CURRICULUM VITAE

• Nama : Dr. H. Harun Hudari, SpPD, FINASIM

• TTL : Palembang, 3 Mei 1970
• Pendidikan : Spesialis Penyakit Dalam FK Universitas
Sriwijaya
Palembang th 2008
• Riwayat Pekerjaan :
• 1. Dokter PTT Puskesmas Muara Rupit 1997 – 2000
2. Dokter PNS RSUD Dr. MM Dunda Gorontalo 2001 – 2004
3. Dokter Spesialis Penyakit Dalam RSUD Banyuasin
2008 – sekarang
4. Dokter Spesialis Penyakit Dalam FK UNSRI/RSMH
Palembang 2009 – sekarang
• HP : 081271621966 / 0711 7301744
FUNGAL INFECTION

Dr. H. Harun Hudari, SpPD, FINASIM

Divisi Penyakit Tropik Infeksi
Bagian Ilmu Penyakit Dalam
RS Dr. Moh. Hoesin/FK UNSRI
2
• The incidence of fungi infection has increased dramatically over 20 year-
period by 207%

• Candida species are the most common cause of infection in patients icu,
accounting for 85% of all documented mycosis :
o C. albicans is responsible for approximately 45- 58%
o C. non albicans ( C. krusei and C. glabrata ) has emerged and
increase to about 44%

• Fungi are the fourth leading pathogen in nosocomial infections in the USA
 THE PROBLEM

o The mortality associated with systemic fungal infection

remains high (20 – 60%)

o The diagnosis is difficult :

 the clinical picture of systemic invasive disease is not
specific
 PCR, Mannan test promising but investigational
 blood culture has a low sensitivity
 its often hard to differentiate colonization from infection
in critically ill patients, especially when receiving broad
spectrum anti-bacterial
“ Clinical suspicion of paramount importance “
Why the issues are so important

Wisplinghoff H et al. Clin infect Dis. 2004 ; 39 : 309-317

Bacterial Infection vs Fungal Infections

Gram +ve Gram -ve Fungal

Identical clinical syndrome in

severe infection/septic shock

Mortality
Bacterial severe sepsis/septic shock 30-50%
Fungal severe sepsis/septic shock 60%+
Dobbs.Bali Meeting 2004
 Voriconazole vs Amphotericin-Fluconazole
Voriconazole Amphotericin P value
(N+248) B/Flu (N=122)

Primary 101 (41%) 50 (41%) 0.96

success

Secondary 162 (65%) 65% (53%) 0.23

success

2 weeks 130 (52%) 52 (42%) 0.99

After therapy

All cause 14 88 (36%) 52 (42%) 0.23

Wk mortality

Kulberg BJ et.al. Lancet 2005:366 1435 - 1442

 Regional Variability of Candida Infection:
SENTRY Program (1997-1999)*
Latin America (n=132)** U.S. (n=589)
1% 7% 9% 2% 2%
16%
11%
45%
55%

25% 21%
6% Europe (n=302)
1% 5% C. albicans
7%
C. glabrata
58% C. parapsilosis
19%
C. tropicalis
C. krusei
Other Candida spp.
10%
*Clinical isolates were obtained from patients with bloodstream infections, and species
identification was done in vitro; **N-values refer to the number of Candida isolates.
Pfaller MA et al. J Clin Microbiol 2001;39:3254-3259.
 Incidence of Invasive Disease (US)

30

25
Incidence per 100,000 patients

20

15 Candida
Aspergillus
10

0
1996 1997 1998 1999 2000 2001 2002 2003

Pfatter M et al. CLINICAL MICROBIOLOGY REVIEWS,Jan. 2007, p. 133-163

Diagnostic studies
Fungus GM BG PCR
Aspergilus + + +
Fumingatus
Aspergilus + + +
non Fumingatus

Fusarium - + +
Zygomycetes - - +
Cryptococcus + + +
Candida + + +
Note: GM, galactomanan; BG, beta 1,3 glucan; PCR, polymerase chain reaction
Pamela Lipsett, SCCM,Honolulu,2008
The Question : why critically ill patients always at risk!!

As Clinician : to identified “the risk patient” as soon as possible

 Diagnosis
Patients were classified according to the
following criteria:

i) Proven :
(a) positive blood culture
or (b) positive culture or histology from a
normally sterile body site or tissue obtained
using a sterile procedure;
• (ii) Probable :
fungal colonization and (a) Candida found in the
urine and/or in BAL (if direct microscopy
revealed yeast) and/or (b) response to antifungal
treatment;

• (iii) Possible :
colonization without fulfilling the criteria above;

• (iv) Unlikely:
no fungal colonization.
The Rules for Identifying high risk ICU patients are as
follow :
 ICU stay greater than or equal to 4 days
 Major risk factors : broad spectrum antibiotics / central venous catheter
 Minor risk factors :TPN/dialysis/major surgery/ pancreatitis/ steroid/
immunocompetent

They should be Treated if the

patient has an ICU greater than or
equal to 4 days and 1 major and 2
minor risk factors

ISICEM 2009 Congress Report

Candida score
Identifying Patients : Prediction Rules

 Clinical sepsis = 2 points;

 Surgery = 1 point;
 TPN = 1 point;
 Multi-focal colonization = 1 point;
5 points possible
 If > 2.5 then sensitivity of 81% and specificity of 74%
 IF > 2.5 RR of infection 7.75*
 [95% CI 4.74, 12.66]
* Intend to treat as initial Empiric antifungal

Leon et al. CCM 2006.34

Antifungal Therapy
 Relationship between hospital mortality and the timing
of appropriate antifungal treatment

35
Hospital mortality (%)

30
25
20
15
10
5
0
< 12 12–24 24–48 > 48

Delay in start of antifungal treatment (hours)

• Initiation of therapy > 12 h after the first positive blood sample was
associated with a greater risk of mortality than appropriate therapy given
within 12 h
Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5
Inadequate Therapy Increased Mortality
in Patients with Bloodstream Infections
Bloodstream infection caused by Candida species was one of the risk
factors for inadequate treatment in ICU patients.
70
Hospital Mortality (%)

60 62%
50
p<0.001
40
30
28%
20
10
0
Inadequate Therapy Adequate Therapy

Adapted from Ibrahim EH et al. Chest 2000;118:146-155.

How to use Antifungal agent :
- Definition
 SYSTEMIC ANTIFUNGALS

Ampho B Deoxycholate
Liposomal Ampho B (Ambisome)
Polyenes Ampho B Colloidal Dispersion
(ABCD)
Ampho B Lipid Complex (ABLC)

Itraconazole, Fluconazole,
Azole Voriconazole, Posatonazole,
Ravuconazole

Echinocandin Caspofungin, Anidulafungin

s Micafungin

Antimetabolit Flucytosine
e
Targets of antifungal therapy.
 How Does One Choose ??

 Know the available agents

 Identify the likely fungal pathogen

 Be familiar with your local pathogens and the sensitivity of

your pathogens

 What is your patient looks like? Do you use azoles?

 Has the patient been exposed to azoles?

 Why Do I Need to Know the Species?
Some species routinely either resistant or partially susceptible to azoles

Species FLU ITRA VORI CANDIN FLYCT AMPHO

C glabrata SDD - R SDD - R S S S S-I

C krusei R SDD - R S S I-R S-I

C lusitaniae S S S S S S-R

C. albicans S S S S S S

C.parapsilo S S S S S S-R
sis

S, susceptible; I, intermediate; R, resistance; SDD, susceptible dose-dependent

Pappas et al CID 2009: 48

 Why Do I need to Know the Species ?

Molds FLU ITRA VORI CANDIN FLYCT AMPHO

Aspergillus
species
A. flavus R S S S I-R SDD-R

A. fumigatus R S S S I-R S

A. terreus R S S S I-R SDD-R

Pappas et al. CID 2004(38) Guidelines for Treatment of Candidiasis

Pappas et al. Treatment Guidelines for Candidiasis.CID 2009,March
 “ Suspected Invasive Candidiasis or Candidemia “
Pappas et al. Treatment Guidelines for Candidiasis.CID 2009,March

-Hemodynamically unstable
-Septic / Neutropenia
-Recent Azole exposure

NO YES

Including : Including No infection

- No risk of infection C.glabrata ** of C.parapsilosis ##
- No risk of concomitant Endocardial
and CNS Candidiasis #

Fluconazole Echinocandin
400 -800 mg/ day iv Micafungin: 100 mg/day iv

Note : ** Risk of C.glabrata infection: elderly, cancer and diabetes patients ; # Echinocandin
(endondocardial candidiasis), Amphotericin B (endocardial and CNS candidiasis) ; ## C.parapsilo
sis (Amphotericin B or Fluconazole susceptible)
Why should be Echinocandins ??
( micafungin = mycamine )

• fungicidal
• favorable safety profile
• very few drug interactions
• demonstrated success in ~ 75% of patients in several
randomized clinical trials
 Echinocandins

• Caspofungin (Cancidas)
• Andulofungin (Eraxis)
• Micafungin (Mycamine)
 Phase III trial micafungin vs. fluconazole for
prophylaxis: treatment success

80
Treatment success rate (%)

70
69.2
60

50 53.3
40

30

20

10

0
n= 39 45
Micafungin Fluconazole
Van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16
 Phase III study micafungin vs. L-AmB: treatment
success by neutropenic status

Overall Non-neutropenic Neutropenic

Treatment success rate (%)

100

80
74.1 76.3
69.6 71.2
60
59.4
56.0
40

20

0
n= 247 215 32 247 222 25
Micafungin L-AmB

Kuse ER, et al. Lancet 2007; 369:1519–27 Modified intent-to-treat (mITT) population
 Phase III study micafungin vs. L-AmB: renal adverse
events

Treatment-related renal AEs1 eGFR2

Mean peak decrease (ml/min/1.73 m2)

Micafungin L-AmB
n= 157 168
15 p = 0.005* 0 –1.3

12.0
–5
Patients (%)

10

–10
5
4.9
–15

–19.1
0
n= 264 267 –20
Micafungin L-AmB p < 0.0001†
*Fisher’s exact test; †ANCOVA
1. Astellas Pharma Europe Ltd. Data on file, December 2005; 2. Kuse ER, et al. Lancet 2007; 369:1519–27
 Fluconazole remains one of the treatment of Candida infections

BUT,

Innate (C.krusei) or emerging (especially C. glabrata and C. guilliermondi)

resistance to azoles among non-albicans Candida spp. has been noted
in various regions in the world

SO,

Limit the use of Fluconazole as empirical therapy for candidemia in

critically ill patients

Pfaller et al. J Clin Microbiol, 2007,45

Bassetti et al. BMC Infect Dis, 2006,6
 Take Home Message
• The incidence of systemic Candida infection in critically ill patients has
been increasing over the last two decades

• Critically ill patients cumulate risk factors for systemic invasive Candiasis
thats why : early identified of high risk of invasive candiasis is essential

• A biological tools are currently unavailable at the bedside, empirical treat

ment relies on clinical strategies on a “ High Risk Group Patients “

• Recently, Echinocandins (micafungin/ mycamin) has become suggested use

for prophylaxis, initial empiric and definitive antifungal therapy in modera
tely severe to severely illness or septic/netropenia and in unit with a high in
cidence of C.glabrata, C.krusei and Aspergillosis
Arigatougozaimashou
Terima Kasih