Invasive Fungal Infections: Candidemia, Aspergillosis & Mucormycosis
Pull the line, pick the right azole, and send mucor to the operating room
Candidemia
Setting. Candida bloodstream infection follows central venous catheters, TPN, broad-spectrum antibiotics, abdominal surgery (especially anastomotic leaks), prolonged ICU stays, hemodialysis, and neutropenia, and it carries high mortality. Candida is never a blood culture contaminant: even one positive bottle means infection that must be treated.
Drug choice. An echinocandin (caspofungin, micafungin, anidulafungin) is first-line. After 5–7 days, patients who are stable, have cleared their cultures, and have a susceptible isolate (C. albicans, C. parapsilosis) step down to fluconazole, which can also be initial therapy in stable patients unlikely to carry resistant species. C. krusei is intrinsically fluconazole-resistant and C. glabrata often has reduced susceptibility, so testing guides step-down.
- Treat every positive cultureStart an echinocandin.
- Remove central linesEarly removal speeds clearance; guidewire exchange is not enough.
- Repeat blood culturesDaily or every other day until negative.
- Dilated eye examIdeally within the first week (after count recovery in neutropenia) to detect chorioretinitis or endophthalmitis, which changes drug choice and duration.
- Duration14 days after the first negative culture if there are no metastatic complications.
Candida auris and candiduria
Candida auris. This emerging yeast is multidrug-resistant: most isolates resist fluconazole and some resist every class. It colonizes skin, persists on surfaces, and causes outbreaks in hospitals and long-term care. Conventional biochemical methods often misidentify it, so MALDI-TOF or molecular identification is needed. Infections are treated with an echinocandin, and patients need contact precautions, disinfectants proven against C. auris, and public health notification.
Candiduria. Candida in the urine of a catheterized or asymptomatic patient is usually colonization: remove or change the catheter and do not treat. Treat symptomatic cystitis or pyelonephritis, neutropenic patients, very-low-birth-weight infants, and patients about to undergo urologic procedures, preferably with fluconazole, which concentrates in urine. Candida in sputum likewise reflects colonization; Candida pneumonia is exceedingly rare.
Aspergillus: one mold, many diseases
Spectrum. Everyone inhales Aspergillus fumigatus conidia; the host decides the disease. Hyperreactive airways develop ABPA, an old cavity harbors an aspergilloma, damaged lungs or mild immunosuppression allow chronic cavitary or necrotizing aspergillosis, and profound immunosuppression permits angioinvasion.
Invasive aspergillosis. Risk factors are prolonged neutropenia (ANC <500 for >10 days), allogeneic HSCT with GVHD, high-dose corticosteroids, lung transplantation, and severe influenza or COVID-19 in the ICU. Fever persists despite antibiotics, with pleuritic pain and hemoptysis as hyphae invade vessels and infarct lung. CT shows nodules with a ground-glass halo of hemorrhage early and an air-crescent sign as neutrophils recover. Serum or BAL galactomannan supports the diagnosis, β-D-glucan is positive but nonspecific, and tissue shows thin septate hyphae branching at acute (~45°) angles. Treatment starts on suspicion.
Treatment. Voriconazole or isavuconazole is first-line, with liposomal amphotericin B as an alternative and echinocandins as salvage. Voriconazole causes transient visual changes and hallucinations, photosensitivity with long-term squamous cell carcinoma risk, hepatotoxicity, QT prolongation, and periostitis; its CYP interactions (tacrolimus, cyclosporine, sirolimus) require drug-level monitoring. Isavuconazole has fewer side effects and interactions and shortens the QT interval. Posaconazole prophylaxis protects patients during AML/MDS induction and with GVHD.
Aspergilloma. A mobile ball of hyphae inside an old cavity (TB, sarcoidosis, bullae) appears as a mass capped by a crescent of air, with positive Aspergillus IgG. Many are silent, but hemoptysis can be massive: bronchial artery embolization controls bleeding and surgical resection is definitive, because antifungals penetrate the ball poorly.
ABPA. A hypersensitivity reaction to airway colonization in asthma or cystic fibrosis: worsening wheeze, brown mucus plugs, fleeting infiltrates, eosinophilia, total IgE ≥500 IU/mL (often >1000, the older cutoff), Aspergillus-specific IgE and IgG, and central bronchiectasis with mucus-filled bronchi in a finger-in-glove pattern. Oral glucocorticoids are the mainstay, with itraconazole as a steroid-sparing agent; falling IgE tracks response and a rising level heralds relapse.
Mucormycosis
Hosts and presentation. Mucorales (Rhizopus, Mucor) thrive in DKA, neutropenia, high-dose steroids, transplantation, and iron overload treated with deferoxamine. Acidosis frees iron from transferrin, and deferoxamine acts as a siderophore delivering iron to Rhizopus. Rhino-orbital-cerebral disease begins as sinusitis with facial pain and swelling, then black necrotic eschar on the turbinates or palate, proptosis, ophthalmoplegia, vision loss, and cranial neuropathies, progressing within days to cavernous sinus thrombosis and brain invasion.
Treatment. Biopsy shows broad, ribbon-like, pauciseptate hyphae branching at wide (~90°) angles and invading vessels. This is a surgical emergency: extensive debridement plus high-dose liposomal amphotericin B, correction of DKA, and reduction of immunosuppression, with step-down to posaconazole or isavuconazole. Voriconazole is inactive, and breakthrough mucormycosis can occur on it.
| Feature | Aspergillus | Mucorales |
|---|---|---|
| Classic host | Prolonged neutropenia, HSCT, steroids | DKA, neutropenia, deferoxamine |
| Hyphae | Thin, septate, acute-angle branching | Broad, pauciseptate, right-angle branching |
| Signature | Halo-sign lung nodules | Black nasal or palatal eschar |
| Antigen tests | Galactomannan, β-D-glucan positive | Both negative |
| Treatment | Voriconazole or isavuconazole | Debridement + liposomal amphotericin B |
Antifungal pharmacology
| Drug | Mechanism | Main uses | Key toxicity or pearl |
|---|---|---|---|
| Amphotericin B | Binds ergosterol, forms pores | Mucormycosis, cryptococcal meningitis, severe endemic mycoses | Nephrotoxicity, low K and Mg, infusion reactions, anemia |
| Echinocandins | Inhibit β-1,3-glucan synthase | Candidemia; salvage for Aspergillus | Poor urine, eye, and CSF penetration |
| Fluconazole | Inhibits 14α-demethylase | Candida step-down, UTI, eye; cryptococcus; cocci | No mold activity |
| Voriconazole | Inhibits 14α-demethylase | Invasive aspergillosis | Visual changes, photosensitivity, CYP interactions; no Mucorales activity |
| Posaconazole, isavuconazole | Inhibit 14α-demethylase | Mold prophylaxis; mucormycosis step-down | Isavuconazole shortens QT |
Penetration matters. Because echinocandins barely reach urine, eye, or CSF, fluconazole treats Candida UTI, and fluconazole or voriconazole treats susceptible Candida chorioretinitis, adding intravitreal therapy when the vitreous or macula is involved. All azoles inhibit CYP enzymes.
Amphotericin toxicity. Afferent arteriolar vasoconstriction plus distal tubular injury cause kidney injury and type 1 RTA with potassium and magnesium wasting; magnesium must be replaced for potassium repletion to succeed. Infusion fever and rigors and anemia from reduced erythropoietin are common. Lipid formulations and saline loading reduce kidney injury.
β-D-glucan detects Candida, Aspergillus, and Pneumocystis but not Mucorales or Cryptococcus.