Fungal Infection - MEG
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Transcript of Fungal Infection - MEG
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