Antifungal treatment: Past and Present Malcolm Richardson PhD, FIBiol, FRCPath University of...

Antifungal treatment:

Past and Present

Malcolm RichardsonPhD, FIBiol, FRCPathUniversity of Helsinki

Introduction

The global and local incidence of systemic fungal infection

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

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

Focus on invasive aspergillosis

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

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

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.

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

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

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


-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010




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

Diagnosis of invasive aspergillosis

Urgent need for early and sensitive diagnosis

Growth of Aspergillus

1-2 mm per hour1-2 mm per hour

EORTC EORTC IFICGIFICG

Diagnosis of aspergillosis

Infectious Disease PhysicianInfectious Disease Physician

ClinicianClinician MicrobiologistMicrobiologist

Pharmaceutical IndustryPharmaceutical Industry

PathologistPathologist

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.

Clinical haste

answeranswer

MicrobiologyMicrobiology

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

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

Clinical manifestations arenon-specific

Conventional diagnostic tests insensitive, positive late in

infection

Inability to perform invasive diagnostic procedures

Why the lack of progress?

New approaches to diagnosis

Nucleic acid amplification

Radiology Serology

Non-culture

Diagnosis: Chest CT scan – air crescent sign

Diagnosis: Chest CT scan – halo sign

© Fungal Research Trust

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

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

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

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

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

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%

Micro-arrays: The New Direction....

Diagnosis tomorrow

Diagnosis tomorrow

Defining systemic fungal infection

Defining systemic fungalinfectious disease

Host factor

Clinical Clinical featurefeature

MycologyMycology

Definite invasive fungal disease

Host factor

Clinical Clinical featuresfeatures

MycologyMycologyTissueTissue++ ++ ++

Invasive Fungal Infections Cooperative Group

Histopathological evidence of IA

Probable invasive fungal infective disease

Host factor


MycologyMycology++ ++


Possible invasive fungal disease

Host factor


MycologyMycology++ OROR


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


PCR in BAL, CSF or PCR in BAL, CSF or bloodblood

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


When to treat?

FUO

New pulmonary infiltrates

Antigenaemia

Culture

DNA-

aemia

Antibody

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


cholesterolcholesterolcholesterolcholesterol

protein synthesisprotein synthesisprotein synthesisprotein synthesis protein synthesisprotein synthesisprotein synthesisprotein synthesis

mannan synthesismannan synthesismannan synthesismannan synthesis

humanhumanhumanhuman fungusfungusfungusfungus

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


pneumocandinspneumocandinseg caspofungineg caspofunginpneumocandinspneumocandinseg caspofungineg caspofungin

glucan synthesisglucan synthesisglucan synthesisglucan synthesis

nikkomycinsnikkomycinsnikkomycinsnikkomycinschitin synthesischitin synthesischitin synthesischitin synthesis

azasordarinsazasordarinsazasordarinsazasordarinsprotein synthesisprotein synthesisprotein synthesisprotein synthesis

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

• 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

Antifungal strategies

• Prophylaxis

• Pre-emptive use

• Early empiric use

• Targeted treatment

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?

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?

Prophylactic Therapy

• Data on the efficacy of prophylaxis are

not definitive.

• There is no clear benefit of prophylaxis in many cases.

IDSA practice guidelinesCandidosis

• Prophylaxis – neutropenic patients

• fluconazole 400 mg/d

• amphotericin B 10-20 mg/d

• AmBisome 1 mg/kg/d

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

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

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

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

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

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

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

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

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

Implementation of empirical amphotericin B

• PUO unresponsive to antibacterials

• Pulmonary infiltrates unresponsive to antibacterials

• Mucosal candidosis

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

Empirical antifungal therapy:Questions asked

• Optimal timing

• Optimal dosage

• Optimal agent

• Optimal spectum

• Optimal cost/benefit ratio

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?


• Empirical therapy for neutropenic patients with prolonged PUO

• amphotericin B 0.5-0.7 mg/kg/d

• AmBisome 3-5 mg/kg/d

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

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

• 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

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

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

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

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

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

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

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


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

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


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


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


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


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

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

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

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

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

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.

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.


• 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


• Candidaemia/disseminated candidosis

• amphotericin B 0.7 mg/kg/d

• AmBisome 3-5 mg/kg/d

• fluconazole 400-800 mg/kg/d

• iv itraconazole

IDSA Practice guidelines

Aspergillosis

• IPA– amphotericin B: response: 14-83%– AmBisome 66%– iv itraconazole– switching therapy

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

Treatment of proven infections

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.

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.


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.


• 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.


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.

Candins

• Potent broad spectrum activity

• Fungicidal

• Novel mechanism of activity

• Low potential for developing resistance

• Well tolerated in humans

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

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

Caspofungin is approved!

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

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

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(%)

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(%)

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

Therapeutic regimens

NyotranNyotran

ravuconazoleravuconazole



oral

Amphotericin BAmphotericin B

AmBisomeAmBisome

AmphotecAmphotec

AbelcetAbelcet

voriconazolevoriconazole

anidulafunginanidulafungin

caspofungincaspofungin

micafunginmicafungin

IV Oral





ravuconazoleravuconazole


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


-7-7 00 77 1414 2121 1212 66 99 1212-14-14 662828 88 1010




ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENTLATE POST-LATE POST-ENGRAFTMENTENGRAFTMENT

IIVV

oraorall

oraorall

VoriconazoleVoriconazoleItraconazoleItraconazolePosaconazole Posaconazole

VoriconazoleVoriconazoleItraconazoleItraconazolePosaconazole Posaconazole

VoriconazoleVoriconazoleItraconazoleItraconazoleCaspofunginCaspofunginAmBisomeAmBisome

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

DIAGNOSTICS

ANTIFUNGALSALONE

ORIN COMBINATION

INTERFERONINTERLEUKINS

G(M)-CSF

SURGERY

HYGIENEISOLATION

ELIMINATION OFRISK FACTORS

Future Antifungal Strategies

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

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

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

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

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.

http://www.medscape.com/

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

Any questions or comments?

[email protected]

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Antifungal treatment: Past and Present Malcolm Richardson PhD, FIBiol, FRCPath University of...

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