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Welcome to Core IM, a virtual medical community! Core IM strives to empower its colleagues of all levels and backgrounds with clinically applicable information as well as inspire curiosity and critical thinking. Core IM promotes its mission through podcasts and other multimodal dialogues. ACP has teamed up with Core IM to offer continuing medical education, available exclusively to ACP members by completing the CME/MOC quiz.

Pearl 1: What is invasive fungal disease, and who is most at risk for developing invasive fungal disease?

• occurs when fungi invade areas that should be sterile
  • Bloodstream infections, abscesses in visceral organs (brain, liver, kidney, and spleen)
• The right host is important. 3 major buckets of hosts:
  • 1)Who: Patients with suppressed immune systems, especially hematopoietic stem cell transplants, solid organ transplants on immunosuppression, patients on high dose steroids. Mechanism: Immune suppression!
  • 2) Who: Patients undergoing high risk abdominal surgery. Mechanism: direct spillage
  • 3) Who: Critically ill patients in the ICU. Mechanism: for fungal growth
  • Immunocompetent individuals can also develop IFD. Highest risk is those with structural lung disease.

Pearl 2: What are the main classes of fungi?

• Yeasts
  • Obligate unicellular growth
  • The most clinically relevant yeasts are (most) candida and cryptococcus.
    • Invasive candidiasis is the most common IFD in non-neutropenic, critically ill adult patients in the ICU, and can have a in those presenting with septic shock
    • Cryptococcus is typically inhaled and can cause lung infections, but the most feared complication is meningoencephalitis
• Molds  
  • Obligate multicellular organisms
  •  The most clinically relevant molds are Aspergillus and Mucor
    • Aspergillus spores are prevalent in the air, and those with in the lungs preventing secretion clearance (like bronchiectasis) or compromised immune systems are at risk.
    • Mucormycosis is particularly seen in individuals with advanced diabetes. Inhalation of Mucor spores in this setting can lead to invasive rhino-cerebral mucormycosis, that can invade sinuses, bone, and the CNS, often requiring surgical resection
• Dimorphics
  • Mold in the environment, yeast in the host. “Mold in the cold, yeast in the beast”
  • Key examples are the “endemic mycoses”: Histoplasmosis, Coccidioidomycosis, and Blastomycosis.
  • Endemic fungi are no longer strictly confined to their
  •  Clinical Pearl: in patients with pneumonia who have failed one round of antibiotics.

Pearl 3: Fungal Diagnostics: PCR/B-D Glucan and Galactomannan

• Beta D Glucan
  • “Pan-fungal marker” detects a cell wall component found in most fungi
    • Notable exceptions:  Cryptococcus, Blastomyces, and Mucorales
  • Sensitive but Non-Specific: Useful for detecting invasive candidiasis and other fungal infections, but cannot localize or specify the fungus.
  • False Positives Are Common: Can result from IVIG, certain antibiotics (e.g., Bactrim, cefepime), albumin, and (especially with ).
  • High values (>500) are more suggestive of true infection; mild elevations may be false positives, especially in dialysis patients.
• Galactomannan Antigen
  •  Detects cell wall components of Aspergillus, Histoplasma, and Fusarium
  • Higher Specificity, Lower Sensitivity: Particularly for Aspergillus; may be negative even in true infections.
  • Susceptible to False Positives: Notably from antibiotics like Zosyn and Unasyn, among others.
  • Cutoffs Vary by Sample: Positive if >0.5 in serum; >1.0 in BAL fluid is more consistent with true infection.
  • Avoid sending galactomannan for patients without risk factors!
• Other Tests
  • Fungus-specific antigen tests
    • Ag test for specific fungi like blastomyces, histoplasma, coccidioides, and cryptococcus
    • A few notable cons: cross reactivity between the different endemic infections, and sensitivity is dependent on the timing of the disease course
  • PCR tests
    • Available for Candida (T2Candida) and Aspergillus (Septifast)
    • A few notable cons: no standard methods yet and lack of validation of these PCR assay, these tests are often send-outs only and have a longer turnaround time or barriers to ordering

Pearl 4: Cultures

• Blood Cultures
  • Sensitivity for invasive candidiasis. A negative result does not rule out infection, especially in high-risk ICU patients.
  • Repeat Testing: , but if 3 sets are negative, further cultures are often not beneficial.
  • Candida in blood is never a contaminant and typically warrants an ID consult and antifungal therapy.
  • Candida forms strong , which may limit shedding into the bloodstream and cause intermittent negatives.
  • Context is Critical: Blood cultures should be interpreted in high-risk hosts (e.g., immunosuppressed, recent surgery, central lines) and used alongside markers like BDG or Galactomannan.

• Urine Cultures
  • Candida in the urine usually does not indicate invasive disease, particularly in asymptomatic patients.
  •  Unless the patient has textbook UTI symptoms or a recent renal transplant, antifungal therapy is generally not indicated.
• Sputum and BAL
  • Candida is Typically a Colonizer: Growth of Candida from BAL is very common and almost never indicates invasive lung disease.
  • Cutoff for Galactomannan in BAL: A in BAL fluid is more consistent with true Aspergillus infection; values between 0.5–1.0 may be false positives.
• “What and Where” Principle: As with all fungal diagnostics, it’s crucial to ask both “what organism?” and “from where?” to determine clinical significance.

Pearl 5: How is invasive fungal disease treated?

• Azoles
  • Mechanism: Inhibit ergosterol synthesis (a vital component of fungal cell membranes).
  • Examples: Fluconazole, Voriconazole, Posaconazole, Itraconazole, Ketoconazole, Econazole, Isavuconazole
  • Key Points:
    • Fluconazole and ketoconazole primarily cover yeasts (Candida, Cryptococcus).
    • Newer azoles (e.g., voriconazole, posaconazole) also cover molds.
      • Voriconazole, Posaconazole, Isavuconazole all generally cover Aspergillus
      • Posaconazole and Isavuconazole generally cover Mucor as well (but Voriconazole does not)
    • Voriconazole is first-line for probable Aspergillus ().
  • Drug Interactions: Major interactions with calcineurin inhibitors (e.g., tacrolimus), QT-prolonging agents (e.g., methadone), and CYP3A4 substrates (anticonvulsants, DOACs, statins, and many psych meds)
    • Carefully check a patient’s medication list before starting an azole!
  • Side Effects: GI discomfort, elevated LFTs
    • For Voriconazole specifically:  photosensitivity, visual hallucinations, bone pain, hepatitis.
    • Counsel patients to use sun protection during therapy
• Echinocandins
  • Mechanism: Inhibit β-glucan synthesis, impairing fungal cell wall integrity
  • Examples: Micafungin, Caspofungin, Anidulafungin
  • Key Points:
    • Excellent activity against Candida spp. → First-line for candidemia, especially in ICU or immunocompromised patients.
    • Limited efficacy against molds
• Polyenes
  • Mechanism: Bind to ergosterol and disrupt fungal cell membrane integrity.
  • Examples: Amphotericin B, Nystatin
  • Key Points:
    • Amphotericin B: First-line for severe fungal infections like cryptococcal meningitis and mucormycosis.
      • Toxicity: nephrotoxicity and infusion reactions.
    • Ambisome (the liposomal form) is strongly preferred at most institutions unless in a resource-limited setting due to less toxicity
    • Nystatin: Used topically or orally (swish & spit) for localized fungal infections (e.g., oral thrush).
• Remember: Local ecology matters! Be aware of local resistance patterns and ask ID to help guide treatment.

Contributors

Shreya Trivedi, MD, ACP Member – Host, Editor
Samantha Schuetz, MD – Host, Editor
Audrey Mahajan, MD - Guest
Andrej Spec, MD - Guest
Michael Mansour, MD – Guest*

Reviewers

Matthew Lee MD
Todd McCarty, MD*
Kendell Bell, PharmD

* Michael Mansour, MD – Consultant: ThermoFisher Scientific, and Vericel Corp.

* Todd McCarty, MD – Grant: Mundipharma, Pfizer Inc., Astellas Pharma US Inc., Basilea, F2G, Mayne Pharma Inc., Scynexis, and T2 Biosystems Inc.

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date:  June 11, 2025

Expiration Date: June 10, 2028

CME Credit

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The �������ý designates this enduring material (podcast) for .75 AMA PRA Category 1 Credit™.  Physicians should claim only the credit commensurate with the extent of their participation in the activity.

ABIM Maintenance of Certification (MOC) Points

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to .75 medical knowledge MOC Point in the American Board of Internal Medicine’s (ABIM) Maintenance of Certification (MOC) program.  Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider’s responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.

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