Clinical Syndromes — Candidiasis, Aspergillosis, Cryptococcosis, Mucormycosis, and Endemic Mycoses

Oropharyngeal candidiasis (thrush) presents as white plaques on erythematous mucosa in the mouth, pharynx, or tongue that can be scraped off, distinguishing them from leukoplakia. It occurs predominantly in patients receiving inhaled corticosteroids (who should rinse the mouth after each use), those with human immunodeficiency virus (HIV) infection with low CD4 counts, patients receiving chemotherapy or antibiotics, denture wearers, and neonates. Fluconazole 200 mg on day one followed by 100 mg daily for seven to 14 days is the drug of choice; topical nystatin suspension is an alternative for mild disease. Esophageal candidiasis presents with odynophagia and dysphagia and requires systemic therapy — fluconazole is significantly more effective than nystatin swish-and-swallow for this indication and is first-line. Vulvovaginal candidiasis, caused predominantly by Candida albicans, is treated with either a single oral fluconazole dose (150 mg) or topical azole preparations; recurrent vulvovaginal candidiasis (four or more episodes per year) warrants maintenance fluconazole suppression.

Candidemia — Candida isolated from blood culture — requires immediate systemic antifungal therapy and a thorough search for deep-seated foci including Candida endophthalmitis (present in five to ten percent of candidemia cases and requiring ophthalmologic evaluation), hepatosplenic candidiasis in patients recovering from neutropenia, Candida endocarditis in patients with prosthetic valves or prolonged candidemia, and osteomyelitis. Risk factors for invasive candidiasis include prolonged broad-spectrum antibiotic use, central venous catheters, total parenteral nutrition (TPN), abdominal surgery, renal replacement therapy, and immunosuppression.

An echinocandin — caspofungin, micafungin, or anidulafungin — is the preferred initial therapy for candidemia in most patients, given superior fungicidal activity and retained efficacy against fluconazole-resistant Candida glabrata. The central venous catheter should be removed as soon as possible in patients with candidemia, as catheter removal improves outcomes and reduces time to blood culture clearance. Step-down to oral fluconazole is appropriate once the patient is clinically stable, blood cultures are negative, and the species is confirmed fluconazole-susceptible. Treatment duration for uncomplicated candidemia is 14 days from the first negative blood culture. Candida auris, the multidrug-resistant emerging pathogen, is typically echinocandin-susceptible; echinocandin therapy is recommended while susceptibility data are pending.

Cryptococcal meningitis typically presents subacutely over days to weeks with headache, fever, malaise, and altered mental status. The subacute course reflects the predominantly fungal rather than inflammatory nature of the infection — the classic signs of bacterial meningitis (meningismus, photophobia, Kernig and Brudzinski signs) are often absent or mild. Cerebrospinal fluid (CSF) examination characteristically shows mild pleocytosis (typically below 50 white blood cells per microliter), mildly elevated protein, and low glucose, with large encapsulated yeast visible on India ink staining in approximately 75 percent of cases. CSF cryptococcal antigen — a lateral flow assay for the Cryptococcus capsular polysaccharide — is positive in essentially all cases of cryptococcal meningitis and is the most sensitive and specific diagnostic test. Elevated CSF opening pressure (above 25 cm H2O) is present in the majority of patients and correlates with mortality; management of elevated intracranial pressure through therapeutic lumbar punctures is a critical and often life-saving component of treatment independent of antifungal therapy.

Treatment of cryptococcal meningitis is organized into three sequential phases. Induction therapy aims to rapidly reduce the fungal burden in the CSF and brain and is the most critical determinant of early mortality. The 2022 World Health Organization (WHO) guidelines recommend a one-week regimen of liposomal amphotericin B (10 mg/kg as a single dose, or 3 to 4 mg/kg daily for one week) plus flucytosine plus fluconazole for settings with access to all three drugs. Where liposomal amphotericin B is unavailable, amphotericin B deoxycholate (1 mg/kg per day) plus flucytosine for one week followed by fluconazole consolidation is an acceptable alternative, superior to fluconazole monotherapy and to amphotericin B without flucytosine. The IDSA 2010 guidelines for non-HIV settings recommend amphotericin B plus flucytosine for at least two weeks of induction.

Consolidation therapy follows induction and aims to maintain fungal suppression while immune function recovers: fluconazole 400 mg daily for eight weeks is standard. Maintenance therapy (secondary prophylaxis) follows consolidation: fluconazole 200 mg daily until the CD4 count exceeds 200 cells per microliter on antiretroviral therapy (ART) for at least six months. Cryptococcal meningitis is an AIDS-defining illness, and initiating ART is essential but must be timed carefully: starting ART too early (within the first two weeks of antifungal induction) dramatically worsens outcomes due to immune reconstitution inflammatory syndrome (IRIS), and current guidelines recommend deferring ART initiation for two to four weeks after antifungal induction.

Histoplasma capsulatum is endemic to the Ohio and Mississippi River valleys of the United States, and to parts of Central and South America. Infection occurs through inhalation of microconidia from soil enriched with bird or bat droppings. The vast majority of infections in immunocompetent hosts are asymptomatic or cause a self-limited flu-like illness that resolves without treatment. Clinically significant disease includes acute pulmonary histoplasmosis (presenting with fever, headache, myalgia, and non-productive cough after heavy exposure), chronic pulmonary histoplasmosis (resembling tuberculosis, occurring in patients with underlying lung disease), and progressive disseminated histoplasmosis (PDH) in immunocompromised patients — particularly those with HIV infection and CD4 counts below 150 cells per microliter — presenting with fever, weight loss, hepatosplenomegaly, mucocutaneous lesions, and cytopenias. Urine Histoplasma antigen is the most sensitive diagnostic test for disseminated and moderate-to-severe pulmonary disease (sensitivity exceeding 90 percent for PDH).

Treatment is severity-based. Mild to moderate pulmonary histoplasmosis: itraconazole 200 mg three times daily for three days (loading), then twice daily for six to twelve weeks. Moderately severe to severe histoplasmosis and PDH in immunocompromised patients: liposomal amphotericin B induction for one to two weeks, followed by itraconazole step-down for at least twelve months. Secondary prophylaxis with itraconazole 200 mg daily is recommended for HIV-positive patients with a history of disseminated disease until the CD4 count exceeds 150 cells per microliter on antiretroviral therapy for at least six months.

Coccidioides immitis (California) and Coccidioides posadasii (other endemic areas) cause coccidioidomycosis in the desert Southwest United States, northern Mexico, and parts of Central and South America. Infection occurs through inhalation of arthroconidia. Approximately 60 percent of infections are asymptomatic; symptomatic primary pulmonary coccidioidomycosis (Valley Fever) presents with fever, cough, chest pain, fatigue, and characteristic skin findings including erythema nodosum and erythema multiforme. The majority of immunocompetent patients recover without antifungal therapy. Dissemination — occurring in less than one percent of immunocompetent patients but in significantly higher proportions of immunocompromised patients, pregnant women, and individuals of African or Filipino ancestry — can involve bone, joints, skin, and the central nervous system (CNS). Coccidioidal meningitis is the most feared complication and requires lifelong antifungal suppression because it cannot be cured with currently available agents.

Treatment: fluconazole is the drug of choice for most non-meningeal and meningeal coccidioidomycosis because of its excellent CNS penetration. Itraconazole is preferred for bone and joint disease. Liposomal amphotericin B is used for severe disseminated disease requiring initial induction before step-down to azole therapy. Coccidioidal meningitis requires lifelong fluconazole suppression at 400 mg daily; intrathecal amphotericin B, historically used for meningitis refractory to azole therapy, is rarely employed today.

Blastomyces dermatitidis is endemic to the Ohio and Mississippi River valleys, Great Lakes region, and parts of Canada. It causes pulmonary infection through inhalation and disseminates to skin, bone, and genitourinary tract more readily than other endemic fungi even in immunocompetent hosts. Cutaneous blastomycosis — verrucous or ulcerative skin lesions — is the most common manifestation of disseminated disease. Treatment follows a severity-based approach: itraconazole for mild to moderate pulmonary and non-life-threatening disseminated disease; liposomal amphotericin B induction for moderately severe to severe pulmonary disease, central nervous system (CNS) involvement, or immunocompromised hosts, followed by itraconazole step-down for twelve months.