Diagnosis and Treatment of

Systemic Fungal Infection

Fungal infections
Yeast
Candida
Candida : - Candida albicans
- Candida non-albicans
C.glabrata, C.krusei, C.parapsilosis
Cryptococcus neoformans var neoformans
Pneumocystis jirovecii
Filamentous fungi or moulds
Aspergillus sp
Scedosporium apiospermum and S. proliferans
Zygomycetes (Mucor, Rhizopus, Rhizomucor)
Fusarium

Diagnosis of Fungal Infection

Proven/definite
Probable
Possible

Proven Invasive Fungal Infections

Deep Tissue Infection

Molds:
- Histo/cytochemistry showing hypae or
spherules with evidence of associated tissue
damage, either microscopically or radiologically
OR
- (+) culture from infection site

 Yeasts :

- Histo/cytochemistry showing yeast cell and/or

pseudohypae from a neddle aspiration or biopsy
(except mucous membrane)
OR
- (+) culture from infection site excluding urine,
sinuses and mucous membranees by a sterile
procedure
OR
- Microscopy or antigen positivity for Cryptococcus in
CSF

Fungemia
Molds:

- (+) blood culture of fungi excluding Aspergillus

sp and Penicillium sp, other than P.marneffei,
accompanied by temporally related organism
clinical signs and symptoms
Yeasts:

- (+) blood culture of Candida and other yeasts in

patients with temporally related organism
clinical signs and symptoms

Endemic fungal infections

(+) culture from systemic or lungs in a host
with symptoms attributed to the fungal
infection
(-) culture histopatological demonstration

of the appropiate morphological forms must

be combined with serological support

Probable Invasive Fungal Infections

At least 1 criterion from host section
AND
1 microbiological criterion
AND
1 major (or 2 minor) clinical criteria from an
abnormal site consistent with infection

Posible Invasive Fungal Infections

At least 1 criterion from host section

AND
1 microbiological OR 1 major (or 2
minor) clinical criteria from an abnormal
site consistent with infection

Host Factors
1.
2.
3.

4.
5.

Neutropenia: neutrophil < 500/mm3 for > 10 days

Persistent fever for > 96 hours refractory to appropiate broad
spectrum antibacterial treatment
Body temperature either> 38oC or < 36oC AND any of the
following predisposing conditions:
- Prolonged neutropenia (>10 days) in the previous
60 days
- Recent or current use of significant immunosupressive
agent
in the previous 30 days
- Invasive fungal infection in previous episode
- Coexixtence of AIDS
Signs and symtoms indicating GVHD
Prolonged use of corticosteroids (> 3 weeks)

Microbiological Criteria (1)

1.

2.
3.
4.
5.

Positive culture of a mold (including Aspergillus

sp, Fusarium sp, zygomycetes, Scedosporium
sp) or C.neoformans from sputum, BAL
Positive culture or cytology/direct microscopy
for mold from sinus aspirate
Positive cytology/direct microscopy for a mold
or Cryptococcus from sputum, BAL
Positive Aspergillus antigen in BAL, CSF or 2
blood samples
Positive cryptococcal antigen in blood

Microbiological Criteria (2)

6.
7.
8.
9.
10.

Positive cytology/direct microscopy for fungal

elements other than Cryptoccocus in sterile body
fluids
2 positive urine cultuires of yeasts in the absence
of urinary catheter
Candida casts in urine in the absence of urinary
catheter
Positive blood culture of Candida sp
Pulmonary abnormality and negative bacterial
cultures of any possible bacteria from any
specimen related to lower respiratory tract
infection, including blood, sputum, BAL, etc

Clinical Criteria
Should be related to the site of
microbiological criteria and temporally
related to the current episode

Lower Respiratory Tract Infection

Major

- Any of the following new infiltrates on CT

imaging
- halo sign
or
- air crescent sign
or
- cavity within area of consolidation
Minor
- Symptoms of LRTI (cough, chest pain,
hemoptisis, dyspneu)
- Physical finding of pleural rub
- Any new infiltrate not fulfilling major criterion

Sinonasal Infection
Major

- Suggestive radiologic evidence of invasive

infection in the sinuses (i.e. erosion of sinus
walls/extension of infection to neighboring
structures, extensive skull base destruction)

Sinonasal Infection

1.
2.
3.
4.
5.

Minor
Upper respiratory symptoms (nasal
discharge, stuffiness etc)
Nose ulceration/eschar of nasal
mucosa/epitaxis
Periorbital swelling
Maxillary tenderness
Black necrotic lesions/perforation of the
hard palate

Central Nervous System Infection

Major

- Suggestive radiologic evidence of CNS

infection (i.e. meningitis extending from a
paranasal, auricular or vertebral process,
intracerebral absces or infarct)


1.

2.
3.
4.

Minor
Focal neurologic symptoms and signs
(including focal seizures, hemiparesis and
cranial nerve palsies)
Mental changes
Meningeal irritation findings
Abnormalities in DSF biochemistry and cell
count

Disseminated Fungal Infection

Papular or nodular skin lesions without any
other explanation
2. Intraocular findings suggestive of
hematogenous fungal chorioretinitis or
endophthalmitis
1.

Chronic Disseminated Candidiosis

Small, peripheral, target-like abscess

(bulls eye) in liver and/or spleen

demonstrated by CT or MRI

Possible Candidemia
No prominent signs or symptoms of

infection in patient with positive blood

culture of Candida

Categories of Risk Groups for

Systemic Fungal Infection
Low

- PBSC autologous BMT

- Childhood acute lymphoblastic leukemia
(except for P. carinii penumonia)
Intermediate: low

- Moderate neutrop[enia 0.1-0.5 x 10 9/L < 3

weeks
- Lymphocytes <0.5 x 109/L + antibiotics, e.g
cotrimoxazole
- Older age/central venous catheter

 Intermediate : high

- Colonized > 1 site or heavy at 1 site

- Lymphocytes < 0.5 to > 0.1 x 109/L > 3 to
<5 weeks
- Acute myeloid leukemia/total body
irradiation
- Allogeneic matched sibling donor BMT

 High

Neutropenia <0.1 x 109/L > 5 week

Colonized by C.tropicalis
Allogeneic unrelated or mismatched donor BMT
GVHD
Netropenia < 0.5x10/L > 5 weeks
Corticosteroids > 1 mg/kg and neutrophils < 1 x
109/L > 1 weeks
- Corticosteroid > 2 mg/kg > 2 weeks
- High dose cytosine arabinoside

Essential clinical examination in neutropenic and solid organ

transplant patients with suspected invasive fungal infection

Organ/system

Features

Likely infection

Skin

Scattered lesions, often

on limbs;
maculopapular,
progressing to pustular
lesions with central
necrosis

Acute disseminated
candidosis,
disseminated
aspergillosis or
Fusarium infection

Sinus

Upper resp tract

Invasive
symptoms with necrotic Aspergillosis or
or ulcerated areas
mucormycosis

Palate

Ulceration, including
the hard palate

Thinocerebral
mucormycosis

Essential clinical examination in neutropenic and solid organ

transplant patients with suspected invasive fungal infection

Organ/system

Features

Likely infection

Chest

Signs are few and nonspecific; all should be

investigated

Invasive pulmonary
aspergillosis, PCP,or
other fungal pneumonia

Eyes

Funduscopy may
Acute disseminated
reveal cotton-wool ball candidosis
lesions of Candida
Choroidoretinitis-rare in
neutropenic patients

Central nervous
system

Headache, altered
mental state, seizure,
focal neurologic signs,
and neck stiffness

Cryptococcal or
candidal meningitis

Essential Investigations for the

Laboratory Diagnosis of Systemic
Fungal Infections
Direct microscopy
Antigen/antibody detection
Culture
PCR

Aspergilosis
Microscopy of sputum, BAL fluid (enhanced by

Calcofluor whitw) and stained biopsy material

Culture of respiratory secretions and biopsy material
EIA for galactomannan (Platelia Aspergillus, Bio-Rad,
FDA approval 2003) in high risk and intermediate
risk patients (variable results between laboratories)
2x/week
Detection of -1,3-D-glucan (glucatel, Associates of
Cape Cod Inc)
PCR screening 2x/week on whole blood in
high/intermediate risk hematology patients (if
available locally)

Candidosis
Microscopy of body fluids (enhanced by Calcofluor

whitw) and stained biopsy material

Culture of blood and other body fluids
Culture of respiratory secretions
Culture of biopsy material
Detection of precipitins by CIE
ELISA for Candida mannan (Bio-Rad) (variable
results between laboratories)
ELISA for Candida anti-mannan (limited value in
immunocompromised patients)
Detection of -1,3-D-glucan (Glucatel)
PCR on wholw blood (if available locally)

Cryptococcosis
Microscopy of CSF or other body fluids and

secretions
Culture of CSF, blood, sputum, urine and prostatic
fluid
Detection of antigen in CSF, urine and blood by
latex agglutination
(e.g Immuno-Mycologics Inc; Meridian
Diagnostics Inc; Bio-Rad) and ELISA (Meridian
Diagnostics Inc)

Histoplasmosis
Microscopy of stained smears of peripheral

blood, sputum, bronchial washings and pus

Culture of blood, sputum, bone marrow, pus
and tissue
Detection of antibody by immunodiffusion and
complement fixation
Detection of antigen by radioimmunoassay in
blood, urine, CSF and BAL

When to start antifungal therapy??

Colonization invasiveness Dissemination

Disease probability

No treatment

Treatment

Depends on
1. Feasibility and predictive values of
diagnostic tests
2. Efficacy of treatment
3. Cost
4. Potential adverse effects of treatment
5. Impacts of no treatment or delay in
treatment

Systemic Fungal Infection Therapy

Concept
1.

2.

3.

4.

Prophylaxis therapy
Antifungal therapy is given based on patients risk factors,
no signs of infection (predictive value > 75%)
Pre-emptive therapy (targeted prophylaxis): Antifungal
therapy is given based on patients risk factors, and
fungal colony is found (or neutropenia), no sign of
infection (predictive value > 75%)
Empiric therapy
Antifungal therapy is given based on patients risk factors,
sign of infection are present but the etiology is not clear
Definitive therapy
Infection signs are present, fungal infectiuon diagnosis is
proven by histopathology examination (fungemia),
specificity > 95%

Current recommended initial strategy;

towards a targeted, risk-based, antifungal
strategy
Risk group

Prophylaxis Empirical

Preemptive

Targeted

Yes

Yes

Low

Intermediate
low; not colonized,
HEPA filtered
high; colonized

Yes

?
Yes

Yes
Not relevant

Yes
Yes

High

Yes

Yes

Not relevant

Yes

Systemic Antifungal
Polyenes

Amphotericin B deoxycholate
Liposomal amphotericin B
Amphotericin B colloidal dispersion
(ABCD)
Amphotericin B lipid complex (ABLC)

Systemic Antifungals
Azole
Imidazole

Ketokonazole
Triazole
Flucinazole
Itraconazole
2nd generation Triazole
Voriconazole (fluconazole congener)
Ravuconazple (fluconazole congener)
Posaconazole (itraconazole congener)

 Candin

(1,3)--D-glucan synthase inhibitor

Pneumocandid caspofungin
Echinocandins
Micafungin
Andulafungin

General Pattern Susceptibility of Candida sp

Candida sp

Fluconazole Itrakonazole Voriconazole Flucytosin Amp B

C. Albicans
C. tropicalis
C.Parapsilosis
C.Glabrata
C.Krusei
C.Lusitaniae

S: sensitive

S
S
S
SDD-R
R
S

S
S
S
SDD-R
SDD-R
S

I: intermediate

R: resisten

S
S
S
S-I
S-I
S

S
S
S
S
I-R
S

S
S
S
S-I
S-I
S-R

SDD: sensitive dose dependent

Fluconazole
Spectrum activity to Candida sp and

Cryptococcus neoformans
Indication: mucocutaneous candidiasis,
Candidemia, Crytococcal meningitis (alternative
drugs/maintenance)
Good bioavaiability (90% oral absorbtion) not
affected by food
Elimination in kidney
High level in CSF (80%)
Potential interaction with phenytoin, glipizide,
glyburide, tolbutamide, warfarin, rifabutin or
cyclosporine
Side effect : increased ALT and AST

Voriconazole
Indication : invasive aspergillosis, other

fungal infection: fusariosis, esophangeal

candidiasis
Good oral bioavailability (96%)
Metabolism in liver
Elimination in kidney
Interaction: rifampicin, warfarin, lipid lowering
agent, benzodiazepin, anticonvulsant, CCB,
sulfonylurea
Side effect (rare): blur vision

Itraconazole
Indication: oral and esophangeal candidiasis,

invasive aspergillosis, histoplasmosis (mild case)

Poor absrobtion especially in capsule form
Bioavaibility 55% (increasing if consume with cola)
Interaction with Rifampin, INH, anticonvulsant,
cisapride, terfenadine, warfarin, benzodiazepin,
cholesterol lowering agent, dyhidropiridine CCB,
digoxin, cyclosporin, tacrolimus, methylprednisolone,
HIV protease inhibitors and vinca alkaloids
Side effect: GI disturbance, increased ALT and AST

Kasus
Seorang Pria 81 th dg riwayat DM, CVD lama

dan ggn fungsi hati

Pasien sudah dirawat selama 10 hr di ICU
karena pneumonia (CAP) dengan kegagalan
pernapasan dalam penggunaan ventilator

 Instrumentasi yang masih digunakan

- tracheostomi
- CVC
- NGT
- Kateter urin

 Hasil lab rutin yang sudah dilakukan:

Hb 9,3, leukosit 12.300, trombosit 401.000,

ureum 60, kreatinin 1,0, SGOT 41, SGPT 38,
albumin 3,3, Procalcitonin 2-10
Hasil pem kultur bakteriologi darah: negatif
sputum ETT : Enterobacter aerogenes

 Terapi diberikan:

Cefepime + moxifloxacin
Nutrisi parenteral parsial
Dilakukan tindakan bronkoskopi untuk
membersihkan brionkus: didapatkan
gambaran bronkus hiperemis
Dilakukan kultur bilasan bronkus
Pada foto thoraks ulang didapatkan kesan
perburukan
Keadaan klinis stabil demam masih belum
turun

Dari hasil kultur bilasan bronkus

tumbuh Klebsiella pneumonia dan
Candida albicans
Ampicillin
Sulbenicillin
Amoxiclav
Pip/tazo
Cefmetazol
Cefotiam
Cefuroxim
Ceftazidim
Cefotaxim
Cefizoxim
Cefo/Sulb

R
R
I(15)
I(19)
S(25)
R
R
R
R
R
I(20)

Cefepime
Amikacin
Dibekacin
Imipenem
Meropenem
Ciprofloxacin
Moxifloxacin
Levofloxacin
Cotrimoxazol
Fosfomycin

R
S (18)
R
S(25)
S(25)
R
R
R
R
S(21)

Pertanyaan 1
Candida albicans yang didapatkan
1.
2.
3.
4.
5.

pada pasien ini merupakan:

Kontaminasi
Kolonisasi
Infeksi jamur lokal
Infeksi jamur invasif
Infeksi jamur sistemik

Pertanyaan 2
Faktor resiko infeksi jamur sistemik
1.
2.
3.
4.
5.

pada pasien ini:

Usia lanjut
Kolonisasi Candida
Penggunaan ventilator
Terapi antibiotika broad spectrum
Hipoalbuminemia

Pertanyaan 3
Terapi antifungal yang akan diberikan:
1. Fluconazole 1x150 mg tab
2. Fluconazole 1x200 mg iv
3. Itraconazole 2x100 mg tab
4. Voriconazole 2x200 mg iv
5. Amfotericin B 0.7 mg/kgBB/hr

Pertanyaan 4
Terapi antifungal yang diberikan
1.
2.
3.
4.

merupakan terapi
Profilaksis
Pre-emptive
Empirik
Definitive

Pertanyaan 5
Lama pemberian antifungal:
1. 5 hari
2. 7 hari
3. 14 hari
4. 3 minggu
5. 6 bulan

DISKUSI

 Pasien mendapatterapi antibiotika

Imipenem 4 x 500 mg iv
Fluconazole 1 x 200 mg iv
selama 14 hari

 Pasien masih demam (temp 37-38oC)

Dilakukan pungsi dan analisis cairan

pleura : eksudat
sel B limposit 90%
BTA negatif
Diberikan terpi empirik OAT

 Hasil kultur darah dan uji CVC tumbuh:

Acinobacter baumanii
Candida lipolytica

Pertanyaan 6
Candida yang terdapat pada pasien
1.
2.
3.
4.

ini merupakan
Kontaminasi
Kolonisasi
Infeksi jamur invasif
Infeksi jamur sistemik

Pertanyaan 7
Terapi antifungal yang diberikan
1.
2.
3.
4.

merupakan terapi
Profilaksis
Pre-emptive
Empirik
Definit

Pertanyaan 8
Terapi antifungal yang akan diberikan:
1. Fluconazole 1x200 mg iv
2. Fluconazole 2x200 mg iv
3. Fluconazole 2x400 mg iv
4. Voriconazole 2x200 mg iv
5. Amfotericin B 0.7 mg/kgBB/hr

Pertanyaan 8
Tindakan yang perlu dilakukan pada
1.
2.
3.
4.
5.

pasien ini:
Ganti CVC
CT scan abdomen
Echocardiografi
Kultur darah ulang
Resistensi candida

Pertanyaan 9
Lama pemberian antifungal:
1. 7 hari
2. 14 hari
3. 1 bulan
4. Sampai kultur darah negatif

dilanjutkan 14 hari
5. 6 bulan