1. Management of systemic fungal infections
Ajai Kumar Garg
Department of Medicine
School of Medical Sciences and Research
Sharda Hospital, Greater Noida
4/15/2019

2. Introduction
Fungi widely distributed in soil, plant debris, and organic substance
Humid climate favorable for growth of fungi
Opportunistic fungi- very low inherent virulence
Uncommon in immunocompetent patients
Usually affect immunocompromised host
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3. Human immunodeficiency virus infection
High prevalence of diabetes mellitus
Use of broad spectrum antibiotics / systemic steroids
Patients receiving immunosuppressive and myelotoxic drugs for autoimmune diseases, malignancies, organ transplantation
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4. Candida and Aspergillus most common systemic fungal infection
Severe disease in advanced HIV state
Cryptococcosis and histoplasmosis: frequently occurring invasive fungal infection in patients with AIDS
Mucormycosis common in diabetics
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5. Causative agents of Invasive Mycoses
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6. Risk factors Neutropenia: neutrophils <500/µl for more than 10 days
2. Prolonged use of corticosteroids
(>3 weeks)
3. Persistent fever (>96 hours) refractory to appropriate broad spectrum antibiotics
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7. Risk factors… Prolonged neutropenia in the previous 60 days
4. Body temperature either >38°C or <36°C with any of the following predisposing conditions:
Prolonged neutropenia in the previous 60 days
Recent or current use of immunosuppressive agents in previous 30 days
Previous episode of invasive fungal infection
Coexistence of AIDS
5. Signs and symptoms indicating GVHD
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8. Risk factors… Prolonged hospitalization (>30 days)
Stay in Intensive Care Unit
Central venous access
Total parenteral nutrition
Invasive mechanical ventilation
Major abdominal surgery, renal transplant
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9. Features suggesting invasive fungal infection
Any new fever during prolonged severe neutropenia or immunosuppression
Fever resistant to broad spectrum antibiotics in neutropenic patient
Symptoms and signs of progressive upper respiratory tract infection
Symptoms and signs of new, resistant or progressive lower respiratory infection
Prolonged severe lymphocytopenia in chronic GVHD and immunosuppression
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10. Features suggesting invasive fungal infection…
Periorbital or maxillary swelling and tenderness
Palatal necrosis or perforation
Features of focal neurological involvement or meningeal irritation with fever
Unexplained mental changes with fever
Papular or nodular skin lesions
Intra-ocular signs of systemic fungal infection
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11. Invasive Candidiasis Candida infection blood born
Usually endogenous from gut
Wide spectrum of clinical manifestation
Acute or chronic
Superficial or deep seated
May involve oral cavity, bronchi, lungs, GI tract, vagina
C. albicans, C. tropicalis, C. glabrata
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12. Diagnosis of Candidiasis
Microscopy of body fluids and biopsy material: hyphae or pseudohyphae can be seen in presence of inflammation
Culture of blood and other body fluids / respiratory secretions / biopsy material
Detection of β1,3 D-glucan : negative predictive value of ~90%, help exclude disseminated disease
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13. Candida species are commensal, their culture from sputum, the mouth, the vagina, urine, stool, or skin does not necessarily indicate an invasive, progressive infection.
Positive cultures of specimens taken from normally sterile sites, such as blood, CSF, pericardium, pericardial fluid, or biopsied tissue, provide definitive evidence that systemic therapy is needed.
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14. Candidiasis
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15. Invasive Aspergillosis
Exogenous infection
Aspergillus fumigatus inhaled as aerosol
Primarily affects lungs and sinuses
Pulmonary aspergillosis can cause:
Progressive destructive cavitary disease
Pulmonary aspergilloma (occasionally complicated by life threatening infection)
ABPA occurs almost exclusively in patients with asthma, cystic fibrosis
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16. Diagnosis of Aspergillosis
Microscopy of sputum, BAL fluid, and stained biopsy material
Culture of respiratory secretions and biopsy material
Aspergillus antigen (galactomannan) in ‘high risk’ patients (positive results precedes clinical disease)
Molecular testing (PCR) on whole blood
Halo signs on HRCT chest: ground glass haziness surrounding a nodule
Fungal ball in the cavity on CT chest
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17. Invasive pulmonary aspergillosis
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18. 4/15/2019

19. Invasive pulmonary aspergillosis
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20. Cryptococcosis Systemic fungal infection with predilection for CNS
C. neoformans ; C. gattii
Isolated from droppings of pigeon and birds, rotting vegetables, fruits, diary products, wood, and soil
Acquired usually in childhood by inhalation of aerosolized infectious particles
Should be included in differential diagnosis in any patient with chronic meningitis
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21. Diagnosis of Cryptococcosis
Demonstration of Cryptococcus by microscopy of CSF or other body fluids / secretions (India Ink preparation)
Detection of Cryptococcal antigen in CSF and blood by latex agglutination
Culture of CSF, blood, sputum, urine, and prostatic fluid
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22. Mucormycosis Most acute and fulminant fungal infection
Frequently fatal
Caused by fungi belonging to class Zygomycetes
Spores acquired via inhalation, percutaneous route, ingestion
India contributes about 40% cases
Associated with DM, immunocompromised state
Typically involves rhino-facio-cranial area and lungs
Invades vessels/arteries  embolization and necrosis of surrounding tissue
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23. Diagnosis of mucormycosis
Microscopy of material from necrotic lesions, sputum, and BAL fluid
Culture of nasal and palatal scrapings, biopsy material, and sputum
PCR on whole blood (if available locally)
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24. Mucormycosis
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25. Mucormycosis
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26. Histoplasmosis Intracellular infection of reticuloendothelial system
Acquired by inhalation
95% cases are subclinical or benign
5% develop chronic progressive lung disease
All stages mimic tuberculosis
CXR: pneumonia, hilar lymphadenopathy
Fungal culture diagnostic gold standard (BAL,BMA, blood)
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27. Blastomycosis Endemic systemic pyogranulomatous mycosis
Acquired by inhalation of conidia of Blastomyces
Sporadically reported from India
Primarily involves lung
Infections may remain asymptomatic or may cause acute or chronic pneumonia
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28. Amphotericin B First systemic antifungal agent
Fungicidal with broad spectrum activity
Active against
Aspergillus species
Candida species
Cryptococcus neoformans
Mucormycosis
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29. Amphotericin B Only IV form available
Infusion related reactions; if given rapidly (fever, chills, nausea, hypotension, hypoxia)
Nephrotoxicity
Lipid complex preparations: to avoid nephrotoxicity and infusion related side effects
Dosage
0.5–1.0 mg/kg/day IV for 10–14 days
Up to 1.5 mg/kg/day for disseminated infections
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30. Precautions: Amphotericin B
Do not dilute with saline or mix with other drugs
Monitor renal function and serum potassium closely
Potassium supplements to compensate urinary losses
Maintain high fluid and sodium intake
Dosage reduced if renal function deteriorates (serum creatinine level rise by more than 50%)
Infusion of mannitol may be useful
Monitor blood count at weekly intervals
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31. Azoles Fungistatic drugs Inhibit ergosterol synthesis in cell wall
Available in both oral and IV forms
Hepatotoxicity main side effect
No renal toxicity
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32. Fluconazole: spectrum of activity
Candida species (reduced activity against C. glabrata, no activity against C. krusei)
Cryptococcus neoformans
Ineffective against Aspergillus and Zygomycetes
Complete absorption after oral administration
Absorption not affected by food
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33. Uses of fluconazole Oropharyngeal candidiasis Cryptococcal meningitis
Deep forms of candidiasis in non-neutropenic patients
With amphotericin B in treatment of cryptococcosis and deep forms of candidiasis (urinary tract and peritoneum)
Prophylaxis against candidiasis
Maintenance treatment to prevent relapse of cryptococcal meningitis in patients with AIDS
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34. Itraconazole: spectrum of activity
Aspergillus species
Candida species
Cryptococcus neoformans
Histoplasma capsulatum
Blastomyces dermatitidis
Ineffective against Zygomycetes
Available in both Oral and IV forms
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35. Uses of Itraconazole Mucocutaneous candidiasis
Alternative to amphotericin B for invasive aspergillosis
Various superficial infections including dermatophytoses, pityriasis versicolor
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36. Voriconazole: spectrum of activity
Candida species
Aspergillus species
Cryptococcus neoformans
Ineffective against Zygomycetes
Poor penetration into CSF
Available in Oral and IV forms
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37. Voriconazole…
Oral forms: dose adjustment not needed in renal insufficiency
IV formulations: not given in moderated to severe renal insufficiency
Dose adjustment needed in liver failure
Visual disturbances, hepatitis, photosensitivity rash, hallucinations
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38. Uses of Voriconazole Fluconazole and itraconazole resistant Candida
Itraconazole and amphotericin B resistant Aspergillus
Not useful for Mucormycosis and Cryptococcal meningitis
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39. Posaconazole New drug with broad spectrum of activity Candida species
Aspergillus
Zygomycetes
Not effective against cryptococcosis
Available in oral forms only
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40. Uses of Posaconazole
Fluconazole / itraconazole resistant oropharyngeal candidiasis
Salvage therapy in immunocompromised patients with refractory aspergillosis
May be used for mucormycosis (400mg q12h)
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41. Echinocandins New safe, parenteral antifungal drugs
Fungicidal for all species of Candida
Inhibit the enzyme β1,3 D-glucan synthase necessary for fungal cell wall synthesis
Mainly used for invasive Candidiasis
Salvage therapy for Aspergillosis
No hepatic or renal toxicity
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42. Caspofungin Potent fungicidal activity against:
• Candida albicans/ C. tropicalis/ C. glabrata
Variable activity against:
• Aspergillus
No activity against:
Cryptococcus neoformans / zygomycetes
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43. Uses of Caspofungin
Invasive forms of Candidiasis; Comparable activity with amphotericin B
Candidaemia
Invasive aspergillosis; in patients who have failed to respond or who are intolerant to other antifungal agents
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44. Micafungin approved for Treatment of oesophageal candidiasis
Prophylaxis in patients receiving stem cell transplant
Anidulafungin approved for
Candidaemia in non-neutropenic patients
Candida oesophagitis, peritonitis, intra-abdominal infections
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45. Flucytosine Fungicidal effect on Candida and Cryptococcus
Act by interfering DNA synthesis
Given orally, good penetration into CSF
Not used as a single agent because of development of resistance
Recommended with amphotericin B for Cryptococcal meningitis and Candida meningitis
Bone marrow depression
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46. Oesophageal candidiasis
Fluconazole 200 mg/day orally;14-21 days
Fluconazole-refractory disease
Itraconazole (oral solution) ≥ 200 mg/day
Amphotericin B: 0.3–0.7 mg/kg/day IV
Caspofungin: 70 mg on first day50 mg/day IV, 7-21 days
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47. Candidaemia Non-neutropenic patients: Catheter removal
Fluconazole 800 mg loading dose, followed by 400 mg/day, 2 weeks
Amphotericin B mg/kg/day, 2 weeks
Persistent neutropenia: Catheter removal
Amphotericin B: 1 mg/kg/day
Liposomal amphotericin B: 1-3 mg/kg/day
Caspofungin: 70mg first day, then 50 mg/day (infuse over 1 h)
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48. Removal of ventricular prosthetic devices
Candida meningitis: Amphotericin B mg/kg/day plus flucytosine 25 mg/kg qid
Removal of ventricular prosthetic devices
Candida endocarditis: Valve resection
Amphotericin B: 0.7 mg/kg/day plus flucytosine 25 mg/kg qid
Candida endophthalmitis: Amphotericin B plus flucytosine, followed by fluconazole 400–800 mg, 6-12 weeks
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49. Acute invasive aspergillosis
Voriconazole: IV 6 mg/kg, q12hx2 doses then 4 mg/kg q12h, followed by 200 mg PO q12 h (when tolerated orally)
Amphotericin B: 1.0–1.5 mg/kg/day or Liposomal amphotericin B: 3–5 mg/kg/day
Itraconazole:
PO 400–600 mg/day x 4 days then 200 mg q12h OR
IV 200 mg q12h 4 doses then 200 mg/day for weeks (infuse over 1 h)
Poor response, if neutrophil count does not recover
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50. Acute invasive aspergillosis…
Caspofungin:
Used in patients who have failed to tolerate other antifungal drugs
Dose: 70 mg IV first day50 mg/day subsequent days (infuse over 1 h)
Variable duration of treatment
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51. Cryptococcosis Meningitis in normal hosts
Amphotericin B: 0.7–1.0 mg/kg/day, plus flucytosine 37.5 mg/kg q6h for 6-10 weeks
Amphotericin B: 0.7–1.0 mg/kg/day, plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg per day for 10 weeks, then 200 mg/day for 6–12 months as maintenance therapy
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52. Cryptococcosis Meningitis in AIDS
Amphotericin B 0.7–1.0 mg/kg/day plus flucytosine 100 mg/kg/day for 2 weeks, followed by fluconazole 400 mg/day for 10 weeks, then 200 mg/day lifelong
If CD4 count increases above 100–200/cmm following HAART, maintenance treatment can be discontinued
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53. Rhinocerebral mucormycosis
Control of diabetic acidosis
Aggressive surgical debridement of all necrotic tissue
Amphotericin B: 1.0–1.5 mg/kg/day
Liposomal amphotericin B: 5-10 mg/kg/d
Should be continued till resolution of clinical and radiological signs and recovery from underlying immunosuppression
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54. Therapeutic choice for fungal infections
Indication
Primary therapy
Secondary therapy
Disseminated candidiasis
Fluconazole
Caspofungin, Amphotericin B
Invasive aspergillosis
Voriconazole
Itraconazole, Amphotericin B,
Posaconazole,
Caspofungin
Cryptococcal meningitis
Liposomal amphotericin B plus flucytosine
Mucormycosis
Amphotericin B
Posaconazole
Persistent neutropenic fever not responding to antibiotics
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55. Summary
Systemic fungal infections are common in immunocompromised patients with persistent neutropenia, DM, HIV infection, and immunosuppressive therapy.
Candida, Aspergillus, Cryptococcus, and Zygomycetes are common systemic fungal infections.
Diagnosis is difficult due to lack of optimum laboratory facilities.
Clinician should have a high index of suspicion for fungal infection in immunocompromised patient with febrile illness not responding to broad spectrum antibiotics.
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56. Thank you
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57. Acute GVHD Erythematous maculopapular rash
Persistent anorexia or diarrhoea
Deranged LFT
Diagnosis by skin or liver biopsy
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58. Chronic GVHD Malar rash Sicca syndrome Arthritis
Obliterative bronchiolitis
Bile duct degeneration
Cholestasis
Develops in 20-50% patients surviving for more than three months
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