Diagnosis and Treatment of

Systemic Fungal Infection

Fungal infectionsYeast 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 InfectionsDeep 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. Neutropenia: neutrophil < 500/mm3 for > 10 days2. Persistent fever for > 96 hours refractory to appropiate broad

spectrum antibacterial treatment3. 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

4. Signs and symtoms indicating GVHD5. Prolonged use of corticosteroids (> 3 weeks)

Microbiological Criteria (1)

1. Positive culture of a mold (including Aspergillus sp, Fusarium sp, zygomycetes, Scedosporium sp) or C.neoformans from sputum, BAL

2. Positive culture or cytology/direct microscopy for mold from sinus aspirate

3. Positive cytology/direct microscopy for a mold or Cryptococcus from sputum, BAL

4. Positive Aspergillus antigen in BAL, CSF or ≥ 2 blood samples

5. Positive cryptococcal antigen in blood

Microbiological Criteria (2)

6. Positive cytology/direct microscopy for fungal elements other than Cryptoccocus in sterile body fluids

7. 2 positive urine cultuires of yeasts in the absence of urinary catheter

8. Candida casts in urine in the absence of urinary catheter

9. Positive blood culture of Candida sp10. 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

Minor1. Upper respiratory symptoms (nasal

discharge, stuffiness etc)2. Nose ulceration/eschar of nasal

mucosa/epitaxis3. Periorbital swelling4. Maxillary tenderness5. 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)

Minor

1. Focal neurologic symptoms and signs (including focal seizures, hemiparesis and cranial nerve palsies)

2. Mental changes

3. Meningeal irritation findings

4. Abnormalities in DSF biochemistry and cell count

Disseminated Fungal Infection

1. Papular or nodular skin lesions without any other explanation

2. Intraocular findings suggestive of hematogenous fungal chorioretinitis or endophthalmitis

Chronic Disseminated Candidiosis

Small, peripheral, target-like abscess (bull’s 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 109/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 symptoms with necrotic or ulcerated areas

Invasive

Aspergillosis or 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 non-specific; all should be investigated

Invasive pulmonary aspergillosis, PCP,or other fungal pneumonia

Eyes Funduscopy may reveal ‘cotton-wool ball’ lesions of Candida

Choroidoretinitis-rare in neutropenic patients

Acute disseminated candidosis

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 β-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 β-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 on1. Feasibility and predictive values of

diagnostic tests2. Efficacy of treatment3. Cost4. Potential adverse effects of treatment5. Impacts of no treatment or delay in

treatment

Systemic Fungal Infection Therapy Concept

1. Prophylaxis therapyAntifungal therapy is given based on patients risk factors, no signs of infection (predictive value > 75%)

2. 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%)

3. Empiric therapyAntifungal therapy is given based on patients risk factors, sign of infection are present but the etiology is not clear

4. Definitive therapyInfection 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

Low - ? Yes Yes

Intermediate

low; not colonized,

HEPA filtered - ? Yes Yes

high; colonized Yes Yes Not relevant 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

FlucinazoleItraconazole

2nd generation TriazoleVoriconazole (fluconazole congener)Ravuconazple (fluconazole congener)Posaconazole (itraconazole congener)

Candin

(1,3)-β-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 S S S S S

C. tropicalis S S S S S

C.Parapsilosis S S S S S

C.Glabrata SDD-R SDD-R S-I S S-I

C.Krusei R SDD-R S-I I-R S-I

C.Lusitaniae S S S S S-R

S: sensitive I: intermediate R: resisten 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 formBioavaibility 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: negatifsputum ETT : Enterobacter aerogenes

Terapi diberikan:Cefepime + moxifloxacinNutrisi 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 R Cefepime R

Sulbenicillin R Amikacin S (18)

Amoxiclav I(15) Dibekacin R

Pip/tazo I(19) ImipenemS(25)

Cefmetazol S(25) Meropenem S(25)

Cefotiam R Ciprofloxacin R

Cefuroxim R Moxifloxacin R

Ceftazidim R Levofloxacin R

Cefotaxim R Cotrimoxazol R

Cefizoxim R Fosfomycin S(21)

Cefo/Sulb I(20)

Pertanyaan 1

Candida albicans yang didapatkan pada pasien ini merupakan:

1. Kontaminasi

2. Kolonisasi

3. Infeksi jamur lokal

4. Infeksi jamur invasif

5. Infeksi jamur sistemik

Pertanyaan 2

Faktor resiko infeksi jamur sistemik pada pasien ini:

1. Usia lanjut

2. Kolonisasi Candida

3. Penggunaan ventilator

4. Terapi antibiotika broad spectrum

5. 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 merupakan terapi

1. Profilaksis

2. Pre-emptive

3. Empirik

4. 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 negatifDiberikan terpi empirik OAT

Hasil kultur darah dan uji CVC tumbuh:

Acinobacter baumanii

Candida lipolytica

Pertanyaan 6

Candida yang terdapat pada pasien ini merupakan

1. Kontaminasi

2. Kolonisasi

3. Infeksi jamur invasif

4. Infeksi jamur sistemik

Pertanyaan 7

Terapi antifungal yang diberikan merupakan terapi

1. Profilaksis

2. Pre-emptive

3. Empirik

4. 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 pasien ini:

1. Ganti CVC

2. CT scan abdomen

3. Echocardiografi

4. Kultur darah ulang

5. 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