Invasive Fungal Disease



Russell E. Lewis
Associate Professor of Infectious Diseases
Department of Molecular Medicine
University of Padua


russelledward.lewis@unipd.it
https://github.com/Russlewisbo
Slides and course materials: www.padovaid.com

Learning Objectives


  1. Describe the epidemiology and risk factors for invasive candidiasis, cryptococcosis, aspergillosis, and mucormycosis
  2. Identify key clinical presentations and diagnostic approaches for each major invasive fungal infection
  3. Select appropriate antifungal therapy based on patient factors, fungal species, and infection site
  4. Recognize antifungal drug toxicities and their management
  5. Apply evidence-based treatment guidelines to clinical scenarios

Part 1: Background & Antifungals

The Hidden Killers


Types of fungal disease


  • Allergies

    • e.g., hypersensitivity to mold spores

  • Mycotoxicosis

    • Ingestion of fungal toxins in contaminated food or mushrooms

Mycotoxicosis

Mycoses-Invasive of living tissue by fungus



Type Location Examples
Superficial Epidermis, nails Dermatophytosis
Subcutaneous Dermis, tissue Sporotrichosis
Systemic (primary) Deep organs Histoplasmosis
Systemic (opportunistic) Deep organs Candidiasis, aspergillosis

Superfical mycoses


Subcutaneous mycoses


Systemic mycoses



Yeast vs. molds

Primary (endemic) vs. 
opportunistic invasive mycoses


Primary infections

  • Can develop even without underlying immunocompromise; more severe in setting of T-cell mediated immunosuppression (e.g., AIDS)

  • “Endemic fungal pathogens”- Histoplasmosis, Blastomycosis, Coccidioidomycosis

    • Molds in the environment- yeast at 37°C

  • Endemic areas changing with global warming?

Opportunistic fungal pathogens

  • Infection in the setting of impaired host immune responses or when inoculated into sterile sites

  • Can disseminate to internal organs and the central nervous system

  • Associated with high mortality if not diagnosed and treated early

Most fungi are not adapted to 37°C

Will this change with global warming:
Loss of thermal barrier immunity?

Ophiocordyceps unilaterali: “Zombie-ant fungus”

WHO fungal priority pathogens list (2022)



CRITICAL

  • Cryptococcus neoformans
  • Candidozyma auris
    (Candida auris)
  • Aspergillus fumigatus
  • Candida albicans

HIGH

  • Candida glabrata
  • Histoplasma spp.
  • Mucorales
  • Fusarium spp.
  • Candida tropicalis

MEDIUM

  • Scedosporium spp.
  • Coccidioides spp.
  • Cryptococcus gattii
  • Pneumocystis jirovecii

Evolution of antifungal therapy




AmB

First truly effective antifungal therapy

Flucytosine

Combination therapy-yeast infections

Ketoconazole

First oral systemic azole

Fluconazole

Revolutionized treatment
of Candida and
Cryptococcus

Lipid AMB formulations

ABLC, Liposomal AMB, and ABCD

Reduced nephrotoxicity

Caspofungin

First in class echnicandin-improved Candida treatment

Voriconazole

First line for invasive aspergillosis

Micafungin

Expanded echnicanocandin indications vs. caspofungin

Anidualfungin

Echinocandin without hepatic metabolism

Posaconazole

Extended spectrum, key prophylaxis agent

Isavuconazole

Broad spectrum, better tolerated than voriconazole

Ibrexafungerp

First oral glucan synthesis inhibitor (triterpenoid)

Oteseconazole

Novel tetrazole, mainly VVC, long half life

Rezafungin

Long-acting echinocandin (once weekly dosing)

Olorofim?, Fosmanogepix?

Novel mechanisms of action, useful for rare pathogens
not Mucorales

Antifungal targets


Antifungal targets



Cell Membrane

  • Polyenes: Bind ergosterol → extract ergosterol →damage cell membrane → cell death
  • Azoles: Inhibit CYP51 (lanosterol 14-α-demethylase) → depleted ergosterol

Cell Wall

  • Echinocandins: Inhibit β-1,3-glucan synthase → cell wall instability

Important

Fungi share eukaryotic machinery with humans - selective toxicity is challenging!

Antifungal spectrum of activity



Agent Candida Aspergillus Cryptococcus Mucorales
Fluconazole ++ - ++ -
Voriconazole +++ +++ + -
Posaconazole +++ +++ + ++
Isavuconazole +++ +++ + ++
Echinocandins +++ ++ - -
Amphotericin B +++ ++ +++ +++

Tissue Distribution Matters!



Drug CSF Eye Urine Lung
Fluconazole +++ +++ +++ ++
Voriconazole ++ ++ + +++
Posaconazole + + - +++
Echinocandins - - - +
Amphotericin B +/- +/- + ++

Warning

Echinocandins should NOT be used for CNS, ocular, or urinary tract infections!

Part 2: Invasive Candidiasis

A brave surgical resident!

A brave surgical resident!

Resident case cont.

We repeat this experiment daily in ICUs

Invasive candidiasis: An overview



  • Most common invasive fungal infection in hospitalized patients
  • Annual incidence: 2-14 per 100,000 persons
  • Attributable mortality: 15-25%
  • Hospital costs: $40,000-$70,000 per episode

Changing epidemiology of Candida species



Species % of Cases Trend
C. albicans 40-60% ↓
C. glabrata 15-25% ↑
C. parapsilosis 10-20% →
C. tropicalis 5-10% →
C. krusei 2-5% →
C. auris Variable ↑↑

Note

Azole exposure drives shift toward non-albicans species- but epidemiology varies by geographical local and patient population

Risk factors for invasive candidiasis



Host Factors

  • Neutropenia
  • Diabetes mellitus
  • Recent surgery (abdominal)
  • Burns
  • Prematurity

Healthcare Exposures

  • Central venous catheters
  • Total parenteral nutrition
  • Broad-spectrum antibiotics
  • ICU stay >3 days
  • Hemodialysis

Continuum of invasive candidiasis

Pathogenesis of Invasive Candidiasis

  • Candida are commensals of GI tract, skin, mucosa- Invasion requires breakdown of defenses
  • Biofilm formation on devices complicates treatment

Clinical presentations



Candidemia

  • Fever unresponsive to antibiotics
  • Often NO localizing signs
  • May develop metastatic complications

Deep-seated

  • Hepatosplenic
    (chronic disseminated)
  • Peritonitis
  • Endocarditis
  • Osteomyelitis

Endophthalmitis

  • Vision changes
  • Eye pain
  • Occurs in 10-15% of candidemia
  • All patients need dilated eye exam

Candida endophthalmitis



  • Chorioretinitis, endophthalmitis- sight threatening if not recognized early

  • Echinocandins do not penetrate vitreous humor- may require intravitreal therapy

  • Suggests disseminated disease or prolonged fungemia- check for

    • Endocarditis (uncommon but also consider in patients with prosthetic valves, injection drug users, patients with persistently positive cultures)

Hepatosplenic candidiasis

Increasing alkaline phosphatase, fever as neutrophils recover

What cultures miss in invasive candidiasis

  • Sensitivity of blood cultures: 21-71%
  • Time to positivity: 2-5 days
  • Some patients may die before cultures turn positive
  • Tissue infections may be blood culture-negative

Histopathology

PAS stain

GMS stain

Non-culture diagnostics



Test Sensitivity Specificity Turnaround
β-D-glucan 75-80% 80% Same day
T2Candida 91% 99% 3-5 hours
Candida PCR 85-95% 90-95% Variable- Test not well standardized or widely used

Tip

  • Combining blood cultures + BDG increases sensitivity to >90%

  • Problems with β-D-glucan- Many sources of false positives-i.e. bandages, dialysis filter membranes, antibiotics…etc.

  • Many centers only use β-D-glucan to “rule out” invasive candidiasis (higher NPV)

Treatment algorithm for candidemia

candidemia A Candidemia B Hemodynamic Status A->B C Echinocandin B->C Unstable D Prior Azole Exposure? B->D Stable F Species ID + Susceptibility C->F D->C Yes E Echinocandin or fluconazole D->E No E->F G De-escalation if appropriate F->G

Note

Meta-analysis and several clinical trials suggest a survival benefit of starting with echinocandins versus triazoles, but the clinical importance of “fungicidal” vs. “fungistatic” activity for invasive candidiasis is debated.

Source control is critical



Central venous catheter removal

  • Associated with improved outcomes
  • Reduces mortality by 40-50%
  • Should be performed whenever feasible
  • Controversial only if:
    • No alternative access
    • CVC tunneled/implanted
    • CVC not clearly the source


Delay in catheter removal = increased mortality

Duration of therapy



  • Uncomplicated candidemia:
    • 14 days after first negative blood culture
    • AND resolution of signs/symptoms
  • Metastatic complications:
    • Extended duration based on site
    • Endocarditis: 6+ weeks after valve surgery
    • Osteomyelitis: 6-12 months

Antifungal susceptibility testing



Species Fluconazole Echinocandins Clinical Note
C. albicans S ≤2 S ≤0.25 Usually susceptible
C. glabrata SDD ≤32 S ≤0.12 Check both!
C. krusei Intrinsic R S Never use fluconazole
C. parapsilosis S ≤2 Higher MICs Fluconazole often preferred, but resistance increasing in some centers
C. auris Often R Variable Test everything


Species identification usually drives empiric therapy

Candida auris: Emerging threat



  • First identified in Japan, 2009
  • Multidrug resistance common
  • Persists in environment
  • Causes healthcare outbreaks
  • Difficult to identify (often misidentified as other species)
  • Associated with high mortality


Important

If C. auris suspected → Contact infection control immediately

Part 3: Cryptococcosis

Cryptococcosis: Global Impact



  • ~220,000 cases annually
  • ~180,000 deaths per year
  • Leading cause of meningitis in adults with HIV in Africa
  • 15% of AIDS-related deaths

Sub-Saharan Africa bears the greatest burden

Epidemiology



  • Usually associated with immunocompromised conditions

  • > 90% of cases associated with advanced HIV (CD4 <100 cells/μL, transplantation, long-term corticosteroids, cirrhosis)

  • In western countries, HIV-associated cases compromise a minority of cases; HIV the dominant cause in resource-poor settings

    • Sub-Saharan Africa
    • South and Southeast Asia
    • Mortality rates can exceed 50% in low-resource settings
    • Co-infections are common in resource-limited settings (25% tuberculosis)
    • Incidence has dropped with widespread availability of ART in Western countries

Cryptococcus species



Species Primary Host Geography Environment
C. neoformans Immunocompromised Worldwide Soil, bird droppings
C. gattii Immunocompetent + compromised Pacific NW, Australia, Tropics Eucalyptus trees

Note

C. gattii can cause disease in immunocompetent hosts! Some differences in clinical presentation — e.g., greater propensity to cause mass-lesions in brain.

Pathogenesis

Immune response to cryptococcosis

Pathogenesis



Virulence Factors:

  1. Polysaccharide capsule - Antiphagocytic, immunomodulatory
  2. Melanin production - Antioxidant protection
  3. Intracellular survival - Trojan horse to CNS
  4. Titan cells - Resist phagocytosis

India ink preparation showing encapsulated yeast

Clinical manifestations



Meningitis

  • Subacute onset (1-2 weeks)
  • Headache (most common)
  • Fever, altered mental status
  • Neck stiffness (less than bacterial)
  • Cranial nerve palsies
  • Elevated ICP is major killer -
    Always ask about vision - papilledema and visual loss indicate elevated ICP

Pulmonary

  • May be asymptomatic
  • Cough, dyspnea, chest pain
  • Nodules or infiltrates
  • Can be incidental finding

Disseminated

  • Skin lesions (umbilicated papules)
  • Bone involvement
  • Prostate (sanctuary site)

Cryptococcal skin lesions

Elevated intracranial pressure



Critical Complication

Opening pressure >25 cm H₂O is associated with poor outcomes

Mechanism:

  • Capsular polysaccharide clogs arachnoid villi
  • Impaired CSF reabsorption
  • NOT usually communicating hydrocephalus

Management:

  • Daily LPs if OP >25 cm H₂O
  • Remove sufficient CSF to reduce by 50% or to <20 cm H₂O
  • Avoid corticosteroids (worse outcomes-COAT trial)
  • Mannitol, acetazolamide NOT effective

ICP management


  • ICP management is arguably more important than antifungal choice in the first few days

  • Patients die from herniation, not the organism itself.

  • Aggressive daily lumbar punctures are the cornerstone. This is uncomfortable but life-saving.

  • Lumbar drains or VP shunts may be needed for refractory cases.

  • Corticosteroids worsen outcomes - this was shown in the COAT trial.

Diagnosis of cryptococcosis



Test Sensitivity Specificity Notes
CSF CrAg (LFA) 99% 99% Point-of-care, rapid
Serum CrAg 99% 99% Precedes symptoms
India ink 75-85% >95% Less sensitive
Culture 95% 100% Takes 3-7 days



Tip

Screen all HIV+ patients with CD4 <100 for serum CrAg

Point of care testing CrAg-A game changer



CSF findings in cryptococcal meningitis



Parameter Typical Finding
Opening pressure Elevated (often >25 cm H₂O)
WBC Elevated (lymphocyte predominant)
Glucose Low
Protein Elevated
CrAg Positive

Treatment phases



Induction (2 weeks) Consolidation (8 weeks) Maintenance
Preferred L-AMB 10 mg/kg × 1 dose
+ Flucytosine × 14 days
+ Fluconazole 1200 mg/day × 14 days		 Fluconazole 800 mg/day Fluconazole 200 mg/day
Alternative AmB deoxycholate 1 mg/kg/day × 7 days
+ Flucytosine × 7 days		 — —
Duration/stop — — CD4 >100 for ≥3 months on ART

The AMBITION trial



  • Induction therapy: L-AMB 10 mg/kg x 1 dose plus

    • Flucytosine 100 mg/kg/day × 14 days

    • Fluconazole 1200 mg/day × 14 days

  • Results:

    • 10-week mortality: 24.8% vs 28.7%

    • Fewer adverse events

  • Simplified treatment

Cryptococcal meningoencephalitis:
Prognostic factors


Poor outcomes associated with:

  • High CSF fungal burden
  • Altered mental status at presentation
  • Elevated opening pressure (> 25 cm H2O)
  • Low CSF white cell count
  • Underlying malignancy
  • Inadequate ICP management
  • Delayed ART initiation (but too early ALSO problematic)

Part 4: Invasive aspergillosis

Spectrum of Aspergillus disease

Aspergillus species



Species Frequency Clinical Significance
A. fumigatus 70-80% Most common; azole resistance emerging
A. flavus 10-15% Sinusitis; aflatoxin producer
A. niger 5-10% Otomycosis; aspergillomas
A. terreus 2-5% Amphotericin B resistant
A. nidulans Rare CGD-associated

Mode of acquisition

Mode of acquisition



Aspergillus Morphology:

  • Conidia (2-3 μm) ubiquitous in air
  • Inhaled daily by everyone
  • Conidiophores produce chains of spores

Host Defenses:

  1. Mucociliary clearance
  2. Alveolar macrophages kill conidia
  3. Neutrophils kill germinating hyphae

Note

Immunocompetent hosts clear thousands of conidia daily without disease

Risk factors for invasive aspergillosis



Classic High-Risk:

  • Prolonged neutropenia (≥3 weeks)
  • Allogeneic Hematopoetic stem cell transplantation
  • Acute leukemia
  • Chronic granulomatous disease

Emerging Risk Groups:

  • High-dose corticosteroids
  • Ibrutinib, BTK inhibitors (used for chronic lymphocytic leukemia)
  • Solid organ transplant
  • ICU patients (post-influenzae, COVID-10)
  • COPD with steroids

Bronchial-Alveolar Phase


Pathology:

  • Conidia germinate in airways
  • Hyphae invade bronchial walls
  • Associated inflammation

Diagnostics:

  • CT: Centrilobular nodules, tree-in-bud
  • Serum GM: Often negative
  • BAL GM/culture: May be positive

Angioinvasive Phase: Progression

Day Pathology CT Finding
0-3 Airway invasion Bronchial thickening,
tree-in-bud
3-7 Hyphal invasion Macronodule ± halo
5-7 Hemorrhage, infarction Dense consolidation
10-12 Extensive necrosis Hypodense sign
15-18 Neutrophil recovery Air-crescent sign

CT findings: Halo sign

Clinical pearl

The halo sign (ground-glass surrounding a dense nodule) is relatively specific for angioinvasive mold infection in the first week in neutropenic patients

Spectrum of infections with dissemination

Disease patterns depend on immune status



Nodule with Halo Sign

  • Angioinvasive 45%
  • Airway invasive 14%
  • Both 9%
  • Neither 32%

Centrilobular Nodules

  • Angioinvasive 13%
  • Airway invasive 44%
  • Both 13%
  • Neither 30%

Galactomannan testing



Sample Cutoff Sensitivity Specificity
Serum ≥0.5 ODI 70-80% 85-90%
BAL ≥1.0 ODI 85-90% 90-95%

Warning

False Positives:

  • Piperacillin-tazobactam (older literature)
  • Mucositis
  • Some foods
  • Cross-reactivity (Fusarium, Histoplasma)

False negatives:

  • Non-neutropenic patients
  • Airway invasive disease
  • Antifungal prophylaxis
  • Pediatric patients

Asperguillus histopathology

GMS in tissue staining

Calcoflour in BAL washing

Diagnosis summary


Culture and histopathology:

  • BAL culture: Sensitivity 50-60%
  • Tissue biopsy: Septate hyphae, acute-angle (45°) branching
  • PAS and GMS stains highlight fungal elements

Biomarkers:

  • Galactomannan (serum and BAL)
  • β-D-glucan (pan-fungal)
  • Aspergillus PCR (emerging evidence-not avaiable everywhere)

Treatment: First-line options



If NO Prior mold-active prophylaxis

Voriconazole

  • Loading: 6 mg/kg IV q12h × 2 doses
  • Maintenance: 4 mg/kg IV q12h or 200-300 mg PO q12h
  • TDM target: 1-5 μg/mL

Alternatives:

  • Isavuconazole: 200 mg q8h × 6, then 200 mg daily
  • Posaconazole: 300 mg q12h × 2, then 300 mg daily

Treatment: Breakthrough aspergillosis



If receiving posaconazole prophylaxis

Switch to a different class initially:

  • Liposomal amphotericin B (3-5 mg/kg/day)
  • Reassess reasons for triazole failure
  • Consider triazole resistance testing
  • May switch to alternative triazole if isolate susceptible and patient stabilizes

Triazole resistance: Emerging threat

  • TR34/L98H, TR46/Y121F/T289A mutations
  • Environmental origin (agricultural fungicides)
  • Prevalence varies geographically
  • Associated with treatment failure
  • Consider resistance testing in high-risk areas

Important

Azole-resistant Aspergillus is a growing concern. The main mechanisms are cyp51A mutations that also confer resistance to agricultural triazole fungicides. This environmental selection pressure is driving resistance. Netherlands and UK have highest rates in Europe. Testing is not routine but should be considered in refractory cases.

Treatment duration and prognosis

Duration:

  • Minimum 6-12 weeks
  • Continue until resolution of lesions
  • Continue until reversal of immunosuppression
  • Consider secondary prophylaxis

Prognosis Depends On:

  • Early diagnosis and treatment
  • Neutrophil recovery
  • Underlying disease control
  • Site of infection
  • Triazole resistance

Part 5: Fusariosis

Breakthrough Fusarium infection during neutropenia

Fusarium meta-static skin, ocular and CNS lesions

Healthcare-associated outbreaks of Fusarium infection

  • A multinational outbreak (185 exposed, 9 cases) of nosocomial fusarium meningitis occurred among immunocompetent patients who had undergone cosmetic surgery with epidural anesthesia in Mexico 

  • The pathogen involved had a high predilection for the brain stem and vertebrobasilar arterial system and was associated with high mortality from vessel injury

General summary: Fusarium infections

  • Most common scenario: Persistent neutropenia 

  • Most common species:

    •  F. solani complex (50%), F. oxysporum* (14%), F. verticillioides (10-11%) 

  • Macroconidia are classic (banana-shaped)

  •  PCR, rRNA in situ hybridization available, still investigational 

  • Positive blood cultures in 30-50% of cases

  • Can be recovered from urine in disseminated infection

  • Drugs of choice: L-AMB +/- voriconazole

Part 6: Mucormycosis

Mucorales: The Scariest Fungi?

Twitter poll of ID specialists:

  • Mucor spp./Mucormycosis: 44%
  • Staph aureus: 24%
  • Candida auris: 18%
  • SARS-CoV-2: 14%

Important

Why so scary?

  • Rapid progression
  • High mortality (40-80%)
  • Requires disfiguring surgery
  • Limited drug options

Ecology of Mucorales

Environmental Sources:

  • Soil
  • Decaying organic matter
  • Bread, fruit
  • Hospital construction/renovation

Morphology:

  • Sporangia contain spores
  • Large, ribbon-like hyphae
  • Pauciseptate (few septa)
  • Right-angle branching

Risk Factors for Mucormycosis

Metabolic:

  • Diabetic ketoacidosis
  • Uncontrolled diabetes
  • Acidosis
  • Iron overload
  • Deferoxamine use

Immunologic:

  • Neutropenia
  • Hematologic malignancy
  • HSCT
  • Solid organ transplant
  • High-dose corticosteroids

Others: Trauma, burns, combat injuries, COVID-19

Common Mucorales Species

Genus Features
Rhizopus Most common (especially R. arrhizus)
Mucor Less common but significant
Lichtheimia Common in immunocompromised
Rhizomucor More aggressive
Cunninghamella Disseminated disease; worst prognosis

Pathogenesis

Important

Deferoxamine acts as a fungal siderophore - increases risk!

Deferasirox does NOT increase risk - use this for iron chelation

Clinical Manifestations: Rhino-orbital-cerebral

Progression:

  1. Sinusitis, facial pain
  2. Nasal congestion, discharge
  3. Periorbital edema
  4. Black eschar (necrotic tissue)
  5. Visual loss, ophthalmoplegia
  6. Cavernous sinus thrombosis
  7. CNS extension → death

Rapid progression with nasal bridge necrosis

MRI: “Black Turbinate Sign”

Imaging Pearl

Loss of enhancement of the turbinates on contrast MRI indicates devitalized tissue - highly suggestive of mucormycosis in the right clinical context

Pulmonary Mucormycosis

CT Features:

  • Multiple nodular infiltrates
  • Large pleural effusions
  • Reverse halo sign (specific)
  • Rapid progression

Reverse halo: ground-glass center with surrounding consolidation

Diagnosis of Mucormycosis

Critical Point

β-D-glucan and galactomannan do NOT detect Mucorales!

Diagnostic Approach:

  • Histopathology: Wide, ribbon-like, pauciseptate hyphae
  • Culture: Rapid growth (“lid lifter”)
  • PCR/sequencing: Available in specialized centers
  • MALDI-TOF: For isolate identification

Treatment Principles


  1. Surgical debridement - Essential, often repeated
  2. Reversal of predisposing conditions - Glucose control, reduce immunosuppression
  3. Antifungal therapy - Start immediately, don’t wait for diagnosis
  4. Source control - Remove infected devices, dead tissue

Antifungal therapy


Initial:

  • Liposomal amphotericin B 5-10 mg/kg/day
  • Higher doses for CNS involvement
  • May need prolonged IV therapy

Step-down:

  • Posaconazole or isavuconazole
  • For patients responding or with toxicity
  • Can be used for consolidation/maintenance

Note

Echinocandins and voriconazole have NO activity alone against Mucorales!

Surgical management


  • Often requires disfiguring resections
  • Facial prosthetics may be needed
  • Survival with surgery: significantly improved
  • Reconstructive surgery after cure

Important

Don’t delay surgery for imaging or culture results in high-risk patients

Part 6: Antifungal toxicities

Amphotericin B: Nephrotoxicity mechanism


  • Afferent arteriole constriction → ↓ renal blood flow
  • Tubuloglomerular feedback → further vasoconstriction
  • LDL-bound AMB accumulates in tubules (LDL receptors)
  • Direct tubular toxicity
  • Electrolyte wasting (K⁺, Mg²⁺, Na⁺)

Liposomal AMB reduces nephrotoxicity



Formulation ≥2-fold SCr Increase
Amphotericin B deoxycholate 26%
Liposomal AMB 10%

Mechanism:

  • Liposomes don’t undergo glomerular filtration
  • Reduced binding to tubular LDL receptors
  • Less direct tubular damage

Triazole toxicities overview



Toxicity Agent(s)
Hepatotoxicity All (especially voriconazole)
QTc prolongation All (less with isavuconazole)
Visual disturbances Voriconazole
Phototoxicity/skin cancer Voriconazole (chronic)
Peripheral neuropathy Itraconazole > voriconazole
Adrenal suppression Itraconazole, posaconazole

Monitoring recommendations


Triazole monitoring

  • Baseline: LFTs, electrolytes, ECG if risk factors
  • Ongoing: Weekly LFTs initially, then periodically
  • TDM:
    • Voriconazole: Target 1-5 μg/mL-all patients need monitoring
    • Posaconazole: >1 μg/mL (efficacy cutoff) >1 μg/mL (prophylaxis)
      • Bioavailable of oral tablet > Oral suspension, also lesss drug interactions
    • Isavuconazole: If concerns about efficacy/toxicity
  • Patient counseling: Visual symptoms, sun protection

Summary

Key Take-Home Messages

  • Blood cultures miss 50% - use BDG if available- consider empiric treatment in high-risk patients
  • Source control (catheter removal) improves outcomes
  • Echinocandins first-line for unstable patients
  • Dilated eye exam exam recommended for most patients
  • Screen HIV+ patients with CD4 <100 for CrAg
  • Single high-dose L-AMB (AMBITION) is preferred
  • Aggressive ICP management is critical
  • Avoid corticosteroids, may be considered if IRIS develops
  • Early CT and GM testing in high-risk patients
  • Voriconazole/isavuconazole/posaconazole for primary therapy if not receiving prophylaxis
  • L-AMB if breakthrough on azole prophylaxis
  • Monitor for azole resistance, TDM for voriconazole
  • BDG and GM do NOT detect Mucorales
  • Surgical debridement is essential
  • High-dose L-AMB (5-10 mg/kg/day)
  • Control underlying conditions

Supplementary Slides

The following slides contain additional reference material and case examples.

Case 1: Candidemia

Clinical Scenario:

55-year-old male, recent abdominal surgery, TPN, central line, develops fever on antibiotics.

Blood culture positive for Candida glabrata

  • What is your first-line therapy?
  • What source control measure is essential?
  • What consultation should you obtain?

Case 2: Cryptococcal Meningitis

Clinical Scenario:

32-year-old male, newly diagnosed HIV (CD4 45), 2-week headache, confusion, fever.

LP: OP 32 cm H₂O, CrAg positive, WBC 15 (lymphs)

Management priorities?

  1. ICP management
  2. Antifungal therapy
  3. ART timing

Case 3: Suspected Invasive Aspergillosis

Clinical Scenario:

60-year-old female, AML induction, neutropenic day 18, persistent fever, new pulmonary nodules with halo sign.

Questions:

  • What diagnostics would you send?
  • What is your empiric therapy?
  • How long will you treat?

Case 4: Rhino-orbital Mucormycosis

Clinical Scenario:

58-year-old male, DKA, facial pain, periorbital swelling, nasal eschar.

Immediate actions:

  1. ENT/Surgery STAT consultation
  2. Start L-AMB 5-10 mg/kg NOW
  3. Correct metabolic abnormalities
  4. Plan for surgical debridement

EORTC/MSG Criteria: Proven IFI


Proven Invasive Fungal Infection:

  • Histopathologic evidence of fungal elements from tissue specimen
  • OR positive culture from normally sterile site
  • OR blood culture positive for fungus (except Aspergillus)

EORTC/MSG: Probable IFI

Requires ALL THREE:

  1. Host factor (neutropenia, HSCT, SOT, steroids, etc.)
  2. Clinical feature (imaging, clinical syndrome)
  3. Mycological evidence (GM, BDG, culture from non-sterile site)

Antifungal Drug Interactions


Key CYP450 Interactions:

Azole CYP Inhibition Major Interactions
Voriconazole 3A4, 2C19, 2C9 Calcineurin inhibitors, sirolimus
Posaconazole 3A4 Calcineurin inhibitors, sirolimus
Isavuconazole 3A4 Calcineurin inhibitors
Fluconazole 3A4, 2C9 Warfarin, calcineurin inhibitors

Antifungal Dosing Reference



Drug Loading Maintenance
Fluconazole 800 mg 400 mg daily
Voriconazole 6 mg/kg q12h × 2 4 mg/kg q12h
Posaconazole DR 300 mg q12h × 2 300 mg daily
Isavuconazole 200 mg q8h × 6 200 mg daily
Caspofungin 70 mg 50 mg daily
Micafungin - 100 mg daily
Anidulafungin 200 mg 100 mg daily
L-AMB - 3-5 mg/kg daily

References

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