690M
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Itraconazole versus amphotericin B as empirical therapy for persistent fever in neutropenic
patients
ResponseItra group (n=179)
Amphotericin B group
(n=181)
Difference
(95% CI)
Breakthrough fungal infections, n
5 5
Candidemia 2 2
Filamentous fungal pneumonia
3 3
HEM/20268M
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Itra Ampho-B
all p
Severe adverse events 37 (21.5) 65 (36) 102 (29) 0.003
Possibly drug related 93 (48) 105 (58) 188 (53) 0.066
Definitely drug related 9 (5) 103 (57) 112 (32) <0.001
Death 16 (9) 23 (13) 39 (11) 0.038
Serious adverse events (including death)
32 (19) 46 (25) 78 (22) 0.123
Permanent stop to study therapy
36 (21) 73 (40) 109 (31) <0.001
Total 172 183 353
Empirical Itraconazole versus AmphoBAdverse events
HEM/80698M
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Large studies on empirical antifungal therapy
Prentice et al., BJH 1997; 98:711
2 studies : 134 adults + 204 children
conventional ampho B (c-Amb.)randomization liposomal ampho B 1 mg/kg/d (I-Amb 1)
liposomal ampho B 3 mg/kg/d (I-Amb 3)
FUO : > 38°C not responding to 4 d broad-spectrum antibioticsNeutropenia : neutrophils < 0.5 x 109/l
HEM/80702M
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Intention-to-treat analysis : all randomized patients
Response:1. < 38°C during 3 consecutive days2.no fungal infection3.> 0.5 x 109 /l neutrophils
Failure : 1. addition of systemic antifungal therapy2.systemic fungal infection
Success: c-Amb 49 %I-Amb1 58% p=0.03I-Amb3 64%
Kaplan Meier analysis : no significant difference in time to defervescence
H.G. Prentice et al., BJH,1997; 98:711
HEM/80703M
Large studies on empirical antifungal therapy
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Toxicity
Severe drug-related : c-Amb : 12%I-Amb : 1 %
Nephrotoxicity: double S-crea: c-Amb: 23% I-Amb3: 3% I-Amb1 : 0%
H.G. Prentice et al., BJH 1997; 98:711
p=0.01
HEM/80704M
Large studies on empirical antifungal therapy
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Walsh et al.,NEJM 1999; 340:764
687 patients
Conventional ampho B (c-Amb.)randomization
Liposomal ampho B 3 mg/kg/d (I-Amb)
FUO: fever not responding to 5 days broad-spectrum antibioticsNeutropenia : neutrophils < 0.5 x 109 /l
HEM/80706M
Large studies on empirical antifungal therapy
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Composite endpoint
liposomal ampho B conventional ampho BSuccess 171/343 (50%) 169/344 (49%)
Breakthrough fungal infections
liposomal ampho B conventional ampho BProven deep FI 41 (3.2%) 27 (7.8%)
P=0.009
Walsh et al. 1999
HEM/80705M
Large studies on empirical antifungal therapy
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Empirical voriconazole study: Primary endpoint
Vori Ambisome
No. of patients 415 422
Success 23.7% 30.1%
Difference between arms -6.1% (-12%, -0.1%)
Voriconazole failed to meet its primary endpoint
Walsh et al, 2002
HEM/20284M
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Empirical voriconazole study: Secondary endpoints
Voriconazole Ambisome difference
Overall stratified 23.7% 30.1% -6.1%
No B/T infection 98.1% 95.0% +3.1%
Survival 92.0% 94.1% -2.1%
No discontinuation 90.1% 93.4% -3.3%
Defervescence 33.0% 36.0% -3.0%
Response in B/L infections 46.0% 67.0% -20.5%
Walsh et al, 2002
HEM/20285M
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Empirical voriconazole study
Voriconazole Ambisome Difference (95% CI)
High risk45/143 (32%)
42/141 (30%)+1.7% (-9.0%,
12.4%)
Moderate risk
63/272 (23%)
87/281 (31%)-7.6% (-15.2%, -
0.4%)
Walsh et al, 2002
Overall response rateSubset analysis by risk of fungal infection
HEM/20286M
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Breakthrough infections
Fewer in voriconazole arm than ambisome arm
Voriconazole Ambisome
1.9% 5.0%
Adjusted for death – FDA analysis
Voriconazole Ambisome
9.2% (38/415)% 9.2% (39/422)%
Walsh et al, 2002
HEM/20288M
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Voriconazole vs Liposomal Amphotericin B as antifungal therapy for neutropenia and fever
Response Voriconazole (n=415)L Ampho B
(n=422)P value
Infusions related reactions
Abnormal vision 91 (21.9) 3 (0.7) < 0.001
Chest pain 1 (0.2) 17 (4.0) < 0.001
Abdominal pain 1 (0.2) 12 (2.8) 0.002
Dyspnea 3 (0.7) 37 (8.8) < 0.001
Flushing 14 (3.4) 46 (10.9) < 0.001
Sweating 3 (0.7) 9 (2.1)
Urticaria 1 (0.2) 3 (0.7)
Cyanosis 0 2 (0.5)
Chills 57 (13.7) 126 (29.9) < 0.001
Cardiac arrest 1 (0.2) 0
Nausea 39 (9.4) 53 (12.6)
Infusion related reactions and laboratory abnormalities in patients treated with voriconazole or liposomal amphotericin B
T. Walsh, NEJM 2002 HEM/20259M
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Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy
in patients with neutropenia and PUO
Key points• overall success rates:
– voriconazole: 26%– 30.6% liposomal amphotericin B
• breakthrough infections:– voriconazole: 1.9%– liposomal amphotericin B: 5.0%
Walsh et al. NEJM 2002; 346: 225-234.
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Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy
in patients with neutropenia and PUO
Discussion pointsQ. Where all breakthrough infections
proven/definite (wording vague)?Q. What dosage where breakthrough infections?Q. Prophylaxis: ?protocol defined, details vague.Q. ”Dose-limiting toxicity”: will monitoring be
prolematic (HPLC)?
Walsh et al. NEJM 2002; 346: 225-234.
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IDSA practice guidelinesCandidosis
• Chronic hepatosplenic candidosis
• (hepatosplenic candidosis)
• fluconazole 400-800 mg/d
• amphotericin B 0.6-0.7 mg/kg/d
• AmBisome 3-5 mg/kg/d or higher
Clinical Infectious Diseases, April 2000
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IDSA practice guidelinesCandidosis
• Candidaemia/disseminated candidosis
• amphotericin B 0.7 mg/kg/d
• AmBisome 3-5 mg/kg/d
• fluconazole 400-800 mg/kg/d
• iv itraconazole
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IDSA Practice guidelines
Aspergillosis
• IPA– amphotericin B: response: 14-83%– AmBisome 66%– iv itraconazole– switching therapy
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Do surveillance cultures predict patients at greatest risk?
• Candida: positive cultures do not always predict systemic infection
• Positive C. tropicalis cultures: greatest risk of infection
• Aspergillus: ?positive nasal swabs useful in predicting outbreaks of invasive aspergillosis
Conclusion: positive surveillance cultures may guide appropriate therapy
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Treatment of proven infections
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EORTC EORTC IFICGIFICG
number ASPERGILLUS CANDIDA
FUNGIZONE®
0.5-1mg/kg/day 45% 60%
ABELCET® up to 6 mg/kg/day 88/279 62% 52%
AMPHOCIL / TEC® up to 6 mg/kg/day 114/69 45% 47%
AMBISOME® 0.5-5 mg/kg/day 45/73 66% 58%
ITRACONAZOLE400 mg/day 189/ 59%
FLUCONAZOLE up to 800 mg/day /443 80%
number ASPERGILLUS CANDIDA
FUNGIZONE®
0.5-1mg/kg/day 45% 60%
ABELCET® up to 6 mg/kg/day 88/279 62% 52%
AMPHOCIL / TEC® up to 6 mg/kg/day 114/69 45% 47%
AMBISOME® 0.5-5 mg/kg/day 45/73 66% 58%
ITRACONAZOLE400 mg/day 189/ 59%
FLUCONAZOLE up to 800 mg/day /443 80%
amp
ho
teri
cin
Comparison of Success Rate in Proven and Presumed Fungal Infections
FUNGIZONE (amphotericin B for injection) is a trademark of Bristol Myers Squibb.ABELCET (amphotericin B lipid complex injection) is a trademark of The Liposome Co., Inc.AMPHOCIL (amphotericin B colloidal dispersion) is a trademark of Sequus Pharmaceuticals, Inc.AMBISOME (amphotericin B liposome for injection) is a trademark of NeXstar Pharmaceuticals.
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Efficacy and safety of voriconazole in the treatment of acute IA
Study overview• Open, multicentre study• 116 patients
– proven IA 48 (41%)– probable 68– voriconazole: as primary therapy 60 (52%)
Denning et al. CID 2002: 34: 563-571.
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Efficacy and safety of voriconazole in the treatment of acute IA
Response Assessed by clinical and radiographic change
– complete response: 16 (14%)– good responses: 56 (48%)– partial response: 40 (34%)
Denning et al. CID 2002: 34: 563-571.
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Efficacy and safety of voriconazole in the treatment of acute IA
• Inclusion criteria– Definite (proven) IA: histopathologic evidence of
tissue invasion with hyphae ”morphologically consistent with Aspergillus”, or a positive culture from a sterile site
– Probable IA: radiologic evidence of acute IA– Probable IA: Aspergillus from respiratory fluids
and characteristic radiography.– In profound neutropenia: radiology and clinical
features with culture: sufficient for enrollment.Denning et al. CID 2002: 34: 563-571.
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Efficacy and safety of voriconazole in the treatment of acute IA
Discussion points• Response compares favourable with
itraconazole, cAMB and liposomal AMB• Patients with positive histological results but
negative cultures were included as definite cases
• No comment about long treatment duration and host response
Denning et al. CID 2002: 34: 563-571.
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Candins
• Potent broad spectrum activity
• Fungicidal
• Novel mechanism of activity
• Low potential for developing resistance
• Well tolerated in humans
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Caspofungin
• Member of a new class of antifungals, the echinocandins– Inhibitors of glucan synthesis in the fungal
cell wall
– Cell wall target absent from mammalian cells
• Spectrum of activity includes Aspergillus and Candida spp.
• Unique mechanism of action results in a lack of cross-resistance with azoles and polyenes
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Caspofungin spectrum of activity
• Spectrum of activity includes Candida albicans, non-albicans Candida spp., and Aspergillus spp.– Caspofungin is fungicidal for Candida spp.– Caspofungin demonstrates clear activity against
Aspergillus spp.• In vitro, no cross-resistance to Candida spp. with
intrinsic or acquired resistance to fluconazole, amphotericin B, or flucytosine
• No activity against Cryptococcus neoformans• Activity against other fungi less well defined
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Caspofungin is approved!
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Caspofungin Clinical Development Program
PK and Proof of Concept (I/IIA)
OPC/Candida Esophagitis
Invasive Infections Caspofungin 70 mg X 1; then
50 mg/d Dose Ranging
Caspofungin 35, 50, 70 mg/d
III Candida Esophagitis
Invasive Candidiasis
Empirical Therapy ofFebrile Neutropenia
Dose Selection
50 mg/d Salvage Aspergillus
Pediatrics
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Caspofungin Salvage Aspergillus Study(Protocol 019) Design
• Multi-center, open-label, non-comparative study – Caspofungin 70 mg qd X 1, followed by 50 mg qd
• Diagnostic criteria – Documented invasive aspergillosis, AND– Meet criteria as refractory to or intolerant of standard
therapy
• Definition of response– Favorable response: Complete or Partial Response– Unfavorable response: Failure, Stable disease
• Cases reviewed by independent Expert Panel
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n/m
Expert Panel Assessment of Outcome
Efficacy Analysis
Primary: All patients with diagnosis who receive at least 1 dose of caspofungin
Secondary: Patients who received > 7 days of caspofungin
26/63 (41.3)
26/52 (50.0)
Favorable Response(%)
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n/m
Expert Panel Assessment of Outcome
Efficacy Analysis
Primary: All patients with diagnosis who receive at least 1 dose of caspofungin
Secondary: Patients who received > 7 days of caspofungin
26/63 (41.3)
26/52 (50.0)
Favorable Response(%)
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Summary of Caspofungin Efficacy in the Salvage Aspergillus Study
• Expert Panel determined that 41% of patients had a Complete or Partial Response at the end of caspofungin therapy
• High prevalence of poor prognostic factors
• Favorable outcomes seen in all high risk groups
– Refractory patients, hematologic malignancies/bone marrow transplant, disseminated disease, corticosteroids, and neutropenia
• Documented relapse uncommon at 4 week follow-up
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Therapeutic regimens
NyotranNyotran
ravuconazoleravuconazole
posaconazoleposaconazole
itraconazoleitraconazole
oral
Amphotericin BAmphotericin B
AmBisomeAmBisome
AmphotecAmphotec
AbelcetAbelcet
voriconazolevoriconazole
anidulafunginanidulafungin
caspofungincaspofungin
micafunginmicafungin
IV Oral
itraconazoleitraconazole
voriconazolevoriconazole
itraconazoleitraconazole
voriconazolevoriconazole
ravuconazoleravuconazole
posaconazoleposaconazole
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Managing mycosis following HSCT
Gra
nu
locy
tes
(log
Gra
nu
locy
tes
(log 101
0 1
x 1
0 1
x 1
066 /L
)/L
)
0.10.1
11
1010
3636
3737
3838
3939
4040
4141
Te
mp
era
ture
°C
Te
mp
era
ture
°C
DaysDays MonthsMonths
-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010
WeeksWeeksTransplantTransplant
ENGRAFTMENTENGRAFTMENTENGRAFTMENTENGRAFTMENTPRE-PRE-TRANSPLANTTRANSPLANTPRE-PRE-TRANSPLANTTRANSPLANT
EARLY POST-EARLY POST-ENGRAFTMENTENGRAFTMENTEARLY POST-EARLY POST-
ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENT
IIVV
oraorall
oraorall
VoriconazoleVoriconazoleItraconazoleItraconazolePosaconazole Posaconazole
VoriconazoleVoriconazoleItraconazoleItraconazolePosaconazole Posaconazole
VoriconazoleVoriconazoleItraconazoleItraconazoleCaspofunginCaspofunginAmBisomeAmBisome
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00
3636
3737
3838
3939
4040
4411
Tem
per
atu
re (
°C)
Tem
per
atu
re (
°C)
Optimal antifungal management?
CultureCultureCultureCulture + TissueTissueTissueTissue +GalactomannanGalactomannanGalactomannanGalactomannan+
PCRPCRPCRPCR +
Treatment
Disease likelihood
-7-7 00 77 1414 2121 2828 3535 4242 4949 5656 6363-14-14
0.10.1
11
1010
Days after transplantDays after transplant
Gra
nu
locy
tes
(lo
gG
ran
ulo
cyte
s (l
og
1010x
10x1099 /
L)
/L)
EmpiricalEmpirical
PossiblePossible
ProphylaxisProphylaxis
RemoteRemote
SpecificSpecific
ProvenProven
Pre-emptivePre-emptive
Probable diseaseProbable disease
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DIAGNOSTICS
ANTIFUNGALSALONE
ORIN COMBINATION
INTERFERONINTERLEUKINS
G(M)-CSF
SURGERY
HYGIENEISOLATION
ELIMINATION OFRISK FACTORS
Future Antifungal Strategies
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Combination therapyIssues
• Clinical trials supporting combination therapy are sparse
• No concensus regarding which combinations are synergistic or antagnostic
• Predicting whether synergy or antagonism will predominate in vivo is extraordinarily difficult
• Extrapolation from in vitro or animal studies is, at best, tenuous.
• Antagnostic interactions can be based on mechanisms of action, but not synergy.
Lewis & Kontoyiannis Pharmacotherapy 2001; 21: 149S-164S
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Itraconazole-amphotericin B combinations: MD Anderson experience
• 67 haematological malignancy patients• Definite IA (EORTC/MSG criteria)• Failure rate, regardless of regimen: 85%• No difference in outcome
– monotherapy– combination therapy– adjunctive therapy
• Major factors: – poor diagnosis tests– extent and duration of immunosuppression
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Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans
• No data on combination of caspofungin + others antifungals
• 2 cases IA:– ALL: A. terreus: Caspo 50 mg/day + Itra 200 mg t.i.d.
po, 8 weeks, no recurrence– Single-lung Tx: A. fumigatus:
• Itra 400 mg/day po + ABLC 5 mg/kg/day• Itra 400 mg/kg/day po + Caspo 70 mg/day• No recurrence
Rubin et al. CID 2002; 34: 1160-1161
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Clinical Implications for Today
• Cryptococcus– Adding 5FC is generally good. +FLU is better?
• Candida– Can combine fluconazole with AmB
• But, probably should avoid in endocarditis• Candins may render this idea moot
• Aspergillus– Candin-based combos look like the way to go
• Keep terbinafine-based combos in mind
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Today’s choicesInvasive aspergillosis
– amphotericin B desoxycholate: 1-1.5 mg/kg/d– Liposomal amphotericin B: 5 mg/kg/d starting dose– Casopofungin: 50/70 mg/d– Voriconazole: 4 mg/kg bid– Itraconazole: 200-600 mg/d– Second-generation antifungal triazoles
(investigational)– Combinations
Groll & Walsh. Infect Med 2002; 19: 326-334.(Medscape: www.medscape.com)Patterson CID 2002; 35: 367-369.
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Conclusions• The echinocandins and new triazoles offer more choice
• There is too little known about the optimum dosage, the need for monitoring and the potential DRAE’s
• Acquisition costs will be high
• Flexible administration is now demanded
• Who should get what and when remains unclear
• Targeting the drugs will require better identification of those at risk and assessment of that risk
• Further studies are need to establish the place of these drugs in clinical practice
• PREVENTION IS BETTER THAN CURE