The State of the Art of Invasive Candidiasis Management in Asia

Prof George Dimopoulos MD, PhD, FCCP

Department of Critical Care

Medical School, University of Athens, Greece

gdimop@med.uoa.gr

Indonesia, 13-15 April 2013

Worldwide incidence of Candida spp ARTEMIS project (134,715 isolates, 127 medical centres, 39 countries) (1991–2006)

Canada 415 isolates 1 study

USA 7,151 isolates 6 studies

Latin America 1,710 isolates

2 studies

Europe 2,089 isolates

8,923 isolates 7 studies

Asia-Pacific 1,344 isolates 1 study

Africa 73 isolates

C. albicans C. glabrata C. parapsilosis C. tropicalis C. krusei Other

Pfaller MA et al, Clin Microbiol Rev 2007;20:133–63,

Tortorano M et al Eur J Clin Micr Infect Dis 2004; 23:317–22, Colombo L et al. Eur J Clin Microbiol Infect Dis 2003;22:470–4

Candida spp the predominant fungal pathogen in the ICU setting

88%

7% 5%

Candida Aspergillus Other

Global surveillance study of

13,796 adults in 1265 ICUs

in 75 countries

Candida responsible for

88% of fungal infections

(n=963)

89% in Europe (n=633)

85% elsewhere (n=330)

Vincent JL et al. JAMA. 2009;302:2323–9

Candida non-albicans in the ICU 4 Geographically Diverse Intensive Care Units

0

20

40

60

80

100

2001 2002 2003 2004 2005 2006

% o

f p

ati

en

ts

0

20

40

60

80

100

Australia Belgium Greece Brazil

% o

f p

ati

en

ts

12

8

13

10

15

15

23

15

19

23

22

14

25

18

29

26

31

18

19

23

Per cent albicans and non-albicans

candidemia over study period

Per cent albicans and non-albicans

candidemia by country

Holley A, Dulhunty JM, Blot SI, Lobo S, Dancer C, Rello J, Lipman J, Dimopoulos G. Intern J Antimicrob Agents 2009

Predominance of Candida tropicalis BSIs in a Singapore teaching hospital

18-month investigation of Candida BSIs in a Singapore hospital where 52 candidemic patients were identified

- 36% C. tropicalis - 29% C. albicans - 10% C. parapsilosis - 21% C. glabrata

A predominant clonal C. tropicalis strain was demonstrated

No association with - ICU stay - prior exposure to fluconazole / broad-spectrum antibiotics or - increased mortality was found

Chai YA, Wang Y, Khoo AL, Chan FY, Chow C, Kumarasinghe G, Singh K, Tambyah PA.

Med Mycol. 2007 Aug;45(5):435-9.

Fungal Infections in India

Indian

Experience

with

Fungaemia

Management of invasive candidiasis

in ICUs in the Asia-Pacific Region

Candida albicans • Predominant cause in ICUs followed by C. tropicalis, C. glabrata and C. parapsilosis

Candida spp • Highly susceptible to fluconazole (>90%)

Asia-Pacific countries • Susceptibility rate of C. glabrata to fluconazole 22%- 72%

Early diagnosis- prompt initiation of antifungal therapy

Considerable regional variability • Local epidemiological knowledge is critical in Asia-Pacific

Hsueh PR et al, Int J Antimicrob Agents. 2009 Sep;34(3):205-9.

SHEEP meeting Sharing Eraxis Experience Program

TREATING INVASIVE FUNGAL INFECTIONS

John Simon,1 Hsin-Yun Sun,2 Hoe Nam Leong,3 Marie Yvette C Barez,4 Po-Yen

Huang,5 Deepak Talwar,6 Jen-Hsien Wang,7 Melor Mansor,8 Bambang Wahjuprajitno,9

Atul Patel,10 Siriporn Wittayachanyapong,11 B Shoib Mohd Sany,8 Sheng-Fong Lin,12

and George Dimopoulos13

1University of Hong Kong, Pokfulam, Hong Kong; 2National Taiwan University Hospital,

Taipei, Taiwan; 3Raffles Medical Hospital, Singapore; 4Davao Doctors Hospital, Davao,

The Philippines; 5Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6Metro Group of

Hospitals and Heart Institute, Delhi, India; 7China Medical College-Hospital, Taichung,

Taiwan; 8Hospital Ampang, Kuala Lumpur, Malaysia; 9Dr Soetomo General Hospital,

Surabaya, Indonesia; 10Vedanta Institute of Medical Sciences, Ahmedabad, India; 11Bangkok-Pattaya Hospital, Chonburi Province, Thailand; 12Pfizer Inc., Hong Kong; 13National and Kapodistrian University of Athens and Department of Critical Care,

University Hospital “Attikon”, Athens, Greece

Sharing Eraxis Experience Program SHEEP meeting Hong Kong 7 October 2010

Mycoses 2013 (in press)

Worldwide incidence of Candida spp.

Data are originally from Pfaller et al. J Clin Microbiol, 2010; 48: 1366-1377 (DOI:

10.1128/JCM.02117-09) and have been reproduced/amended with permission from

American Society for Microbiology.

Predisposing and risk factors for Candida spp.

infections in critically ill patients

Host factors Iatrogenic factors

Neutropenia

Candida spp. colonization

Necrotizing pancreatitis

Gastrointestinal perforation

Acute renal failure

Bacterial sepsis

Malignant haematological disease

High Acute Physiology And Chronic

Health Evaluation (APACHE) II score

Diabetes mellitus

Increased age

Mucositis

Immunosuppressive therapy

Broad-spectrum antibiotic therapy

Total parenteral nutrition

Central venous catheter

Mechanical ventilation

Major surgical procedures

Leaking gastrointestinal anastomosis

Antineoplastic chemotherapy

Haemodialysis

Radiotherapy

Corticosteroids

Hospital environment

Predisposing Factors for

Fungal Infections in the ICU

Immune system alterations

↑ AIDS patients

Aggressive treatments

↑ BMT, SOT

↑ Number of elderly patients

Medical technology advances

Mechanical ventilation

Medical devices

Main risk factors

Chemotherapy (agent, dose, duration)

Radiotherapy

Corticosteroids

Immunosuppression

Antibiotics

Central venous lines

Mucositis

TPN/malnutrition

Hospital environment

Dimopoulos G, Vincent JL. Clin Intens Care 2002;13(1):1-12.

What we know………..

What we don’t know………..

What we practice………..

Overgrowth Modified microbiota

Diabetes Burns

Neutropenia Antibiotics

Prematurity

Mucosal colonization

Oropharyngeal Upper-Lower GT

Genital Tract Urinary Tract

Micro-invasion

Multiple antibiotics Vascular accesses

Parenteral nutrition ICU stay > 7 days

Candida colonisation Renal failure

Major abdominal surgery

Candidaemia

Candidaemia

Disseminated disease

Endophthalmitis Endocarditis

Catheter-related Abscess

CNS Hepatosplenic

Eggimann P, et al. Ann Intens Care 2011;1:37

…. the diagnosis is a challenge

Diagnosis is often delayed

• Non-specific signs and symptoms

• Cultures may become positive late

• Serologic tests or molecular methods

not currently used in clinical practice

• Blood cultures

positive in only approximately 50% of patients

Groll AH et al, J Infect 1996;33(1):23-32 Ellepola AN et al, J Microbiol. 2005;43:65-84

Diagnosis of fungal infections

Laboratory

• Microscopic Examination

• Culture & Identification

• Histopathology

• Antibody detection

• Antigen detection

• PCR

“High tech”

• Antibodies

• Metabolites

• Fungal cell wall components

• Fungal PCR

Van Burik J et al. J Clin Microbiol 1998;36:1169-75, Obayashi T et al. Lancet 1995;345:17-20, Yeo SF & Wong B, Clin Microbiol Rev 2002;15:465

Non-culture approaches to fungal diagnosis

Candida Aspergillus Detection

Cell wall components

Cytoplasmic antigens

Metabolites

Genomic DNA sequences

Mannans 1,3--D-glucans

chitin

Enolase HSP-90

Arabinitol

C-14 lanosterol demethylase

Chitin synthase, Actin Aspartate proteinase

Ribosomal RNA genes

Galactomannan 1,3--D-glucans chitin

D-mannitol

C-14-lanosterol demethylase Alkaline protease Mitochondrial DNA HSP-90 Ribosomal RNA genes

LA, ELISA RIA Amebocyte lysate assay Spectrophotometry

PCR

GLC Mass spectroscopy

ELISA Immunoblot

(1,3)-Beta-D-Glucan Detection Glucatell® test, FDA license for IFI, May 21st, 2004

It takes 2 h

Test detects

yeast

filamentous fungi

no differential

diagnostic potential

No Detection

Mucorales

Cryptococcus spp.

Cut-off value

> 60 pg/ml

Specificity:

90% single test

96% for 2

sequential positive

results

Odabasi et al. CID 2004; 39: 199-205

Kinetics of BG

(1→3) Beta-D-glucan (BG) Assay Sensitivity in IFI

Fungitell 80 pg/ml +/total (%) Reference Year

Candidiasis 72/92(78%)

10/12 (83%)

13/15 (87%)

10/35 (29%)

Ostrosky

Odabasi

Pickering

Digby

2005

2004

2005

2003

Aspergillosis 10/10(100%)

4/4 (100%)

Ostrosky

Odabasi

2005

2004

Time to onset of candidemia and relation

between mortality and start of therapy

0

5

10

15

20

25

30

35

1-2 days 3-7 days 8-14days

15-21days

22-28days

>28 days

% CASES

Days of hospitalization

Garey 2006 CID

0

5

10

15

20

25

30

35

40

45

Culture day Day 1 Day 2 > Day 3

% Mortality

Days to start fluconazole

Empirical treatment using “Candida Score” in

non-neutropenic critically ill patient staying ≥ 7 days in ICU

León C, et al, Crit Care Med. 2009;37:1624-1633.

How to use “Candida Score”

Variables are coded (0) when absent and (1) when present (sever sepsis coded “2” when present)

A “Candida Score” ≥3 selected patients at high risk for invasive candidiasis (IC) – A linear association between increasing the value of CS and IC rate was observed (P≤0.001)

0 or 2

0 or 1

0 or 1

0 or 1

Early diagnosis of candidemia in the ICU (1-3)-b-D-glucan assay vs Candida score vs Colonization Index

Flow chart of the study patients ROC AUC curves of BG, CS and CI for proven IC cases The AUC of BG was significantly higher than those of CS (P < 0.001) and colonization index (P < 0.001)

Posteraro B et al, Crit Care 2011, 15:R249

Inappropriate treatment and outcome

No (%) of patients Fungal isolate

Inappropriate

treatment Hospital mortality Total

81 (96.4) 24 (28.6) 84 (53.5) C. albicans

25 (100) 6 (24) 25 (15.9) C. parapsilosis

19 (95) 8(40) 20 (12.7) C. glabrata

19 (95) 10(50) 20 (12.7) C. tropicalis

2 (100) 1 (50) 2 (1.3) C. krusei

Morrell et al AAC 2005

Catheter removal decreases mortality

Population-based candidaemia survey of 288 episodes of Candidaemia

in those with malignancies, including 150 in those with solid tumours

Removal of the central venous catheter at the time of or within 5 days of diagnosis of candidaemia decreased mortality (p=0.0096)

0 10 20 30

1.00

0.75

0.50

0.25

0.00

Analysis time(days)

Catheter removed after diagnosis Catheter not removed after diagnosis

Survivor function for removal of catheter

Slavin et al. J Antimicrob Chemother 2010

Just pull it out !!!!

Antifungal prophylaxis in critically ill patients ?

Guidelines Preemptive treatment

Prophylaxis

BSAC CID 1994 yes

Edwards CID 1997 data

Vincent ICM 1998 SDD ?

Rex CID 2000 yes, but

Buchner EJCMID 2002 yes at risk patients

Denning Lancet ID 2003

Pappas CID 2004 carfully selected pts

SFAR/SPILF/SRLF 2004 yes, but indication

FUNGINOS 2006 yes, but carfully selected pts

IDSA CID 2008 ? ?

AmB and Azoles

Amphotericin B

• Toxicity – nephrotoxicity

infusion-related toxicity

hypokalemia

hypomagnesemia

LFT abnormalities

• Limited efficacy (toxicity)

At times lack of efficacy mortality rates > 40%

• Lipid formulations

– too costly

Azoles

• Well tolerated

• Good safety profile

• Resistance Candida glabrata

Candida krusei (fluconazole)

• Cross resistance Candida glabrata (voriconazole)

In vitro antifungal susceptibilities of Candida from patients with IC in Kuala Lumpur Hospital

159 Candida species, patients with IC in Kuala Lumpur Hospital

Amphotericin B, fluconazole, voriconazole, itraconazole, caspofungin

C. albicans (71), C. parapsilosis (42), C. tropicalis (27), C. glabrata (12)

E-test, MIC breakpoits CLSI

- Amphotericin B, Voriconazole = best activities

1 C. lusitaniae R to amphotericin B

2 C. albicans, 2 C. parapsilosis, 1 C. tropicalis , 1 C. glabrata R to fluconazole

All these isolates showed cross-resistance to itraconazole

- MIC90 of itraconazole was highest for C. glabrata and C. parapsilosis

- Caspofungin was active against all the isolates except for 5 of C. parapsilosis

Amran F, Aziz MN, Ibrahim HM, Atiqah NH, Parameswari S, Hafiza MR, Ifwat M. Med Microbiol. 2011 Sep;60(Pt 9):1312-6.

Antifungal therapies - Clinical trials

Fluconazole AMB

Phillips, 1995

P=.04

Flu

AMB + Flu Rex, 2003

Voriconazole AMB->Flu

Kullberg, 2005

P=.82

Caspofungin Micafungin

Pappas, 2007

Micafungin

Liposomal AMB Kuse, 2007

P=.27

AMB

Caspofungin Mora-Duarte, 2002

P=.09 P=.64

Anidulafungin Fluconazole Reboli, 2007

P=.009 Fl

uco

naz

ole

(8

00

)

Am

ph

ote

rici

n B

+ F

lu

Cas

po

fun

gin

Mic

afu

ngi

n

L-A

mp

ho

teri

cin

B

Mic

afu

ngi

n

Cas

po

fun

gin

Am

ph

ote

rici

n B

Am

ph

ote

rici

n B

F

luco

naz

ole

Vo

rico

naz

ole

Flu

con

azo

le

An

idu

lafu

ngi

n

Am

ph

ote

rici

n B

Flu

con

azo

le

56%

69% 71% 72% 74% 70%

62%

73% 72% 72%

60%

76%

53% 50%

P=.39

Adapted from Kullberg BJ, et al. Lancet. 2007;366:1435-1442

2011 ESCMID Guidelines for Candida Diseases Targeted Treatment of Candidaemia in the ICU Setting

ECCMID, 2011 Milan EW16 Working Group, CMI 2012

Compound SoR QoE Comments

Echinocandins - Anidulafungin 200/100 mg daily

- Caspofungin 70/50 mg daily

- Micafungin 100 mg daily

A

I

Broad spectrum, safety, no drug-drug

interactions, C. glabrata and C. krusei rare resistance, fungicidal

Voriconazole B I Less broad spectrum that –candins,

drug interactions, IV in renal failure,

Fluconazole C I Limited spectrum, inferiority to

anidulafungin (high APACHE II scores)

Polyenes - Amphotericin B liposomal

- Amphotericin B lipid complex

- Amphotericin B colloidal dispersion

- Amphotericin B deoxycholate

B

C

D

D

I

IIa

Iia

I

Similar efficacy with echinocandins,

More AEs

Higher toxicity

Other antifungal classes or

combinations with biological agents

C or

D

No data or without superiority

regarding efficacy

SoR = Strength of Recommendation, QoE = Quality of Evidence.

Critically ill patient

Fungal infection

Suspected

Proven Blood cultures (+) Biopsy (+)

Targeted treatment according to - Guidelines

- Local Epidemiology

How to select the antifungal agent ?

Hemodynamically unstable patient

NO

Azole resistance Recent exposure

Local epidemiology Colonization

NO

FLUCONAZOLE

Alternatives -Echinocandins

-Voriconazole -L-AmphoB

YES

Alternative

L-AmphoB

Echinocandins

Risk factors (+) Clinical signs (-) Biomarkers (-) Mycology (-)

Prophylaxis Fluconazole

Risk factors (+) Biomarkers (+) Clinical signs (-) Mycology (-)

Pre-emptive Treatment

Risk factors (+) Clinical signs (+) Biomarkers (-) Mycology (-)

Empirical treatment

YES

Patient is stabilized ? Consider step-down to

Voriconazole or Fluconazole

Dimopoulos G et al J Crit Care 2013 (in press)

Echinocandins

Masterton et al, CMI in press

Differences among echinocandins (I)

Variable Caspofungin Micafungin Anidulafungin

PAFE ± SD (h) Candida albicans

5.6 ± 0.57

5.0 ± 1.0

>12

MIC90 (µg/mL) All Candida spp.

C. albicans C. glabrata C. tropicalis C. krusei C. parapsilosis C. guilliermondii

0.25 0.06 0.06 0.06 0.25

1 1

1

0.03 0.03 0.06 0.12

2 1

2

0.12 0.12 0.06 0.06

4 2

Cmax (g/mL) 9.9 10.1 7.2

t½ (h) 9–11 11–17 24–26

Volume of distribution (L/kg) * 0.26 0.57

AUC (mg·h/L) 87.9–114.8 11.3 44.4–53.0

Protein binding, % 96 99.8 84

Mycoses 2013 Sharing Eraxis Experience Program

SHEEP meeting

Hong Kong 7 October 2010

Differences among echinocandins (II)

Variable Caspofungin Micafungin Anidulafungin

Metabolism

Hydrolysis and N-acetylation.

Spontaneously degrades to

inactive product

Catechol-O- methylt-

ransferase Pathway Chemical degradation

Clearance (mL/min) 10.0–12.5 10.5 12.5–19.2

Elimination 35% faeces. 41% urine

(1.4% as unchanged drug)

40% faeces.

<15% urine

Primarily in faeces

(<10% intact drug), 1% urine

CSF penetration* ? low ? low <0.1%

Urinary concentration* 1.4% 0.7% <0.1%

Renal insufficiency No dose adjustment needed No dose adjustment needed No dose adjustment needed

Hepatic insufficiency

Child-Pugh 7–9: (Reduce

maintenance dose to 35 mg/day)

Child-Pugh >9: No data

Child-Pugh 7–9)

Cmax not significantly

decreased compared with

healthy subjects

No dose adjustment needed

*% of plasma)

Simon et al , Mycoses 2013

Sharing Eraxis Experience Program SHEEP meeting Hong Kong 7 October 2010

Economic Evaluation of Micafungin for the Treatment

of Candidaemia and Invasive Candidiasis

Vs Caspofungin

• micafungin (AU$52,816) : lower total

cost than caspofungin (AU$52,976)

• Net cost-saving of $160 per patient

• Lower cost associated with alternative

antifungal treatment in the micafungin

arm

• Micafungin was cost-equivalent to

caspofungin in treating candidaemia/IC

Vs Liposomal Amphotericin B

- micafungin (AU$61 426) : lower total cost

than LAmB (AU$72 382)

- Net cost-saving of AU$10 957 per patient

- lower cost associated with initial antifungal

treatment and shorter length of stay for

patients in the micafungin arm

- Micafungin was non-inferior to liposomal

amphotericin B (LAmB) for the treatment

of candidaemia and IC

Main outcomes ( treatment success and treatment failure due to mycological persistence, or death

Neoh CF et al, Mycoses. 2013 Mar 18. doi: 10.1111/myc.12071 Neoh CF et al, Intern Med J. 2013 Mar 6. doi: 10.1111/imj.12110.

Persistent Candidemia : what you have to do ?

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Study Day

0

10

20

30

40

50

60

70

80

90

100%

Caspofungin (N=92)

Amphotericin B (N=94)

20% still candidaemic by Day 4

11% still candidaemic by Day 7

6% candidaemic beyond Day 10

Time to clearance of Candida from the blood stream

% o

f p

atients

still

ca

nd

idaem

ic

Mora-Duarte et al. N Engl J Med 2002

Prolonged candidaemia

Post-op Hickman cath-related Candidaemia and tissue involvment

Vitreous body aspirate C. albicans

Septic thromphoplebitis of the left subclavian and jugular vein

due to Candida albicans

Rare fungal infections in the ICU

Digital nephrostomogram from the left (a)

and right (b) nephrostomy catheter depicts

moderate dilatation and multiple fillings

defects which are caused by the fungus balls

located in the pelvicalyceals systems.

Digital nephrostomogram obtained fifteen

days following the bilateral percutaneous

nephrostomies depict resolution of the

filling defects of the both the left (A), and

the right (C) kidneys. Note good patency

of the distal anastomosis (B).

Dimopoulos et al, Mycoses (under review)

Rare fungal infections in the ICU

Dimopoulos et al, Mycoses (under review)

Candida meningitis

Brain MRI showing high signal intensity of

fast fluid attenuated inversion recovery

(FLAIR), involving periventricular and

subcortical gray matter of bilateral brain

hemispheres, hippocampus, internal capsule

bilaterally, thalami, pons, cerebral peduncles

and substantianigra of midbrain.

Rare fungal infections in the ICU

Dimopoulos et al, Mycoses (under review)

Necrotic lesions with a blackish

escharto the left cheek and upper

lip, extended rapidly to the tongue

and the hard and soft palate.

Chest computer tomography revealing

thrombophlebitis of left internal jugular vein, left

subclavian vein and left brachiocephalic vein.

Practical

Scientific

Prospective clinical trials

Animal studies In vitro studies

Mechanisms of synergy

Spectrum of therapy Intensity of therapy

Safety of therapy

Pragmatism vs. Science and

Decisions to Use Combination Therapy

Lewis REL & Kontoyiannis DP. Br J Hematology 2005

In conclusion

• Fungal infections in Asia

– Local epidemiology

– Risk factors

– Early Diagnosis

– Prevention

- Prophylaxis (selected cases in the ICU)

- Antifungal agents - safe

- well tolerated and

- with broad spectrum activity

- Echinocandins - Attractive option

- Differences among them (mainly safety and Pk/PDs)