What it is:A grab-bag of six organisms grouped into this chapter because they all cause deep, invasive fungal disease rather than superficial skin/nail infections. They split cleanly into two families that behave completely differently.
The core problem:Half of these fungi (histoplasma, blastomyces, coccidioides) live in soil in specific parts of the country and infect people through the lungs regardless of immune status if the inoculum is big enough. The other half (candida, cryptococcus, aspergillus) are opportunists, ubiquitous or already living on/in the patient, and they only cause invasive disease when a specific piece of host defense fails.
What you do about it:Identify which family you're dealing with using geography and host risk factors, then match the drug to the organism's spectrum and the site of infection (CNS penetration matters enormously here).
Every organism in this chapter has a signature "who gets it and where" story. Learn the story, not just the drug list.Once you know a patient inhaled dust in the Arizona desert, or has been neutropenic for two weeks post-transplant, or has a central line and has been on three antibiotics for ten days, the organism is basically handed to you before any culture comes back.
Don't study these six organisms as one undifferentiated list. They fall into two families with opposite logic, and mixing them up is the fastest way to miss an easy exam question.
| Organism | Family | Where it lives / who's exposed | Classic host | Signature presentation |
|---|---|---|---|---|
| Histoplasma capsulatum | Endemic dimorphic | Soil with bird/bat droppings, Ohio & Mississippi river valleys | Anyone with high inoculum; disseminates in immunocompromised | Flu-like pulmonary illness |
| Blastomyces dermatitidis | Endemic dimorphic | Wooded areas, waterways, overlapping with histo plus the Great Lakes basin | Anyone; can mimic TB or bacterial pneumonia | Productive cough, broad-based budding yeaston stain |
| Coccidioides immitis/posadasii | Endemic dimorphic | Desert dust, Lower Sonoran Zone (CA to TX, "Valley Fever") | Anyone inhaling arthroconidia in endemic soil | Flu-like illness plus diffuse rash |
| Cryptococcus neoformans | Opportunistic yeast | Soil contaminated with pigeon/bird droppings, essentially everywhere | Low CD4 / HIV, transplant, chronic steroids | Pulmonary infection that disseminates to CNS meningoencephalitis |
| Candida spp. | Opportunistic yeast | Endogenouscommensal of skin, GI tract, genital tract - not inhaled from the environment | Central lines, TPN, broad-spectrum antibiotics, neutropenia, ICU | Candidemia, mucosal or urinary disease |
| Aspergillus fumigatus(most common), A. flavus | Opportunistic mold | Ubiquitous airborne conidia (2.5–3 mm, small enough to reach alveoli/sinuses) | Prolonged neutropenia (>10 days): AML, allogeneic HSCT | Angioinvasive pulmonary disease mimicking PE |
Dimorphic means it lives as a mold in the environment (25°C) and switches to a yeast form at body temperature (37°C).That's true for histo, blasto, and cocci and explains why they infect otherwise healthy people who simply inhaled enough of it. Candida, cryptococcus, and aspergillus don't need that switch, they just need a host defense gap: neutrophils missing (candida, aspergillus) or T-cell/cell-mediated immunity missing (cryptococcus).
For the endemic three, an immunocompetent person can get seriously ill purely from a large exposure (spelunkers and histo, construction workers and cocci are the classic vignettes), while an immunocompromised host can get disseminated, life-threatening disease from an exposure a healthy person would clear without ever knowing. For the opportunistic three, a normal host essentially doesn't get invasive disease at all; the organism itself is not the variable, the failure of a specific arm of host defense is. That's why the "10+ days neutropenic AML patient" stem always points to aspergillus or candida, and the "CD4 <100" stem always points to cryptococcus.
Four drug classes cover essentially this entire chapter. Learn what each one hits and, just as important, where each one doesn'treach, because that determines which drug fails even against a susceptible organism.
Binds ergosterol, punches pores in the fungal membrane. Broadest spectrum, fungicidal, the rescue drug.
Block ergosterol synthesis via CYP51/14-alpha-demethylase. Mostly fungistatic, oral, the maintenance workhorses.
Block beta-1,3-glucan synthase, a fungal cell-wall target humans don't have. Fungicidal against candida.
Converted to 5-FU inside the fungal cell, disrupts nucleic acid synthesis. Only ever used in combination.
Amphotericin B (plus flucytosine) and fluconazole/voriconazole cross into the CNS. Echinocandins and itraconazole do not, and echinocandins also don't reach the urine.Never reach for an echinocandin to treat cryptococcal or candida meningitis, and never use one for urinary candidiasis, even against a fully susceptible organism. This is a favorite distractor: the bug is "sensitive" on the susceptibility report, but the drug physically can't get to the site of infection.
Amphotericin B binds ergosterol in the fungal cell membrane and forms pores that leak ions and kill the cell. It's fungicidal and covers essentially everything in this chapter, which is exactly why it's the reserve/rescue agent for severe, CNS, or refractory disease across almost every organism here.
Deoxycholateis the older, cheaper formulation. It's markedly nephrotoxic and causes infusion reactions (rigors, fever, chills) that get worse with repeated dosing if not pre-treated. Lipid formulations(liposomal amphotericin B, amphotericin B lipid complex/ABLC) wrap the drug in a lipid carrier that reduces renal exposure, so they're preferred in patients with marginal renal function, on other nephrotoxins, or who need prolonged courses. They cost more, which is the only real reason not to default to them.
Pregnancy note:azoles are teratogenic. Amphotericin B is the preferred antifungal in pregnancy across essentially every organism in this chapter when treatment can't wait.
Fluconazolehas excellent oral bioavailability and excellent CNS penetration, which is why it's the maintenance/suppressive drug for both cryptococcus and candida. Its spectrum is narrower than the other azoles: no activity against molds, and two important gaps among yeasts, C. krusei is intrinsically resistant and C. glabrata has reduced, dose-dependent susceptibility.
Itraconazoleis broader and is the default oral step-down for the endemic dimorphic fungi (histo, blasto, cocci). Its absorption is poor and erratic, especially with acid suppression, which is exactly why itraconazole levels get checked, something you don't routinely do with fluconazole.
Voriconazoleis the drug of choice for invasive aspergillosis. It's metabolized through CYP2C19, which has enough genetic polymorphism that levels vary widely between patients on an identical dose, another reason this specific azole gets level monitoring.
All azoles are potent CYP3A4 inhibitors themselves,not just substrates, so they're one of the most interaction-dense drug classes you'll counsel on: statins, calcium channel blockers, benzodiazepines, some anticoagulants, and many others need review at initiation.
Echinocandins block beta-1,3-glucan synthase, an enzyme that builds the fungal cell wall. Because human cells have no cell wall at all, this target doesn't exist in mammalian tissue, which is why echinocandins are remarkably well tolerated compared to amphotericin B or the azoles.
They're fungicidal against candida and are first-line for candidemia in patients who are moderately-to-severely ill or who've had recent azole exposure, and they're the automatic choice for C. glabrata and C. kruseigiven those species' reduced fluconazole susceptibility. Standard dosing: caspofungin 70 mg IV loading dose then 50 mg IV daily; micafungin 100 mg IV daily; anidulafungin 200 mg IV loading dose then 100 mg IV daily.
Their weakness is penetration. Poor CNS and urine concentrationstake them off the table for meningitis (crypto or candida) and for urinary candidiasis, no matter how susceptible the isolate looks on paper.
Flucytosine gets converted to 5-fluorouracil inside the fungal cell by an enzyme mammalian cells don't have, then disrupts DNA, RNA, and protein synthesis. It's used almost exclusively in combination with amphotericin B for induction therapy of cryptococcal meningitis, because resistance emerges rapidly when it's used alone.
The major toxicity is bone marrow suppression, and because it's renally cleared, doses must be adjusted for renal function. Drug level monitoring is strongly advised, especially with any renal impairment, to avoid accumulation and toxicity.
Histoplasma capsulatum, inhaled dust-borne microconidia, most disease clustered along the Ohio and Mississippi river valleys.Severity tracks almost entirely with inoculum size and host immune status.
Serology (complement fixation or immunodiffusion) is the primary method. Antigen EIA in urine, blood, or BAL fluidgives faster results and is especially useful in patients who are severely ill and can't wait on serology to turn positive.
| Disease severity | Regimen |
|---|---|
| Asymptomatic / mild, sx <4 wk | No therapy needed |
| Mild, sx >1 month | Itraconazole 200 mg TID x3 days, then 200 mg once–twice daily x6–12 weeks |
| Moderate–severe diffuse pulmonary | Lipid amphotericin B 3–5 mg/kg/day IV x1–2 wk → itraconazole 200 mg TID x3 days then BID, total 12 weeks. Add methylprednisolone 0.5–1 mg/kg/day IVx1–2 wk if hypoxemia/respiratory distress |
| CNS histoplasmosis | Lipid amphotericin B 5 mg/kg/day IV to a total dose of 175 mg/kg (4–6 wk) → itraconazole 200 mg BID–TID x≥1 year, some lifelong. Follow with repeat LPs (antigen, WBC, CSF antibody) |
| Progressive disseminated, moderate–severe | Liposomal ampho B 3 mg/kg/day, ABLC 5 mg/kg/day, or deoxycholate 0.7–1 mg/kg/day x1–2 wk → itraconazole 200 mg BID x≥12 months |
| Progressive disseminated, mild–moderate | Itraconazole 200 mg BID x≥12 months; immunosuppressed may need lifelong200 mg daily |
Check a plasma level during the second weekof therapy. Below 1 mcg/mL, absorption is likely inadequate or an interaction is accelerating metabolism, raise the dose. Above 10 mcg/mL, the dose can come down.
After finishing initial therapy, lifelong suppressive azole is recommended because relapse is so common. Relapse rates in AIDS patients not on maintenance therapy run 50–90%.That number is the entire justification for why suppression doesn't stop just because symptoms did.
Blastomyces dermatitidis, geographic range overlapping histo plus the Great Lakes basin. Pulmonary disease can mimic TB, bacterial pneumonia, other fungi, or malignancy, which is exactly why it's a classic diagnostic trap.
Acute pulmonary infection: fever, shaking chills, productive purulent cough, sometimes hemoptysis. A sporadic/chronic form looks more like TB: low-grade fever, night sweats, weight loss, productive cough over weeks to months.
Diagnosis is often made just by direct microscopy: large, multinucleated yeast with broad-based budding."Broad-based budding yeast" on a vignette is blastomyces, full stop, contrast with cryptococcus's narrow-based budding.
In immunocompetent hosts, mild acute pulmonary disease can be self-limited and may not strictly require treatment, but most clinicians treat anyway to prevent later extrapulmonary spread. Anyone with moderate-severe pneumonia, disseminated disease, or immunocompromise needs therapy.
| Disease | Regimen |
|---|---|
| Mild–moderate pulmonary | Itraconazole 200 mg TID x3 days, then 200 mg BID, total 6 months |
| Moderate–severe pulmonary | Lipid ampho B 3–5 mg/kg/day or deoxycholate 0.7–1 mg/kg/day x1–2 wk (total dose 1.5–2.5 g) → itraconazole 200 mg TID x3 days then BID, total 6–12 months |
| CNS disease | Induction: lipid ampho B 5 mg/kg/day x4–6 wk. Consolidation: fluconazole 800 mg/day, or itraconazole 200 mg BID–TID, or voriconazole 200–400 mg BID, x≥12 months and until CSF normalizes |
| Disseminated / extrapulmonary, mod–severe | Lipid ampho B or deoxycholate x1–2 wk → itraconazole 200 mg TID x3 days then BID, x6–12 months. Osteoarticular disease gets a full 12 months |
| Immunocompromised, acute disease | Lipid ampho B or deoxycholate x1–2 wk, then suppressive itraconazole 200 mg TID x3 days then BID, x≥12 months. Lifelong suppression (200 mg daily) if immunosuppression can't be reversed, or after relapse |
Azoles should not be used during pregnancy for blastomycosis, same rule as everywhere else in this chapter. Use amphotericin B instead.
Coccidioides immitisand C. posadasii, endemic to the semiarid Southwest, the Lower Sonoran Zone from California to Texas.Exposure is via inhaled arthroconidia in dust.
Therapy is difficult and outcomes are unpredictable, but the bigger point: only about 5% of infected people ever require treatment.The vast majority clear it on their own.
Azoles, mainly fluconazole and itraconazole, are first-line for chronic pulmonary or disseminated disease. Fluconazole 400–800 mg/day(up to 1200 mg/day has been used without issue) or itraconazole 200–300 mg BID–TID.Therapy commonly runs many months to years, and some patients need lifelong suppression to prevent relapse.
Amphotericin B is now reservedfor respiratory failure from coccidioidal infection, rapidly progressive disease, or pregnancy. Extrapulmonary disease gets an oral azole 400 mg/day. For meningeal disease, fluconazole 400 mg/dayis standard, though some clinicians start at 800–1000 mg/day; itraconazole 400–600 mg/day is comparable.
Coccidioidal meningitis relapses at very high rates if therapy is discontinued. In practice, once a patient has coccidioidal meningitis, they're typically on fluconazole indefinitely.
Cryptococcus neoformans, an encapsulated soil yeast. This is the one where the exam wants you to think immediately about CNS disease and HIV/immunosuppression.
Primary infection is almost always pulmonary (cough, rales, dyspnea), often resolving on its own. Disease can stay localized to the lung or disseminate, most importantly to the CNS, causing meningoencephalitis.
In non-AIDS patients, cryptococcal meningitis produces the expected picture: headache, fever, nausea/vomiting, mental status change, neck stiffness. In AIDS patients, fever and headache are common but meningismus and photophobia are much less frequent.A blunted inflammatory response means fewer classic meningeal signs despite equal or worse disease, don't let a soft exam reassure you in this population.
CSF findings: elevated opening pressure, lymphocytic pleocytosis, low glucose, high protein, and a positive cryptococcal antigen by latex agglutination. India ink is positive in ~60%; culture is positive in >96%.
This three-phase structure is the single most important organizing idea for cryptococcal (and severe histo/blasto CNS) therapy: amphotericin B (± flucytosine) knocks down the bulk fungal burden, high-dose fluconazole mops up what's left, then low-dose fluconazole prevents relapse.
| Population / disease | Regimen |
|---|---|
| Non-immunocompromised, meningoencephalitis, no neuro complications | Induction: amphotericin B 0.7–1 mg/kg/day + flucytosine 100 mg/kg/day (4 divided doses) x≥4 weeks |
| ...with neurologic complications | Same induction, consider extending to a total of 6 weeks |
| All the above, consolidation/maintenance | Consolidation: fluconazole 400–800 mg/day x8 weeks. Maintenance: fluconazole 200 mg/day x6–12 months |
| Mild–moderate pulmonary (non-meningeal) | Fluconazole 400 mg/day x6–12 months |
| Severe pulmonary or cryptococcemia (non-meningeal, non-pulmonary) | Treat identically to CNS disease, x12 months |
| HIV-infected, preferred induction | Amphotericin B 0.7–1 mg/kg/day + flucytosine 100 mg/kg/day x≥2 weeks |
| HIV-infected, alternative inductions (if flucytosine unavailable) | Ampho B alone x4–6 wk, or liposomal ampho B 3–4 mg/kg/day x4–6 wk, or ABLC 5 mg/kg/day x4–6 wk, or ampho B + fluconazole 800 mg/day, or fluconazole 800–1200 mg/day + flucytosine, or fluconazole alone (≥1200 mg/day preferred if used alone) |
| HIV-infected, consolidation/maintenance | Consolidation: fluconazole 400 mg/day x≥8 weeks. Maintenance: fluconazole 200 mg/day x≥1 year |
| Transplant recipients, mild–moderate non-CNS | Fluconazole 400 mg/day x6–12 months |
| Transplant recipients, CNS or severe disease | Induction: liposomal ampho B 3–4 mg/kg/day or ABLC 5 mg/kg/day + flucytosine x≥2 weeks → consolidation fluconazole 400–800 mg/day x8 wk → maintenance fluconazole 200–400 mg/day x6–12 months |
Intrathecal amphotericin B is reserved for very ill patients or recurrent/progressive disease despite aggressive IV therapy, it's too neurotoxic for routine use. Lipid IV formulations are preferredbecause patients are more likely to actually complete the full course.
Relapse occurs in ~50% of AIDS patientsafter finishing primary therapy without maintenance, hence the year of suppressive fluconazole. In HIV-infected patients, maintenance can be considered for discontinuation once CD4 ≥100 cells/μL and HIV RNA is undetectable/very low for ≥3 months(with a minimum of 12 months of antifungal therapy total). Restart maintenance if CD4 drops back below 100.
Eight species matter clinically: C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. stellatoidea, C. guilliermondii, C. lusitaniae, C. glabrata.C. albicans is a normal commensalof skin, the female genital tract, and the entire GI tract, which is the key conceptual difference from every other organism in this chapter: candida disease comes from the patient's own flora, not an environmental exposure.
Major risk factors for hematogenous candidiasis: central venous catheters, TPN, broad-spectrum antibiotics, extensive surgery/burns, renal failure/hemodialysis, mechanical ventilation, and prior fungal colonization.Immunosuppressed patients (hematologic malignancy, diabetes, high-dose steroids, chemotherapy) are also high risk. Dissemination from the GI tract, or via an indwelling line, can seed the kidney, brain, myocardium, skin, eye, bone, or joints.
| Setting | Approach |
|---|---|
| Prophylaxis, non-neutropenic | Not recommended, except severely ill/high-risk patients: fluconazole 400 mg/day IV/oral |
| Prophylaxis, neutropenic | Fluconazole 400 mg/day, itraconazole solution 2.5 mg/kg q12h, or micafungin 50 mg/day (1 mg/kg if <50 kg), for at least the at-risk neutropenic period |
| Prophylaxis, solid-organ/liver transplant with risk factors | Fluconazole 400 mg/day preferred |
| Empirical, febrile non-neutropenic | Not recommended, data don't support a clear target population |
| Empirical, febrile neutropenic with suspected candidiasis | Lipid ampho B, caspofungin, micafungin, voriconazole, isavuconazole, posaconazole, or itraconazole, for the duration of neutropenia |
| Clinical picture | Regimen |
|---|---|
| Less critically ill, no recent azole exposure | Remove central line if feasible + fluconazole IV (load 800 mg, then 400 mg/day) or an echinocandin; treat 2 weeks after last positive blood culture and resolution of symptoms |
| Recent azole exposure, mod-severe illness, or risk of C. glabrata/krusei | Echinocandin first. Step down to fluconazole if clinically stable and the isolate (e.g. C. albicans) is likely susceptible |
C. krusei is intrinsically fluconazole-resistant.C. glabrata has reduced, unpredictable fluconazole susceptibilityand shouldn't be stepped down to fluconazole or voriconazole without confirming susceptibility first. Both start on an echinocandin. C. lusitaniaegets fluconazole. Voriconazole is efficacious across most species but offers little advantage over fluconazole except as oral step-down for C. krusei or a voriconazole-susceptible C. glabrata isolate.
Asymptomatic disease generally needs no therapy.Symptomatic or high-risk patients (neutropenic, low-birth-weight infants, anyone facing urologic instrumentation): remove catheters/stents, plus 7–14 days of fluconazole 200 mg/day or amphotericin B 0.3–1 mg/kg/day.Echinocandins are not an option here, they don't achieve adequate urinary concentrations regardless of susceptibility.
Aspergillus fumigatusis the most common pathogen, followed by A. flavus.Acquired by inhaling airborne conidia small enough (2.5–3 mm) to reach the alveoli or paranasal sinuses. Invasive disease clusters in immunocompromised patients, especially AML and allogeneic HSCT recipients with prolonged neutropenia (>10 days).
ABPA is an allergic phenomenon; therapy is aimed at minimizing antigen exposure in the airway, and antifungals generally aren't indicated, though itraconazole has been shown to reduce glucocorticoid requirements in some patients. Seeing "aspergillus" and reflexively reaching for voriconazole is the trap here, ABPA gets steroids, not antifungals, as first-line.
Patients present with blunted or nonspecific signs of infection, because impaired inflammatory responses (neutropenia) blunt the usual cues. The classic picture actually mimics acute pulmonary embolism: pleuritic chest pain, fever, hemoptysis, and friction rubs.That's because the organism is angioinvasive, it invades blood vessels and causes infarct-like lung injury. Diagnosis is most firmly made by repeated culture and microscopy of tissue.
Voriconazole is the drug of choice for primary therapy of most invasive aspergillosis, shown to improve survival with fewer side effects than the alternatives. If a patient can't tolerate it, amphotericin B is next, at full doses (1–1.5 mg/kg/day), with response tracked by defervescence and radiographic clearing. Lipid formulations are preferred if renal function is marginal or the patient is on other nephrotoxins. Duration of therapy is individualized, there's no fixed endpoint. Caspofungin is reserved for patients refractory to or intolerant of other therapy, and response rates are lower there. Prophylactic voriconazole is recommended to prevent primary infection or reactivation during subsequent chemotherapy courses in high-risk patients.
| Parameter | When | Watching for |
|---|---|---|
| Renal function & electrolytes (K⁺, Mg²⁺) | Baseline and throughout amphotericin B therapy | Nephrotoxicity and renal tubular wasting of potassium/magnesium |
| Infusion tolerance | Every amphotericin B infusion, especially the first few | Rigors, fever, chills - premedicate with acetaminophen/diphenhydramine ± hydrocortisone |
| CBC | Throughout flucytosine therapy; periodically on other agents | Bone marrow suppression (flucytosine) |
| LFTs | Baseline and periodically on any azole | Hepatotoxicity |
| Itraconazole level | During week 2 of therapy | Target >1 mcg/mL; reduce dose if >10 mcg/mL |
| Flucytosine level | With renal impairment or dose changes | Accumulation and marrow toxicity - level monitoring strongly advised |
| CSF studies(cryptococcal antigen, WBC, culture) | Per LP schedule during CNS fungal treatment | Confirming sterilization before de-escalating therapy |
| CD4 count / HIV RNA | Periodically during crypto maintenance in HIV+ patients | Whether maintenance can stop (CD4 ≥100 x≥3 months, undetectable viral load) |
| Symptoms and relapse markers | Throughout suppressive/maintenance therapy | Recurrence - histo and crypto both carry high relapse rates without lifelong suppression in immunosuppressed hosts |